What is the role of genetics in the etiology of hypogonadotropic hypogonadism?

Updated: Apr 03, 2019
  • Author: Maria G Vogiatzi, MD; Chief Editor: George T Griffing, MD  more...
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Answer

Genetics of hypogonadotropic hypogonadism

To date, numerous genes have been identified as causes of hypogonadotropic hypogonadism. The genes include the following:

  • KAL is located on the X chromosome, just below the pseudoautosomal region. An abnormality in this gene results in Kallmann syndrome, which is characterized by anosmia and hypogonadotropic hypogonadism.  FGFR1, FGF8, PROK2, and  PROKR2 have also been associated with Kallmann syndrome. The relationship with Kallmann syndrome is thought to be due to the relation of these genes to the development and migration of gonadotropin-releasing hormone (GnRH) neurons.
  • The  DAX1 gene is associated with X-linked adrenal hypoplasia congenita (hypogonadotropic hypogonadism and adrenal insufficiency).
  • GNRHR is the gene associated with the GnRH (LHRH) receptor.
  • GNRH1, KISS1R, and  GNRHR genes have been associated with normosmic (sense of smell is not disrupted) hypogonadotropic hypogonadism.
  • TAC3 and  TACR3 mutations have also been associated with normosmic hypogonadotropic hypogonadism, although their exact functions are unclear.
  • CHD7 mutation, which has been associated with CHARGE syndrome, has also been found in patients with both normosmic and anosmic hypogonadotropic hypogonadism.
  • PC1 is the gene for prohormone convertase 1. Abnormality of this gene causes hypogonadotropic hypogonadism and defects in prohormone processing.
  • In addition, mutations in the  PROP1 gene have resulted in absence of several pituitary hormones, including growth hormone, thyroid-stimulating hormone, prolactin, and gonadotropins.  PROP1 encodes a protein expressed in the embryonic pituitary, which is necessary for function of  POU1F1 (formerly  PIT1), which codes for a pituitary transcription factor.
  • In addition, mutation of the gene  HESX1 has been associated with septooptic dysplasia, which may include poor development of the pituitary.

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