Mutation Linked to Hypogonadism in Siblings

Investigation into idiopathic hypogonadotropic hypogonadism uncovers GNRH1 mutation

WEDNESDAY, June 17 (HealthDay News) -- A mutation in the GNRH1 gene was found in a teenage brother and sister with normosmic idiopathic hypogonadotropic hypogonadism (IHH), which was transmitted as an autosomal recessive trait, according to a report published online June 17 in the New England Journal of Medicine.

Jerome Bouligand, Ph.D., of the Universite Paris-Sud, and colleagues describe an 18-year-old man and his 17-year-old sister, who both had complete hypogonadism and sexual infantilism. Both had normal sense of smell (IHH is sometimes associated with anosmia or hyposmia). The siblings had an unaffected brother and sister, and the parents had normal reproductive development.

The affected siblings were found to have a homozygous GNRH1 frameshift mutation that deleted the gonadotropin-releasing hormone (GnRH) decapeptide sequence. The parents and unaffected sister were heterozygous for the mutation, and the unaffected brother was free of the mutation. The homozygous mutation leads to defective endogenous synthesis of GnRH and faulty secretion into hypothalamic-pituitary portal blood by GnRH neurons, the authors note.

"In keeping with previous reports, GNRH1 mutations are probably very rare, implying that other developmental, environmental, or genetic factors can cause IHH. In conclusion, the GNRH1 mutation reported here appears to be a unique example of a genetic aberration causing complete inactivation of a human hypothalamic hypophysiotropic neurohormone gene," Bouligand and colleagues write.

A co-author reported grant support from Ferring and Merck Serono France.

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