Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by incomplete or absent puberty caused by the lack or deficient number of hypothalamic GnRH neurons, disturbed secretion or action of GnRH, or both. The association of CHH and a defective sense of smell (anosmia or hyposmia) found in approximately half of the CHH patients is termed Kallmann syndrome (KS). CHH is clinically and genetically heterogeneous, and >25 different causal genes have been identified to date. Genetic testing for CHH is useful for diagnosis, prognosis, and genetic counselling. In the majority of cases, however, the molecular genetic cause remains unresolved, implying there are still new genes to be found. Various patterns of inheritance have been observed in association with this condition, including X-linked, autosomal dominant, and autosomal recessive, as well as di- and oligogenic inheritance. Recently, CHH has been found to overlap both phenotypically and genetically with several other syndromes, which underlines the need for careful clinical examination and the importance of family background analysis before genetic testing. Next-generation sequencing techniques allow the simultaneous investigation of several genes, but identification of the real causal mutations among the variants detected poses another challenge, especially when the patterns of inheritance vary. In addition, many mutations display variable penetrance and variable phenotypic expressivity, and defining the contribution of each mutation involved in oligogenic inheritance is difficult. The genetic data must thus be interpreted with caution, and the real clinical value of the findings carefully evaluated before reported to the patient.
Funding: This work was supported by the Academy of Finland (grant number 138124) and Jalmari and Rauha Ahokas Foundation.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology