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·Promotor Prof. Dr J. J G. PRICK ·GARGOYLISM Academisch proefschrift ter terkrijging ian de graad tan doctor in de geneeskunde aan de r.-k. unirersiteit ran Nijmegen, op gezag ran de rector magnificus Dr.]. P. M. van der Ploeg, hoogleraar in de faculteit der godgeleerdheid, in het openbaar te verdedigen op rrijdag 9 december 1960 des namiddags te 2 uur door JAN FERDINAND VAN PELT geboren 1 Kerkdriel ·ALDERTS DRUKKERIJEN SITTARD

·Aan de nagedachtenis
tan mn Moeder
dan myn Vader
aan Wres en de kinderen

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·CONTENTS 7 11 12 12 12 12 12 13 13 17 18 19 22 Prelace Chapter 1 Bnej synopsis of the tersiune The first appearsace of the sindsome in the literarure Nomenclature Dutch publications Occurrence Heredity Clinical vacations The typus E The Spat.Hurler type The Hurler' type and the "Hurter" The abortive types The typus Amstelodamensis The clinical picture X-ray examination Laboratory studies Pathological anatomy The chemical nature of the accumulaced substance The cause, nature and origin of the disease as Bell as the originarion of 10$ symptoms Diagnosis and differential diagnosis Prognosis and therapy Chapter Chinal remarks uwb reference to the Sterature Is gargoylism a lipidosis Is gargoylism an endochnopathy The corneal cloudings seen in respect to the differential diagnosis with Morquco's disease Typus E (gargoy lism without neurohifidosis) Chapter 13 Gargoyles from the anthropogeneist point of veu Chapter IV Clonsal case reports Chapter V Post mortem and biopsy reports Chapter VI Summary and distusson of the clmical data Past hisrory Biometric data Facial expression and habitus Eye examinatson Cochlear and vesubular functions Medical and endocrine anomalies and laboracory findings Neuropsychiatric disturbances X-ray findings 23 28 29 30 30 31 32 31 37 20 101 101 105 10G 107 108 108 114 116 120 Chapter VII Gergoglism from the biochemicsl point of user' Chapter Vill Essential features of gargoylısm Chapter IX Diagnosis and differentia! dugaosss Summary List of publications Lus of authors 121 132 134 130 9

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·CONTENTS 7 12 12 12 12 13 14 17 18 19 22 Preface Chapter ! Eneljnopsis of the luterature The first appearance of the spodrome in the literature Nomenclature Dutch publications Occurrence Heredity Clinical vartations The typus E The Spar-Hurler type The "Hurler" type and the Hurter' type The abortive types The tipus Amstelodamensis The clinical prcture X-ray examination Laboratory studies Pathological anatomy The chemical nature of the accumulated substance The cause, nature and origin of the disease as well as the origination of Its symptoms Diagnosis and differential diagnosis Prognosis and therapy Chapter II Cortical remarks with reference to be fiterature is gargoylism a lipidosis) Is gargoylism an endocrinopathy) The corneal cloudings seen in respect to the differential diagnosis with Morquio's disease Typus E (gargoylism without neurolipidosis) Chapter II Gargoylısm trom sbe anibropogenetic posnk of a reu Chapter 1 Clinsal case reports Chapter V Post mortem and biopsy reports Chapter VI Summary and discu$5107 of she clinscal desta Past history Biometric data Facsal expression and habitus Eye examination Cochlear and vestibular functions Medical and endocride anomalies and laboratory findings Neuropsychiatric disturbances X ray findings 23 28 29 30 30 31 32 31 37 45 90 101 103 105 106 107 109 108 111 114 116 120 Chapter VII Gargoylism from the bloubemical point of use Chapter VIII Essential festures of gargolis Chapter IX Diagnosis and dofferential diagnoses Summary List of publications Lun of authors 124 132 134 150 9

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·Chapter 1 BRIEF SYNOPSIS OF THE LITERATURE THE FIRST APPEARANCE OF THE SYNDROME IS THE LITERATURE In 1917 HUNTER ? demonsuured "A Rare Disease in Two Brothers" and in 1919 HURLER' (from the Clinic of Pfaundler) published "Ober einen Typ mulripler Abartungen, roru iegend am Skelecosystem"; boch appeared independently from each other and were considered to be the first studies on gargoylism Later is appeared that medical attention had previously been drawn to these patients (THOMPSON in 1900 and BERKHAN in 1907) 58 217 NOMENCLATURE HUSLER (1923) uses the name "Dysostosis Multiplex mit Schwachsinn, Typus Hurter" is ELLIS, SHELDON and CAPON (1936) on account of the large head, the grotesque inhuman facial expression and the deformed extremities to quote these authors — derecred a similarity to che gargoyles of the Gothic Cathedrals. They give preference to a desonpine name, owing to the fact that the arrio logy of the disease was still uncertain and thus chose the name of gargoylastn One of the objections brought forward against the use of this name was thar the demonic and incelligent qualıcies characteristic of the gargoyle are pre- Cisely those which are lacking in the facial expression of the patient with gargoytiszt 247 The name of lipochandrodystrophy originating from WASHINGTON (Brenneman's Practice of Pediatrics) - went more or less out of use when the correctness of the concepcions which formed the basis of this name was doubred"? The syndrome has been described under masy names; the name of gargoylism occurs most frequently. The following synonyms have been used: Harter's (and or Hunter's and/or Pfaundler's) syndrome, 11

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·For a correct idea of what is the literature is to be underscood by "Spate Husles" type, the main points of similarity and difference between gargoylism and Morquio's disease should now be pointed out. In both diseases an osteoligamentusy syndrome accurs, shich is to a very large extent similar althoug's usually differing in detail, for instance, in gargoylism there are ligamentary contractures (manifested among ocher signs, by claw--hands), whereas, on the contrary, in Alorquio's disease the ligaments are merely flabby In boch deseases there are signs of osteochondrodystrophy, which results in prominent changes on X-ray. In gargoylism these are mainly meta-epiphysia), whereas in Morquio's disease the changes are focalised more epi-metaphysielly. In gargoylism these changes predominare in the upper extremities; in Mor. quio's disease, to the contrary, in the lower ones. Generally Morquio's disease can be differentiated from gai goyliss by means of the particular differences in the ostcoligamentary syndrome. This is not alu ays the case for repeatedly transitional forms are observed in which cerrain particulars of the osteoligamentary syndrome show A resemblance to that of Alorquio's disease, and others to that of gargoylism. Today, therefore, it is assumed that is not possible to establish, with certainty, the differential diagnosis between the so clinical pictures on the osteoligamentary syndrome alone. There is, however, a point of difference by means of which it is indeed possible to establish the differential diagnosis, namely: The PCIENCE of scorige phenomena in gargoylism and their absence in Mosquio's discase (including, amongst others, enlargement of liver and spleon and corneal cloudings) Moreover, in Norqwo's disease the facial expression that is typical of gargoylism, is absent the so-called "Hurler-lace"). In the literature included under the "Spar Hurler" form of gargoylism arc those clinical p:ctures, in which on initial examination, exclusively signs of 3 Morquro-hke osteoligamentary Syndrome are observed (the "Hurler-face" and storage phenomena being completely lacking), on which the diagnosis of Morquio's disease ought to be based, shereas later on (usually not unul the 20th-40th year of life), signs of accumulacion become manifest (Especially corneal cloudings) on account of which the diagnosis escablished can no longer be maintained and must be changed in gargoylism (The "Hurler" type and the "Hunter" type McKUSICK 274 differenziates between a Hurler and a Hunter type, according to the presence or absence of corneal cloudings in the patient. (Contrary 10 HURLER, Corneal cloudings were not found by HUNTER). Various Investigators consider the presence or absence of corneal cloudings due to 2 difference in inheritance D The aborite typer By these are means those cases of gargoylism that deviate from the classical clinical picture by presenung slighter signs, so that in isolated cases they 11 ·Polydystrophy of the Hurler (and/or Hunter, and/or Paundier) cype. Chondroosteodystrophy of the Hurler (and/or Hunter, and/or Pfaundler) cype. Dysoscoric idiocy. DUTCH PUBLICATIONS In the literature on gargoylism the numerous publications of C. de LANGE occupy a special place IS, 80, 81, 92. She also published in collaboration with WOLTRING" and GERLINGS, de KLEYN and LETTINGA 104. Other Dutch publications on the same subject arc thosc of MURK JANS- SEN", con BOKKEL HUININK3, H. D. BOUMAN, JACOBI and WAARDENBURG , van WESTRIENEN 65, ROCHAT 82, 83, ZEEMAN 8, BROUWER-FROMMANN', WAARDENBURG“, 18, EDGAR 264, 265 and JELGERSMA 3*. BROEKEMA published a case of Morquio's disease " The patients described by BEEBE and FORMEL, and one of the patients described by JERVIS, were of Durch descent 157, 238, van CREVELD 224 OCCURRENCE . The disease is not a rarity. This appears from a publication by LAMY et al 308, who in 1957 carried out statistics on 269 patients. At least 30 post mortem reports have been published 224 The discase is not limited to any race 12. Two-thirds of the number of patients examined arc males" 308. The age varied becween 42 months 128 and 47 years ". IREDITY The literature bearing on the genetic aspects of the disease will be discussed 10 chapter III. CLINICAL VARIATIONS A. The typus E Dc LANGE and WOLTRING " called two cases "The Typus E", because - some signs being absent they ware at first uncertain as to the diagnosis When, however, the diagnosis of gargoylism had been established beyond doubt as the result of postmortem findings, the differentiation of this type was no longer made 34, 104 B. The "Spal-Hurler" type The "Spar-Hurler" type was distinguished by ULLRICH" because in clus type, signs appear from which the diagnosis of gargoylism may be made later than is usually the case in gargoylism (as late as the 2nd, 3rd or 4th decade), while in the period prior to the appearance of these symptoms, this clinical picture is similar to that of Morquio's disease. 17 ·there is an umbilical hernia and a diastasis of the right abdominal muscles. The scrotum may be oedemarous. On the skin of the lower legs changes may occur resembling livedo racemosum Furthermore, acrocyanosis has been described The nails are often deformed. The hands are short and broad and the fingers crooked. The little finger is bent radially. In the feet and. logaus changes may be observed although in a lesser degree The cheeks which generally gives a are usually a vivid red The hair on the head - brıscly impression - is irregularly spread. The eyebrons are joined over a broad and flat or sunken nasal bridge. The forehead is arched. Moustachegrowth may also be observed The lips, tongue and gums are coarse and thick; the teeth small and widely spaced. The tonsils are large. The cars are coarse and the lobes especially large. Examination of the back may reveal a scoliosis, kyphosis or kyphoscoliosis at the junction of the choracic and lumbar vertebrat of a lumbar hypolordosis, The posture is stiff. In scanding, ic is remarkable chat the upper legs are held in a flexed position; movements are marked by a lack of suppleness. In most joints movement is limited on account of ligamentary contractures The most striking of these are the tendo contractures of the fingers (mainly at the second interphalangial joint) and the tendon contracture of the upper legs. Movement of the spinal column appears also to be lunited, as well as the expansion of the thorax on inspiration ". Resprauon is accompanied, to a greater or lesser degree by a sterrorous sound. Physical examination may reveal signs of cardiovascular disturbaxce? " 239 391. Very often there is a chronic bronchitis The liver is frequently enlarged and the spleen also, although this is less often. Enlargement of the lymph glands may occur Oederna is rare. Gastro-intestinal disturbances are generally absent. In many cases the impression is given that audnion decreases progressively; deafness may also occur. It is not sur. prising that data on aural function, timing fork tests and audiometric examinacion are scarce in the literature, when one remembers that as a rule the patients cannot render the co-operation required for these teses, ou ing to their limited intellectual poners *3 17 16. Data on the caloric irritability of the labyrinth are liken ise scarce"? 107 156 27. ULLRICH points out that the labyrinth functions are generally described as being normal". DUHAMEL, 10* and FONTAN et al 15% found the labyrinth irritability abolished, while TURPIN and LAFOURCADE 29 established normal labyrinth reactions in their patients In 709% of the cases corneal cloudings are found 16%. In cases that are negative on using a magnifying glass, slie lamp examination is necessary in order to exclude the condition with certainty 17. Should there be corneal cloudings, examination of the fundus may be difficult if not impossible, so thar an existing optic atrophy may escape diagnosis. The cloudings as such are usually not accompanied by blindness, in the latter cases there is generally an optic atrophy Incidentally the eye examina ·cannot or hardly ever be diagnosed as gargoylism. With the help of herc. dicary data it is ultimately possible to arrive at the diagnosis of "forms fruste" of gargoylism. Some publications have been dedicated to the sympto. matology of the "formes frustes" 157, 171, 174, 200 E. The lypus Amstelodamensis The typus Amstelodamensis, introduced by C. de LANGE"S as a type of gargoylism, offers few perspectives for the study of a possible connection with gargoylism, owing to the lack of post mortem findings and its extreme rarity. THE CLINICAL PICTURE According to a statistical survey by A. GIAMPALMO and V. GIAMPALMO 19 the signs most frequently occurring are corneal cloudings, enlargement of the liver, spleen, skeletal changes and psychic disturbances With the exception of the skeletal changes, - which, once developed, remain well-nigh constant — the changes are of a progressive nature. It often appears that the birth was difficult (breech presentation or forceps delivery) which gives rise to the supposition that the skull was already deformed at birth. As a rule the case histories mention the frequent occurrence of infections of the respiratory tracts, It is striking that when gargoylism is diagnosed the early signs are generally observed during the first decade According to whether the first appear before or after the third year of life, referance is sometimes made to an "early", or "late" form of the disease in the literature. Completely independent of this is that clinical form of gargoylısm referred to in the literature as the "Spat-Hurler" type, as we mentioned before, The patient's general appearance may alonc yield important data for the arriving at a diagnosis The disharmonious dwarfism with the large head which seems to rest on the trunk and especially the gargoylic facial expression give a particular aspect to the appearance, at once raising in those familiar with the picture, suspicion as to the correct diagnosis. The dwarfism is not an obligatory symptom An above normal body height, however, is only very rarely described "'. Owing to the deposition of fat in the gluteal region, the fat protruding abdomen, che wide thorax and the large head, the extremities, and especially their distal parts, sometimes appear hypoplastic Hypertrichosis occurs in 30% of the patients 192 The excessive growth of hair affects particularly the back and the extensor sides of the limbs. The skin is generally chickened and its elasticity lessoned 20. In some cases nodules were observed berween the scapula and the axillary line 20, 25, or changes in pigmentation resembling a disseminated melano- Sis 305. Also vitiligo and "mongolian spors" may be present. Very often 128 179 ·conmentioned a. 4, 111, 11223, 227 14. Rasely che following symptoms are described. atherosis , abundant flox of salıva , lessening of pain-sense"}, ataxia 202, bilatesal spastic pyramidal syndrome 1% 1% 20, nystagmus vulsions '11, 227 and hyperthermia of a diencephalic origin's Important observacions in the field of gaigoplism were made by SERVIS". At the examination of a patient at the age of five, he found no neurologic changes The pneumcencephalogram was normal. At the age of six there was 2 mild spastic patesis of the legs and bilaterally a Babinski sign Since then the hypertonia noc only increased in the legs, but also extended to the arms. Ar the post mortem of the patient aged eleven years a slight ventricular dilatation was found Electroencephalographic examination has repeatedly been described "17. 1,7 *®, 157 159 192 210 277, 233 239 267 23 314. Generally, diffuse, slow dysthythmias are recorded, sometimes of an abnormally high voltage 15* *** The sercebral anomalies frequently occurring in the thoracolumbar region seem seldom accompanied by symptoms of a transverse lesion or of a peripheral nervous affection. That a partial obstruction of the spinal canal may exsst was proved by McKUSICK by means of myelography 274 The musculature of the legs may be hypotrophic and the periost reflexes sometimes lovered. Scong atrophues, fascicular contractions and hypotonia are not found as a rule. Electromyographic examinations are not mentioned in tile literature. XRAY EXAMINATION X-ray examination generally reveals numerous changes The most important of these are the following The fontanel closing is often delayed. The skull circumference is nearly always too large; the skull may be relatively high, long or broad. Microcephaly is only seldom observed 19 100 The frontal bane is prominent. The wall of the skull may be either thick, normal or thin, in cases of marked hydrocephalus, a thin calvarium is often observed. In the region of the skull sutures, the bone may be thickened The body of the sphenoid is generally too high, and the distance from the ala magna to the base of the nose decreased. Hypertelorism is a frequently occurring symptom The pneumatisation of the mastoid bone is generally qualified as poor. The sella turcica may be normal, but it can also be enlarged (in a balloon- or shoe-shaped form). The jans are strongly developed and the angle of the toner jas may be too obnese. Thorax The clavicles are 100 massive, especially as far as the sternal paft is concerned The thorax is broad and the ribs, shich are thickened, run in an undulating and horizontal manner. On the level of the artachment to the sternum and the vertebrae the lower ribs are narron ed Icke a thin paint brush, ·- tion may reveal varied changes. The most frequent among these arc apare from corneal cloudings megalocornea (generally without incrcised intra-ocular increase of tension) and optic atrophy. Moreover a retarded reaction to mydriatics is repeatedly found 1,60 74. For a full survey on ocular changes occurring in gargoylism reference is made to the literature on the subject concerned 61, 74, 90, 180, 194, 208, 221, 224, 261, 269 24, 311. 137 Psychic disturbances occur, according to A. GIAMPALMO and V. GIAM. PALMO 172, in 74.5% of the number of cases observed. The scriousness of the psychic disturbances depends, according to LIESSENS, on the rare at which the morbid process develops, and on the time at which the first symptoms manifest themselves 243, 27. The earlier they appear the more serious the psychic symptoms. There are, however, exceptions to this rule. The "early" cases are generally characterized by a recarded psychomotor development, These patients learn to walk late and the development of speech is very deficient. They are conspicuous for cheir anxious disposition and negativistic attitude. Their behaviour necessitates constant supervision. Grave types of oligophrenia are not rare, while in the long run psychic decerioration eventually manifests itself 7. In the "late" cases (the first signs appearing after the age of three years) clear psychic disturbances may be absene. Usually, however, psychomotor development is normal at first, later on however progressive deterioration takes place. It is difficult to decide exactly in how far the sensory discurbances play a pare therein 273 Regarding the specificıy of the psychic disturbances LIESSENS scates "Le deficit intellectuel et psychique ne présente aucun cype particulier, ni aucun caraccèrc spécifique" 273 In a small number of cases the psychic functions are and remain normal. The examiner may be severely hampered by the psychic disturbances, char.c. ceristic of these patients. The chuldren may ward off his hand. Palpation and reflex examination are not simpic under such circumstances. One ofron fails to coax the patient into co-operating Incontinence is usually present Even. tually most patients become bed-ridden. Generally, owing to increasing disturbance in behaviour, admission to an institution becomes necessary at an earlier stage. Symmetrical generalized dilatation of the cerebral-ventricles and hydrocephalus are the most outstanding changes found on neurological cxammation In the publicacions by HUNTER and HURLER these changes are nor mentioned by name, but at the post mortem of one of HURLER's patients, a hydrocephalus was found 'S. DAVIS and CURRIER ? and ever since, many other investigators 195 found dilatation of the ventricles by means of Thc cxistcncc pncumocncephalography. Cortical atrophy may occur of a hydrocephalus may be indicated by a too large and sull increasing circumference of the skull, a rarefaction of the skull-vault and a cracked por sound. Opric atrophy and pigmentary anomalies in the tundus are seldom 28 31 132, 156, 157, 227 26), 207 16 ·of alpha 2 globulins is often increased sometimes there is hypochromic anaemia Cupremis may be present 31 as also hypermucoproteinemia SI, The lipoproteins so the blood serum may show qualitative and quantitative changes 275, 39, and the neuraminic acid content of the blood serum may be Increased 280 The blood sugar curse is within normal límits Marked and constant changes in the calcium, phosporus and phosphatase values are absent. The cholesterol content is sometimes markedly increased. The liver function teses are nearly always normal. Routine urine tests reveal fer peculiarities. DOREMAN and LORINCZ 303 and MEYER al" proved that in the urine of gargoyle pazients a mixture of mucopolysaccharides was present, which according to MEYER er al consists mainly of chondroitine-sulphuric acid B (CH S-B) and hepatitin sulphuric acid Incidencally changes were found in the hormonal excretion BINDSCHED. LER and co-workers" found decreased secretion of adenohypophysary hor. mones in the urine (2 cases). SARTORI 187 found a normal excretion of 17 Actosteroids in the urine, together with an increased excretion of 11 oxy. corticosteroids RODECK * also found a normal excretion of 17 hetoscerods GUELI and SEVERI 23 by means of Thorn's test found normal values. In paperchromatographic tests of the urine, changes were sometimes found" (pathologic aminoacidursa). The basal metabolic race may be either normal, decreased or increased GILLILAND 13 found a normal excretion of radioactive iodine 133. Routine studies of the spinal fluid, Pandy, Nonne, cells, protein content and colloidal curves afford no peculiarities PATHOLOGICAL ANATOMY Prominent is the "gargoyle" cell change. This gargoyle cell change is charac. terised by swelling, enlargement, vacuolısauon of the cytoplasma (creating a foamy appearance) and aso by eccentric position of the nuclei The cells rive the imhreccinn afh... - tilinge. Besides cellular changes, extracellular ones may bx observed, eg 13 the form of proliferation of collagen fibres and increase of the basal substance ! For a complete survey of the changes found in gargoylism, we refer to publications relating to this matcer 23 IN 20397. Only the most important data are now enumerated Liter This organ is often considerably enlarged The liver cells, and sometimes also she Kupffer cells, then show the typical gargoyle cell change. in ·Spinal column The centre of the anomalies is the choracolumbar junction, The adjoining vertebrae may have changed in a similar though generally less spectacular way. There may be an arcuate kyphosis, possibly kyphoscoliosis or a spon. dylolisthesis. The lumbar lordosis is generally flattened. The bodies of the twelfth thoracic and the first lumbar vertebrae are often too small, while the frontal top quarter is wholly or partially invisible in X-ray films ("fishhool." shape). Sometimes these changes occur combined with those especially typical for Morquio's disease (generalised platyspondylia and tongue-shaped projeccions on the front of the vertebral body). Hands Generally the phalanges are suppository-shaped. The phalanges and mecacarpals are short and broad, and the diaphysery trabeculation is coarse. The base of the metacarpals may taper off to a point. The number of ossified nuclei carpal centres may be small in proportion to the age. On the feet analogous changes may be observed, although they are always less intensive. Humerus and femur The heads of humerus and femur are often flattened. The neck is too broad The epiphyses are of irregular shape. The joint socker is often shallow. Coxa valga and genua valga frequently occur. CAFFEY 202 observed in three cases in which classical symptoms of gargoylism only appeared later, in carly youth the occurrence of a serious generalised "demineralisation". CRAIG 250 did not see abnormalities on an X-ray film made a fortnight before the birth of cwins (a brother and sister) Later the twins developed unmistakable symptoms of gargoylism Extensive surveys of radiologic changes occurring in gargoylism were published, among others, by HARVEY, GUY and LERIQUE, LEFEBRE and co-workers, SEYSS, MERLEN, van den DORP and MERLEN, LACKNER and ZELLWEGER and co-workers 69 161 162 163 191 228 234 307 Also the radiological differences between gargoylism and Morquio's disease generally form a point of discussion in these publications. LABORATORY STUDIES These afford few positive data of importance for the diagnosis an exception to this is Reilly's anomaly (abnormal granules in the leucocyces) which can be shown to be present in a number of cases * This abnormal granulation can be made yısıble by means of the Gremsa-Wright staining method ", GRIF- FITHS and FINDLAY!!9 and BUHOT 30 333 stare the occurrence of "ringshaped inclusions" in the plasma cells of the bone marrow and "granular inclusions" in the histiocytes in to cases where the anomaly of Reilly was absent. According to LOWENTHAL *** the percentage in the blood serum 18 ·of alpha 2 globulins is often increased Sometimes there is hypochromic anzemia. Cupremis may be present as also hypermucoproteinemi: 31. The lipoproteins in the blood serum may show qualitative and quantitative changes 273 309, and the neuraminic acid content of the blood serum may be increased 200 The blood sugar curve is within normal limits. Masked and constant changes in the calcium, phosporus and phosphatase values are absent. The cholesterol content is sometimes markedly increased. The liver function reses are nearly always normal. Routine urine tests reveal few peculiarities DORFMAN and LORINCZ 305 and MEYER et al "7 proved that in the urine of gargoyle pauents a mixture of mucopolysaccharides was present, nhoch according to MEYER er al consists mainly of chandroitine-sulphuric acid B (CH S-B) and heparitin sulphuric acid. Incidenrally changes were found in the hormonal excretion BINDSCHED. LER and co-workers" found decreased secretion of adenohypophysary hor. mones in the urine (2 cases) SARTORI " found a normal excretion of 17 kerosteroids in the urine, together with an increased excretion of 11 oxycorticosteroids RODECK - also found a normal excretion of 17 letosceroids GUELI and SEVERI *3 by means of Thorn's test found normal values. in paperchromatographic tests of the urine, changes were sometimes found (pathologic aminoaciduria). The basal metabolic rate may be either normal, decreased or increased. GILLILAND 8 found a normal excretion of radioactive iodine 1". Rou. tine studies of the spinal fluid, Pandy, Nonne, cells, protein content and colloidal curves afford no peculiarities. PATHOLOGICAL ANATOHY Prominent is the "gargoyle" cell change 274. This gargoyle cell change is characterised by swelling, enlargement, vacuolisation of the cytoplasma (creating a foamy appearance) and aso by eccentric position of the nuclei The cells give the impression of being "inflated". Especially the liver parenchyma cell is affected by this gorgoyle change, but in principle any organ or tissue may contain cells that have undergone such a change. Besides cellular changes, extracellular ones may be observed, es in the form of proliferation of collagen fibres and increase of the basal subscance 13). for a complete survey of the changes found in gargoylısm, we refer to publications relating to this mattes "23 13 21 174. Only the most important data are now enumerated. Lafer This organ is often considerably enlarged. The liver cells, and sometimes also the Kupffer cells, then show the typical gargoyle cell change. 10 ·Spleen The spleen is also often enlarged, although in a lesser degree than the liver. At histological examination the reticuloendothelial cells surrounding the sinuses may prove to be considerably enlarged, and many enlarged mononu. clear cells may be found in the spaces among the sinuses 201. Kidney Here also gargoyle cell changes are sometimes found. Then the tubular cells are mostly affected 9. Heart and blood vessels According to EMANUEL 229, in 77.7% of the number of post mortems, cardiac changes are found. The valves may be chickened and contain large vacuolised cells. Besides calcification, chondroid changes may be found 106. In the cardiac muscle vacuolated cells are sometimes found 59 131. The blood vessels, among which the coronary artery, may show similar changes, causing the lumen to be narrowed. A survey and a detailed description of the cardiovascular sclerosis, sometimes found, is given by COTTIER 292. Lungs The lung parenchyma frequently shon's numerous vacuolated macrophages lining the alveolar walls 29, 39, 123, 133 180 253 339 and occasionally a thickening of the alveolar membrane is found 39 Trachea Sometimes pathological processes are seen involving the cartilage and perichondrial tissues of the trachea 194 113. Eyes In the cornea, Bowman's membrane may be replaced in many places by large, vacuolised cells. In the interlamellar spaces granular matter may be found. The ganglion cells of the renina may show gargoyle cell changes ! 225 2. In the sclera gargoyle cells may be found 18 Skin The cutis may be thickened owing to thickening of the collagen fibres which are irregularly arranged 195 204 20. Thymus gland This organ is sometimes enlarged 25 138, 288 Ears Histological examinations mention the occurrence of stenosis of the auditory canal 8, ankylosis of the joints been een the tympanic bones 08 277, atrophy of Corti's organ 104 small crystae ampullares , rregular lumen of the 20 ·semicircular Canals , and degenerative or thesaurismotic changes in the cells of the cochlear and vestibular ganglions *, 27, Reticuloendothelul system Histopathological changes of the reticuloendothelial system are often found, marked by proliferation and gargoyle cell change in the elements belonging to this system Pornstary gland When ac a post mortem an enlarged pituitary gland is found, it is generally the anterior pars that is scen to be enlarged and especially the chromophobic cells, besides increase, shox abnormal vacuolation 1, 79 11 13 JH 239, 2014 Skeleton, cartilage and joints SCHMIDT", de LANGE et al '', HIENZ 440 445 and NISBET and CUPIT have found discusbances of the enchandral cssification. The carrilage cells may slow gargoyle changes. The ligaments and periarticular tissues may show chuckening and gelatinous changes. GIROL and BENEDETTI have found duphşsial changes in one case as 3 result of massive inhiltration of foam cells in the bone marrow Sternal puncture and blood In a number of cases REILLY proved by Giems.1-Wright's staining method the presence of large dark lilac coloured granules in the leucocytes (especially the polynuclear ones) of the peripheral blood and also in the sternal punctare flud. Sumilar granules sere found by BUHOT 10 in the plasma cells and histiocytes of the bone marrow, ahile GRIFFITHS and FINDLAY"mention che occurrence of "ring-shaped inclusions" in the plasma cells of the bone martow. , The nertout system The first organ of which histological examination is mentioned in the literature, concerns the cerebrum of one of the patients, described by HURLER 19 16 111 which dilaranion of the lateral sentricles was found. From the post mortem reports it appears that hidrocephalus or a slight dilatation of the lateral sestricles occurs frequently There is sometures local atrophy of the cerebral cortex. Besides, it may also occur that the sulcs are straight by broadening of the Anna The leptomeninges are often shickened 's I 287. As a consequence of the meningeal changes and the hydroxephalus, the opric nerves may have a pronounced abnormal course 13. Os oictoscopal examinanon, the changes in the nerve cells come to the fore, which are morphologically difficult to disainguish from the changes of the ganglion cells in Tay Sachs, Stock-Spielmeyer.Vogi's, Niemann-Pick's and Gaucher's diseases. These are characterised by considerable enlargement of the cell and eccentric nuclear position. The neurofibrils biten lie on the periphery ·Spleen The spleen is also oftcn cnlarged, although in a lesser degree than the liver. At histological examination the reticulocndothelial cells surrounding the sinuses may prove to be considerably enlarged, and many enlarged mononu. clear cells may be found in the spaces among the sinuses 201. Kidney Here also gargoyle cell changes are sometimes found. Then the cubular cells arc mostly affecred Heart and blood vessels According to EMANUEL 2, in 77.7% of the number of post mortems, cara diac changes are found. The valves may be thickened and contain large VICUO lised coils. Besides calcification, chondroid changes may be found 106. In the cardiac muscle vacuolased cells ase sometimes found 99 ". The blood vessels, among which the coronary artery, may show similar changes, causing the lumen to be narrowed. A survey and a detailed description of the cardiovascular sclerosis, sometimes found, is given by COTTIER 193. Lungs The Jung parenchyma frequently shows numerous vacuolated macrophages lining the alveolar walls 29, 39, 123 133, 186 233 139 and occasionally a thickening of the alveolar membrane is found 39. Trachea Sometimes pathological processes are seen involving the carulage and pers chondrial tissues of the trachea 164 133 Eyes In the cornea, Bowman's membrane may be replaced in many places by large, vacuolised cells. In the interlamellar spaces granular matrer may be found. The ganglion cells of the retna may show gargoyle cell changes." 235, 249. In the sclera gargoyle cells may be found 180 Skin The cutis may be thickened owing to chickening of the collagen fibres which are irregularly arranged 195 754 280 Thymus gland This organ is sometimes cnlarged? 29 118 288 Ears Hiscological examinations mention the occurrence of scenosis of the auditory canal , ankylosis of the joints berween the tympanic bones os m7, atrophy of Corti's organ '04, small crystae ampullares of irregular lumen of the 20 ·semicircular canals 6s, and degenerative or thesauresmotic changes in the cells of the cochlear and vestibular ganglions $ 271. Rericuloendothelial system Histopathological changes of the reticuloendothelial system are often found, marked by proliferation and gargoyle cell change in the elements belonging to this system 21 Prulary gland When at a post mortem an enlarged pituitary gland is found, it is generally the angerior part that is seen to be enlarged and especially the chromophobic cells, besides increase, show abnormal vacuolation 19 79 81, 11) 1M 249 281 24 Skeleton, canlage and joints SCHMIDT", de LANGE et al ', HIENZ 210, *** and NISBET and CUPIT? have found disturbances of the enchondral ossification. The cartilage cells may show gargoyle changes The ligaments and períarticular tissues may shou: thickening and gelatinous changes. GIROL and BENEDETTI have found diaphysial changes in one case as a result of massive infiltration of foam cells in the bone marron 321 Sternal puncture and blood In a number of cases REILLY proved by Giemsa-Wright's staining method the presence of large dark lelac coloured granules in the leucocytes (espacially the polynuclear ones) of the peripheral blood and also in the sternal punctare flud. Similar granules sere found by BUHOT " in the plasma cells and histrocytes of the bone marrow, shule GRIFFITHS and FINDLAY 18 mention the occurrence of "ring-shaped inclusions" in the plasma cells of the bonc marrow The nert ous system The first organ of which histological examination is mentioned in the literature, concerns the cerebrum of one of the patients, described by HURLER 10 11 in which dilatation of the lateral ventricles was found from the post mortem reports it appears chat hydrocephalus or a slight dilatation of the lateral ven. tricles occurs frequently. There is sometimes local atrophy of the cerebra) cortex Besides, it may also occur that the sulcı are straight by broadening of the gyrı" The lepromeninges are often thickened 158. 180 247 As a consequence of the meningeal changes and the hydrocephalus, the optr nerves may have a pronounced abnormal course", On Miroscopical examination, the changes in the nerve cells come to the fore, which are morphologically difficult to distinguish from the changes of the ganglion cells in Tay Sachs, Scock-Spielmeyer-Vogt's, Niemann-Pick's and Gaucher's diseases These are characterised by considerable enlargement of the cell and eccentric nuclear position The neurofibrils ofren lie on the periphery ·and Nissi's bodies are reduced or have disappeared. The cytoplasma usually has a granulaced aspect, and sometimes small vacuoles are observed Tite number of nerve cells is generally not notably reduced. Demyelinisation and gliaproliferacion are not prominent features 85, 266 345. Within a certain formation (layer or nuclear region) the degree of cellular change is more or less equal, but among the various formations there may be considerable differen ces in this respect 266. Especially in the brainstem important contrases may occur. Why the cells in certain formations are not or hardly, and in others grcadly changed, might be linked up with certain morphological cell characteristics 2-4 According to some authors, the big cells in the nucleus caudatus and the pura men are changed in a large measure, whereas in the small ones hardly any morphological changes can be observed 206, 315. The perivascular spaces may be broadened (especially in the white matter) and the vascular endothelium proliferated "8, 127, 133, 186, 217. The dendritic processes of the cells of Purkinje may be swollen in an oval manner 17. 284. In the spinal cord it is especially the anterior horn cells that show changes similar to the ganglion cell changes in the cerebrum. In the spinal cord the enlargement of the cells is even more pronounced than in the cerebrum Also the ganglion cells of the peripheral and autonomic nervous system may show changes analogous to those of the cerebrum, Adrenals, gonads, thyroid gland Sporadically, in the parenchymatous cells of these organs, gargoyle cell changes are found. Pancreas Only seldom typical cell changes have been observed in a case, described by NJA", the pancreas was stated to be degenerated diffusely THE CHEMICAL NATURE OF THE ACCUMULATED SUBSTANLI 204 01 A In the ricrie cells All investigators with the exception of BISHTON et al 28* find an increase of hexosamine and or neuraminic acid in the cerebral cortex 116 109 and on the strength of these findings (because neuraminic acid and hexosamıne are components of gangliosides) they assume a surplus of gangliosides. This glycolipid is supposed to be mainly localised in the nerve cells to According to DIEZEL and SEITELBERGER the substances accumulated in the nerve cells are difficult to dissolve as a result of their combr. nations with proteins So far, it has not been proved that the chemical composition of the accumulated gangliosides is markedly different from those occurring normally in the cells — as was shown for the first cimc by KLENK BRANTE considers only the excess of gangliosides in the nerve cells co bc 303 22 ·123 pathological and not the nature of the gangliosides themselves 29. Of the chemical staining methods applied, especially the PAS. and Sudan stains, and the Nile blue sulphate method are often posicise 159, 253 2: 234 29 JP5. A. In the misceral organs What substances are accumulated in the gargoyle cells of the liver, spleen and other organs? At fucse it was thought to be lipids, but the quantities shown staining were generally not in accordance with the measure of cell enlargement. Somctimes no lipid could be demonstrated to C. de LANGE", STRAUSS CS. and HENDERSON c.* found no increase of the lipid percentage in the liver. Neither did the glycogen percentage of the liver appear to be markedly altered. BRANTE » considers the cause of the difficulties in respect of identification of the accumulared substance to be the dissolving of the vacuolar content in the fluids gencrally used for fixation. In connection with this, the use of special fixation fluids (eg, lead acetate or glacial acetic acid) *** 2is recommended. Besides BRANTE other investigutors have also succeeded in sraining the vacuoles in this manner 207 208 *** 341. BRANTE shon ed an excess of mucopolysacchandes Morcover, the 83rgoyle cells contain neutral færs only in insignificant quantities, and also much gly. cogen, the percentage of which does not seem sufficient to call it unphysio logical Sometimes 100, sanglioside-like substances could be proved to be present in the gargoyle cells of different organs. Apart from the above mencioned surplus of mucopolysaccharides, the strong solubility must bc considered abnormal, as well as the fact that they are mosrly found intrcellularly 28 SEITELBERGER 1720), contrary to BRANTE, is of opinion that the mucopolysaccharides do not occur in a free form, but are chemically combined to tipids, and he therefore speaks of accumulation of glycolipids. DIEZEL, GUELI and SEVERJ 205 299 are of opinion that the accumulation products may differ from case to case. UZMAN arrives at the conclusion that in the accumulation product to subs stances of different chemical composition are present, a complex polysaccha. ride and a glycolipid 27 STACEY and BARKER ** and MEYER et al 17 conclude that a hepatintike substance as present which normally is not found THE CAUSE, XATURE AND ORIGIOF THE DISEASE AS TELL AS THE ORIGINATION OF ITS SYMPTOMS A The cause of the disease Is studying the literatute it is quite cleat chat the cause of the disease is defi- Astely not know . More and more invesugators are of opinion that in the * ·266 and Nissi's bodies are reduced or have disappeared. The cytoplasma usually has a granulared aspect, and sometimes small vacuoles are observed. The number of nerve cells is generally not notably reduced. Demyelinisation and gliaproliferation are not prominent features 1. 26. 315. Within a certain for. mation (layer or nuclear region) the degree of cellular change is more or less cqual, but among the various formations there may be considerable differen. ces in this respect Especially in the brainstem important contrasts may occur. Why the cells in certain formations are not or hardly, and in others greatly changed, might be linked up with certain morphological cell characteristics 20%. According to some authors, the big cells in the nucleus caudacus and the puta men are changed in a large measure, whereas in the small ones hardly any morphological changes can be observed 266. 31 The perivascular spaces may be broadened (especially in the white matter) and the vascular endothelium proliferated 18, 127, 133, 186. 217. The dendritic processes of the cells of Purhinje may be swollen in an oval manner 157 234. In the spinal cord it is cspecially the anterior horn cells that show changes similar to the ganglion cell changes in the cerebrum. In the spinal cord the enlargement of the cells is cven more pronounced than in the cerebrum. Also the ganglion cells of the peripheral and autonomic nervous syscom may show changes analogous to those of the cerebrum. Adrenals, gonads, thyroid gland Sporadically, in the parenchymatous cells of these organs, gargoyle cell changes are found. Pancreas Only seldom typical cell changes have been observed. In a case, described by NJA 113, the pancreas was stated to be degenerated diffusely. THE CHEMICAL NATURE OF THE ACCUMULATID SUBSTANCI 116 J19 264 301 A. In the nerve cells All investigators with the exception of BISHTON et al 24 find an increase of hexosamine and or neuraminic acid in the cerebral cortex and on the strength of these findings (because neuraminic acid and hexosamine are components of gangliosides) they assume a surplus of ganglio. sides This glycolipid is supposed to be mainly localised in the nerve cells ing According to DIEZEL and SEITELBERGER the substances accumulated in the nerve cells are difficult to dissolve 294 30s, as a result of their combinanons with proteins. So far, it has not been proved that the chemical composition of the accumulated gangliosides is markedly different from those occurring normally in the cells — as was shown for the first time by KLENK BRANTE considers only the excess of gangliosides in the nerve cells to be 22 ·leads to disturbances in the supporting tissues and secondly to accu. mulation of mucopolysacchacides in the organs. 1954 WIEDEMANN 29; disturbance in the reach of proreincarbohydrates metabolism. 1955 UZMAN 257. a generic determined defect of the structural polysacchia rides. 1955 SEITFLBERGER 272. default of the inter-cellular glycolipid metabolism. 1957 BRANTEN. it is possible that primarily the protein metabolism is disturbed and subsequently the binding process berucen the proteins and the mucopolysaccharides proceeds in an abnormal manner, 1958 MEYER, GRUMBACH, LINKER, HOFFASAN 12: gargoylism represents an overproduction of certain mucopolysaccharides due to a genetically determined error of differentiation of fibroblasts From this enumeration is can be seen that by far the greatest number of the Investigators are in agreement that in the nosological system gargoylism should be classified among the metabolic diseases, while with regard to the question hat chemical substances are involved in this metabolic disturbance no una. numity exists At first n was assumed that the disease would be the expression of an abnor. mal course of the far metabolism". This opinion has been reconsidered and now the disease is rather seen as the expression of an abnormal course of the metabolic processes in the reach of the mucopolysaccharides ** 27. 1 glycolipids 272, os of the carbohydrates and or procein metabolism 19. Besides that, most investigators assume that the metabolic disorders are cou. pled with accumulation, and they are of opinion that gargoylism should be classified amond the scorage reticuloses "2 209 327, in this respect then, they see a resemblance with Tay-Sachs, Stock-Sprelmeyer-Voge's, Gaucher's, Niemann-Pick's diseases and the xanthomatoses osseum. BIELSCHOWSKY 130 n ho made an intensive study of the pathogenesis of the storage reticuloses is of opinion that the product stored in the reticuloendothelial system and to the nerve cells is accumulared as a result of a metabolic anomaly sith regard to the chemical substance that is stored. Opposed to the opinion of BIELSCHOWSKY is that of SCHAFFER ", who assumes that the storage is not the result of an excess of a certain chemical substance, but that it should be seen as a metabolic error affecting the protoplasms of that particular cell system, the cause of shich us soll unknown. In the light of this opinion, the substances accumulating in abnormal quascities within the cells need not be taken as emanating from an excess in the blood, but they appear as the manifestation of a disturbed cell metabolism, so that it is a question of phanerom. In the literature on gargoylism we encounter these fondamentally different views on the origin of the accumulacion ·origin of the disease, disturbances in certain enzymes must be regarded as an important conditional factor. The view of ERNOULD 137 that disturbance of the thyreotropic hormone of the pituitary gland is of great significance was not shared by other investigators, because the existence of this deviation could actually not be proved. A very striking factor is the heredity. That gargoylism is a hereditary disease is now generally accepted. This means that in one or both parents or in their ascendants, a pathological gene change has taken place which is a conditional faccor for the origin of gargoylısm. This change might, according to certain authors, come about by abortifacients or by alcoholism '7. The generic aspects are to be elucidated in chapter III. 2 B. Nature and aetiology of the disease The opinions on the aetiology has repeatedly been altered. We chronologically quote some of them 1917 PARKES-WEBER? (discussion after demonstration by Hunter): cn. docrine disturbance. 1917 BLUNDELL-BANHART? (discussion after demonstration by Hunter), multiple congenital developmental errors 1917 HURLER !: developmental errors combined with degenerative characteristics and endocrine-like conditions, 1919 PFAUNDLER", S. a familiar divergence, which mainly cffects ris supporting tissue. 1936 ELLIS 28. disturbance of metabolism, comparable with Gaucher's discase. 1936 COCKAYNE *. disturbances of lipid metabolism with accumulation in liver and spleen. 1937 ASHBY et al ? disease resembling amaurouc idiocy. 1940 HENDERSON 58. congenital disturbance of the lipid metabolism. 1940 HASSLER 63 gargoylism is the fourth lipidosis 1942 DE LANGE 9. gargoylism must be looked upon as a lipidosis on account of the large conformity of the cerebral defects with those of Tay-Sachs and Niemann-Pick 1948 STRAUSS disturbance intra-cellular metabolism The question whether gargoylism is a form of lipidosis remains to be seen. 1948 REILLY-LINDSAY '12. hereditary constitutional metabolic disease probably in the reach of combined carbohydrates coupled with accumulation 1952 SMITH-HEMPELMANN-MOORE-BARR 19 dysmecabolism of a substance related to glycogen. 1952 BRANTE 29: a dysmetabolism of mucopolysaccharides which primarily 131 24 ·leads to disturbances in the supporting issues and secondly to accu. mulation of mucopolysaccharides in the organs. 1954 WIEDEMANN 29. disturbance in the reach of proreincarbohydrates metabolism. 1955 UZMAN 17. a genetic determined defect of the structural polysacchatides 1955 SEITELBERGER 27: default of the inter-cellular glycolipid metabolism. 1957 BRANTE *, it is possible char primarily the protein metabolism is disturbed and subsequently the binding process between the proteins and the mucopolysaccharides proceeds in an abnormal manner, 1958 MEYER, GRUMBACH, LINKER, HOFFMAN57. gargoylism re presents an overproduction of certain mucopolysaccharides due to a genetically determined error of differentiation of fibroblasts. From this enumeration it can be seen this by far the greatest number of the univesagators are in agreement that in the nosological system gargoylism should be classified among the metabolic diseases, while with regard to the question what chemical substances are involved in this metabolic disturbance no una. nimiry exists At first it was assumed that the disease would be the expression of an abnormal course of the fac metabolism". This opinion has been reconsidered and now the disease is rather seen as the expression of an abnormal course of the metabolic processes in the reach of the mucopolysaccharides 38 17 17 glyco lipids 22, or of the carbohydrates andor protein metabolism 19. Besides that, most investigators assume that the metabolic disorders are coupled with accumulation, and they are of opinion that gargoylism should be classified amond the storage reticuloses 112. 209 187. In this respect then, they see a resemblance with Tay-Sachs, Scock-Spielmeyer-Vogt's, Gaucher's, Niemann-Pick's diseases and the xanthomatoses osseum BIELSCHOWSKY1 ho made an intensive study of the pathogenesis of the storage reçiculoses is of opinton that the product stored in the reticulocndo thelial system and in the nerve cells is accumulated as a result of a mera. bolic anomaly with regard to the chemical substance that is stored Opposed to the opinion of BIELSCHOWSKY is that of SCHAFFER '', who assumes that the scorage is not the result of an excess of a certain chemical substance, but that it should be seen as a metabolic error affecung the protoplasma of that parucular cell system, the cause of which is still unknos n. In the light of this opinion, the substances accumulating in abnormal quantities within the cells need not be taken as emanating from an excess in the blood, but they appear as the manifestation of a disturbed cell metabolism, so that it is a question of phanerosis. In the literature on gargoylism we encounter these fundamentally different views on the origin of the accu. mulation ·327 LINDSAY 132, HUEPER, TOLENTINO and TERRAGENA", conduced animal experiments in which, after intravenous injection of macromolecular carbohydrate, they saw disturbances appear which - according to these authors showed a resemblance to those in gargoylism and concluded that the substance accumulated in the cells emanates from an excess in the blood MEYER et al give as hypothesis that mucopolysaccharides are accumulated as a result of an over-production of these substances caused by metal. bolic disturbances taking place in the connective cissuc. Contrary to this opinion STRAUSS 131, KLENK 272, SEITELBERGER 272 and BAMATTER 349 consider that the accumulation is a manifestation of a metabolic disorder taking place in the cells concerned. C. Origin of the individual symptoms Enchondral dysostosis Thc epiphysial carcilage ossification disturbances and the dwarfism connected with them arc seen by some investigators as manifestations of an endocrine dysfunctioning, by others as a primary result of metabolic disturb.inces localised in the connective tissue itself 19 112 133, 209, 237 Based on the topographic distribution of the skcietal changes, MAU considers it probable that the pa. thogenic accion cakes place at a certain stage of the embryonic development, and that the Icngth of this influence is bound to a certain time limit " b. Umbilical and inguinal hernias, ligamentary contructures and sko changes The umbilical and inguinal hernias, skin changes and contractures are generally considered the result of metabolic disturbances in the connective a. tissuc. c. The enlargement of liver and spleen The enlargement of liver and spleen are attributed to enlargement of the parenchyma cells, and sometimes to the increase of cells belonging to the rericulocndothelial system. Cardiac changes The cardiopathy was at first considered erroneously to be a congenital development anomaly. Later on, however, cardiovascular sclerosis was found be prescot in a number of cases, as the result of gargoylc metabolic distur. bances 19, 122, 153, 229, 292 Corneal clondings The corneal cloudings are, according to most authors, caused by the presence of gargoyle cells in Bouman's membranc 3 NEWELL and KOISTIN. NEN", however, consider it unlikely that these phenomena shoukl in any way be connected. They are more inclined to assume that structural changes in the connective tissue of the cornea have a causal relation to the cloudings to 26 ·f Deaners In the literature no unanimity is reached on the explananion of the presence of deafness or impaired heating MEYER and OKNER " find that they musi assume Otosclerosis whereas WOLFF $ is more inclined to assume conduction deafness in this case. In her Or case VOLFF observed a greatly reduced diameter of the external auditory meatus The malleoincudal joints were found to be ankyloric. The organ of Coni was normal in the brain histological changes were absent. De LANGE, GERLINGS, de KLEYN and LETTINGA 14 ascribe the deafness to acrophy of the organ of Corti. Here too, histological changes were absent TURPIN, LEFEBRE, CHASSAGNE and DUCHÉNE"? nore a conduction dealness as a result of ankylosis of the auditory ossicles RICCI and ANCETTI attribute the deafness to degenerative or thesaurismotis changes in the cells of the cochlear ganglion ?". S Reilly's anomaly The abnormal granules discovered by REILLY in the leucocytes in a tumber of cases were taken to be a maturasing disturbance. According to BRUGSCH "" Reilly's anomaly had previously been described by JURGENS, and there is much resemblance with Alder's anomaly, in which similar granules are found in the leucocytes of seemingly healthy children who afterwards developed serious osseous deformities, ALDER IW states that all the cases observed by him iete accompanied by bonegrowch disturbances, but he considered the granules not to be the result thereof. It is a maturating disturbance of the blood cells, in which a hereditary factor is of real significance LAVES 19 mikes known that the granules mainly contain a poly. saccharide component curresponding to a hyaluronic acid ester, After treatment with hyaluronidase the granules disappeared. ULLRICH and WIEDEMANN 15 segard Alder's and Reilly's anomalies as sdesitical phenomena UNDRITZ 24 also supports this idea, GUELI and SEVERI 223 suggest the hypothesis that Reilly's anomaly is noching but an altered stainability of the eosinophile cells. h Piychic disturbances. The Organic changes in the brain must be held responsible, according to REILLY, LINDSAY and MCGILLIVRAY, for the psychic discurbances 112 **). 1. Hydrocephalus. In respect of the cause of the hydrocephalus, the conception of BISKTON and c-sorkers 14 is the most popular one. These authors consider the thickening of the pia and asschnoud responsible for a partial or complete obstruction of the subarachnoidal space According to these suthors, in cases accompanied by leptomeningeal thicke ning, ventricular aidening was ala ays found **. STRAUSS 19 ascribes the ·a. LINDSAY 13, HUEPER, TOLENTINO and TERRAGENA 289, conducted animal experiments in which, after intravenous injection of macromolecular carbohydrate, they saw disturbances appear which according to these authors showed a resemblance to those in gargoylism and concluded that the substance accumulated in the cells cmanates from an excess in the blood. MEYER et al 27 give as hypothesis that mucopolysaccharides are accumulated as a result of an over-production of these substances caused by metabolic disturbances taking place in the connective tissue. Contrary to this opinion STRAUSS 131, KLENK", SEITELBERGER and BAMATTER 24 consider that the accumulation is a manifestation of a metabolic disorder taking place in the cells concerned. C Origin of the indiridnal symptoms Enchondral dysostosis The epiphysial cartilage ossification disturbances and the dwarfism connccted with them are seen by some investigators as manifestations of an endocrine dysfunctioning, by others as a primary result of metabolic discurbances loca. lised in the connective cissue itself 39 132, 133, 209 237 Based on the topographic distribution of the skeletal changes, MAU considers it probable that the palo chogenic action takes place at a certain stage of the embryonic development, and that the length of this influence is bound to a certain time limit 315 b. Umbilical and inguinal hernias, ligamentary contractures and skm changes The umbilical and inguinal hernias, skin changes and contractures are sc. nerally considered the result of metabolic disturbances in the connective tissue. с The enlargement of liver and spleen The enlargement of liver and spleen are attributed to enlargement of the parenchyma cells, and sometimes to the increase of cells belonging to the rcriculoendothelial system. d. Cardiac changes The cardiopathy was at first considered erroneously to be a congenital development anomaly Later on, however, cardiovascular sclerosis was found to be present in a number of cases, as the result of gargoyle mctabolic disturbances 39, 122 153 229 292 Corneal cloudings The corneal cloudings are, according to most authors, causcd by the presence of gargoyle cells in Bouman's membrane" NEWELL and KOISTIN- NEN 209, however, consider it unlikely that these phenomena should in any way be connected. They are more inclined to assume that structural changes in the connective tissue of the cornen have a causal relation to the cloudings e. 26 ·of one disease º3, 132, 197 167. 362 Most authors are of opinion that there are sufficient clinical differences berneen gargoylism and Morquio's disease to maintain them for the time being as separate syndromes ! 18. PROGNOSIS AND THERAPY The patients generally do not get older than ten to fifteen jears. According to FALCHI and MIDULLA che average span of life for girls is 8 years 4 months, and for boys 11 years. A higher age may be reached. The latter holds tre mainly for the abortive cases and for the cases without mental deterioration 199. They generally die as the result of cardiopathy or -- ouing to decreased thoracic mobility — from an pulmonary affection ". A number of patients died after a seemingly harmless operacion * T, or as the result of an anaesthetic 104 201 Of the symptomatic therapy (a causal therapy has not yet been described), ne mention the, in fact unimportant, improvement sometimes achieved by means of thyroid preparations. ERNOULD I saw remporary improvement, but no lasting result, from oral administration of thyroid preparations combined with X-ray treatment of the pituitary gland ULLRICH and WIEDEMANN 216 propose that investigations should be made concerning the influence of injections with hyaluronidase on Reilly: granules and on the histological changes in liver and spleen.

·hydrocephalus to obstructions resulting from bony changes of the base of the skull. According to PRICK hydrocephalus has also been described as the result of aqueduct stenosis. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS 274 Diagnosis is stated to be difficult only in abortive forms or in the initial stage of the discase. As a differential diagnosis the following diseases are men. tioned: rachitis, hypothyreosis €9, 10S, 185, 136, and mongoloid idiocy; cleido cranial dysostosis, hyperplastic periostal dysostosis and Crouzon's hereditary craniofacial dysostosis?. Also pituitary dwarfism and chondrodystrophy, as well as arthrogryposis are mentioned KRESSLER and AEGERTER discuss some points of difference with the lipid and the glycogen storage diseasesWhether Alorquio's disease belongs to gargoylism, or should be differentiated as a separate syndrome distinct from the latter, is a question not yet answered unanimously. Both diseases are characterised by an osteoligamentary syndrome, Morquio's disease is limited to this syndrome The syndrome generally disunguishes itself in Marquia's disease, among others, by "hyperlaxite ligamentaire" of the joints of the hands, more pronounced thoracic deformity, grencer excension of the vertebral anomalies and predominance of the skeletal changes in the lower extremities Especially a more or less generalised platyspondylia (broad vertebrae) is seen, whereas in gargoylism the malformacions remain limited to the thoracolum. bar transition where microspondylia, spondylolysthesis and the absence of the anterior upper quadrant of the vertebral body ("fish-hook shape") are the most frequent findings These differences do not necessarily always occur. Platyspondylia occurs as an exception in gargoylism 30 72 and in Morquio's disease also the "fish hook shape" is occasionally scen Although generally different, the skeletal changes, in so far as they can be seen by X-ray photos, may resemble each other so closely that most authors now assume that it is not possible to establish the differential diagnosis only by means of the X-ray picture Alorquio's disease furthermore, distinguishes itself by the lack of accumulation symptoms. Neither is there a Hurler face In all publicarions on the differential diagnosis berteen gargoylism and Morquio's disease, 18 19 mentioned that corneal cloudings are absent in the latter WIEDEMANN *** doubts the correctness of this statement and quotes rao Morquio cases orth corneal cloudings, moreover the liver and spleen were found to be cnlırged on palpation. He concludes from this that also in Morquio's discase deposits of pathological material may occur Gargoylism and Morquio's disease are sometimes considered as manifestations 186 198 Oral information 28 ·are of opinion that neither Tag-Sachs disease belongs to the lipidoses Personal opinion is that the conception, thar gargoylism should belong to the lipidoses is only partially acceptable; it can only be maintained for the changes in the central nervous system Furthermore, it should be remembered that the occurrence of these changes is not even imperative in gargoylism is Gargoylum an Endocrinopathy? The general appearance of the sufferer of gargoylisen in some respects resembles that of the patient with endocrine disorders. It must be attributed to this sesemblance that investigators unfamiliar with the clinical picture sometimes wrongly diagnose it as infantile myxoedema or cretinism ** From the discussion follosing the demonstration by HUNTER' it appears that the possibility of an codoctine disturbance was considered Especially the premature plethoric appearance as thought to be remarkable in this respect HURLER thoughe a certain relationship with endocrine conditions to be present' NONNE' saw in his case a combination of "imperfekter Chondrodystrofie mit imperfekter Myxoedema infantile" (imperfect chondrodystrophy with imperfect infantile myxoedema) SHELDON" described the picture is a "fosm of gigantism with splenomegaly" in a pacient in whom too strong growth occurred instead of dwariisin REILLY called the disease "an atypical familiar endocrinopathy with a syndrome of other defects". ERNOULD *as struck by the discordance between the hypertrophy of Citain organs on one hand, and developmental arrest or functional insuf. facency of various organs on the other, and sees in this symptomatology the resultant of acromegaly and hypothyreodism, for which he considers a piruitary dysfunction responsible, or an altered sensitivity of the periferal cssues for hormones as the result of an enzymopathy According to a statistical inquiry by A. GIAMPALMO and Y GIAMPALMO 177, sells changes are observed in 50% of the cases, at post mortem an cnlarged pituitary gland is seldom found. When the pituitary is large, the enlargement is generally adenohypophysial, and it is mainly the chro mophobe cells that shou gas goyle cell changes 99 79 11 13 14 262 263 24 Furcuonal disturbances of the pancreas are not meanoned in the literature Sporadically sexual infantilism is described 7 93 The thymus gland is sometimes enlarged 3 13% 253 DUHAMEL denies that in gargoylism glandulas disturbances should play a part 17 Some regard the dwarfism and the skeletal changes as manifestations of an endocrine dysfunc. tion Others appreciate the essors of growth as primary results of metabolic disturbances localised in the connectile tissue seselt ">} 209 in cretinism radiological changes of the spinai coluna may occur showing a resemblance to those seen in gargoylism, which may make it difficult to ·Chapter 11 CRITICAL REMARKS WITH REFERENCE TO THE LITERATURE Is Gargoylism a Lipidosis: The discussion in the literature on the question whether or not gargoylism belongs to the lipidoses is extremely lively and, in fact, undecided. In favour of the opinion that gargoylism belongs to the lipidoses is the fact that in this discase all typical ganglion cell changes are found, such as are described in certain forms of lipidosis (Niemann-Pick and Tay-Sachs) as well as the particular relationship in histochemical and biochemical respect, to che Tay-Sachs' disease. Indeed in both diseases there are indications for the supposition of ganglioside increase, on the ground of an excess of hexosamine and ncuramınıc acid in the brain tissue, Also the conviction of some investigators that the accumulacion in the viscera and the nervous system is accribucable to a metabolic disorder of the glyco. lipids could be used as an argument in favour of this conception A counter-argument is the opinion strengthened by experiment of some investigators that gargoylism is primarily a disorder of the metabolism of complex carbohydrates which co-incides with accumulation LINDSAY in jected rabbits intravenously with macromolecular carbohydrate and then saw changes arising (in intesunes and cornca) resembling those of gargoylism Similar experiments were also made by HUEPER and TOLENTINO in cooperation with TERRAGENA 285. The latter two discovered that, if very young rabbits are subjected to these experiments, besides thesaurismonic change in the liver and cornea, also chondrodystrophic changes may appear The occurrence of hexosamin both in mucopolysaccharides and in gangliosides, according to some investigators, also pleads for a primary discurbance in tlic metabolism of the combined carbohydrates. Morcover, as a further argument is the fact that in quantitative chemical cxa. mination some investigators have found no increase of the percentage of lipids in the viscera. The reticuloendothetial system is regularly affected in a considerable mcasure according to HENDERSON et al 201. Other investigators deny this and consequently reject gargoylism as a lipidosis For similar reasons they 112 285 30 ·are of opinion that neither Tay-Sachs' disease belongs to the lipidoses ? Personal opinion is that the conception, that gargoyliss should belong to the Tipidoses is only pacually acceptable, it mn only be maintained for the changes in the central nervous system. Turthermore, it should be remembered that the occurrence of these changes is nor esens imperative in gargoylism Is Gargoylum an Endocrinopath). The general appearance of the sufferer of gargoylism in some respects resembles that of the pacient sith endocrine disorders. It must be attributed to this resemblance that investigators unlamiliar with the clinical picture sometimes wrongly diagnose it as infantile myxoedema or cretinism 9. From the discussion following the demonstration by HUNTER' ie aspears that the possibility of an endocrine disturbance 13s considered. Especially the premature plerharic appearance was thought to be remarkable in this HURLER thought a certain sciationship with endocrinc conditions to be presenc' NONNE saw in his case a combination of "impetíchter Chondrodystrofte mit imperfekter Myxocdema infantile" (imperfect chon. drodystrophy with imperfect infantile myxoedema). SHELDON " described the picture as a "form of gigantism with splenome. baly" in a patient in shom to strong grow the occurred instead of dwarfism, REILLY » called the discase "an atypical famituar endocrinopathy with a syndrome of other defects". ERNOULD 14 was struck by the discordance between the hypertrophy of ceratin organs on one hand, and developmental assest os funcional insula fxcrency of various organs on the ocher, and sees in this symptomacology ano resultant of acromegaly and hypothyreodism, for which he considers a pituitary dysfunction responsible, or an altered sensitisty of the periferal tissues for hormones as the result of an enzymopathy. According to a statistical inquiry by A. GIAMPALMO and V. GIAMPALMO sella changes are observed in 50% of the cases; ar post mortem un enlarged picuitary gland is seldom found. When the piruisary is large, the enlargement is generally ade nohypopkysisl, and it is mainly the chromophobe cells thac show gargoyle cell changes 99, 79 is, 1314 262 263 264. Functional discurbances of the pancreas are not mentioned in the firecacure. Sporadically sexual infantilism is described 7. 191 The thymus gland is sometimes enlarged S, 13$ 24. DUHAMEL dentes that in gargoylism glandular disturbances should play a part 107 Some regard the dnarfism and the skeletal changes as manifestations of an endocrine dysfunction Ochers appreciate the crtors of growth as primary results of metabolic disturbances localised in the connective tissue itself "3, 209. in crocinism radiological changes of the spinal column may occur showing a resemblance to those sen in gargoylism, which may make it difficult to 31 ·establish the differential diagnosis of cretinism by means of the X-rays 69, 145, 186, 236 In gargoylism che ossification of the metacarpal centres is sometimes delayed? Several investigators consider that in gargoylism secondary endocrinc distur. bances are present, due to the affection of the cndocrine apparatus by die same metabolic discurbances occurring the other organs. Hormone determination in the urine is hardly mentioned in the literature, so chat it is not yet clear what value should be atcached to the fact that patho. logical findings have been noted in this respect, The corncal cloudings seen in respect to the differential diagnosis a'uth Aforquio's discase. The presence or absence of corncal cloudings is considered an important differential diagnostic criterium between gargoylism and Morquio's discase. According to the general opinion, the occurrence of corneal cloudings excludes the diagnosis of Morquio's disease. Both conditions resemble cach other in great similarity of the ostcoligamentary syndrome. The main point of differcnce is that gargoylism is coupled with storage manifestations and the disease of Morquio not. To the present day post mortems (3 in all) "S 133 186 of patients with Morquio's disease, have indeed not revealed any storage manifestations. Hepatosplenomegaly owing to accumulation has not been found in Mosquio's disease Apparent enlargement of liver and spleen, however, is described as the result of displacement by strong thorax deformity or through other cau. ses "IS_239There are cases of Morquio's disease on record in which corneal cloudings became visible only at an older age, and consequently (corneal cloudings being considered as scorage manifestations) the diagnosis changed inco gargoylismº 22 41, 42 73 97 145 338. This form of gargoylism is known in the literacure as "Spat-Hurler" type of gargoylism WIEDEMANN counts these cases under torquio's disease, as he is of opinion that Morquio's disease may also be coupled with symptoms of accu. mulation. There are also investigators who see gargoylism, Morquio's discase and the so-called "Spar-Hurler" type as manifestations of one disease 112 197 167 262, these investigators maintain the difference between the Morquio type and gargoylism on the basis of the presence or absence of accumulation symptoms, In support of this view they quote BOCKER " who stated that in several families Morquio and Hurler cases were observed simultaneously Later on all of these proved to be "Spar-Hurler" cases, in which the members of the family who presented a Morquio-like osteoligamentary syndrome werc looked upon as Morquio-cases and the others - presenting the same syn- 32 ·drome, but in show afternards corneal corneal cloudings were found, as cases of gargoylism" N " *2 73 McKUSICK, as the result of personal experiences, doubts hechos boch af. flictions have occurred in one family 27. On histological examination of the bony and caruiageous tissue in gargoylism and in Morquo's disease the only point of difference, according to MAU, would appear to be, that in gargoylism "Surgoyle cell" changes are sometimes observed in these tissues and neter in Morquio's tissues. This does not, according to MAU, exclude uniformity in the cluse of the changes in the bony and carulageous tissue in both diseases 16, Returning to the view that corneal cloudings are a manifestation of acowmulation, brought about by foam-like cells in Box man's membrane, it should be mentioned that there are seasons to Surmise thac in gargoylist is cannot be taken for granted that the corneal cloudings should be accumulation syrnptoms KRESSIER and AEGERTER , in a case of gargoylism attended with corneal cloudings, did not find any histological changes on examining the eye. NEWELL and KOISTINNEN *9 found the cloudings to be most pronounced is the central part of the corne2, whereas the foam cells were chielly found near the corneoscleral limbus. They consider it unlikely that these cells have any relation to the cornesi cloudings They are mare inclined to suppose thar structural changes of the corneal connectise eissue are in causal relation to the cloudings. BISHTON et al. 234 found no histological changes in the cornea ipost mortem at the age of 6 years), in a typical case a here corneal cloudings had been diagnosed (at 2 years of age). Personal opinion is that it is of importance for the differential diagnosis that the pathology of the corneal cloudings should be elucidated. If the latter prove to be due to scructural changes, then the Spat-Hurler type of gargoylism oughc indeed to be counted as belonging to Morquio's disease (as WIEDE- MANN considers for different reasons), However, should it appear that the prevalent opinion abour the cause of corteal coudings, namely, that they are to be attributed to accumulation, is correct, then this symprom can be main tained as an important differential-diagnostic criterium berseen Morquro's discase and gargoylısm It is, hos ever, also conceivable that both factors accumulation and struc- Tural errors curring either separately or combined, might result in the phenomenon of corneal cloudings. In the former case, the phenomenon would be of little value for the differenual diagnosis, in the latter, it would keep its salue, otherwise agreeing with the opinion of most investigators that there are sufficient differences between gargoylism and Morquio's disease to juspy maintaining the two is separate syndromes for the time being in 196 Boch syndromes can be traced back to a hereditary metabolic change. It is, honeter, sub} unknown to a hat extent the metabolic changes in these two syndromes ate mutually related. 17 ·establish the differential diagnosis of cretinism by means of the X-rays 69, 165, 186, 236 In gargoylism the ossification of the metacarpal centres is sometimes delayed? Several investigators consider that in gargoylism secondary endocrine disturbances are present, due to the affection of the endocrine apparatus by the same metabolic disturbances occurring in the other organs. Hormone determination in the urine is hardly mentioned in the literature, so that it is not yet clear what value should be attached to the fact that pathological findings have been noted in this respect. The corneal clondings seen in respect to the differential dugnosis with Morqnio's disease. The presence or absence of corneal cloudings is considered an important differential diagnostic criterium between gargoylısm and Morquio's disease. According to the general opinion, the occurrence of corncal cloudings excludes the diagnosis of Morquio's disease Both condicions resemble cach other in great similarity of the Osceolig! mentary syndrome. The main point of difference is that gargoylısm is coupled with storage manifestations and the disease of Morquio not. To the present day post mortems (3 in all) '15, 193, 186 of patients with Morquio's disease, have indecd not revealed any storage manifescations Hepatosplenomegaly owing to accumulation has not been found in Morquio's disease. Apparent enlargement of liver and spleen, however, is described as the result of displacement by strong thorax deformity or through other cau- 115. 235. There are cases of Morquio's disease on record in which corneal cloudings became visible only at an older age, and consequently (corneal cloudings being considered as storage manifestations) che diagnosis changed into gargoylismº, 22, 41 42 73 97 145 338. This form of gargoylism is known in the literature as "Spat-Hurler" cype of gargoylism WIEDEMANN 249 counts these cases under Morquio's disease, as he is of opinion that Morquio's disease may also be coupled with symptoms of accu. mulation, There are also investigators who see gargoylism, Morquio's dise.se and the so-called "Spar-Hurler” cype as manifestations of one disease !92 157 17 202, chess investigators maintain the difference berween the Morquio type and gargoylism on the basis of the presence or absence of accumulation symptoms In support of this view they quote BOCKER" who stated that in several families Morquio and Hurler cases were observed simultancously. Later on all of these proved to be "Spat-Hurler" cases, in which the members of the family who presented a Morquio-like osteoligamentary syndrome were looked upon as Morquio-cases and the others – presenting the same synses 32 ·1. Psychic deterioration is a conspicuous symp:orn (McGILLIVRAYS, LIES- SENS 273. Ventricular dilation in combination with hydrocephalus is often seen 2. Generally the patients do not get older than 10-15 years 3 Corneal cloudings are often observed 4. Here, too, serious forms of deafness may be found. 5. Sella widening is commonly seen, as well as kyphosis dorsalis 6 Here 100, considerable enlargement of the laer is often seen, a strong positive Best-stain however in the minority of cases only. Compacison of the classical picture with typus E - Mith a view to obtain an insight into the question thich functional disturbances or phenomena are purely the sequelae of the neurolipidosis gives rise to the fol. loning remarks: 1. Based on the obvious differences between typus E and the classical syndrome (the resp absence or prominence of psychic deterioration) it is acceptable indeed that the presence or absence of neurolipidosis may be decisive for the occurrence or absence of psychic deterioration. Absence of psychic disturbances does not exclude neurolipidosis as appears from some of the case histories and post mortems published by STRAUSS c al "?. The part played by the hydrocephalus and or the cerebral vascular or perivascular mansfestations is not taken into account here. 2 The absence of neurolipidosis may be of importance for the prognosis. 3. That in the cases of typus E menrioned above no corneal cloudings have been observed, should not be attributed to the abscence of neurolipidosis, but to the fact that the greater number, possibly all, belong to the sexlinked inherited form of gargoylısı 11 which corneal clouding does not generally occur. It is not believed that typus E limited to the X chromosomal pattern of inheritance. The autosomal pattern of inheritance in cases where the clinical picture gives rise to the presumption that neurolipidosis is not present (prolonged life span, absence of psychic deterioration and hydrocephalus) have been repeatedly described in the literature ? 38 45 106 in several of these cases corneal clouding does occur. However, no post mortem nas made, so that there is no certainty with regard to the question whether neurolipidosis is present or nor. Typus E seems to be represented exceptionally strongly in the sex-linked group. This question rell be further gone into in the chapter on the anthropogenetic aspects 4 Seeing that both in yous E and in the classical form serious deafness may occur, it is obvious that the cause of this deafness should not, in the first place, be looked for in the neurolipidosis This does not, of course, exclude the neurolipidosis as primary or secondary ·There is, however, an objection to the view that Morquio's disease should be a forme fruste of gargoylism, because the skeletal changes are more conspicuous in Morquio's disease than in gargoylism, which is hardly comp.: tible with the view of it being a forme fruste. TYPUST - ?) 91 (GARGOYLISM WITHOUT NEUROLITIDOSIS) Owing to the accumulation of sphingolipids in the ganglion cells, KLENK, EDGAR and DIEZEL count gargoylism among the sphingolipidoses 2W. To the sphingolipids the following substances belong :- ganglioside, sphingomyelin and cerebroside. According to these authors the following diseases belong to che sphingolipidoses. I Tay Sachs' (accumulation of gangliosides) II Gaucher's cerebrosides) III Nieman-Pick's sphingomyelins) IV Gargoyltsm gangliosides) For convenience sake the affection which is present in the nervous system in gargoylism will, in future, be called neurolipidosis. In gargoylism the ncurolipidosis is not an obligatory affection, although mention should be made that it is not often absent. C de LANGE 104 was the first to observe that the neurolipidosis may be completely absent She made this discovery during the post mortem of a patient whose syndrome had shown some remarkable features (absence of the following signs. corncal cloudingskyphosis and widening of the sella curcica), on which basis (in collaboration with WOLTRING) it was deemed advisable for the ume being to set this syndrome apart from the classical form as Typus E. 34 104 Since then, similar observations have been made by WOLFF*, SMITH ct al '94, REILLY and LINDSAY 132 and BEEBE and FORMEL in which also the absence of neurolipidosis was verified by post mortem. A summary of the most important characterisucs of these observations (ie of Typus E), follow's. 1 Psychic deterioration and neurological changes were lacking. 2. The age reached (19-43 years) was considerably higher than the classical standard of gargoylısm 3 Corneal cloudings were not observed. 4 Most patients showed a serious form of deafness 5. Sella widening was noted in this type, but in most cases it was absent The same is true of the kyphosis 6. In all cases the liver was greatly en and in the majority of cases the Best-stain was strongly positive. A comparison of these data with the classical syndrome of gargoylism (10. coupled with neurolipidosis) now follows. 218 26 ·Chapter III GARGOYLISA FROM THE ANTHROPOGENETIC POINT OF VIEV From the outset gargoylism has been suspected to be a hereditary disease. Since the publications of HALPERIN and CURTIS ", who shoued it to be a recessive heredity determined by a single autosomal gene, this view has become an established fact DE RUDDER * * confirms that gargoylısm is a recessive hereditary affection, bur is of opinion that only the simultaneous presence of mo genes (a "Morquio gene" and a "Phosphaud-drashesis-gene") produces this affection, while it is nos yer clear a hecher boch genes are situated in one chromosome This conception is supported by BOCKER ", based on a probable occurrence of cuses of Morguio's disease and of gargoylism in one family. ULL- RICH” considers the disease a recessive heredicary affection based on a pleiotrophic gene. SCHINZ" sees in gargoylism and Morquio's disease a recessive hereditary affection determined by one gene with polyphaner Mani. festation und Subletaln erkung“ (polyphany and sublethal action) WAAR- DENBURG" thinks it justified to class the disease among the recessively hereditasy autosomal characteristics JERVIS 157, JANSSEUNE 2+2 and WJE- DEMANN 1" are of the same opinion WOLFF" demonstrates the existence of a hereditary form of gargoylism linked to the male sex, while NJA the first to point out that in this type of gargoylısm corneal cloudings are absent IS On the strength of the data given in the literature, it may now be assumed that the follos ing hereditary transmissions exist A Reressfi'e Autosomal This form of hereditary transmission is characterised by the absence of symptoms in the patents of the patient, by its equal occurrence in female as in male members of the family and the high frequency of consanguinity, which increases the chance of concurrence of recessive genes. 37 ·pathogenetic factor in the classical form of gargoylism. C. de LANGE 10 found an atrophy of the organ of Corti, while WOLFF 88 gives the follow. ing description: "The organ of Corti preserved its normal contour, but no abnormal cells could be identified" (these two patients belong to typus E). 167 RICCI and ANCETTI 271 (in the classical form of gargoylism) found changes in the cochlear ganglion resembling neurolipidosis. In any case, from this it is apparent that the conception of the deafness as a symptom of neurolipidosis is not quite correct. 5. From the fact that the sella widening may occur in the Typus E as well, it appears that this symptom cannot, without any question, be considered as an exponent of the neurolipidosis. 6. The results of histo- and biochemical examination of the liver in che typus E and in the classical form merit comparison. Sofar only observations of typus E confirmed by post mortem have been considered However, in the literature there undoubtedly figure more typus E cases in which the absence of neurolipidosis has not been verified by histologica! cxamination From the clinical picture alone it is not yet possible to conclude with certainty whether or not the disease is attended with neurolipidosis Some general rules, however, could be given. A. The following symptoms are in favour of the presence of neurolipidosis. a Hydrocephalus, b Mental deterioracion ad a: Although no observation is known in which hydrocephalus was found and neurolipidosis was not, yet the possibility ought to be taken into account that the two may occur separately ad. b: The possibilicy that mental deterioration in some cases where neurolipidosis is absent is brought about by vascular or perivascular processes in the brain, should be considered B. The permanent absence of psychic deterioration does, it is true, justify the supposition that neurolipidosis is not present, but there is no guarantee to this.

·Chapler III GARGOYLISH FROM THE ANTHROPOGENETIC POINT OF VIEW From the outset gargoylism has been suspected to be a hercdrary discasc. Since the publicacions of HALPERIN and CURTIS", tho showed it to be a recessate heredıy determined by a single autosomal genc, this view has become an established fact, DE RUDDER 05 " confirms that gargoylism is a recessive hereditary affection, but is of opinion that only the simultaneous presence of two genes (1 "Mosquio gene" and a "Phosphacid-diathesis-gene") produces thus affection, while it is not ser clear wherher both genes are situated in one chromosome. This conception is supported by BOCKER ", based on a probable occur. Fence of cases of Morquio's disease and ol gargoylism in one family. ULL- RICH" considers the disease a recessive hereditary affection based on : plesotrophic gene SCHINZ" secs in Bargoylism and Mornwo's disasc a recessive hereditary affection determined by one gene with „flyphanet Man) destacan und Subletatwirkung“ (polyphany and sublethal accion). WAAR. DENBURG"" chiaks i justified to class the disease among the recessively hereditary autosomal characteristics. JER VIS'S, JANSSEUNC" and WIC- DEMANN ?" are of the same opinion WOLFF" demonstrates the existence ol a hereditary form of gargoylism linked to the male sex, while NJA" is the first to point out that in this type of gargoylum corneal cloudings are absens On the strength of the data given in the literasure, it may now be assume! chat the following heredicsty transmissions exist: A Recessite Antoiomal This forma of herediary transmission is characterised by the absence of symptoms in the parents of the pacient, by its equal occurrence in female as in male members of the family and the high frequcacy of consanguinity, which increases the chance of concurrence of recessise gones ·pathogenetic factor in the classical form of gargoylism. C. de LANGE 104 found an acrophy of the organ of Corci, while WOLFF 88 gives the following description: "The organ of Corti preserved its normal contour, but no abnormal cells could be identified" (these two patients belong to typus E). RICCI and ANCETTI 2?1 (in the classical form of gargoylism) found changes in the cochlear ganglion resembling neurolipidosis. In any case, from this it is apparent that the conception of the deafness as a symptom of neurolipidosis 167 is not quite correct. 5. From the fact that the sella widening may occur in the Typus e as well, it appears that this symptom cannot, without any question, be considered as an exponent of the neurolipidosis. 6. The results of histo- and biochemical examination of the liver in the typus E and in the classical form merit comparison. Sofar only observations of typus E confirmed by post mortem have been considered. However, in the literature there undoubtedly figure more typus E cases in which the absence of neurolipidosis has not been verified by histologica! examination From the clinical picture alone it is not yet possible to conclude wich certainty whether or not the disease is attended with neurolipidosis. Some general rules, however, could be given: A. The following symptoms are in favour of the presence of neurolipidosis a Hydrocephalus, b. Mental deterioration ad a: Although no observation known in which hydrocephalus was found and neurolipidosis was not, yet the possibility ought to be taken into account that the two may occur separately ad. b: The possibility that mental deterioration in some cases where new. rolipidosis is absent is brought about by vascular or perivascular processes in the brain, should be considered. B. The permanent absence of psychic deterioration does, it is true, justify the supposition that neurolipidosis is not present, but there is no guarantee to this.

·condicions are enumerated. vertebral changes and isolated occurring cornea! 30$ cloudings 61, anomalies of the ribs 286 cranial hyperoscosis and oligophrenia ULLRICH WIEDEMANN 26 and BAMATTER · LAMIY 3 looked in vain among the relatives of their respective recessive autosomal and X. chromosomal cases of gargoylism for such-like microsymptoms. Returning to the statistical researches of HERNDON et al 25 they compile statistics on the frequency of certain clinical symptoms in a group of 96 cases of the autosomal type, and compare these with the frequency of the same clinical symptoms in a group of 21 cases of the X-chromosomal type and 129 cases of unknown genetic type (avrosomal or X-chromosomal) with a view to tracing possible significant differences. For this statistical comparative investigation they select the follon ing signs corneal cloudings, dwarfism, deafness, limitation of movability of joints, gargoyle facial expression, cranial anomalies, hepatosplenomegaly, mental defect, changes in the vertebral column, herniae, short neck, otitis media occurring in the case history, hypererichosis and an enlarged sella turcica. As pointed out, in this manner significant differences are found with regard to corneal cloudings and dealness The X-chromosomal form, contrary to the autosomal type, is seen to be characterized by the absence of coracal cloudings and a significant increase of deafness LAMY et al arrives ar these conclusions by means of a similar statistical comparative investi. Batson With regard to the results of these investigations, the following remarks must be made 30$ 1 WIEDEMANN 14 215 has pointed out that corneal cloudings are only to be excluded with certainty by means of sker lamp examination. As chis examination took place only in a small section of the number of cases from the limited X-chromosomal group, che possibility must be taken into account that in a number of these cases where this examination did not take place corneal cloudings have nevertheless been presens. The view that corneal cloudings would be absent in the X-chromosomal form can be considered as 3 rash and perhaps incorrect conclusion. 2 The predominance of deafness should be expected in the autosomal group of the already earlier quoted opinions of GUY, LERIQUE, TURPIN and LAFOURCADE 161 227 are correct. Against the acceptance of a significant greater frequency of deafness in the X-chromosomal group the following objections are raised: In the first place, in scudying the small number of patients of the X-chromo. somal type, is noted that the com 50 many parents with a good mentality Deatness ISHULL Ht is quite simple to establish in patients with normal mentalıy. In many cases of gargoylism, however, osing to the mental deterioration, it is difficult or practically impossible to 39 ·B. Recessite X-Chromosomal In this sex-linked form the morbific gene is transmitted by female members, whereas the symptoms are only observed in males (on account of absence of one X-chromosome in the male). The parents have no morbid symptoms, It is important to point out here that the disposition to develop gargoylism is linked to the single pathogenic X-chromosomal genc or to the two pathogenic autosomal genes. Having considered that only these two forms of hereditary transmissions occur, HERNDON et al and LAMY et al have calculated that in about thothirds of the number of cases the transmission is determined to be recessivcautosomal and in one-third recessive X-chromosomal 254, 30%. GUY and LERIQUE 16 saate that in cases with clear corneac, the individual clinical symptoms, as well as the radiological changes develop less strongly than in the cases with corneal cloudings. TURPIN and LAFOURCADE explain this difference of intensity by con. cluding that the gene could exercise a quancitative effect: "le gargoylisme, maladre récessive autosomique, serait plus grave ct sans doute plus précoce que la variété gonosomique, parce que toute maladie relevant d'un gène à l'écar duplex, même récessif, apparair plus tôt et est plus expressive que la variété provoqués par un gène à l'état simplex, Cette opposition entre ces deux variétés de gargoylism serait un exemple de plus d'un fait déja note en patho. logie héréditaire" 227 HERNDON er al and LAMY et al, by means of statistics try to find signifi cant differences between the frequency of the various clinical signs in the two genetic forms of gargoylism and arrive at the conclusion that the sex-linked form, not only distinguishes itself by the absence of corncal cloudings, but also by the considerably greater frequency of deafness (42.9% as against 5.2% in the autosomal form 254 108) In the recessive autosomal form the occurrence of corneal cloudings is calculated to be 813%255, in other words, one-fifth of the number of cases with recessive autosomal transmission also have clear corncae. KLEIN et al 261 think ir noreworthy that in some cases of the X-chromosomal type, skin changes were found with the same topographic distribution 199 200 305 343 They wonder whether this is perhaps a phenotypical equivalent of the missing corneal affection. Gargoylısm is a disease with a deadly course The sufferer only occasionally reaches the marriageable age. It is, therefore, generally excluded that the patient transmits the pathogenic gene to posterity. Therefore, as there arc no indications that the frequency is decreasing, it is likely that gene mucation plays a part in sustaining gargoylism as a syndrome. Relatives of sufferers from gargoylism have been examined for the presence of microsymptoms of the disease which might be interpreted as manifestations of the pathogenic gene being present in a heterozygotic condition. In the literature the following ·else -O 0: 7 Ho 23 O 1, o FOR Ont Figure 1 Ancestry of male sex-linked gargoylism Male sex O Female sex O Transmits the disease Patient with gargoy list Patient with probable gargoylism y 4 Children of unknown sex 60 Twins of uncertain idectory Abortion + Dead under the age of 10 Examined personally Examined by another investigator . males that died at an early age aere not sufficient to diagnose gargoylist In V-14 the diagnosis was made on the ground of an extensive clinical examination undertaken elsewhere V 18, 23, 32, 39, 40 and 41 were examined personally. In IV 6, 7, 12, 20, 27 and V 21 the description given by lay people suggested the diagnosis of 41 ·establish exactly auditory disturbances. Therefore, it could be said that in the X-chromosomal group a greater number of cases occur in which, owing to the relatively favourable mental aspect and the more advanced age, it is possible to diagnose deafness Moreover, it is important to consider the fact that both in the X-chromosomal and the autosomal group, - as was stated in the previous chapter - at least two different types of gargoylism occur: the classical form (coupled with neurolipidosis) and the typus E (characterised by the absence of neurolipi. dosis). It is conceivable that deafness is more frequent in the one type than in the other. Further it should be mentioned that up till now the typus E dominates in the X-chromosomal group. If one really wants to establish whether the difference of heredity has any influence on the occurrence of deafness in gargoylism, then only the cypus E. cases from the X-chromosomal and autosomal groups have to be compared apart from the classical cases occurring in both groups As this has not been done, it is doubtful whether the view, that deafness in the chromosomal group obviously occurs more than in the autosomal and that this symptom should be inherent to the way of transmission, is correct Publications on families in which gargoylism is presumably inherited as a recessive X-chromosomal disease are now surveyed Such families have been described by WOLFF 88 NJA", LUNDSTROM 121, MCGILLIVRAY", MILLMAN and WHITTICK 1:4, HOOPER "", COLE et al 19, BEEBE and FORMEL 298CUNNINGHAM 24, McKUSICK 274 and BAMATTER and LAMY 305 274 were intellec In two cases the cerebrum was examined histologically without any changes being found. These cases concerned patients with normal intellectual faculces and a relatively advanced age (resp. 28 and 43 years). Also the patients described by HOOPER 192 and McKUSICK tually normal. Those described by NJA, MCGILLIVRAY and LAMY and BAMATTER, on the other hand, are characterised by serious and progressive dementia and the age reached, as in most cases of gargoylısın, is not high A relacively high age was reached by the patients described by WOLFF, HOOPER, COLE et al, BEEBE and FORMEL and McKUSICK PERSONAL OBSERVATIONS An opportunity occurred to examine some patients with gargoylısm from a family in which the classical form of this disease occurs as a recessive X-cluro. mosomal hereditary atfection In fourteen male relatives the diagnosis of gargoylism was established of which twelve certain and to probable It is possible that the actual number of cases in this family is still larger, because the available daca concerning ten 60 ·Vercoruh, JU CIK + + Typust Classic ເtt 1 Wollis 2 N311 8 28 30t 1 yrs b Il est C Normal 2 Fat below normal b Psychic deterioration cls able to walk, can. not walk Imbecilery Psychic deterioracion (I Q lower than 30) Classic Classic 73rs 8 mths IV 3 Lundstrom 12 1 McGillyray 3555 Classic Dilated ventricles 5 Millman and Whatrck 14 151 a 13 yrs mehst b 167537 c. 21 yrst el 25 yrst a Imbecility b Analphabetism c Less strongly disrur. bed than a d Backward Normal Tyrus L? Tytus E.? 6 Hooper 197 7 Colc « al 195 1 37355 6yrs b 23151 Cerebrum, no changes Typus E. Det be and Tormel ?IN 9 IV 13 yrst Normal or moderately impaired Mental uciect Mencal defect Normal. 9 Cunningham 2 12 III a 9yrs 6mths h. Syrs 3 mths 111 Classic Classic Tyrus E.? Classic? 1 22 yrs 10 McKusick 274 11 Bumaccer and Lamy ԿՑ 6 JI! 7715 12 the author it 6yrs 10 mehs b 3 yrs 3 mths C. 3 6 mths d & 2 mths C. Syrs omths Very pronounce retandeness Psychic deterioration. Psychic retardancss. Psychic deterioration Psychic deterioration. Psychic detstioration Psychic retintalness !!!!!+! Classic Classic Classic Classic Classic C135516 Dilared vcntricles. Dilated enticles. Tyrical crebral chan. ges, but no dilated ven. intis, acre found on mortem nt 1 Verified by shit lamp examination ·IV 27 and V 49 there was, moreover, a photograph available, which simplified establishing the diagnosis A detailed description of the alcerations found in six of these pacients, is given elsewhere in this publication (See Chapter IV, case I up to VI). Of fourteen patients five are still alive: V 18 6 months V 32 8 years 3 months V 39 - 11 years V 10 V 49 9 years 1 year and nine dead: 4 years 9 years IV 6 IV 7 IV 12 IV 20 IV 27 V 14 V 21 V 23 V 41 1 year years 6 months 3 years 9 months 6 years 11 months 2 years 9 months - - 13 months 5 years 6 months The main data concerning these patients may be summed up as follows: 1. Gargoyle facial expression, 2. Large skull circumference. 3. Oligophrenia, at a later age together with progressive dementia and neurological signs. 4 Hepato-splenomegaly. 5. Typical skeletal changes and ligamentary contractures 6. Once (V 14) slight corneal clouding was diagnosed in several cases corncal cloudings could be excluded by slit lamp cxamination 7. On caloric stimulation of the labyrınths no vestibular reaction was scen Disturbances in auditory functions could not be exactly determined on account of psychic disorders 8. Reilly's anomaly could not be shown. 2. The skin anomalies described by COLE et al, ANDERSSON · TAND. BERG and LAMY - BAMATTER were not found in these cases In the cases examined the symptoms manifested themsclves carly (before the third year of life) so that here an "carly" form of cargoylism can be assumed Some relatives not suffering from gargoylism were examined for the presence of microsymptoms of the disease (IV 24, V 38, 42) The result of this cx.ummination was negative. For the sake of completeness let it be noted here that in V 12 a slight chorciform restlessness and genua recurvata were observed. A list of data from the literature and patients personally examined with male sex-linked gargoylısm:

·Chapter 1
CLINICAL CASE REPORTS
CASE 1
BOY A Ancestry, Fig 1, V 23, Picture Fix 2 and 3
EXMANINATION (Age 6 years 10 months)
Data about the past history are lacking
The child, recently admitted to a home for mentally deficient children, shows on
inspection the following features
A for gargoylism typical facial expression, an enlarge head and cars, marked hyr.
telorism, a broad and sunken nose rooc, a large protruding tongus, red checks, a broad
and short neck, a broad thorax with sunken sternum, a protruding abdomen with an
umbilical hernia, a considerable kyphosis present at the thoracic lumbar junction,
Cuse I. bor , age 6 yrs 10 mths

·Comparison of the literature data with personal observations leads to the following conclusions: 1. Contrary to the literature it is thought that in sex-linked girgoylism corncal cloudings may occur, although less frequently and in a mitigated form, 2. Up till now the X-chromosomal group comprises a relatively large number of patients of whom it may be supposed - taking into account the absence of mental disturbances and neurological signs - that there is no cercbral localisation of the disease (Typus E). 3. It is not considered proven that in the X-chromosomal group deafness occurs more than in the autosomal group 324 linally it should be remarked that the findings of FALCHI and MIDULLA viz, that the average span of life is 11 yrs for males and 8 yrs for females, may possibly point to a more favourable course of the homozygous condition, as this condition is supposed to be present in half of the malcs 254, .

·Chapter IV
CLINICAL CASE REPORTS
CASE
1. Ancestry. Fig I, V 23, Picture Fig. 2 and 3.
CXAMINATION: (Age 6 years 10 moncha)
Data about the past history are lacking
The child, recently admitted to a home for mentally deficient children, shows on
inspection the following leacures
A for gargoylism typical facial espression, an enlarged head and cars, marked hyper.
tetorism, a broad and sunken pose root, a large protruding tongus, red checks, 2 broad
and short nech, a broad thorax with sunken sternum, a protruding abdomen with an
umbilical hea, a considerable kyphosis present at the thoracic lumbar function,
rog 2
Case I, boy 1, age 6 rs 10 mihs

·ho rig. 3. Case I, boy 1, age 6 yrs 10 mths short and broad hands and fingers, flexion contractures of arms and legs — the fingers are crooked and the feet held in a pointed position —, increased hairgrowth at the back and the extensor sides of the extremities and acrocyanosis. The corneae are clear Further examination reveals a greatly enlarged liver and a less pronounced enlargement of the spleen No cardiovascular abnormalities The mouth contains, due to difficulties in swallowing, much saliva The pharynx reflex is low There are signs of a spastic diplegia, predominating in the lower extremities On both sides Babinski's sign is present There is a mental deficiency comparable to the severest form of imbecility Tag 4 Angulur kyphosis Spondylolysthesis fashhool-shape of L 1 and 2 46 ·XRay findings Skull The skull is too high and broad The roof is chickened a bulgy frontal bone The sutures are closed No strenghtening of the impressiones digitatac. The sella is nor enlarged The mastards contain battle air Thorax The clavicles are hefty (especially on the sternal end) showing a definite S-shaped curve Broad and horizonrally turning tibs The ends of the loner ribs are narrowed The thorax is barrel-shaped. Vertebral column (Fig 4) Angulat kyphosis at the junction of the 12th thoracic and first lumbat vertebra There is a clear lysthez:s to the front of Th 12 in relation to Li Concave front of Th 11 and 12 Fishhook shape of L 1 and 2 Hand The first and second phalanges are cone-shapxd Pseudoepiphyses a metacarpal I Broad and heavy metacarpals There are four ossified metacarpal centres visible Biometrical data Laboratory findings:** Before a more detailed examination had been carried out, the child died as the result of pneumonia at the age of 6 years 11 months CASE 11 BOY B hnetstry, Fig 1, V 14*** PAST HISTORY: No details are known about his birth Normal dentition Started walking when he was 17 months old EXAMINATION. (Age 3 years 3 months). The facial expression is typical of gargoylısm The head is large and the root of the nose sunken The conchae of the cars are coarse The tongue hangs out of his mouth "The tonsils are enlarged There is a slight clouding of the cornea on both sides There are no Opatitics of the leas The intra-ocular tension " normal Slit-lam examination is not possible as the retuk of the poor co-operation of the child Hean and lungs are found to be normal The liver is enlarged The spleen is just palpable There is a large umbilical hernia Genitals no special features The hands are short and broad, the nails short and curved in to directions The back shows an extensive diffuse haur-growth The child makes a friendly but stupid impression He is cheerful, laughs a great deale plays continually and tries to seek contact It is not clear whether he can hear normally He does not talk yet and cannot understand the spoken instrucuon. On the whole he gives an impression to have a mental age of about to years X Ray finding: Skull The skull-wall is fairly thuck The frontal bone is prominent The distance of the ala magna to the base of the nose is too small The sella is not enlarged The mastoids contain little ast 47 ·Tig) Case I, boy d, uge 6 yrs 10 mbs short and broad hands and fingers, flexion contractures of arms and legs - the fingers are crooked and the fece held in a pointed position, increased hairgrowth at the back and the extensor sides of the estremities and acrocyanosis The cornesc are clear. Further examination reveals a greatly enlarged liver and a less pronounced enlargement of the spleen No cardiovascular abnormalities The mouth concains, due to difficultics in swallowing, much saliva The pharynx reflex is low There are signs of a spastic diplegia, predominaring in the lower extremities On both sides Babinski's sign is present. There is a mental deficiency comparable to the severese form of imbecility, ris Angular kyphosis Spond, lolisthesis Tushbook shape of L 1 and 2 ·The neck is short and broad Heart and lungs are posma) Normal ECG Blood pressure 125.80. There is s small umbilical rupture The liver is enlarged The spleen is not palpable Frg 6 Case Ill, boy C. uge 8 yrs 3 mths The hands are short and broad The end phalanges of the fingers are kept in a curvcu position The little tiger is curved in a sadial direction The Dails 210 normally shaxud There are no anomalies of the hair growth, Deuther is there acrocyanosis euro psscbmtric Examination (Age 5 years 5 months) The motor functions of the cranial nerves are intact Speech is impacted and restricted to some hardly audible words The muscularure is normally developed. The power of the muscles does not show anything abnormal No fascicular contractions are observed The patient shows stereo pt movements of which the following are the most important thythmic gang movements of the trunk, continuous walking to and fro with the arms on his back and running with the arms Extended in front of his bowly While running he makus «creaming noises The movements are characterised by a lack of grace and sunpieness Apart from this, there is apraxia, which is obvious from the continual trying of certain actions which, a few months ago, he could still perform The sensibility cannot be judged exactly There is no ataTy when walking or standing. The gripmovements are well co-ordinated There are no tremors Spontancous nystignus 15 not present while the optokinetic nystagmus can be activated in both directions The pupils are of a middlewidth, equal in size and react well to light and convergence The oculopalpebral reflex is clearly strengthened and the reflexogenous zone is ex. tended to the back of the head The corneal - masseter and then taloon --- L. . and cre The TI The cou I LIC Ukulture is normal 'The cog-wheel phenomenon is absent When anxious sometimes an affective loss of tone occurs Eyesighs and hearing cannot 42 ·Hand. The first and second phalanges are cone-shaped There are two hand-roor nuclet visible The child died some months later from complications arising from an operation for umbilical rupture CAST II! BOY G. Ancestry, Fig. 1, V 32, Picture Fig 3, 6 and 7 CASE HISTORY: Delivery was slow. Ac birth it was observed that the head was large and the forchicad prominent The hair on the head, which was originally shiny and curly, became brisely The closing of the fontanelles was delayed. The development of the cashiesr childhood expresses stself in the following Jara sitting 5/12, first teeth 12/12, walking 13/12 When 18 months old, Die could speak some words, but since then there was no further progress He often had colds and bronchitis Due to his aggressiveness he was admitted to an instirution for mencally deficient children FIRST EXAMINATION. (Age 5 years 5 months) His head is relatively too long The forehead is prominent A cracked por sound is present The facial expression is typical for gargoylism The cyebrows are grown together, above a sunken nasal root The conchac of the car are large There is a macroglossia The teeth are small and far apare The voice 15 high-pitched The colour of the checks is of a bright red as the result of great dilatation of the skin capillaries On both sides the corncal diameter of the eyes is normal All layers of the cornea are of normal clearness (slit-lamp examination) The fundi ocul are sound F185 Case III, boy C, age 8 ir 3 mth.

·The Deck is short and broad. Heart and lungs are normal Normal ECG Blood pressure 125,80 There is 3 small vmbilical rupture The liver is cnlarged The spleen is not palpable. Tag 6. Case Ni, bot C. Age 8 yrs 3 mths The hands are short and broad The end phalanges of the fingers are kept in a curved position. The little finger is curved in a radial direction The nails are normally sharou There are no anomalies of the hair growth, neither is there acrocyanosis Neuro psychiatric Examination (Age 5 years 5 months) The motor functions of the cranial nerves are intact Speech is impaired and Elstriciti to some hardly audible words The musculature is normally developed The poner of the muscles docs not show anything abnormal No fascicular contractions are observed The patient shows stereo type movements of which the following are the most important rhythmic swing movements of the trunk, continuous walking to and fro with the arms on his back and running with the arms extended in front of his body While running he makes screaming noises The movements are characterised by a lack of grace and suppleness Apart from this, there is apraxia, which is obvious from the conuoual trying of certain actions which, a few months ago, he could still perform The sensibility cannot be judged exactly There is no ataxy when walking or scanding The gripmovements are well co-ordinated There are no tremors Spontancous nystagmus is not present while the optokinetic nystagmus can be activated in both directions The propuls are of a middlewidth, equal in size and reace well to light and convergence The oculopalpebral reflex is clearly strengthened and the reflexogenous zone is ex. tended to the back of the head The corneal - masseter and pharyox reflexes can be normally activated The abdominal and cremastcric reflexes are lively as well as the periosteal reflexes of the extremities The Trommer reflex is absent Cloni cannot be evoked Normal foorsal reflexes The tone of the musculature is normal The cog-wheel phenomenon is absent When anxious sometimes an affective loss of tone xcurs Eyesight and hearing cannot 49 ·exactly be determineu, On caloric vestibular stimulation not a single reaction is observed. The development of the intellectual functions is retarded The kvel obtained is comparable with severe imbecılıty Memory and imprint are insufficiently developed and even have deteriorated Speech - unul recently the patient spoke a few words. shows a recession Until recently the game still contained constructive elements, but now the patient show's no real interest in his toys. He only picks them up to throw away. His attention can only be drawn for a shore time by a moving objece The recognition of persons is limited to those who look after him daily. The affecti vity is grcatly influenced by factors in his surroundings. He is excitcable Ho seks contact with adults and laughs as soon as they look at him He has no interest in children F1g 7 Case III, boj C, age 8 385 3 mibs There is Juttle variation in his feelings and also little depeh The instinctive behaviour can be classified as amorphous The spatial orientation is limited to the ncarest surroundings He is still not clean He likes to suck his fingers His sexuality is not present in a more differentiated form Hunger, thirst and sleep are normal Hus temperament is lively He has a great deal of energy and does not sit still for a moment. He particularly lives in a visual spruce There are no signs of manifest aggression towards his surroundings He gets soon frightened and is extremely dependant on those who take care of him. He never looses sight of them His psychomotorism is poorly developed Patient makes a clumsy impression which should be partly attributed to apraxia His laugh is stereotype His crying makes a rudimentary impression and remains limited to moaning The facial expression sometimes has a clown-like character On examination he is not co-operative and automatically repulses forcefully everything that touches him He keeps on laughing at the physician who examines, but makes repulsive movements at the same time It is noticeable that he continues to laugh in a friendly way at the examiner to whom he objects This proves the inadequacy of his emotional expression ·Electroencephalographic examination When the eyes Here open only occasionally some parsero-occipital activity of 8 'sec. Has registered sith moderate amplitudes A fuely strong beta activity was noticed, also in the posterior regions The sleep record was irregular, without asymmetry, sleep-spindles on both sides of 12 sec On arousal a bulateral symmetric irregular activity of thor and delta frequencies was observed with a relatively high amplitude. Photic-stimulation was follored by a pronounced occipital driving sesponse in the frequency range of the alpha and beca shythm The EEG sas rudged to be diffusely disturbed to a slight degree. Joints Shouders. The abduction, elevation and endorotation are limited The exorotation is normal Elbous Flexion, estension, pronation and supisation are limited Wrists The movements in all directions are lemned fingers The extension is limited Hips The flexion and adduction are good The following movements are limit. extension, endorotation and erorotation The abduction is slightly sestricted Knees Fletion and extension are limited Ankles The ankle movements are normal Toes Extcosion-restriction is similar to that of the fingers X Ray fundmgs Skull Dolichocephal,c forma of skull Normal thickness of the skull 311 The frontal bone is prominent The sutures are closed The sells 13 shoc-shared and slightly enlarged The mbastosd contains lustle air Thorax The clavicles ate sung The ribs are broad and fave a horizontal course The extremities of the lowest rabs shoa a nacron ing Barrel-shaped thorax Vertebral column The lowest vertebrae are broad and flar Intervertrebral discs are natron, specially beta een L 1 2 Slight kyphosis at the level L 1 2 Anteriorly Th 11 and 12. L 3, 4 and 5 are concave Peless The alat are too lat Funur Coxae valgae The head of the femur is medially Bartened Hand The first and second phalanges are cone-shaped Pseudoepiphysis ar metacarpal 1 Broad and plump metacarpals There are fous Ossified carpai centres visible SECOND EXAMINATION. (Age 8 years 3 months) The fact has become meet and has a more found aspect The corneae are still clear A reaction is noted only to loud sounds Speech has become worse The massetesreflex is lively The phanax reflex is lou There is now a slight spastic tetrapasests accompankd by hypetrellcxia Da boch sides ao ankle clonus can be elicited, The Babinski reflex is present The telier of Trompet is bilaterally sight positive Parede salks with his feet pointed The to and fro movements are nos eboisshed No tog-wheel phenomenon is presene During walking no atala is observed. The behaviour of the parent 13 stall hyperkiBETIC la comparison with the previous examigation it is, honeter, noticed that the faulent does not like salking any longer He gives the impression that he gets tired very quickly He saill seeks contact with adults but does not recognize them Toys do not interest him, nor tyen 1 throw them away When eating he does not even try to hold his spoor The child contaually sucks his fingers, hile he is orally aggressive 10ards to clorhes and chess them. 51 ·cxactly be determined On caloric vestibular stimulation not a single reaction is obscrved. The development of the intellectual functions is retarded The level obtained is comparable with severe imbecility. Memory and imprint are insufficiently developed and even have deteriorated Speecli - until recently the pacient spoke a few words. shows a recession Until recently the game still contained constructive clements, but now the patient shows no rcal interest in his toys He only picks them up to throw away. His attention can only be drawn for a short time by a moving object The recognition of persons is limited to those who look after him daily. The affecti vity is greatly influenced by factors in his surroundings He is excitcable le seeks contact with adults and laughs as soon as they look at him. He has no interest in children Fog 7 Case III, boy C. age 8 375 3 mhs There is litele variation in his feelings and also little depth The instinctive behaviour can be classified as amorphous The spatial orientation is limited to the nearest surroundings He is still not clean He likes to suck his fingers His sexuality is not present in a more differentiated form Hunger, thirst and sleep are normal His temperament is lively He has a great deal of energy and does not sit still for a moment He particularly lives in a visual sphere There arc no signs of manifest aggression towards his surroundings He gets soon frightened and is extremely dependant on those who take care of bım He never looses sighe of them His psychomotorism is poorly developed Patient makes a clumsy impression which should be partly attributed to apraxia His laugh is stereotype His crying makes a rudimentary impression and remains limited to moaning The facial expression sometimes has a clown-like character On examination he is not co-operative and automatically repulses forcefully cverything that touches him He keeps on laughing at the physician who examines, but makes repulsive movements at the same time it is noticeable that he continues to laugh in a friendly way at the examiner to whom he objects This proves the inadequacy of his emotional expression ·Electro-encephalographic examination When the eyes were open only occasionally some parieto-occipital activity of S'sec was registered with moderate amplitudes A fairly strong beta activity was noticed also sa the posterior regions The sleep record was irregular, without asymmetry; sleep-spindles on both sides of 12 'sec. On arousal a bilateral symmetric irregular activity of theta and delta frequencies A as observed with a relatively high amplıcude Photic-stimulation as follon ed by a pronounced occipital driving response in the frequency range of the alpha and beta rhythm The EEG was judged to be diffusely disturbed to a slight degree, Joints Shoulders The abduction, elevation and endorotation are limited The exortation is Dormal Elbons Flexion, extension, pronation and supination are limited Wrist The movements in all directions are limited Fingers The exteosion is limited. Hips The flexion and adduction are good The following movements are limited extension, eodorotation and expretation The abduction is slightly restricted Kaecs Flexion and extension are limited. Ankles The ankle movements are normal Toes Extension-restriction is similar to that of the fingers X-Ray findings Skull Dolichocephalic form of skull Normal thickness of the skull wall The frontal bone is prominent. The sucures are closed The sella is shoe-shared and slightly enlarged The mastoid contains little air Thorax The clavicles are strong The ribs are broad and have a horizontal course. The excessities of the losesc abs show 2 Sarrowing Barsel-shaped thorax Vertebral column The lowest vertebrae are broad and flat. Intervertebral discs are narrow, specially between L 1/2 Slight kyphosis at the level L. 1'2 Anteriorly 'Th 11 and 12, L 3, 4 and 5 are concave Pelvys The alae are too flat Femur Coxae valgae The head of the femur is medially flattened Hand The first and second phalanges are cone-shaped Pseudoepiphysis ar metacarpal 1 Broad and plump metacarpals There are four ossthed carpal centres visible SECOND EXAMINATIO (Age 8 years 3 months) The face has become thicker and has a more sound aspect The corneae are still clear A reaction is noted only to loud sounds Speech has become worse The massetecccflex is lovely The pharynx reflex is low There is now a slight spastic tetrapacesis accompanied by hyperreflexia Oa both sides ag ankle clonus can be elicited. The Babieska reflex is present The reflex of Trömmer is bilaterally slight positive. Patsent walks with his fett pointed The to and fro movements are not abolished No cog-wheel phenomenon is present During walking no ataxia is observed The bebavour of the patient is still hyperkinetic. In comparison with the prerrous examination it is, however, noticed that the patient does not like walking any longer He gives the pression that he gets tired very quickly He still seeks contact with adults but does not recognize them Toys do box interest him, not even to throw them axas When eating he does not even try to hold his spoon The child conunually sucks his fingers, while he is orally aggressive towards his cloches and chews them ·CASE IV BOY D: Ancestry Fig. 1, V 39, Picture lig 8 and 9 CASE HISTORY: Normal birth on cime. Data from childhood. tonsillectomy, operation for umbilical hernia, recurrent colds, measles and bronchopneumonia. Could sit at 18 months, walk at 2 years 3 months, could talk from his 3rd year Patient has only learned to speak a few words from his third and a half years he has gained no fresh knowledge, and deteriorated gradually He has never been clean Owing to his tempor and attacks of fury, he was admittal to an institute for mentally deficient children. The last two years it was noticed thur he became abnormally dull and thirsty Now, however, he hardly cats and drinks. A few months ago he broke his lower left leg, since then patient cannot walk without support although healing of the fracture was successful (188 Case IV. bo) Duge Ilir FIRST EXAMINATION: (Age 8 years 2 months) The facial expression is typical for gargoy lism The hair of the head is dry and bristly and the margin of the hair irregular The conchac of the cars are large The nasal root 15 sunken Hypertelorism is absent The skin of the face is dry and scaly and the checks are red There is macroglossta The teeth are small and far spurt On both sides the corneal diameter is slightly increased The retina and chorioidea show no abnormalities nor the macula lucea The papillae of the optic nerve are normal. In the corneac no parcicular substances or deposits are nouced (slit lampy examination) The eyelids are thick and flabby, causing the eye-slots to be narrow The neck is short and broad The thorax is broad, and it is noticeable that the centre part of the sternum is prominent Heart examination shows no abnormality The ECG. is normal The bloodpressure is 110/80 Bronchitic sounds are heard The abdomen is hefty, and there is a distinct hepatosplenomegaly Specially the liver is greatly enlarged. The genitals are normal The skin of the scrotum is thick The arms and legs are thin in comparison to the fat trunk and large head The louer 52 ·hinners limbs give a hypoplastic pression The little finger is curved radially the An intense hair-growth is noticed lower lucobs The skin is tease and on the back and extensor side of the extenties squamous lesions are noticed. The subcutaneous fat-13; er is strongly deselored Fig 2 Case IV', boy D, oge il y Neuro psichotrse extindion Age 6 years 2 months) The motor functions of the cranial cerves are intact. The speech 15 paired The muscles of the head, neck and trunk are normally developed The musculature of the extremiues 15 hypoplastic, specially with reference to the distal parts The muscle foner appears to be normal. No fascicular contractions are observed The patient has choteiform movements, the head keeps on moving and the artigude of trunk and excremities is continually changing. Nonceable is the frequent bliaking of the eyes The patient is able to stand zlone and with help to walk some steps He walks with his legs apart and drags them The accompanying movements of the arms are not suspended during walking The sens.bility is - 23 far as can be gathered - place. There is no atasia 18 standing or walking. There are no tremors Nystagmus is absent. The optokinetic nystagmus 18 nostal The pupils ate of medium-width, equal 18 size and react sell to light. The oculo. palpebral reflex is strongly positive The reflexogenic zone thereof is extended to the back of the head The patient reacts to loud sounds with an increased eye-blink reflex, also to menacıog movements The corneal., masseter and pharynx reflex can normally be elicited Primitive sucking and bung reflexes are observed The mouth contains too losle saliva The patrent continually snacks his lips when ·one wipes around his mouth, a spastic grin appears, at the same time his mouth opens The arm reflexes are lively; the Trommer reflex is negative. The abdominal and cremaster reflexes are low. The periost reflexes of the legs are not increased No pathological foot.sole reflexes can be elicited. The musclc-tonus appears to be increased Sometimes it is possible to clicit an ankle clonus. Hearing and sight cannot exactly be determined. On caloric vestibular crami. nation not a single reaction is observed in the cramination of the intellectual functions, it appears that the development is very backward; the level reached compares with the severest form of imbecility, there is also a deterioration in the sense of demencia Memory and imprint are greatly disturbed. He only knows those who regularly look after him He is not interested in toys, and it is impossible to attract his attention even for a short period The patient often makes a sleepy impression. Now and then he looks up and blinks a great deal with his cye-lids It is not possible to obtain an affective contact with the patient. His mood is apathetic and filled tvith feelings of disdain He just looks for a moment at adults and does not interest himself at all in children On coming closer to the patient, the motoric restlessness increascs. He sometimes produces a groaning noise The patient is completely dirty The saus fying of his desires has a definite oral character. Patient cats and drinks abnormally little and sleeps too much His attention is limited to the visual sphere The psycho motorism is poorly developed He has a fixed grin on his face Apart from this the pacient makes a helpless and unhappy impression Spinal fluid The pressure and composition of the fluid are normal The colloidal tests (mastix, gold and benzoic acid) show a normal curve The pneumoencephalogram obtained by lumbar insufflation shons a definite widening of the third and side ventricles Electro-encephalographic examination When the eyes were open no obvious alpha thythm was observed The EEG con. tained many theca components of moderate amplitudes, as well as a fairly strong beta activity, also in the posterior regions. On photic-stimulation a pronounced occipital driving response was seen, especially in the frequency range of the alpha rhythm The EEG was classificd as to be diffusely discurbed to a slight extent Joints: The possibility of movement is restricted in many joints The scapulac are high In the shoulder-blades the abduction and elevation are restricted The rotations are greatly restricted in the elbow joints all movements are diminished, as well as in the pulse in the hip joint all the movements are diminished, specially the adduction and endorotation, which are practically nil The flexion and extension in the knee joints are clearly restricted The toes are crooked, just like the fingers X-Ray findings Skull Brachycephalic form of skull The top of the skull is somewhat thin Deepened vascular impressions Thc sutures are open the entrance of the sella is enlarged The mastoids contain little air Thorax Very massive clavicles (especially sternal) Broad ribs The extremities of the lower ribs show a narrowing, like a paint-brush The outline of the heart is normal Barrel-shaped thorar Vertebral column Angular, right convex kyphoscoliosis at the level of the thora- 54

·columbar junction The lumbar vertebrae are broad and have a concave margin in
front whereby the lowest epiphystal plate is prominent (specially L. 2)
The lon est thoracic vertebrae have a concave front
Peltis The ischial and pubic bones stand up-right and the alae of the iliac bone lic
fLIL. The pelvis-ring is somen hat narrow at the level of the acetabul Flat acetabuli
Corae valgae The head of the femur is medially flattened and the epiphyses have an
irregular lumi
T 10
Cone-shaped phalanges
Broud metacarpals
Coarse trubeculation
Hand (Fig 10) Pseudoepiphysis at metacarpal I The phalanges are coneshaped
There are fout ossified carpal centres visible Broad and plump metacarpals
Foot (Fig 11) Coarse phalanges and mesatarsals
SECOND EXAMINATION (Age 11 years)
Patient has now a distinct full-moon face
The cordeae are still clear The hepatosplenomegaly has markedly increased There
is still leukonychia. The masseterreflex js very houple The nhu.
The matte
www.dultun is only on sumul in the immediate neighbourhood, the patient
Teacts only to loud sounds
He now fails to recognize people
55

·Tig 11. Broad metatarsal I. ht CASCV BOY E. Ancestry, Fig 1, V 40, Picture Fig 12 and 13 CASE HISTORY. Normal birth The mental development was retarded Patient commenced to walk when he was 18 months old He has only learned to speak a few words Apart from recurrent colds and consillectomy, he has had no special illnesses or operacions At the age of 4 years he was admitted to an institute for mentally deficient children FIRST EXAMINATION (Age 5 years 6 months) His facial expression is typically gargoyle The hair on the head is thick The ac brows are grown together The eats are large The skin of the forehead and checks is red, dry and scaly Hypertelorism is absent The nasal root is sunken The teeth are small and far apart The tongue protrudes from the mouth There is no macroglossia Mucus comes from the pharynx and nose The corneal diameter is normal The fundus is normal The lenses are clear as the child is frightened and restless the examination with the magnifying glass and slit. lamp is difficult No opalescence is found in the cornea, but it was not possible to exclude same with certainty The neck is broad and short Heart and lungs are found to be normal The blood pressure is 125/80, and the ECG normal The liver is greatly enlarged The spleen is only just palpable There is a thuck 56

·panniculus adiposis The abdomen is bulg; There is no umbilical hernia The penis
and testicles are hefry
The skin of the back and extensor side of the arms is dry and scaly, and here the
hair-growth is clearly intensified No acrocyanosis
The hands are short and broad, as well as the fingers a hich are crooked The Little
fingers are curved radially The nails are normal
rog 12
Case V, boy E, age 3 29 6 mihs
Tt8 13.
Case V, boy E, age 99
57

·Fig. 11. Broad maluarsal I. CAST V BOY E. Ancestry, Fig 1, V 40, Picture Fig 12 and 13 CASE HISTORY Normal birth The mental development was retarded Patient commenced to walk when he was 18 months old He has only learned to spycak a few words Apart from recurrent colds and tonsillectomy, he has had no special illnesses or operations At the age of 4 years he was admitted to an institute for mentally deficient children FIRST EXAMINATION (Age 5 years 6 months) His facial expression is typically gargoyle The hair on the head is thick The cyc. brows are grown together The ears are large The skin of the forehead and checks 18 red, dry and scaly Hypertelorism is absent The nasal root is sunken The tech are small and far apart The tongue protrudes from the mouth There is no macroglossia Mucus comes from the pharynx and nose The corneal diameter is normal The fundus is normal The lenses atc clear As the child is frightened and restless the examination with the magnifying glass and sliclamp is difficult No opalescence is found in the cornca, but it was not possible to exclude same with certainty The neck is broad and short Heart and lungs are found to be normal Thc blood pressure is 125/80, and the LCG normal The liver is greatly enlarged The spleen is only just palpable There is a thich 56 ·Elbons Flexion extension, pronation and supination are restricted The extension of the fingers is limited, Wrists Movements are moderately limited in all directions Back The back as flat There is no lumbar lordosis or scoliosis Hips Flexioo, extension, exorotation and endororation is limited Knets Extension and flexion are restricted dokles Movements are sub-normal X Ruy finding Skull The skull wall is rather thin The Sutures are open. Fairly prominent vasculus impressions The distance of the ala magna to the base of the nose is too small The sella is shoe shaped and slighily enlarged. Thorax The clavicles ate hefty and the ribs broad The ends of the lowest ribs are narrowed (fig 14) The course is horizonta! The sternum is prominent Barrel shaped thorax Vertebral column There is a small bend at the level of L 1/2 The vertebrae are higher in front than at the back, In the thoracolumbar transition region the anieros side of the vertebral body is coacave, stule the distal epiphyseal plate is prominent Pelvis (Fig 15) The alae are flat The acetabulum is flat and irregularly formed Hip Coxae valgae Knees Coarse epiphyses Hands Coarse cone-shaped phalanges and metacarpals There are two ossified carpal centres visible Pseudoepiphysis at metacarpal i SECOND EXAMINATION. (Age 8 years) The motor behaviour has deteriorated When he has to walk he sits dos agas ratmediately, he does sit up, hon ever, ahen in bed There is mororic festlessness The upper part of his body moves thythmically Patient still often whistles and also grunds his teeth It is uncooperative during physical examination He keeps on laughing at the rhysician who examines him but in the meantime makes repulsivc movements Eating on his one is no longer possible He does not show any interest even if the food is Maced in front of him He grabs his spoon to throw it an as. He has a great deal of interest in his nurse, laughs and tries to draw her attention He also shows an interest in his fellow patients. On neurological examination no changes are obscuel from the previous one THIRD EXAMINATION: (Age 9 years) The face is now emaciated The colour of the cheeks 15 now pale There is leuconychua of the finger- and toenails The motor functions have still further deteriorated. The Matient can raise himself a little by leaning on the side of his clbox, He cannor walk or stand and only sits with and His speech has entirely disappeared Swallowing is disturbed, he can only take fluids The motorie restlessness has disappeared The pupils are narrow and only moderately dulate in the dark. The oculopalpebral reflex is too strongly positive The reflexogenic zone 15 extended to the back of the head The pharyoz-rellex is low The masseter-refles is rather lively la elicting same there also ensues a contractios of facial musculature Patient has stofred whistling nor docs he grind his teeth. He yawns a lo: There is a tetraparesis with moderare hypertonia and slight hyperreflexia. Babinskis reflexes are present on both sides It is possible to evoke a slighe ankle clonus The corneal and fuodus examinazion shons no abnormalities On loud sounds the patrene shons a slight reaction The intellectual functions have deteriorated Patient ·Neuropsychiatric examination: (Age 5 years 6 months). The motor functions of the cranial nerves are intact. Speech is limited to some word. sounds. The muscles of the head, neck, trunk and extremities are normally descloped The muscle power is normal. No fascicular contractions are observed. There is a motoric restlessness, in the shape of rhythmic movements to and fro The movements lack suppleness. While walking simultaneous movements of the arms are observed The sensory functions scem not to be disturbed. There is no araxia while walking or standing Tremors are not scen Spontaneous nystagmus is absent. The optokinetic nystagmus can be clicited The pupils are of medium-width, cqual in size and react well to light and convergence The oculopalpebral reflex is not increased The corncal-, masseter- and pharynx reflexes are normal Percussing the area round the mouth a tonic spasm arises in the facial musculature The arm, abdominal and cremaster reflexes do not show any abnormalities The periost reflexes of the legs are lively Clont cannot be clicited The foot-sole reflexes are normal The muscle tonus is good The cog-wheel phenomenon is absent The vision and hearing cannot be exactly determined. There is a reaction to loud sound stimule On caloric vestibular examination no reaction is observed The intellectual functions show a retarded development from the past history it is also obvious that there is detcrioration The level reached compares with the scverest form of imbecility. In the past the patient was able to speak a few words Speech has now become inaudible and verbal contact is impossible. The memory and imprint function is insufficient The patient has an interest in toys The play-level is low He touches everything, opens what can be opened, and spreads the contents around him The duration of interest for cach obicct is very short He also puts objects into his mouth Paper is caten when he gets a chance Patient reacts when a hand is extended to him and then gives an impression of apraxia The emotional behaviour is unstable and in the highest degree dependant on factors in the vicinity His mood is excited and gay Noticeable is the stercotype whistling which increases when excited His laugh misse's gradacion and crying is limited to groaning He does not like being made a fuss of He knows how to orientate himself The state of cleanliness is not reached The urge to satisfy his hunger and thirst is small He has great passion for biting, licking or anything elsс of an oral character Patient grinds his teeth, yawns much and makes stereoty rc rhythmic movements His sleep is not disturbed There is a certain interest in huis fellow-patients He lives in a visual sphere There are no signs of manifest aggression He makes a clumsy impression which should be parthattubuted to apraxia The psychomotorism is limited He has a fixed grin The facial express10n is inadequate and often has a clown-like character On examination there is a lack of co-ojxration He defends himself automatically against any touch Examination of the Spinal Fluid This does not show any abnormalities The colloutal curves (mastie, gold and benzoic-acid) show a normal pattern The pneumocncephalogram obtained by Jumbar unsufflanon show's a slight but clear symmetrical widening of the third and sade ventricies Electro-encephalographic examination When the eyes were oren no clar alpha rhythm was scen There was much diffuse activity of theta frequencies with moderate amplitudes phoric-stimulation occipital driving was seen in the frequency range of the alphi chythm The EEG was classified as to be without definite abnormalities Jomnts Shoulders Abduction, clevation, crorotation and endorotation are limited 58 ·no longer recognizes his nurse He has lost interest in his toys He makes a side and helpless mpression During the day the patient sleeps a great deal but is often awake during the night His appetite has greatly diminished His personality has devitalized Panent still observes what happens in his immediate surroundings, but he sticks to details and does not 18vznise the people as such He grabs a hand in the same manner as he Mould grab an objekt He looks much older than his age CASE V1 BOY T. Ancestry Fis 1, V 41. PAST HISTORY: Burth on time, delivery normal Weight at birth 3000 gr Apart from recurrent colds the patient has not been ill. EXAMINATION. (Age 1 year) (Admission on account of acute otitis medis) The head is nouceably large The forehead is bulgy. The large fontanelle is saill very open. The nose-root is sunken in The tongue is normal Two incisor teeth are visible The corneac are clear Hean and lungs are normal The abdominal wall is flabby The laver enlarged The spleen is nor fele The hands are short and broad and the fingers stubby The reflexes are normal 1 Ray fundings Thorax Hefty claviculae, specially at the sternal end The ribs are strong and have a horizontal course The ends of the lowest ribs are narrowed 'The thorax is barrel-shaped Vertebral column Arcuate kyphosis at the level of 1 1/2 L 2 en 3 are fish-hook shaped Pelvis Flat alae Flat acetabulum Hips Coxae valgae and broadened neck of the femur. Hands The first and second phalanges are cone-shared Two hand roots are visible Broad and coasse metacarpa)s Passear died as the result of broncho-pneumonia after measles, at the age of 2 years 9 months, in a home for mentally deficient children CASE V11 BOYF CASE HISTORY Patient is the eldest of no children he brother also has gargoylum (sce case VIII) Birth on time. Forceps delivery was performed after which a cyanosis of short duration ensued The weight at birth as 2500 grams There is no blood-relationship of parents The patient ofrea had colds He was operated for an umbuical hernia A consilectomy was dons First teeth at 13 months, able to $1 a 18 months; xalk at 272 years, talk ar 29 jears The pacient had to be helped when eating His walking deteriorated gradually and now he can no longer walk rithout help ELAAUNATION (Age 7 years 4 months). The patient has a typka! Huikt face The hair on the head is abundant and bristly The forehead 15 prominent There is hypertelosssss The broadened nose has a sunken

·Fig. 14
Narrow'cd ends of the lou er ribs.
Tug 13
Elut and stregular shaped acetabuli Corse ulgue
60

·ands (Fig 16). Rough trabeculation of the phalanges and metacarpals. The pha. nges are cone shaped Pseudoepiphyseal shaping at the distal end of the mecaarpal I There are seven ossificd carpal centres visible Patient died, at the age of 7 years and 5 months, having been ill for a few days, of mucopurulent bronchitis Fig 16 Cone shaped phalanges Pseudoepiphyns af metacarpul I Coarse trabeculation CASE U1 BOY H Picture Fig 17 CASE HISTORY Patient is the youngest of two children The brother also suffers from gargoylism (Case VII) Birth was on time by means of a Caesarean section Furst teeth at 8 months, able to sit at 12 months, to stand at 13 months At the age of one year the liver mas enlarged EXAMINATION (Age 1 year 5 months) The facial expression is suspect for gargoylism The head is large The fontanel is wide oren Light fair curly hair on his head. The black eyebrors are grown together above a broad and sunked-in nose-roor The cars are Jarge The checks are pale. The teeth are far apart. There is no macroglossia No corneal cloudings (slic lamp examination) Norsual fundi oculi Retarded pups delstation with homatropine The neck is broad and short. Heart and langs are normal The thorax is flat and broad The abdomen is far and there is a small umbilical hernia ·roor The eyebrows are grown together. The ears are coarse. The colour of the cheeks is bright red. The widely-spaced teeth are small There is macroglossia and a noticcable hairgrowth on the upper lip The corneae are clear (slit lamp examination). The corneal diameter is normal Normal fundi oculi. The neck is short and broad. No cardiovascular abnormalities Lungs are normal The abdomen is balloon-shaped and there is an operation scar due to an umbilical hernia There is a diastasis of the rectus muscle of the abdomen The liver and spleen are greatly enlarged The femoral arteries pulsate well The testicles are small There is poor elasticity of the skin There is intensive hair growth on the shoulders and uprcr arms Acrocyanosis is noticed and leukonychia of the finger and toe nails Neuropsychiatric examination: (Age 7 years 4 months) In percussing the enlarged skull, a cracked pot sound is heard The motor functions of the cranial nerves are intact There is slight dysarthry The muscles show no abnormalities Patient can sit and stand, but can only walk with aid The sensory functions cannot exactly be determined There is no ataxia Tremors at absent. Spontancous nystagmus is absent The pupils react to light and are equal in size The corneal., masseter. and pharynxreflexes are normal The periost reflexes of the arms and legs are lively Pathological pyramidal reflexes, as well as cloni are absene The abdominal and cremaster reflexes are weakly The cog-wheel phenomenon is ab. sent. The visus and hearing cannot exactly be determined Patient reacts to strong sounds On caloric vestibular stimulation no reaction is observed There is a retarded development of the intellectual ability The level can be compared with that of imbecility Patient produces repeatedly short senseless words The spoken word is not understood He shows no interest in what happens around him He is friendly and his behaviour apathetic He is not clean He continually smacks his ligos Hunger, thirst and sleep are not disturbed The psychomotorisın is poorly developed There is no gradation in his laughter, which makes the impression of a tense grin There is no co-operation on physical examination Touch is automatically resisced Joints The distal phalanx of the fingers is in a flexed contraction The extension of the fingers is limited In the elbows flexion and extension is limited The dorsal flexion of the pulse is diminished Limited abduction, elevation and endororacion in both shoulder joints Slight flexion contracture of the hips The abduction and cxororation are sufficient, but the endorotation is obviously diminished Genua valga Slight pes calcaneus Thc toes are in a varus position Vertebral column slightly curved thoracolumbar kyphosis The whole vertebral column is suff, including the cervical region X-Ray findings: Skull Large skull with prominent frontal bone The roof is thin and the sutures are open Fairly prominent vascular impressions The pneumatisation of the mastoids is defective The balloon-shaped sella is enlarged The occipital protuberance seems to be displaced downwards Thorax Hefty clavicles The thorax is broad and the ribs are strong and follow a horizontal undulating course The ends of the third and fourth, as well as the eleventh and welfth ribs are narrowed Normal outline of the heart Barrel-shaped thorax Vertebral column The lumbar lordosis is flat Slight curved kyphosis at the level of Th 12/L 1 The front of Th. 11, 12, L 1, 2 and 3 15 dented in the middle 62 ·His temperament is slow. He is not tiresome He has a passive attitude He does svor make any attempt to draw attention He can stand, but only tries it when stimu. lated to do so The chuld seems to be capable of doing more than can be concluded from his spontaneous activities The psychomotorista e poorly developed The spinal fluid shows no deficiencies as far as pressure and composition is con. cerned The cell and protein content are normal. The flocculoreaction of proteins (gold, benzoic acid and mastixsol) shons a normal curve The pneumoencephalogram shous a symmetrical widening of the ventricular system X Ruy findings Skulls (Fig 18). The skull wall is thin. The large fontanel is open the frontal bone is prominent Rather promtaent vascular impressions The Sutures are open The shoe-shaped sellais enlarged The entrance of the sella is widened The mastoids cont410 very little air Fsg 18 Thon skull u all Large fontanel unely open Prominent 1 arcular impressions Shoe-shaped enlarged sella, uith urdened entrance Thorax Heity clavicles The tabs are broad and run a horizontal course. The extre. mities of the lower ribs show a narroning, like a paint brush Barrel-shaped thorax. Vertebral column Slight kyphosis at the lever of Th 12, L. 1 Fish hook shape of Th. 12 and L1 The fumbar lordosis is flattened Pelsis The pelvis is broad and flat The acetabula ate normally shaped Femur Coxae valgae The neck is broadened Hands The first and second phalanges ate cone-shaped Coarse trabeculation of the diaphyses There is an ealarged articular space between the metacarpals and phalanges Broad and plump metacarpals There are two hand-190t pecler 65 ·The liver is enlarged The spleen is not palpable The genitals are normal. The hands are short and brojd, as well as the fingers There is a flexion contracture of the terminal phalanx of the little finger, which is radially curved. The nails are well shaped. There is no acrocyanosis The skin is somewhat fasty, The skin of the back is covered with black hairs The lumbar lordosis is flattened There are slight genua valga Slight flexion contracture in the hip joint Neuro-psychrutric examination: (Age I șcar 5 months) The motor functions of the cranial nerves are intact. The speech is still undeveloper There arc no abnormalities of the musculature There is no motoric testlessness Pacient can stand and walk with and As far as can be judged, the sensibility is intact There is no ataxis while walking or standing The grip-movements are also well co-ordinated There are no tremors Nystagmus is absent The optokinenc nystagmus is normal The pupils are of medium width, (qual in size and react well to light The corncal., masseter- and pharynx reflexes are normal The reflex cxamination of the extremitics shows no special features The abdominal and cremascer reflexes are also normal Cloni cannot be clicited The muscle tone is unchanged The cog-u hec phenomenon is absent The visus does not seem to be disturbed, neither the hearing Fug 17 Boi II, age I gr 5 mths The caloric vestibular stimulation produces a lengthened latency time, as well as a short nystagmus duration The intellectual level seems to be equal to that of a child of 11 or 12 months There are no signs pointing to deterioration The mood is friendly The instinctive bchaviour is poorly developed The Ibido development in the psychoanalytic sense is present in the oral phase Hunger, thirst and slech are definitely not disturbed ·mental home for a leagthy period There is no blood relationship beta een the parents The child had recurrent otitis media and nasal colds Adenotomy was performed The stools were itregular (commencing with consti. ration, later the motions were thin) Twice she had (at the age of 10 months) an attack of sctcaming, accompanied by a tresor of the whole body The buth was spontaneous and on time. The weight at birth was 2900 grams Laughing 2/12, first teeth 7/12, sitting 8/12, standing 10/12. From the tenth month onwards the development of the child was recarde F18 19 Case , girl ). age 5 grs 10 mobs FIRST EXAMINATION (Observation from 2 years 3 months unol 2 ycars - months) The child has a very large skull and the forehead protrudes strongly, sunken-in nosc root and hypertelorism The juns strongly frotrude fornard. There is a cracked for sound, the fontanel is not closed The hairs are thin and of varying colour The Jentures consist of small, somex bat gray teeth which are far apart and stand in a broad proc alveolaris The palate is small and high The mouth is broad, the tongue is too large The pupils react to light The cornsae are cloudy caused by a large number of dotshaped opacities These are spread through the hole of the parenchyma, from the membrane of Bon man to that of Descemet. + Prof Dr J P Slooff kindly gave us the case-history ·CASE IX GIRL I* CASE HISTORY: There is no blood relacionship between the parents Patient is the eldest of 4 children The second one (a girl) has epilepsy and the youngest (a brocher) probably suffers from gargoylism The third child (a giel) died two days after birth with signs of cyanosis The mother had one miscarriage. The patient was born by means of a forceps delivery At birth it was already notice that the head was too large. Pacient suffered from parathyphoid and had often colds She underwent adenoidectomy, tonsillectomy and was operated for umbilical hernis and for a polyp in the left nostri! She could walk and talk from about 18 months, from 3/2 years onwards the psychic functions deteriorated It was also noticed that vision became worse From its 4th year the child vas practically totally blind as the result of optic atrophy EXAMINATION: (Age 5 years 9 months) The head is very large and the forehead high and bulgy There is hypertelorism The back of the nose is broad and sunken The hair of the head is bristly and abundant. The lips are thick and the congue too big The teeth are far apurt The corneae are cloudy The pupil reactions appear to be notmal From the left nostril a small polyp procrudes The right nostril also has polyps The nose septum is thin and possibly perforated The neck is short and broad The liver and spleen are obviously enlarged The upper arms and thighs as well as the shoulders are very harry There is a lumbar scoliosis There are slighe contractures of the arms and legs The foot-sole reflexes are indil. ferenc The tension on both arms is high, up to 200 140 The tension on the legs is much lower, about 60 mm systolic. The femoral arteries pulsate only slightly. Above the heart or the aorta no murmur is heard The ECG 18 normal. X-Ray findings Skull The skull is noticeably large and elongated The wall is rather thick 'Tlic sutures are wide open, excepting the lambda-suture which is invisible The mastoids contain very little air The sella is abnormally large, the anterior wall is missing Thorax Coarse claviculae The ribs are broad and run a horizontal course The extremities of the lower ribs show a narrowing, like a paine-brush. Vertebral column Slight kyphosis at the level of Th 12'L I Cash-hock shape of L 1, 3 and 4 Hands The first and second phalanges are conc-shaped Broad and plump metacarpais Seven ossified carpal centres are visible CASEY GIRL J: Fig 19 CASE HISTORY: She is the second of four children The eldest was born prematurity and died at the age of 6 months MP had diabetes and on account of depression was nursed in a Prof Dr J P Sloofl kindly gave us the case history

·There is a reaction to sound stimul Caloric vestibular examination was not carried our
The psichiatric examination can be summed up as follows from the past history
it is obvious that there is retardment in development, principally a lassing behind of
the intellectual functions Later, on the basis hereof a demontu declared. Although
:
-
[18-20
Enlarged, abis skull, stb open sutures. Shoe-shaped, enlurged
sello Destension of the occipital region
Fog 21
Fishbook shape of Lland ?
Kyphosss
Spondylolythesis

·the parents is not known A nephew (on father's side) died shortly after birth as the result of congenital brain anomaly Patient was born by means of forceps (weight at birth 3160 gr.). At birth the skull appeared to be noticeably large. A variance of the back was also noticed (kyphosis) The tongue was large and furrowed The fontanel closure was normal From the age of 16 months the girl could walk. Initially the mental development was fairly good, cven though there was certainly a delay, The girl learned to speak bur was never able to make sentences from her sixth year, specch gradually togally dis. appeased At the age of two the girl was clean at night, but latct enuresis appeared She often had colds and pneumonia Tonsillectomy and adenotomy was performed Ar the age of 52 years she was practically sorally blind. From the age of 6 she was completely bed-ridden from the age of 9 scars, she regularly had epileptic fies Patient has always been keen on music. EXAMINATION: (Age 11 years 9 months) Thc facial expression is typically gargoyle, Large, conspicuous long skull The large auricles are implanted lowly There is hypericlorism The cycbrons are very developed, but are not grown together. The back of the nose is broad and sunlen in The facial colour is bright red There is macroglossia. The corneae seem large and are cloudy. Consequently the pupil reactions cannor be determined. The mouth contains a supxrfluous amount of saliva Thc pharynx reflex is nearly absent The iccth are curious Many parts are absent Those tooth which are cft, arc far apart The neck is short and broad On physical cxamination of heart and lungs, bronchitic sounds are heard as well as a systolic murmer at the aper of the heart The abdominal wall is weak There is a diasticis of the rectus abdominal muscle There is an umbilical hernia The liver is greatly enlarged The spleen is not felt The vertebral column shows a hyphoscolosis at the level of the thoracic lumbar conversion The skin of the back is very harry The fingers are bent Apart from this the little fingers are radially curved The hands are short and broad The movements in the shoulder, elbow and hip joints are nouceably restricted There are genua valga The nails are not malformed and are of a soft consistency Neuro-psychiatrie examination. (Age 11 years 9 months) On percussion of the skull a cracked pot sound is heard Nystagmord movements of the cye-balls are observed The muscles of the face are not paralysed Patient cannot swallow normally and cannot talk The mouth contains a lot of saliva, probably as the result of discurbance in swallowing Repeatedly smacking movements are obscrved The muscles of the neck and trunk appear to be normally developed the extremities. especially the distal paris, make an impression of hyporrophy, probably as the result of inactivity Fascicular contractions are not seen The power of the arms is clearly diminished The legs are paralysed The sensory functions cannot exactly be judged Tremors are not noticed As the result of corncal cloudiness the pupils cannot be examined The corncal reflex is normal The masseter reflex is very lively and the pharynx reflex is practically absent. The reflex examination of the arms does not show any abnormality The abdominal reflexes are low There is hyper reflexion of the legs On both skics foot solc reflexes of Babinskı can be elicited The feet are kepe in a grointed position The tons of the leg muscles is increased There is no cog-wheel phenomenon The taste and smell function cannot be exactly determined Patient is totally blind 70

·There is a reaction to sound stimuli. Galoric sestibular examination was not carried out
The psychiatric examination can be summed up as follons: From the past history
ic is obvious that there is retardmeat in development, principally a lagging behind of
the cellectual functions Later, on the basis hereof a dementia developed Although
Fig.20
Enlarged. then skull, uish open sutures Shoe-shaped, enlurged
sella Distension of the occipital regson.
Frg 21
Pusthook shape of Li and 2
Kyphosis
Spondylolysthesis
71

·it was not possible to examine the child anymore by means of psychological tests and to calculate and measure the intellect, it is definite that the child is gravely mentally disturbed This fact is obvious as no contact can possibly be obtained in the gnostic nor accoustic sphere X-Ray fundings: Skull: (Fig 20) Large, especially long skull Thin skull wall The frontal bone is prominent The sutures are gaping The distance of the ala magna of the sphenoid to the base of the nose is small The shoe-shaped sella is enlarged. Vertebral column. (Fig. 21) Fish-hook shape of L 1 and 2. Crack at the level of Th 12/L 1. Dislocation of L I in a dorsal direction Thorax Broad clavicles and ribs. Ribs run horizontally The thorax is borrel-shaped Humerus. The head of the humerus is flattened and irregular of share The shaft of the humerus is very coarse Hins Coxac valgae Hands 'The first and second phalanges are conc-shaped Very broad hand Coarse crabeculacion of the metacarpals There are 1 handroot nucici visible Parient dicul at the age of 12 years as the result of starvation caused by not being able to swallow. CASI GIRL L. CASE HISTORY: She is an only child 'The birth was on time and was lengthy Patient ofron had a cold She was opcrated for an umbilical hernia She could sit at the age of 6 months Now, she can, with and, make a few steps Two children of a sister of the mother (resp 15 and 16 years old), are supposed to have an affection of the thyroid gland CXAMINATION (Age 14 months) The facial expression is typically gargoyle The large fontanci is nearly closcut The auricles are large The cyebrows are grown together, above a sunkcn-in nasc root The forehead is prominent The eyelids are somewhat pasty The corncac are clear on both sides, also with slic. lamp examination The fundus is normal on both sides, also the populli of the optic nerve and the macula region The rccth and congue show no abnormalities Heart and lungs are found to be normal The neck is short and broad The abdomen protrudes and an operation scar is visible (umbilical lernia) The liver is just palpable. the spleen cannot be felt There are small brown pigmentations to be scen at the level of the right shoulder and right inguinal region The tack is covered with black hair The hands are shore and broad The formation of the nails is not abnormal The Intl fingers are somewhat curved There is no acrocyanosis The lumbar lordosis has disappeared There is no restriction of joint movement Pacient walks a few steps with and, with legs far apart Neuro.psychiatric examinatson' (age 14 months) No abnormalities are found There is, however, a weak reaction on caloric vestibular stimulation Patient shows a good reaction to sound stimuls Dr M L M Houben of Hecrien kindly gave us the opportunity to examine the patient 2

·Electroencephalographic examint10n
Only a sleep tecord could be obtained (seconal) No abnormalities were found.
Rafmdrags
Skull Rather thin skull wall The frontal bone is prominent The sutures are open
The large fontanel is not closed Increased impressiones digitatae The sella is slightly
enlarged The entrance is shighly enlarged. The mastoids contain lipsle ass
Thorax Hefty clavicles (especially the sternal parts) Broad barrel-shared thorax
Vertebral column Fishbook shape of L 1 and L 2
Peless Coxae valgie
Hands The first and second phalanges are cone shaped Brod hands Broad and
plump metacarpals There are four hand-root nuclei visible
CASE 111
GIRL. A Fig 22
CASE HISTORY
There is no blood-relationship in the family
The girl, which is an only child, was born normally and has had no special illnesses
The sister of the mother suffers from a progressive affection of the nervous system,
the nature of which is unknoan
ست
Fig 22 Case XIII. gırl M, age 6 montbs
EXAMINATION (Observation age 5 to 7 months)
Shu has a typical Hurler-face
The large fontanel is still wide open The hair on the head is light blond and curly
The auricles are large There is hypertelorism The colour of the face is pale The
73

·corneae are cloudy in all layers on both sides. Basically this cloudiness is more pronounced The slit-lamp examination does not produce further details The pupils dilate moderately with mydriatics. The fundus appears to be undamaged, but more delicate structural abnormalities could be camouflaged by corncal cloudiness The back of the nose is broad and sunken in the eyebrows are grown together. The shape of the tongue is normal The mouth is broad and the lips are thick Tech are absent There are a few hairs on the upper lip The liver is greatly enlarged. An umbilical hernia is absent The skin is sound. 'Thu trunk and extremities are hairy The lumbar lordosis is flattened and extension of the vertebral column is limited Heart Examination. The heart is enlarged 1 cm to the left. No praecordial bulging, no cyanosis and no thrill. When pacient does not breathe a hard blowing systolic murmur is heard over the praecordium, with maximum intensity at the basc of the heart. Low, along the left sternal edge hardly a murmur is heard The murmur is continued to the back, interscapularily. The second pulmonary sound is normal Alany conducted sounds over the thorax The femoral artery pulsares far weaker than the brachial artery Thu tension of the left arm is systolically about 110, and that of the right leg about 70 Electro-cardiogram Normal axis Probably combined right and left hypertrophy, Thorax Scrcening The heart is enlarged especially to the left The pulmonary arch is straighe The filling of the lung is normal The progress of the aorta is to the left and the course of the oesophagus is normal Neuro-psychiatrie examination. (Age 6 months) The motor functions of the cranial nerves are intact. The muscles are normally developed There is no motoric restlessness The sensory funcions, as far as can be gathered, are intact Cerebellar function disturbances are not present The pupils are middle-wide and react well to light The oculopalpebral reflex is not increased Normal corncalmasseter and pharynx reflexes The reflex examination of the abdomen and cxtremities show no abnormalities The muscle cone is normal There is a good reaction to light and sound stimuli The caloric vestibular examination shows a long lasency period as well as a short nystagmus duration The intellectual functions are certainly defective The motoric development is definitely recarded The head is not yet raised the actual grasſomovement is not yet done by the patient, although some activity of the arm muscles is noticed the affectivity is not disturbed The appetite is small The child has a friendly character The psychomotility is poorly developed Clectro-encephalographic examination. There was no alpha-equivalent rhythm In its stead an irregular tracing was recorded consisting of varying theta-components whereon somewhat quicker activity was super imposed without constant asymmetry When crying, pronounced rhythmic activity of 3 per sccond ensued, above the posterior skull The EEG was very irregular without constant asymmetries I was classified as to be diffusely disturbed, to slight degree X-Ray findings Skull Thın skull wall The large fontanel is open the sutures are open The scili is not enlarged The mastoids contain little air Thorax (Fig 23). The course of the ribs is horizontal Hefty clavicles (especially the sternal portion) The heart is enlarged to the left The thorax is barrel-shaped Vertebral Columa Kyphosis at the level of L 1/2 Tishhook share of L 2 and 1 3

·Hards. Broad band. The 1st and 2nd phalanges are core-shaped Plump and broad
metacarpals One assified carpa) centre is visible
Peltis Subluxation of the head of the femur Corae valgae.
F1g 33
Hefty claticles
Heari enlarged to the lefs
Hepstomegaly
CASL YSY
GIRL N F1 24
CASE HISTORY
There is no blood relationship between the parenes Parient is the fourth of five
children, of which the eldest (boy) died at the age of 7 months as the result of an
acute stomach and intestinal catarch and the youngest (boy) died, tleyen hours after
a breach presençatson, probably as the result of erytroblastosis foecalis The mother
had three miscarriages (no thesusantagonism)
The birth of the patient was normal She could walk at the age of 16 months, and
was clean in one she underwent a tonsillectomy
EXAMINATION Age 4 years 2 months)
The facial expression is gargoyle
The skull is too large The large fontanel is closed No bony ridges are felt on the

·skull The forehead is prominent. The hair on the head is thick, stift and shiny. There is hypericlorism The base of the nose is broad and sunken in. The cycbrow's are not grown together. The corncae are clear (slit-lamp examination). No megalocorncas The discantia pupillac is incrcased The large and broad congue hangs out of the mouth. The lips are chick The tecth are small and far apart The colour of the face is pale. The cars arc coarse. The girl has a low voice. Heart and lungs ate normal. The liver and spleen are slightly cnlarged. There is 1 small umbilical hernia The abdominal wall is thick. On the extremitics some impai ginous spots arc scen Acrocyanosis, malformation of the hands and anomalies of the nails are not present. Neuro-psichiatric Examination: (Age 4 years 2 months) The moror functions of the cranial nerves are normal. Patiene says a few words, but these are barely audible. There is strong motoric restk ssness. Patient makes grimaces The musculature is normally developxed. The muscular power is good fascicular contractions are not notic The sensibility seems not to be discurbed There no ataxia in walking or stunding The grasping movements are well coordinated There are no tremors Spontancous nystagmus is absent. The optokinetic nystagmus is normal The pupils are middle wide and react well to light and convergence The oculoralpebral reflex is not increased The cornta-, massctct and pharynx teiler Pop 24 Case XIV, gırl N. age 4 1853 mihs is normal The abdominal refleres arc low The periose reflcres of arms and icgs are lively The Trommet reflex is negative There is inclination of extension of the big toc by cliciting the foot-sole refky Cloni cannot be clicited The muscle tone is normal The cog.wheel phenomenon is absent Smell and taste sensations cannot exactly be examined Pacjent reacts to visual and auditory stimula On caloric vestibular stimulation no reaction is seen of the left labyrinth The right labyrinth shows a long latency period and a short nystagmus duration The examinacion of the intellectual functions is made difficult by the negativistic and ·· Guined , setms notion of her surroundings and her own body At times she is very reserved, taughs into space and stares upwards At times there is a noticeable somnolence The development of speech is retarded Pacieat does not react to oral instructions She can only fulfil a task after it has been shown a few times The imprint here seems to be slow When contacting strangers, the patient is negativistic, suspicious and anxious She is very atuached to her parents The mood is to a high degree dependant on factors in her surroundings She easily flies into tantrums There are manifestations which point to an increased oral libido Pacient continually sucks her fingers, and frequen•ly puts articles in her mouth She also delights in throwing things anay, but not until she has touched them with her mouth The appetite is good. The sleep rhythm is quite disturbed The facial expression is fixed On physical examination the patient is nor cooperatise Electro encephalographic examinton The EEG contained too many bilateral synchronous theta and delta activity, especially in the occipital regions The sleep record was normal The EEG was classified as a typx pointing to diffuse cerebral discusbances 1 Fig 25 Strong iascular impressions Sboe-shaped selle XR findings Skull (Fig 25) The all of the skull is of normal thickness Strong vascular im. pressions The sutures are open. The frontal bane s prominenc The shoe-shaped sella is not enlarged The poeumatisation of the mastoids us scanty ·skull. The forehead is prominent The hair on the head is thick, stiff and shiny There is hypertelorism The base of the nose is broad and sunken in. The eyebrows are not grown together The corneae ate cleat (slit-lamp examinacion) No megalucorncac. The distantia pupillae is increased The large and broad tongue hangs out of the mouth. The lips are thick. The teeth are small and far apart The colour of the face is palc. The ears are coarse The girl has a low voice Heart and lungs are normal The liver and spleen arc slightly enlarged. There is 1 small umbilical hernia The abdominal wall is thick On the extremities some impetu ginous spocs are seen Acrocyanosis, malformation of the hands and anomalies of the nails are not present. Neuro.psychiatric Examination: (Age 4 years 2 months) The motor functions of the cranial nerves are normal Patient says a few words, but these are barely audibic There is strong motoric restlessness. Patient makes grimaces The musculature is normally developed The muscular power is good Fascicular contractions are not noticcable. The sensibility seems not to be disturbed There is no ataxia in walking or standing The grasping movements are well coordinated There are no tremors Spontanicous nystagmus is absent The opiokinetic nystagmus is normal, The pupils are middle wide and react well to light and convergence. The oculopalpebral reflex is not increased the cornea., masseter and pharynx refler Fig 24 Case XIV, gırl N, age 4 995 2 mths. 1 is normal The abdominal reflexes are low The periost reflexes of arms and legs are livels The Trommer reflex is negative There is inclination of errension of the big toc by cliciting the toot-sole reflex Cloni cannot be elicited The muscle tone is normal The cog-wheel phenomenon is absent Smell and taste sensations cannot exactly be examined Patient reacts to visual and auditory stimuli On caloric vestibular stimulation no reaction is seen of the left labyrinth The right labyrinth shows a long latency period and a shott nystagmus duration The examination of the intellectual functions is made difficult by the negativistic and ·Patient could walk at the age of 14 months Speech development was clearly delayed at the age of 2 years he was clean. FIRST EXAMINATION: (Age 6 years 3 months) The facial expression has gargoyle features the hair on the head is thick The forc. head is not prominent The ears are large. The ese-brons are grown together. These is hypertelorism The root of the nose is sunken in. The small teeth as far apart Some rudiments are missing Macroglossia is not observed The colour of the face is pale The cheeks are chubby. The structure and clearness of the cornea is normal (slit-lamp examination). The neck is broad and short Heart and lungs are normal BP. 110/80 Broad thorax with chicken breast and Harrison's grooves The lives i slightly mipable The spleen cannot be felt. Thick panniculus adiposis. The abdomen is prontinent There is no umbilical hernia. The penis is normal. The right testicle 15 not descended (it is present in the inguinal canal) The left testicle is not to be founı! (ocither in the scrotum nor the groin). The skin is slighely oedematous There are many Sarge and small cafe au lait spois to be seen on the trunk. The back and extensor sides of the arms are hairy No acroc, 2005 The hands are noticeably large and broad The fingers are relatively short and broad The nails are normal The little fingers are radially curved. The vertebral column shows no scoliosis or kyphosis Thc lumbar lordosis is not Plattened in the hip and knee point there is a slight flexion contractur- Neuro-psychistne examination (Age 6 years 3 months); The motor functions of the craaral nerves are intact The sitch is slow. The patient sometimes scutters The muscles are normally developed. The muscle power is good No fascicular contractions are observed The movements are slow While walking, normal accompanying movements of the arms are noticed. There is no motoric restlessness The sensory functions are intact in every way. There is no ataxia while standing or walking The grip-movements are well co-ordinated There are no tremors Pombergs test 15 negative Normal floger to nose test as well as that of knee and her! Spontaneous nystagmus is absent. The optokinetic nystagmus is normal The pupils are of medium width, equal in size and react well to light and convergence The xulopalsbral reflex is not increased The corncal-, masseter and pharynx reflexes are normal The abilominal and cremaster rel'exes are lively The arm reflexes are normal and the prost reflexes of the kes lively it is possible to elicit some ankle cloni on both sides On evoking the foot-solc Teflex the inchination to extend the big too is seen on both sides The muscle tont 18 normal The cog-whcel phenomenon us absent. The stoell and taste sensations are not disturbed The visus is bad, owing 10 hypermettory on both sides The audiogram Dormal The caloric vestibular examination shows an equal reaction on both skics, but the stability seems to be somewhat lower than usual On examination of the intellectual functions, the impression is gained that there is a retarding of development, The imprint is slow Speech development appears to be partially disturbed The patient speaks with a few sords and never makes a complete sentence. It is not possible to get him to sepeat short sentences The naming of articles and pictures of objects is fairly good He has difficulty in spontaneously finding the correct name for example, he says tea instead of Ica-pot. However, he does koow to give a defins. tion how to use these objets Vocabulary and knowledge of numbers are more or less even a che som applied to this age The achievements, according to fast history data, have gradually improved It was noticed motoricity remained slun His disposition is friendly He is not anxious ·Fig. 26 Fishhook-shaped rertebral bodies Tongue-like projections Alicrospondylia o/ L 4 and 5 F18 27 Case XV, boj o age 6 yrs 3 mths ; Thorax Barrel-shaped thorax Hefty clacivles, especially the sternal portion The ribs are broad and run a horizontal course The ends of the lowest ribs are narrowed, like a paint brush Vertebral column (Fig 26) The vertebral bodies are "fish-hook" shaped in the thoracolumbar transicion arca There is an arcuate kyphosis at the level of Th 10/11 Th 11 is clearly flatter than Th 10 and Th 12 Th 11 shows a tongue-like projection to the forc, in the middle of the vertebral body The vertebral body of L 1 and LS 1s small Hands The first and second phalanges are cone-shaped There is a pseudocpiphysis at the distal end of metacarpal | The metacarpals are fairly plump Pelvis The pelvis is broad and flat The acetabuli are well shayxd The neck of the femur is far too thick and creat Pronounced coxac valgae CASE YV BOY O. Fig 27 CASE HISTORY. Patient is the fifth of five children A brother died as the result of pneumonia (712 years) and a small brother died 2 days after birth (icterus) The mother is very nervous The birth of the patient took a long time Patient had often colds and suffered repeatedly from infectious diseases The motions are mostly fairly hard A tonsillectomy was done

·level of his developmeat can be called normal in so far as Intellectual functions
are concerned The patient has remained definitely slow in his thoughts, imprint.
fraction and action
CASE YYT
GIRL P. Fig 29 and 30
CASE HISTORY,
Parienę is the third of three children. The birth as normal A first cousin dicu 17
hours after birth, as a result of fibroelascosis of the myocardium of the left senrrick
UNATION. (Age 2 years 1 month)
L. The
kot 5
ound
s heard Le lidt via
sunken in
The eyebrons are not grown together The fundus is normal on both sides. The
corneae are sported by tiny flakes on both sides in all layers, at the periphery a little
more than central The tongue is broad The normally shaped teeth are somewhat
100 lar apart. The tonsils are large and purulent
Fug 29
Case XVI, gol Page 3 gts
The reck is short and broad. The thorst is broad Her breaching is stercorous Share
of the heart and heart sounds are normal. The abdomen is broad Liver and spleen
are not palpable No umbilical hernia The abdominal wall is thickened The buttocks
show enthro squamous lesions as the result of monuia tafection. The skin of the
head, lower arms and legs us dry and scaly There is also some oedema of the skin
The child can stand if it is supported There is a pronounced thoracolumbar scoliosis
of the vertebral column No kyphosis
The hands are short and broad as well as the fingers

·The appetite and sleep are good Patient is clean The spontaneous activity is small Patient only plays when he is forced to do so. He is passive, slow and apathetic. He has a decisive visual interest. The psychomotorism is poor The patient gives every assistance when physically examined. Electro-encephalographic examination: The alpha thyth was rather slow and to much intermingled with slower components Intermittent series were present of theta waves especially in parietal areas, to the right somewhat stronger than to the left, increasing during hyperventilation The EEG indicates moderate diffuse disturbances, with the maximum in deeper structures, to the right more than to the left X-Ray findings: Skull The skull is noticeably high and broad The roof of the skull is fairy thin Increased impressiones digitatae The sella is normal Pneumatisation of the mastouls is also normal Thorax. Strong ribs and clavicles Barrel-shaped thorax Pelvis The pelvis is high and narrow Coxac valgae The acetabulac are normally shaped Plump metaphyses of the femur Vertebral column. Broad lumbar vertebrae L 2 and L 3 are fish-hook shaped Hands. Broad and short fingers The first and second phalanges are conc-shaped On the right there are 7 and on the left 6 hand-root nucle: visible Broad and plump metacarpals Feet (Fig 28) Very broad mecatarsal bone I The epiphysis of the 1st phalanx digit II and III shows a wedge-shaped distal limitation Fig 28 Brond metatarsal 1 W'edge-shaped epiphysis of the 1st phalanx digui II and III SECOND EXAMINATION: (Age 7 years 2 months) Since the correction of his visus (spectacles, resp + 3 and +4), the efficiency of the patient has reasonably improved He now follows elementary school The speech is still slow He sometimes stutters Patient can copyy sentences and spontancously makes well-formed sentences He now correctly names objects The cfficiency in arithmetics is comparable with that of the norm at his age Hc draws badly The 80 ·psychomoulicy is poor On examination the behaviour is negativistic, but not anxious Electro-eacephalographic examination With closed eyes there was an alpha thythm with normal frequency in series sub. stituted by activity of half the frequency Diffusely there was too much theta-activity During sleep there was a 0, a pronounced beta-activity 19 series, to the left stronger than the sight, up to 80 micro V. The described findings point to asi on merric disturbances of deep structures. X-Ray findings Skall (Fig 31). Thın skull all Noticeably short, high and broad skull The large foncanel is open. The sutures are open The sella-entrance is widened Vertebral column Thoracolumbar scoliosis Open arch of St; L 1 and L 2 have a concave limitation at the cont. Pelvis Corie valgae Hands The shape of the hand is broad and short. The skeleton shons no abnormalities Thorax The thorax is broad The course of the ribs is horizontal Fug 31 Large fontanel uidely open Widened sells entranee SECOND EXAMINATION (Age 3 years). The face has now suspect gargoyle features The large fontabel is still open. The face has become fatter The teeth show do abnormalities The colour of the cheeks is slightly red The calls are not malformed The speech is limited to murmur sounds There is still motoric testlessness, patient 83 ·Neuro-psychiatric Examination: (Age 2 years 1 month) The motor functions of the cranial nerves seem to be intact. The muscles are normally developed. There is motoric restlessness, The sensory functions cannot exactly be judged. Cerebellar function disturbances are absent. The pupils are middle wide and react well to light. The oculopalqxebral refix is increased and the reflexogenous area shereof is extended to the back of the head The masseter reflex is lively. Normal corneal reflex. The pharynx reflex is weak. The periost reflexes of the arms are lively. Normal abdominal skin reflexes The periost reflexes of the legs are normal. In eliciting the foor-sole reflex, inclination to extend she large toe is seen on both sides F18, 30 Case XVI, girl P, age 3 grs The tone of the muscle is normal The smell and taste cannot be determined The patient reacts well on light stimul. She does not react to sound stimuli on the right, but does so on the left On caloric vestibular examination, the long latency period and the short nystagmus duration give the impression that irritability is diminished (right stronger than left) The intellectual functions show a retardness in development The obtained kyel is about the same which is to be expected in a normal development at the age of * months Speech is not yet developed Only murmur sounds are produced Patient makes continual movements with the hands, but scarcely moves the legs Only now and then she sits down, but she cannot maintain this for any length of time Shc can drink by herself, but has to be helped with food Her affectivity is disturbed It is not possible to make the patient lavgh She docs nor seck social contact, neither with the person who looks after her, nor with the children in her vicinity She is not tiresome Her mood is quiet Her instinctive behaviour is weakly developed She likes to make sounds by means of toys and laughs when the expected sound is heard The 82

·Fig 32 Case XVII, boy ,
age 4 yrs 6 mobs
more than
Fig 33
Case XVII, boy Q.
age 4 jis 6 mtbs
85

·makes rhythmic rolling movements of the trunk. Further she gnashes her teeth a great deal There are slight chorerform movements arms, but signs of scratching cannot be seen. Patient can stand with aid and walk a few steps. She mostly lays on her back with her legs elevated, like a baby. In gripmovements, sometimes a slight tremor of the hands is noticed. There is no nystagmus The masseter reflex is lively and the pharynx reflex is low. The oculopalpebral reflex is strongly positive In percussing the perioral arca, no spasm of the muscles of the face is noticed The periost reflexes of the arms are lively. The reflex of Trommer is bilaterally positive The abdominal reflexes are weakly positive. The periost reflexes of the legs are normal. Cloni cannot be elicited, In evoking the foot-sole reflex on both sides, extension of the large toe is observed Patient shows still no interest in other children around her She often puts her thumb in her mouth and then makes sucking movements She sleeps conspiciously a great deal CASE XVII BOY ( Illus Fig 32 and 33 * CASE HISTORY: Patient is the youngest of two children The brother is healthy. At the bırı — which was spontaneous and on time the patient was noted to have large ears. The weight at birth was 3500 gram. Patient was operated for an anal fistula at the age of 6 months He had often colds and ouitis media, he also had a tonsillectomy donc The closure of the fontanels was delayed Patient was late in walking, he was clean from 37/2 years EXAMINATION: (Age 41/2 years). The facial expression is typical of that of gargoylism The skull is noticeable long and broad The hair on the head is bristly The forehead is prominent The colour of the cheeks is pale. The broad nasal root is sunken in The eyebrows are grown together. The ears are large The small teeth are too far apart His voice is shall The lips are thick Hair is visible on the upper lip The tongue is not enlarged, On eye-cxami. nation no corneal cloudiness is found The neck is short and broad No cardiovascular abnormalities On auscultation bronchitic sounds are heard There is a small umbilical hernia The liver is enlarged The spleen is not felt The hands and fingers are broud and thick The fingers are curved Morcover the little finger is radially curved The nails are short There is increased hair growth on the back and the extensor sides of the extremities The skin of the right thigh shows a few "café au lait" spots Neuro-psychiatric examination (age 4/2 yrs) The motor functions of the cranial nerves are intact the speech is not disturbed Normal developed musculature The muscle power is normal fascicular contractions are absent. Motoric restlessness is noticeable The movements are unwieldy and stuff As the result of this, the patient has a cumbersome and heavy walk During walking, normal accompanying movements of the arms are seen No sensory disturbances can be detecte + We thank Dr J M J Tans that he gave us the opportunity to examine this patient 84 ·CASE YV11 BOY' R Fig 31 and 35. CASE HISTORY: Pauent is the eldest of tho children The sister is healthy. The macher noticed that during pregnancy she felt little movement of the child on the photo of the pelvis bich was taken shortly prior to the birth of the patient the position of the child was normal. The head, howeser, was enlarged. The birth was terminated by means of forceps extraction The eight at birth as 4:120 grams At birth a large swelling, due to the continement, mas noticed at the back of the head, as well as bruses on the forehead, as the result of the forceps extraction The breathing com. menced immediately. On medical inspection immcdiately after birth, besides the enlarged head, there was also seo an under development of the external genitals On the X-Ray phoros -- Inade a few days after birth a shoe-shaped sella was visible During the first few months of hfe, the desclopment did not worry the parents. Gradually, however, it became obvious that there was a retardedness of the motoric developmaear and thar the circumference of the shall had increased in an alarming manget Fig. 34. Case XVII, boy R, age 8 mihs FIRST EXAAIINATION (Age 8 months) There is a cracked pot sound The head is Doticeably fong The fore-head us pro- Dinent. The large fontanel is wide open The hair on the head is light and sofr The ears are not calarged The eye-brows are grow together above a sunken nesebridge There is hypertelorism innry The first tooth is visible Ag og Strabismus convergens With 15 Setu The Desk is short and broad Heart and lungs are found to be normal There is ng umbilical berala. The livet is Enlarged The spleen is not palpable There ·There is no ataxy when walking or standing The grip movements are well coorde nated. Spontaneous nystagmus is absent while optokinetic nystagmus can be cvoked in both directions. The pupils are middle wide, equal in size and react well to light and convergence The oculopalpebral reflex is lively, but pathologically not clearly increased The cornea., masscter and pharynx reflex are normally clicited. The arm rcflexes ar lively. The abdominal and cromaster reflexes are positive The reflexes of the legs are normal The muscle tone is not increased The cog-whcel phenomenon is absent Parient reacts well to light and sound stimuli. The intellectual functions are retarded. The general level is that of debility The imprint is slow and perseveration is noted The vocabulary and the language he uses shows only a small retardness as compared with the norm for the age. The patient has difficulty in concentration and shows lack of perseverance. The mood is friendly and anxious There is little liveliness when contacting the patient For this age there exists a coo strong desire to be in contact with his mother. In the instinctive behaviour the patient shows definite shortcomings. He is fond of music Further, he likes to colour pictures and does simple puzzles Now and then he sucks his fingers without it being conspicious in his behaviour He does not allow anything to be taken away from him and becomes aggressive if he docs not get his own way He has cantrums He soon tires on erercion, His aprotite and sleep are undisturbed The psychomotility is hardly differentiated Spinal fluid. The liquor is normal in pressure and composition The flocculorcaction of proteins (mastix, gold and benzoic acid) shows a normal curve Electro-encephalographic examination. With closed cjes there was an alpha-thythm of 7-9 per sec., mixed with theta and delta components, persistant with eye opening Photic-stimulation induced some occi. pital following (alpha frequencics) The EEG was classifıcd as to be abnormal, pointing to slight disturbances in deep structures Joints There is a hunching of the shoulders The lordosis of the lumbar vertebral column is increased The pronation and sups. nation of the lower arms show a clear restriction All movements of the extremistics are limited Genua valga X-Ray fundings. Skull The roof of the skull has a normal thickness The frontal bond is prominent The lambdoid and parieto-temporal sutures are open Rather strong vascular impres. sions The sella is enlarged and shoe-shaped The entrance of the sella is widened The mastoids contain little air Thorax Hefty clavicles (specially at the sternal end) Broad ribs, running practically in a horizontal direction The 4 lowest ribs are oar-shaped The outline of the hcart is normal The thorax is barrel-shaped Vertebral column The lowest and upper limitation of the vertebrac in the thoracal area are convex The inccrvertebral discs are narrow. The frontal limitation of the vertebral body of Th 2 to inclusive Th 8 is concave The frontal limitation of Th 9 to inclusive L 3 is characterised by the protrusion of the centre part of the verte. bral body Pelvis No anomalıcs are noticed Hands The first and second phalanges are cone-shaped Course trabeculations of the diaphysis of the metacarpals and phalanges The proximal ends of the metacarpals are irregular in shape Four ossified carpal centres are visible reer These shows similar findings but kss extensive 6 ·CASE YVIJI BOY R. Fig 31 and 35 CASE HISTORY: Patient is the eldest of two children. The sister is healthy. The mother noticed that during pregnancy she felt little movement of the child On the photo of the pelvis hich was taken shortly prior to the birth of the patient - the position of the child was norma! The head, however, Ris eolarged The birth was terminated by means of forces extraction The weight at birth was 4420 grams At birth a large suelling, due to the continereat, kas noticed at the back of the head, as aell as bruises on the forehead, as the result of the forceps extraction. The breathing commenced immedsately On medical inspection immediately after birth, besides the enlarged head, there was also seen an under-development of the external genitais. On the X-Ray photos - made a few days after birth a shoc-shaped selle was Visible During the futst few months of life, the development did not worry the pareots Gradually, hon ever, it became obvious that there was a recardedness of the motoric development and that the circumference of the skull had increased in an alarmins manner Fig 34 Case XVIII, boy R, age 8 mtbs FIRST EXAMINATION (Age 8 months) There is a cracked pot sound The head is noticeably long The fore head 35 prominent The large fontanel as wide open The hair the head is light and soft The ears ate not enlarged The ese brows are grow together above 1 sunkea nosebridge There is hypertelorism On inspection of the mouth no anomalies are observed The first tooth is visible Ao opuc atrophy is found on both sides There is periodic strabismus convergeds With slı-lamp examination to corneal cloudiness is seen The neck is short and broad Heart and lungs are found to be normal. There is no umbilical hernia The liver is enlarged The spleen is not palpable There 07 ·is hypogenitalism The penis is conspiciously small. A small hard testis is felt on both sides in the scrotum The hands and feet are short and broad. The nails are normally shared the hair growth is normal The feet are slightly red Neuro-psychiatric examination: (Age 8 months). The motor functions of the cranial nerves are intact, apart from the already mentioned periodic strabismus convergens, which must be attributed to the diminished visus The child murmurs rog 35 Case XVIII, boy R, age 8 mths The muscles are normally developed, and the power of same is not disturbed The spontaneous motoric activity is noticeably small Only movements of the arms are noticed, but there are practically no movements of the legs The head can turn but cannot be raised the child cannot turn himself, and is not able to sit The sensory functions scem to be intact The grip movements betray no ataxia There are no tremors Spontaneous nystagmus is absent, while oprokinetic nystagmus can be evoked in both directions The pupils are middle-wide, equal in size and react well to lighe The menacc-retler is not increased The oculopalpebral reflex is clearly increased, and the reflexogenous area thereof is extended The corneal, masscter- and pharynxreflexcs are normal The reflexes of the extremities are normal Bilaterally the Babinskı reflex can be evokedd, which is normal for the age The abdominal and cremaster reflexes are positive Cloni cannot be elicited The muscle tone is normal The cog.wheel phenomenon is absent Smell and taste cannot exactly be determined The vision is disturbed as the result of a double-sided optic atrophy There is good reaction to sound stimul In caloric vestibular stimulation a long latency period is observed on both sides The nystagmus duration is shorter on the left than on the right side The development of the intellectual functions is retarded the retardation is also clear in respect of the motor functions and instinctive behaviour This is more noticeable when the mood is rather lively There is little spontancous interest The affectivity shows no noticeable disturbances 88 ·The appetite and sleep are not disturbed The child has no difficult character. The emouonal expression shons an adequate differentiation, Electro-encephalographic examination There was an alpha equivalent rhythm with a normal frequency with high ampli. rudes Diffusely thera-activity was poted Also the sleep record was marked by high amplitudes on photic-stimulation brile following was seen The E.E.G. Nas classified as to be diffusely disturbed, to a slight extent, as the result of disturbances mainly of deep structures Joints There are no contractures -Ray findings Skull Thin skull wall The frontal bone is prominent The large fontanel is wide open The skull sutures are open, except the coronary sutures The sella is shoe-shaped The mastoids contain file air The angle of the jaw is noticeably blunt Thorax Hefty curved clavicles Helry ribs have a horizontal course. Burrel-shaped thorax Vertebral column Flattened lumbar lordosis Pelvis Corse valgac Broad lac bones Hands Brachyphalangia of the metacarpall There is one ossified carpal centre visible SECOND EXAMINATION. (Age 1 yr) The large fontanel is still wide open The face bas become broader and the cheeks fatter. The colour of the checks is bright red The teeth present, (four above and two below) are angular and fas apart. The liver is somen hat more enlarged than at the previous examination On neurological examination, apart from the double-sided optic atrophy and a too lively oculopalpebral reflex, st IS DON noticed that the child moves his arms and legs less than before Clont cannot be evoked The pupils react to light Sitting is still not possible He puts articles, presented to hum, into his mouth The aprenite as excessive There is a preference for certain foods The mood is apathetic and the demeanour passive ·Chapter V POST MORTEM AND BIOPSY REPORTS A POST MORTEM REPORTS The reports are the result of a close co-operation with several pathologists The following review precedes the description of the available data Report No Pathologist Clinical case. report Sex Agc 1'ost Mortens F 1 yr 2 M 01 Wyers H J G and Slooff J L XIII Botman Th and Tans J MJ VI Schillings P. H M х Botman Th VII Kramer W XI 19 hrs after death 2 yrs 9 mths 30 6 yrs 6 mths 60 7 yrs 5 mths 31 3 F 4 M 10 5 12 yrs 11 * The Roman figures refer to the clinical case reports in Chapter IV POST MORTEM OF A FEMALL (HILDAGI 1 YEAR Height 67 cm Well nourished High forehead, large cranial vault The lobes are completely adherenc The eyebrows are continuous above the somewhat sunken-in nasal bridge. The tongue is normal in size The neck is very short Under the jaw, in both axıllae and both groins small lymph glands are felt No icterus, cyanosis or abnormal pigmentation External genitals normal On opening up, the liver seems considerably enlarged and lies in the medioclavicular line about 3 fingers below the arch of the ribs Spleen and stomach are not visible. There is no large omentum present No free fluid in the abdomen in the right pleural cavity 54 cc clear yellow fluid is present, while in the left pleural cavity only 5 cc The lungs collapse moderately The thymus appears smaller than one would expect. The thyroid is normal in size and shape The heart is slightly enlarged The apxx is formed by the left ventricle The epicardium is smooth throughout The cavities of the heart are not widened The foramen ovale is closed The mitral, tricuspid and pulmonary valves are completely normal The papillary muscles and trabeculi are normal The endocardium is sound, except for about 12 cm below the aortic valves where the endocard is clearly thickened and grey of colour with canary.yellow spots The aortic valves are also grey and clearly thickened, and somewhat rigid so that they 90 ·Fig 36 Heart muscle Vacuolssatson of many muscle libres T18 37 Hearl muscle Vacrolisation of the fibres es pecially next to the nucler Belueen some fobres Large cells ustb scuolur protoplasm and small dark nucleus Fog 38. Aorta To be left medu, to be right greatly thickened inismu, containing many large cells. Fug 39 Aorta Thickened malims Alany large cells urth cacuolur proloplum Tog 40 Later Intense racuolssation of liver cells, especially around the friangle of Kiernan a few large cells at the edges of sbese triangles, be niere of which is for ·Chapter 1 POST MORTEM AND BIOPSY REPORTS A. POST MORTEM REPORTS The reports are the result of a close co-operation with several pathologists. The following revicw precedes the description of the available dara Report No Pathologist Clinical case rerort Sex Agc Tost Morten F 10 11 2 3 Wyers H J. G and Slooft ] L XIII Botman Th and Tans J M J. VI Schillings P HM X Botman Th VII Kramer W XI 1 yr 19 hrs after death 2 yrs 9 mths 30 6 yrs 6 mths 60 7 yrs 5 mths 31 6 M г M г 10 5 12 yrs 19 The Roman figures refer to the clinical case reports in Chapter IV 1 POST MORTEMOT ATEMAL 1 (HILD AGUILAR Height 67 cm Well nourished High forehead, large cranial vault The lobes are completely adherent. The eyebrows are continuous above the somewhar sunken-in nasal bridge The tongue is normal in size The neck is very short Under the jaw, in both axıllae and both groins small lymph glands are felt No icterus, cyanosis or abnormal pigmentation External genitals normal On opening up, the liver seems considerably enlarged and lies in the medioclavicular line about 3 fingers below the arch of the ribs Spken and stomach are not visible. There is no largo omenrum present No free fluid in the abdomen in the right pleural cavity 54 cc. clear yellow fluid is present, while in the left pleural cavity only 5 cc The lungs collapse moderately The thymus apixats smaller than one would expxat The thyroid is normal in size and share Thc heart is slightly cnlarged The arex is formed by the left ventricle The cpicardium is smooth throughour The cavities of the heart are not widened The foramen ovale is closed The mitral, tricuspid and pulmonary valves are completely normal The popullary muscles and trabeculi arc normal The endocardium is sound, except for about 12 cm below the aortic valves where the endocard is clearly thickened and grey of colour with canary-scllow spors The aortic valves are also grey and clearly thickened, and somewhat rigid so that they

·Tug 42
ter Vacrolisation of the Iner cells; to the Lymph glund Desquamaled su ollen and on
eft some lurge tacuolised cells, the nature of Cuolised cells on the medullary sinus
bich is not clear
T13 43
Corned [pithelium intact Bou.
man's membrane not impures
Oedematous substanist propria
Fox 15
Spinal cord Anterior born cells Hjaline and
Iscuolur suelling of the protoplasm Tigrod.
wubstance aften marginally displaced
Tag 45
Spinal cord Clarke's column Fairly normal
aspect

·do not collapsc. The beginning of the aorta is thickened and resistant on cutting The inside shows the same spotty canary.jellow markings. The descending aorti, also the abdominal part, seems thickened but shows no yellow spots The lungs show a smooth pleura. There are marked differences in consistency and colour, on cutting, both lungs show several pink and yellow.pink, somewhat granular, foc: Along the main bronchi and at the bifurcation there are various stollen lymph glands In the mesentery many fairly large lymph glands are seen, on cutting some are found to be pink, others canary.yellow The liver is enlarged (weight 450 grams) The surface is smooth, spotty, varying from brown-red to yellow The spleen is somewhat larger than normal (weight 35 grams), and shows normal follicular and trabecular markings The vertebral column has a straight course; the physiological curves are totally absent. On opening the skull, adherence of the Jura to the skull is seen, neither skull nor brains show macroscopical anomalies In completing the postmortem no anomalies or special features are seen in the other organs Microscopical examination. The heart (Fig 36 and 37) shows slight interstical ociema wherein exudatc cells and mast-cells are also found in the outer margins of the advenceia of the msocardial vessels, here and there fairly large cells are seen with vacuolar protoplasm Everywhere the endocardium is fairly thick, and contains some empty vacuoles In this thickened endocardium some large cells are also found, similar to those in the adventitia of the vessels In the large cpicardial vessels a rather noticeably broadening of the intima is found, with an increase of connective tissue, ocdema and some large cells with vacuolar protoplasm With Sudan III and PAS staining there is nexther in the vacuoles of the connective tissue nor of the large cells Sudan positive or PAS positive material present The sections through the aorta show a definite thickened intima (Fig 38 and 39), whereby intcrstices and cavities between the fibrous structures arc scen wluch either show a foamy structure or appear to be empty With various Sudan-technics no Sudan.positive material is seen There is no double rcfraction visible and also with osmic-acid no blackstaining can be obtained Sporadıcally a small amount of glycogen (PAS) is present The structure of the liver is seen to be normal The central veins are somewhat widened and che portal spaccs probably have more connective tissue than normal The liver cells (Tig 10 and 41) show fairly strong vacuolisation, sometimes foamy and sometimes course The Kupffer star-cells are also swollen and slightly vacuolar in the liver cells and also in the Kupffer star-cells a slight amount of glycogen is found (PAS-staining with and without ptyaline) With Sudan III and Sudan-black very little fat is found in the liver cells, and neither the PAS-staining nor the farstainings give sufficient explanation about the contents of the vacuoles in the liver and Kupffer cells With polarised light no double refraction in the frozen sections can be demonstrata! The kidneys are very decomposed Probably there are no important anomalies excepe. ing swelling and vacuolisation of the tubulus epithelia, probably <spxcially of the tubuli contorti II The spleen shows nothing abnormal The lymph-glands (Fig 12) show lymphord tissue with relatively few cells, and a slight increase of the recicular-cells, of which a few show a somewhat vacuolised protoplasm The lungs show multiple bronchopheumonic foci with desquamation of many alveolar epithelia The sections through the cornca (lig 43) show no anomalies of Bowman membrane There is no increase of cells or nucle: The larncllae of the substant propria are pressed aside greatly through oedema, neither in the PAS-staining nor

·:
Fig 16
Spinal cord Anterior born cells Osmium te
troxyde Slight Osmium-posite substance in
the ganglion cells
Tug 47.
Spinal cord Clurke's column Intense bluck.
Janing ustb osmium Jetroryde
Tag 49
Brain Enlarged part of T18 48
in the aduentilu some lurge cells
usb racholur protoplasm.
Fug 48
Brain Wadenet Vorchou Robin space Perr
Idulur increase of cells
Fız 50
Brain (Fezrter) Suollen and some but 18-
cuolssed ganglion cells usb duplacement of
be nucleus fouards the perspbery

·with Sudan, are substances found in the vacuoles capable of taking these stains Spinal cord The upper part of the spinal cord is examined in two levels They show approsi. mately the same picture, although the anomalies in the lower situated sections are clearer than the higher ones. The anterior horn cells (Fig 44) are clearly swollen and show accumulation of a granular somewhat brown material in the protoplasm, whereby the nucleus and the tigroid-substance is pressed to one side. The tigroid-substance is crumbled. Ocher cells show a more equal glassy structure of a portion of the protoplasm and show pictures which somewhat resemble the so-called "Primare Reizung" (Primary irritation). The large cells of Clarke's column show the anomalies in a lesser degree (Fig. 45). Moreover here the pictures of a primary irritation are normal The Azan. staining colours the granular substances in the ganglion cells somewhat pink In the anterior horn cells stained with Sudan III only slight orange colouring is found With PAS staining, nowhere pink or red colouring is seen. In the anterior horn cells, when stained with osmic-acid, only a few small black granules or globules are seen (Fig 46) The cells of Clarke's column and those of the posterior horn are stained intensely black (F1g 47) Brains Sections are made of the brain from the frontal lobe, the motoric zone, the occipital lobe and the basal ganglia in all sections a clear broadened Virchow-Robin space is scen (Fig 48 and 49) The ganglion cells of the motoric area are swollen and rounded in places There 15 a slight pyknosis of the nucleus and the nucleolus is hardly visible (Fig 50 and 57) In other sections similar anomalies are seen in some nerve cells, but in a lesser degree in PAS scasning many ganglion cells appear to take on a somewhat pink colour, especially in the occipital area, but definitely not more intense than the normal ganglion cells do In Sudan-staining of the paraffin sections slight orange colouring of the nerve cells is found in the occipital area Summary As cause death the disse nated bronchopneumoniae are considered Further, there is a peculiar thickening of the aorta valve and the endocardium below The intima of the aorta is also abnormally thickened further there is a vacuolar abnormality in the liver cells and in many reticuloendothelial system cells About the contents of these cells, no opinion could be obtained A number of spinal cord cells show degenerative anomalies in the brain cells also some anomalies are seen, which however are less clear 2 POST MORTEM OF A MALT CHILD AGI 2 YEARS 9 MONTHS Height 82 cm Well fed The large forehead projects to the front Large skull roof The large fontanel is not entirely closed The teeth are quite normal The neck is fairly short The chest is flat and broad in both groins some small lymph glands are felt On opening up, the liver appears to lie 3 cm below the arch of the ribs The spleen reaches up the arch of the ribs There is no free fluid in the abdomen The thymus weighs 10 grams The heart is normal The intims of the aorta and of the pulmonary artery is sound The liver (715 grams) and the spleen (45 grams) are enlarged The weight of the brain is 1300 grams The pituitary body is not enlarged. The lateral ventricles of the brain are not obviously widened The fourth ·Fig 46 Spinal cord Anterior born cells Osmium te- Iroxyde Slight osmium-positie substance in the gunglion cells Tog 47. Spinal cord Clarke's column Intense bluck. utzining uitb osmium felroxyde. Tig 49 Brass Enlarged purt of lig 48 In the alventilss some large cells usb racuolor protoplasm F1g 48 Bruin l'atened Virchou-Robin space Pers- Laculur increase of cells Fug 50 Brain (Terler) Su ollen and someu hat 1acuolused ganglion cells usb displacement of the nucleus touards she periphery ·a ventricle and the aquacduct are normal, On section of the lowest third part of the pucanen a cystic space is present measuring 7x12 mm. In the complete post mortem, no anomalies or special features are seen in the other organs Oficroscopical examination: The examination of the heart shows no abnormalicies The liver cells are large and contain vacuolar procoplasm. The cuenly-shaped nuclei are mostly struared jeri. pherally. The Best-staining is weakly positive. With Sudan very little or no fat is visible The kidneys show no important anomalies, Apart from vacuolisation of the protoplasm of cubulus cpithelia, especially of the cubul contorti. The Sudan staining is negative, There are no double refracting crystals visible In the lungs bronchopneumonic foci are found Spinal cord: All ganglion cells are swollen, especially the anterior horn cells and the cells of Clarke. (lig 52 and 53) The nucleus and tigrord substance are pressed to the periphery The nucleus is some times curved inwards The protoplasm 15 minutely granular The changes are most pronounced in the anterior horn cells Cochlear and vestibular ganglion (Fig 51) The ganglion cells are swollen, The protoplasm is granular vacuolar The nuclei are partially pyknotic and mostly pressed towards the periphery Brains Horizontal scction through the right temporal lobe and internal capsule (Paraffin material). In Kluver-staining the marrow shows, in some places, diffusc pallor, bosales this the Virchow-Robin spaces around the vessels are greatly thickened In the cortex many ganglion cells contain in the protoplasm granular material, wluch cakes on a slight colour with fat-staining substances This is particularly noticeable in the 3rd an in a lesser degree in the 5th and 6th cortical layer, bus in no luzer chese pathological cells are absent. It is striking that in decper corter layer hoch completely normal cells are found and pathological ones In the dentare gyrus the ganglion cells contain relatively less pathological material, on the ocher hand in the hippocampus gytus large quantities The pathological material in the protoplasın of the ganglion cells when stuned with Kluver curns blue, with huematoxyline-cosinc honcver, it is only sery slightly coloured (pink) In PAS staining ic is only slightly Sitive, in the crosyl-violut no staining cakes place, while in the Bodian-staining dirty black granuks in the proto. plasm are scen There is no sign of ghia-reaction in the cortex b Sagittal section through the right temporal lobe (Paraffin and frozen matcrial) In this section also in Woc Icke and Kluyer stainings a diffuse de mychnisation is encountered as well as many very widencu Virchow-Robin spaces The largest amount of pathological material is found in the ganglion cells in the 3rd layer Practically all cells in this layer are affected in the other layers there are still normal cells Whccher there is a diminishing of ganglion cells is not possible to judge through the increase of volume of the cells With Kluver staining the matonai rurns blue, ncarly black with Woelcke-staining, and in the nile-blue sulphate colouring it is a Jerry-blue With haemaroxyline.cosine staining it is barely coloured (pink), ! is only weak P.A.S positive (with and without ptsaline) and it does not stain with ·Fig 31 Fog 52 Brute Swollen and tacuolised ganglion cells Spinal cord: Clarke's colum Suelling of ibe usb flattening and displacement of the nucleus protoplasm Nuclear displacement fou urds the periphery Fig 53 Spinal cord Clarke's column Suelling of the protoplasm Nu. clear displucement Fit 34 Fig SS Cochlear ganglion A group of ganglion cells Retins Szoller cells in the ganglion-cell layer usb granulur tacuolar protoplasm Pyknotic unb dssplacement of the nucles nucles ·cresyl-violer. In scarlet-red and Sudan-black staining it is weak positive, in Bodian. preparation in the protoplasm of the ganglion cells light-black granules are seen In frozen sections, vith Sudan-black, Sudan III or scarlet-red pathological material is stained weakly positive, and definitely not stronger than in equivalent paraffin sections In the cortex every trace of glia-reaction is absent, Pituitary body: Mainly cosinophil and chromophobe cells are found The basophil cells are definitely in the minority. 3 POST MORTEM OF A FEMALE CHILD AGD 6 YEARS 6 MONTHS Height 101 cm. The corpse is already very decomposed The child is moderately fed The head is Ercatly deformed and the forehead is very prominent Great cloudiness of the corneae does not allow further inspection of the cyes. In the pleural cavity bloody fluid is present. The valves of the heart ate all somewhat thickened but otherwise are well moveable. The chordae tendineae are plump. The myocardium is discoloured in a sporty yellow. The intima of the pulmonary artery and aorta are greatly haemorrhagia cally imbued Numerous yellow discoloured somewhat elevated spots are seen The lungs show macroscopically nothing abnormal. The abdominal organs show autolyuc changes In cutting the meninges some turbid liquor appears. The leptomeninges are scrongly oedematous and look turbid There is a striking enlargement of the cerebrum, of which the gyrı are broadened and the suici flattened On seccion the ventricles are strongly dilated The thickness of the wall of the hemispheres is very relucel. The picuitary is normal in size The microscopical examination is made difficult through autolysis The most important finding seems an atheromatosis, as well in small as in large circulation, a strong stearosis of the liver, while the anomalies of the lungs (aspi. rarion pneumonia) can possibly be considered a direct cause of death. The origin of the hydrocephalus is attributed to a thickening of the meninges In the recina (Fig 35) foam-cells are found in the layer of ganglion cells 4 POST MORTEM OF A ALALE CHILD AGE 7 YEARS 5 MONTHS Height 119 cm Well fed Large skull roof The neck is short and broad The chest is flac and broad There is no swelling of the lymph-glands The intima of the aorta and pulmonary artery is sound The liver weighs 1360 grams and the thymus 30 grams On examination of the heart it is found to be normal The spleen (220 grams) is enlarged The vertebral colomn shor's definite protrusion of the incervertebral discs In orening the skull the sutures are seen to be ossified, except the crown suture, which is syndesmotically closed In the middle skull sulcus, below the foramina rotunda et Ovalia, elevations are seen which are normally absent The lepromebinges are curbid and thickened The brain-weight is 1455 grams On section the cerebrum show's an equally widencj ventricular system The pituitary body is enlarged (weight 0,825 gram) in the complere post mortem no anomalies of any importance are seen in the other organs Alecroscopical Examination, The heart is quite normal The liver cells are enlarged and show vacuolisation of 98

·Fig. 56
Fug 57
Reima Su ollen ganglion cell with displace- Retina Swollen ganglion cell
ment of the nucleus and racholur protoplasm
Py&notic nucleus
F1g 58
Petrows bone Encbondul bone
ush globuls interosses
rus 59
Spinal cord Anterior born celle Suollen gang
{son tells usługbi t'acwolisation of she
protoplasm und displacement of the nucleus
Suollen dendronts
Fug 60
Spinal cord Anterior born cells Suollen gang
lion cells and displacement of the nucleus

·cresyl-violet In scarlet-fed and Sudan-black staining it is weak positive, in Boduan. preparation in the protoplasm of the ganglion cells lighe-black granules are seen In frozen sections, vich Sudan-black, Sudan III or scarlet-red pathological material is stained weakly positive, and definitely not stronger than in equivalent paraffin sections in the correx every trace of glia-reaction is absent Pituitary body: Mainly cosinophil and chromophobe cells are found The basophil cells are definitely in the minority 3. POST MORTEM OF A FEMALE CHILD AGED 6 YEARS 6 MONTHS Height 101 cm The corpse is already very decomposed. The child is moderately fed. The head is greatly deformed and the forehead is very prominent Great cloudiness of the corncac docs not allow further inspection of the eyes. In the pleural cavity bloody fluid is present. The valves of the heart are all somewhat thickened but otherwise are well moveable The chordae (endinese are plump The myocardium is discoloured in a spotty yellow The intima of the pulmonary artery and sorra are greatly haemorrhagically imbued. Numerous yellow discoloured somewhat clevated spots are scen The lungs show macroscopically nothing abnormal The abdominal organs show autolytic changes In curring the meninges some turbid liquor appears. The leptomeninges are strongly oedematous and look curbid. There is a striking enlargement of the cerebrum, of which the syn are broadened and the suici flattened On section the ventricles are strongly dilated The thickness of the wall of the hemispheres is very reduced. The pituitary is normal in size The microscopical examination is made difficul through autolysis. The most important finding seems an atheromatosis, as well in small as in large circulation, a strong secatosis of the liver, while the anomalies of the lungs (aspi. ration pneumonia) can possibly be considered a direct cause of death The origin of the hydrocephalus is attributed to a thickening of the meninges In the retina (Fig 55) foam-cells are found in the layer of ganglion cells 4 POST MORTEM OF A MALE CHILD AG 7 YEARS S MONTHS Height 119 cm Well fed Large skull roof The neck is short and broad The chest is flat and broad There is no swelling of the lymph-glands The intima of the aorta and pulmonary artery 15 sound The liver weighs 1360 grams and the thymus 30 grams On examination of the heart it is found to be normal. The spleen (220 grams) is enlarged The vertebral colomn shows definite protrusion of the intervertebral discs In opening the skull the sutures are seen to be ossified, except the crown suture, which is syndesmotically closed in the middle skull sulcus, below the foramina rotunda et ovalia, elevations are seen which are normally absent. The leptomeninges are turbid and thickened The brain-weight is 1455 grams On section the cerebrum shows an equally widened ventricular system. The pituitary body is enlarged (weight 0,825 gram) In the com. plete post mortem no anomalies of any importance are seen in the other organs Aficroscopical Examination: The heart is quite normal The liver cells are enlarged and show vacuolisation of 98

·Fig 36
Retonu Su ollen ganglion cell uw displace
ment of the nucleus and 1 acholar protoplam
Pyknotic nucleus
Fug 57.
Retins Suollen ganglion cell.
118 58
Petrows bone Enchondral bone
usb globuls interosses
Fiz 60
FIX 59
Spinal cord Anichior born cells. Su ollen gang
logo sells #sh sligh: Lacuolssatson of the
Ptoloplim and displacement of the nucleus
Swollen dendron
Spinal cord Aftersos horn cells Suollen $an.
lion cells usb desplacement of the nucleus

·the protoplasm. The nuclei are regularly shaped and lie mostly peripherally. The Kupffer scar.cells are also swollen and have a vacuolar protoplasm The Best, Sujan and scarlet-red staining give no clear positive result, neither in the lead acetate, aethanol or formaline fixed preparation, nor in the non-fixed preparation, which was kepe in deep-freeze The staining with toluidine-blue is clearly positive On applying this staining method after the action of hyason or after diastasis, no colouring of the preparation was observed In the lymphatic structure of the spleen, some cells with vacuolar contents are seen The lungs show bronchopneumonic foci. In the retina – specially in the arca of cntry of the optic nerve - wide-spread, large, swollen ganglion cells are found with vacuolisation of the protoplasm and eccentric, sometimes pyknotic nuclei (Fig 56 and 57) In the other structures of the eys, namely in Bowman's menibranc, no anomalies are found. Petrous portion of the temple bone The enchondral ossification presents an aspect as shown in rig 58 Spinal cord (Fig 59 and 60) Distinct swelling of the anterior horn cells The protoplasm is granular vacuolar, The nucleus and the tigrord are pressed to the periphery The nucleus is sometimes curved inwards The Clarke-cells show these changes in a minor degree Cochlear and vestibular ganglion. The ganglion cells are swollen The nucles are partially pyknotic and pressed to the periphery The protoplasm is granular-vacuolar. The anomalies in the larger cells of the vestibular ganglion are far less obvious than in the smaller ones (lig 61. 62 and 63) Cercbrum Sections were made of the brain, namely of the motor area of the correr in the sections most of the ganglion cells appear to be stvollen. The protoplasm is granularvacuolar, and the nuclei lie mostly peripherally. With the PAS staining the ganghon cells appear to be PA S positive With the Sudan-staining the ganglion cells are stained light-orange The Virchow-Robin spaces are widened Pituitary Body The anterior lobe is obviously enlarged There is colloid-ac nulation in the acini Only a few basophil cells are seen Some eosinophil cells are multi-nuclear. 5 POST MORTEM OF A FEMALT CHILD AGTD 12 YEARS Height 102 cm The general condition of the body shows under-nourishment In the lungs emphy. sema of the lower lobes is found it is difficult to dissect all the organs as they are too tough The heart muscle is coloured yellow and tough of consistency There is much coagulated blood in the heart, part of which is removed for laboratory examination The liver is greatly enlarged and has an uneven surface (ucight 750 grams) The pancreas is large and has a yellow colour Skull section The largest circumference is 64 cm. The roof of the skull is paper thin and the dura markedly thickened The sinuses are passable The brain convolutions are broad and the grooves flattened There is turbidity and thickening of the arachnoids In removing the brains 1550 cc liquor is collected The weight of the brains is 1250 grams. On cutting strongly dılared ventricles are found the wall of the hemispheres is reduced to a membrane of only 1/2 cm thickness Numerous small cysts are found 100 ·Fug 61 Vestsbular ganglion A group of large gang. hon cells usth slight granulatson and many small talvoler on the protoplasma Fię 62. Vestibular ganglion A group of lurge sung. lion cells with wheten stained prosoplum Fig 63. Vestibulur ganglion A group of small cells usth numeTOH TACHOles of nearly et en size Nucles are prily Pyknone Tug 67 Fig 65 Brzi Amorphous substances in globular. Nasal polip Around the blood tested some Whaped rollen ganglion cells, the stucture of large cells usb granular tacuolar protoplasm ufub u loss Next sa them, some ganglion To sbe night a detached cell tells usb amorphous substances in the sto. plum, onlt 4 spora fin and ·the protoplasm The nuclei are regularly shaped and lie mostly peripherally. The Kupffer star-cells are also swollen and have a vacuolar protoplasm The Best, Sudan and scarlet-red staining give no clear positive result, neither in the lead acciare, acthanol or formaline fixed preparation, nor in the non-fixed preparation, which was kepe in deep-freeze. The staining with coluıdınc-blue is clearly positive On applying this staining method after the action of hyason or after diastasis, no colouring of the preparation was observed In the lymphatic structure of the spleen, some cells with vacuolar contents are seen The lungs show bronchopneumonic foci In the retina – specially in the area of ('ntry of the optic nerve - wide-spread, large, swollen ganglion cells are found with vacuolisation of the protoplasm and eccentric, sometimes pyknotic nuclei (Tig 56 and 57) In the other structures of the eye, namely in Bowman's membranc, no anomalies are found Petrous portion of the temple bone The enchondral ossification presents an aspect as shown in Fig. 58 Spinal cord. (Fig 59 and 60) Distinct swelling of the anterior horn cells Thc protoplasm is granular vacuolat The nucleus and the tigroid are pressed to the periphery The nucleus is sometimes curved inwards The Clarke-cells show these changes in a minor degree Cochlear and vestibular ganglion The ganglion cells are swollen The nuclei are partially pyknotic and pressed to the periphery The protoplasm is granular-vacuolar The anomalies in the larger cells of the vestibular ganglion are far less obvious than in the smaller oncs (Fig 61, 62 and 63) Cerebrum Sections were made of the brain, namely of the motor area of the correr in the seccions most of the ganglion cells appear to be swollen The protoplasm is granularvacuolar, and the nuclei lie mostly peripherally with the PAS staining the ganglion cells appear to be PA S positive With the Sudan-staining the ganglion cells are stained light-orange The Virchow-Robin spaces are widened Pituitary Body The anterior lobe is obviously enlarged There is colloid-accumulation in the acını Only a few basophil cells are seen Some cosinophil cells are multi-nuclear $ POST MORTEMOT ATUMALE CHILD AGED 12 YEARS Height 102 cm The general condition of the body shows under-nourishment in the lungs emphy. sema of the lower lobes is found it is difficult to dissect all the organs as they are too tough The heart muscle is coloured yellow and tough of consistency There is much coagulated blood in the heart, part of which is removed for laboratory (x2- mination The liver is greatly enlarged and has an uneven surface (weight 750 grams) The pancreas is large and has a yellow colour Skull section The largest circumference is 64 cm The roof of the skull is paper thin and the dura markedly thickened The sinuses are passable The brain convolu. tions are broad and the grooves flattened There is turbidity and chickening of the arachnoids In removing the brains + 1550 cc liquor is collected The weight of the brains 1s 1250 grams On cutting strongly dilated ventricles are found The wall of the hemispheres is reduced to a membrane of only 192 cm thickness Numerous small cysts are found 100 ·With P.A.S.starning (Fig 63) this same material reacts positive. In the sections treated with posaline this substance is hardly less stained than without With Sudan. black the granules in the cells stact positive la consequence of the fact that the substance found in the farge cells of the polyp, reacts positive to Sudan, Sudan black and PAS SESIOs, ut is concluded that these cells possibly contain a substance, probably a glicolipid (ganglioside) In the polyp also some Russel-bodies are seen, which is not surprising considering the number of plasma-cells Summary Oedematous, inflamed nasal-mucous membrane polyp, with large macrophages, which contain a ganglios.de-like substance : LITER (CASF Y) In the sections the liver-cells appear to be slightly swollen and contain a great deal of glycogen (P.AS scanning) The glycogen is evenly distributed over the liver. trabeculi Apart from the glycogen the liver-cells contain another substance, because they are somewhat vacuolar, but in the sacuoles no substances are found which take on the PAS, Sudan Ill or Sudan-black stains Conspicuous are some large cells with small dark nucles and with sharply circumscribed protoplasm, which shows a somewhat screakly light vacuolar character These cells lie csfacially in and around the Kiernan's triangles They are considered to be cells which have accumulated some kind of substance Neither the cells, nor their localisation are typical enough to define them in more detail Wich Azan-stainings, the protoplast in the cells stains a bright blue The reticulin-statnings do not give a further discernment. LYMPK.GLAND In the sections through the lymph-gland, a proliferation of reticulo-endothelia is found, of subcapsular and medullary sinus Also in the medullary sinus a number of large cells are seen of the same type as those of the large cells around the Kiernan's triangles ·in the white as well as in the grey marter. The floor of the third ventricle is very chin and to a certain exccnc ventrally distended The aquaeduce is very wide and as far as can be investigated, the foramen of Magendi is wide open It seems pos. sible that in the posterior skull groove a cyst was present at the distal side of the cerebellum, which has pressed the vermis and tonsils dorsally and the medulla oblongata ventrally, Microscopical examination: The pia mater is somewhat thickened due to the increase of connective tissue fibrils and cells. The cortex of the hemispheres has become very narrow, and lamination is lost. The number of blood vessels has greatly increased and the space of Virchow. Robin around the blood vessels greatly enlarged There is a definite marginal sclerosis. In the ganglion cells (Fig 64), as well as in the ghia-cells an amorphous substance is present, whereby these cells have been blown up to a balloon-shape while the nucleus has been pressed to the edge. Sometimes round masses of an amorphous substance are noticed, in which cell structures co longer can be recognised Not only the neurones but also the glu-cells contain this amorphous mass. There are numerous hazy ganglion cells The number of glia-cells 1$ greatly increased The myelin substance has been completely lost and replaced by 1 gla-network with numerous fibrillous astrocytes Some U-fibres are maintained On the border of the white and grey matter numerous microcysts are present, which, as far as can be gathered, have developed from peri-vascular spaces There is an intense proliferation of the periadventitious cells of the blood vessels in the wall of the blood vessels a homogeneous substance is scen In places signs of an ependymiris granularis are observed Nor only in the grey marter of the brain, but also in the cerebellum, cells are noticed loaded with amorphous substances, surrounded by degenerated tissue products Everywhere the white matter is atrophic. In the pons it is noticed that the tegmentum is narrow, while the base has normal proportions. Summary Great destruction of the grey and white matter of the CNS caused by the Joposition of amorphous substances in the cells As a result of this the white as well as the grey matter is to the greater pare lost, while a compensatory hyperplasia of the glia-cells has developed No certain expla. nation is found for the enormous hydrocephalus, but probably this is the result of a cyst situated in the cisterna magna Not only in the central nervous system accumulation products are found, but also these are found in spinal ganglia, pancreas, liver, spleen, lungs, heart, kidneys, ovaries. aorta, thymus and cartilage The accumulation products, in as well as outside the central nervous system, arc stained in a large measure with PAS staining and with Sudan staining B BIOPSY REPORTS NASAL POLYP (CASI The polyp consists of oedematous connective tissue with a firly thick infiltration of plasma-cells, lymphocytes and granulocytes It is covered with normal ciliard pseudostratified columnar epithelium in the stroma, apart from the cells mentioned, some cells are seen with vacuolar, barely stained protoplasm and small nuclews in the paraffin-sections of formaline-fixed issue stained with Sudan, in a number of these large cells, granulat matter is scen which has a light brownish-red colour ·6 Early childhood As far as could be established the patents described gave evidence of insufficient development of their mental powers during the first three years of their lives. There are, therefore, no patients with a so-called "late" form of gargoylism, in which only after the third year life clinical signs become manifest Most of them started walking late. In the majority of cases speech development was disturbed Usually between 3-6 yrs. a mental deterioration was noticed in the more severe cases. Further, the anamnestic data are in conformity with the opinion, reflecred in the literature, that gargoylism is a conditioning factor for the acquiring of pneumonia, bronchitis, pharyngitis, rhinitis, tonsillitus, otitis media and other chronic or recurrent affections of the respiratory tract B BIOMETRIC DATA The data referring to herght, weight and skull circumference ate summarized in the following table, arranged according to the age of the patient: Height Weight ااه 51 Age Case ID Cin Sex In Carcomtrehce of skull 19 (la complet Cm Bon with the normal Sre standard) yrs (In compart son vith the normal aga standardy inths (In comparison with the normal standard Height Ate) Lonachi ideb Inem 0 VIII +96 +4 0 +12,8% XIII F 06 63 - 4,5% 5,68 -13.9% -23 % 41 -6,7% XVIII F 0-8 71 + 1,3% 10,9 +26,7% +28,2% 54,6 +9 XVIII F 1-O 78 + 4,1% 12 +16,5% +23,7% 56.5 +19,7% 19 114.5 XIT F 77 + 1,70 11 +11,1% +15 % 47 + 6,6% F 1-5 80 - 1,2% 13,6 +24,8% +23,6% 53 17 115 XVI F 82 – 3,3% 11,04 + 0,46% - 3,150 + 3,5 15 114 X F 2-6 94 + 5,6% 15,2 + 9.3% +20,6% 57 +16,8% VI F 2-) 82 -11,5% 52 17,5/15 XVI F 88 - 5,6% 14 +15,7% + 3,7% 51,8 + 5,1% 15 /14 11 33 97 + 0,5% 18,8 +25,1% +25,3% 57 XIV M 42 96 – 5,5% 16,5 +14,6% + 4,4% 52 +4 02 XVIIM 4.6 56,5 + 9,50 111 M 5-S 119 +6,7% 30 +37,6% +57,9% 55 + 6,6% 19 113 V M 5- 6 108 – 3,2% 26,4 +48 % +39,753 + 2,3% 16 15 IX M 5-9 93 -16,7% 16,3 +21,3% -12% M 5--10 101 – 9,76 225 +48 % +20,3% 59,5 +15,5% 20 (15 XV M 6 3 123 + 6,4% 26 +11,5% +27,5% 52 M 6-10 108 - 8,86% - 1,3% 17 /15 56 VII + 7,3% 1915 ME 1-4 119 — 2,906 28 +28,9% +22,306 60 +14,1% 20 116,5 IV M 82 113 -10,9% 27 It! +39,2% +12.5% 53 + 0,8% 16 15 8-3 123 - 2,6% 32,5 +39,5% +32,1% 58 M +13 % 19 115 90 118 -11% % 27,5 +28,5% + 0,7% 55 IV M 117 -16,5% 33 + 3,6% 17,5115 +37,8% + 1,8% 54,5 + 1,7% 16 116 XI M 102 -29,6 62 +16,3% 21 116 Calculated accordiag to the tables in the Textbook of Endocrinology by RH Williams MD ·Chapter VI SUMMARY AND DISCUSSION OF THE CLINICAL DATA DESCRIBED IN CHAPTER IV A PAST HISTORY 1. Consanguinity No consanguinity was found in the parents of the patients described before Perhaps this is related to the fact that in at least six (Case I up to and including VI) and possibly even in eleven (Cascs VII, VIII, XV, XVII, XVIII) of the eighteen patients the disease is sex-linked. 2 Familial incidence The familial incidence is most obvious in Cases I to VI inclusive, The patients described are all boys, belonging to one ancestry, wherein the disease appeared at least in fourteen persons. The second family with multiple cases is represented by Cases VII and VIII; these patients are brothers A third family where a multiple incidence is found, is represented by Case IX A brother of this patient is possibly also a gargoyle patient 3. Heredity In Cases I to VI inclusive, there is a recessive-X-chromosomal inheritance (sce ancestry Fig. 1) In Case IX recessive autosomal inheritance may be presumed because a brother of this female patient probably also suffers from gargoylism In the remaining patients it is not clear whether the condition is homozygous or heterozygous Neither is it clear whether there are patients in which the disease must be attributed to a genc mutation 4. Pre-natal peculiarities Perhaps it is worthwhile mentioning that the mother of onc patient (Case XVII) during pregnancy observed abnormally listle focial movement In this patient, after the birth, there was definite motor inertia 5. Birth In 8 of the 18 patients the birth was abnormal (long duration of labour, Caesarian section or forceps extraction). In three of the eight patients an abnormally large skull was noticed at birth. 104 ·Hart Teeth enamolies Macroglossa Umbilical hernia Case Contractores anamolics 1 + il III +++ VII VIII IX х XI XII XIII XIV XV XVI XVII XVIII ++++ + ++++++++ ++ ) + + + + + + + + + + + 1 + ] 1 +++++ 10 11 +11+++ 1 + 11 + + + The numerous café au lait spots mentioned in case XV are of interest in connection with a publication of NOLLER 19, in which a patient is described with both gargoylism and skin fibromata. SALAM and ZELLWEGER 1 213 described a family with a case of gargoylism as well as one of Reckling hausen's disease. Further, it is of interest to nore the presence of leukonychia 10 Cases IV, V and VII. D EYE EXAMINATION Summary Cax Sex Corneal Cloudiness She lamp stamination performed Optic-strophy Special Features weak + M M M M M по no yes yes yes no yes yes II III IV V VI VII VIII LX X XI XII XIII XIV ҳу XVI XVII M M F F F F F F M F ME 11111+++1+11+11 DO yes yes Yes jes yes yes yes III+ hypermetropy XVIII 107 ·From this survey it is obvious that the height is below the normal age standard. Macked degrees of retardation in growth are conspicuous in the higher age group. These dara support the opinion of ZELLWEGER et al 307 that there is a progressive retardation of growth with increasing age. The body-weight usually exceeds the normal standard for age and height. The circumference of the skull is usually greater than is normal according 10 age. In general it may be said that the moderately cnlarged skulls are brachycephalic and the greatly enlarged skulls mesocephalic. C FACIAL EXPRISSION AND HABITUS Practically all patients had the Hurler-facies to a greater or lesser extent The facial expression cypical of gargoylism became increasingly obvious with age. To the description given in che literature we may add that the face of many of the patients is reminiscent of somcone with a bad cold, about to snceze. The grin of short duration, which precedes sneezing, appears constantly on the face of the gargoyle patient, giving it a stark and painful expression. A clown-like expression also occurs (see Fig 7) The resemblance between the intrafamilial cases, as described in the first six cases, was striking. However, the facial expression in Case IV was different from that of the other patients. In some patients the cheeks were bright red, but in others this phenomenon was lacking Moreover, it was noticed that the bright red colour disappears during the course of the disease (Case V). Howcver much the patients resembled each other on account of their facial expression, there was a still grcater resemblance in their habitus. Generally speaking thcy could be considered as pyknic. The relatively large head, the short, broad neck, the flat broad thorax, the far abdomen, che plump broad hands and fingers lend the general appearance of the gargoyle patient an aspect that is even more characteristic of the disease than the facial expression because, in our opinion, it is neither dependent on the phase of the disease, nor on the age of the patient Another typical aspect, dependent on the age of the patient and the phase of the disease, is the posture of the patient when standing and walking, viz., the flattened lumbar lordosis, sometimes accompanied by a thoracolumbar kyphosis, and the flexion contracture position of the legs, ar the hip and knee joints and the often present genua valga. We shall not go more deeply into derails noticed on inspection, such as contractures, skin and hair anomalies, the occurrence of an umbilical hernu, teeth, congue and nail anomalies Suffice it to give a broad survey of the appearance of some of these anomalies 106 ·The heart in mo patients was definitely abnormal, suggescive of a congenital anomaly, in these cases the blood pressure of the femoral arteries was too low, while in another pacient thete nas a definice hypertension. On electrocardiographic examination, no abnormalities were registered In some patients a systolic murmur kas detected above the base of the heart, and in one an enlargement of the heart to the left Diffuse glandular enlargement was observed in one case only. Most patients suffered from a chronic coryza According to McKUSICR *** and MURRAY"" the mobility of the thorax is deminished in a lasge number of patients. Although our case histories included no data pertaining to this feature, it is reasonable to assume that a diminished mobility existed on account of the broad and flar shape of the thorix and the horizontal course of the ribs in the majority of our patients. I should be menuaned here that in eo cases microgenitalism was presenc, while in other pacieaes the external genitals were well deseloped A large number of labo rarody rests have been carried out on most of the patients, including the determination of sodium, potassium, chloride, phosphorus, urea, cholesterol, acid and alkaline phosphatase and the copper content of the blood. Further, the protein spectrum of the blood was determined by means of paper-electrophoresis. Apart from derermining the fasung blood sugar level in many cases a glucose tolerance-curve was also made Liver function tests were carried out. The urine was examined chromatographically by means of paper-electrophoresis for the presence of animo-acids In some cases the hormone content of the urine was estimated Blood and urine examination was routine in all cases Apart from thes, slides were made of the peripheral blood-picture, 10 demonstrate the anomaly of Reilly (Genisa-Wright staining). This anomaly, horever, was not found 10 any of our patients. The sternal puncture was examined in cases IX, X and XIII, la Case X there was an increase in reticular cells, a spongy structure of the protoplasm and a large, sometimes eccentric and flattened nucleus. The basal metabolism could only be examined in the few cooperative patients, The following values kere found Case X BM 3,6 resp. - 10; resp. - 14 Case XY BM + 12 In case X tracer investigation with 1"" gave remarkable results because this subszarace was almost entirely retained by the thyroid Hormone excretion via the urine (mg per 24 hours). Cuc Y 111 1,4 0,3 0,3 17-ketosteroids 17-hydroxycorticosteroids Gonadotropic hormones Oestrogeait hormones 6,9 0,0 15 U 2,3 14,9 SU 7 U 5,6 ·Optic atrophy was diagnosed in two patients (Cases IX and XVIII). On account of pronounced corneal cloudiness, it was impossible to examine oculi in Cases X and XI. A "cherry-red macula", which may occur in amaurocic idiocy, was not noticed in any of the patients. The corneal cloudiness in Case II is noteworthy, because this was a case of sex-linked heredity. According to the literature corneal cloudiness is not seen in sex-linked cases. Delayed pupil widening with my. driatics was observed in Cases VII and XIII. This phenomenon is repeatedly mentioned in the literature. 1. 7. The importance of detecting errors of rcfraction is obvious from Case XV, in which a hypermetropia was diagnosed. After correction of vision there was an obvious improvement in his achievements at school, E COCHLEAR AND VESTIBULAR FUNCTIONS The results of the investigations are represented in the following summary Case Age Reactions to sound stimul Reaction to caloric stimulation X111 XVIII 0,6 0,8 + + + + XII VIII XVI 1, 2 1, S 2, 1 + + Right – Left + + + + Impression of the sensitiveness of the labyrinth, rudged by nystagmus duranton and latency period diminished diminished, left more than right diminished diminished diminished, right more than Icht left abolished right diminished abolished abolished abolished slightly diminished abolished aboltshed XIV 4, 2 + Left Right + III V х XV VII IV 5, 5 5, 6 5,10 6, 3 7, 4 8, 2 + + + Normal audiogram + + ill+II It is important to note that in cases with mental deficiency, it was practically impossible to accurately establish the auditory disturbances The impression gained from the patients was that there was a gradually decreasing reaction to sound stimuli, which of course does not imply either that the organs of hearing ded, or did not, function normally From the summary the smpression is gained that in most cases there is a diminishing sensitiveness of the labyrınth during the course of the disease F MEDICAL AND ENDOCRINLANOMALIES AND LABORATORY FINDINGS As in cases reported in the literature, a hepatosplenomegaly was found in most of our patients. Intestinal disorders, seldom mentioned in the literature, were also seldom encountered in our patients. 100 ·The heart in mo patients sas definitely abaormal, suggestive of a congenital anomaly. In these cases the blood pressure of the femoral arteries was too los, while in another patient there was a definite hypertension. On electrocardiographic examination, no abnormalities were registered. In some patients a systolic murmur was detected above the base of the heart, and in one an enlargement of the heart to the left. Diffuse glandular enlargement was observed in one case only. Most parients suffered from a chronic coryza. According to McKUSICK *** and MURRAYshe mobility of the chorax is diminished in a large number of patients Although our case histories included no data pertaining to this feature, it is reasonable to assume that a diminished mobility existed on account of the broad and flat shape of the thorax and the horizontal course of the ribs in the majority of our patients It should be mentioned here that in two cases microgenitalism was present, while in other patients the external genitals were well developed. A large number of labo ratory tests have been carried out on most of the patients, including the determination of sodium, potassium, chloride, phosphorus, urea, cholesterol, acid and alkalıne phosphatase and the copper content of the blood. Further, the protein spectrum of the blood was determined by means of paper-electro. phoresis Apart from determining the fasting blood sugar level in many cases a glucose tolerance-curse was also made. Liver function tests were carried out. The urine was examined chromatographically by means of paper-electrophoresis for the presence of anıno-acids. In some cases the hormone content of the urine was estimated Blood and urine examination was routine in all cases Apart from this, slides were made of the peripheral blood-picture, to demonstrate the anomaly of Reilly (Gremsa-Wright staining) This anomaly, honever, was not found in any of our patients. The sternal Punctate sas examined in cases IX, X and XIII In Case X there was an increase in reticular cells, a spongy structure of the protoplasm and a large, sometimes eccentric and flattered nucleus. The basal metabolism could only be examined in the few cooperative patients. The following values were found Case X BM – 3,6 resp. — 10, resp 14. Case XV BM + 12. In case X tracer investigation with I" gave remarkable results because thus substance was almost entsrely retained by the thyroid Hormone excretion via the urine (mg. per 24 hours). Case 1Y IY X111 YY YVINI 0,3 0,3 17-ketosteroids 17-hydroxycorticosteroids Gonadotropic hormones Destrogenic hormones 6,9 0,0 15 U 2,3 14,9 5 U 7 U 1,0 9,6 ·The usefulness of the laboratory examinations proved to be small when considered in relation to the number carried out. We shall therefore restrict ourselves to a recording of the positive results: Cholesterol PBI Alkaline Serum proteins (paper ckctrophores) Copper phospha. Albumun Globulin tase alpha 11 alpha I bets fami1 Tout protein 4-7 mal ves 130- 250 mgr% 98-124 y% 5-1 SE KA 54. 6.2. 7.8 - 64 85 11.4 rel% rel% rel.% >% 91. 12.1. 130 17.6 rel.% rel.% 6.8 gro ase II M 249 5,8 125 47,1 8,6 15 13,6 15,7 7 20 17,2 29 28 3,9 4,6 196 198 6,7 48 50,2 5,9 7,3 13,4 18,3 14,3 12,8 14,8 15,2 7 IV V VI ZII III IX X 292 253 196 140 187,5 125 380 205 41,1 16,5 22,5 40,58 60 36,6 9,6 6,2 3,1 17,8 13,0 8,6 15,1 11,5 6,7 9,2 6,6 6,9 6 6,2 XI 163 III IV (V VI 268 188 198 237 237 24,2 35,2 18,5 34 34 14,9 17,7 24,2 14,3 131 42,7 44,2 53,2 48,2 50,5 67,0 56,7 7,5 9,2 8,1 8,9 8,3 18,5 19,4 11,3 11,6 6,5 5,8 11,5 14,3 12,2 11,6 12,7 9,0 12,2 19,6 12,2 14,4 19,7 13,8 10,0 11,8 5,3 6,7 6,2 7 6,1 7,9 6,5 14,7 2,5 III 11,5 12,3 147,7 7,1 6,2 Lipid spectrum of the blood. Standard Case Case % Tot, amount of lipids Lipid phosphorus Neutral far Cholesterol 500--900 mg % 7-49 ms % 0-400 mg % 150-280 mg % 1112 mg 14 mg 360 mg 0 380 ms 70 0 525 mg 55 mg 262 ms yo 125 ms % From these surveys it appears that hypercholesterolaemia was present in several cases In one of our cases (Case X) practically all fractions of the lipid spectrum of the blood were increased. Similar findings have been described in the liceracure P1. In some pacients the copper content of the blood-serum was definitely increased, a phenomenon also described in the literature 25: The alkaline phosphatase level in the blood was in most cases moderately raised. In the literature normal levels predominare 20 21 103 141 167 186, 191 197 198 227 250, although in a minority of cases moderately raised levels have been observed ("? 26 293 39), and only exceptionelly low levels ('* 186). The protein spectrum (paper-electrophoresis) presented, as a rule, the following features 1. Normal protein content. 2. Decreased albumin/globulin ratio. 110 ·3 Increased alpha-2-globulin fraction. (This is in agreement with the findings of LOWENTHAL ?). 4 Incidental deviations from the normal levels of the ocher globulin fractions Although in various patients signs were observed, suggestive of Cushing's disease, acromegaly and myxoedema, the results of our investigations desproved the presence of these conditions in our cases as in the literature, the endoarnological investigation results vary from case to case. This variability seems understandable, at least to some extent, in gargoylism, for whereas in some cases the pituitary is of normal size, in other cases the adenohypophysis is enlarged and in still another category of patients the pituitary body is reduced in size as result of pressure in the presence of a variable degree of hydrocephalus, which reself can cause hypothalamico-endocrinological disturbances. It seems worthwhile to mention here that the X-Ray picture of the sella does not provide reliable information as to the true size of the pituitary. GNEUROPSYCHIATRIC DISTURBANCES In Chapter II it has already been explained how our study of the literature - specially the publication of C. de LANGE and WOLTRING — sesulted in a distinction being made berseen no types, viz., the classic type, where the disease as accompanied by neurolipidosis, and the typus E where this is absent Clinically, it may be remembered, the difference between the two Types consists in the presence or absence of psychic or neurological abnor. malities for further details reference may be made to Chapter II. An example of typus e probably does not appear in our own material. Although it is true that there are some cases in which progressive mental deterio ration is absent, the other signs of the disease are so slight that it is perhaps more correct to consider these cases abortive. Apart from these latter cases, the anomalies found can be summarized as follows. I A progressive deterioration process preceded by Oligophrenia II A very slowly progressive neurological condicion, resulting in a spastic tetraparesis or terraplegia and cortical, sub-cornical, striate and brainstem lessons III. Hydrocephalus, as a rule of a progressive character, in the large majority of cases Ad! The oligophrenic development which clinically precedes the deterioration is marked by a progressive regarding in development tempo and by malfor. mation of the personality of the child which leads finally to complete developmental arrest Only when this has taken place do the signs of a progressive deterioration become conspicuous 111 ·The usefulness of the laboratory examinations proved to be small when con. sidered in relation to the number carried out. We shall therefore restrict ourselves to a recording of the positive results: Choleste rol TDI Copper Alkaline Seruni protein (paper electrophoresa) phospha- Albumin Globulin tase alpha 11 alpha beta Raminta Total proteini ormai alues 4-7 130- 250 mgr% 98-124 y% 5. ISE KA 54 - 62. 78. 64 85 11.4 rel% rel.% rel.% 2.1. 121 - 130 17.6 fel.% rel% 6-8 kr.10 Case JI III 249 5,8 125 47,1 8,6 15 13,6 15,7 7 IV 20 17,2 29 28 3,9 4,6 196 198 18 50,2 5,2 7,3 14,3 12,8 13,4 14,8 18,3 15,2 6,7 7 205 292 253 196 140 187,5 125 380 17,8 VI VII VIII IX X mm WVW川区x www 22,5 40,58 41,1 60 36,6 9,6 6,2 3,1 13,0 8,6 15,1 11,5 6,7 26,5 9,2 6,6 6,2 6 6,2 42,7 14,9 163 131 268 188 198 237 237 18,5 19,4 7,5 9,2 8,1 24,2 35,2 18,5 34 34 14,1 17,7 24,2 14,3 XI KIIT XIV XV KVI VII VIII 53,2 11,3 6,5 5,8 8,9 48,2 50,5 67,0 56,7 11,5 14,3 12,9 11,6 12,7 2,0 12,2 11,6 14,7 11,5 12,3 19,6 12,2 14,4 19.7 13,8 10,0 11,8 5,3 6,7 6,2 7 6,4 7,9 6,8 8,3 2,5 6,2 147,7 7,1 Lipid spectrum of the blood Standard Case v Case TV 0 525 1112 mg % mg zo 55 ms Tot. amount of lipids Lipid phosphorus Neutral fat Cholesterol 500-900 mg mg 0-100 mg 150-280 mg % 14 mg 360 mg % 380 mg 0 ój 262 125 ms 70 mg % From these surveys it appears that hypercholesterolacmia w.is present in several cases. In one of our cases (Case X) practically all fractions of the iperd spectrum of the blood were increased. Similar findings have been described in the literacure. In some patients the copper content of the blood-serum was definitely increased, a phenomenon also described in the litcrature 1. The alkaline phosphatase level in the blood was in most cases moderately raised. In the literature normal levels predominate 28. 21_103141 187, 186 191 197 198 227 250, although in a minority of cascs moderately raised levels have been observed ("? 236 235 5), and only exceptionelly low levels (1 186) The protein spectrum (p.per.electrophoresis) presented, as a rule, the following features: 1. Normal protein content. 2. Decreased albumin globulin ratio ·of being angular. As a rule an increase in the oculopalpebral seflex with extension of the reflexogenic zone was detectable, sooner or later. This pheno. menon nas absent only in the light cases. The further course of the disease was characterized by an increasingly inadequate and imperfect progress of motoric behaviour pattern; the patient usually impressed one as being aprac- NIC This was commonly folloned by a slowly progressive spastic diplega, firstly of the loner and later also of the upper extremities, while, at the same time not only bulbar but also the pseudobulbar phenomena appeared. These included primitive mouth reflexes, deglutition disturbances, depression of the pharynx reflex, increase of the masseter-reflex, a strongly positive facial reflex and an increased reaction to threat. It was often noticed that the mouth contained excessive amounts of saliva and this was attributed to difficulties experienced in swallon ing. In one patient insufficient saliva secretion was observed (Case IV) In the beginning of the illness various patients gave one an impression of suffering enhanced sensations of hunger and thirst. In the later stages however, it was usual to nore a progressive decreasc of appetite, as nell as pathological increase of desire for sleep In one patient (Case II) affective loss of tonus was observed. Sensory exami. nation was difficult to carry out efficiently on account of the lack of intcl. lectual power of most of the patients. It was, however, noticed that many disliked being couched They reacted also to pain stimult. Definite cerebellar anomalies were not observed. One pacient suffered from epileptic fits (Case XI). In tuo cases there was a bilateral optic-acrophy. In a number of cases examination of the papillae nervi optici was not possible because of corneal cloudings In the most advanced stages of the disease the patient lay practically motionless in bed, with extended arms as well as the legs and with fees in a pointed position Further, it should be remarked that there were no signs of disturbance of the periferal nervous system Electromyographic examination could not be carried out on this group of patients It may be mentioned in passing that the patients shon ed a gradually decreasing reaction to sound stimuli. In the final stages they did not react at all to vestibular stimul la some patients, with a slighe symptomatology, the abovementioned neurological anomalies could not be detected. It is, however, possible that is such abortive cases these signs will sell appear at a later date The results of electro-encephalographic examination may be summarized as follows 1. As a rule no constant asymmetries 2 No focal or generalized epileptic activity 3 Generally speaking excessive slos activity. We are grateful to our colleague J Mol, neurologist at Heerlen General Hospital, for his assistance to recording and interpreting the EEG tracings 112 ·Inicial examination revealed, apart from a retardation in the striving after and the acquiring of sensual and intellectual knowledge, a disturbance of temperament, character, vitality and psychomotility, a disturbance, in other words of the complere personality. Following upon this period of inadequate and progressive retardation in development a stage is finally reached of complete arrest, as already scated. This did not happen simultaneously in all fields, namely in behaviour cxperience and function; in some pacients for example, there was cessation in speech development, while some progress was still being made in other fields of motor development. Most pacients started walking late. Progressive detcrioration signs generally appeared between the third and sixth year. The patients gave to an increasing degree the impression of being apractic. Pathological deterioration involved the break down of most cerebral functions, with psychiatric as well as neurological manifestations. It was particularly noticeable that, together with the intellectual deterioration, primitive, oral libidinous behaviour patterns came to the forc. Compared with the behaviour and experiences of normal children of the same age and sex, there not only appeared to exist quantitative differences but also qualitative ones. In certain of their behaviour patterns and experiences they appeared to be even less differentiated than are normal healthy infants. All in all this may be said to add up to a deficiency in the majority of the specific human quali ties. What remained were fragments of behaviour and a complecely disordered psychic life based principally at the animal-vegetative and biological-sensitive level. This was accompanied by an increasing disturbance of social contacts In a few patients with a slighter symptomatology, there was only an oligophrenic personality development. Follow-up will show whe pathological deterioration will still take place. In one of the abortive case's noticeable improvement took place, as judged by school achievement after an hypermetropy had been corrected. The majority of the patients was unable to follow infant school training or even that provided in a special school for backward children Only one patient seemed capable of following the ordinary elementary school course (Case XV). Ad.II. On reviewing the whole range of neurological anomalies, one may conclude that a prominent feature was a decreasing tempo in the development of the neuromotor and psychomotor functions resulung in a steady lowering in the level reached. Speech development was nearly always discurbed and this was most pronounced in those patients in whom walking had begun late In some motor inertia was seen, in others however, there was a nouceable hyperkinetic behaviour, chiefly in the form of primitive rhythmic movements, but also in other forms of motor restlessness, it someames having a chores. form character. The movements were typically suff and gave the impression In these ses ·The vascular impressions, however were often pronounced. In the minority of cases the shape of the sella was considered to be normal; usually shoe-shaped and sometimes a ballooned sella was seen in more than half of the cases the sella was enlarged and the sella entrance widened In most of the cases the pneumatisation of the mastoids was slight. Tborar The thorax was broadened in practically all cases, and there were changes in the clavicles and ribs typical of gargoylism. Vertebral column: In most of the patients "fish-hook" shaped vertebral bodies were seen in the thoracolumbar region of the vertebral column. Occasionally tongue-like projections were found on the anterior surface of the vertebral bodies. Some degree of kyphosis was seen in practically all patients Spondylolysthesis occurred in three cases Other signs Coxae valgae and changes typical of gargoylism in the bones of the hand and to a lesser degree of the foot, were seldom absent. In Cases I, IV and V the number of ossified carpal centres was below the normal age standard. 11 ·4. Sometimes excessive beta-activity. 5. Tendency to respond on photic-stimulation, with higher frequencies than those of the background rhythms, with a pronounced occipital driving. Ad, ill. In 8 patients an impression could be gained as to the size of the cerebral ventricles by means of pneumo-encephalography in 3 cases and by the examination of post-mortem material in 5 cases. In 6 of these che ventricular system was dilated to a varying degree: Symbols express Case Corcumference of Age the skull in compa- Skull mehs Tison with the nor Length/Wight mal age standard Brain ventricles yrs sing the degree of dilation X 2 0 XIII VI 1,0 2,9 6,7% + 4 % X + VIII V IV VII х XI 17 115 16 115 16 115 1,5 5,6 8,2 7,5 6,5 12,0 No dilarion 17,5/15 Dubious dilation of sideventricles Clearly dilated Clearly dilated Clearly dilated 20 /16,5 Strongly dılaced 20 115 Very strongly dilated 21 116 Very strongly dilate + 9 % + 2,3% + 0,8% +14,1% +15,5% +16,5% X х +++ x Post mortem Encephalography This survey shows a correlation between the degree of ventricular dilacion and cranial enlargement. It is remarkable that the mesocephaly only occurs in cases with a pronounced ventricular dilation (Cases VII, X, XI), contrary to the brachycephaly seen in the other cases. As appears from the autopsy reports un chapter V, abnormal thickened lepro. meninges have been found in these cases In Case XI, moreover it was considcred possible that the dilation of the ventricles has been caused by a cyst, situated in the cisterna magna. 11 RAY FINDINGS The main findings may be summarized as follow's Skull: The skull was enlarged in most of the cases, to a varying degree. The shape of the skull was mesocephalic in some cases, brachycephalic in others. A thin skull roof as well as open sutures were seen in most of the cases. In minority of the cases the impressiones digitatae were emphasized.

·by KLENK, 1ho was the first to discover and define gangliosides". KLENK showed that this glycolipid contains a substance which he called neuraminic acid. Non adays it has been established, amongst others by the work of BLIX, that neuraminic acid besides being a constituent of the gangliosides, occurs also in certain mucoproteins. According to recent publications neuraminic acid has various important biological functions. Besides neuraminic acid gangliosides contain hexosamine. Further components of gangliosides are fatty acids, galactose and sphingosine. Sphingosine was so named by THUDICHUM on account of the problems he said is presented to the enquirer 332 II. Disturbances of mucoid substances Before describing these anomalies some remarks may be made. of the mucoid substances, the mucopolysaccharides form an ill-defined subdivision. This is obvious from the introduction given by MORGAN at a congress on the chemistry and biology of mucopolysaccharides in 1958: "It must be admired that there is no generally accepted definition of a mucopolysacchande and for that reason, at this stage in the development of the subject, we must be prepared to include a wide range of carbohydrate containing complexes in our discussion" 325. ROSEMAN gives the following definition "In general the mucopolysaccharides may be defined as polysaccharides which usually contain hexosamine and are associated with protein, but which can be separated from protein by relatively mild technics"}}}. The anomalies in the mucoid substances present in gargoylism involve the acid mucopolysaccharides. According to KARL MEYER , a pioneer in this treld, these substances can be subdivided as follows: 1 Polyuronides, to which hyaluronic acid and chondroitin belong. 2 Sulphated polyuronides, to which chondroitin sulphate A, B and C belong as well as heparitin sulphate, also known as heparin monosulphate. 3 Polysulphates of which, up to the present, only the kararosulphates have been identified 335 BRANTE 209 in 1952, was the first to notice an increased mucopolysacchaside content in most of the tissues and organs of gargoyle patients DORFMAN er al demonstrated an excess of mucopolysaccharides in the urine 3 KARL MEYER confirmed this and also proved mucopolysaccharides to be present in excess in the brain tissue. He shored the increased mucopolysacchandes to consist principally of Ino substances chondroitin sulphate B (ChS-B) and heparitin sulphare According to KARL MEYER 34, in the publication wherein one also finds the results of his investigation of two of the patients described by us in Chapter IV (Case VII and XI), the ratio of ChS-B to hepatitis sulphate in the urme is usually 2.1. In cases without ·Chapter VII GARGOYLISM FROM THE BIOCHEMICAL POINT OF VIEW Only in the last decade and thanks to the work of prominent biochemises has it become possible to describe gargoylism in biochemical terms. Thar obscure points have remained unexplained is not surprising when one recalls that the biochemical processes involved are those dealing with the still poorly understood metabolism of the lipids and mucoid substances 1. Disturbances of lipids: Before describing these anomalies, some general remarks should be made. In some countries a distinction is made between lipids and lipoids, i.c. between falts and fatty substances In other the term "lipids" is used to denote both groups and in this meaning it is used here. The lipids can be defined chemically as an heterogenous group of naturally occurring subscances, characterized by their solubility properties. They are non-soluble in water and soluble in fac-solvents such as benzol, aether, acetonc and tetrachlorc-carbon The lipids, can, according to FOLCH, be sub-divided as follows. 1 Simple lipids, comprising the triglycerides and waxes; 2. Conjugate lipids, consisting of a fatty acid, an alcohol and one or several addicional groups. This group comprises the various phospholipids (leci thins, cephalins and sphingomyelins), glycolipids (cerebrosides and gangliosides) and sulpholipids (e.g a cerebroside containing sulphuric acid isolated by BLIX from nervous tissue). 3. Derived lipids, "porental" fatty acid compounds, e.g cholesterol and substances derived from the preceding group, cg. sphingosine, higher aldehydes, fatty acids The anomalies described thus far in gargoylism are mainly of the gangliosides and appear to be of a quantitative nature In 1951 BRANTE 169 found an increase of gangliosides in thc cerebrum of a gargoyle patient. These findings were later confirmed by other investigators amongse others 116 ·by KLENK, who was the first to discover and define gangliosides". KLENK showed that this glycolipid contains a substance which he called neuraminic acid Nowadays it has been established, amongst others by the work of BLIX, thae neuraminic acid besides being a constituent of the gangliosides, occurs also in certain mucoproteins. According to recent publications neuraminic acid has various important biological functions Besides neuraminic acid gangliosides contain hexosamine Further components of gangliosides are fatty acids, galactose and sphingosine Sphingosine was so named by THUDICHUM on account of the problems he said it presented to the enquirer ». 11 Disturbances of mucout substances Before describing these anomalies some remarks may be made. Of the mucoid substances, the mucopolysaccharides form an ill-defined subdrvasion This is obvious from the introduction given by MORGAN at a congress on the chemistry and biology of mucopolysaccharides 10 1958: "It must be admired that there is no generally accepted definition of a mucopolysaccharide and for that reason, at this stage in the development of the subject, He must be prepared to include a wide range of carbohydrate cancaining complexes in our discussion" $25. ROSEMAN gives the following definition: "In general the mucopolysaccharides may be defined as polysaccharides suhich usually contain hexosamine and are associated with protein, but which can be separated from prorein by relatively mild technics"}}} The anomalies in the mucoid substances present in gargoylısm involve the acid mucopolysaccharides According to KARL MEYER a pioneer in thes Field, these substances can be subdivided as follows: 1 Polyuronides, to which hyaluronic acid and chondroitin belong 2. Sulphated polyuronides, to which chondroitin sulphate A, B and C belong as well as heparion sulphate, also known as heparın monosulphate, 3 Polysulphates of which, up to the present, only the karatosulphates have been identified 335 BRANTE 29 in 1952, was the first to notice an increased mucopolysacchande content in most of the ussues and organs of gargoyle patients DORFMAN et al demonstrated an excess of mucopolysaccharides in the urine 32, KARL MEYER confirmed this and also proved mucopolysaccharides to be present in excess in the brain tissue He showed the increased mucopolysaccharides to consist principally of two substances chondroitin sulphate B (ChS-B) and heparin sulphate According to KARL MEYER 135, in the publicatson wherein one also finds the results of his investigation of two of the patients described by us in Chapter IV (Case VII and XI), the ratio of ChS B to hepatitin sulphate in the urine is usually 2:1. In cases without ·Chapter VII GARGOYLISM FROM THE BIOCHEMICAL POINT OF VIEW Only in the last decade and chanks to the work of prominent biochemists has it become possible to describe gargoylism in biochemical terms That obscure points have remained unexplained is not surprising when one recalls that the biochemical processes involved are those dealing with the still poorly understood metabolism of the lipids and mucoid substances. 1. Disturbances of lipids Before describing these anomalies, some general remarks should be made. In some countries a distinction is made between lipids and lipoids, 1 e. between fats and fatty substances In other the term "lipids" is used to denote both groups and in this meaning it is used here The lipids can be defined chemically as an heterogenous group of naturally. occurring substances, characterized by their solubility properties. They are non-soluble in water and soluble in fat-solvents such as benzol, aether, acetone and tetrachlore-carbon The lipids, can, according to FOLCH, be sub-divided as follows 1 Simple lipids, comprising the riglycerides and waxes, 2 Conjugate lipids, consisting of a fatty acid, an alcohol and one or several additional groups This group comprises the various phospholipids (lectthins, cephalins and sphingomyelins), glycolipids (cerebrosides and ganglio. sides) and sulpholipids (eg a cerebroside containing sulphuric acid 150- lated by BLIX from nervous tissue). 3. Derived lipids, "potential" fatty acid compounds, eg. cholesterol and substances derived from the preceding group, e.g sphingosine, higher aldehydes, fatty acids. The anomalies described thus far in gargoylism are mainly of the gangliosides and appear to be of a quantitative nature. In 1951 BRANTE 169 found an increase of gangliosides in the cerebrum of a gargoyle patient. These findings were later confirmed by other investigators amongst others 116 ·bolism of the mucopolysaccharide or of some of its components, or as regards the binding of the mucopolysaccharide 10 protein, etc." From this it appears that the gangliosidosis is not an essential, or at least not the most essenua} aspect of the disease. IV. Summary and ducussion: According to more recent viens, the basic defect in gargoylism is supposed 10 be a disorder of mucopolysaccharide metabolism *, 2011. An excess of mucopolysaccharides has been demonstrated in the liver, spleen, meninges, urine 209 257 276, 19 327 and also although to a lesser extent, in the brain tissue of patients with gargoylism 135. The ganglosidosis, affecting principally the nervous system but also, to a lesser degree other tissues and organs *. 116 149 264 * has to be considered as non-obligatory and constitutes in this sense a secondary phenomenon We suspect the gangliosidosis to be absent in typus E, because here there is no cerebral involvement It may be important to knon whether or not there are differences berween the classical types and typus e as to the chemical nature of mucopoly. saccharides in the organs and urine. This may possibly allon more insight into the interrelationship between the gangliosidosis and the mucopolysacchat dosis Further detailed clinico-chemical and anatomico-chemical research may yield new facts by means of which the crue significance of the undoubtedly imporcant fact that gargoylism is associated with an excess of certain mucopoly. saccharides will be better appreciated Adduronal knowledge may deepen insight into certain other affections. In this connection it should be remembered that gargoylism may be accompanied by cardiovascular sclerosis. A better understanding of the mechanisms resulting in arteriosclerosis in gargoylesm, may further our knon ledge of the aetiology of arteriosclerosis in general ·skeletal anomalies he found no ChS-B in the urine. He found an equal proportion of ChS-B to heparitin sulphate to be present in the spleen, kidney's and brain. In the liver, however, heparitin sulphate predominated. The chemical analysis by KARL MEYER of post mortem material from cases VII and XI (the results of the analysis of case XIII are not yet knoun) yielded the following results: Pausent SET Tinue Total seld of mucopoly. *scch of the bus of detasred dry night CH5-B fracties 11epatitup suiptare fraruos Case VII) M 7 stars 5 months Brain Hepar 0,84% 1.2 % 40%! 5% 30% 9026 K Case XI) 12 stars Brain 2,2 % 85% 15% III. Comparison of the anomalies in the gangliosides and she acid mucopoly. saccharides. The composition of the three substances which are usually present in excess in gargoylism, ie. gangliosides, ChS-B and heparitin sulphate is as follous: Lipada ܚܡܢܬ % eura- Hexos TJDE HraunoDC and Acetate Hero- Sul phate Pound to proteina FOUDE Nos acud CI Galac- + Ganglio sidos Fatty acids Galacto samine rose ChS-B N-acetyl L-Idu. calaco. TODIC Senint aad Heparitin sulphate D-gluco D-glusamine curonic acid 7 290 From this survey it appears that both the gangliosides and the mucopols. saccharides contain herosamine. On account of this fact BRANTE suggests the following pathogenesis "As to the pathogenesis, it is interesting to sore that a connecting link between the gangliosides and the mucopolysaccharides is to be found in their both containing hexosamine in a polysaccharidic structure. The lipids aith ganglio side properties are not seen in esery case of gas colism, a hereas the above described mucopolysaccharides seem to be. This suggests that the ganglioside deposition might be a conssquence, in proper cases, of the mucopolysaccharide surplus, the latter substance perhaps providing raw material for the former. The flooding of the tissuss by mucopolysaccharide may, in its turn, be a consequence of some congenital enzyme disturbance as regards the meta. 118 ·urine bolism of the mucopolysaccharide or of some of its components, or as regards the binding of the mucopolysaccharide to protein, etc." From this it appears that che gangliosidosis is not an essential, or at least noc che most essential aspect of the disease. Il'. Summary and discussion According to more recent viens, the basic defect in gurgoylism is supposed to be a disorder of mucopolysaccharide metabolism 700, ** 595. An excess of mucopolysaccharides has been demonstrated in the livet, spleen, meninges, 279 27 270 *** 327 and also although to a lesser extent, in the brain tissue of patients with gargoylism »). The gangliosidosis, affecting principally the nervous system but also, to a lesser degree other vissues and organs** 116 169 264 * has to be considered as non-obligatory and constitutes in this sense a secondary phenomenon Wc suspect the sanglosidosis to be absent in typus E, because here there is no cerebral involvement. It may be important to know whether or not there are differences between the classical types and typus E as to the chemical nature of mucopoly. saccharides in the organs and urine This may possibly allow more insight anto the interrelationship between the gangliosidosis and the mucopolysacchardosis Further detailed clinico-chemical and anatomico-chemical research may yield new facts by means of which the true significance of the undoubtedly imporcant fact that gargoylısm is associated with an excess of certain mucopoly. saccharides will be better appreciated. Additional knowledge may deepen insight into certain other affections. In this connection it should be remembered that gargoylism may be accom. panied by cardiovascular sclerosis, A better understanding of the mechanisms sesuling in arteriosclerosis in gargoylism, may further our knowledge of the aetiology of arteriosclerosis in general ·skeletal anomalies he found no ChS-B in the urine. He found an equal pro portion of ChS-B to heparitin sulphare to be present in the spleen, kidney's and brain. In the liver, however, heparitin sulphate predominated. The chemi. cal analysis by KARI MEYER of post morcem material from cases VII and XI (the results of the analysis of case XIII are not yet known) yielded the following results: Patient Sex Agc Tissue sacch on the basis of defatted dry tight ChS-B fraction Heparitin sulphate Iration G Case VII) M 7 years 0,84% 1,2 % Brain Hepar 400/ 300 5 months 5% 10 K (Case XI) F 12 years Brain 2,2 % 85% 15% III. Comparison of the anomalies in the gangliosides and the acid mucopoly. saccharides, The composition of the three substances which are usually present in excess in gargoylism, ie gangliosides, ChS-B and heparitin sulphate is as follows Lipids Sphin- Rosine Neura minic acid Herosamine Ieturonic aud Sulphate Acctate Hexo ses Flound to proteins + + Ganglio. sides Fatty acids Galactosamine Galac. + tosc ChS-B N-acetyl L-Idu. galacto. ronic $amine acid + + + Hepari tin sul phate D-gluco- D-glu. $3mine curonic acid 2 + From this survey 10 appears that both the gangliosides and the mucopoly. saccharides contain hexosamine. On account of this fact BRANTE 29 suggests the following pathogenesis. "As to the pathogenesis, it is interesting to note that a connecting link betueen the gangliosides and the mucopolysaccharides is to be found in their both containing hexosamine in a polysaccharidic structure. The lipids with ganglio. side properties are not seen in every case of gargoylism, whereas the above described mucopolysaccharides seem to be This suggests that the ganglioside deposition might be a consequence, in proper cases, of the mucopolysaccharide surplus, the latter substance perhaps providing rasy material for the former. The flooding of the tissues by mucopolysaccharide may, in its turn, be a consequence of some congenital cnzyme disturbance as regards the meta- 118 ·lesion consists of snelling of the cytoplasm, usually followed by calargement. The cytoplasm may have a vacuolar, granular or clear appearance. Generally speaking the extra-cellular lesions are characterized by an abnormal fibrillary structure and swelling of the connectise tissue. It is not clear whether the one category is dependent on the other. Certain organs or systems are usually involved, others less frequently. In most cases the reticulo-endothelial system has been found to be affected. It should be mentioned, however, that cases are knorn, as appears from a publication af GUELI and SEVERI 9, in which typical lesions of the liver parenchym cells are found without involvement of the cells of Kupffer. It is striking that in one of our cases (Chapt V, report No 1), in which the illness was present in the initial stage, lesions were found in both lner parenchym and Kupffer cells, while in another case (Chapt V, report 2), in a more advanced stage, lesions of the liver parenchyma only appeared to be present. Neither from the literature nor from our own experience is it clear whether or nor the anomalies of the R.ES precede those outside this system The pathological processes are progressive. Apart from differences according to the stage of the disease, there are also differences which seem to be urrespective of the stage. Amongst these may be mentioned the absence of neuronal changes in certain cases Changes in the liver cells may not occur; cartilage ossification disturbances may be absent as well as heart, R.CS, cyc anomalies etc. Thus differences are found in the distribution of the pathological lesions, which are dependent neither on the severity nor on the stage of the disease Approaching the essentials of the disease from the histochemical standpoint, one is struck by the difficulty experienced in identifying in many cases the chemical nature of the material(s)s present in the swollen and or enlarged cells Here a distinction should be made between the chemical analysis of the central nervous system and the other organs and tissues In most cases bisto-chemical evidence may be obtained of the presence of an excess of ganglios.de-like material in the neurons The amount of the material in the other organs and tissues, however, docs not coincide in most cases with the degree of cellular enlargement, therefore the products (lipids, glycogen) can only be regarded as accessory More satisfying results are only obtained in those cases in whuch one has succeeded in demonstrating the presence of mucopolysaccharides in these cases the amount of the substance demonstrated appeared to vary according to the degree of cellular enlargement The conception of BRANTE namely that, in the extra-neuronal tissues and organs, abnormally strong soluble mucopolysaccharides are stored, ss in this connection acceptable. Other investigators consider the nature of the stored substances to vary according to the type of cell ·Chapter VIII ESSENTIAL FEATURES OF GARGOYLISM We shall now endeavour to summarize the most essential features of gargoylism by reviewing the following: a. The clinical data, b. The pathological and histochemical data. c. The clinico-anatomical relationship. d. The biochemical data e. The genetic data Ad. a. The vividness of the clinical picture depends on the stage as well as on the type of the disease. There are more signs in the final stage of the disease Typus E is less rich in clinical signs than the classical type, The most outstanding clinical feature and one invariably present in all types, is the typical gargoyle habitus. All other signs, such as the Hurler-face, cardiopathy, hydrocephalus, oligophrenia and mental deteriorarion are not invariably present From the literature the impression is gained, that there is no clear correlation between the several possible signs of the disease. X-Ray evidence of skolecal anomalies can be lacking in cases which otherwis.. show a classical picture 195, 135 Hydrocephalus was described in patients where neither the liver nor spleen were cnlarged 23 156 158 There are also cases in which distinct skeletal anomalies were unaccompanied by hepatosplenomegaly" 199. It should, however, be mentioned that in such patients hepatosplenomegaly may still develop 19 There are cascs known without skeletal anomalies but with hepatosplenomegaly The nervous system may remain unaffected, as has been explained in Chapter 11 From the preceding follows that there are no reasons for assuming that a fixed correlation exists between the various possible signs of the disease Ad b. Gargoylism is, in fact, distinguished by intra- and extra-cellular lesions, without a fixed pattern in respect to topographic distribution The cellular 195 120 ·bance of the eighth nerve seems to be not satisfactorily explained. Perhaps by a minute investigation of the whole vestibular and cochlear apparatus 1 correlaure pathological substratum could be traced. Apart from these details there is the important question whether on patho logical examination a correlative or explanatory subscraturn is to be found los the outstanding clinical phenomenon. the typical habitus of gargoylism. There is no generally accepted opinion about it. As a sule is has proved to be impossible to shox a convincing relationship between the pathological substrarum and the abnormal habitus of the gargoyle patient. In cases associated a ich da arfism, disturbances are often found at the epiphysial lines, yet such clinical and pathological findings may be lacking in cases which exhibit the abnormal habitus. Nerther is there sufficient evidence for assuming a correlation becucen the abnormal habitus and pathological anomalies of the endocrine system Add BRANTE and KARL MEYER shoned that a surplus of mucopolysaccharides is present in most organs. This obviously points to a disturbance in the metabolism of the mucopolysaccharides. Whecher this is a primary or a secondary discurbance, is nor yer known unh any certainty Its aeriology is also as yet unku nown. Most investigators think 16 to be due to an enzymopathy, while others consider a possible hormonal defccr. Ade The heredity data can be summarized as follows. The disease can be associated with the anomaly of a single gene, situated in the X-chromosome, or with no genes, of which the one is situated in an autosome of the father and the other in the corresponding gene of the mother. The single gene defece usually coincides with the absence, the double gene defect usually with the presence of corneal cloudings TURPIN and LAFOUR- CADE 229 regard this as the confirmation of a well known rule that the tuo dosc thomozygous) condition is more extreme than the one dose (heterozygous) condition Summarizing that has been said in ad a, b, c, d, and e, it may be said that the crucial symptom connecting the different types of gargoylesm is the typical habitus The varying symptomatology corresponds with the varying distribution of the pathological lesions In the disease great significance should be attributed to the disturbeu mecabolism of the mucopolysaccharides whether this be a primary or secondary characteristic, the cause of this condition is not jer known A striking conditioning factor is the heredity. The heterozygous condition seems to be less Severe than the hornozygous one.

·The essentials of the histochemical findings may be summarized as follows: It is generally agreed that in the neurones abnormal quantities of a ganglioside-like material are present. Regarding the nature of the accumulated material in the extra-neuronal tissucs and organs, there is a divergence of opinion: Some are of the opinion that it consists mainly of mucopolysaccharides; others assume char the chemical nature of the products varies according to the kind of cell in which it is stored. Ad. c. In Chapter I a survey is given of what is known, according to the literature, of the correlation between the clinical findings and the pathological processes. These findings will not be repeated here. We shall restrict ourselcs to the following additions based on our own investigations: 1. What pathological substratum is responsible for the corneal cloudings> The gencral opinion expressed in the literature is that these are brought about by the presence of gargoyle cells in Bowman's membrane. However, we found in the literature several cases with corneal cloudings without gargoyle cells in Bowman's membrane and other cases in which the topography of the cells does not tally with the distribution of the cloudings, in our own marerial, one patient (Chapt. IV, case XIII) with corncal cloudings, proved (Chapt. V first report) to have a normal membrane of Bowman In this case however a pronounced oedema of the subscantia propri. was observed From this it appears that there is not always relationship between corncal cloudings and the presence of gargoyle cells. 2. In the literacure deafness or diminished hearing is assumed to be a frcqucnt symptom. In Chapter III we stated that on account of psychical disturbances it is diffi. cult in most patients, to escablish exactly whether or not the bearing is impaired. There is also little known in the lecerature regarding the vestibular function of the patients examined. Caloric stimulation of the labyrinth did not produce a single vestibular reaction in many of the patients described in Chapter IV while in most of the remaining patients the impression was gained that irritability was subnormal. All these patients, however reacted to sound stimuli. From this it may be concluded that in several patients there was a dissociated function discurbance of the eighth nerve. In one of these (Chapter IV, Case VII), the pathological findings (Chapter V, fourth report) were in agreement with those of RICCI and ANCETTI , viz., degenerative or thesaurismoric changes were found in the ganglion cells, as well in those of the vestibular as in those of the cochlear ganglion The changes in the vestibular ganglion were not more marked than in the cochlear ganglion. The dissociated function-discur- 122 ·bance of the eighth nerve seems to be not satisfactorily explained. Perhaps by a minute investigation of the whole vestibular and cochlear apparatus a correlative pathological substratum could be traced. Apart from these details there is the important question whether on pathological examination a correlative or explanatory substrarurn is to be found for the outstanding clinical phenomenon. the typical habitus of gargoylism. There is no generally accepted opituon about it. As a rule it has proved to be impossible to show a convincing relationship becueen the pathological sub stratum and the abnormal habitus of the gargoyle patient. In cases associated aith da arfism, disturbances are often found at the epiphysial lines, yer such claical and pathological findings may be lacking in cases which exhibit the abnormal habitus Nesther is there sufficient evidence for assuming a correlation between the abnormal habitus and pathological anomalies of the endocrine system. BRANTE and KARL. MEYER showed that a surplus of mucopolysaccharidus present in most organs This obviously points to a disturbance in the metabolism of the mucopolysaccharides. Whether thus is a primary or a secondary discurbance, is not yet known with any certainty Its aetiology is also as yet unkt nonn Most investigators think it to be due to an enzymapachy, while others consider a possible hocmonal defect. Ad e The heredity data can be summarized as folloss, The disease can be associated with the anomaly of a single gene, situated in the X-chromosome, or with no genes, of which the one is situated in an autosome of the father and the other in the corresponding gene of the mother. The single gene defect usually coincides with the absence, the double gent defect usually sath the presence of corneal cloudings TURPIN and LAFOUR- CADE?? regard this as the confirmation of a well known rule that the two dose (homozygous) condition is more extreme than the one dose (heterozygous) condition Summarizing what has been said 15 ad, a, b, c, d, and it may be said that the crucial symptom connecting the different types of gargoyless us the orical habitus The varying symptomatology corresponds with the varying distribution of the pathological lesions In the disease great significance should be attributed to the disturbed metabolism of the mucopolysaccharides whether thuis be a primary or secondary characteristic, the cause of this condition is not yet known A seruling conditioning factor is the heredity. The hererozygous condition seems to be less sesere than the homozygous one ·Chapter IX DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS A. Diagnosis: The diagnostic criteria for the different types of gargoylism may be summ.i. fized as follows. Type Classic Type Typus E Abortive cases Cases with the discase in its initial stage + + + Gargoyl habitus Hurler's face Hepatomegaly Typical X-Ray findings Sella anomalies Contractures Typical neuropsychiatric disturbances | + H+ + + + + It It It It II + + Cardiovascular sclerosis Splenomegaly Corncal cloudings Tecth anomalies Macroglossia Nail anomalies Hair anomalies Herniae Disturbance in labyrinth function Reilly's anomaly + it + + Present Absent + Opcional The alpha-2 globulin fraction of the blood is commonly incrc.sed. The determination of the nature and amount of mucopolysaccharides excreted in the urine is important for diagnostic reasons However the determination of this parameter is not yet possible in most laboratories on account of the technical difficulties involved.

·Up to the present a simple and reliable method of demonstrating abnormal muantities of mucopolysaccharides in the urine is not available. marronhi. B Differential dugnosis: On account of the varied symptomatology there are points of contacts with many other diseases As such mention should be made of all conditions accompanied by: 1. Hydrocephalus 2. Hepatosplenomegaly. 3 Cardiovascular sclerosis or congenital cardiac malformation. 4 Neurolipidosis, whether accompanied by reticulosis or not 5 Enchondral dysostosis 6 Corneal cloudings 7. Opuc atrophy. & Sella enlargement. 9 Spasuc diplegia 10 Infancile endocrine disturbances. 11 Ligamentary anomalies and joint affections. 12 Inborn errors of metabolism 13 Oligophreny, accompanied or not by dementia 14 Dwarfism 15 Leucocytic granulation anomalies Ad 1 Pathological conditions in early youth which are accompanied by hydrocephalus include hydrocephalus communicans as disease sui generis, toxoplasmosis hominis, obstructive hydrocephalus as a result of meningitis or meningoencephalitis, traumatic hydrocephalus, hydrocephalus as the result of cysternitis chronica productiva, hydrocephalus as the result of a cerebral cumour with obstruction of the aquaeduct, intra-ventricular cumours of the third ventricle with occlusion of the foramina of Monro Ad 2 Hepatosplenomegaly in early youth is seen in cases of congenital syphilis, glycogen-storage disease, definite storage diseases, such as the disease of Niemann-Pick, Gaucher's disease, chronic infectious diseases, such as tuber. culosis, malaria, certain benign and malignant reticuloses, cirrhosis of the Inver, amyloidosis, blood diseases such as chronic leukaemiae and others Ad 3 Cardiovascular anomalies are found in youth, in, for example, progeria, periarteritis nodoss and congenital heart disease ·Ad. 4. Examples include: Tay-Sachs's, Niemann-Pick's and Gaucher's diseases Ad. 5. The most obvious example is the disease of MORQUIO?; also may be mentioned further cystinosis 126 and the disease of ELLIS-van CREVELDS Ad. 6. Corneal cloudings have been described in ao angiokeratoma corporis dif. fusum Fabry '25. A detailed differential diagnosis is described by GASTEIGER and LIEBE- NAM Ad. 7. Opric atrophy is seen ao in oxycephaly; scaphocephaly; Leber's disease; arachnitis chiasmatis, diffuse sclerosis, amaurotic idiocy; disease of Lawrence- Moon-Bicdi. Ad. 8 Sella enlargement is found in intra-sellar tumours; suprascllar tumours; hydrocephalus; some cases of cretinism, a.o. Ad. 9. Diplegia spastica infantilis is seen in several neurological affections in youth, as manifestation of the complicated syndrome of Little. One should be extrc. mely cautious in attributing such like symptoms to anoxia as a result of an abnormal course of birth, Ad. 10. The differential diagnosis from cretinism may be particularly difficult. Ad. 11. Amongst these may a o. be included arthrogryposis and Marfan's disease 274. Ad. 12. As examples may be mentioned Folling's diseasc, galactosaemia, cysteinurca 20.330. Ad. 13. These include ao mongolism, the disease of Tay-Sachs, phenylketonuria and cretinism, Ad. 14, Primary dwarfism should be distinguished from the sccondary form Gargoylism must be differentiated here from the discase of MORQUIO, the discase of ELLIS-van CREVELD and cystinosis As examples of other forms of secondary dwarfism may be mentioned cerebral, hypophyseal, thyrogenic, gonadal, adrenal and renal dwarfism Further it is seen in rickers, cystic fibrosis of the pancreas; infectious processes, ·such as congenical syphilis, tuberculosis and toxoplasmosis; and in many affections of unknown or little understood aetiology. Ad 15 Hereditary anomalies of the white blood cells are described a o. by JORDANS 399. It is important to note here that in juvenile amaurouc idiocy vacuolar and granulu anomalies have been described resembling those found in case goylism 4. MORQUIO'S DISEASE As is stated in Chapter II the absence of storage phenomena in Morquio's disease is accepted by most authors as important in the differential diagnosis from gargoylism As long as the contrary view has not been convincingly proved, this criterion should be maintained As stated in Chapt. II and VIII, there are reasons for not considering corneal cloudings as evidence of accumulation Accordingly, it seems incorrect to change the diagnosis in an others ise clear case of Morquio's disease to one of gargoylısm, as soon as corneal cloudings appear. Looked at from this point of view, the "Spat.Hurler" type of ULLRICH" should constitute a form of Morquio's disease. What is more reliable than the presence or not of storage phenomena in Morquio's disease, is the difference in general appearance in the two discases for, as in gargoyle patients there is also a similarity in appearance in Morquio-patients It is not easy to define precisely this differences in general appearance, In general it may be said that in gargoylism sthenic features predominate, whereas Morquio-patients give a less sthenic impression, X-Ray findings cannot adequately differentiate berrecn those two forms However « may be mentioned that in Morquio's disease the Hurler-face 15 absent, as also the anomaly of Reilly and possibly also the increase of the alpha 2 globulin fraction in the blood serum, perhaps also the abnormal quantity and quality of mucopolysaccharides in the urine is absent Morquio's disease is further characterized by ligamentary hyperlaxity as opposed to the hypolaxıty in gargoylism Morquto's disease, is, like gargoylism, characterized by the recessive-autosomal or the recessive X-chromosomal hercdity, but in addition this disease may also be the result of a dominant inheritance Life expectancy in Morquio's disease is favourable, in this way differing from the frequently bad prognosis 15 cases of gargoylism דר 1 ·Fig. 66, Case XIX, Boy S, age 6 years. w CASE XIX BOY S. (Fig. 66) CASE HISTORY. Patient is the first of two children. Mp and m² are sisters, sm and m? are undersized, fm is thought to be suffering from disseminated sclerosis At the age of one year the patient underwent a double-sided osteotomy for knock-knees. EXAMINATION (at 6 years) Length 92 cms (-22,3 cms), weight 15,3 kg (-4,6 kg), largest skull cir. cumference 52 cms (-0,7 cms), skull length width 17 14 cms Thc head presents no abnormalities, the facial expression is asthenic. Further inspection reveals. a short broad neck, marked kyphoscoliosis de the level of the thoracolumbar junction, a broad thorax with pigeon-chest, * We thank colleague B Bockwinkel that he gave us the opportunity to cxamine this patient

·genus valga and flat feet. The back is very hairy. The musculature is poorly
developed
The hands and fingers are short and broad. The little fingers are radially
curved. There is a marked hyperlaxity of the ligaments of the wrist, hand
and fingerjoints (concertina phenomenon).
The movements in the elbows, shoulder and knee joints are limited.
On slie-lamp examination no corneal cloudings are seen. The fundi oculi are
normal Hearing is normal Vesubular stimulation results in normal reactions.
Cardio-vascular examination reveals a murmur over all ostia, most pronoun.
ced over the aorta The liver is just palpable.
On neuropsychiatric examination no abnormalities are found, apart from
unmature asthenic psychomotılıy.
Fig 67
Hetty clauscles, especially tbe
sternal part
Narrou ed ends of louer subs
F18 68
Generalized plałyspondylia
Fishhookshape of L 1 and 2
Tongue-like progressons of sbe
I ertebral bodies
Backu ard displacement of L 2
and 3

·Fig. 69. Brod and short metacarpals and phalanges. Coarse trabeculation Pseudoepiphysis at met scarpul I. Pointed proximal ends of mets- Carpals Psychological tests show an 1.0 of 96 resp. 119 (Stanfort-Binet, resp Pintner- Cunningham). Electroencephalographic examination yielded a somewhat irregular cracing because alpha-rhychm is interspersed with cheta waves Further a marked reaction to hyperventilation is scen. The E.E G. is considered to be without clear abnormalities. X-Ray findings: Skull. No anomalies Thorax (Fig. 67). Sturdy clavicles, specially the sternal portion The ends of che lower ribs are narrowed. Vertebral column (Fig. 68): Generalized platyspondylia Tonguc-like processes project from the anterior surface of most of the vertebral bodies Backward displacement of L 2 and L 3. Fish-hook shape of L 1 and 2. Microspondylia of I 2. Kyphoscoliosis at the level of the thoraco-lumbar junction. Pelvis. High and small in shape. Coxae valgae et magnae. Hands (Fig. 69). Broad, short metacarpals and phalanges with coarse da. physiary trabeculation, running pointedly from the proximal ends of some of the metacarpals. Pseudoepiphysis ar metacarpal I. Cone-shaped phalanges. There are six carpal centres of ossification visible Laboratory findings: Blood-serum was normal in respect to the following determinations calcium (10,6 mg %), phosphorus (3,6 %), cholesterol (240 mg %), acid phosphatasis (2,5 KA U), alkaline phosphatasıs (9 KA U) Protein spectrum of the ·blood-serum is normal regarding the following values. calcium (10,6 mg%), phosphorus (3,6%), cholesterol (240 mg%), acid phosphatasis (2,5 KA U), alkaline phosphatasis (9 KA U) Protein spectrum of the blood serum determined by means of paper-electrophoresis: albumin: 66,4%, alpha i globulin 1,4%; alpha 2 globulin 8,6%, beta globulin 61%; gamma globulin 17,5% The routine blood and urine examination is normal. Reilly's anomaly is not present Dugnosis Morquio's disease. The diagnosis is based on the following considerations 1 The typical Morquio-habitus 2 The absence of the Hurler-face. 3 Absence of storage phenomena. 4. Generalized plaryspondylia. 5 Ligamentary hypolaxity. Ad 3 Apart from the absence of phenomena indicating neurolipidosis, the underweight also suggests an absence of storage. The liver, hos ever, is just palpable. Should this be attributed to displacement by the thoracical deformity? WIEDEMANN is of opinion that Morquio's disease may be accompanied by liver enlargement or other storage phenomena. Liver biopsy should in our opinion be the procedure of choice in the settling of this question ·SUMMARY The term GARGOYLISM represents a syndrome of which there are a number of types. Typus E, distinguished from the classical type by C. de LANGE and WOL- TRING, is characterized by an absence of neurolipidosis and the clinical symptoms associated with this condition. Clinically typus e scems to carry a more favourable life expectancy and neurological complications and mental deterioration are not detectable. Since in both the classical type and in typus E deafness and sella anomalies may occur, it appears that the primary cause of these signs should not be sought for in the neurolipidosis The classical type is accompanied by an excess of mucopolysaccharides and gangliosides, but in typus E, on the other hand, the latter is probably absent There is much variety in the clinical picture, the most prominent feature being the typical gargoyle habitus; all other signs are facultative A clinical investigation of eighteen patients resulted in the discovery of a number of signs which have not, to the best of our knowledge, been described in the literature, these are namely, leukonychia, a dissociated functional discurbance of the eighth nerve, and an association of a small degree of cranial enlargement with mesocephaly. The neuropsychiatric features may be summarized as follows. 1. A progressive deterioration process preceded by oligophrenia 2. A slowly progressive neurological condition, finally resulting in a spastic tetraparesis or tetraplegia and cortical, subcortical, striate and brainstem lesions. 3. Hydrocephalus in the great majority of cases. There was much variation in the neuropsychiatric picture, for example apathy, as well as erechic patterns of behaviour were found Similarly both motor inertia and restlessness were to be observed. A rather frequently encountered phenomenon was an increased oculopalpebral reflex with extension of its reflexogenic zone Primitive oral libidinous behaviour characteristics were ofron present in the later stages of the disease.

·The part played by the reticuloendothelial system in the disease as a n hole is not easily understood. Anomalies of the RES were present in most cases. Clinico-pathological comparisons brought the following facts to light a Corneal cloudings are not necessarily evidence of the presence of gargoyle cells in the cornea, 5 In our material a correlation was found berneen the degree of cranial enlargement and ventricular dilation. From the biochemical standpoint the disease is associated with either a primary or secondary metabolic disturbance of mucopolysaccharides, the cause of which is unknown In this publication a sex-linked case of gargoylism is presented which was complicated by corneal cloudings, a phenomenon believed previously to be invariably lacking in these cases; it is concluded that as a rule the homozygous condition is more extreme than the heterozygous one, owing to the fact that the former is characterized by a higher incidence of cornea cloudings and a poorer life expectancy It is not considered proven that the homozygous condition is accompanied by a bagher incidence of heaong defects. The disease of Morquio, although in many respects an allied disorder, has its onn typcial characteristics and therefore should be distinguished from far. goylison ERRATUM On page 132 lines 17 and 18, read an association of a small degree of cranial enlargement with brachy. cephaly and a high degree with mesocephaly On page 133 lines 16 and 17, read it is not considered proven that the heterozygous condition is accompanied by a higher incidence of bearing defects 1 22 ·SUMMARY The term GARGOYLISM represents a syndrome of which there are a number of types. Typus E, distinguished from the classical type by C de LANGE and WOL- TRING, is characterized by an absence of neurolipidosis and the clinical symptoms associated with this condition Clinically typus E seems to carry a more favourable life expectancy and neurological complications and mental deterioration are not detectable. Since in both the classical суре E deafness and sella anomalies may occur, it appears that the primary cause of these signs should not be sought for in the neurolipidosis. The classical type is accompanied by an excess of mucopolysaccharides and gangliosides, De P. dan michacother hand, the latter, is probably absenc. and in typus Primitive oral libidinous DCHA VIU. later stages of the disease.

·The part played by the rericuloendothelial system in the disease as a whole is nor casily understood Anomalies of the RES were present in most cases. Clinico-pathological comparisons brought the following facts to light. a Corneal cloudings ate not necessarily evidence of the presence of gargoyle cells in the cornea. b In our material a correlation was found berween the degree of cranial enlargement and ventricular dilation, From the blochemical standpoint the disease is associated with either a primary of secondary metabolic disturbance of mucopolysaccharides, the cause of sbuch is unknown, In this publication a sex-linked case of gargoylism is presented which was complicated by corneal cloudings, a phenomenon believed previously to be invariably lacking in these cases, it is concluded that as a rule the homozygous condition is more extreme than the heterozygous one, on ing to the LUHULOLL AS accompanied by a higher incidence of hearing defects The disease of Morquo, although in many respects an allied disorder, has its ona typcial characteristics and therefore should be distinguished from gargoylism ·LIST OF PUBLICATIONS (in chronological order) 1 Berkhan, O. Zwe. Falle von Skaphokephalie Archiv fur Anthropologie. 34: 8-11 1907. 2. Hunter Ch. A Rare Disease in Two Brothers Proc. Royal Soc Med. 10: 104-116 1917 3 Hurler, G Uber einen Typ multipler Abartungen, vorwiegend am Skelettsystem Ztschr f. Kinderheilk. 24: 220-234 1919. 4 Pfaundler. V Demonstration uber einen Typus kindlicher Dysostose. Muncher med Wochenschr 66 1011 1919 5 Pfaundler, V Demonstrationen uber einen Typus kindlicher Dysostose Jahrbuch I, Kinderheilk 42: 420-421, 1920. 6 Jewesbury. C. Spence, 1 C Two cases 1) oxycephaly, 2) acrocephaly with other cong deformities, Proc Royal Soc Med. 14: 27-42 1921 7. Nonne, M Familiares Vorkommen (3 Geschwister) einer Kombination von imperfekter Chondrodystrophie mit imperfektem Myxoedema infantile Dtsch Ztschr f. Nervenheilk, 82: 263-273 1924 8 Putnam MC, Pelkan, K F A case of scaphocephaly with malformations of the squeleton and other tissues Amer. J Dis Chud, 29; 51-58 1925 9 Schinz H R. Furtwaengler, A Zur Kenntnis einer hereditaren Osteoarthropathie mit resessivem Erbgange Dtsch Ztschr Chir 207 398-416 1928 10. Zierl. F Uber Skeletveranderungen bei der juvenilen Form der Amaurotischen Idiotie Ztschr ges. Neur u Psych 131 400-420 1931 11 Ruggles, H E Dwarfism due to disordered epiphyseal development The American J of Roentgenology. 25: 91-94 1931 12 Helmholtz, HF, Harrington, ERA syndrome characterized by congenital clouding of the cornea and by other anomalies Amer J of diseases of children 41: 793-800 1931 13 Ullech, o Uber die Dysostosis Multiplex (Typus Hurler) Ztschr 1 Kinderheulk 54: 699 1932. 14 Ullrich, 0 Nachtrag zur Arbeit „Uber die Dysostosis Multiplex (Typus Hurler) Ztschr. f Kinderhlk 55: 470-471 1933 134 ·15 Lange, C de Sur un type nouveau de dégénération its pus Amstelodamensis) Arch de Med & Ent 36: 713.719, 1993, 15 Binsuz anger. E, Ullrich, O. Uber de Dysostosis Muluplex (Typus Hurler) und ihre Beziehungen zu anderen Konstitutionsanomalien Ztsch Kinderhik. St: 699-712 1933 17 Nurk Jansen liber Chondrodystrophie (achondroplasie) und uber eine noch nicht beschriebene angeborene Wachstumsstörung des Knochensystems Metaphysåre Dysostosis Ztschr I, ortopädische Chir, 61: 253-286 1934 13 Tothill C. R Juvenile Amaurotic Idiocy, Archoses of Neurol and Psychiat 32 193-209 1934 19 Sheldon W A form of gigantism with splanchromegaly. Proc Royal Soc Med 27 part 2 1003-1007 1934 20 Ellis RW. B Hepatosplenomegaly with mental deficiency and bone changes Proc Royal Soc Med 27 1022-1025 1934 21 Poynton, F). Lightuood, R C Ellss. R. W B Hepatosplenomegaly with mental dehciency and bone changes Proc Royal Soc Med 27 1025-1028 1934 22 Horsch K Uber bereditaire degenerative Osteoarthropathie Arch I orthop und Unfall Chir. 34 536-510 1934 23 Davis, D B. Currier, F P Morquios disease Amer Med Assoc 102 2173-2176 1934 24 Morquo, L. Sur une forme de dystrophie osseuse familiale Arcb de Méd. des Enf 33 5-24 1935 25 Reilly. W A An atypical familial endocrinopathy in males with a syndrome of other defects Endocrinology 19 639 678 1935 26. Golding F C Chondro osteodystrophie Bril. 1 of Radiology 8 457-465 1935 27 Cockayne. E A Hepatosplenomegaly associated with mental deliciency and bone changes Proc Royal Soc Med 28 1067-1070 1935 28 Ells, RWB Gargoylısm (Chondro-osteodystrophy. Corneal opacities. Hepa. tosplenomegaly and mental deficiency) Proc Royal Soc Med 30 1 158-160 1936 29 Elits R WB Sheldon W Caport AIB Gargoylism The Quarterly Journ Med 5 119-141 1536 30 Cockayne, EA Gargoylism (Chondro-osteodystrophy. hepatosplenomegaly, deafness in two brothers) Proc Royal Soc Med 301 104-107 1936 11 Bokkel Huraink A ten Gargoylisme Maandschrift v Kindergeneeskunde 6 449-452 1936-37 32 Ashby W R. Stewart R M. Walker, I H Chondeo-osteodystrophy of the Hurler type (Gargoylasm) A pathological study Brain 60 151-180 1937 33 Galtzer, A La Maladie de Morque Thèse-Montpellier 1937 34 Lange, C de Woltrang. L. Der Typus E Multiple Skelettabartungen, Hepa. tosplenomegaly geistige Rückständigkeit Acta Paediatrica 19 71-79 1937 35 Bouman, H D Gargoylism Ned Tv Geneesk. 81 3001-3002 1937 36 Nordmann, Deux cas de Gargoy lisce Ball soc ophtalm Paris 19 256-258 1937.

·37. Washington. ) A Dysostosis Multiplex. Brennemann Practice of Pediatrics Ed 4 1-6. 1937 38 Gastciger, H., Liebenam. L. Beitrag zur Dysostosis Multiplex unter besonderer Berucksichtigung des Augenbefundes Klin Monatsbl f. Augenheilk, 99 433-447. 1937. 39 Kressler, R. ); Aegerter, E Hurler's Syndrome (Gargoylism) The Journ of Pediatrics 12. 579-591. 1938 40 Reilly, WA Dysostosis Multiplex. Endocrinology 22. 616 1938. 41. Schmidt Eine bisher nog nicht beschriebene Form familiaren Hornhautentartung in verbindung mit Osteoarthropathie. Mbl Augenheilk. 100 616-617, 1938 42. Stens, E. Über eine familiare diffuse Hornhautdystrophie in verbindung mit ciner Osteoarthropathie rezessiven Erbgangs beobachtet bei zwei Geschwistern Inaugural-Dissertation 1938 Freiburg im Breisgau 43 Bindschedler, ) ), Rodier, 1 M. Heinz-Bertsch La Polydystrophie du Type Hurler (Maladie congénitale et familiale) Revue Francaise de Pédiatrie 14 116-134 1938 44. Besdztek, Ilse Zur Kenntnis der angeborenen Miszbildungen des Skelets (2 Falle von Dysostosis Multiplex aus einer Familie und eine andere Multiple Knochenmis:bildung) Monatsch f Kinderheilk 76 305-321 1938 45 Lebenam. L Beitrag zur Dysostosis Multiplex Zeitschr f Kinderheilk 59. 91-123 1938 46 Berliner, AI L Lipin Keratitis of Hurler's Syndrome. (Gargoylism or Dysostosis Multiplex ) Arch, of Ophthalmology 22 97-103 1939 47 Crawford, T. A A case of Morquio's disease Arch of disease in Childh 14 70-77 1939 48 Broekcma, H Een zeldzame beenziekte de ziekte van Morquio Maandschr. v Kindergeneesk 9 240-251 1939/40 49 Meyer, S 1. Okner, H B Dysostosis Multiplex with special reference to ocular findings Amer Journ of ophthalmology 22 713-722 1939 50 Jacobsen, AW Hereditary Osteochondrodytrophia Deformans Jour Amer Med Association 113 121-124 1939 III 51 Engel. D Dysostosis Multiplex Pfaundler-Hurler Syndrome Report of two cases Archives of Disease in Childhood 14 217-230 1939 52 Nissler, H Gargoylismus (Osteo-chondro-dystrophie) Zeitschr f Kinderheilk. 90 271-278 1939 53 Braithwaite, 1 v. Hillar, 1 H Hepatosplenomegaly resembling Niemann- Picks Disease Recovery following liver therapy Arch of disease in Childhood 15 61-64 1940 54 Comby, l Le Gargoylisme Arch Med d Enfants, 43 279-285 1940 55 Bert, ! A. Gubert H L Klinische und anat Untersuchung zur Kenntnis der familiaren osteoligamentaren Dystrophie von Morquio Ann d'anat path 16 1209-1220 1940 56. Ellis, RW B. Creveld S van A Syndrome characterized by ectodermal dysplasia, polydactyly, chondrodysplasia and congenital morbus cordis Arch of Disease in Childhood 15 65-81 1940 57. Ellis, RWB Report of an additional case of Gargoylism Arch of Diseases in Childhood 15 215 1940 ·59 Henderson, 1 L. Gargoylism, Arch of Diseases in Childhood 15 201-214 1940. 59 Engel D Etology of Multiple Delortarties. Amer 1 of Dis of Chsich. 60 562-579 1910. 60 Jacobi. AI L; Waardenburg, P ]. Een geval van dysostosis Multiplex van Hur. ler (Gargoylısme) Mladschr v Kindergeneesk. 9 175.186 1940 6! Waardenburg. P. 1 Uber Dysostosis multiplex Hurler und die dabei vorkommenden Augensymptome Ophthalmologica 99 307-332. 1940 62. Romanus R Chondro-astro-dystrophy (Brails!ord) and its relations to other bone diseases Acta Orthopaedica Scandina ka 11 31-69. 1940 63 Mássim, E Hurlersche Erkrankung (Dysostosis Multiplex.Gargoylisme - dysostousche Idiote), eine Form der Luposdosen Desch Z Verdauungs u Stollw, Krankh 4 124 1910 bt Gespre, ). B Segling.) A. D, sostosis Multiplex I Bone and Jarne Surg 22 171-175 1940 65 Bonetto. 1 D, sostosis multiplex Rev Ped Sao Paulo 11 405-516 1940 66 tesnener, A can Een atypisch gesal y Gargoylisme NTYGS 3459 1940 67 Einhorn N Moore, 1. Ostrum. H. 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Jewesbury, C6 Joannsdes. ... 219 Eichenberger, K 236 Einhorn, N 67, 115 Grumbach R. 143. 25 Jordanis GH W. 313, 127 Elus, RW.B 20. 21. 28. Gtuszkou oka 281 Ioseph. R 134 29. 56. 57. 347. 11. Gucli, u 205, 223 19.23 Josephy H 138 24 126 27, 121 Emandel, RW 229 Guibert. H L. 55 Kammerer "Th 267 Engel, D 51. 59 Guin GH 318 Kaplan M 143 Epps, R P. 317 Gupta, A SMS Das 287 Kenncally E V. 224 Ernould, H ) 110.137.146. Guy, E. 16). 162, 13 38. Klein D. 261 35 237. 14, 29, 31 39 Klenk E 84 310. 22. 26. H. Escribano 326 117 Esteve. R 282 Halperin, SL 91, 37 Kleyn. A de 104. 12. 27 Enende R 170. 181 Harrington, E. R 12 Kny, W. 79 Exposto, L 101, 141 Harvey. R M 89, 19 Kobielowa, Z. 336 Hässler. E 63. 69 24 Koistinnen. A. 269. 26. 33 Farback, HA 110 Hanke. W A 71 Koskenoja, M. 337 Falcbi. G 324 Heinz-Bertsch Kressler, RJ 39.25 33 Fancon. F 126 Helmholtz Hf 12 Kutscher, 211 Fanconi, G 119 Hempelman: Th C 194. Kutzin. H 116 Farren. M) 76, 34 24 Kyriakides, V. 219 Feria, A de 101 141 Henderson, 1 L 58, 201 Findlay, M 319 18. 21 23. 24 30 Labégorre, 296 Furzlı, S 198 Herndon, CN 254, 35, 37 Lackses 234.15 Fittoo-Jackson S 279 Herrault. A PA. 159 Lafourcade, 1 227. 15, 35 Fleischmajer. R 346 Hienz, AH 210, 345 39 123 Loncin 1 F 263, 266 Hoffman, P 327, 25 Lahdensuu, S 93 Fontan 156 15 Hogar MI 90, 109 Forrgel PF 238. 12. 40 Holden, R. 20) Lahey. M E. 124 Cranceschetti, A 261 Hooper. I M D 192. 40 Lamy. M 128. 149. 305. Francois. 197 Horsch, K. 22 308, 330. 12. 38, 39, Frezal. 330 Hauet. R 136 10.42 Fntzsche. H 314 Hubeny, M J 68 Lange C de 15. 31, 80, 81. Fritzsche ſ 314 Hunter. Ch 2 11 13 16. 92. 104.50 13. 14, Furtadenyler, H 9 32 21, 23, 24, 27, 34, Hurler 3.1 3.16.23. 36. 112 132 Gagne. R A 193 24 31 Laroche, 263 Galdo A 277 Hurtado F75 141 Larson S 94 Lasceve 1 293 Galuer A 33 Lausacker H 240 Garasına. B R 310 Irving. R C. 195 Gasteiger H 33, 126 Israel, L. 233 Laves W 188. 27 Let OS 182 Gerlings P104 12 27 Gractau L 198 Jaccoltet, M 95 Lefebre, l. 117, 162. 18.27 Letevte, A 231 Giampalmo A 172 14 10 Jackson, WPM 168 Giampalmo V. 172, 14, 16 Jackson W 199 Lelong, M 134 31 Jacobi M L 60, 12 Leito Teixeira. MF 259 Gilberg E F 318 Jacobsen. AW 50 Lemahieu S. F 151 152 Guespit I B 64 Jammet, ML 128, 149 Lerique, 161, 162, 13 39 Gilland I C 185, 19 Saasen, Murk 1712 39 Giraud P 120 Janssêune, H 242, 37 Lepre, M 297 Garo M 321 21 Jean R 260 Letunga T 104 12 27 Golding FC 26 Telgessma HC 314 12 Levevre A B 278 Goodman H 25+ felke, H 171,200. 270 Levin S 343 Gotham Th 133 jensen, VI 294 Levy. S 103 Grebe H 95 Jeppt. 199 Lezgna. A M V 232 Greta, MA 127 Jervis GA 78. 137, 12. Lichty, I A 94 17. 37 Liebesar 38. 45, 126 ·LIST OF AUTHORS The numbers refer to the list of publications, the italics to the page-number(s) on which the authors are quoted in the text Aegerter, E. 39, 28. 33 Aegler, O 167 Alder, A 160, 27 Amorien, E 268 Ancetti, A 271, 27, 36, 122 Andersson, B 204, 42 Arnould. P 127. 129 Aronson, S M 280 Ashby, WR 32. 24 Aussannaire, M 128. 149 Aycock, E, K 296 Ayres Pereiza, J R 259 Babel, 261 Bader, J P 308 Balcells-Gorina, A 326 Bamatter, F 288. 305, 26, 39, 10. 42 Barker. S A. 276, 23 Barr, DP. 194. 24 Baruffaldı, O 225 Bastos Aquilar, L. 231 Bazelis, R 153 Beebe, R T 238, 12. 34 40 Begaux, 290 Belcour, H 207 Benassi, P 258 Benda, CE. 186 Benedetti, GB 321, 21 Berardinelli. W 289 Berkhan, 01.11 Berliner, ML 46 Bernard, R 120 Bernheim, M 170 Bert, J M 55 Besdziek, Ilse 44 Bindschedler. I 13, 19 Binswanger. E 16 Bushton, RL 284, 22, 27, 33 Bocker, E 77, 32 37 Constantinides. E 219 Bokkel Huinink, A. ten 31, Corbo, S. 213 12 Cordes, F. C. 90, 109 Boldt, L. 100 Costa Marques. 1 231 Bonazzola, N 310 Costello, P 230 Bonetto, ) 65 Cotelessa. G 215 Bonncnfant. I 212 Cottier, H 292, 20 Borel, J 263 Coutau, Mlle 156 Borel-Maisonny, 134 Craig, W. S 250. 13 Bouman, H D 35. 12 Crawford, T A 47 Braithwaite. J V 53 Creveld. S van 56, 226. 12. Brante, G 169, 209, 298, 22. 126 23. 24. 25. 116 117 Cruciani, Ch 143 118. 121, 123 Cruz, M 277 Brockema. H 48. 12 Curings. J N 332 Brouwer-Frommann, H M Cunningham, R C 246, 40 114, 12 Cupit, B F 247, 21 Brown, A 71 Currier, P P 23. 16 Brugsch, H 148, 27 Curtis, G M 91. 37 Buhot, 330, 338, 1S. 21 Burnier. J Penido 196 Dameno. RD 232 Burton, P244 Daumanian, 11 307 David, B 222 Caffey, J 202, 18 David, PR 254 Campo, CI 260 Davis. DB 23. 16 Capon, MB 29, 11 Davis P 290 Cavalca, L 309 Dawson, I MP 253 Cavallotti, A M 189 Decock, G 290 Chanaarond, 155 Delahousse, J 293 Chaptal. 260 Delano, P 68 Chaput, 128 Delong. V 262 Chassagne. P 117. 27 Demoulin. P 135 Chorémis, C 219 Depaulat. A 207 Ciaccai, L 198 Diezel, P B 252, 299, 300, Clara, R 139 22. 23. 34 Clersz. J L 143 Dominguez, ) R102 Cocchi M 154 Donelli A 258 Cockayne, E A 27. 33. 21 Dorfman, A 303. 19 17 Cole, HN 195. 40. 42 Duchêne, H 117, 27 Comby. J 5+ Duhamel, N 107, 15. 31 1*n ·1onesbury. C 6 219 Joseph. R. 134 . 43 Jeune, ML. 170 Gnifiths, S B 319 Edgar. GWF 261, 265 12 34 Gnisbach, MM 327, 15 21 Joannides. Eichenberger, K 236 Einhorn. N 67, 115 Grumbach, R. 113. 25 Jordans, G H W. 313. 127 Ellis, R. W. B 20, 21, 28, Gtuszkou oka 281 29 56. 57, 317, 11, Guel, U 205 223. 19. 23. Josephy H 135 24 126 21. 121 Emanuel RW 229 Guibert, H L 55 Kammerer Th 267 Engel. D 51, 59 Guin, G H 318 Kaplan M 143 Epps, R P 317 Gupta. A SMS Das 287 Kenneally L. V. 224 Emould H 110.137, 146, Guy. E. 161, 162, 19 39. Klein, D 261 35 237. 24 29, 31 39 Klenk E. 84 340.22. 26.34 Eschbano. 326 117 Esten, R 232 Halperin. SL 91. 37 Kleyn. A de 104, 12, 27 Enende R 170. 181 Harrington, ER 12 Kny. W. 79 Expos ro, L. 101, 141 Harvey, R. M 89, 19 Kobieloua. 2. 336 Hässler, E 63, 69, 24 Koistinnen A 269 26. 33 Farback. HA110 Hauke, W. A 71 Koskenoja. M 333 Falch, G 324 Heinz-Bertsch, Kressles. R I 39. 28 33 Fanconi, F. 126 Helmholtz, H, P. 12 Kutscher. 211 Fanconi, G 119 Hempelmann. Th. C. 191, Kutzım, H 116 Farrell Al 1 76 31 Kyriakides, V 219 Feria A de 101, 141 Henderson) L 58, 201. Findlay, M 319,13 21 23 24, 30 Labégorre. 296 Forzh, S 198 Herndon, C N 251, 35. 39 Lackner J 234 15 Fotos-Jackson S 279 Herrault. APA 159 Lafourcade, 227. 15. 38. Flerschmajer R 346 Hieoz, AH 210, 345 39, 123 Concin, F 263, 266 Hoffman, P. 327, 25 Lahdensuu, S 93 Fontan 156. 15 Hogar, M. I 90, 109 Formel PF 238. 12. 40 Holden R. 201 Lahey, ME 124 Franceschetti, A 261 Hooper, I A D 192. 40 Lasy. M 178, 149. 305. Francois J 197 Horsch, K 22 308. 330. 12. 39 39. Frezal, 330 Houet, R 136 40. 12 Fritische H 314 Hubery, M 68 Lange C. de 15. 34. 80 81. Fritzsche 314 Hunter Ch. 2. 11 13. 16 92. 104. 150 13 14 l'urta aengler H 9 31 21. 23 24 27. 34 Hurler, G 311. 13. 16. 21. 36, 112 132 Gagne R A 193 24. 31 Laroche. 263 Galdo, A 277 Hurtado, F 75. 141 Larson, S 97 Lasceve. 1 293 Galger, A 33 Garasino, BR 310 In ing RC 195 Lausecker. H 240 Gasteiger H 38.126 Israel, L 233 Laves W 188, 27 Gerlings. P 104 12 27 Lee, O S 182 Giaccat L 198 Jaccottet M 95 Lelebre. J 117, 162, 16 27 Glampalmo. A 172,14 16 Jackson. W. PM 168 Lefevre. A 231 Giampalmo V 172 14 16, Jackson, W 199 Lelong M 134 31 Jacobi, ML 60, 12 Leito Teixeira M. F 259 Giberg. E F 318 Jacobsen AW 50 Lemahen, S F 151 152 Gillespie. J B 64 Jammet ML 128, 149 Lerique. 1 161, 162. 18 38. Gillsland I C 185, 19 Janseo. Murk 17. 12 39 Gissud P 120 Jansseune H 242. 37 Lepre M 297 Girol M 321 21 Jean R 260 Lettinga T 104, 12, 27 Golding FC 26 Jelgersma H C 344, 12 Lerevre A B 278 Goodman HO 254 Jelke, H. 171, 200, 270 Levin S343 Gotham Th 133 Jensen, VI 294 Levy. S 103 Grebe H 95 Jeppe. C 199 Lezana, AM V 232 Green MA 177 Jervis GA 78. 157. 12. Lichty ) A 91 Liebenam, L 38 45 126 17. 37 ·Liessens, P, 243, 273, 16, Morris, P. 214 Radeck, H 206, 220, 19 35 Mulhim, R. 307 Rodier, J. H. 43 Lightwood. R. C 21 Muller, R. 177 Rodrigues, ). 268 Lindsay, S. 132, 133, 24. Murray, I F. 339, 109 Rohmer, F. 233 26, 27, 30. 34 Romanus, R. 62 Linker, A 327, 25 Nadbath, R, P. 182 Ronchi, O. J. 310 Lokey, J. 275 Naidoo. D 217 Roseman, S. PhD, 333 Loinas, R. D. 124 Neimann, N 129 Ross, J. R. 71 Loper Borrasca, A 326 Neuhold, R 302 Royer, P. 330, 337 Lorincz, E 303, 19 Newell, F. W, 269,26 Rowntree, L. 67. 115 Lowenthal, A. 241, 18. 111 Nisbet, N. W. 247, 21 Rudder, B, de 85, 99, 37 Lucci, R. 256 Nissler, H. 52 Ruggles. H E. 11 Lund, H. Z. 195 Ni. AA 112, 22, 37, 40 Ruiter, M 125, 126 Lundstrom. R. 121, 40 Noller, F. 106, 107 Lurie, L 103 Nonne, M 7. 31 Saufer, A 280 Nordmann, J 36 Salam, M 306, 312. 107 McDonald. R. 166 Nordman. RM 284, 315 Sancher Villares, E 326 McGillivray, R C. 183, 27, Notter, G 344 Sapuppo. C 221 35, 40 Noufflard, Mlle 105 Sarın, L. R 287 McGregor, A R 201 Sartori, E. 187, 225, 251, McKusick, V. A. 274, 334, 19 342, 13, 17, 33, 40. Okner, HB 49, 27 Schaichet. M 130 109 Opie, WH 166 Scharf. 73 Maddox, J. K. 111 Oranger, A 297 Orsini, A 120 Schermann, J 268 Magee, K. R. 158 Ostrum, H, 67 Schierwagen, E 206 Maloney. I. D. 76 Schinz, H. R 9. 97. 37 Marchand, L. 263 Schmidt, MB 87. 21 Marchand, 156 Pau, H 220 Schmidt. 41 Marck, Z. 336 Paufique, L, 181 Schneider, R. W 195 Marie. J 105. 263 Paul Jr, J. R 296 Schonenberg, H 245 Marini, G. 309 Pelkan, K F8 Schwarz, H 193 Markowa, M 336 Penido Burnier. I 196 Scott, RB 317 Marateaux, P 308 Périer. R 128 Sear, HR 111 Marshall, A HE 283 Perrimond, G. 120 Seitelberger. F 272. 301. Mathis, M 267 Pfaundler, V 4. 5. 24 302. 22. 23 25. 26 Mathos, CA G. 278 Platt. R304 Seringe, Ph 105 Polanska, B. 281 Mathyus, A 255 Severi, F 205, 223. 19. 23. Mau, H. 316. 26. 33 Pompen, A 125, 126 27, 121 Maurice, P. 105 Pomponio, N 286 Seyss R 163. 18 Menger, W 179 Pontoriers, N. 286 Sheldon, W. 19. 29 11. 31 Mercer, R. D 195 Potier, R 143 Siegling. ) A 64 Merlen, G 191, 228, 18 Poynton, F 21 Sjolin, KE 174 Merliss, R 123 Prick-Hoefnagels. J AM Sjolin, S. 203 Metha, RS 328 164 Skahen, R 133 Meyer, K 327, 335, 19, 23. Prick, I J G 150, 164. Skoog T. 203 25, 26. 117 291. 322, 23 Smith, EB 194. 24. 34 Meyer, S ). 49, 27 Putnam, MC8 Sonze e Silva. O E de 231 Midulla. M 324, 29. 44 Spence, J C6 Millar, ) HD 53 Rabacy, M 197 Stacey, M 276. 23 Millman, C. G 184. 40 Radermecker, ) 239 Steen, RE 331 Monbrun, A. 143 Randall, J 279 Stens, E 42 Moli, S Li 190 Reilly, WA 25, 40, 70, Stewart, RM 32 Monnet, P. 178 132, 133, 21, 24, 27. Stocckel. KH 72 Moore, J 67. 115, 24 31. 34 Strauss, L 122. 131. 301, Moore, J R 115 Reiser, R 123 24 26, 27 Moore, Sh. 194 Reviglio, GM 176 Strauss R 123, 23, JS Morgan, W T 325 Ricci. V 271, 27. 36. 122 Suvanto, E 337 Moro, F 311 Robinow, M 323 Swoboda, V 173 Rochat, G F 82, 83, 12 Morquio, L. 24, 126 Szmigiel, C 281 ·Tandberg. O 204. 12 Tempesta, M 295 Terragna. A 285, 26, 30 Thannhauser, S 201,320 Thomson, 165. II Thys, L 139 Tingey. A 284 Tolentino, P 215, 285. 26. 30 Tondut, Th A 293 Townsend Coles, WF 235 Turpin, R 117, 227,13 27. 35 39, 123 Tuthill CR 18 Valente, N I 278 Vandendorp, F 228 Veasy, CA 74 Verger, . 156 Vesterda! 165 Viala, J L 260 Valtel, M 170. 181 Villa A. ML 309 Volk, B W. 280 Wiedemann, H R. 145, 147, 216, 249, 25 27. 28 29, 32, 33, 37, 39, 131 \Vilde, R 218 Willemin-Clog, L 142 Wolff, D. 83. 27. 34 36. 37. 10 Wolff. 1 108 Woltring L 34, 12, 34. 111. 132 Worth, T. 124 Wyers, H J G 125, 126 Yakovlev, PI 76 Yannakos. D 219 Yi-Yung Hsia. D 329 Uinch. O 13. 14 16. 97, 216. 12 15. 27. 37 39 127 Undrit: E. 248 27 Ungari. C 295 Urban, N 206 Usman, L. L. 257, 23 25 Waals v d, H G. 322 Waardenburg P.) 60, 61, 118. 12. 37 Wackenheim. . 233 Wagner, F 175 Waldman, P. 214 Washington. I A. 37, 11 Watkin. ) H 32 Weidenmüller, HS 113 Westricten. A van 66. 12 Wettler, H 208 Wexler, D 180 Whittick, J W 184. 40 Zeeman. W. P. C. 86. 12 Zellweger. H. 130. 198. 306. 307. 312, 19. 106. 107 Zierl, F 10 Zymars, M C 280

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