Genetic Basis and Heterogeneity of Congenital Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by absent or incomplete pubertal development due to impaired production, secretion, or action of gonadotropin-releasing hormone (GnRH). When associated with anosmia or hyposmia, it is termed Kallmann syndrome. CHH exhibits striking clinical and genetic heterogeneity, encompassing either sporadic or familial cases, with inheritance patterns that include X-linked, autosomal dominant, and autosomal recessive transmission. Over the past few decades, major advances uncovered the molecular basis of CHH, shedding light on the intricate neuroendocrine regulation of human reproduction. A growing repertoire of genes has been implicated in CHH molecular pathogenesis, encoding proteins involved in the ontogeny and function of GnRH neurons. Notably, pathogenic variants in genes typically associated with complex syndromes have also been identified in patients with isolated CHH or subtle syndromic manifestations, suggesting a wide spectrum of expressivity and incomplete penetrance. Furthermore, spontaneous hypogonadism reversal, either permanent or temporary, may occur in some patients, suggesting a potential neuroplasticity within the GnRH neuronal network. This review summarizes recent advances in the molecular genetics of CHH, emphasizing the expanding spectrum of causative genes and their inheritance patterns. · Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive disorder caused by impaired production, secretion, or action of gonadotropin-releasing hormone (GnRH). When CHH is associated with olfactory defects (hyposmia or anosmia), it is termed Kallmann syndrome.. · CHH is a complex clinical and genetic heterogeneous condition with both sporadic and familial cases. Inheritance can be X-linked, autosomal recessive, or dominant.. · Although more than 60 genes have been implicated in the molecular pathogenesis of CHH, approximately 50% of cases remain without molecular diagnosis.. · CHH-associated genes encode proteins involved either in GnRH neuron ontogeny and migration or in GnRH synthesis, secretion, or action.. · Digenic or oligogenic inheritance accounts for up to 20% of CHH cases and may explain the high phenotypic variability observed among affected families.. · Pathogenic variants in genes associated with complex syndromes have been identified in cases of isolated CHH or in cases with only one additional phenotypic feature, resembling mild or incomplete forms of the original syndrome.. · Spontaneous recovery of reproductive function may occur in 10 to 20% of patients with CHH, including those harboring rare pathogenic variants in typical CHH-associated genes..