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Home , Pseudohermaphroditism, XY gonadal dysgenesis

J Med Genet: first published as 10.1136/jmg.7.2.105 on 1 June 1970. Downloaded from Journal of (1970). 7, 105.

Familial XY * JUAN CHEMKEj,t ROBERT CARMICHAEL, JANET M. STEWART, RICHARD H. GEER, and ARTHUR ROBINSONt From the Eleanor Roosevelt Institute for Cancer Research, Department of Biophysics; University of Colorado Medical Center; and the National3Jewish Hospital, Denver, Colorado, U.S.A.

Gonadal dysgenesis is a condition characterized mother. The child's behaviour pattern was definitely by streak in subjects who present the pheno- masculine. At he developed masculine secon- typic appearance of . In pure gonadal dary sex characteristics, and showed heterosexual dysgenesis, unlike Turner's syndrome, no associ- inclinations. ated somatic anomalies are found; the adult is of At the time of admission at age 17 years, he was well normal or above stature masculinized and had the following pertinent physical average and may have findings: height 170 cm., arm span 183 cm., weight 52 eunuchoidal proportions (Sohval, 1965). kg., a moderate amount of facial and axillary hair, and a The term 'XY gonadal dysgenesis' refers to male escutcheon. Bilateral inguinal herniae were pre- patients with pure gonadal dysgenesis who are sent, the left one containing a mass which was thought to chromosomal males (Federman, 1967). In contrast, be a . He had an underdeveloped bifid scrotum, a the term 'dysgenetic male ' large phallus with marked , a perineal urethra, refers to an incomplete form of maldevelopment and a and bilateral patent Fallopian tubes, as of the embryonic testis in patients in whom demonstrated by vaginogram. The remaining physical varying degrees of masculinization and genital examination was non-contributory. copyright. ambiguity are found either at birth or at the time of puberty (Table I). TABLE I GENITAL AND GONADAL FINDINGS IN SUBJECTS In this report we present a family in which three WITH GONADAL DYSGENESIS sibs have abnormal gonads and incomplete sexual Gonadal External God Sex development: two phenotypic females with pure Dysgenesis Genitalia nas Chromosomes gonadal dysgenesis and a phenotypic male with http://jmg.bmj.com/ Turner's syndrome Streaks XO dysgenetic pseudohermaphroditism (Fig. 1 and 2: Pure gonadal Female Streaks and/ XY and dysgenesis or or tumours XO/XY II.6; 11.7; II.8). These two entities have been XY gonadal mosaicism reported in sibs on only one previous occasion (Barr dysgenesis Dysgenetic male Ambiguous Maldeveloped XY and et al., 1967). pseudoherma- testis XO/XY phroditism mosaicism Case Reports Case 1. The propositus (Fig. 1 and 2: I.7) is a 17- An exploratory laparotomy revealed a small on September 26, 2021 by guest. Protected year-old phenotypic male who was admitted to the and two Fallopian tubes. The left hernia sac contained hospital for investigation of ambiguous genitalia. He a small , with and epididymis; the was born after a full-term, uneventful pregnancy, and right sac was empty. Attached to the right Fallopian was pronounced a female by the attending physician. tube was a second gonad (Fig. 3). The bilateral herniae However, this was not accepted by his parents and he were repaired; a left orchipexy was performed, and the was raised as a boy. At 5 years of age, when first ad- uterus, Fallopian tubes, and vagina removed. Later mitted to the Colorado General Hospital, he was surgical procedures focused on releasing the chordee thought to be a pseudohermaphrodite of undetermined and constructing a male urethra. sex; an exploratory laparotomy was refused by his Histological examination of the biopsy of the left gonad and the extirpated right gonad revealed testicular Received 10 November 1969. * This investigation was supported in part by grants from the U.S. tissue with inactive, partially hyalinized seminiferous Public Health Service (FR 00051), National Institutes of Health, the tubules eumeshed in a greatly increased number of inter- Genetics Foundation, and The National Foundation-March of stitial cells and containing Sertoli cells. Additional Dimes. tubular structures t Present address: Department of Pediatrics and Pediatric Re- resembled epididymis and also rete search, Kaplan Hospital, Rehovot, Israel. testis. In multiple sections, there was no evidence of t Reprint requests: Department of Biophysics, 4200 East Ninth ovarian or neoplastic tissue. Avenue, Denver, Colorado 80220, U.S.A. Diagnosis. Dysgenetic male pseudohermaphroditism. 1 1105 J Med Genet: first published as 10.1136/jmg.7.2.105 on 1 June 1970. Downloaded from 105 Chemke, Carmichael, Stewart, Geer, and Robinson

FIG. 1. The three patients: 11.6, pure gonadal dysgenesis; I1.7, dvsgenetic male pseudohermaphroditism; I1.S, pure gonadal dysgenesis. 11.6 and 11.8 were on cyclic hormone therapy at this time. copyright. http://jmg.bmj.com/ 1 2 3 4 5 6 7

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1 2 3 4 5 6 e7 8 on September 26, 2021 by guest. Protected

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Examined - Normal female Pure gonadal dyagenesis

Not examined Dyagenetic male paeudobermaphroditiam

CQy * Abortion Deceased

FIG. 2. Pedigree. J Med Genet: first published as 10.1136/jmg.7.2.105 on 1 June 1970. Downloaded from Familial XY Gonadal Dysgenesis 107

FIG. 3. Surgical findings in Case 1: (A) dysgenetic testis in left hemia sac, with vas deferens and epididymis; (B) dysgenetic testis attached to right ; (C) hypoplastic uterus. Case 2. The older sister of the propositus (Fig. 1 and since then had withdrawal bleeding and breast and 2: II.6) is a 19-year-old phenotypic female who had development. At 8 years of age, a dysgerminoma of the primary amenorrhoea and lack of spontaneous develop- right gonad was removed. On the left was a streak ment of secondary sex characteristics. She had been on gonad which was left in situ.

cyclic oestrogen/progesterone therapy for six months Physical examination revealed a normal appearing copyright. before admission, and since then had regular withdrawal female. Her height was 171 cm., weight 52 kg., and bleeding and development of breasts and pubic hair. arm span 175 cm. She had multiple small naevi on her Physical examination revealed a tall, bony female, skin. There was slight clinodactyly of the fifth fingers. with eunuchoidal proportions, height 185 cm., arm span Axillary hair was sparse, but pubic hair was adequate 193 cm., and weight 56 kg. She had multiple small and of female distribution. The breasts were normally naevi on her skin, with no special distribution, and a developed. On rectal examination, a small firm uterus

hairy naevus on the anterior portion of her right thigh. was felt, without adnexal masses. The external genitalia http://jmg.bmj.com/ Her ears were large, with hypoplastic antihelices, and the were normal for a female, without clitoral enlargement. mandible was slightly prognathic. She had a mild con- Diagnosis. Pure gonadal dysgenesis. Right dys- ductive hearing loss probably secondary to recurrent germinoma. otitis in childhood. A type I bifid uvula was found in Family History the otherwise unremarkable palate. Cubitus valgus was present. Axillary hair and pubic hair were abundant The three patients (Fig. 2: II.6; II.7; II.8) are the last and of normal distribution. The breasts were nor- three sibs in a sibship of seven. Of the other four mally developed, with pigmented areolae. Her external sibs, two are married and have children (Fig. 2: II.2; genitalia were female with normal labia majora and II.3); one, who died at 11 years of age from a ruptured on September 26, 2021 by guest. Protected minora and a moderately hypertrophied . appendix (Fig. 2: II.4), was said to have normal early An exploratory laparotomy revealed bilateral streak breast development, and the other (Fig. 2: II.5) is a gonads which were removed. Anormal-sized nulliparous normally developed female. uterus and normal Fallopian tubes were present. Histo- All seven sibs were purportedly conceived by the logical examination of the streak gonads revealed ovarian same father, who died in an accident at 62 years of age type stroma which contained scattered tubular elements (Fig. 2: I.2). He worked in a uranium mine from one lined by columnar epithelium, presumably of celomic year before the conception of the affected sibs until epithelial origin. No ova, follicles, or neoplastic tissues death. were seen. The mother (Fig. 2: I.3) was 37 years old at the time Diagnosis. Pure gonadal dysgenesis. her youngest daughter was born. She was examined by us at 51 years of age and found to be a normal post- Case 3. The younger sister of the propositus (Fig. 1 menopausal female. and 2: II.8) is a 14-year-old phenotypic female who had not menstruated and had not developed secondary sex Laboratory Studies characteristics. She too was placed on cyclic oestrogen/ The following laboratory tests were within normal progesterone therapy for six months before admission, limits on all three patients: complete blood count, 108 Chemke, Carmichael, Stewart, Geer, and Robinson J Med Genet: first published as 10.1136/jmg.7.2.105 on 1 June 1970. Downloaded from TABLE II CYTOGENETIC STUDIES

Sex Chromosome Analysis Family Chromatin Member (buccal No. smear) Tissue of < 45 45 46 47 > 47 Karyotype Cells I.3 Positive Lymphocytes 30 1 29 46,XX I.5 Positive I Lymphocytes 20 1 19 46,XX LymphocytesL 30 1 29 46,XY I1.6 Negative oSkin 15 1 14 46,XY Fallopiantube 15 15 46,XY LymphocytesL 30 1 28 1 46,XY 11.7 Negative oSkin 20 20 46,XY } Gonad 20 1 4 15 46,XY Lymphocytes 11.8 Negative lSkin I1305 3015 46,XY urinalysis, blood urea nitrogen, creatinine, serum both chromatin positive, and had a normal 46,XX karyo- electrolytes, and total carbon dioxide, and skull and chest type (Table II). x-rays. Case 2 (II.6) had a retarded bone age (bone A series of steroid analyses was carried out on blood age 13 years at chronological age of 19 years), whereas and urine samples from the three patients (Table III). the other two patients had normal bone ages. was determined by gas chromatography Dermatoglyphic analyses were not unusual. equipped with an electron capture detector (Exley, Perceptual and psychological tests revealed that all 1967). The fractionated 1l-deoxy-17-ketosteroids were three patients were of normal intelligence. The two estimated using a combination of glass fibre paper chro- sisters have problems with visual integration, more matography and gas liquid chromatography equipped marked in the younger one (Case 3: IL.8). with a flame ionization detector (Wotiz and Martin, Blood groups from the mother and all her children 1962). were determined, as well as haptoglobin, G6PD, colour The blood and urinary testosterone levels showed some blindness, and phenylthiourea tasting test. Since interesting abnormalities. They were low in the

pro- copyright. neither the father nor a paternal uncle were available, positus when compared to a normal male; the corres- these studies were not revealing. ponding values in the two sisters (on therapy) were much lower than those of the propositus, but still higher than normal female values. Other steroid levels were low to Cytogenetic and Endocrine Studies normal. Buccal smears for sex chromatin bodies and lympho- In order to investigate the source of the in cyte and fibroblast cultures were performed by modi- the propositus, dexamethasone was given to suppress http://jmg.bmj.com/ fications of standard techniques (Moorhead et al., 1960; adrenal synthesis of testosterone. Two days later, Tjio and Puck, 1958). The three patients were chro- while continuing the dexamethasone, human chorionic matin negative, and chromosome analysis of all examined (HCG) was also given in order to stimulate tissues revealed a 46,XY karyotype, with no evidence of the testicular production of testosterone (Table IV; Fig. mosaicism. Their mother and one normal sister were 4). The patient's urinary levels of testosterone fell

TABLE III HORMONE LEVELS on September 26, 2021 by guest. Protected

Urinary Excretion Patients Normal Adult Values (mg./24 .) Case 1 Case 2 Case 3 Male Female Total 17-ketosteroids 11-2 4-6 5-7 7-22 5-20 Total 17-OH corticoids 13-5 8-8 7-4 7-22 5-20 Androsterone 1*9 0*85 0*6 1*5-3*8 1*0-2*5 Etiocholanolone 2-0 1-0 0 9 10-3 0 1-5-3*5 Dehydroisoandrosterone 0-67 0 55 0 3 0-5-1-5 0-2-1-0 Pregnanediol 0-8 1-3 1-5 1-0 1-5-4 0 11-OH androsterone 0 7 0 5 0-3 0-5-1-0 0-4-0-8 11-0 androsterone 0 3 0-1 0-1 0 2-0-5 0-20-5 11-OH etiocholanolone 0-95 0.45 0-6 0-7-1-5 0-5-1-2 11-0 etiocholanolone 0-2 0-1 0-2 01-0-5 0-01--5 FSH (m.U.) + 6/-105 + 50/-100 + 16/-50 + 6/-105 Testosterone Blood (,ug./100 ml.) ( ± 0-05 = 2 SD)* 0 44 0 04 0-05 0-45-1-1 0-01-004 Urine (gg./24 hr.) (±3=2 SD) 39 5 19-4 20-4 45-125 2-17

*SD, standard deviation. J Med Genet: first published as 10.1136/jmg.7.2.105 on 1 June 1970. Downloaded from Familial XY Gonadal Dysgenesis 109 from a basal value of 39-5 tg./24 hours to a suppression Canton, 1962; Frasier, Bashore, and Mosier, 1964; value of 5-4 jAg./24 hours, and did not rise with HCG Stemnberg, Barclay, and Kloepfer, 1968). Before stimulation. Blood testosterone and other steroid the present report, no phenotypic males had been fractions followed a similar pattern. All levels returned described in association to their previous values only after cessation of the dexa- with familial XY gonadal dysgenesis, though the first case of Barr et al. (1967) showed definite signs of masculinization at 80- the onset of puberty. This patient was a male 1- pseudohermaphrodite; the sister had pure 70Q x x Normal male control x gonadal dysgenesis. All the other patients have had pure a 60- gonadal dysgenesis, and 46,XY . In v the only reported 45,X/46,XY mosaic in this 4,5Q50 Lower limit group x-L of and normal male range (Cohen Shaw, 1965), the 45,X line was found in 50% of the mitoses from one gonad only. Table V cx 30* ,' summarizes the principal characteristics of all these 40 11-7 ;- 20 patients, including our three cases. Only in the 0 cases reported by Cohen and Shaw (1965) and by 10 Br0gger and Strand (1965), were marker chromo- somes found. 1 HCG In our patient with dysgenetic male pseudo- Dexamethasone hermaphroditism, there was no response to gonado- r-_ after dexamethasone o 2 3 4 5 6 tropin administration, and Days testosterone levels did not rise until adrenal was terminated. FIG. 4. Urinary testosterone response to dexamethasone (7 5 mg./ suppression The primary source day) and HCG (1500 I.V./day), in Case 1 and in a normal 20-year- of testosterone, therefore, is the adrenal, and the old man (Carmichael and Jenkins, in press). patient has little if any steroid of testicular origin. The serum and testosterone urinary values in the copyright. methasone administration. The values of the other two sisters were raised as steroid compared with a normal fractions showed the same pattem as did testo- but lower than a normal sterone. In contrast, the normal control male responded female, male. High to dexamethasone with a similar drop in testosterone, urinary testosterone levels in phenotypic females which rose considerably after HCG stimulation. with male karyotypes have been reported on several occasions (Federman, Davidoff, and Ouellette, TABLE IV 1967; Ismail et al., 1968; Josso et al., 1969). The DEXAMETHASONE SUPPRESSION AND HCG adrenals of chromosomal males (whether pheno- http://jmg.bmj.com/ STIMULATION IN CASE 1 typically male or female) produce more androgens 1* 2t 3t 45i than those of chromosomal females. The reason for this is not Urinary excretion (mg./24 hr.) completely understood. The foetal Total 17-ketosteroids 12*7 5-3 4-8 10*2 testis synthesizes testosterone early during dif- Total 17-OH corticoids 14-5 4-8 3-6 13-9 Androsterone 2-7 0 9 0 7 2-0 ferentiation (Villee, 1969), and Tata (cited by Max Etiocholanolone 2*3 0*5 0*5 2*5 that Dehydroisoandrosterone 0-8 0-2 0-1 0.5 Hamburgh, 1969) hypothesized the primary

11-OH androsterone 0-8 0-2 0-2 0-6 action of these hormones on developing target struc- on September 26, 2021 by guest. Protected 11-O androsterone 0-3 0 0 01l 11-OH etiocholanolone 1-2 0 3 0-1 0-8 tures is the stimulation of some transcriptional RNA 11-0 etiocholanolone 0-3 0 0 0-2 Testosterone synthesis. These data suggest that the foetal testis Blood (Mg./100 ml.) 0-52 0-13 0-13 0-56 programs the adrenal for increased testosterone Urine (jAg./24 hr.) 39*5 5 4 5*4 35-6 production at a later developmental stage. * Baseline levels. The various types of gonadal dysgenesis here t During adrenal suppression. considered probably have their determining t During adrenal suppression and HCG administration. steps § Baseline levels, 10 days after 3t. occurring early in foetal development. The ex- periments of Jost (1953) have shown that a func- Discussion tioning testis is essential for the stimulation of Wolffian duct derivatives and the inhibition of The familial occurrence of XY gonadal dysgenesis Miillerian duct derivatives. The foetal testis is in a single as well as in different sibships has been thought normally to secrete an inducer or organizer reported by several authors (Barr et al., 1967; substance which evokes these effects through a local Bartlett et al., 1968; Br0gger and Strand, 1965; action. Jost showed that early castration of male Cohen and Shaw, 1965; Fine, Mellinger, and embryos prevents the resorption of the Mullerian 110 Stewart, Geer, and Robinson

Chemke, Carmichael, J Med Genet: first published as 10.1136/jmg.7.2.105 on 1 June 1970. Downloaded from TABLE SUMMARY OF FINDINGS IN FAMILIAL

Case 1 Case 2 Case 3 Fine et al. (1962) Cohen and Shaw (1965) Barr et al. (1967) Relationship Sibs Sibs Sibs* I Sibs Age (yr.) 17 19 14 22 21 27 16 25 Phenotype M F F F F F F F F Primary amenorrhoea + + + + + + + + Breast development _ _ _ + + + + + Areolar pigmentation _ _ + _ Axillary hair + - _ 4 + + + Pubic hair + + + + + 4- External genitalia M/F F F F F F F Enlarged clitoris + _ + + _ + Hypoplastic uterus + - + + + + + + + Fallopian tubes + + + + + + + + + Gonads T S S S S S S T S Undifferentiated gonadal tumour _ - D G - G G - Sex chromatin Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg Karyotype 46,XY 46,XY 46,XY 46,XY 45,X/ 46,XY 46,XY 46,XY 46,XY * Two marker chromosomes: one B group chromosome with marked secondary constriction present in mother, 1 normal, and 1 affected sister; one G group chromosome with long short arms present in mother and 2 patients. t Marker chromosome present in affected sisters only: D group chromosome with unusually large satellites. t Three additional phenotypic females (deceased) had primary amenorrhoea and were physically similar to the patients. duct system with absent or abnormal masculiniza- ment. All have apparently normal male karyotypes. tion of the external genitalia. Endocrinological studies in the patient with dys- It is therefore possible that the defect in the genetic male pseudohermaphroditism revealed a abnormal foetal gonad may lie in the structure, the non-functioning testis, and it was shown that his amount, or the time of production of the inducer testosterone was of adrenal origin. It is concluded substance. Complete failure of inducer action that the various manifestations of pure gonadal would be analogous to early castration, in which a dysgenesis and dysgenetic male pseudohermaphro- streak gonad is produced which is incapable of ditism differ only in the degree of severity. The copyright. inducing masculinization even though a Y chro- genetics ofthis familial condition is unknown though mosome is present. A lesser abnormality of the a gene mutation is suggested. foetal testis would then produce a dysgenetic male pseudohermaphrodite with varying degrees of Thanks are due to the Department of Obstetrics and masculinization of the genitalia. Gynecology and the Department of Urology of the University of Colorado Medical Center for their co- The aetiology of the defects in this family is un- operation in the study ofthis family; and to Dr. Theodore http://jmg.bmj.com/ known, but the involvement of three out of seven T. Puck for his suggestions and advice. sibs suggests a genetic origin. Since the chromo- somes appear normal, gene mutation seems a likely REFPENCES mechanism. The genes involved could be carried Barr, M. L., Carr, D. H., Plunkett, E. R., Soltan, H. C., and Wiens, R. G. (1967). Male pseudohermaphroditism and pure gonadal on the as a sex-linked recessive trait dysgenesis in sisters. American Journal of Obstetrics and Gyne- or on an autosome and inherited in a sex-limited cology, 99, 1047-1055. Bartlett, D. J., Grant, J. K., Pugh, M. A., and Adherne, W. (1968). autosomal dominant manner. If this condition A familial feminizing syndrome. A family showing were transmitted by the father, a translocation must characteristics with XY chromosomes in three female members. on September 26, 2021 by guest. Protected occurred between the Y and the X chromosome Journal of Obstetrics and of the British Commonwealth, have 75, 199-210. during meiosis. This is most unlikely since three Br0gger, A., and Strand, A. (1965). Contribution to the study of children are involved. the so-called pure gonadal dysgenesis. Acta Endocrinologica (Kobenhavn), 48, 490-505. Of particular interest is the fact that the affected Carmichael, R., and Jenkins, D. (In press). sibs have apparently identical XY chromosomal Cohen, M. M., and Shaw, M. W. (1965). Two XY siblings with gonadal dysgenesis and a female phenotype. New England constitutions, and yet exhibit two different clinical Journal of Medicine, 272, 1083-1088. types of gonadal dysgenesis. It is likely that these Exley, D. (1967). The ultramicro detection of steroids, using gas two clinical entities share a common defect liquid chromatography with electron capture detection. Memoirs genetic of the Society for , 16, 117-128. and that other modifying genetic or environmental Federman, D. D. (1967). Disorders of sexual development. New factors may have influenced the various phenotypes. EnglandJournal of Medicine, 277, 351-360. - , Davidoff, F. M., and Ouellette, E. (1967). Presumptive Y/D translocation in mixed gonadal dysgenesis. Journal of Medical Summary Genetics, 4, 36-40. Fine, G., Mellinger, R. C., and Canton, J. N. (1962). Gonadoblas- A family is presented in which three sibs have toma occurring in a patient with familial gonadal dysgenesis. dysgenetic gonads and abnormal sexual develop- American journal ofClinical Pathology, 38, 615-629. J Med Genet: first published as 10.1136/jmg.7.2.105 on 1 June 1970. Downloaded from Familial XY Gonadal Dysgenesis 111

XY GONADAL DYSGENESIS

Frasier et al. (1964) Stemnberg et al. (1968) Brogger and Strand (1965) Bartlett et al. (1968) Monozygotic twins First cousins and maternal aunt Sibst First cousins and maternal aunt* Relationship 6 6 13 16 25 21 18 24 Age (yr.) F F F F FFF F F F Phenotype + + + + + + + + Primary amenorrhoea _ _ _ + + + + Breast development _ _ _ + Areolar pigmentation * _ + + + Axillary hair _ _ + + + + Pubic hair F F F F F F F External genitalia s- _ + - _ _ _ + Enlarged clitoris + - + + -Hypoplastic uterus + + + + + + Fallopian tubes * S S S S S Gonads Undifferentiated G G _ D D gonadal tumour .F,. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Sex chromatin 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY Karyotype

Symbols: M-Masculine T-Testis G-Gonadoblastoma F -Feminine S-Streak D-Dysgerminoma M/F -Ambiguous Blank spaces-No information available

Frasier, S. D., Bashore, R. A., and Mosier, H. D. (1964). Gonado- Hungerford, D. A. (1960). Chromosome preparations of leuko- blastoma associated with pure gonadal dysgenesis in monozygous cytes cultured from human peripheral blood. Experimental Cell twins. journal of Pediatrics, 64, 740-745. Research, 20, 613-616. Hamburgh, M. (1969). Hormones in development. Science, 164, Sohval, A. R. (1965). The syndrome of pure gonadal dysgenesis. 1191. AmericanJournal ofMedicine, 38, 615-625. Ismail, A. A. A., Harkness, R. A., Kirkham, K. E., Loraine, J. A., Sternberg, W. H., Barclay, D. L., and Kloepfer, H. W. (1968). Whatmore, P. B., and Brittain, R. P. (1968). Effect of abnormal Familial XY gonadal dysgenesis. New England Journal of Medi- sex-chromosome complements on urinary testosterone levels. cine, 278, 695-700. Lancet, 1, 220-222. Tjio, J. H., and Puck, T. T. (1958). Genetics of somatic mam- Josso, N., Nezelof, C., Picon, R., de Grouchy, J., Dray, F., and malian cells. II. Chromosomal constitution of cells in tissue copyright. Rappaport, R. (1969). Gonadoblastoma in gonadal dysgenesis: a culture. Journal of Experimental Medicine, 108, 259-268. report of two cases with 46,XY/45,X mosaicism. Journal of Villee, D. B. (1969). Development of endocrine function in the Pediatrics, 74, 425-437. human placenta and fetus. New England Journal of Medicine, Jost, A. (1953). Problems of fetal endocrinology: the gonadal and 281, 533-541. hypophyseal hormones. Recent Progress in Hormone Research, 8, Wotiz, H. H., and Martin, H. F. (1962). Studies in steroid meta- 379-418. bolism. XI. Gas chromatographic determination of in Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., and human pregnancy urine. Analytical Biochemistry, 3, 97-108. http://jmg.bmj.com/ on September 26, 2021 by guest. Protected