Endocrine Abstracts

Kallmann syndrome is a developmental disorder that associates anosmia, related to olfactory bulb aplasia, with congenital hypogonadotropic hypogonadism caused by GnRH deficiency, clinically characterized by the absence of spontaneous puberty and infertility. GnRH deficiency results from the incomplete embryonic migration of neuroendocrine GnRH-cells from the nasal epithelium to the hypothalamic region of the brain, as a consequence of the premature interruption of olfactory, vomeronasal and terminal nerve fibres, which normally guide these cells during their migration to the brain. This developmental connection between the central control of reproductive organs and the peripheral olfactory system (both affected in Kallmann syndrome) accounts for the aforementioned olfacto-genital pathological sequence. Kallmann syndrome can be isolated or associated with various non-reproductive non-olfactory additional anomalies, depending on the causal genes. Kallmann syndrome is genetically heterogeneous, with several different modes of transmission: X chromosome-linked recessive, autosomal dominant, autosomal recessive, and presumably oligogenic. The best characterized causal genes include ANOS1 (anosmin 1), FGFR1 (fibroblast growth factor receptor 1, also involved in Hartsfield syndrome), FGF8 (fibroblast growth factor 8), PROKR2 (prokineticin receptor 2), PROK2 (prokineticin 2), FEZF1 (FEZ family zinc finger 1), SOX10 (sex determining region Y-box 10, also involved in Waardenburg syndrome), and CHD7 (chromodomain helicase DNA-binding protein 7, also involved in the CHARGE association). Notably, this list implicates at least two different cell signalling systems (i.e., signallings by FGFs and by prokineticins) in Kallmann syndrome molecular pathogenesis. However, mutations in any of these genes are found in less than 50% of the patients, indicating that other disease genes remain to be discovered. The complex genetics of Kallmann syndrome, including a biased sex ratio (predominance of affected males) and monogenic versus oligogenic modes of transmission, will be discussed.