THE COEXISTENCE of congenital

Familial Hypogonadotrophic Eunuchoidism with Cerebellar Ataxia ROBERT VOLPE, M.D., F.R.C.P.(C), WILLIAM S. METZLER, M.D., F.R.C.P.(C) AND M A C A L L ...
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Familial Hypogonadotrophic Eunuchoidism with Cerebellar Ataxia ROBERT VOLPE, M.D., F.R.C.P.(C), WILLIAM S. METZLER, M.D., F.R.C.P.(C) AND M A C A L L I S T E R W. JOHNSTON, M.D., F.R.C.P.(C) Department of Medicine, University of Toronto, and the Medical Services, Toronto General Hospital and St. Joseph's Hospital, Toronto, Canada

ABSTRACT. Two brothers, aged 23 and 31, exhibiting hypogonadotrophic eunuchoidism with cerebellar ataxia have been studied. The chromosome examinations revealed a normal male karyotype in each. A maternal uncle (not studied) apparently has the same syndrome. Seminiferous tubular dysgenesis and hypogonadotrophic eunuchoidism have been described previously in association with Friedreich's ataxia, of which cerebellar ataxia is a variant. While seminiferous tubular dysgenesis has also been described with cerebellar ataxia, the patients reported herein appear to be the first cases of hypogonadotrophic eunuchoidism in association with cerebellar ataxia to be reported. The disease entity could be due to either multiple gene linkage or a single mutant gene, but the available family data are insufficient to permit formulation of the genetic defect in these patients.

T

HE COEXISTENCE of congenital male gonadal abnormalities and certain congenital or abiotrophic diseases of the nervous system has been given increasing attention in recent years. These neurologic diseases (often familial as well as congenital) include mental retardation (1 3), myotonia dystrophica (4-7), Friedreich's ataxia (8-12), Marie's cerebellar ataxia (13-15) (probably a variant of Friedreich's disease) and LawrenceMoon-Biedl syndrome (16, 17). The two main types of gonadal dysfunction reported in association with these neurologic diseases are seminiferous tubular dysgenesis (Klinefelter's syndrome) (1 8, 13, 14, 16) and hypogonadotrophic eunuchoidism (10-12, 17); both of these congenital gonadal diseases may be sporadic or familial (18-20). It is the purpose of this paper to report the cases of two brothers with coincidental hypogonadotrophic eunuchoidism and cerebellar ataxia. It is hardly necessary to recall that Friedreich's ataxia is a chronic, slowly progressive, familial heredodegenerative disease, involving the lateral and posterior columns of the spinal cord, as well as the cerebellum (21 23). In addition to the neurologic signs, pes cavus, spina bifida occulta, electrocardiographic changes (34) and various other abnormalities may be Received June 21, 1962.

associated with it. Marie's cerebellar ataxia appears to be a variant of Friedreich's disease, occurring later and mainly involving the cerebellum (22-24). Transitional forms between the spinal (Friedreich's) and cerebellar (Marie) forms are described. Although the precise incidence of the association of male hypogonadism with either Friedreich's ataxia or its variant, cerebellar ataxia, is unknown, it appears to be more than coincidence. Some of the pertinent case reports from the literature are cited below: Cooper et al. (8) have reported a 21-yearold male suffering from a heredofamilial myelopathy, probably representing atypical Friedreich's ataxia. He was also found to have diabetes mellitus and optic atrophy

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(both found in others in the family), as well as gynecomastia and prostatic and testicular hypoplasia. His 24-hr excretion of 17 ketosteroids was reduced to 3.4 mg, and his urinary gonadotrophins were found to be 5 rat units per liter (normals 5-20 rat units). A testicular needle biopsy showed atrophy of the germinal epithelium of the seminiferous tubules, aspermatogenesis and thickening of the basement membrane, with hypertrophy of the Leydig cells. Although Cooper et al. did not attempt to characterize the type of hypogonadism, it would appear to be a case of seminiferous tubular dysgenesis. Spota and Novizki (9) have reported the case of a 21-yr-old man with Friedreich's ataxia, mental retardation, obesity, diabetes insipidus and hypogonadism. His low 17ketosteroid excretion was combined with a normal excretion of gonadotrophins; however, his testicular biopsy showed hypoplastic tubules without Sertoli cells or spermatogenesis, and the interstitial tissue was composed only of fibrous tissue without Leydig cells. This case was characterized in the report as one of dystrophia adiposogenitalis, although no actual lesion of the hypothalamus could be demonstrated. Hammel (10) has reviewed the literature concerning reported endocrinopathies in Friedreich's ataxia, and was able to find 42 observations suggesting such associations. Twenty-four of these 42 patients suffered from diabetes mellitus. Hypogonadism appeared to be present in 14 cases, but many of these reports were not well documented. However, the 2 cases cited above, showing more definite findings, were also summarized by Hammel. Subsequently, cases of seminiferous tubular dysgenesis in association with familial cerebellar ataxia have been reported by Boudin et al. (13) and Hecht and Ruskin (14). These 2 cases were very similar in their clinical and laboratory manifestations; however, the sex chromatin was negative in Boudin's case and positive in Hecht's patient.

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ondary to the gonadotrophin deficiency, and thus Leydig cells are absent or decreased. Hypogonadotrophic eunuchoidism as a cause for eunuchoidism is fairly common (25), and its familial occurrence has already been described (20). However, only the following two previously reported cases, in which there were similar associated neurologic disorders, would appear to approximate our cases {vide infra) to any degree:

The first of these is the case of Vignalou et al. (11) [previously reported from the neurologic viewpoint by Boitelle et al. (12) and also included in Hammel's (10) thesis]. This was a 36-yr-old male suffering from Friedreich's ataxia (with pes cavus), who, since age 20, had manifested clinical hypogonadism, with a eunuchoid habitus, long tapering extremities, but no gynecomastia. His genitalia were infantile, and he had a prepubertal appearance. His bone age was 13-14 yr. Laboratory studies showed a low 17-ketosteroid excretion and a very low urinary gonadotrophin excretion. Sex chromatin studies indicated that his genetic sex was male. A testicular biopsy showed atrophy and hyalinization of tubules, without Sertoli cells or spermatogenesis; interstitial fibrosis without Leydig cells was also noted. The second of these, reported as an unclassifiable syndrome, was recently described by Ryan (17). This was a 24-yr-old man who showed evidence of Lawrence-Moon-Biedl syndrome (with retinitis pigmentosa, mental retardation, obesity, pes cavus and genu valgum, but no polydactyly or syndactyly), but who also had distinct Friedreich's ataxia. He had a eunuchoid habitus, infantile genitalia and prepubertal appearance. His bone age was 15 yr; urinary 17-ketosteroids were reduced and urinary gonadotrophins were undetectable. A buccal smear showed that less than 5% of the cells showed a nuclear chromatin body, within normal The foregoing cases must be differenlimits for males. This man's 16-yr-old brother tiated from cases of hypogonadotrophic had a virtually identical syndrome. eunuchoidism, in which there is a specific deficiency in pituitary gonadotrophins; The preceding two patients cited from in contrast with seminiferous tubular the literature therefore have hypogondysgenesis, the testicular failure is sec- adotrophic eunuchoidism with Fried-

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reich's ataxia. The second case, in which the hypogonadotrophism was clearly familial, also had some features suggestive of Lawrence-Moon-Biedl syndrome. It would appear that the cases of the two brothers to be recorded below are the first reported cases of familial hypogonadotrophic eunuchoidism associated with the Marie type of cerebellar ataxia, although it is evident from the foregoing that there are many closely related syndromes already published. Case Reports Case 1

A.T. (TGH. G68938), a 23-yr-old male (when investigated in 1957), was the youngest of 3 siblings. This patient had a normal childhood until the age of expected puberty. Thereafter, he continued to grow, but his features remained childish. His genitalia failed to grow, his voice did not deepen, and he failed to grow hair on face and body. His musculature remained poorly developed. He stated that his libido was "normal," but he had only rare phallic erections and no seminal ejaculations. At age 20, he began to note involuntary shaking of his head, and occasional tremor of his extremities. This was quite mild and did not lead to overt ataxia. The tremor had remained virtually stable after the first year of its onset. Physical examination (February, 1957). Examination revealed a tall, thin young man, with prepubertal facial appearance and a eunuchoid habitus (Fig. 1). He had long tapering extremities, fingers and toes. His weight was 140 pounds, height 70 inches, with an arm span of 74 \ inches and symphysis-to-floor measurement of 37 \ inches (these measurements indicate prolonged extremities proportionate to the torso). His voice was high pitched; his scalp hair was fine and there was no temporal balding. There was no growth of facial, axillary or body hair, other than a scant growth of pubic hair in a female distribution. His penis was small, and his scrotum contained 2 small hypoplastic testes measuring approximately 1X0.5X0.5 cm. The prostate gland was very small. His musculature was poorly developed and his skin was fine and

FIG. 1. A.T., then aged 23. Note eunuchoid habitus and undeveloped genitalia. The pectus excavatum is not clearly evident in this photograph.

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soft. There was no gynecomastia. An examination of the chest revealed moderate pectus excavatum. There were no clinical cardiovascular abnormalities. Mild pes cavus was evident bilaterally. Neurologic examination revealed moderate titubation of the head, nystagmus in all directions and minimal intention tremor. There were no signs of sensory or pyramidal tract involvement; there was slight reduction in muscle tone, but the reflexes were normal throughout. Pertinent investigations (see Table 1). Treatment and subsequent course. Human chorionic gonadotrophin (APL1) was administered in doses of 3,000 IU twice weekly; this was continued for 3 months. The therapy caused a gradual increase in hair growth, FIG. 2. T.T., then aged 31. He shows a eunuchoid habitus similar to that manifested by his brother. The shortening of his left leg is due to osteomyelitis.

1 APL = Ayerst-McKenna brand of human chorionic gonadotrophin.

FIG. 3. Testicular biopsy from T.T., showing small seminiferous tubules without lumina, Sertoli cells or any evidence of spermatogenesis. The interstitial tissue contained no Leydig cells. The appearance was that of an infantile testis. (The biopsy from A.T. had an identical appearance.)

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TABLE 1

Normal Range Test 24-hr urinary gonado- 6-90 mouse units troph.n excretion (26) 24-hr urinary 17-keto- 8-20 mg/day steroid excretion (27)

A.T., aged 23

T.T., aged 31

less than 6 mouse units (twice) 6.0 and 6.3 mg/day (2 successive days)

Less than 6 mouse units (twice) 4.5 and 6.5 mg/day (2 successive days)

24-hr urinary 17-hy- 1-10 mg/day droxycorticoid excretion (28)

2.3 and 2.8 mg/day (2 4.0 and 4.3 (2 successive successive days) days)

2-day ACTH test (29)

normal adrenocortical response

serum protein-bound iodine (30)

3.5-6.5 ^g/100 ml in 5.0 Mg/100 ml our laboratory (31)

normal adrenocortical response 4.6 Mg/100 ml

24-hr thyroidal uptake 10-40 % of I131

17%

21%

glucose tolerance test

normal

normal

buccal scraping for sex chromatin (32)

chromatin-negative

chromatin-negative

chromosome pattern (33)

carr"ed out in 1961 normal male karyotype by Dr. P. Conen

normal male karyotype

testicular biopsy

In biopsies in both patients, there are small seminiferous tubules without lumina, without Sertoli cells or any evidence of spermatogenesis. The interstitial tissue contained some undifferentiated mesenchymal cells, but no Leydig cells. The appearance in each was that of an infantile testis (see Fig. 3).

Bone age by epiphysial x-ray films

14-15 yr

Electroca rd iogra m

incomplete right bundle same branch block, suggestive of right ventricular hypertrophy (Fig. 4)

Skull Films

somewhat shallow pos- same terior fossa, and some benign frontal hyperostosis (Fig. 5)

potency, libido and weight. Toward the end of this course of treatment, his urinary excretion of 17-ketosteroids was 13.8 mg/day. Since he remained azospermic, and the frequent visits were not convenient, this form of therapy was abandoned; his signs of maturation soon regressed. He was then begun on monthly intramuscular injections of 300 mg testosterone cyclopentylpropionate (Depotestosterone2). 2 Depotestosterone = Upjohn testosterone cyclopentylpropionate .

15 yr

He again began to gain weight (to 160 pounds) and experienced greatly increased libido, erections and potency. He felt more energetic and stronger; his voice became deeper; and there has been gradually increasing hair growth on his face and body. He has continued on this therapy until the present time (March, 1962) and has reached a plateau of masculinization. There has been only slight progression in his cerebellar signs, although his speech has become overtly halting.

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T.T. (TGH. B15593), aged 31, is A.T.'s oldest brother (Fig. 2). His history is very similar to that of his brother, as recorded above. Aside from chronic osteomyelitis of the left femur, he was well during childhood. At the time of expected puberty, he became aware that he was not developing normally. His body remained childish despite continued growth in stature; he was easily fatigued, with poor muscular development; sexual maturation did not begin, and his voice remained high pitched. At about age 16, he first noticed diplopia while looking at close objects, some oscillopsia, halting of speech, intermittent instability of his extremities, and shaking of the head. These symptoms had progressed very slowly over several years. Physical examination (1957). The patient was a tall, thin male with a small head, prepubertal features, high voice and typical eunuchoid habitus with long tapering extremities. His weight was 125 pounds, height 701 inches, arm span 74} inches and symphysis-to-floor measurement of 38 inches. The skin was soft and fine. The scalp hair was fine, and there was no temporal balding. There was no facial, axillary or body hair other than scant growth of pubic hair in a female distribution. His penis was small and his testes were small and soft. The prostate gland was very tiny; muscular development was poor; there was no gynecomastia. Neurologic examination demonstrated halting speech, titubation of the head, nystagmus in all directions and mild intention tremor. There were no signs indicative of posterolateral spinal tract involvement. The muscle tone was minimally reduced, and reflexes were normal throughout. Marked pectus excavatum was noted, as was mild pes cavus. Pertinent investigations (see Table 1). Treatment and subsequent course. The pa-

FIG. 4. Electrocardiograph^ tracing (A.T., 1957) showing incomplete right bundle branch block, and also suggestive of right ventricular hypertrophy. (The tracing from T.T. was similar in all details.)

tient has been treated with monthly intramuscular injections of 300 mg testosterone cyclopentylpropionate (Depotestosterone). Over the past 4 years on this medication, he has gained 32 pounds, become stronger and moderately well masculinized, with deepening voice, moderate growth of facial hair, slight growth of body hair, increased libido and potency. His symptoms and signs of cerebellar

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disease are progressing at a very minimal rate. Family History There is a third sibling, another male, who is normal, married, and has small children. The parents of the propositi are both normal. However, one maternal uncle has the same complete syndrome these patients have. This uncle lives in a distant rural district 3,000 miles away; we have not had the opportunity to study him. Aside from this man and the brothers reported above, there is no known history in this family of persons afflicted with either the neurologic or endocrinologic components. However, only the immediate family is known, as shown in Fig. 6.

Discussion The brothers described above clearly have hypogonadotrophic eunuchoidism with cerebellar ataxia. There were no neurologic signs suggestive of spinal involvement, so the neurologic component may be considered to be Marie's type of cerebellar degeneration rather than typical Friedreich's ataxia. In addition, each patient had pes cavus, pectus excavatum, and incomplete right bundle branch block in the electrocardiogram. It is of further interest that T.T. demonstrated obvious titubation and tremor, whereas A.T.'s neurologic signs were initially somewhat more occult. Despite the occurrence of a similar syndrome in a maternal uncle (who could not be investigated), no other family history of a similar syndrome or any component thereof could be obtained. However, a strong familial trend is seen in at least these two generations, although obviously the component of hypogonadotrophic eunuchoidism is a self-limiting trait. A course of chorionic gonadotrophin was utilized in patient A.T., in view of its reported efficacy in occasionally stimulating spermatogenesis in hypogonadotrophic eunuchoidism (35-39).

FIG. 5. Skull film (A.T.) showing a somewhat shallow posterior fossa and mild hyperostosis frontalis. (T.T.'s skull films were similar.)

He was therefore given 3,000 units chorionic gonadotrophin twice weekly for three months; while this treatment did lead to a moderate increase in virilism and potency, as well as a rise in 17-ketosteroid excretion, he continued to be

Or-D

6

6

b o o on

fil A.T.

T.T.

FIG. 6. Hypogonadotrophic eunuchoidism with cerebellar ataxia. Pedigree of family. The propositi are shown with initials below. Unfortunately, it was not possible to collect information from more distant members of the family. The paternal side of the propositi is not included, as there is no history of any similar condition.

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azospermic. The treatment was then abandoned, and the pubertal maturation regressed. In view of the success of others (35-39) in causing fertility in similar patients with much more prolonged treatment with chorionic gonadotrophin, it may well be that the treatment was given up too soon. Both patients have undergone the anticipated masculinization on androgen therapy, but have remained azospermic, as expected. [However, androgen therapy has twice been reported to induce spermatogenesis in such patients (36, 40).] It seems evident that the patients described above inherited a group of genetic defects which otherwise appear to have little or no relationship to one another. It is not known whether the cases described above are (a) the result of the inheritance of multiple abnormal genes in a chance or random association, (b) due to linkage of genes on a single chromosome, or (c) the result of a single gene. The first possibility, i.e., that perhaps this syndrome is due to the random association of more than one genetic defect, is belied by the observation that all three afflicted members of the family have the whole group of clinical abnormalities (the phenocopy is the same); if this group of clinical manifestations represented a chance association of more than one gene, it would be expected that some members of the family would exhibit only part of the syndrome complex, e.g., cerebellar ataxia alone. Since this was not th,e case, it is not possible to explain the foregoing cases by such a random association of genes. It is not possible to decide from the available evidence which of the last two possibilities is the more likely genetic mechanism. Gene linkage (in which multiple genes lie close together on a

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single chromosome and are passed on to descendants as an intact complex) could explain this syndrome. However, it is well known that single genes may result in multiple clinical defects, e.g., Lawrence-Moon-Biedl syndrome (15) and Marfan's syndrome (41). A single mutant gene would seem to have at least as much in its favor as the possibility of multiple linked genes. This point cannot be resolved at present. Similarly, the family data are insufficient to distinguish between the possibility of sex-linked inheritance and an autosomal dominant trait with variable penetrance and expressivity. It is of interest, however, that hereditary ataxia may occasionally be a sex-linked recessive characteristic (42). It is clearly evident that further evidence is necessary to allow a more precise formulation of the genetic defects in such cases. Acknowledgments Grateful acknowledgement is made to Dr. L. John Sullivan, Dr. A. Hudson, Dr. H. H. Hyland, Dr. John C. Laidlaw, Dr. Patrick Conen, Dr. Lawrence Mautner and Dr. James Henning for their assistance in the investigation of these patients. We are also indebted to Dr. Ed. Reed for his helpful comments regarding the genetic aspects, and to Professor K. J. R. Wrightman for his review of the manuscript.

References 1. Ferguson-Smith, M. A., Lancet 1: 928, 1958. 2. , Lancet 1: 219, 1959. 3. Prader, A., J. Schneider, W. Ziiblin, J. M. France's and K. Ruedi, Schweiz. Med. Wschr. 88: 917, 1958. 4. Nadler, C. S., W. A. Steiger, M. Troncelletti and T. M. Durant, J. Clin. Endocrinol. 10: 630, 1950. 5. Grumbach, M. M., W. A. Blanc and E. T. Engle, J. Clin. Endocrinol. & Metab. 17: 703, 1957. 6. Christy, N. P., W. D. Drucker and W. A. Blanc: Abstracts of 42nd Annual Meeting, Endocrine Society, Miami, Florida, p. 47, June, 1960. 7. Drucker, W. D., L. P. Rowland, K. Sterline and N. P. Christy, Amer. J. Med. 31: 941, 1961.

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8. Cooper, I. S., E. H. Rynearson, A. A. Bailey and C. S. MacCarty, Proc. Mayo Clin. 25: 320, 1950. 9. Spota, B. B. and I. Novizki, Prensa Med. Argent. 4 1 : 1223, 1954. 10. Hammel, A. C : Contribution a l'Etude de l'Hypogonadisme Hypogonadotrophique, Theses de Paris, 1958. 11. Vignalow, J., P. Berthaux, C. Gouygou, J. F. Colas-Belcour, A. Lemarchal and A. Hammel, Ann. Endocr. 20: 172, 1959. 12. Boitelle, G., P. Delteil, P. Noel and J. F. Foncin, Ann. Medicopsychol. 2: 839, 1956. 13. Boudin, G., J. Barbizet, B. Pepin and J. B. Wiart, Soc. Med. Hop. Paris 76: 908, 1960. 14. Hecht, A. and H. Ruskin, J. Clin. Endocrinol. & Metab. 20: 1184, 1960. 15. Altschul, R. and K. Kotlowsky, J. Nerv. Ment. Dis. 123: 112, 1956. 16. Oettle", A. G., D. Rabinowitz and H. C. Seftel, J. Clin. Endocrinol. & Metab. 20: 683,1960. 17. Ryan, R. J.: Male Hypogonadism, Diseasea-Month, Year Book Publishers, Chicago, 111., p. 27, March, 1961. 18. Reifenstein, E. C , Jr., Proc. Amer. Fed. Clin. Res. 3: 86,1947. 19. Holub, D. A., M. M. Grumbach and J. W. Jailer, J. Clin. Endocrinol. & Metab. 18: 1359, 1958. 20. Biben, R. L. and G. S. Gordan, J. Clin. Endocrinol. & Metab. 1 5 : 931, 1955. 21. Friedreich, N., Virchow. Arch. Path. Anat. 68: 145, 1876. 22. Greenfield, J. G.: The Spino-Cerebellar Degenerations, Charles C Thomas, Springfield, Illinois, 1954. 23. Merritt, H. H.: A Textbook of Neurology, Lea & Febiger, Philadelphia, Pa., 1955. 24. Marie, P., Sem. Med. 13: 444, 1893. 25. Nelson, W. O., Fertil. Steril. 1: 277, 1950.

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26. Klinefelter, H. F., Jr., F. Albright and G. C. Griswold, J. Clin. Endocrinol. 3: 529, 1943. 27. Dreckter, I. J., A. Heisler, G. R. Seism, S. Stern, S. Pearson and T. H. McGavock, J. Clin. Endocrinol. & Metab. 12: 55, 1952. 28. Reddy, W. J., Metabolism 3: 489, 1954. 29. Laidlaw, J. C , W. J. Reddy, D. Jenkins, N. J. Haydar, A. E. Renold and G. W. Thorn, New Engl. J. Med. 253: 747, 1955. 30. Barker, S. B., M. F. Humphrey and M. H. Soley, J. Clin. Invest. 30: 55, 1951. 31. Huber, N., Canad. J. Med. Techn. 18: 77, 1956. 32. Moore, K. L. and M. L. Barr, Lancet 2: 57, 1955. 33. Moorhead, P. S., P. C. No well, W. J. Mellman, D. M. Battips and D. A. Hungerford, Exp. Cell Res. 20: 613, 1960. 34. Evans, W. and G. Wright, Brit. Heart J. 4: 91, 1942. 35. Bartter, F. C , R. C. Sniffen, M. D. Simmons, F. Albright and R. P. Howard, J. Clin. Endocrinol. & Metab. 12: 1532, 1952. 36. Hurxthal, L. M., H. J. Bruns and N. Musulin, J. Clin. Endocrinol. 9: 1245, 1949. 37. Nielsen, R. L., R. C. Sniffen, F. A. Simmons, F. Albright and P. H. Henneman, J. Clin. Endocrinol. & Metab. 16: 968, 1956 (Abstract) . 38. Raboch, J., Fertil. Steril. 11: 19, 1960. 39. Paulsen, C. A.: In Williams, R. H. (ed.): Textbook of Endocrinology, ed. 3, W. B. Saunders Co., Philadelphia, Pa., and London, England, p. 416, 1962. 40. Werner, S. C , J. Clin. Endocrinol. 11: 612, 1951. 41. Neel, J. V. and W. J. Schull: Human Heredity, University of Chicago Press, Chicago, 111., p. 52, 1954. 42. Turner, E. V. and E. Roberts, J. Nerv. Ment. Dis. 87: 74, 1938.

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