Hypogonadotropic Hypogonadism 24 Without Anosmia

A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-24 without anosmia (HH24) is caused by homozygous or compound heterozygous mutation in the gene encoding the beta chain of follicle-stimulating hormone (FSHB; 136530) on chromosome 11p14.

For a general phenotypic description and discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see 147950.

Clinical Features

Rabin et al. (1972) described a 22-year-old Israeli woman with primary amenorrhea, high luteinizing hormone (LH; see 152780), undetectable serum FSH, and, on biopsy of the ovaries, primordial follicles which had not matured to the stage of antral formation. The defect was thought to be at the level of the pituitary, not the hypothalamus. Bell et al. (1975) reported that administration of luteinizing hormone-releasing hormone (GNRH1; 152760) to this patient resulted in a significant rise in serum LH, but FSH levels remained undetectable. Rabinowitz et al. (1979) published a follow-up on the patient reported by Rabin et al. (1972). The patient had anti-FSH antibody in her serum, after 2 courses of human menopausal gonadotropins. Ovulation and conception were induced, with subsequent uneventful pregnancy, by saturation of endogenous antibody with high doses of the gonadotropins.

Matthews et al. (1993) studied a 27-year-old Italian woman with primary amenorrhea who was originally reported by Benedetti and Tedeschini (1991). At 13 years of age, she had normal axillary and pubic hair, but neither menarche nor thelarche had occurred. At 18 years of age, treatment with a sequential estrogen-progestin combination induced cyclical withdrawal bleeding. She was the only child of nonconsanguineous parents. Her mother had a long history of menstrual irregularity, with several episodes of amenorrhea; conception occurred after 6 years of apparent infertility. The patient's father was deceased, and no information was available regarding his fertility. Examination revealed a eunuchoid habitus with poor breast development. She had high LH and undetectable FSH levels; administration of GNRH increased LH levels 3-fold, but there was no FSH response. Patient serum did not induce aromatase activity in cultured rat Sertoli cells, indicating absence of biologically active FSH. Treatment with FSH resulted in follicular maturation, ovulation, and a postovulatory rise in progesterone, and she later underwent a successful pregnancy. Her postmenopausal mother had inappropriately low immunoreactive and bioactive FSH levels as well as low LH; LH rose in response to GnRH, but the FSH response was markedly impaired.

Layman et al. (1997) reported a girl of almost 16 years with primary amenorrhea. She had undergone pubarche at age 13, but there was no evidence of thelarche. She had a bone age of 14 years. Serum FSH was undetectable, LH was high, and estradiol was low; LH but not FSH increased in response to GnRH administration. There was no family history of delayed puberty or infertility.

Phillip et al. (1998) studied an 18-year-old 46,XY man with delayed puberty, who reported normal erections and ejaculatory orgasms but had a prepubertal physique and underdeveloped muscles. He had Tanner stage 4 pubic hair, scant axillary hair, no facial hair, and small testicles. Endocrinologic analysis showed low serum testosterone and FSH with high LH levels; administration of GnRH resulted in increase of LH, but FSH remained unchanged. Semen analysis revealed azoospermia. Bone age was 16 years. The proband's father and brother had undergone normal puberty and sexual development, and LH, FSH, and testosterone levels were normal in both. His mother underwent menarche at 12.5 years and had given birth to 3 children.

Lindstedt et al. (1998) reported a 28-year-old Serbian man who presented with infertility in both his first and second marriages, despite normal puberty and virilization as well as normal libido. Examination revealed small soft testicles and azoospermia, and testicular biopsy showed presence of Leydig cells but evidence of spermatogenic arrest. On biochemical analysis, FSH was undetectable both before and after administration of GnRH, LH was moderately elevated and increased 4-fold after GnRH, inhibin B (see 147290) was very low, and testosterone was at the low end of the normal range. The proband had 1 sister with primary amenorrhea and another who had normal menstruation and was pregnant. Lindstedt et al. (1998) referred to the proband's condition as 'Aigeus syndrome,' from the Greek myth describing King Aigeus of Athens who, having experienced 2 infertile marriages, consulted the Delphic oracle regarding the prospects of having a son.

Layman et al. (2002) described an affected sister and brother from a consanguineous Brazilian family with isolated FSH deficiency and infertility. The 32-year-old sister had delayed thelarche and primary amenorrhea with a low estradiol level. Her 30-year-old brother underwent normal puberty, but he had small testes and was azoospermic; testicular biopsy showed Leydig cell hyperplasia and sparse small seminiferous tubules with germinal cell aplasia, peritubular fibrosis, and few Sertoli cells. Both sibs had low serum FSH and elevated LH levels, both basally and after GnRH stimulation.

Molecular Genetics

In an Italian woman with primary amenorrhea and infertility associated with isolated deficiency of pituitary FSH and normal luteinizing hormone secretion, Matthews et al. (1993) identified homozygosity for a 2-bp frameshift deletion in codon 61 of the FSHB gene (136530.0001). The proband's mother, who was heterozygous for the mutation, had been amenorrheic and infertile for 6 years before conception of the proband, her only child. Matthews et al. (1993) suggested that abnormalities of FSH structure or function may represent an underrecognized but treatable cause of infertility; in their patient, ovulation was induced by administration of exogenous FSH and resulted in a successful pregnancy.

Matthews and Chatterjee (1997) restudied the Israeli patient reported by Rabin et al. (1972) and found that she was homozygous for the same 2-bp deletion found in the Italian patient by Matthews et al. (1993). The proband's 18-year-old daughter and her sister were both heterozygous for the 2-bp deletion; both had normal serum FSH levels and regular menstrual cycles, and the sister had 3 normal pregnancies, suggesting that reproductive function is not compromised in female heterozygotes.

In a 16-year-old girl with primary amenorrhea and FSH deficiency, Layman et al. (1997) identified compound heterozygosity for the 2-bp deletion in codon 61 and a missense mutation in the FSHB gene (C51G; 136530.0002). Her unaffected parents were each heterozygous for 1 of the mutations; a sister and a half sister who were heterozygous for the missense mutation had 2 and 3 children, respectively, and a half brother who carried C51G had normal puberty and normal semen analysis.

In an 18-year-old man with hypogonadism and isolated deficiency of FSH, Phillip et al. (1998) identified homozygosity for the 2-bp deletion in codon 61 of the FSHB gene. His unaffected parents and brother were heterozygous for the deletion.

In a 28-year-old Serbian man with infertility, azoospermia, and undetectable FSH, Lindstedt et al. (1998) analyzed the FSHB gene and identified homozygosity for a missense mutation (C82R; 136530.0004).

In an affected sister and brother from a consanguineous Brazilian family with isolated FSH deficiency and infertility, Layman et al. (2002) identified homozygosity for a nonsense mutation in the FSHB gene (Y76X; 136530.0003). Their unaffected parents were heterozygous for the mutation, as were 2 sisters who had normal puberty and fertility.