Endocrine Abstracts

Kallmann syndrome (KS) combines hypogonadotropic hypogona dism and anosmia. Anosmia is related to the hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone (GnRH), and probably results from a failure of the embryonic migration of GnRH-synthesizing neurons. This is a genetically heterogeneous disease, which affects 1:8000 males and five times less females. Loss-of-function mutations in KAL1 and FGFR1 account for the X-chromosome linked form and an autosomal dominant form of the disease, respectively. KAL1 encodes anosmin-1, a locally restricted glycoprotein of embryonic extracellular matrices, which is likely to be involved in FGF-signaling through FGFR1. Nearly 80% of the KS patients, however, do not carry a mutation in either of these genes.

We considered the genes, encoding the PROKR2 and PROK2, most relevant candidates because olfactory bulbs do not develop normally in prokr2^−/− or in prok2^−/− mice. Prokr2^−/− mice have a severe atrophia of the reproductive system related to the absence of GnRH-synthesizing neurons in the hypothalamus. We sought mutations in PROKR2 and PROK2 in a cohort of 192 unrelated individuals affected by KS. Ten different PROKR2 mutations were detected in 14 patients in heterozygous, homozygous, or compound heterozygous state, and heterozygous PROK2 mutations were found in 4 KS patients. Notably, PROKR2 and PROK2 mutations were also present in some clinically unaffected individuals. These results shed new light on the complex genetics of KS.