The Genetics of Hypogonadotropic Hypogonadism

An up-to-date review of the genetic aspects of idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS) is presented. Because proper development of the neuroendocrine axis must occur for normal puberty and reproductive function, gonadotropin-releasing hormone (GnRH) neuron migration is outlined first, followed by an introduction to the in vitro analysis of GnRH neuron migration. The normal hypothalamic-pituitary-gonadal (HPG) axis at different ages is discussed, along with a brief overview of normal and delayed puberty in both boys and girls. The phenotype of IHH/KS is discussed in detail, with its relation to Mendelian inheritance and chromosomal translocations. The molecular basis of IHH/KS is reviewed, with particular emphasis on the three most common genes ( KAL1, FGFR1, and GNRHR) that possess mutations in these patients. However, all other known genes for which mutations occur are also addressed briefly. The goal of this review is to provide a comprehensive discussion of IHH/KS, and to include both basic science and clinical findings that should allow a more complete understanding of hypothalamic-pituitary neuroendocrinology that is important in puberty and reproduction.