Male transmission of the gene for isolated gonadotropin-releasing hormone deficiency

Vol. 43, No, 2, February 1985 Printed in UBA.

FERTILITY AND STERILITY Copyright < 1985 The American Fertility Society

Male transmission of the gene for isolated gonadotropin-releasing hormone deficiency

Robert J. Norman, M.D.* Kogie Reddi, M.B., Ch.B.*t Amanda Richards, M.B., Ch.B.:j: Michael G. Hammond, Ph.D.§ Septimus M. Joubert, M.8c., M.B., Ch.B.* South African Medical Research Council Preclinical Diagnostic Chemistry Research Unit, University of Natal, Congelia, and The Natal Institute of Immunology, Durban, Republic of South Africa

Three black women, daughters of the same father but three unrelated mothers, presented with isolated gonadotropin deficiency (lCD). Clinically, the patients had no midline defects and intact smell and taste senses. Biochemically, the essential feature was very low unstimulated and stimulated follicle-stimulating hormone and luteinizing hormone levels, even after priming with gonadotropin-releasing hormone over a 5-day period. Crowth hormone response to insulin-induced hypoglycemia was somewhat blunted, but prolactin, cortisol, and thyroid-stimulating hormone responses were quite normal. All three patients had the 46,xX karyotype; clinical or biochemical aberrations could not be demonstated in any of the remaining family members. The disorder was, apparently, transmitted by the deceased father, who manifestly did not have an ICD deficiency nor any of the midline stigmata associated with ICD. The mode of inheritance seems most likely to be autosomal dominant with variable penetrance. Fertil Steril43:225, 1985

The syndrome of isolated gonadotropin deficiency (IGD), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) has been well characterized in terms of the clinical and endocrine presentation. 1 , 2 It is now generally recognized that the syndrome is the result of a congenital deficiency of hypothalamic gonadotropin-releasing hormone (GnRH). Kallman et al. 3 first drew Received March 2, 1984; revised and accepted September 24,1984. *South African Medical Research Council Preclinical Diagnostic Chemistry Research Unit, Department of Chemical Pathology, University of Natal. tReprint requests: Dr. K. Reddi, Department of Chemical Pathology, University of Natal, P.O. Box 17039, Congella 4013, South Africa. :j:Department of Obstetrics and Gynecology, University of Natal. §Natal Institute ofImmunology. Vol. 43, No.2, February 1985

attention to an occurrence of the syndrome in three kindreds. Subsequently, reports suggested that the disorder was transmitted by female carriers to male offspring. 4 , 5 In this article, a black family is reported in which a father had three apparently affected daughters by three unrelated mothers. Three half sisters presented to the gynecologic endocrine clinic within 12 months with delayed puberty and primary amenorrhea. They had the same father, but each had a different unrelated mother (Fig. 1). CASE REPORTS CASE 1 (11.6)

N. N. first presented to the gynecologic clinic at the age of 18 with primary amenorrhea and unNorman et a1. Male transmission of gene for IGD

225

1

I 1935 A2SIAl B14 BS CwS Cw7

2

1

3

7

4

Figure 1

11 1962 A1r26 BS Bu Cw7Cw3 OR3 Blank

1966

1965

AllA30 ~A26 BS Bu A2Sr26 B14 Bu A2SIA30 B14 Bu Bu Cw7 Cw2CwS Cw3 CwS Cw2 Cw7 Cw3

A30r32 Bu B58 Cw2 Cw6 DRS DR4

derwent laparoscopy; an infantile uterus and normal ovaries and fallopian tubes were found. She was seen again at the age of 28, when she was noted to be eunuchoid (arm span greater than height by 8 cm). There was scanty pubic and axillary hair, and breast development was retarded. CASE 2 (ILl)

G. N. presented for the first time at the age of 20 with amenorrhea, no breast development, and scanty pubic and axillary hair and was also eunuchoid. CASE 3 (11.7)

P. N. was 25 years old when she was seen at the clinic with features similar to those of patients 1 and 2. There were no midline facial defects or anosmia in any patient. X-rays of the skull and ophthalmologic examination were normal in all three patients. Unstimulated LH and FSH levels were less than the reference range in all three patients (reference range, LH, 3.5 to 30 mIU/ml; FSH, 3 to 16 mIU/ml). Plasma estradiol was low in all three patients (reference range, 30 to 80 pg/ml). There was no withdrawal bleeding after medication with medroxyprogesterone acetate (Provera, The Upjohn Company, Kalamazoo, MI), 15 mg/day for 5 days, but the patients did bleed on Ovral (0.05 mg ethinyl estradiol, 0.5 mg norgestrel; Wyeth, Isando, RSA) withdrawal after 21 days of medication. 228

Norman et aI. Male transmission of gene for IGD

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HLA status of family members studied. The probable HLA status of the deceased father was based on those of the children begotten by mother 1.1.

GnRH, 100 ....g, thyrotropin-releasing hormone (TRH, 200 ....g), and insulin tolerance tests (insulin, 0.1 to 0.15 Ulkg body weight) were performed in all three patients. In addition, GnRH (100 ....g) was given subcutaneously for 5 days, and the intravenous stimulation was repeated at the end of the period of priming. The GnRH test was also performed on all available nonaffected members of the family. Unfortunately, two of the mothers (1.2 and 1.3) were not available to be studied, and the father had died in 1980 of an unknown cause. Human leukocyte antigen (HLA) typing was performed as published previously.6

RESULTS The genetic relationships and HLA status of each patient are shown in Figure 1. Each patient allegedly had the same father but a different mother (1.1, 2, 3). The presumed HLA status of the father was determined by study of the family members n.1 to 5. It is obvious from Figure 1 that the disorder is not linked to HLA type, and the disorder appeared to be transferred from father to daughters. The results of the GnRH test in patients and relatives are shown in Tables 1 and 2. Although two of the affected patients demonstrated an increased response of LH to stimulation after priming, these values did not reach the reference range concentrations for unaffected patients in the follicular phase of the cycle. Thyroid function was normal in the three patients, and dynamic testing of the hypothalamic-pituitary axis showed Fertility and Sterility

Table 1. FSH and LH (U/lJ Before and After Injection of GnRH (ZOO f,Lg) Patient"

N.N. Pre Post G.N. Pre Post P.M. Pre Post

LH

FSH

o min

15 min

30 min

60 min

2.0 2.0

2.4 2.2

4.4 1.4

5.4 2.0

< 1.6 2.1

< 1.6 < 1.6

3.2 3.5

< 1.6 < 1.6

< 1.6 < 1.6

< 1.6 < 1.6

-15 min

-15 min

o min

5.7 1.3

<3 <3

6.1 5.9

8.1 7.1

< 1.6 < 1.6

< 1.6 < 1.6

15 min

30 min

60 min

<3 <3

3.5 14.0

4.5 17.0

3.8 9.6

<3 <3

<3 <3

4.1 7.6

3.2 12.0

<3 12.8

<3 <3

<3 <3

<3 <3

<3 <3

<3 <3

apre, test done before priming; Post, test done after priming with 100 f,Lg GnRH daily for 5 days.

normal responses to insulin-induced hypoglycemia and TRH stimulation. Serum and urine osmolality levels indicated that the posterior pituitary function was normal. Prestimulation gonadotropin concentrations and levels after GnRH stimulation in other members of the family are shown in Table 2. Mother (I.1) is postmenopausal, and one of her daughters (11.2) was pregnant. Patient 11.5, although 12 years old and prepubertal, had a normal adult pattern increase of FSH and LH. All family members had a karyotype appropriate to the phenotypic sex. DISCUSSION

In the present study, the probable HLA status of the deceased father was based on those of the children begotten by the mother I.1 in Figure l. The HLA typing of the two daughters born to mothers I.2 and 1.3, respectively, is consistent with the haplotype assigned to the presumed father. Objective evidence supporting the paternity claim of patients 11.6 and II.7, therefore, exists. If this is correct, this family is probably unique in-

asmuch as it demonstrates that the disorder can be transmitted by a male to his daughters without manifestly expressing the disorder himself. As far as could be ascertained, the father did not have other associated features of IGD, such as midline defects. It was not possible to establish whether subtle features, such as anosmia or hyposmia, were present in the deceased father. Other studies 5,7 have shown more than one member of the same family affected by IGD, and in the majority of recorded instances female to male transmission appeared more likely. In the two kindreds described by Santen and Paulsen,5 male to male transmission of anosmia was clearly demonstrated, but they did not unequivocally show transmission ofIGD. In both these families, male to male transmission, therefore, clearly excludes an X-linked condition. In the present study the mode of inheritance seems most likely to be autosomal dominant with variable penetrance. This is supported by the absence of the syndrome in patients II.2 and II.5, coupled with the disorder being milder in the father and of varying severity in the three affected daughters. Autosomal recessive inheritance is

Table 2. FSH and LH (UIl) in Members of the Family Shown in Figure la

LH

FSH Case

1.1 (J. N., 47 yrs) II.2 (G. N., 20 yrs) II.3 (G. N., 17 yrs) II.4 (G. N., 15 yrs) II.5 (C. N., 12 yrs)

-15 min

o min

15 min

30 min

60 min

-15 min

o min

153.2

73.1

187.0

157.7

223.0

110.1

107.3

8.2

6.4

10.0

12.0

12.4

7.1

12.2

6.0

4.4

6.1

7.1

8.6

7.0

5.5

17.5

15.0

30.0

26.3

25.6

12.0

16.2

15 min

> 200

30 min

60 min

> 200

> 200

Pregnant 40.0

39.0

40.8

42.6

32.4

96.1

66.0

59.0

aGnRH (100 f,Lg) was injected intravenously at time O. Vol. 43, No.2, February 1985

Norman et al. Male transmission of gene for IGD

227

most unlikely, because the three mothers are unrelated. There is no evidence of HLA linkage of IGD in this study. The present study, therefore, confirms the heterogeneity of the syndrome of IGD, in that the youngest affected patient (11.1) was more severely affected than the other two, both in terms of clinical features and the response to GnRH before and after priming of the pituitary gland. However, none of the patients showed any of the associated features of anosmia, cleft palate, and hare lip; the present family may, indeed, have a condition unrelated to that of some of the patients reported in other series.

228

Norman et aI. Male transmission of gene for IGD

REFERENCES 1. Boyar RM, Finkelstein JW, Witkin M, Kapen S, Weitzman E,' Hellman L: Studies of endocrine function in "isolated" gonadotropin deficiency. Metabolism 36:64, 1973 2. Spitz 1M, Diamant Y, Rosen E, Bell J, Ben David M, Polishuk W, Rabinowitz D: Isolated gonadotropin deficiency. N Engl J Med 290:10, 1974 3. Kallman FJ, Schoenfeld WA, Barrera SE: The genetic aspects of primary eunuchoidism. Am J Ment Defic 48:204, 1944 4. Le Marquand HS: Congenital hypogonadotropic hypogonadism in five members of a family. Proc R Soc Med 47:442, 1954 5. Santen RJ, Paulsen CA: Hypogonadotropic hypogonadism: clinical study of mode of inheritance. J Clin Endocrinol Metab 36:47, 1973 6. Hammond MG, Asmal AC, Omar MAK: HLA typing and insulin-dependent diabetes in South African Negroes. Diabetologia 19:101, 1980 7. Sparkes RS, Simpson RW, Paulsen CA: Familial hypogonadotropic hypogonadism with anosmia. Arch Intern Med 121:534, 1968

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