Hypogonadotropic Hypogonadism 12 With Or Without Anosmia

A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-12 with or without anosmia (HH12) is caused by homozygous mutation in the GNRH1 gene (152760) on chromosome 8p21. One such family has been reported.

Description

Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).'

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

Clinical Features

Biben and Gordan (1955) described affected males and females in a family with what they designated 'familial hypogonadotropic eunuchoidism.' Hurxthal (1943) reported a family in which only members of 1 generation were affected. Le Marquand (1954) described 3 affected brothers and 2 affected sisters from a nonconsanguineous family.

Ewer (1968) observed an affected brother and 2 sisters from a marriage of second cousins once removed. Another male sib, deceased, was probably affected. Absence of secondary sex characteristics and relatively long extremities were the only abnormal findings. Clomiphene administration had no effect.

Toledo et al. (1983) reported 2 brothers and a sister with a hypothalamic form of hypogonadism that the authors designated 'familial idiopathic gonadotropin deficiency' (FIGD). Toledo et al. (1983) concluded that this disorder is due to insufficiency of GNRH secretion and that sensitivity of Leydig cells to human chorionic gonadotropin (hCG; see 118860) is normal in FIGD. They also stated that luteinizing hormone-releasing hormone (LRH) treatment may be helpful; that associated hypothalamic-pituitary-prolactin dysfunction may be present; and that FIGD and the Kallmann syndrome (see 147950) are distinct entities.

To further define the genetic and phenotypic variability of FIGD, Waldstreicher et al. (1996) reviewed detailed family histories of 106 cases of GNRH deficiency with or without anosmia, i.e., Kallmann syndrome or idiopathic hypogonadotropic hypogonadism (IHH). The great majority of cases appeared to be sporadic, with only 19 probands (18%) having at least 1 family member with GNRH deficiency. However, of the families in which the proband was the sole member affected by Kallmann syndrome or IHH, 9 had individuals with isolated anosmia, and 8 had a strong history of delayed puberty. If these phenotypes were considered as variable expressions of Kallmann syndrome or IHH seen in the proband, then 34% of the cases could be considered familial. The proportion of familial cases that could be attributed to an X-linked mode of inheritance was no greater than 36% in any of these analyses. Waldstreicher et al. (1996) concluded that (1) most cases of GNRH deficiency in humans are sporadic and thus could represent new mutations; (2) the X-linked form is the least common among familial cases of Kallmann syndrome or IHH; (3) defects in at least 2 autosomal genes can cause GNRH deficiency; and (4) associated clinical defects may provide clues to the nature and/or location of these autosomal genes.

Bouligand et al. (2009) studied a Romanian brother and sister with normosmic hypogonadotropic hypogonadism. The brother, who was referred at 18 years of age because pubertal development had not occurred, exhibited typical signs of complete hypogonadism, with small intrascrotal testes, no pubic hair, and microphallus. His bone age was 13.0 years; he had a normal sense of smell on olfactometry, and had no renal or craniofacial abnormalities. His affected sister, who was evaluated at 17 years of age, also had complete hypogonadism and a normal sense of smell on olfactometry. She had no breast development and no pubic hair, and menarche had not occurred. Pelvic sonography showed a small uterus and 2 small ovaries with no visible follicles. The sibs' karyotypes were 46,XY and 46,XX, respectively. Hormone assays revealed very low plasma testosterone levels in the affected brother and an almost undetectable plasma estradiol level in the affected sister. Both sibs had very low levels of plasma gonadotropin (see 118860) and normal levels of prolactin (176760). They both showed a blunted response to GnRH bolus administration, but otherwise had normal function of the anterior pituitary, thyroid, and adrenal glands, as well as normal levels of ferritin (see 134790) and serum insulin-like growth factor-1 (IGF1; 147440) and normal findings on MRI of the pituitary and olfactory bulbs. The sister had basal nonpulsatile luteinizing hormone (LH; see 152780) secretion, but LH pulses, occurring synchronously with GnRH boluses, were detected on day 13 of pulsatile GnRH administration. Pulsatile GnRH administration also resulted in increased circulating levels of estradiol and inhibin-beta (see 147290) and in the recruitment of a single dominant 14-mm follicle seen on ultrasonography. The sibs' unrelated parents reported normal puberty, and the mother had spontaneous regular menses, unassisted conception, and normal pregnancies; there were also 2 unaffected sibs who had normal puberty and normal sex steroid and gonadotropin levels.

Molecular Genetics

In an 18-year-old Romanian man from a Transylvanian mountain village who had normosmic hypogonadotropic hypogonadism and was negative for mutation in the GNRHR1, GPR54, KISS1, FGFR1, and GNRH2 genes, Bouligand et al. (2009) identified homozygosity for a 1-bp insertion in the GNRH1 gene (152760.0001). His affected sister was also homozygous for the mutation, and his unaffected parents and an unaffected sister were heterozygotes, as was 1 of 200 ancestrally matched Romanian controls; haplotype analysis suggested a founding event 8 to 50 generations earlier. The mutation was not found in 100 unrelated Caucasian eugonadal individuals or in 145 unrelated Caucasian patients with sporadic normosmic IHH.

For discussion of a possible second homozygous mutation in the GNRH1 gene causing hypogonadotropic hypogonadism, see 152760.0002.

Oligogenic Inheritance

In a cohort of 310 patients with normosmic HH, Chan et al. (2009) analyzed the HH-associated genes GNRH1, FGFR1 (136350), and PROKR2 (607123), and identified rare heterozygous variants in all 3 genes in the proband of a 3-generation pedigree: R31C in GNRH1, I239T in FGFR1, and S202G in PROKR2. The proband had affected twin daughters, one of whom carried the GNRH1 and FGFR1 variants, whereas the other carried only the GNRH1 variant. A niece who was originally diagnosed with hypothalamic amenorrhea, in which the reproductive phenotype becomes apparent only in the presence of an external stressor, also carried only the GNRH1 variant. Chan (2011) stated that the niece's phenotype was later revised to normosmic HH. In addition, 2 paternal aunts of the proband had HH, but DNA was not available for study. At 42 years of age, the proband exhibited reversal of HH, with normal menstrual cycles after stopping hormone therapy.

Animal Model

Beier and Dluhy (2003) noted that mutation in the GNRH1 gene had been identified as the cause of hypogonadotropic hypogonadism in mice.