A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-22 with or without anosmia (HH22) is caused by homozygous mutation in the FEZF1 gene (613301) on chromosome 7q31.

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 is 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.

Kotan et al. (2014) studied 4 patients from 2 unrelated consanguineous Kurdish families with hypogonadotropic hypogonadism and anosmia. In the first family, the proband was a 19-year-old man who presented at 14 years of age with absent pubertal development. After he received treatment with testosterone and human chorionic gonadotropin (HCG; see 118850) and underwent orchiopexy for undescended testicles, his penis developed to normal adult size, but his testicles remained small. His 24-year-old sister had absent breast development and primary amenorrhea, and began estrogen replacement at 18 years of age. In the second family, a boy presented at 2 years of age with micropenis and undescended testicles and underwent HCG and testosterone treatments, followed by orchiopexy. At 14 years of age, he had 1-ml testicles bilaterally and a 4-cm phallus with stage 2 axillary and pubic hair; a GNRH stimulation test elicited a prepubertal response. His 8.5-year-old brother also had micropenis and undescended testicles, and underwent orchiopexy at 2 years of age after failure of HCG treatment. He was prepubertal with 1-ml testicles bilaterally and a 3.6-cm phallus with stage 1 axillary and pubic hair. All 4 affected individuals had anosmia, as documented by quantitative smell-identification analysis that included a culturally appropriate 20-item test, and brain MRI revealed bilateral aplasia of the olfactory bulbs in the probands from both families. None of the 4 patients had any other dysmorphic features or developmental anomalies, and their parents and other sibs had no history of problems in pubertal development or fertility.

Kotan et al. (2014) performed whole-exome sequencing in a cohort of 30 individuals with hypogonadotropic hypogonadism and anosmia, in whom mutations in known Kallmann syndrome-associated genes had been excluded. In 4 affected individuals from 2 unrelated consanguineous Kurdish families, they identified homozygosity for a missense mutation (H278Y; 613301.0001) and a 1-bp deletion (c.651delT; 613301.0002), respectively, in the FEZF1 gene. The mutations, which segregated with disease in each family, were not found in 100 ethnically matched controls, 36 in-house whole exomes, or public SNP databases. In the affected sibs from the family with the FEZF1 missense mutation, Kotan et al. (2014) also identified homozygosity for a nonsense mutation (R724X) in the CCDC141 gene (616031); the unaffected parents and 3 unafected sibs were all heterozygous for both the FEZF1 and the CCDC141 mutations.