To address this issue, we studied 2 families, one with Kallmann syndrome (IHH and anosmia) and another with normosmic IHH, in which a single-gene defect had been identified: a heterozygous FGF receptor 1 (FGFR1) mutation in pedigree 1 and a compound heterozygous gonadotropin-releasing hormone receptor (GNRHR) mutation in pedigree 2, both of which varied markedly in expressivity within and across families.
Genotype-phenotype correlations in IHH due to GnRHR and GPR54 mutations indicate that similar mutations may lead to a variable phenotype and suggest that the pituitary might have its own pubertal maturation independent from GnRH.
This case thus expands the emerging clinical spectrum of GnRH-R mutations, provides the first genetic basis for the fertile eunuch variant of IHH and documents the occurrence of reversible IHH in a patient with a GnRH-R mutation.
To identify and determine the frequency of mutations in the coding region of the gonadotropin-releasing hormone receptor (GnRHR) gene in forty Chinese patients with normosmic idiopathic hypogonadotropic hypogonadism (IHH) and establish genotype/phenotype correlations where possible.
Mutations in the GnRH receptor (GnRHR) have been shown to be responsible for a significant number of autosomic recessive and, less commonly, sporadic cases of idiopathic hypogonadotropic hypogonadism.
Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism.
This case thus expands the emerging clinical spectrum of GnRH-R mutations, provides the first genetic basis for the fertile eunuch variant of IHH and documents the occurrence of reversible IHH in a patient with a GnRH-R mutation.
All patients with complete idiopathic hypogonadotropic hypogonadism had the same GnRHR mutations, but clinical presentations and endocrinologic responses were heterogeneous.
The molecular basis of IHH/KS is reviewed, with particular emphasis on the three most common genes ( KAL1, FGFR1, and GNRHR) that possess mutations in these patients.
To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied.