INTRODUCTION: Mutations of the human GNRH1 gene are an extremely rare cause of normosmic idiopathic hypogonadotropic hypogonadism (nIHH), with only 6 mutations so far described. PATIENTS: As part of a larger study, families with IHH were screened for mutations in genes known to be associated with IHH. In family 1, a 15-year and 9-month-old boy first presented during infancy with micropenis and bilateral cryptorchidism. His pubic and axillary hair is at stage 4 and 2, respectively. His testes are 1 ml bilaterally, and his stretched penile length is 3.6 cm. In family 2, a 19-year and 2-month-old man was referred because of absence of secondary sexual characteristics. His 13-year and 8-month-old sister did not have any breast development. RESULTS: In 3 patients from 2 independent families we identified GNRH1 mutations. In the proband from family 1, a homozygous 1-base deletion (c.87delA) leading to a frameshift mutation (p.G29GfsX12) was identified. In family 2, the affected siblings had a novel homozygous mutation of c.G92A leading to p.R31H. CONCLUSION: Both mutations in these families are located in the region encoding the decapeptide and in the loci where the mutations have been described before. Therefore, these areas can be considered as mutational hot spots, indicating priority for routine diagnostic gene mutation analysis.
INTRODUCTION: Mutations of the humanGNRH1 gene are an extremely rare cause of normosmic idiopathic hypogonadotropic hypogonadism (nIHH), with only 6 mutations so far described. PATIENTS: As part of a larger study, families with IHH were screened for mutations in genes known to be associated with IHH. In family 1, a 15-year and 9-month-old boy first presented during infancy with micropenis and bilateral cryptorchidism. His pubic and axillary hair is at stage 4 and 2, respectively. His testes are 1 ml bilaterally, and his stretched penile length is 3.6 cm. In family 2, a 19-year and 2-month-old man was referred because of absence of secondary sexual characteristics. His 13-year and 8-month-old sister did not have any breast development. RESULTS: In 3 patients from 2 independent families we identified GNRH1 mutations. In the proband from family 1, a homozygous 1-base deletion (c.87delA) leading to a frameshift mutation (p.G29GfsX12) was identified. In family 2, the affected siblings had a novel homozygous mutation of c.G92A leading to p.R31H. CONCLUSION: Both mutations in these families are located in the region encoding the decapeptide and in the loci where the mutations have been described before. Therefore, these areas can be considered as mutational hot spots, indicating priority for routine diagnostic gene mutation analysis.