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The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) has an incidence of 1–10 cases per 100,000 births. About 60% of patients with IHH present with associated anosmia, also known as Kallmann syndrome, characterized by total or partial loss of olfaction. Many of the gene mutations associated with Kallmann syndrome have been mapped to KAL1 or FGFR1. However, together, these mutations account for only about 15% of Kallmann syndrome cases. More recently, mutations in PROK2 and PROKR2 have been linked to the syndrome and may account for an additional 5–10% of cases. The remaining 40% of patients with IHH have a normal sense of smell. Prior to 2003, the only gene linked to normosmic IHH was the gonadotropin-releasing hormone receptor gene. However, mutations in this receptor are believed to account for only 10% of cases. Subsequently, mutations in KISS1R, TAC3 and TACR3 were identified as causes of normosmic IHH. Certain genes, including PROK2 and FGFR1, are associated with both anosmic and normosmic IHH. Despite recent advances in the field, the genetic causes of the majority of cases of IHH remain unknown. This Review discusses genes associated with hypogonadotropic disorders and the molecular mechanisms by which mutations in these genes may result in IHH.

Key Points

  • The genetic basis of the vast majority of cases of idiopathic hypogonadotropic hypogonadism (IHH) remains unknown

  • IHH with anosmia (Kallmann syndrome) is caused by the defective developmental migration of gonadotropin-releasing hormone (GnRH) and olfactory neurons; associated genes encode proteins involved in this migration

  • Molecular mechanisms that underlie IHH in patients with a normal sense of smell are diverse and may involve genes that regulate development and/or GnRH secretion or action

  • A considerable number of IHH cases probably involve mutations in more than one gene; that is, these cases are polygenic

  • Sex-associated factors also contribute to the IHH phenotype

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Figure 1: The genetic basis of idiopathic hypogonadotropic hypogonadism.

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Acknowledgements

This work was supported in part by grants from the NICHD/NIH through cooperative agreement U54 HD28138 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (U. B. Kaiser), NIH R01 HD19938 (U. B. Kaiser), NIH BIRCWH K12HD051959 (S. D. C. Bianco), NIH R21 HD059015-01 (S. D. C. Bianco) and by the Charles H. Hood Foundation Child Health Research Award (S. D. C. Bianco).

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Bianco, S., Kaiser, U. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol 5, 569–576 (2009). https://doi.org/10.1038/nrendo.2009.177

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