Abstract

Hypogonadotropic hypogonadism, which may be normosmic (nHH) or anosmic/hyposmic, known as Kallmann syndrome (KS), is due to gonadotropin-releasing hormone deficiency, which results in absent puberty and infertility. Investigation of the genetic basis of nHH/KS over the past 35 years has yielded a substantial increase in our understanding, as variants in 44 genes in OMIM account for ~50% of cases. The first genes for KS (ANOS1) and nHH (GNRHR) were followed by the discovery that FGFR1 variants may cause either nHH or KS. Associated anomalies include midline facial defects, neurologic deficits, cardiac anomalies, and renal agenesis, among others. Mouse models for all but one gene (ANOS1) generally support findings in humans. About half of the known genes implicated in nHH/KS are inherited as autosomal dominant and half are autosomal recessive, whereas only 7% are X-linked recessive. Digenic and oligogenic inheritance has been reported in 2-20% of patients, most commonly with variants in genes that may result in either nHH or KS inherited in an autosomal dominant fashion. In vitro analyses have only been conducted for both gene variants in eight cases and for one gene variant in 20 cases. Rigorous confirmation that two gene variants in the same individual cause the nHH/KS phenotype is lacking for most. Clinical diagnosis is probably best accomplished by targeted next generation sequencing of the known candidate genes with confirmation by Sanger sequencing. Elucidation of the genetic basis of nHH/KS has resulted in an enhanced understanding of this disorder, as well as normal puberty, which makes genetic diagnosis clinically relevant.