Kallmann syndrome: fibroblast growth factor signaling insufficiency?

J Mol Med (Berl). 2004 Nov;82(11):725-34. doi: 10.1007/s00109-004-0571-y. Epub 2004 Sep 8.


Kallmann syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes anosmin-1, an approximately 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann syndrome (KAL2), combined with the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of anosmin-1 is to enhance FGF signaling and suggest that the gender difference in anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.

Publication types

  • Review

MeSH terms

  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Fibroblast Growth Factors / metabolism*
  • Genetic Heterogeneity
  • Gonadotropin-Releasing Hormone / metabolism
  • Humans
  • Kallmann Syndrome / genetics
  • Kallmann Syndrome / metabolism*
  • Kallmann Syndrome / physiopathology
  • Male
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Olfactory Mucosa / embryology
  • Olfactory Mucosa / metabolism
  • Sequence Analysis, Protein


  • ANOS1 protein, human
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Gonadotropin-Releasing Hormone
  • Fibroblast Growth Factors