·Translated from the Danish
by
ANNA LA COUR
re Classica

·HANS RAHBEK SØRENSEN
HYPOSPADIAS
WITH SPECIAL REFERENCE
TO ÆTIOLOGY
HEREDITARIAE
HUMANAE
DOMUS BIOLOGIA
em
UNIVERSITATIS
HATNIENSIS
MUNKSGAARD
1933

·DENNE AFHANDLING
ER AF DET LÆGEVIDENSKABELIGE
FAKULTET VED KOBENHAVNS UNIVERSITET ANTAGET
TIL OFFENTLIG AT FORSVARES FOR DEN
MEDICINSKE DOKTORGRAD
Kebensbau des 19 februar 1933
P PLUM
pro decen
COPYRIGHT 1933
BY
EINAR MUNKSGAARD COPENHAGEN
Printed 1 Dedmark
Andreassen & Co. Bogtryk

·PRLFACI The studies to be reported were commenced 1946 during my home of service in Surgical Clinic C of Rigshospitalet Copenhagen at the initiative of Professor E Dahl Iversen VD The essential part of the material however was collected while I was assistant to the mersils Institute of lluman Genetics To ils chief Professor Tage kemp VID and to Professor F Dahl Iversen VD I owe i debt of gratitude for aduce guidance and practical assistance rendered in the course of my studies The patients were dernied in part from 1 ying in Deparlment B of Rigshospitalet in part from the following surgical departments Iniversity Clinics C and D) of Rigshospitalet Departments I ind i of the Copenhagen Cits Hospital Departments A and D of Bispe bora llengual the Anrhus University Clinic and the Aarhus (mmunls Hospital Inn indebted to Professor I bbe Brandstrup V Proſes xor / Dahl Iversen VD Professor Shargaan! VID) Profesor Otto Sukelsen D Torben houdtzon VID Professor Jens regert VID) Professor II Hetlev Ibrahamsen D Professor 1 Alk, er 1) and J I abricius aller for hung hindi ermitled me to use the casc records from their departments I urthermore I want to thank those colleagues ulio lave eximineel patients for nie afforded me impulses through discussions or helped in other wiss Quite particularls I im genteful to Johs Dossin / ) for assistance in connection with the possimptominte similarity tests and to 111 lleimeg Larsen D for buidance in statistical tallers ·Mr Ole 7 onnisen Frederiksen afforded help in drawing thic pedigrees and Miss Gerda Olesen un typing the manuscript My thanks are due for economic support from P Carl Petersen's Fond and for a grant awarded me by Vera og Carl Johan Michaelsen's Fond after the investigations were concluded Copenhagen, February 1953 Ilans Rahbek Sorenschl ·(O\TI.IS Ingr INTRODUCTION Ohject of the present study 9 Chapter 1 VORTHOS OGS Il urding 13 Writers grading 13 Diagnosis 15 I rroneous diagnoses in the present material 16 Writers morphological studies – Incidence of ret neil testes in las pospadins 19 Chapter 2 INCIDI \CT 23 Previous investigations 23 Writers investigations Determination of the incidence among nei born babies 24 Gitneral alcals of the incidence found 25 Incidence of the various degrees Previous investigations 97 Writers investigations 27 (hapter 1 I INTIIT) 27 Previous investigations 29 Writers insestigations Frequency of marriage imong hypospadians 80 Sexual function 30 tertility and morpholons 32 Chapter 1 PRI VOUS 57 DILS OS TIL HI RODIT) OF POSPIDS Chapter 5 VODI 01 COLLECTING, AND LIVING THE I'LSTYT SI RIES 43 Selection of the probands 43 I satination of the prohund material i ffectiveness of the examination 11 Twin material $ ·8 Page 16 46 Chaler 6 WRITERS VATLRIAI The proband material families examined Families partially eximine Families ruled out Families of interest but not belonging ta tle malerul The twin malerial 59 60 60 61 Chapter 7 ELAI UITION OF WRITI RS YATHRIAI Uniformity Incidence of the defect among the probands relaties Concordance and discordance among twins Heredity 63 63 6+ 67 60 68 63 Chapter 8 REL \TION Or II) POSP DIAS TO SOVE INTERSI \UALITY THEORIES Goldschmidts intersexuality theory Writers investigations Sex distribution among the offspring of hypospadians Sex distribution in sibships including hypospadians Occurrence of sex linked recessive characters in hypospadians Hormonal intersexuality Writers investigations Chapter 9 LTOGENOUS ETIOI OCICA I ACTORS Il riters investigations Combination with ollier malformations 79 -3 7+ 6 7 P9 Chapter 10 CO\CI USIO AND DISCUSSION OF TIF I RACTICAI SIGNIFICANCE OF THE RESULTS Conclusion Eugenic measures Operative indications AL A1 8 62 SUVIVARI XI SUVVARI IN DANISHI 87 REFERF\CES 90 ·INTRODUCTIOX Ilypospadias is a congenital defect which in sciere cases may be a cause of great concern to the patients and their parents The worry is not only due to the difficulty of micturition and the fear that the patient will he unable to lead a normal sexual life, but also to the widespread idea that there is something inferior about malformed genitals This inferiority complex is often led by the attempts of well-meaning parents to hide their child's defect Surgical correction has been connected with great difficulties, and cien though the results are constantly improving, a sciere case may require several operations The deformity is generalls considered anberilable by Mendelian dominance perhaps with failing minifestation This opinion is based on the case reports of more or less thoroughly studied families Therefore, the mode of inherilance has not yet been definitely established Object of the Present Study This study was designed munly to cluckdate the heredits liga proband studs including an investigation of the genclic relation be. tween the various degrees of this deformity Thus involved a determinttion of the incidence of the defect and of the fertility among the pa. tients in the course of the study inorcoser, it proved necessary to look for a tulogical factors ollier than genetic ones In addition it was endeavoured to elucidale the relation of hyjnopadas to roldschmidt's intersexuality theory by statistical generlogical methods This volume does not by any means prelend to be a monographı on ·10 hy pospidias Vany aspects are not considered an analysis of the lher? peutic results imight have been desirable But the material was not suit able In part t is derived from a period during which great adiances have taken place within 1 lastic surgery and in part the surgical me thods used were so varied that an evaluation of the results would have Deen difficult On the other hand the material may serve in evaluating the operatie criteri?

·Chapter 1 MORPHOLOGY Hypospadias i Kenerally defined as the congenital opening of the tirethra on the under side of the penis (Kaufmann (1886), frangenheini (1928), Schneider (1928). Johnson (1929), Jeanbrau (1937), VcCrea (1910), Goldstein (1916) ) Thic abnormal orlice m.is bc anyuliere between the glans and the perineum so that the deformity may be more or less pronounced The appearance of the prepuce is characteristic It is split on the inferior aspect and siluated dorsolaterally, forming a hood oser the glans The latter is often somewhat plump flattened in the antero-posterior direcfion, and furnished with groove on the under side or, inare rarely. with the fossnastoularis ending in a blind procket on the top The frunulum is absent P'roxinal to the abnormal opening the raphe de Sales into two more or less well-defined branches extending laterally .and terminating on the dorsal spect of the prepuce, at times in one or two rosette-shaped figures, "les your dorsaux" (Ombredanne (1932)) Between the glans and the opening there is a mucosa-lihe strip of shin overlying a scar-lihe bine causing a downward cunature of this part of the penis Thus curvature is sometimes increased by the tension of a Short urethra and oneris ing skin wuch also pulls the corpora cavernosa bich towards the perineum The curvature may be complicated by torsion of the body of the penis in severe cases, the penis is insariably sin iller than normal but its smallness is due in part to the curvature 113 mii le alioun by successful surgical repair Thie scrolum is always cleft when the opening is situuled proximil to the peno-scrolat junc. lion, but in mild cases it may be normal or slightly trifid In other words lypospadias 18 nol only a localized uretlır. defert. but malformation of the male external genitals, Onbrddanne (1992) puts at "Les formes de I'lypospadias sont les differents degrés de la plaie de la face inférieure de la verge".

·or immediately proximal to the latter on the distil one fifth of the pendulous part (2) Penıle hypospadias with the opening situated more proximal at any point up to the penoscrotal junction (3) Penoscrotal hypospadias with the opening in the inmediate vicinity of the penoscrotal junction (4) Perineoscrotal hypospadias with the opening between the two halses of the cleft scrotum or behind it In classifying a case it is important to consider the situation of the opening in relation to the proximal part of the genitals without trying to straighten the curvature of the penis If that is attempted the opening is pulled forward the urethra is tightened and this gives a false im pression of a milder case No such regard could be paid in a classifica tion based on case records In the majority of cases however the classification did not cause major difficulties but it cannot be ruled out that exceptional cases may perhaps have belonged to onc of the neighbouring groups 1o designate the morphological transitions between normal genitals and hypospadras the following terms were used Low seated opening The opening is situated on the glans It may be intranavicular but it is separated from the fossi navicularis by transverse fold The prepuce is normal or slightly cleft Fig 1 Juxtaglandular hypospadias bordering on penile hypospadras Stenosis of opening ·15 Fig 2 I'm nos rotal hipospadys rlos Perineoscrot il luy pospalis Short urethra The penis is flexed downwards but the openin, is of a normal situation The prepuce my Ine slightly cleft Diagnosis As a rule the charncteristic appear ince of the malformation whes the diagnosis an easy matter here have been cases loncier in which palients with hypospidias have spent a short or long period of their lives an girls because an erroneous ser diagnosis has been made nt buurth (Teugebauer (1908) homics (1912)) an error which has been made in Ieninnrk too (Sand (1910) When hypospadus is associated with undescended testes there is an possibility of erroneous dignosis As emphasized by Sanil (1910) ex Iloritory laporotoms is required to determine the sex with certains This opinion is shared by Ilooks (1919) At about the same time he received innsatients with hypospadis ang bilateral cryptorchidem 1 xploratori tuparotoms showed the connds to be ovaries in both cases This made him assume a more actre altitude in examining Ins pralients with tapospidus and in the cours of a furly short time he di ignosca une case of true herma hroditest (with a left sided ovars ind a right sided testis) Inother one not vet completelt csamnined was clienci to biseosotestes To an explorators inlenention insolver even slight risk His therefore } rotuhls the best thing to ascert in the nature of the hands ·16 Defore undertaking plastic reprir of the gentals in cases of hy pospadias associated with uni- or builateral cryptorchidism. Injection of gonadotroplun at the age of puherty may perhaps show The trend of the development (Dia: (1913)) It must be inentioned ini passing that injury may tend the genitais the exact appearance of liypo- “]).atf1.4 Erroneous Diagnoses in the Present Material. In Denmark the risk of a wrong diagnosis in hypospadias is probably slight to-day The midwies are well educated and physicians are very often in altendance If an error does happen, there are great chances of making it good at the prophylactic inſant examinations, medical examinations of children belou school age, and the examinations by the school medical officers In one case of the present series a wrong sex diagnosis was made in 1928 Case with wrong sex diagnosze (the proband) in Pedigree 77) At birth the sex was stated to be female In childhood, however the parents realized that "something was wrong with the genitais" The patient had no medical ex. amination, was reared as a girl and affended a girls' school About the age of 14, however, the patient became strangely coarse, and when the sexual desire wakened it was clirected towards girls The patient was very unhappy, believed for a time that he was homosexual, but gradually realized that he must be a man At a medical exumination for another reason, the physician noliced the genital condition and took action An application for a male Fig. 4 Patient with penoscrotal hypospadias Probe in the urethra Penis partly erected the patient was reared as a girl ·17 nume was filed (through Professor Sand of the University Institute of l'orinste Medicine) and granfeul The patient was then admitted to hospital for plastic surgery. Admission examination The 19-year-olti patient is cornew hat belon me dium fight, built and hairing masculine Lxternal genitals (Fig ) Penis greally flexed dos nuards and gives the appearance of being rather wall, but the corpora cavernosa are well de veloped the penis is saluated between the two halves of a slightly cleft seroturn The prepuce is most developed on the dors il aspect, absent on the under surface The glans is clelt on the under side The orifice is situate! between the anterior part of the scrotal has rudimentary vagina Tesles normu on palpation, with epididymuides and vad deferenha, and tuated in the scrotuit Digital examination of the rectum An org in suggesting the prostate is pulpable Only one case of pseudovaginal lypop dus occurred in this series This type differs from the others by the persistent rudimentary vagina Morphologicalls it must therefore le considered a peaal vriels which cannot be included in the probind material as a whole As the utent however, as living as a woman, the case history will be briefis reported The pro l'alient with prendovaginal hyposprendis living as a woman band in Pedigree 17+) The pallent (HR 5) bad fred all the time as a Woman but of puberty the breasts failed to develop, instead growth of heard set in the patient denteel having any hido, Iraif been engiged w the fentate purtner) for u time Recently norlules had descloped in both groins On a mission, at the age of 29, the patient Rove u masculine impression The voice was deep and the breasts undeveloped flairing masculine with vigorous growth of beard and biry ches! Muscle, well developers Internal genitals Mullus 5 cm in length, as thick as the file finger TKU Kenital folds itatea loy bodies, as large as pigeon's eggs, which felt like festes with epithymides. The opening of the urethra was between these folds Behind the opening, there was a numentary aging, almout 2 cm deep eniling in u blind procket Digital examination of the reclum revealed a and shaped structure ex tending from the floor of the rudimentary vagina towards the abdomen Exploratory laparotomy showed a peiris of masculine appearance, with dern reclosedicil pouch, but no signs of a ulerus or its appendages Tie gonus were seen on both sides They were somewhat atrophic festes, which otherwise fusheel normal, will epiilismuides and was deferentia Biopsies were obtained from both sides, and histological examination showed test kular fissur with atrophy, filirosis, and an inescascil number of Leydig's cells The patient was made acquainted with the condition change of nante i proposal and the patient sprted, but after having brenrelerreu to l'rofessor Sand, she changed fier mind and went on living her life as woman hen seen later, the patient states that the growth of beard Lottern her mout Ilahi Wetu a ·18 Tlic patient has a sister who is hospitalized and showed the sine condition In this case however the testes had not descended In addition there is 1 eise of real dignostic error, i case of true hermaphroditisin diagnosed as hypospadias True hermaplıroditism diagnosed as hypospadias (the proband of Pedigree 175) Hospitalized for the first time it the age of six showing downwar! curvature of the penis with a dorsal prepuce The glans was clell on the under side and from this side band shaped structure extendil to the urethral opening which is situated on the anterior aspect of the partly Jeft scrotum The right testis was in the scrotum whereas the left one was in the superficial inguinal ring the downward flexion of the penis was corrected At the age of 13 the patient had Jelt suled orchuomobilization and fierniotomy The teslis was found to be inserted outside the superficial Inguinal ring There was a congenital hydrocele the abdominal part of which contained omentum 1 ollow ing isolation of the spermahc cord up to the deep inguinal ring the teslis could be mobilized almost down into the scrotum On several subsequent occasions the patient had plastic operations to re construct the urethra. At the 4 of 15 the patient returned because of increasing swelling of the left half of the scrotum Puncture yielded a lot morrhagic fluid A tumor was Fug 5 Patient with pseudo vaginal hypospa lias Ining as Honiin Fig 6 A case of true hermaphroditism Testis on the right osary on the left I unnel slıyped urethral opening on the anterior aspect of the scrotum ·19 pifpable in the scrolum The palunt was admitted and lund esploratory laparotomy which showed the "lumour' to be a ultrus In addition, I allopian tube and a normal orary with follicular cysts The bleeding has presumably teen an ovulation hleeling the right gonal was non cxposed al prove I lo be a normal leslis with epuuty mis and was deferens Biors Specimens of the gonads on both sides showed orarian tissue on the left ind testicular tissue with spermiogenesis on the right A few weeks later the uterus tube and ovary were removed 1 xamination of the operative specimen revealed a small cauty on the uterus with endometrium in the early proliferalise piiuse a normal tute ind a normal ovary This case raises the question whether the probund material may be consulunud uniform despite the even transition is regards the appear ince of the external genitals In several cases the hypospadias may have buon combined witlt undescended testes and the true nature of the hans is not hown I rulers Vorphological Studies Incidence of Retained Testes in lyospadias The incidence of undescended testes in the various degrees of hypo padiis has not been nutitrie illy elucidated in an ilsis of this nature is of particular interest to the present study since lulateral cryptor budistui tint amount to sterility (Torben Svenit Ilansen (1915)) An increased incidence of cryptorchidism in pospadias would therefore contribute to reducing the fertililt ind consequently influence the trinsinin son of morbid henes if any Vorover it would die interesting to retain whether an increased 1 unce of this piestomenon is peculiar to the severe forms of the condition is this might justify I sharper duision of severe from mild Thus an ses i lased on the case records for atients with hypo- » dis admitted to the University Hospull Copenh on Surrient Departments ( and 1) the (openhusen (its Thospital Surgical Depart ments and the Best sljerg Hospital Surgical Departments A and 1) and the Surkea Dej kriments of tt Aarhus innerst (linic and the Aarhus (munts llospital The maternl includes also cases of hyposa dias excurring among the point to ends relatives The polients used inter as probands were seen jersonally wherers in the remaining hill in iints mild ons - the dotn are based exclusieis uncine records The nintendis set out in Tible 1 xhich shows that in a certain num bar al cases the records do nittite nether the testes had descende ·20 to the scrotum As these cases are counted as normal, the calculated incidence of cryptorchidism represents ninunum values the material is classified not only according to the degree of hypospadins, but also according to age at the time of examination, since undescended testes often descend spontaneously during boy hood. The results may be compared with other Danish studies of cryptorchidism at various ages Perusing the record cards of the School Medicat Officers, Engberg, in 1918 found 1535 cases among 34,000 bozs aged 6-7 years, I c an incidence of 451 % in this age group In Engberg's opinion, however, the incidence is somewhat lowcr; he believes that some of the cases have been pseudocryptorchidiyin A follow-lip exami- Table 1. incidence of cryptorchids in his pospadias The material is classified according to the degree of hypospadias an patient's age Testes Unlercepiled testes Megree or Bu prosnachas Lacking data Tout cases Experient number 1 unclescendent testes Scrotum right) litt Tolls total 24 2 6 3 11 Jurluglandular 0-9 yrs 30 -17 yrs. 18 and over Total 75 17 31 110 21 40 493 0 32 D 20 9 123 37 2 3 11 171 5 47 1 1 4 l'entle 0--9 yrs 10---17 yrs 18 and over Total 2 1 1 4 6 10 5 6 0 72 008 003 21 1 1 3 5 27 083 12 1 1 4 7 3 12 4 1 25 8 18 1 13 D 12 009 15 2 1 1 31 3 2 11 17 51 1 34 Penoscrotal 0--9 yrs 10-17 yrs 18 and over Total Perineoscrofa! 0-9 yrs 10--17 yrs 18 and over Total Total cases 0-9 yrs 10---17 yrs 18 and over Total 8 3 2 3 2 2 1 2 5 3 4 13 6 6 0 59 009 003 2 13 2 5 5 12 25 71 26 106 28 4 4 3 2 2 5 3 32 8 5 40 70 738 0 60 0 35 11 188 #1 18 22 45 8 33 274 ·21 nation of a large number of these boys after they had passed their 10th year roscaled spontaneous descent in two thirds Perusals of the medical conscription protocols (cryptorchidism is a ground for rejection) Ingberg (1948) and Torben Svend Hansen (1913) found 527 cases among 108 )13 men ringing in age from 18 to 30 that is an incidence of 4 86 per thousand From a report on the worh of the Baby and Child Health Stations (Gori" (1931)) in estate may be formed of the in cidence of cryptorchidism in the youngest age groups In 1918 a total of 10 402 children were examined at the Child Ilealth Stations of them 108 showed cryptorchidism which is in incidence of 2 08 % provided that half the children are boys At the Baby Health Stations where habies under one year of age are examined the corresponding incidence was only 1 12 % These values must be regarded with some reserve if only for the reason that the mothers can have the prophylactic examina tions carried out also by their own physicians if they want them done at all This material is therefore selected and the criteria of selection ire unhnown On the basis of the studies mentioned the following norinnl values will be used in the present paper 0- 9 years 45% with indescended testes 10-17 15% 18 years and over 0 5% with From these normal values which must be considered rather high the expected number of cases of hypospadi is with undescended testes was calculated for the individual groups The results are given in the list column of Table 1 Table 2 Increasing inci lence of undescendie i testes with increasing secrets of hypospa liis I in Juxtagl indulat bypospatllas 20) lenile hypoxpili 18 52 1, in Pin 14 51 271 17 31 543 54 37 17 39 7421 22 82 24 40 10 58 ( cdovrat? les gadis 33 33 Ierincoscrutiny plaas 48 00 Total cases 51 16 42 ·22 Table 2 shows how many times the actunl findings exceed the expected values in the different inrieties of liypospadias In addition (1) the incidence P() and its upper and lower confidence ummd Pm were calculated according to the formula -#(*++*** (n-1) 11 221) hemp (1142) 10 11 12 The incidences found do not apply to all series of hypospadias is the patients age influences the incidence of cryptorchıdısın in the groups penile perineoscroful ind penoserotal hipospadias howcier the values show that the incidence of retained testes is increased in hypospadias the lower confidence limit being higher than the 43% in the youngest age groups of the normal series In juxtaglandulir hypospadias the lower confidence limit is lower than 45% The actual number with undescended testcs was therefore compared with the expected number by means of the x test The result 1s 001 <p < 0 02 (f=1 = 576) The <ifference is not significant but extremely prohibie particularly when considering that the normal values are rather high In 48 9% the cryptorchidism was bilateral In a series of 256 cases Bjerre (1935) found 36 7 % bilateral in series of this small size the difference is not real As Bjerre found only 16 3 % llateral among 900 cases froin the Internture the incidence of bilateral cases in hypospadins may still be increased Jt will be seen that an increased incidence of cryptorcludism characteristic of all degrees of hypospadias increasing with increas severity of the hypospadias This quantitative difference does not afford any justification for 1 morphological division of the mild and severe rieties The increased incidence of cryptorchidishi and the possible relative increise in bilateral cryptorchidisin entails reduced fertility in hypo spadias particularly in the most severe degrees ·Chapter 2 INCIDLACI Previous Investigations Hypos adias is a fairly common defect Various authors have ana Issed the incidence but the results have varied owing to inadequate selection and a too sinall size of the materials in seteral instances The highest incidence has been reported by Alccrea (1910) Anong 150 men he found hypospadias or a low seated urethral opening in 1% The material is too small and nothing is stated as to how it has been collected Wowry (1919) found 2 among 10 000 soldiers suited only for Tumited military service It cannot be ruled out that hypospadias may have been the cause why 1 soldier has been declared unfit for full mali tary service This material is therefore possibly selected for the same reason the onlyses of the incidence among patients with urinary tract discases are of little value in series of this category Barragan (1911) has found 26 cases among 14 000 and Burckhardt (according to Schner ter (1928)) 22 aniong 1819 The best materials are Rennes (1831) 3000 recruits among whom 10 cases of hypospadius occurred and Campbells (1947) post mortem scries of 12 280 children with an incidence of hyos dias of one in 1100 boys Tofmolls finding (cited by I angstein (1910)) of only 13 cases in 101 446 children (the largest series reported hitherto) must be due to insufficiently thorough examination Tengebatter s (1908) incidence of one in 1000 15 presumably merely in estimate and it is not clear hon von Schurer his arrued at his rare of one in 60 Dirths The incidence of his pospadias in Denmark has not been analysed I rom a report on the work of the rophylactic Child and Baby Health ·2 Stations (Gort: (1951)) it is apparent that during the first year of their cxistence --- 1918 -- 17 cases of hypospadias were found among 822 babies under one year of age (Baby Health Stations) and 7 among 10,402 children aged 1-7 (Child Ilcalth Stations). Since, howeser, the prophylactic child examinations may be carried out by the child's own physician and are moreoser voluntary, unknown factors may have caused a selection of the material Nevertheless, a certain estimate may he formed of the incidence, which is rather more than 4 per thousand among the younger age group and less than 2 per thousand in tlic older group This presupposes that half the children examined are boją This difference in the incidence may be due to the small numbers involved, but it may also be due to incongruence between the two series. Writer's Investigations Determination of the Incidence among Newborn Babies To this end, the writer chose the case records from Lying-in Depart. ment 13, Rigshospitalet, Copenhagen from the year it was opened in 1910 up to and including 1915 In this department the newborn babies are examined for congenital defects at birth, on the rounds on the fol lowing day, and immediately before discharge This series was, therefore, thoroughly examined Nevertheless, all the mild cases had not been entered on the diagnostic card index, and therefore every record had to be perused A total of 60,680 records were perused Among them there were 27 613 boys ahe on discharge, 90 had hypospadias The cases are described only in brief outline Often the case records give merely the diagnosis It cannot be ruled out that one case has been a lon-sented orifice and another one a short urethra Including the last two cases, the incidence among the long dischar. gcd boys aged thout 10 days (shen mother and child are usually discharged) is one in 307 or 3 26 per thousand + 16 I's fier thousand im per thousand 238 (calculated according to the formula (Kenip (1912) 53) zín - 2) 1 1+9 + + 221 n , fܐ ·23 General Validity of the Inculence Found Most of these children were born of young, unmarried women who have a preference for admission to this department The material 19, therefore, selected If Büchts (1950) theory, 112 that habies with hypospadias are more often born of young than of older women, holds gooil, the incidence found in the present material must be higher than among all newborn boys As shown later, the author is not in a position to confirm Buchi's theory, and no regard was paid to this selection of the series There does not seem to be any reason to presume that patients with hypospadias are subject to a particularly high mortality A priori, however, it cannot be ruled out that an increased mortality may be caused in part by the lesion itself and in part by a possible inferior general condition of the malformed babies if so, the incidence must decrease with advancing age, and that found in the present material becomes too high Since the unmarried mothers are registered only by number (the names being entered in secret protocols) it was impossible to trace these 90 children in order to ascertain their stability Their birth weight did not differ significantly from that in normal series (vide infra) In this respect, therefore children with hypospadias do not show an in. ferior general condition To procure a material with which to compare the incidence of hypospadias among the new born, all boys aged 7 14 in the municipal schools of Lisbjerg on the west coast of Denmark were examined with a special view to hypospadias The defect was found in 13 out of about 2950 hoys (Jacobsen (1919)) The material is not particularly large, but it accords well with that from the Lying-in Depart. ment, the incidence is 447 per thousand, P, calculated her thousand being 9 87 and P 1 93 Hypospadias muy pare the way for urinary tract infection, as the stenosis of the urethral opening, present particularly in mild cases, inay Anc rise to dilatation of the urinary tract Campbell (1913) cremined 152 chuldren under 14 years of age with stenosis of the urethral opening of them 98 % were congenital and some of these patients had luy prospadias Urinary tract infection was present in 25% f'ruhmann Sternberg (1930) have reported a case of hypospadias with structure of the urethral orilice The patient succumbed to an ascending urinary tract infection Several patients of the present series hid stricture and urinary tract infeclion Only one patient succumbed to a urinary tract lenton Jurtaglandular hypospadiar with structure of the urethral orifice and falal hidney disease (the proband of Pedigree 118) Tie patient was adnulled at ·26 the ise of 33 For the past 2 or 3 years he had been complaining of falilu headache and swelling of the legs About one ve ir before admission ne phritis was diagnosed and treated with dielary measures The palent 1128 admitted because of fangue luch except for brief periods had incapacit ated him for the past year On admission the patient looked quite well lle brad muid hypospulis with a small opening The urin 11 stre 21 pas lin Chmiel ermination revenled no other abnormalities No oeclemas Temperature 37 5° C BP 170/125 Urne contained alumin Specific gravity bout 1 010 increasing in the concentration test to 1015 and deciersing on wifer tolerance test to 1 007 With some difficulty catheterization was performet with catheter No 8 It yielded i slightly bloody urine On microscopical examination the cell findings corresponded to the lemorrhage No bacterii and no growth upon culture Owing to the greatly impured renal function bilateral decapsulation of the hidneys was performed a fortnight after admission (in March 1924) The kidners were hard slirund and granulated on the surface and there Mert fibrous adhesions to the capsule Postoperative pyrexin ind pulmonary symplonis The pallent succumbed three days after the operation Necrops Chronic nephrits secuels of nepltrolysis bronchopneumonia oedema of the lungs and pleurae clironic fibrinous pleurisy cystitis his pospadias Dilatation of the renal pelves or urelers was not observed In this case the diagnosis was presumably glomerulonephritis The patient had not at any time exhibited signs of urinary tract infection He had no bacteriuri or dilatation of the urinary tract Therefore hypospadias associated with a slight stenosis of the urethral orifico cin hardly have been responsible for the fatal issue It is worth considering also whether in increased mortality may be caused by malignant degeneration in the retained testes which are unduly common in hypospadias (cf Chapter 1) Carroll (1919) his severely criticized the statistical investigations which have shown 1 relatively common malignant degeneration in retnined testes He has moreover studied the problem by sending questionnaires to a large number of urologists He concludes that it has not been suffictentis proved that malignant tumours are particularly common in retained testes that malignant tumours of the testes are rare that they are ex tremely rare in criptorchidism Accordingly there does not scein to he any reason to presume that this may lead to an increased mortality among patients with hypospadias Seminoma occurred in only one case of the present series Perincoscrotal hypospadiats with unilateral cryptorchide m 1bdonninal seminoma of unknown origin (The proband of Pedigree 141) 4 24 year old man was admitted with the diagnoses perineal hypospadias inversion of the righ testis right sided inguinal hernia ·27 The penis was rather small and downwari flexed with dorsolateral foreskin which was cleft on the under surface The urethral orifice was situated between the two hahes of the cleft scrolum The left testis v2 normal on palpation and situated in the scrotum whereas the right one WIS Impalpable The penis was straightened and orchidomobilization was performed on the right the right testis was small atrophic and Inverted at the super ficial inguinal ring When 5 months later the patient was re dmlled for plastic reconstruc tion of the urelhra the right testis was at the superficial inguinal ring slupping in and out Moreover there was oedema of the right leg The patient complained of a feeling of tension in the abdomen Mo abnormality was detected hy palpation or digital examination of the rectum Two months later a swelling is found in the lower abdomen Median inferior laparotomy revealed a large tumour which surrounded the aliac vessels on 1he right The tumour which moreover had invaded the coecum and the lower portion of the ileum was inoperable Histological examination of biopsy specimen showed seminoma The tumour yielded to Yradiation 1 total of 2800 At follow up three years after the operation there were no signs of re currence The patient complained of allocks of subacute intestinal obstruc lion and the circumference of the right lower limb dad incrensed by 5 cm The point of origin of this tumour is unknown So tumour was at any time palpable in the normal left or in the atropluc right teslis Accordingly this maternal affords no evidence that an inferior sene ral condition urinary tract infection or malignant testicular growth should give rise to essentially increased mortality among patients with hypospadias The incidence found among the newborn – 326 per thousand will therefore be used to represent the incidence among the entire male population Incidence of the larious Degrees Previous Investigations The mild degrees are by far most common All Rennes (1831) CISN were mild and so were most of Wowrys (1919) According to Ilugins (1947) 70–75 % are of the glandular variety These values are presum ably derived from 1 hospital series and accord well with Barragona (1911) and Burcl harits (cited hy Schneider (1929)) findings of the Hindular inricły in 11 out of 26 and in 16 out of 22 patients respec lively Il rulers Investigations Table 1 (p 20) Gives the incidence of the various degrees in a series consisting predomin intls of hospital cases About 62 ucre juxta hlandular Perineoscrotal hypospadias made up only about This ·28 does not honcler represent the incidence among the general popull tion since it must be presumed that onls tlic severe cases are ho spitalized In the scries from Iying in Department Bit is not possible to classify the hypospadias in all cases The case records which state only the diagnosis often add an adjectis such as mild slight some or nurhcd All the cases classified as penoscrotal or perineal however are tho roughly described Since 1 follow up examination was out of the question the wuthor tried to identify the cases with the patients from the surgica) series by their -- and in some cases the mothers date and place of birth Two instances described as slight hypospadias and three is mild could be classified among the juxtaglandular cases One casc called hypospadias was identified as a case of penile hypospadias None of the non classi fied cuses could be identified as one of the two severe groups Table 3 Classification of 90 cases of his pospadi is among new born boys 1 1 29 8 Short urethra I ow seated orifice Juxtaglandular hypospadias Vild hypospadias Slight hypospadias Some hvpospadi is Hypospadias Penile hypospadits Varhed hypospadias Penoscrotal hypospadias Perineoscrotal hypospadias 3 8 2 4 5 The exact incidence of the different degrees cannot be decided on the basis of the diagnoses listed in Table 3 At an estimate the juxtaglandu Iur cnses made up about three quarters the pendle ones about one eighth and the penoscrotal and perineoscrotal together about one eighth ·Chapter 3 IRTILITY Previous Investigations No report seems to have been published of the fertility in hypospa das Ihere is reason to presume however that on the severe degrees It is reduced However deformities severe enough to give occasion to a wrong diagnosis need not be tantamount to absolute sterility Ven gebauers collected work from 1908 reports the case of a hypospadın having as a woman who impregnated her fellow servint who give birth to a boy with hypospadias In many authors opinion (Vayo (1901) Vowry (1919) Ombredanne (1932) Varr (1938)) the fertility is reduced even in the glandular inriety Vayo (1901) goes as far as stating that the majority of the patients are impotent In Ombretlanne s (1932) opinion the fertility is reduced because the sperm is not slung towards the os externun uteri but instend deposited in the posterior forrix To doubt these theoretical considerations have led to an incorrect result At least part of the pre sent series with glandular hypospadias published in 1948 (Rahbek Sorensen) did not show reduced fertility In the most severe cases the fertility is influenced by several factors (omplicating bilateral retention of the testes will present reproduction Downward flexion of the penis makes coitus difficult If the urethral opening is at the scrotum it may be impossible to deposit the sperm in the vagina The two last mentioned difficulties may be improved in surgery This is no doubt what made the two Germin workers War: (1938) and zon Schurer (1939) propose that reconstruction of the urethra bu performed only if the patient submits to sterilization so as to present the transmission of the morbid gene ·30 Il riler s Investigations Owing to the mari ed morphological differences between mid und severe cases between treated and untrented numerical evaluation of the fertility in a given series is less interesting thin an evaluation of the fertility in the various degrees and of the significance of treatment The writer therefore insestigated whether hypospadians marry as often as others Moreover the fertility of the married patients will be evaluated while due regard is paid to the extent of the defect and the result of treatment if any Frequency of Varriage Among Hypospadians The series includes 77 patients - probands and their relatives - aged 20 or over These cases are classified in Table + according to civil status age and degree of deformity This table also gnes the expected number of married and single persons in the various groups of severity und age groups The expected values were calculated on the basis of the number of single men and the total number of men in the Danish popu lation at the 1910 census (Statistique du Danemark 1945) Despite the small figures insolved the table shows a striking con formity between the actual and expected number of married and single patients in each of the four groups of hypospadians There ure 30 single patients as against the expected 30 31 In other words hypospadians marry just as often as other men and the degree of the malformation does not appear to influence the frequency of marriage Serual Function The married patients were questioned as to whether coitus caused difficulties and whether it could be accomplished to the satisfaction of both partners Three patients had complaints in this respect (1) The proband of Pedigree 129 A man aged 34 who married before hus penoscrotal hy pospadias had been treated Since sexual intercourse was carried out with difficulty and little saficfaction to either partner te patient was admitted for surgery after two years of married life A success ful surgical correction and reconstruction of the urethra was performed At follow up about two years later the patient reporte l that now coitus could be performed without difficulty ani to the satisfaction of both partners (2) The proband of Pedigree 143 A 39 year old man with perineoscrotal hypospadis Surgical correction had been tried in several hospitals At ·Table 1 Varried hipospadians in rious ige groups compared with the expected rule of in irriage Te let 1 епочег ІІІ. Peri uver tlh Valuatin lan lull Ixpect tiul ilal 1 :ր: : 1101 11th peite 1 $ on 11 1 ??? mi 13 31 I 1.3 7 113 017 2 922 179 178 2 21 3193 22 131 2. 2") 1 11 2 1 0 18 100 1 08.) 08 023 0 (91 077 2 0 16 3-39 01 2 1 30 206 1 01) 0 46 000 () 14 000 0 m 2 16 2141 14 20 1012. 8670 7373 31 444 1 82 009) 091 31 1807 161116 1743.) 111918 128.31 112144 { 881 3 7801 57.89 10172 21214) 18417 ( 18 02 008 I 9 124 073 1961 1291 007 007 007 093 093 - 1 - Tenal 1} 2+ 132 2338 1 1 66 31 12 12 10.1 |13 41 1 #23 = single m = marnicl ·32 follow up the penis was somewhat small and flexed downward by a scar lihe band The urethral opening was at the penoscrotal junction The patient complained of difficulty in performing the sexual act (3) The proband of Pedigree 162 A 35 year old man with previously trented penoscrotal hypospadias At follow up the pems was rather small ul with marked downwari flexion due to scar like bands The new formed uiethra opened at the corona A fistula at the penoscrotal junction The patient complained of difficulty in performing the sexual act due to the flexion His wife hardly ever obtained org ism in the patients opinion because of the small size of the penis In all three instances the difficulty in performing the sexual act was due to a rather marked flexion of the jenis Many of the remaining patents had had surgical correction of severe flexion before marrying but even so several had slight to moderate flexion of the glans or the penis (cf Tubles -8) According to the patients statements such flexion has not caused any discomfort Perhaps these statements should be accepted with some reserve especially as regards the wifes satis faction It seems however that the matrimonial relations and sexual intercourse of hypospadians do not differ essentially from normal once severe flexion has been corrected The fertility then depends only on the more or less adequate deposition of the sperm and on the quality of the latter Fertility and Morphology In an endeavour to evaluate the fertility of each degree separately each group was tabulated separately the tables (5--8) gne cach pa atent s age morphological features number of children and abortions and by comparison the number of children begotten by his normal married brothers Juxtaglandular hypospadias The cases are presented in Table 5 which comprises 24 patients All but three had children Two of the last mentioned patients wives how ever had had miscarriages one of them twice because of intoxication of pregnancy This couple did not want another pregnancy One mar ried man aged 50 was childless against his null The number of children ranged from 1 to 8 averaging 2 26 In com parison 23 normal brothers had an average of 1 70 children each No difference in fertility could be demonstrated between the treated und untreated cases ·33 Penile Hypospadias Table 6 presents 6 patients all of whom had children ranging in number from 1 to 3 and averaging 167 Nine normal brothers had on the average 1 56 children each In this group no difference was found in the fertility of treated and untreated cases (or cases in which the treatment had been unsuccessful) Penoscrotal Hypospadias Of the 12 patients listed in Table 7 four had children Moreover the wife of a 24 year old patient had had two miscarriages The wives of seven patients had never been pregnant In one of these cases the steri lity was due to bilateral retention of the testes The four fertile patients had 4 4 2 and 1 children respectively The average number of children per patient was 09) Five normal brothers had an average of 18 children All the patients had been treated Among the fertile ones the reconstruction of the urethra had been a failure in two (with 4 and 2 children) and partially successful in two (with 4 and 1 children) Perineoscrotal Hypospadias This group comprises only five patients who are listed in Table 8 None of the patients had children in three of these cases the sterility is explained by bilateral cryptorchidism In addition one patient with left sided cryptorchidism had been hospitalized at an adult age because of right sided epididymitis In the remaining case the testes were nor mal but the urethral opening was situated between the two halves of a cleft scrotum In juxtaglandular hypospadias the fertility appears to be normal and in the penile variety it is not definitely reduced in these two varieties treatment does not appear to influence the fertility In penoscrotal cases the fertility must be presumed to be reduced in untreated cases or in those in which treatment has failed although the possibility of procreation is present This series does not permit con clusions regarding the influence of successful treatment on the fertility as it dates several years back and therefore includes few successful corrections Hallek Sore sen 3 ·Table 5. Juxlaglandular hypospadias Fertily and morphological fealures her ותט\ Pedigree Mo Status in family Treaſed Ilexion Site of urethral opening Istut Sate of 1 st Sumber of children \umber of 1 carnages of brothers wathout hypo spadias Tuinbes \umber ol of Brothers children children per brother 33 no 2 Father Father Corona \one Scrotum 3 3 05 Slight of glans Yone 80 JO Coron lone Scrotum 0 6 Paternal grandfather 8 l'aternal uncle 55 no Slight of glans Corona Lone Scrotum + 0 12 30 34 71 no 9 l'ioband Corona None Scrotum 8 2 05 22 23 Proband jes Glans None Scrotum 0 1 0 23 no 50 Proband Corona Yone Scrottum 0 0 Slight of glans Slight of glans Slight of glans None 44 51 I'roband ves Glans None Scrotum 0 0 0 52 no Corona Yone Scrotum 2 0 2 0 00 12 Vateinal grandfather 12 Vnternal hrandfather's brother 52 10 None (orona lone Scrotum 4) 2 0 00 ·Scrotum 4 ( oiona Tone 0 20 40 2 70 ut Hather Slight of plans \one Scrolum (orona 6 + Sone 0 no Scrotum 2 Coron? 3 0 one 27 \one no + Scrolum 18 Tone (orona 0 20 Tone по 41 (oroni Tone no 0 Scrotun 5 0 Slight of glans Tone 32 Sonc 0 jes 20 Scrotum Prox to Coron? 75 Maternal Lrandfather 69 Brother 72 Inther 98 Father 107 Probant 108 1 roband 110 l'roband 111 Proband 112 Proban 113 1 roband 114 Proband 32 Ves Sone (oroni Tone Scrotun 2 0 0 37 ses one Scrotum (orona 20 2 35 0 + Voderate of glans None 54 y es ( lans Xone Scrotum 1 0 0 42 es Slight of Glans Tone Scrolum 3 0 1 20 2 distal part 23 es Tone (orona Tone Scrofumi 0 0 22 jes Glans Tone Serotum 0 0 115 al no Slight of glans Slight of Llans Vone (orona Tone Scrotum 0 33 no Corona Tone Scrotum 4 0 1 roband 118 1 robind 119 Probund 42 no (oront Tone Scrofun 2 U 10 Slight of glans ·Table 6. Penile hypospadias Fertility and morphological features Pedigree Mo Status in family Age Treated Treated Flexion Flexion Sile of urethral opening Fistula Site ol testes Number of children Sumber Sumber of brothers of mis without cartages hy po spadias Tumher Tumber of of Isrothers children children per brother 48 no Slight of pents \one Scrotum 0 1 6 6 paternal uncle Distal part of body 15 29 Ves 57 Proband Scrotum 2 0 1 2 20 36 36 по GG Proband Scrotum 1 0 3 17 34 126 Proband ves Slight of Glins Vone penis Slight of Distal part None distal part of body Sught of On glass Vone glans Slight of Distal part Sone glans of body Yot followed up Scrotum 2 0 1 10 36 127 Proband yes Scrotum 0 0 38 159 Proband 3 0 ·Table 7 Penoscrotal hypospadias Tertility and morphological features Pedigte e la Slatus ja taly Tumler Sumber um er or brothers of of mis without children carriages $pa lias Site of testes Somler \umlar of 1 rothers ch 1 trent ct illret per brother Site of urethrul penin. Troute ! Ige I lcxion [istult hypo Scrotu 4 0 2 8 40 17 ves Scrotun 0 0 69 proband 73 proband 72 proband Moderate of penis Moderate of penis Tone 28 ves Scrotum 0 0 0 \es l'ecoscrotal Tone junction (orona Pinhend at ridex Glans 1 small at radix 1 small in pend tart Penoscrotal Vestige of Junction urethre at glans Glans Small near the top Vidille of one fiend post Rus Tone 0 43 1 o 0 0 80 proband ves Moderate of pesss Operated bilateral cryptorch Scrotuum 37 4 1 1 1 1 30 ves Scrotun 0 2 0 ves Slight of penis Slight ol penis Slight of penis \one Scrotum 2 Coron? One at radu Scrotum 0 34 0 0 89 probani 9.3 proband 128 proband 129 proband 132 proband 133 proband 162 proband 16+ proband 40 Glans 0 0 0 yes 0 Slight of penis Tone 2 on middle Scrotum of pepel part Vone Scrotum 27 Ves les rudas 0 0 0 3.) ves Corona Onc at rulix Scrotuin 0 0 Marked of penis Slight of penis 39 ves Radix Tone Scrotum 0 0 ·Table 8 Perineoscrotal hypospadias Fertility and morphological features Peligree lo Slati in family Agi 1 realed Fler 11 Srt of urt hral on nah listul 138 proband Sale of listes 24 les Tumler of chil tren Sunil er Vunder of brothers of mis without carriage y po umber Number c! of rothers chill Iren chllirea fper brother 28 *paellas no 0 0 0 31 139 proband 112 proband 143 proband 172 proband 0 0 0 32 Shght of Glans Very small Bilateral penis in perineum cryptorch Varhed of In 1 cleft Tone Bilateral penis scrotum cryptorch lot followed up Bilateral cryptorch Varkeri in a cleft Tone Scrotum scrotum jes 0 0 38 of penis 37 0 0 Sot followed up 1 10 0 () 0 left side cryptorch Scquele of right sided epdady mitis ·39 In perineoscrotal hypospadias the fertility is greatly reduced if only because of the high incidence of bilateral cryptorchidism It is difficult to say whether surgical treatment might render some of the patients fertile From the point of view of genetics this means that the incidence of severe cases among the probands' fathers is lower than might be ex pected according to the mode of inheritance ·Chapter 4. PREVIOUS STUDIES ON THE HCRCDITY OF HYPOSPADIAS The heredity of hypospadias has never been elucidated by a proband study According to case reports, however, it is considered to be transmitted by irregular dominance (Kemp (1910), Weitz (1910), Gates (1916)) Kemp, in 1940, collected all familial cases published up to 1909, mainly on the basis of Bulloch's (1909) and Neugebauer's collected works This revealed that hypospadias had been reported it times in 2 brothers, 7 times in 3 brothers, twice in 4 brothers, once in 5 brothers, 9 times in father and son, 3 times in father, son, and grandson, twice in 5 generations, and once in 6 generations Since that time no large families have been reported, but soine surgeons (Ombredanne (1932), Loughran (1918), Schaefer & Erbes (1950)) have seen several familial cases Reports of two or three cases in the same family are of little interest considering the common incidence of the defect. Large and thoroughly examined families, on the other hand, may gue a hint as to the inheritance The largest fainily was reported by Lingard (1884) He found hypospadias through 6 generations in direct lineage In this family there was a striking number of cases, even when considering the dominant character of the defect It is not apparent however, how many of the patients Lingard had seen personally ·11 TODOTTI Ing 7 Lingard s family with hypospadu is through 6 generations In lessers family (1889) the inheritance appears to have been by irregular dominance Only two of the 11 members afflicted had been seen personally The data regarding the remaining 9 and the persons who were presumed to be affected were given by the mother of the two subjects examined Although I esser states that this woman was trust Morthy I do not attach much importance to this family knowing from experience that information about hypospadins in relatives supplied by members of the families is extremely unreliable go HOR 1602 hig 8 Tesser s family with frregular donunance Also in Strong s lamily (1906) (cited by Bulloch (1909) with lypo padıns in 5 generations the affected members had not been crimined personally The data were supplied by a patient with juxtagl indular hypospadias Therefore this family also is of little interest ·12 In several instances, concordant hypospadias has been observed in monozygotic twins (Lehmann (1936), Steiner (1936), von Verschuer (1940), Rhodes (1943)) Moreover, Camerer (1938) las reported a case of discordance in monozygotic twins. Lamy (1932) has collected a twin material of three purs of concordant and three of discordant monozygotic as well as of four pairs of discordant dizygotic twins These twins were part of a twin material exceeding 900 pairs collected from schools and hospitals in Paris The studies mentioned above hne not definitely cstablished the hereditary nature of hypospadias Since discordance has been found in monozygotic twins, exogenous factors must play a certain ætiological rôle Exogenous factors may be imagined to act upon both twin foetuses at the same time and thus make for concordancc which in that case is independent of inono- or dizygocily Lamy's twin material indicates the etiological rôle of heredity, as concordance was cncountered in monozygotic, but not in dızygotic twins The numbers invols cd are, however, too small to make the difference statistically significant ·Chapter 5 MODE OF COLLECTING AND EXAMINING THE PRESENT SERICS In order to elucidatc the heredity of hypospadias the writer collected a proband and a twin material The incidence found in these series was then compared with that found among the new born and schoolboys (cf Chapter 2) Selection of Probands As probands the writer selected patients admitted to Surgical Depart. inents C and D of the University Hospital, Copenhagen during the period 1915 to 1945, including a few out-patients This material was supplemented with cases of penile, penoscrotal, and perineoscrotal hypospadias admitted to Surgical Departments A and D of the Bispebjerg Hospital, Copenhagen, Surgical Departments I and l of the Copenhagen City Hospital, and the surgical departments of the Aarhus County Hospital and the Aarhus University Clinic This proband material does not represent a cross section of the population, not merely because in the last sıx departments the mild cases were excluded, but also because a hospital material is bound to include more severe cases than mild The material was selected in this way, because the most severe cases are of most eugenic interest Eramination of the Proband Material By personal application to each proband or his parents, if he was a child, the writer obtained the family history, examined the proband and asked for permission to apply personally to all male relatives All the male relatives were then visited and, if they did not refuse, submitted to an examination usually restricted to the external genitals ·Relatıcs in inilitary service were examined by the medical officers concerned and hospital patients is the hospital doctors I few reinties wished to be examined by their own physicians and a fex living in distant parts of Denmark were also examined by their own physicians True the examinntion of all male relatives was cumbersome und time consuming but it prosed necessary as the probands or his parents drta very often did not confort to the result of the examination On The one hand there would he cises in the family about which they hund no idea and on the other hand relatives belici ed to be afflicted proud to have normal genitilia Fffectiveness of the Framurali n The majority of the patients (ind parents) were willing to co operate but a les refused to file inc permission to uply to the relatives in most of these instances the defect had licen concealed from the greater art of the family I did not try to persuade these probands as it is dilficult to renlize the psychic suffering which might thereby has been inflicted on the often rather sensitive patients Instend I asked per mission to examine the closest relatises ho knew about the defect In this way it proved possible to examine several relatnes usually fathers ind brothers Moreover this vielded further data int al about con sanguinity A few exceptional patients or parents however refused to line anything to do with this study Another few had to be excluded because they could not be traced were adopted or foster children or Juscd abrond Accordingly the materni is divisible into three groups I 103 {imilies examined 33 familles partly exuined 111 27 families cxcluded To these 173 flics mas be added two which in fact do not belong to this material A family with (seudosaginal hy paspadias Afumiy with truc hermaphrodit.fm Only 61% of the funiljes were exainined as thoroughly 7s might be desired but there is no reason to believe that any selection of frinilies with famihat or with fton famill occurrence of the defect has taken place Naturally enough ? relatively large number of the patients with seiere deformity did not want to huse their relatives examined Some of the relatives refused to le examined and were therefore ruled out Froni Table 9 it will be seen how many relatives refused to ·45 have the examination and how large a percentage they made up of those who might have been examined This table furthermore contains a group called Others not examined comprising relatives living abroad sailors etc and a group of deceased relatives There is no reason to believe that this has made for a selection of malformed or non mal formed relatives It is evident from the table that the percentage of refusal was higher among distant than among close relatives this accords with the ex jerience that the more distant relatives are less interested in the study There is no reason to believe that the very persons who refused to be examuned should be hypospadians Table 9 \umber examined and not examined in the various categories of relatives Cra ined 1 Refuel ta examin! O hers not examine 1 Decease! Fathers Brothers Grandfathers Paternal or maternal uncles Cousins Other relatives Total 96 83 81 277 563 410 1 (1 03 %) 1 (1 19 %) 3 (3 57 %) 15 (5 14 %) 34 (5 70 %) 21 (4 87 %) 75 (4 73 %) 1 10 25 59 31 6 12 112 78 54 31 1510 126 293 Twin Material The twin material comprises all boy twins contacted Sıx pairs of twins are contained in the proband material four pairs were derived trom the case records of lying in Department B one pair from the University Institute of Human Genetics and one from Surgical Depart ment C of the University Hospital In most instances a polysymptomatic similarity test was used to decide the zygocity This test was in some cases supplemented by blood grouping In a few instances the diagnosis of monozygocity was based on the appearance of the placenta Jn these cases there was orte a centa two inerbrines in the septum and large superficial vascular anastonioses

·Chapter 6
WRITERS VATI RIAI
1III ROBIS II U11
The material was divided into the groups listed on 14 according
to the effectueness of the examination
In addition the famihes examined were divided according to the
severity of the probands defect the familial cases are illustrated by
pedigrees in which the following symbols are used for the males
examined genitals normal
refused to be examined
not examined for some other reason
Ох
died before the investigation was performed
short urethri or low sealed orifice
juxtaglandular hypospadias
penile hs pospadias
penoscrotal hypospadias
perineoscrotal hypospadias
more severe malformation of the genitals
In other words each pedigree sets out the result as well as the effec
tiveness of the examination l amilies with soltary cases are listed in
tables showing the number of relatises of each category who were

·47
examined and the number of relaties who refused to be examined or
who were not examined for some other reason as well as deceased
relatives (Tables 10-13) These tables give also the number of sisters
and the total number of brothers in the family, the latter in brackets
after the number of brothers examined
The classification of the other groups of the material will be seen
from the respective tables
1 Families examined
Probands with Jattaglandular llypospadias
Pedigrees representing families with famtal occurrence
Pedigree 1
ogo
ago
.
1
TTT. 6000060
Pedigree 2
9 7 7797
63000bron 876 53
669066 1676
Pedigree 3
Pedigree 4

·Pedigree 7
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Ped!gree 6
Miomis
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Pedigree 5
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၂-၃ ပုံ ၄ ဦး
Ruhbek Sorensen
( ၃ ခုံ ၃၃ ၃ ဦ၂ ၃၃၃ ၃ ၃ ၃ ၃ ၃ ၃ ၃ ဦ၃ ၃ ၃ ၃၄ ၃
၄ , စံ ၃ ၃ ၃ ၃ ၃ ၃ ၃ ၃ ၃ ၃၄ ၃၃ ၃၄ မှ

·}} ခခJ5p4
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.
오오오모
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appeti
# ၃ ၃ ၃ ၃ ၃ ၃ ၃ ၃ဝံ၃ ၃ ၃ ၃ ၃ ၃ ၃ ၃ ၃ ၃ ပုံ မှ
6
T,

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၃ ဦး
ဝ ဝင်
Pedigree 12
5
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4
రెల్
Pedigree 13

·52 Table 10 Solitary cases of juxtaglandular hypospadias Piligrie Stere Irlare talhers Sony yo Iaternal (10 ant fathers maternal Cousins Others onley Refused to he examined Otherg not examine 1 1 0 2 3 0 0 1 1 2 1 1 1 1 1 0 3 1 6 3 2 7 4 2 7 6 0 0 0 0 0 0 1 0 0 0 0 1 1 1 2 1 0 2 1 1 1 1 1 0 0 0 2 0 0 0 3 0 0 0 0 0 0 + 1 1 0 2 1 0 0 0 1 1 J 0 0 0 D 0 1 2 1 1 1 1 0 2 4 2 1 0 0 0 1) 0 1 0 0 0 4 1 15 16 17 18 19 20 21 22 23 21 23 26 27 28 29 30 31 32 33 34 35 3G 37 38 39 40 1 1 1 1 1 1 1 3 0 5 0 0 1 17 20 4 1 1 0 3 0 2 2 0 0 2 1 0 1 6 2 (2) 0 (0) 1 (1) 1 (1) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (3) 2 (2) 1 (2) 0 (0) 2 (2) (0) 1 (1) 0 (0) 1 (2) 0 (1) 1 (1) 3 (3) 2 (3) 1 (2) 0 (0) 2 (2) 1 (1) 0 (0) 1 (1) 1 (1) 0 2 0 1 1 1 4 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 3 0 1 0 1 3 1 1 1 3 2 3 1 2 1 2 4 2 2 4 0 4 0 0 D 0 0 1 1 1 0 4 0 11 0 0 1 1 1 1 2 0 1 1 1 1 1 0 1 1 2 2 10 17 3 4 1 0 42 43 44 12 2 1 3 0 0 0 0 0 1 5 10 9 6 5 4 5 2 1 2 1 1 0 0 1 4 0 1 2 1 0 1 6 0 18 5 2 1 13 0 10 0 3 15 14 0 0 2 1 0 0 0 0 0 2 3 6 1 47 1 1 3 10 2 2 1 2 2 4 1 0 0 0 0 49 50 51 1 1) 0 0 0 5 ( 1 1

·53
Probands with Pentle Hypospadias
Pedigrees representing families with familial occurrence
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100
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Pedigree 52
To
62567362
066
Pedigree 53
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Pedigree 54
T: To
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513 666
Pedigree 55

·54 T 50 • 6000 Pedigree 56 HO+ ਕਰਤਾਰ ਦੇ ਚਰਨ 00 t + Pedigree 57 1 able 11 Solitary cases of penile hypospallas Peiligree Sisters lo Brochurs Father Song Pafernal Grand and fatbers maternal Cousand Others uncles Refused Others to te nut examined examinest 1 D 2 3 1 D 0 (0) 0 (0) 1 3 1 1 8 1 58 59 60 61 52 63 2 2 2 0 O 3 1 1 1 1 2 8 0 6 0 0 0 () 1 3 1 (1) 0 (0) 0 (0) ! (0) 1 (4) D 0 0 0 0 0 O 0 0 0 0 0 1 6 3 4 1 5 1 1 0 1 1 0 1 1 6 3 0 0 0 0 8 1 65 66 1 5 3 2 1 1 1 1

·35
Probands with Peroscrotal Hypospadias
Pedigrees representing families with familial occurrence
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Pedigree 67
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Pedigree 68
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50
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Pedigree 71
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Pedigree 72
Pedigree 73

·67 Table 12 Solitary cases of penoscrotal hypospadias Redigree Systers Brothers Fathers Sons \ Paternal Grand anct fathers maternat Lo Obers uncles consume Refused Others y lue n} examined examined 1 1 ਤੇ 1 71 75 76 0 1 1 1 1 4 1 ਹੈ = 1 5 0 0 0 ਹੈ 0 0 } 1 1 1 1 0 t D 0. D 0 0 0 0 1 0 2 0 1 1 1 78 79 80 81 82 83 81 35 86 87 88 8 0 1 0 0 5 ਉ 1 ? 10 1 1 0 3 0 0 7 3 2 2 1 7 0 1 1 2 6 0 3 ਹੈ 6 6 1 1 5 2 23 1 19 0 2 2 ! 3 = 0 (0) 1 (2) 1 (1) 3 (3) 9 (0) 0 () 1 (1) 1 (1) 0 (0) 3 (3) 9 (0) 4 (0) 0 (10) ਹੈ 13 1 (1) 1 (1) 1 (1) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) ਰੂ 10 ? 2 0 7 1 1 7 $ } 5 h 6 10 0 1 2 0 6 0 1 1 1 t 1 0 0 0 . 2 ਨੂੰ 1 1 1 1 1 5 D 0 ਹੈ 1 0 1 0 0 1 1 1 0 1 0 0 9 6 0 8 16 4 7 2 19 12 3 12 5 12 8 28 9 03 41 1 1 1 2 1 0 1 1 0 5 8 3 2 1 0 4 2 Probands with Perineoscrotal Hypospadias Pedigrees representing families with familial occurrence ht ਤਹਿ ਠੇਠ Pedigree 96

·Pedigree 98
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Pedigree 97
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·59 Table 13 Solitary cases of perineoscrotal hypospadias Paternal Tediree Sisters Brolhers Futhers Sons Grand and No fathens maternal Cousins Olbers uncins Refused Others to be not examined examine 0 1 2 0 1 1 0 0 1 1 99 100 101 102 103 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 2 0 0 0 0 2 2 0 0 2 0 6 7 1 2 5 19 10 0 1 1 8 2 0 0 0 0 2 2 0 Il Families Partially Eramined With famulal occurrence Oo OTTO P Pedigree 104 PP Pedigree 105 Families without nown familial occurrence 7 able 1 Mussber of relatives examined in partially examined (milies without know familial occurrence Perces Tos 1) grue of hypospadla Grant Tathers Brothers fathers {}thers 106 122 Juxliglandular hypospadias 8 8 24 123—127 Penile hypospadias 4 2 128-136 Penoscrotal hypospadias 4 1 3 137-145 Perintoscrotal hypospadias 4 3 3 ·60 Jl. Families Ruled Out Table 15 Reason why 27 families were not examined Pedigree No Degret of hypospadias (annot be Iraced Foster and adopted chulitren Refused to be expencal 147--157 Juxtaglandular hypospadias 7 3 1 158-159 Penile hypospadias 1 ܝܕ 160-166 Penoscrotal hypospadias 3 2 2 167-173 Perineoscrotal hypospadras 2 1 4 Total 12 7 8 I ramılıcs of Interest, but not Belonging to the Material DO ਠਨੂੰ Go Pedigree 174 Pseudovaginal ly pospidias in two "sislers" (Casc repost on p 17) + T° TIT రం $300 Pedigree 175 True hermaphroditisin (case report p 18) and juxtaglandular hypospadias in the same family ·61 The Twin Material Voro yqotic I wins concordant (1) Pedigree 52 Aged 10 years Alike pliysically so as to be inistahın at a distance also by their parents and mentally Polysymptomatic si milarity test retealed nonozygocity Both twins had blood gronp B Genitals i Penile hypospadias II Juxtaglandular hypospadias (2) Pedigree 12 Aged 54 years I ooked so much alike that they were mistaken by their acquaintances Both had operations for right sided inguinal hernia at a few years interval Began wearing spectacles be cause of farsightedness almost at the same time Polysymptomatic sinh larity test revealed monozygocity Both twins had blood groups A, NP (+c D Ee+ Le (a ) Fy (a+) Kell + Genitals Juxtaglandular hypo spidias in both (3) Pedigree 115 Aged 5 years Looked so much alike that they were mistaken by their acquaintances but not by their parents Both weighed 2000 g at birth Polysymptomatic similanty test revealed mono zygocity Both twins had blood groups OMP+ C+ D+ Genitals Juxta glandular hypospadias in both (4) Umversity Hospital Lying in Dept B case rec 483/18 I weighed 1800 g and II 2200 g at birth Placenta One egg with superficial vas cular anastomoses Genitals Both infants had slight hypospadias of exactly the same appearance I died a few days after birth (5) University Institute of Hunan Genetics Aged 39 years Outward resemblance so striking that they were mistaken by their acquaintances Polysymptomatic similarity test revealed monozygocity Both had blood groups O MN P+ C++D Ce+ Le (+) Fy (a ) hell Genitals FX lination of the penis showed in both twins the scar of a successful correction of hypospadias by the method of Beck By the appearance of the scar the defect must have been of the juxtaglandular variety in loth 7ses Discordant (6) Pedigree 95 Aged 26 years Outward resemblance so striking that they were mistaken by acquaintances Polysymptomatic similarity test revealed monozy goeity Both had blood groups O VA P+ C+c+D+C le (a ) Te (b+) Gentials I Penoscrotal hypospadias II Tormal Genitals ·62 (7) Iying in Dept B Rigshospitalet Copenhagen case rec 391/00 Birth weights I 3550 g II 2350 g Placenta One large placenta septum with two membranes superficial anastomoses between the two halves Both had blood groups AP C+7+D+1 2+ Le (a ) Genitals I Nor mal II Juxtaglandular hypospadias (8) Lying in Dept B Rigshospitalet Copenhagen case rec 1514/51 Birth weights | 1900 g II 900 g No information regarding the pla centa (the delivery took place at home) Polysymptomatic similarity test (at the age of 22 months) revealed exactly the same eyes and ears Both had blood groups ON P+ C+D+I + Ic (1+) I u (a ) Fy (1+) Genitals 1 Normal II Penoscrotal hy pospadias (9) University Hospital Surgical Dept C case rec 702/52 Aged 15 years Birth weights I 3100 g II 3350 g Placenta Septum with two membranes Outward resemblance so striking that they were mistaken by their acquaintances Polysymptomatic similarity test revealed mono zygocity Both had blood groups A1 VP+ C++ D+I et le (a + ) Fy (a+) Genitals I Scar following operation for penoscrotal hypospadias by the method of Dennis Browne II Morm! Dizygotic Twins Discordant (10) Pedigree 31 Aged 12 years Are never mistaken for each other Polysymptomatic similarity test revealed dizygocity Both have blood group 0 Genitals I Normal II Juxtaglandular hypospadias (11) Pedigree 32 Aged 6 years Are never mistaken for each other Birth weights I 2750 g II 2600 g Polysymptomatic similarity test revealed dızy gacity Genitals I Normal II Juxtaglandular hyposp dias A pair of twins whose zygocity was not ascertained (12) Lying in Dept B Rigshospitalet Copenhagen case rec 381/38 Birth weights I 1930 g II 1000 g Placenta Two completely separated placentae with a septum of four membrines Genitals II Hypospadias Died four days post partum ·Chapter 7 EVALUATION OF WRITER'S MATERIAL Uniformity In this inaterial the diagnosis of hypospadias had been made by clinical examination As mentioned above, therefore some erroneous diagnoses cannot be ruled out among the cases combined with cryptorchudism, as the gonads were not always examined in exploratory laparotony Although a natural grading is impossible, it would be interesting to investigate whether æbiological differences appear to exist between the different degrees set up artificially considering the marked morphological differences between mild and severe cases From the genetic point of view, it must be ascertained, whether familial occurrence is met with an all degrees and whether intrafamilial variations occur Table 16 gives the incidence of familial cases classified according to the severity of the proband's defect It is evident that familial cases were encountered in an arerage of 28 1 % of the families When considering that the numbers involved are small, we find no difference in the incidence of the different degrees Studying the individual families with familial occurrence (including 104 and 105) with a view to intrafamilial variation, we find the same Table 16 Inudence of fun cunes grouped according to the severity of the proband's defect Juxtaglandulircises 13 full out of 51 (235) Penile Cases , 15 (40%) l'enoscrotal cases 7 29 (211%) Perincoscrotal case 3 8 (3754) 21 Total (Se 29 full out of 103 (28 1 %) ·62 (7) Iying in Dept B Rigshospitalet Copenhngen case rec 391/50 Birth weights 1 3550 g II 2350 g Placenta One large placenta septum with two membranes superficial anastomoses between the two halses Both had blood groups A. P C+++D+1 2+ le (1) Genitals 1 Mor mal II Juxtaglandular hypospadias (8) Iying in Dept B Rigshospitalet Copenhagen case rec 1514/51 Birth weights I 1900 g II 900 g No information regarding the pla centa (the delivery took place at home) Polysymptomatic similarity lest (at the age of 242 months) revealed exactly the same eyes and ears Both had blood groups ON P+ C+D+] + lc (1+) Iu (a ) Fy (a+) Genitals I Normal II Penoscrotal hypospadias (9) Unnersity Hospital Surgical Dept C case rec 702/52 Aged 15 years Birth weights 1 3100 g II 3330 g Placenta Septum with two membranes Outward resemblance so striking that they were mistaken by their acquaintances Polysymptomatic similarity test revealed mono 7ygocity Both had blood groups A1 V P+ C+++ D+ C+ le (a+) Fy (a+) Genitals I Scar following operation for penoscrotal hypospadias lys the method of Dennis Browne II Mormal Dizygotic Twins Discordant (10) Pedigree 31 Aged 12 years Are never mistaken for each other Polysymptomalic similarity text rei caled dizygocity Both have blood group 0 Genitals I Normal II Juxtaglandular hypospadias (11) Pedigree 32 Aged 6 years Are never mistaken for each other Birth weights I 2750 g II 2600 g Polysymptomatic simularity test revealed dizygocity Genitals I Normal II Juxtaglandular hypospa dias A pair of twins whose zygocity was not ascertained (12) I ying in Dept B Rigshospitalet Copenhagen case rec 384/38 Birth weights I 1930g II 1000 g Placenta Two completely separated placentae with a septum of four membranes Genitals II Hypospadias Died four days post partum

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·64 type in 14 families and a variation in the seserity in 17 (cf Table 17) The variation may be so marked that the very mildest and the most senere cises occur in the same family Since 10 difference is demonstrable in the incidence of the familial occurrence of the different degrees of the lesion and wince marked intrafamilial variation in degree may be encountered the aggregate material will be considered as one in studying the utrological signific ince of heredits Tabel 17 Degree of luypospadias in the malformul individuals within the same family Same degree in 14 families Juxtaglandular hypospadius 4 cases in 1 family Juxtaglandular hypospadias 2 cases in 10 families Penoscrotal hypospadias 2 cases in 2 families Perineoscrotal hypospadias 2 cases in 1 fatis Tarying degree in 17 families Low seated orifice and juxtaglandular hypospadias in 1 family I ow seated orifice and penile hypospadias in 1 family tox sealed orifice and penoscrotal hypospadias in 2 families Juxtaglandular and penile hypospadias in 5 families Juxtaglandular and penoscrotal hypospadias in 3 families Juxtnglandular and perineoscrotal hypospadias in 2 families Juxtaglandular - 2 cases and penile hypospadias in 1 family Juxtaglandular penile and penoscrofa) hypospadias in 1 family Penile hypospadias and 2 cases af penoscrotal hypospadias in 1 family Incidence of the Defect Among the Probands Relatwes A total of 1590 relatives were examined Twenty erght had hypospa dias and four well defined short urethra or low seated orifice In other words the incidence among the probands relatives is 1 76 % which is statistically higher - at the 1% significance level — than that among the total male population which was 0 33% Thus the standard error of the difference equals 0 52 % according to the formula Vpa 1-P)x (in 1 + n1 (hemp 1942 p 99) and 1 76 % -- 0 33% – 1 43% > 258 x 032 % - 1 34% The 75 relatives who refused to be examined glie rise to an uncertainty but even though they are counted as normal the difference between the two groups is definite at the 1% significance level since the standard error of the difference equals 0 51 % and 1 68 % - 033 % = 1 35 % > 2 58 X 051 % = 1 32% ·63 Table 18 Incidence of hyposp dias among the various categories of relatives. With \\ Ithout 1x pospadus Typospadias hypospadias 10 2 + 0 96 74 35 00 Brothers Wall-brothers Fathers Sons Grindfathers Paternal or maternal uncles Nephews Cousins Others 3 94 23 111 17 79 277 58 560 337 2 2 4 5 07 33 07 15 Total 32 1558 20 The incidence in the various groups of relatives will be seen froin Table 18 This table includes the 4 cases of low-seated orifice and short urethra, all of which occurred among the close relatives Concordance and Discordance among Twins In Table 19 Lamys (1952) twin material is compared with the pre- Sent malerial of tuns Table 19 Concordance and discordance among mono and dızygoli lans Dexygalie tuin Manozygotic tuins Con DIS cordare cordance (on coralance TI cortune 3 3 + Lami's series Writer's series > 0 en 4 2 7 0 6 The xạ test, using Yates' correction (Kemp (1942), p 128), shows a tendency that concordance is more common among monozygotic llian among d1zygotic lwins (x = 315, f = 1, p = 007) Ileredity Since hypospadias occurs with an increared incidence among the relatives of hypospadians and since concordance appears to be more 159)bek Yelen > ·66 common among monozygotic than dızygotic twins, it must be inferred that the lesion is dependent on inherited factors Although hypospadias occurs only in men, the gene may be transmitted by somen (Pedigrees 3, 4, 7, 9, 10, 11, 12, 55, 57, 67, 71, 73, and 96) as well as by normal (Pedigrees 1,5, 6, 8, 10, 11, 56, 57, and 73) and afflicted men (Pedigrees 2, 6, 12, 54, 55, 72, and 98) As mentioned above, the lesion must depend on exogenous factors, as only 8 out of 15 pairs of monozygotic twins showed concordance. At 2 58 times the standard deviation — 99% probability level -- this ineans that concordance must erist in hetween 36 6 and 875 % of the monozygotic twins This corresponds to a degree of manifestation somewhere between 1 and 93 % (cf hemp (1943) p 117–118) A similar degree of manifestation must be present in the proband material The mode of inheritance may, thus, be indicated by the degree of manifestatron, since the numbers involved are too small to be treated by the 2) statistical methods Table 20 lists the actual and expected number of cases occurring in some categories of relatives at dominant and recessive heredity respectively. The expected number was calculated on the basis of Dahlberg & Hultkrantz' formulas (Kemp (1943) p 112 -113) The actual number is 19 = 2 58 X 436, while the expected number was 225 1 at pure Mendelian dominance At a probability level of 99 %, therefore, the degree of manifestation must be between 3 4 and 135 % providing dominant heredity with failing manifestation These values do not accord with the degree of manifestation calculated on the basis of the twin material, and this mode of inheritance is, therefore, unlikely In recessive heredity the expected number of cases is 50 3, corresponding to a degree of manifestation between 15 4 and 60 1 % with a probability of 99% In recessive heredity with faiting manifestation, thus, the degree of manifestation accords rather well with that in tuin material and the proband series Table 20 shows, moreover, a rather constant ratio between the actual number and that expected in the various categories of relatives, provided that the heredity is recessive This calculation, however, has the draw back of not holding good, if too many of the cases depend exclusiely on exogenous factors In practice however, it may be expected that in a large series the cases are distributed as a lesion transmitted by recessive heredity with failing manifestation Although the high incidence of hypospadias nieans that the gene of tlus lesion must be commonly present among the population, it must probably be assumed that the frequency of consanguinty is increased if lypospadias is a recessie character in 124 families, three cases of consanguinity occurred among the probands' parents This exceeds the ·67 Table 20 Number of Hypospadians in various categories of relalıves compared with the number expected at dominant and at recessive heredity Dominant Total number Fxpected Papeeted relatie alfected affected Actual umber Recessive Fxpected Fupecled affected affected 0 17 101 50 13 50 11 85 52 1 5 72 27 80 10 28 9 10 367 25 21 925 5 301 11 0 Children Brothers Grandfathers Grandchildren Pitcrnu ind ma ternal uncles LOUIS Greatgrundlatliers Total 565 12 75 720 4 1 67 94 1053 2251 19 503 ordinary incidence of consanguinity in Denmark, which is believed to be lower than 1% Owing to the small numbers involved, however, this finding cannot be attributed with much significance It may be concluded that hypospadias is dependent on exogenous as well as endogenous factors The latter are probably transmitted as recessive characters ·Chapter 8 RELATION OF HYPOSPADIAS TO SOVIT INTLRSCXUALITY THLORILS An interscy is defined by Goldschmidt (1915) as an individual developing against its genetic ser According to the original sex, a di stinction is made between male and female intersexes A distinction is made also (1931) between zygotic intersexuality in wuch the scx inversion takes place at the moment of fertilization, and hormonal inteisexuality induced by the hormones of the opposite sex Goldschmidt's Interseruality Theory (Zygotic Intersexuality) Goldschmidt's intersexuality theory is briefly as follows In mile as well as female indnduals the chromosomes contain both mascu line and feminine sex delermining factors These factors are inherited and may be of varying strength Weak and strong factors may be combined in a 173 so is to give rise to divergence froni normal in the ratio masculine and feminine factors, and an intersexual individual results For instance, the combination of strong masculinızıng and feminizing factors in a genetically female individual results in a female intersex The fechanisoi of the develop ment of intersex is explained as follows During early foetal life, the in Jesidual develops according to its original sex, but at some juncture, the furn ung point, the factors of the opposite sex prevail and after that time, the development takes the opposite direction If the preponderance of the oppo site sex is very strong the turning point occurs at an early stage of foetal life and the individual develops maihedly against its genetic sex Goldschmid! (1911, 1915, 1931, 1933) proved his theory on the moth Lymantria in innumerable crossing experiments between various geo grapluc varieties, the sex-determining factors of which were of varying strength By applying this theory to normal embryology and the moi- ·69 pholow of sent al malformations Goldschmitt (1931) expl umed Targe number of malformations in animals and man As far as the human race is concerned the female is supposed to I ossess two feminizing and two musculaizing factors and the male one feminizing and two masculinızıng factors Im inın only female intersexuality is s ud to occur Severe cases of hypospadrs are regarded i female interseres while the milder ones are interpreted as inomalies of developinental trest is patients with mild hypospadias huc hd normal sans According to this theory female intersecs -- w110 thus [lossess two chromosomes ---C19 hue only daughters or interserul children Berblinger (1936) shores Goldschmidt s Siow while Vosczho- LICS (1936) has gone even further interpreting also inild cases of ligpospadias retention of the testes and liomosexuality is intersexual Mchomena On the basis of embryological studies on the development of the masculine and the feinine prepuce Popper (1937) states that the Vrepuce of hypospadians is feminine and he therefore subscribes to Vosczkowics ideas Writer s Investigations In order to assess the validity of the intersexuality theory w hypo padias the writer employed the methods used in Goldschmidt in Studying the lymantrii (1) Sex distribution among the offspriu, (2) Scx distribution in the websbil (*) Occurrence of sex dinled recessive charters in intersecs und their 1 irents Ser Distribution Imong the Offspring of Hypospadians The series counts i tots of 68 persons with hypospadiac Cathers 1ible 21 g11es dhe se distribution of these persons classified according Table 1 The sex distrilution imong the chuldren of hypospi hity shows no divergence from normal Boys Hint hipost Turn al real 3 7 Juxlagl indul ir y os dias Penile hipospi luas l'enoscrot il lypospadias Total 20 5 5 5 G 17 3 4 2 2 30 38 3 24 11 ·70 Table 22 Distribution of male and female individu ils in the sibships, when juxtaglanzdular cases are interpreted partly as male, partiy as female Good conformity with the expected number will be seen in the former, lacking conformity in the latter case. Sthship Hypospadians Interpreted as males Interpreted as fi malos Fxpected Actual Expected Actual nunler ol number of number of numer of males males feniales females Sumber or sbships Xot Size of Number of 23 15 9 2 3 4 5 6 10 30 667 25 710 19 197 15 486 12 192 5 005 5 503 31 31 23 16 13 4 6 30 667 25 710 19 197 15 486 12 192 5 005 5 503 39 30 22 20 15 7 6 5 106 7 350 7038 6 492 5 516 2 478 2 737 4 1 1 59 113 760 124 113 760 12% + 6 06 x 3 139 36 717 139 + 606 X 3 Table 23 Distribution of male and female individuals in the subships, compared with the expected number, wien penile hypospadians are interpreted in part as genchcally male, in part as genetically female A belter conformity as found, when the patients are interpreted as mule Sibship Ify pospadine Interpreted as bales Interpreted as females I xpected Actual Expected Actual truniber ol number of nur ber of nuon ber of males males females females Nuniler of xihships Xo Size of Sumber of 2 3 4 6 7 7 3 5 9 333 5142 10 665 3048 7 056 12 4 7 5 10 I 333 5 142 10 665 3018 7056 1 10 1 554 8 1 470 18 3 910 2 1 379 6 3 334 11 647 44 + 3 X 341 2 18 35 244 38 35 244 38 = 3 X 3 41 ·Table 24 Distribution of male and female individuals in sibships, when penoscrotal cases are interpreted partly as male, partls as female andividuals Good conformity with the expected number in the former, lacking conformity in the latter case. Subshir Hypospadians Interpreted as males Interpreted as females Fxpected actual Fxpected Actual purister of husaber of number o! number of niales males females females Tumher of sbships Xa? Size of Number of 2 3 4 5 0 7 8 10 12 12 6 7 2 2 1 16 000 10 284 14 931 5 162 G096 3528 4 016 5 005 6 001 16 16 000 11 10 284 17 14 931 7 5 162 7 6096 2 35 5 4016 5 5 005 5 6 001 75 71 023 75 + 3 X 500 22 14 19 6 9 6 2 664 2 940 5 474 2 164 2 758 1 667 1 945 2 478 2 992 4 1 1 7 7 1 33 71 023 91 25 082 94 + 3 X 500 Table 25 Distribution of male and female individuals in the shships, when perineo scrotal cases are interpieted partly as male and partly as females individuals Good conformity with the expected number in the former, lacking conformity in the latter case Sibship 11) pospaslians Interpreted as males Interpreted as femala Fxpecteil Actual Expecter Actual number of number of number of number of males males fi maks Nunsber ol Tumor of Ilships Xo? Size of temalis 6 3 2 2 3 14 5 6 11 8 000 5 142 4 266 2 581 3 018 5 503 10 5 3 2 3 3 8 000 5 142 4 266 2 581 1 3018 8 1 332 8 1 470 7 1 564 1 082 4 1 379 9 2 478 40 9 305 40 + 3 x 305 1 5 503 28 540 20 28 510 26 = 3 X 305 ·to the degree of the father's malformation This lable shouts also low many of the boys had been erainined and hon many were normal. All degrees of hypospadias, apart from perineoscrotal cases, are represented There were normal boys in all groups, and the sex distrie bution did not differ from normal Ser Distribution in Sibshups Including Hypospadians Yor cach of the four varicties of pospadias 1 calculated the crpected number of male and female individuals among the patients' siblings, in part when the patients are interpreted as genetically male and in part when they are interpreted as genetically female This calculation was carried out by means of Koller's tables (holler (1940) The results are presented in Tahics 22-25 with the actual number and the calculated standard deviation In juntaglandular, penoserolal and pericoscrotal cases there a statistically significant difference between the expected and actual 14911- ber of fenilles, when the hypospadians are interpreted as genetically female while food conformity is seen, when they are interpreted as genetically male in the pontic cases, the numbers involved are loo small to permit a statistical evaluation Lien so, the results accord better when the liy pospadians are considered genetically male Occurrence of Sex-linked Recessive Characters in llypospadians Colour blindness is a common, recessive, sex-linked character in man Determined by the Ishihara test, it is sud to occur in about 8 % of all males and in about 05 % of all females (ll'aaler (1927)) Therefore, large number of the probands and their parents were exammed for colour blindness by means of Ishihara's plates (1936) in an endeavour to determine the genetic act of the hypospadians The result is set out in Table 26 Colour blindness occurred in all Table 26 Distribution of colour blindness among the hypospadins, their noruial fatliers and mothers Mothers Prohinils Total Colour Ilin 1 atbers Colour Tola! blandt Iolal ( oinar blind! 3 7 1 Juxtaglandular hypospadias Pemile ho pospadias Penoscrotal 113 pospadias Perincoscrotat hypospidis 1 56 10 28 10 2 11 22 42 12 22 0 D $ (0) 2 0 1 from 1 7 101 7 Total 79 9 83 0 ·73 degrees of hypospadias When regard is paid to the small numbers involsed there does not appear to he any difference in the incidence among the hypospadians and their fathers Voreover the incidence --- 673 (r, in % is 18 03 and Pm in % 231) - does not differ from that applying to normal males On the other hand it is too high for gen ctically female individuals If a colour blind hypost adrn is interpreted as genetically ſemale it inust also be demanded on account of the mode of inheritance of recessive sex linked characters — that the father is colour blind pro vided that he cannot be interpreted as intersexual due to a genital inal formation In this series two colour blind patients with juxtaglandular and one with penale hypospadias had fathers with normal colour vision and normal genitals One colour blind patient with perineoscrotal hypo spadras had a father with a normal colour vision but with juxtaglandu lar hypospadias In the last case both juxtaglandular and per eoscro tal cascs of hypospadrs would have to be interpreted as intersexes if the child with perineoscrotal hypospadias is to be interpreted as such The fathers of the remaining colour blind hypospadians had died but as far as was known they had had normal colour vision and normal genitalia Therefore neither the sex distribution found among the children ind the siblings of the hypospadians nor the incidence of the sex linked recessive character colour blindness indicate that hypospadias mild or severe -- should be on the whole interpretable as genetically intersexual Hormonal Intersexuality It has been shown repeatedly in ammal experiments that the normal development of the loclal genitals may be changed by the administra tion of sex hormones to the mother (cf Dantchahofl (1938) Greene (1912 1914) Moore (1941)) This even applies to species 14 superior Is monkeys (van lagenen & Hamilton (1913)) These experiments were carried out to elucidate the mechanisin of the normal desclo ment of the genitals but they have also given rise to speculalions regarding the etiology and alhogenesis of genital malformations nous authors have tried to relate the a tiology of the malformations to their theories regarding the normal ser differentiation In addition to the gonads it has been suggested that the adrenals might be of significance in sex differentiation and development of intersexuality (Brostre (1947)) Despite marked divergences between the different views rcddin, the significance of hormones and their mode of action in the develop ·Chapter 9 LIOGLNOUS ÆTIOLOGICAL TAC TORS Recently, it has been realized that inalforinalions may be the result of foetal infection with rubella (of Albaugh (1945) Bardram < Brandstrup (1917)) Such malformations are mainly localized to the eyes, heart and brun but a few cases of hypospadias have been reported following maternal rubella during pregnancy (Prendergast (1946), Keizer (1950)) When considering the high incidence of hypospadias, howcicr these may have been chance coincidences Also anım ul experiments have shown that exogenous factors may, ut the internal organism, cause malformation of a foctus. If pregnant experimental animals are exposed to vitumn deficiency, part of the litter will be born with malformations The nature of such malformations depends on whiclistamin is withdrawn from the diet (Warhany (1918)) Avtaminosis A has been followed hy int al genital malfortafions (Bendiren (1944)) Lien a quite hric oxigen defterency may cause malformations Ingalls, Curley & Prindle (1950) exposed pregmint mice to anoxi? Among their offspring congenital defects were far more common thip in a control series Valformations have also hcen induced by treating pregnant mice with cortisone Thus resulted ut it in larclip in the offspring (Fraser & rainstal (1951)) The number of mice with harclip proved to depend upon which strain was used in the experiment In other words, there must have been a certain interplay between genetic factors and the erogenous action of the cortisonc l'oxic damage of the spermatozoon may also he mentioned among the cluses of experimental malformations Artificial insemination with spermatozoa treated with colchieine in low concentrations has resulted in offspring with a bugh incidence of spina bifida (Nachtsheim (1951)) ·77 The nature of the malformation depends on the stage of foetal life at which the exogenous factor is active According to Ingalls experi ments (1950) rapidly growing tissues sustained most damage in the case of rubella also the malforintion depends on the time of the deleferious action (Dods (19481) Moreover combined malformations may occur in tissues of the same embryological age (Ipsen jr & Ollele (1932) Grunfekler & lasch (1919)) As far as human malformations are concerned it is difficult to elucidate the nature of the exogenous factors It is impossihle to procure 1 suitable material Birth records have the advantage that the history has been taken at the termination of pregnancy but the draw back th it at has not been taken with a view to the utrology of malformations This is obtained by taking the data from the parents of malformed chi cren hut in such cases many years may have passed from the preg nancy concerned so that presumably the data ire not quite reliable Il rulers Investigations Despite some scepticism regarding the possibility of demonstrating exogenous factors the writer rerused the 90 records from Lying in Department B with such factors in mind furthermore I interviewed the mothers of 31 hypospadians regarding the course of the pregnancy If an exogenous factor is to be attributed with any significance it inust have been active before the development of the urethra has been completed i e before the end of the fourth month of gestation (Spanid ing (1921)) For this reason I looked only for abnormalities during the first four months of gestation This material was jerused with a view to Infectious diseases which were not reported in any case Avitaminoses of which I found no evidence Also there was no case of hyperemesis which might be imagined to cause vitamin deficiency Somaftc and psychic tranma No well defined cases II.emorrhages During the first four months there were 7 cases of hemorrhage among 124 patients The humorrhage was houerer mild in all cases and the incidence is not high enough to be attributed with iny significance Intoricaltons lhe parents of a perineoscrotal hypospadian reported that they had both been under the influence of alcohol ihen the child is conccused It will be seen that the present series permits no conclusions regard ing the nature of the exogenous factors As mentioned above however the series is not particularly suit ible for this purpose and despite ·78 the negative findings, some of the factors mentioned may have been operative Seeing that infectious dise ises are subject to seasonal variations, a seasonal variation in the incidence of hypospadias in the new born might be expected if infection is an actiological factor Such a variation might also be imagined to be caused by a possible atrological vitamin deficiency, as the supply of vitamins is at a minimum during the Spring Therefore, the birth dates of the 262 hypospadians are presented mi Table 29 compared with the expected number, calculated on the basis of the birth dates of boys born in 1944 (Statistique du Danemark, 1945) lhe difference between the actual and expected number is seen to be quite irregularly distributed on the 12 months of the year The ya test shows no significant difference between the autual and expected number of cases (F = 11, y2 = 11 08, 05 > p > 04) Ainong the twin material there are 5 discordant cases in which the birth weight is known in all these cases, the malformed twin had the lowest birth weight or 473, 51 2,66 2, 92 5, and 916 % respectively of the healthy twin's weight. Table 29 262 cases of liy pospadias classified according to the month of birth compared with the expected number born in each month No seasonal vriation (n* Sumber of boys Jurn in 1902 (ases of ly pospodias | xpected Actual a u January Februit March Apial Mas June July August September October November December 3,896 3,884 4,379 4,195 4,142 3,915 4 026 3,946 3,924 3,850 3 790 3,934 21 32 21 25 23 96 22 95 22 67 21 42 22 03 21 59 21 47 21 07 20 74 21 53 30 19 30 19 17 25 17 25 23 22 17 18 8 68 3 5338 + 2 25 02382 104 1 5226 + 395 0 6798 + 5 67 1 4182 - 3 58 05983 + 503 1 1481 0 5385 1 53 0 1090 0 93 00410 + 3 74 0 6744 + 3 53 0 5787 47,881 262 00 262 11 0808 Occasioned by this finding, the writer studied the birth weight of 90 hypospadians born in Lying-in Department B compared with that of all boys discharged aluse every fifth year during the same period These ·79 values are set out in Table 30 True this table shows a higher incidence than expected in the low and a lower incidence in the high weight groups but the difference is not statistical (1-7X 973 p Table 30 Birth weight of 90 hj pospadians comp red will that of 5a93 normal Hors disch irgoul aluse no statistical difference Ну чра та я ipecte actual Der fa 1 1 ril (trol sres n tnler IL امرا را 1 11 Under 2500 K 2550-2750 S 2800-3000 g 300-3250 8 3300_3500 g 3550 3750 g 3800 1000 6 over 1001 512 449 704 990 1070 870 515 127 82 72 113 159 173 140 41 f9 11 19 22 9 3 5 08689 00000 0 0287 05910 12070) 1 7881 40300 0 5070 5593 900) 90 9738 (ombination with Other Valformations Other congenital defects occurred in 9 of the 173 prolinds 12 three with juxtaglandular two with penalt one with penoscrotal and three with perineoscrotal hypospadias On the basis of the small numbers involved it is impossible to state whether the incidence of other in ilformations is increased in fry posp dians of such a combination is to be explained on the basis of a com inon trological factor the development of the affecled organs must take place at the same foetal stage as that of the urethin which is completed in the fourth month of gestation The other congenital defects were as follows Hardness of hearing due to a perceptive defect in three patients with juxtaglandulir penile and penoscrotal hypospadiis respectively The degree of hypovpads and denfness was proportional As the inner eur 11 15 yriticalls teiched its definite form in the 8th focłal xech (dreu (1942) p 496) the juncture corresponds fairly well with that of the urclliral development llarelp and cleft palate in (no cases one of juxtaglandular and one of perineoscrotal lipospadius The union of the two lialues of the palite usunil takes place in the 9th foetal week ( 1rey (1942) p 198) ·80 This defect therefore may also be related chronologically to hypo spadias Wegacolon and anal structure in one case of familial juxtaglandular hypospadias Owing to the close relation between the development of the rectum and the urogenital organs it is natural to relate these two malformations to each other Clubfoot in the last mentioned patient and in one with perineoscrotal lis pospadias la the latter case clubfoot as well as hypospadias were familial It is impossible to state whether clubfool and hypospadias may be related rhiologically True the development of the limbs sets in al a very early stage but that of the skeleton of the foot ranges over a very long period Teeblemindedness in two cases A patient with penile hypospadias suffered from mild feeblemindedness which occurred also among other inembers of the otherwise intelligent family The other patient with perincoscrotal hypospadias was an imbecile This patient also had Littles disease Therefore it cannot be ruled out that the feeble mindedness may have been due to birth injury A number of the congenital defects encountered in the hypospadians may be explained as developmental arrest due to one or more inhibitory factors which at the same time have arrested the development of the genitals The atrological factors may also be imagined to have given rise to a generalized inhibition of growth At least this would explan why the hypospadian among a pair of discordant twins is invariably the smaller one These presumptions however «lo not receive sufficient support from the present material ·Chapter 10 CONCLUSION AND DISCUSSION OF THI PRACTICAL SIGNIFICANCE OF THE RI SULIS Although the etiolosy of hypospadias has not been fully elucidated the results of the present study are of practical significance from the 1 oint of view of cugenics as well as operative criteria Before discussing these aspects the author would like to give a brief Summary of the results Conclusion Hypospadias is a congenital defect occurring in about 0 33% of the male population There are mild and severe cases with even transitions The foreskin and urethri are invariably deforined hut the other ex ternal 18 well 7s the internal genitals may also be involved For ex umple retention of the lestes is common associated phenomenon Ilypospadians marry is often as do normal men In mild cases their Sexual relalions are normal whereas in severe enses surgical correction if the pemile flexion is required The fertility is normal in mild cases decreasing with increasing everity of the defect The lesion is familial in about one-quarter of all cases and within the same family there may Ic wide variations in degree As far as the rtiology is concerned both endogenous inherited — and unknown exogenous factors must be considered the mode of inheritance appears to be recessive with failing manifestation The patients genetic sex is male They cannot be inter i reted is internexes according to Goldschmidt s theory Eugenic Veasures In Denmark it is permitted to interrupt a pregnancy when there is a risk that the child will be affected with 1 serius incurable inherited 1tanlerne 6 ·82 disease The criteria must, thus be based on the risk as well as on the more or less serious nature of the disease. Since the heredity of hypospadias appears to be recessite with failing manifestation, the risk of familial cases is slight It is highest for the brothers of a hypospadian, but at the mode of inheritance mentioned. it does not by any means reach 25% in other words, if a couple have had one child with hypospadias, the risk that their next child will be affected has been reduced to considerably less than 12 5 %, as the ratio hoys/girls in these sibships does not differ from normal The next highest risk will be found in the group sons of hypospadians In this group), however, the risk is far lower than among the brothers But regard must be paid also to the nature of the lesson The fact is that only about 25 % of the patients have complaints necessitating surgical correction The latter has caused some difficulty in the course of time, but recently good results have been obtained, also in Denmark (Fogh-Andersen (1953)). Hypospadias, therefore, is probably not an indication for interruption not even in the most severe cases Owing to the intrafamilial variation, it is impossible to tell how severe the next case in the family will be In the general run of eugenic consultation, there is probably no reason to advise against having children or against marriage between first cousins, even though the male partner is affected with hypospadias Since about three-quarters of the patients have shown normal fertility and since there is intrafamilial variation in the severity, the absence of eugenic measures will probably not have much influence on the incidence of the defect or on the distribution of mild and severe c'eses Operative Indications According to these eugenic considerations, there is hardly any reason to deprive hypospadians of the pleasure of having children Therefore, the possibility of improving a reduced fertility must be taken into consideration in setting up the operature indications Juxtaglandular cases require no treatment apart from dilatation and perhaps meatotomy of a constricted orifice The difficulty of micturition is slight and fertility as well as sexual funchon normal Penıle hypospadias is a transitional variety, in each individual case the advisability of surgical treatment must be considered. In more severe cases, the flexion of the penis has to be straightened to render sexual functions ·83 normal, and reconstruction of the urethra is required to obunte difficulties of miciurition and improve the fertility In other words, three-quarters of all cases require no treatment The new surgical procedures for juxtaglandular hypospadias which are still being worhed out (Mahoum (1917), Brendler (1918)) must be taken as contributions to cosmetic surgery The treatment of the last onequarter demands experience and care It is therefore worth considering whether the approximately 30 new cases annually should not be centralized in a few departments 6 ·SUM VAR Introduction The main object of the present study was to elucidate the etiology of hypospadias Chapter 1 Reviewing the morphological features of the disease the water finds an even transition between the mild and severe degrecs I or the pur poses of the present worl it is most practical to subdivide the condition into juxtagl indular penile penoscrotal and perincoscrotal cises The incidence of complicating retention of the testes among 2/4 liyo spadians is compared with the incidence among the general Danish population This reveals an increased incidence of retention in all de grees of hypospadias Chapter 2 After reviewing previous studies on the incidence of hypospadias the writer reports his own findings Ninety cases occurred among 27 613 baby boys nged about 10 days This is taken to represent the incidence among the total mile population is there is no reason to believe th it the mortality imong hypospadians is particularly high About three quarters of the cases wert juxtaglandular about one eighth jenile and bout one eighth penoscrotal or perineoscrotal Chapter 3 Ile views regarding the fertility of hypospadians advanced so for hive been bused mainly on theoretical considerations In the present study the frequency of marriage iniong 77 patients over 20 years of ne proved to accord with that among the gener il male population The patients sexual relations do not u pear to differ essentially fiom nor 11 al once surgical correction of the sesere forms of penıle flexion 117s ·85 been accomplished The fertility of 17 married patienls in relation to the severity of their defect proved normal in juxtaglandular - and perhaps also in penile — cises whereas in more severe cases it was reduced but not abolished (hapter 4 Previous genclic studies consist of case reports comprising more or less thoroughly insestigated families and twin series -- apart from I amys series of 10 parrs of twins Uicrefore although indicated by various findings the hereditary nature of the lesion has not been protcd so far I xogenous factors must be presumed to play a part as I amy reported discordance in three out of six pairs of monozygotic twins Chapter 3 To study the genetic aspect the wriler collected a proband and 1 Iw series Out of 173 proband families 103 were examined 13, ar trally cxamined whilc 27 had to be ruled out The genitals of the male rclatuscs were examined except in 18% who refused to submit to the cxamination Chapter 6 The familial cases are presented in pedigrees and the solitary ones in talles The number of males examined ind not examined in each family is given the study of the 12 pairs of twins is reported Chapter 7 1 he material is considered 15 1 whol since there is familial occur rence in all degrees of the lesion — in an average of about 28 - ind inarked intrafamilial variation in the severity The defect is interpreted 14 m inherited lesion 15 the incidence was increased wong the probands relatives and is concordance was found more often in mono zygotre than dizygotic twins The writer conipires the degree of minifestation in the tuin series with the degree of manifestation calculated on the basis of the actunl findings and the number of cises expected among the close relatives at domin int and recessive heredity respectively This calculation in dented recessive heredity with failing manifestation It cannot be ruled out that some instances are of purely exogenous origin Consanguinits occurred in three out of 124 patients parents (24) ·86 Chapter 8 This chapter deals with Goldschmidt's intersexuality thicory and certarn veus regarding the relation of hs pospadias to this theory If liye pospadins are interseres according to this theory, their genetic sex must be female The writer, therefore, set out to study the sex distribution among the children and siblings of the hypospadians in the present series According to the findings, hypospadians cannot be interpreted as female individuals. The distribution of a sex-linked recessive character in this case colour blindness – imong the patients and their parents also does not accord with the view that hypospadins is a form of intersexuality according to the theory of Goldschinıdt The mothers datı regarding hormonal disturbances during pregnuncy were studied This gave no cvidence to interpret hypospadias as 1 hormonal form of intersexuality The age distribution among the mothers does not differ from that expected Chapter 9 Perusal of 90 birth records and data regarding the pregnancy of 34 mothers afforded no reason to attach ætiological significance to foetal infections defective nutrition somatic or psychic traumas, intoxications or hæmorrhages during pregnancy Reporting the complicating malformations in the present series, thic writer tries to rclate them to the hypospadras In the five cases of discordant twins "hosc birth weight is known, the malformed twin was the smaller one On the other hand the birth weight of hypospadruns on the whole did nol differ from the expected values Chapter 10 Lugenics and operative indications are discussed There is no in dication for eugenic measures There is no reason to advise hypospadians against hasing children The possibility of improving the fertility, 1f reduced must therefore be included in one's contemplations regard ing the operative indications In the author's opinion, there is no in dication to operate in juxtaglandular cases ·RESUM L Indledning Arbejdets formal cr hovedsageligt at belyse hypospadiens æetiologi hapitel 1 Ved en gennemgang af lidelsens morfologi påpeges, al der findes en Javn overgang mellem lette og svære grader For det foreliggende arbejde er det mest prahtiske en inddeling 1 juxtaglandærc, penile, penoscrotalc og perineale tilfælde Differentialdiagnosen diskuteres på basis af egne tilfælde Hyppigheden af homplicerende testisretention hos 274 hypospadipatienter sammenlignes med testisretentioncns hyppighed 1 den danske befolkning Herred findes forogel hyppighed af testisretontion for alle hypospadigrader Kapitel 2 Efter en kritisk gennemgang af tidligere undersogelser over hypospadiens hyppighed, gøres rede for egne undersngelser Ved disse fandt man 90 tilfælde blandt 27 613 ca 10 dage gamle drengeborn Denne hyppighed benyttes som et udtryk for hyppigheden i den samlede mandlige befolkning da hypospadipatienter næppe har nogen overdodelig. hed Man finder, at ca *, af tilfaldene er juxtaglandare, ca 13 penile og ca peno crotnle og perincoscrotale Kapitel 3 De tidligere anskuelser om hypospadipatienters fertilitet, der va sent. Tigt er baseret pi teoretiske hefragtninger, omtales i egne undersøgel- Ser findes hyppigheden af ægteskaber for 77 patienter over 20 år at slenme overens med hyppigheden af gteskaber i den mandlige bcfolkning Patienlernes sexuelle forhold synes thke at afvige væsentligt fra det normale, når en sia rere krumning af penis cr operativt udrettet ·88 Os ved en vurdering af 47 gifte patienters fertilitet sammenholdt med deres misdannelses sværhed findes normal fertilitet for de juxtaglandære — og måshe de penile - tilfælde, for de sværere nedsat, men ikke ophævet fertilitet Kapitel 4 Da de tidligere undersøgelser over arveligheden består af hasuistiske meddelelser om mere eller mindre selundersøgte slægter og tullingpar, bortset fra Lamy's tvillingmateriale på 10 par, er det ikhe tidligere bevist, at hypospadi er arvelig, selvom forskellige forhold taler herfor Exogene faktorer er formentlig af betydning, da Lamy fandt diskordans 13 af de 6 cenæggede tullingpar Kapitel 5 Til arbejdets arielighedsundersogelse er indsamlet et proband- og et tvillingmateriale Af 173 probandslægter er 103 undersøgte, 43 delvist undersøgte, medens 27 udgår De mandlinge slægtninges genitalia er undersøgte, dog har 4,8% af de opsogte slægtninge afslået en sådan undersogelsc hapitel 6 De famulere tilfælde er illustreret ved slægtsskemaer og de soltere er opstillet i tabeller Antallet af undersøgte og ikke undersogte mandlige slægtninge er markeret hver enkelt slægt Undersogelsen af de 12 tvillingpar er anført Kapitel 7 Materialet vurdercs under et, da der findes familiar forekomst for alle grader af lidelsen - gennemsnitlig i ca 28 % – og der forekommer en betydelig intrafamiliær variation i tilfældenes sværhed Man anser lidelsen for arvelig, da den findes med forsget hyppighed blandt probandernes slægtninge, og eenæggede tyllingpar hyppigere end toæggede udviser konkordans Manitestationsgraden i tullingmaterialet og manifestationsgraden, udregnet på basis af det fundne og det for henholdsvis dominant og recessiv arvegang for entede antal tilfælde i de nærmeste slægtningegrupper sammenlignes Herved findes størst sandsynlighed for recessiv ariegang med svigtende manifestation Det han ikke udelukkes at nogle tilfælde er rent exogent betingede Indgifte fandtes hos 3 af 124 patienters forældre (2,4 %) ·89 hapitel 8 Goldschmidts interscrutlileisteori og nogle anskuelser om 'pospa diens relation til denne omtales 1 r hypospadipatienter interserer efter denne teori må deres genetiske hon i tre hunligt I dette innteriale har man derfor undersøgt kønsfordelingen blandt hipospadtpatienternes born og i deres søskendellohke Disse fordelinger tillader ikke at hypo Spadipatienter opfattes soni hunlige individer Fordelingen af en hons bundet recessai egenskab som farieblindhed blandt patienterne og deres foreldre stemmer heller ikke overens med anskuelsen om hypo spidi som en intersexualitetsform efter Goldschmidts teori Van har gennemgtet oplysninger om modrene med henblik på har monale forstyrrelser Der blev i dette materiale ikke fundet holdepunkter for at hypospadi hunne opfattes som en hormonal intersexualitetsform fordelingen af modrenes ilder afsiger ikke fra den forventede hamiel od en gennemgang af 90 fødejournaler og oplysninger om 34 modres graviditet findes ingen holdepunhter for at fotale infektioner ern ningsmangler somatiske eller psykishe traumer intoxicationer eller hledninger i siangerskibet er af ætiologisk betydning De komplicerende misdannelser i coet materiale omtales of min oger it suite udvihlingen af disse relation til udviklingen af hypo padi I odselsigten var mindst hos den misdannede tulling i de 5 af materialets tullingpar med dishordans hvor man havde oplysninger om fodselsiegten Ven 90 hypospad patienters fodselsiegt afveg ih he fra det forventede hapitel 10 Ariehygiejne og operationsindikationer diskuteres Der er ihke in dikation for triehygiejniske forholdsregler Der er ingen grund til at fraråde hvpospadipatienter at få bora Vulgheden af at bedre en et nedsat fertilitet må derfor inddrages i overvejelserne om operations indikation Van finder det ikke indiceret at operere de juxtaglandere tus de ·88 Og ved en vurdering af 47 gifte patienters fertılitet samninenholdt med deres misdannelses sværhed findes normal fertilitet for de juxtaglan durc- og måske de penile - tilfelde for de sværerc nedsat men ikke ophiciet fertilitet hapilel ! Du de tidligere undersogelser over Tricligheden bestir n( kasuistiske meddelelser om mere eller mindre iclundersagte slegter og tullingpar hortset fra Lamy s tullingmateriale pi 10 par cr det il ke tidligere he vist at hypospadi er arvelig selvom forskellige forhold taler herfor Lxogene faktorer er formentlig af betydning dn Lamy fundt diskordans 13 af de 6 ceneggede tvillingpar hapitel 5 Til arbejdets ur clighedsundersøgelse er indsamlet et proband og et fullingmateriale Ar 173 probandsigter er 103 undersogte 43 delvist undersogte medens 27 udgår De mandlinge slegtninges genitalia cr undersogte dog har 48% af de opsagte slutninge nfsliet en sådın undersogelse kapitel 6 De famılıure tilfrelde er illustreret ved sirgsskemaer og de solitere er opstillet i tabeller Antallet af undersøgte og ikke underson te mund lige slagtninge er markeret i hver enkelt slugt Undersogelsen af de 12 tullingpar er anfort hapitel 7 Materialet vurderes under et du der findes familier forckomst for alle grader af lidelsen — gennemsnitlig 1 c1 28 % - og der forekom mer en betydelig intrafamiliar variation i tufuidenes sværhed in anser ledelsen for arvelig da den findes med foroget hyppighed blandt probandernes slegtninge og centagede tullingpır hyppigere end to agacde udviser konkordans Manifestationsgraden i tullingmaterialet og manifestationsgraden udregnet på basis af det fundne og det for henholdsvis dominant og recessis arveging for entede antal tilf elde i de nærmeste slegtninge grupper sunmenlignes Herved findes størst sandsynlighed for recessiv irvegang med svigtende manifestation Det kan ikke udelul kes at nogle tilfelde er rent exogent betingede Indgifte fandtes hos 3 af 124 patienters foraldre (24 %) ·89 Kapitel 8 Goldschmidts interscxualitetsteori og nogle anskuelser om hypospa diens relation til denne omtales Er hypospadipatienter interserer efter denne teori, må deres genetske hon e're hunligt I dette materiale har man derfor undersagt konsfordelingen blandt hypospadiipatienternes barn og i deres soshendeflohhe Disse fordelinger tillader ikke, at hypospadipatienter opfattes som hundige individer Fordelingen af en konsbundet recesse egenskab som farveblindhed blandt patienterne og deres fora Idre stemmer heller ihhe overens med anskuelsen om hypospids som en intersexualitetsform efter Goldschmidts teori. Han har gennemgået oplysninger om modrene med henblik på hor. monale forstyrrelser Der blev i dette materiale ikke fundet holdepunkter for, at hypospadi kunne opfattes som en hormonal interserualitetsform fordelingen af modrenes alder afviger ikke fra den for entede. Kapitel 9 Ved en gennemgang af 90 fodejournaler og oplysninger om 34 modres Graviditet findes ingen holdepunkter for, at fotale infektioner, erneringsmangler, somatiske eller psykiske traumer intoxicationer eller blodninger i svangershabet er af a biologisk betydning De homplicerende misdannelser i eget materiale omtales og man Soger at sutte udviklingen af disse i relation til udviklingen af hypopadi Podselstagten var mindst hos den musdannede tulling i de 5 af materniets tuningpar med diskordans hvor man havde oplysninger om fodselsvægten Ven 90 hypospadipatienters fodselsvagt alveg ikke fra det forventede Kapitel 10 Arsehygiejne og operationsindikationer diskuteres Der er ikke indikation for arı chygicjanske forholdsregler Der er ingen grund til at fraride hypospadipatienter at få born Juligheden af at bedre en est nedsat fertilitet må derfor inddrages i overvejelserne om operalionsindikation Man finder det ihke indiceret at operere de juxtaglandıre tilfælde ·REILRCNCLS (\bbresalions in conformity with the Quarterly Cummulative Index Vedicus The figures in brackets indicale the pages in the present work on which the respective author has been cited) 1) Albaugh C II Congenital anomalies following maternal rubella in early weeks of pregnancy JAVA 129 711-723 1945 (76) 2) Irey Leslie Brainerd Developmental anatomy Philadelphia and I on don WB Saunders Company 1942 Pp 612 (79) 3) Bardram Mogens & Poul Brændstrup Maternal rubella during preg nancy as a cause of congenital catarict and other congenital malforma trons Acla ophth 25 353-367, 1947 (76) 4) Barragan Critique des differentes méthodes operatoires de 1 hypospa dias Rev de chir Paris 43 887--888 1911 (23 27) 5) Bendixen II C Iittery occurrence of anopthalmia or mucrophtalmia together with other malformations in swine - Presumably due to vitamin A deficiency of the maternal dret in the first stage of pregnancy and preceding period Acta path et microbiol Scandina suppl 54 161 1944 (76) 6) Berblinger W Mannlicher Geschlechtsapparat In Pathologische Ann tomie Herausgeben von Ludwig Aschoff Achte Auflage Bd II Jena Verlag von Gustav Fischer 1936 P 494 (69) 7) Bjerre Tians Kliniske undersogelser over ingvinalkrypthorchismen hos mennesket Copenhagen Ejnar Munksgaard 1935 Pp 274 P 50 Diss (22) 8) Brendler Herbert A new method for the construction of a glandular urethra in hypospadits iepair J Urol 59 1164-1168 1948 (83) 9) Broster LR The adrenals in sex Practitioner 158 307–314 1947 (73) 10) Buch EC Uber die Abhangigkeit der Missbildungen von Gebaralter Archd Julius Klaus Stiftg 1 Vererbungsforschg 25 61-65 1950 (2574) 11) Bulloch 11 Hereditary malformations of the genital organs Herma phroditism In Treasury of human inheritance Part II London & Edinburgh Cambridge University Press 1909 P 50—61 (40 41) 12) Camerer J IV Diskordantes Vorkommen einer Hypospadie bei einem einerigen Zwillingspaar Erbartz 5 105 1938 (42) 13) Campbell Meredith F Stenosis of the external urethral meatus J Urol 50 740-746 1913 (25) ·91 11) Campiell Meredith llypospadiis Ilien to operate (Ldilorial) Ani J Surg Tew Series 74 791-796 1917 (23) 15) Carroll #illiam 1 Vignancy in <ryptorchidism J Urol 61 396- 401 1919 (26) 10) Cheyne # katson Fr Burghard manual of surgical treatment Sex York Bombay and Calcutta longmans Green & Company, 1913 I'p (18 P 323-33? 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