The recent genetics of hypogonadotrophic hypogonadism - novel insights and new questions

• Published in: Clinical endocrinology (Oxford) Vol. 72; no. 4; pp. 427 - 435
• Main Authors: Semple, Robert K., Topaloglu, A. Kemal
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2010; Blackwell; Wiley Subscription Services, Inc
• Subjects: Biological and medical sciences; Consanguinity; Endocrinopathies; Extracellular Matrix Proteins - genetics; Female; Fibroblast Growth Factor 8 - genetics; Fundamental and applied biological sciences. Psychology; Gastrointestinal Hormones - genetics; Genetics; Gonads - physiopathology; Humans; Hypogonadism - genetics; Hypogonadism - pathology; Hypogonadism - physiopathology; Hypothalamo-Hypophyseal System - physiopathology; Kallmann Syndrome - genetics; Kisspeptins; Male; Medical sciences; Nerve Tissue Proteins - genetics; Neurokinin B - genetics; Neuropeptides - genetics; Phenotype; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptors, G-Protein-Coupled - genetics; Receptors, Kisspeptin-1; Receptors, Neurokinin-3 - genetics; Receptors, Peptide - genetics; Sexual Maturation - genetics; Tumor Suppressor Proteins - physiology; Vertebrates: endocrinology; Genetics; Knowledge; Endocrinology; Hypogonadism; Genital diseases
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2009.03687.x

Summary The complex organization and regulation of the human hypothalamic–pituitary–gonadal axis render it susceptible to dysfunction in the face of a variety of genetic insults, leading to different degrees of hypogonadotrophic hypogonadism (HH). Although the genetic basis of some HH was recognized more than 60 years ago the first specific pathogenic defect, in the KAL1 gene, was only identified within the last 20 years. In the past decade, the rate of genetic discovery has dramatically accelerated, with defects in more than 10 genes now associated with HH. Several themes have emerged as the genetic basis of HH has gradually been uncovered, including the association of some genes such as FGFR1, FGF8, PROK2 and PROKR2, both with HH in association with hyposmia/anosmia (Kallmann syndrome) and with normosmic HH, thus blurring the clinical distinction between ontogenic and purely functional defects in the axis. Many examples of digenic inheritance of HH have also been reported, sometimes producing variable reproductive and accessory phenotypes within a family with non‐Mendelian inheritance patterns. In strictly normosmic HH, human genetics has made a particularly dramatic impact in the past 6 years through homozygosity mapping in consanguineous families, first through identification of a key role for kisspeptin in triggering GnRH release, and very recently through demonstration of a critical role for neurokinin B in normal sexual maturation. This review summarises current understanding of the genetic architecture of HH, as well as its diagnostic and mechanistic implications.