Familial hypogonadotropic hypogonadism with alopecia IBRAHIM S. SALTI, MD, FRCP[C]; ZAW SALEM, MD In one family several male and female members had hypogonadism and frontoparietal alopecia, whereas other members with normal sexual development had normal scalp hair. Clinical and laboratory evaluation of three affected young men (two brothers and their cousin) revealed that the hypogonadism was the result of decreased serum concentrations of follicle stimulating and luteinizing hormones. There was no evidence of a deficiency of any other pituitary hormone. Long-term treatment of the three patients with human chorionic gonadotropin resulted in an increase in the serum testosterone concentration, the appearance of male secondary sex characteristics and an increase in the size of the external genitalia. Plusieurs membres (hommes et femmes) d'une mime famille furent atteints d'un hypogonadisme avec alopecie frontopari6tale, alors que des autres membres de Ia famille presentaient un developpement sexuel normal et avaient une chevelure normale. L'evaluation clinique et les 6preuves de laboratoire de trois jeunes gens touch6s par cette affection (deux fr.res et leur cousin) revelerent que l'hypogonadisme resultait d'une diminution des concentrations seriques en hormones luteinisantes et folliculostimulantes. On n'a observe aucun signe d'une deficience des autres hormones hypophysaires. Le traitement a long terme de ces trois patients A l'aide de gonadotrophine chorionique humaine a donne comme r6sultat une augmentation des concentrations seriques de testosterone, l'apparition des caract6ristiques secondaires mAles et un elargissement des organes g6nitaux externes.

Hypogonadotropic hypogonadism is a well recognized entity that may be either sporadic14 or familial.1'5-7 Some of the familial forms are characterized by certain nongonadal abnormalities, such as anosmia (Kallmann's syndrome),8-11 congenital ichthyosis,12 gynecomastia1m and cerebellar ataxia.1416 In addition, hypogonadotropic hypogonadism is a common feature of certain hereditary disorders, such as the Laurence-Moon-Biedi syndrome,17'18 the M6bius syndrome19 and the PraderWilli syndrome.10 Recently Crandall and associates21 described three brothers with hypogonadotropic hypogonadism, total alopecia and neurosensory deafness. Our report concerns a family (Fig. 1) in which several members of both sexes had hypogonadism and partial alopecia; studies in three members of the family have shown that the hypogonadism is of the hypogonadotropic type.

partial alopecia, which had been evident since infancy. Except for failure of sexual development, physical and mental development had been normal.

The boy was 158 cm tall and weighed 49 kg. He had a high-pitched voice, a eunuchoidal habitus, an upper: lower segment ratio of 78:80 and an arm span of 167 cm. There was absence of facial, axillary and pubic hair. Scalp hair was fine and generally scanty, but was totally absent in the frontoparietal areas. The external genitalia were infantile and unpigmented (Fig. 2): the phallus was 3 cm long, the right testis, which measured 1.5 x 1.0 cm, was soft, and the left testis was undescended. The prostate gland could not be palpated rectally. There was no olfactory or auditory deficit and no gynecomastia. The rest of the physical and neurologic findings were normal. Case 2 The 20-year-old brother (V,9) of patient 1 also presented because of failure of sexual development. In general appearance he strikingly resembled his brother, having the same fine scanty scalp hair and frontoparietal alopecia dating back to early childhood. He was 164 cm tall and weighed 58 kg. His voice was highpitched and his habitus was eunuchoidal, with an

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V 1 Age 25

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34 19

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U: hypogonadism and alopecia Cl: prepubertal

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c%1: identical twins DO: consanguineous marriage

FIG. 1-Pedigree of family with hypogonadism and alopecia. Age in years.

Case reports Case 1 A 16-year-old boy (V, 10) presented because of failure of sexual development. He was born after a normal pregnancy and an uneventful delivery. No abnormalities were noted during childhood except for From the division of endocrinology, department of internal medicine, school of medicine, American University of Beirut, Beirut, Lebanon Reprint requests to: Dr. Ibrahim S. Salti, American University of Beirut Hospital, Beirut, Lebanon 428 CMA JOURNAL/AUGUST 18, 1979/VOL 121

FIG. 2-Case 1: external genitalia before treatment.

upper:lower segment ratio of 74:90 and an arm span of 175 cm. There was absence of facial, axillary and pubic hair. The external genitalia were small and Unpigmented; the phallus was 3 cm long and both testes were soft and measured 1.5 x 1.0 cm. There was no olfactory or auditory deficit or gynecomastia. The rest of the physical and neurologic findings were normal. Case 3 A 21-year-old maternal cousin (V,3) of patients 1 and 2 also had hypogonadism and the same type of alopecia dating back to early childhood. He was 170 cm tall and weighed 66 kg. Abnormal physical findings included a high-pitched voice, eunuchoidal habitus, a symphysis-to-sole length of 89 cm, an arm span of 183 cm, absence of facial, axillary and pubic hair, and infantile genitalia, with a phallus 4 cm long and soft testes that measured 3 x 2 cm. There was no olfactory or auditory deficit or gynecomastia. The rest of the examination revealed no other abnormalities. Family history The mothers of the three patients (IV,3 and IV,4)

paternal first cousin and had five offspring, three boys and two girls. Two of the sons (V,1 and V,3) and one of the daughters (V,2) had hypogonadism and partial alopecia. The remaining two offspring had normal sexual development and normal scalp hair. The other mother (IV,4) married a maternal second cousin and had seven offspring. Two of the sons (V,9 and V, 10) and one of the daughters (V,7) had hypogonadism and partial alopecia. One boy (V.12) and one girl (VA 1) were prepubertal but had no alopecia, and the remaining offspring had normal sexual development and scalp hair. The affected daughters (V,2 and V,7) were both 23 years old. Their pronounced alopecia, which, as with all the affected members of the family, had first been noted in early childhood, necessitated the use of a wig. Both had primary amenorrhea, absence of axillary and pubic hair, and lack of breast development. Both experienced vaginal bleeding following a course of oral estrogen-progestin therapy. The fathers of the three patients were unrelated. Laboratory studies Methods Radioimmunoassay techniques were used to measure the plasma or serum concentrations of growth hormone,22 thyroid stimulating hormone,23 testosterone,24 prolactin,22 follicle stimulating hormone26 and luteinizing hormone.27 The concentrations of the last two were expressed in terms of milli-international units of the second international reference preparation of human menopausal gonadotropin. Competitive protein-binding techniques were used to measure the serum thyroxine28 and plasma cortisol'9 concentrations. Urine concentrations of 1 7-hydroxycorticosteroids were measured according to the method of Reddy2' and those of 17ketosteroids according to the method of Drekter and colleagues.31 Results The hemograms of all three patients were normal, as were the serum concentrations of glucose (with the patients fasting), urea nitrogen, uric acid, cholesterol, triglycerides, sodium, potassium, chloride, calcium, phosphate and total protein. The serum alkaline phosphatase value was elevated in patients 1 and 2 (9.1 and 8.4 Bodansky units respectively; normal range of values for adults 1 to 4 Bodansky units). In all three patients bone maturation was significantly delayed. Skull roentgenograms revealed a normal sella turcica in each. All three patients had a normal male karyotype. A biopsy of the scalp of patient 3 revealed a decreased number of hair follicles. Baseline hormone concentrations are presented in Table I. All three patients had decreased values for serum testosterone, follicle stimulating and luteinizing hormones and urine 1 7-ketosteroids. Values for plasma growth hormone (with the patients fasting), serum thyroxine, serum thyroid stimulating hormone, plasma cortisol (at 8 am), serum prolactin and urine 1 7-hydroxycorticosteroids were normal in the three patients. Insulin-induced hypoglycemia produced a normal increase in the plasma growth hormone and cortisol CMA JOURNAL/AUGUST 18, 1979/VOL. 121

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1*1. Ill-Effect of 200 ..g of IuteifIfztng hormone releasing hofluoI.eIven intrayrn.ous yin a.IngIfttIose

Time 0 10 40 U

Serum values (mw/mi) Patient 2 Pattept I fbiltcie Feilkie stimplating Lutelnizing sthnuletlng Lutelniziuig hormone hormone hormone hormone 3.4 4.5 1.2 2.5 3.2 4.2 1.1 4.5 3.4 3.1 1.1 3.0 3.4 0.9 3.0 4.0 40 1.5 4i

Serum testosterone value was 408 ng/dl and the serum alkaline phosphatase value was 8.3 Bodansky units. According to a note from his family physician the results of treatment with human chorionic gonadotropin in patient 3 were similar to those of his cousins. After 1 year of therapy he had undergone the same changes in physique, voice and external genitalia. Discussion The clinical and laboratory findings in the three patients studied indicated that the hypogonadism was the result of gonadotropin deficiency. This conclusion was further supported by the adequate masculinization and the rise, after prolonged therapy with human chorionic gonadotropin, in the serum testosterone concentration to values normally found in men.32'33 The drop in concentration to pretreatment values in one patient shortly after treatment was stopped provides further evidence for a deficiency in endogenous gonadotropin secretion. The available data suggest that hypogonadotropism was the only hormonal defect of these patients. Thyroid function was normal in all three, and there was a normal increase in the serum concentration of thyroid stimulating hormone after stimulation with thyrotropin releasing hormone in the two patients in whom this test was performed. The serum prolactin concentration also increased normally with stimulation. Although adrenocorticotropin secretion was not studied directly, the normal values for plasma cortisol and urine 1 7-hydroxycorticosteroids suggest that the secretion of adrenocorticotropin was normal. In one patient there was a normal increase in the plasma cortisol value with insulin-induced hypoglycemia. The fact that all three patients were of normal prepubertal height makes growth hormone deficiency unlikely, and in patient 3 insulin-induced hypoglycemia resulted in a normal increase in the plasma growth hormone value. Whether the gonadotropic deficiency was of pituitary or hypothalamic origin has not been determined with certainty. The lack of increase in serum gonadotropin values after a single intravenous injection of luteinizing hormone releasing hormone does not necessarily indicate defective gonadotropin secretion, for such a sluggish response may be expected after prolonged absence of hypothalamic stimulation.34 However, the lack of response of patient 2 to repeated infusions of this releasing hormone favours a diagnosis of pituitary gonadotropin deficiency.35 For this reason a trial of clomiphene citrate therapy was not undertaken in these patients. The modes of inheritance of the different syndromes of familial hypogonadotropism have been difficult to determine with certainty because untreated affected individuals are usually sterile. In some syndromes an X-linked recessive pattern of transmission is considered the most likely,12'13 while in others an autosomal recessive pattern has been suggested.7"7 Autosomal dominant transmission with varying degrees of penetrance has been suggested as the most likely mode of inheritance of Kallmann's syndrome.'0 The same is probably true of the condition described in our report. Presumably the mothers, who were identical twins, were carriers of the affected gene or genes responsible

for the expression of this condition in some of their children. Autosomal recessive inheritance was unlikely since the probability that both fathers (who were unrelated) were carriers of the same rare mutant gene was extremely small. X-linked recessive inheritance was also unlikely in view of the occurrence of the condition in both males and females. However, X-linked dominant inheritance cannot be completely ruled out. It is interesting that partial alopecia occurred in all the family members with hypogonadism but in none of the members who had presumably normal sexual development. Hereditary partial or total alopecia is rare,36 and in only one family has it been associated with hypogonadotropic hypogonadism and neurosensory deafness.21 Research for this paper was supported by grant 38-5720 of the Endocrine Research Fund. References 1. ALBERT A, UNDERDAHL LO, GREENE LF, et al: Male

hypogonadism: the testis in prepubertal or pubertal gonadotropic failure. Proc Mayo Cliii 29: 131, 1954 2. MOLDAWER MC, ALBRIGHT F, BENEDICT PH, et al:

Eunuchoidism with low urinary follicle stimulating hormone in the female: comparison with this syndrome in the male and with the premenarchal menopause. J Cliii Endocrinol Metab 18: 1, 1958 3. BELL J, SPITZ I, SLONIM A, et al: Heterogeneity of gonadotropin response to LH-RH in hypogonadotropic hypo-

gonadism. J C/in Endocrinol Metab 36: 791, 1973 4. SPITZ TM, 1)IAMANT Y, ROSEN E, et al: Isolated gonadotropin deficiency: a heterogenous syndrome. N Engi J Med 290: 10, 1974 5. Li MARQUAND HS: Congenital hypogonadotropic hypogonadism in five members of a family, three brothers and

two sisters. Proc R Soc Med 47: 442, 1954 6. BIBEN RL, GORDAN GS: Familial hypogonadotropic eunuchoidism. J C/in Endocrinol Metab 15: 931, 1955 7. EWER RW: Familial monotropic pituitary gonadotropin insufficiency. J C/in Endocrinol Metab 28: 783, 1968 8. KALLMANN FJ, SCHONFELF WA, BARRERA SE: The genetic

aspects of primary eunuchoidism. Am J Ment Defic 48: 203, 1944 9. SPARKES RS, SIMPSON RW, PAULSEN CA: Familial hypogonadotropic hypogonadism with anosmia. Arch intern Med 121: 534, 1968 10. SATEN RJ, PAULSEN CA: Hypogonadotropic eunuchoidism. I. Clinical study of the mode of inheritance. J C/in Endo-

crinol Metab 36: 47, 1973 11. MALES JL, TOWSEND IL, SCHNEIDER RA: Hypogonado-

tropic hypogonadism with anosmia - Kallmann's syndrome. A disorder of olfactory and hypothalamic function. Arch Intern Med 131: 501, 1973 12. LYNCH HT, OZER F, MCNUTT CW, et al: Secondary male hypogonadism and congenital ichthyosis: association of

two rare genetic diseases. Am J Hum Genet 12: 440, 1960 13. ROSEWATER 5, GwINUP G, HAMwI GJ: Familial gyne-

comastia. Ann Intern Med 63: 377, 1965 14. VOLP. R, METZLER WS, JOHNSTON MAW: Familial hypogonadotropic eunuchoidism with cerebellar ataxia. J C/in Endocrinol Metab 23: 107, 1963 15. MATHEWS WB, RUNDLE AT: Familial cerebellar ataxia and hypogonadism. Brain 87: 463, 1964 16. BOUCHER BJ, GIBBERD F: Familial ataxia, hypogonadism and retinal degeneration. Acta Neurol Scaiid 45: 507, 1969 17. BOWEN P, FERGUSON-SMITH MA, MOSIER D, et al: The Laurence-Moon syndrome. Association with hypogonado-

tropic hypogonadism and sex-chromosome aneuploidy. Arch Intern Med 116: 598, 1965 18. REINFRANK RF, NICHOLS FL: Hypogonadotropic hypogonadism in the Laurence-Moon syndrome. J C/in Endo-

crinol Metab 24: 48, 1964

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19. OLSON WH, BARDIN CW, WALSH GO, et al: Moebius syndrome: lower motor neuron involvement and hypogonadotropic hypogonadism. Neurology (Minneap) 20: 1002, 1970 20. HALL BD, SMITH DW: Prader-Willi syndrome. A resume of 32 cases including an instance of affected first cousins,

one of whom is of normal stature and intelligence. J Pedjair 81: 286, 1972 21. CRANDALL BF, SAMEC L, SPARKES RS, et al: A familial syndrome of deafness, alopecia, and hypogonadism. J

Fedjair 82: 461, 1973 22. MOLINATTI GM, MASSARA F, STRUMIA E, et al: Radioimmunoassay of human growth hormone. J Nuci Bid Med

13: 26, 1969 23. UTIGER RD: Radioimmunoassay of human plasma thyrotropin. J Clin invest 44: 1277, 1965 24. DUFAU ML, CATT KJ, TSURUHARA T, et al: Radioimmunoassay of plasma testosterone. Clin Chim Ada 37: 109,

1972 25. HWANG P, GUYDA H, FRIESEN 1-i: A radioimmunoassay for human prolactin. Proc Nail Acad Sci USA 68: 1902,

1971 26. M!DGLFY AR JR: Radioimmunoassay for human follicle-

stimulating hormone. J Clin Endocrinol Metab 27: 295, 1967 27. Idem: Radioimmunoassay: a method for human chorionic

gonadotropin and human luteinizing hormone. Endocrinology 79: 10, 1966 28. MURPHY BP: The determination of thyroxine by competitive protein-binding analysis employing an anion-exchange resin and radiothyroxine. J Lab Clin Med 66: 161, 1965

29. Idem: Some studies of the protein-binding of steroids and their application to the routine micro and ultramicro measurement of various steroids in body fluids by competitive protein-binding* radioassay. J C/in Endocrinol Metab 27: 973, 1967 30. REDDY WJ: Modification of Reddy-Jenkins-Thorn method for estimation of 17-hydroxycorticoids in urine. Metabolism 3: 489, 1954 31. DREKTER IJ, HEISLER A, ScIsN GR, et al: The determination of urinary steroids. The preparation of pigmentfree extracts and a simplified procedure for the estimation of total 17-ketosteroids. J C/in Endocrinol Metab 12: 55, 1952 32. BOYAR RM, FINKELSTEIN JW, WITKIN M, et al: Studies of endocrine function in "isolated" gonadotropin deficiency. J C/in Endocrinol Metab 36: 64, 1973 33. SATEN RJ, PAULSEN CA: Hypogonadotropic eunuchoidism. II. Gonadal responsiveness to exogenous gonadotropins. ibid, p 55 34. ROTH JC, KELCH RP, KAPLAN SL, et al: FSH and LH response to luteinizing hormone-releasing factor in prepubertal and pubertal children, adult males and patients with hypogonadotropic and hypertropic hypogonadism. J C/in Endocrinol Metab 35: 926, 1972 35. REITER EO, ROOT AW, DUCKETT GE:

LH and FSH

levels in urine and serum of prepubertal and pubertal children receiving a 3-hour infusion of LH-RH. J C/in Endocrinol Metab 44: 56, 1977 36. TILLMANN WG: Alopecia congenita: report of 2 families. Br Med J 2: 428, 1952

Survival following renal transplantation in Saskatchewan, 1970-74: follow-up study using medical insurance records JULIAN B. MOEN,* BA; GERRY B. HILL,f MB, CH B, M Sc

The patient history file of a medical care insurance plan can be used for statistical purposes in many ways. This is illustrated by the use of the records of the Saskatchewan Medical Care Insurance Commission to study the survival of patients receiving kidney transplants in the period 1970-74. During this period 48 males and 23 females received at least one renal transplant; these patients represented 340/o of all males and 280/0 of all females undergoing regular renal dialysis. These period prevalence estimates are consistent with calculations based on incidence and point prevalence reported elsewhere. Life-table calculations showed the 4-year survival rate following first kidney transplantation in Saskatchewan to be 450/0 for all patients, 550/0 for those less than 45 years of age and 260/o for those 45 years of age or older. On peut utiliser les dossiers des plans d'assurance-maladie pour fins de statistiques de plusieurs fa.ons. C'est ainsi qu'on a utilise les dossiers de Ia Saskatchewan Medical Care Insurance Commission pour etudier Ia survie des patients qui avaient subi une transplantation renale pendant les annees 1970-74. Durant cette periode 48 patients de sexe masculin et 23 patientes de sexe feminin ont subi au moms une transplantation renale, ce qui represente From *the health division, Statistics Canada, and Ithe health services directorate, Department of National Health and Welfare Reprint requests to: Mr. Julian B. Moen, R.H. Coats Building, 17th floor, Tunney's Pasture, Ottawa, Ont. KlA 0T6

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340/0 des patients de sexe masculin et 280/0 des patientes de sexe feminin recevant regulierement des services de dialyse. Ces estimations de frequence correspondent bien a des calculs bases sur l'incidence et Ia prevalence rapportes ailleurs. D'apres le tableau de mortalite le taux de survie de 4 ans apres Ia premiere transplantation renale est de 450/0 pour tous les patients, 550/0 pour ceux qui ont moms de 45 ans et 260/0 pour ceux de 45 ans et plus.

Since the implementation of universal medical care insurance in Canada, each province has accumulated a mass of computer records of claims for medical services. Although the data available differ from province to province, particularly in relation to diagnosis, there is no doubt that these records provide a mine of information concerning the morbidity of the population and the performance of the health care system. Lack of homogeneity has prevented the publication of descriptive statistics on a national basis, but figures on the use of medical services in selected provinces have been published.1'2 The records of the Saskatchewan Medical Care Insurance Commission (SMCIC) include detailed information, and these data have been used for both descriptive1 and epidemiologic3 purposes. In Saskatchewan, as in most provinces, it is possible to bring together the medical insurance records of individual patients in order to do longitudinal studies in addition to the more usual cross-sectional statistics.

Familial hypogonadotropic hypogonadism with alopecia.

Familial hypogonadotropic hypogonadism with alopecia IBRAHIM S. SALTI, MD, FRCP[C]; ZAW SALEM, MD In one family several male and female members had hy...
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