Endocrine Abstracts

Objective: To determine the frequency of mutations of the gonadotropin-releasing hormone receptor (GnRHR) and of the G protein-coupled receptor 54 (GPR54) genes in normosmic idiopathic hypogonadotropic hypogonadism patients (IHH).

Methods: In a retrospective study we analysed the GnRHR and the GPR54 genes of 327 IHH patients including 105 females (36.5%) and 183 males (63.5%). Among the index cases (288 siblings) 267 were sporadic form (92.7%) and the others were included in 21 families (7.3%) with at least two affected siblings. Only 170 patients were tested for GPR54 mutations. All females were diagnosed with primary amenorrhoea and 30.4% males presented with cryptorchidism. After informed consent, genomic DNA was amplified by PCR to obtain partially overlapping amplicons encompassing the exon-intron boundaries of the GnRHR and GPR54 genes and analyzed by DNA sequencing.

Results: Familial cases: ten of 21 (47.6%) IHH patients tested had mutations in either the GnRHR or the GPR54 gene. Among the eight (38.1%) individuals bearing GNRHR mutations, 5 (23.8%) were homozygous or compound heterozygous and 3 (14.3%) were simple heterozygous. Among the 11 remaining patients, mutations of GPR54 were found in two patients (18.2%): one (9.1%) at the homozygous state and the other one at the heterozygous state. GnRHR and GPR54 mutations account for 7.5% and 2.5% respectively of sporadic cases.

The phenotype is depending on the nature of the genetic defect. GnRH administration fails to stimulate gonadotropin secretion when the biological activity of the mutated GnRHR is abolished (R139H, A129D, R139C) while a response is observed when the defect is partial (Q106R, R262Q).

Conclusion: The prevalence of GnRHR mutations is about three fold higher than that of GPR54. No genetic defect was identified in half of familial cases suggesting that additional genes play an important role in normal puberty.