A number sign (#) is used with this entry because of evidence that susceptibility to hypogonadotropic hypogonadism-16 with or without anosmia (HH16) is conferred by variation in the SEMA3A gene (603961) on chromosome 7, sometimes in association with mutations in other genes, e.g., KAL1 (300836) and FGFR1 (136350).

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 as well as a discussion of oligogenicity of this disorder, see 147950.

Young et al. (2012) studied a family segregating autosomal dominant anosmic hypogonadotropic hypogonadism. The proband presented at 17 years of age because of pubertal failure, and was found to have features of complete hypogonadism, with mean testicular volume of 2.5 mL and right cryptorchidism; he did not have micropenis. Olfactometry showed hyposmia, and MRI revealed bilateral hypoplasia of the olfactory bulbs, with normal hypothalamus and pituitary. He had very low serum levels of testosterone, LH (152780), and FSH (136530), and the 2 gonadotropins responded only weakly to GnRH challenge. His sister presented at 18 years of age for primary amenorrhea and pubertal failure (Tanner breast stage I). She had very low serum levels of estradiol, LH, and FSH, and was anosmic. Their father had been evaluated for pubertal failure associated with hyposmic HH at 19 years of age. At age 21, he began treatment with replacement GnRH with normalization of gonadotropin and testosterone levels; androgen therapy resulted in satisfactory virilization, but after 5 years his testicular volume was still low and he was azoospermic. Injections with hMG and hCG resulted in induction of spermatogenesis and fertility. Reexamination 6 months after stopping testosterone replacement therapy at 54 years of age showed persistence of his congenital gonadotropin deficiency, with low testicular volume and low gonadotropin and testosterone levels. Family interviews revealed that the father had 2 paternal aunts who also had anosmia, absent pubertal development, and infertility, and his deceased father had isolated anosmia, with normal puberty and fertility without medical assistance.

Dai et al. (2020) identified 3 Chinese patients with HH, 2 (patients 1 and 3) with anosmia and 1 (patient 2) without anosmia. Patients 1 and 3 had visual defects (high myopia and anomalous trichromatism, respectively), patients 2 and 3 had cryptorchidism, and patient 1 had scoliosis.

Using whole-genome microarray analysis in 48 probands with anosmic hypogonadotropic hypogonadism who did not have mutations in known Kallmann syndrome-associated genes and who had no chromosomal abnormalities on standard karyotyping, Young et al. (2012) identified 1 proband with a heterozygous 231-kb deletion involving the last 11 exons of the SEMA3A gene (603961.0001). RT-PCR demonstrated the presence of the deletion in the proband's affected father and sister; the deletion was not detected by microarray analysis in 520 controls. Sequencing of the nondeleted SEMA3A allele and of 12 known HH-associated genes in affected members of the family did not reveal any other mutations. Young et al. (2012) concluded that SEMA3A plays a role in anosmic hypogonadotropic hypogonadism.

Because mutant mice lacking a functional Sema3a-binding domain in Nrp1 (602069) have a Kallmann syndrome-like phenotype, Hanchate et al. (2012) sequenced the SEMA3A gene in 386 unrelated KS patients, including 297 males and 89 females. All had hyposmic/anosmic HH, and 88 (23%) of the patients were known to carry a heterozygous mutation in 1 of 5 previously tested KS-associated genes (KAL1, 300836; FGFR1, 136350; PROKR2, 607123; PROK2, 607002; and FGF8, 600483). Heterozygosity for 8 different nonsynonymous mutations in SEMA3A were identified in 24 patients (see, e.g., 603961.0002 and 603961.0003), including 2 patients already known to carry a mutation in PROKR2 and 1 each with a mutation in KAL1, FGFR1, and PROK2, respectively. Based on the seemingly normal reproductive phenotype of Sema3a +/- mice, Hanchate et al. (2012) concluded that monoallelic mutations in SEMA3A are not sufficient to induce the abnormal phenotype in patients, but contribute to the pathogenesis of KS through synergistic effects with mutant alleles of other disease-associated genes.

In 2 Chinese patients with HH without anosmia (patiente 1 and 2), Dai et al. (2020) identified heterozygous missense mutations in the SEMA3A gene (R197Q, 603961.0004 and R617Q, 603961.0006, respectively). In a Chinese patient with anosmic HH (patient 2), they identified a heterozygous V458I mutation in the SEMA3A gene (603961.0005). Transfection of a plasmid containing SEMA3A with the R197Q or R617Q mutation showed normal secretion but absence of FAK phosphorylation in GN11 cells and failure to stimulate GN11 cell migration; transfection with the V458I mutation showed abnormal secretion, failure to phosphorylate FAK in GN11 cells, and failure to stimulate GN11 cell migration. Patient 2 also had heterozygous mutations in the CCDC141 (616031) and PROKR2 genes, leading Dai et al. (2020) to consider oligogenic inheritance in this patient.