Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjun...
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.
▼ Clinical Features
Bo-Abbas et al. (2003) described a large Saudi Arabian family in which 2 brothers and a sister in 1 sibship married 2 sisters and a brother in a first-cousin sibship. The family sought medical attention for infertility. Six of the 19 offspring in the 3 sibships (4 men and 2 women), at least 1 from each mating, met the standard diagnostic criteria for idiopathic hypogonadotropic hypogonadism, including inappropriately low gonadotropin concentrations in the presence of prepubertal concentrations of sex steroids, normal anterior pituitary function, and normal findings on brain imaging. Affected individuals were responsive to exogenous pulsatile gonadotropin-releasing hormone (GNRH; see 152760 and 602352).
Tenenbaum-Rakover et al. (2007) studied 5 patients with normosmic HH from 2 unrelated Arab Muslim families from Syria and Israel. Phenotypic analysis revealed variable expressivity within the same family, with affected individuals exhibiting either partial or complete gonadotropic deficiency. Luteinizing hormone (LH; see 152780) pulsatility analysis showed peaks with normal frequency but low amplitude. Repeated GNRH tests performed between 12 and 21 years of age in 1 affected male revealed progressive changes in pituitary response from an early pubertal to an almost full pubertal pattern.
Brioude et al. (2013) reported a consanguineous family from Portugal in which a 55-year-old male had gynecomastia and typical hypogonadism, including small intrascrotal testes, near-normal pubic hair, and small penis. He had a normal sense of smell on olfactometry, and pituitary and olfactory bulb MRI and renal ultrasound were normal. He had 2 affected sisters who had complete hypogonadism, with absent breast development and primary amenorrhea but near-normal pubic hair at 30 and 32 years of age, respectively. Both sisters reported a normal sense of smell. The 3 affected individuals had very low serum LH and follicle-stimulating hormone (FSH; see 136530) levels, as well as low testosterone and estradiol, respectively. Brioude et al. (2013) also reported a French Caucasian man, born to nonconsanguineous parents, who had no pubertal development at 19 years of age. Examination revealed small intrascrotal testes and small penis, with very low serum levels of testosterone, LH, and FSH, which did not respond to GNRH challenge. Pituitary and olfactory bulb MRI were normal, and olfactometry showed a normal sense of smell. Reevaluation at 27 years of age showed restoration of pulsatile LH secretion as well as testosterone secretion in response to pulsatile GNRH administration. He was azoospermic and underwent combined gonadotropin therapy with successful induction of spermatogenesis; the first 2 pregnancies with his partner ended in early miscarriages, but the third pregnancy resulted in a healthy boy.
Acierno et al. (2003) performed a genomewide scan on a large consanguineous Saudi family with autosomal recessive idiopathic hypogonadotropic hypogonadism, previously studied by Bo-Abbas et al. (2003). Linkage over a 1.06-Mb interval on chromosome 19p13.3 was established with a maximal 2-point lod score of 5.17.
In a consanguineous family in which 5 sibs had normosmic hypogonadotropic hypogonadism, de Roux et al. (2003) performed homozygosity mapping and identified a locus on chromosome 19p13.
▼ Molecular Genetics
In affected individuals from the large consanguineous Saudi family with autosomal recessive normosmic hypogonadotropic hypogonadism mapping to chromosome 19p13.3, originally reported by Bo-Abbas et al. (2003), Seminara et al. (2003) identified homozygosity for a missense mutation in the GPR54 gene (L148S; 604161.0001), located within the critical linkage region. Analysis of 63 additional unrelated patients with normosmic idiopathic hypogonadotropic hypogonadism and 20 patients with anosmic hypogonadotropic hypogonadism revealed 1 normosmic HH patient with 2 compound heterozygous mutations in GPR54: R331X (604161.0002) and X399R (604161.0003).
In 5 affected sibs from a consanguineous family with normosmic hypogonadotropic hypogonadism mapping to chromosome 19p13, de Roux et al. (2003) sequenced 5 candidate genes and identified homozygosity for a 155-bp deletion within the GPR54 gene (604161.0004).
In 5 patients with normosmic hypogonadotropic hypogonadism from 2 unrelated Arab-Muslim families from Syria and Israel, Tenenbaum-Rakover et al. (2007) identified homozygosity for a missense mutation in the GPR54 gene (L102P; 604161.0005).
In a male patient with anosmic hypogonadotropic hypogonadism, Miraoui et al. (2013) identified 2 heterozygous missense mutations, 1 in the KISS1R gene (A194D; 604161.0007) and 1 in the IL17RD gene (A735P; 606807.0003).
In affected members of 2 unrelated families with normosmic hypogonadotropic hypogonadism (HH), Brioude et al. (2013) analyzed 9 HH-associated genes and identified mutations in the KISS1R gene in both families: 3 affected sibs from a consanguineous family from Portugal were homozygous for a missense mutation (Y313H; 604161.0008), whereas a French Caucasian male proband was compound heterozygous for 2 missense mutations, X399R and L102P. Brioude et al. (2013) noted that the observed restoration of gonadotropic secretion by exogenous GNRH administration in these patients further supported the hypothalamic origin of the gonadotropin deficiency in this genetic form of normosmic HH.
Bo-Abbas et al. (2003) studied 4 families with autosomal recessive idiopathic hypogonadotropic hypogonadism, including a consanguineous pedigree from the Middle East. Defects within the genomic coding sequences of GNRH1 (152760) and GNRHR were excluded by temperature-gradient gel electrophoresis (TGGE), direct sequencing, and haplotypes created from simple sequence polymorphisms flanking the GNRH1 and GHRHR loci.