Introduction: Idiopathic hypogonadotrophic hypogonadism (IHH) with normal sense of smell is a complex and rare disease entity characterised by insufficient gonadotropin releasing hormone (GnRH) neuronal action on an intact hypothalamopituitarygonadal axis. IHH has an incidence of 110 in 100 000 live births with a variable mode of inheritance and five-fold male predominance. Gene mutations have been discovered of which 1040% of the familial cases are due to GnRH receptor mutation. We report a case of normosmic IHH due to a novel familial GnRH1 mutation.
Case: A 17-year-old male presented with delayed puberty. He was born three months premature by caesarean section. His parents were second cousins in a consanguineous marriage. The patient had normal growth with no learning difficulties. On examination he had small testes, micropenis and bilateral gynaecomastia. He had normal sense of smell. Pituitary profile showed low luteinising hormone (<1 U/l), follicle stimulation hormone (<1 U/l), testosterone (0.3 nmol/l) and androstenedione (<1.1) levels with normal prolactin, vitamin D and thyroid hormone levels. MRI scan of the pituitary was normal. Bone density scan revealed osteopenia. Chromosomal analysis revealed 46XY phenotype and genetic analysis revealed a homozygous variant in GnRH1 [c.119_122dupGAGA, p.(Asp41Glufs*8)]. The patients sister, born with a cleft palate, was also found to be homozygous for the GnRH1 mutation. She is currently on hormone replacement therapy. Genetic testing of the both parents revealed heterozygous carriers for the same mutation. The patient continues to show progressive sexual development on hormone replacement therapy.
Discussion: Mutations in the GnRH1 gene are a rare cause of IHH. Family members can be affected with variable penetrance of the gene mutation. We present a new gene mutation, which most likely has an autosomal recessive pattern of inheritance. Early diagnosis is essential to mitigate psychological distress and physical sequelae, and to restore fertility in affected individuals.