Kallmann syndrome (KS) typically combines severe congenital hypogonadotropic hypogonadism (HH) with anosmia. The degree of the hypogonadism and that of the smell deficiency can, however, vary significantly, not only between unrelated patients, but also within affected families. Some patients may also have non-reproductive, non-olfactory additional anomalies. Five causal genes have been identified to date, namely, KAL1, FGFR1, FGF8, PROKR2, and PROK2. Mutations (mainly nonsense or frameshift mutations) in KAL1 encoding the extracellular glycoprotein anosmin-1, underlie the X chromosome-linked form, which accounts for roughly 8% of all KS cases. Loss-of-function mutations (mainly missense mutations) in FGFR1 or FGF8 encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance, which accounts for ~10% of KS cases. Notably, as many as 30% of the FGFR1 mutations found in the patients could be de novo mutations. Finally, putative loss-of-function mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, respectively, have been detected in ~9% of the KS patients. Most of these mutations are missense mutations, and many are also present in apparently unaffected individuals, thus initially raising questions regarding their pathogenic role in the disease. For most of these mutations, however, deleterious effects on prokineticin-signalling have been shown. The finding of both heterozygous and homozygous unrelated patients for given PROKR2 and PROK2 mutations is quite remarkable, and raises the question of a possible digenic or oligogenic mode of inheritance in heterozygous patients. Digenic inheritance has indeed been shown in a few patients who carry missense mutations both in PROKR2 and PROK2, KAL1, FGFR1, or genes responsible for normosmic HH such as GNRHR and KISS1R. Most patients heterozygous for PROKR2 or PROK2 mutations, however, are expected to carry additional mutations in as-yet-undiscovered KS genes. Indeed, mutations in the genes identified so far have been found in <30% of all KS patients, indicating that other disease genes remain to be discovered.
24 - 28 Apr 2010
European Society of Endocrinology