The Genetics of Growth and Growth Disorders: From the Hypothalamus to the Epiphysis

At least 423 common variants with low effect size have been identified by genome-wide association studies (GWAS) to have an effect on height in normal range. Mutations in >130 genes have been found in patients with short stature and in 16 with overgrowth (1,2). The SHOX gene appears to be the "master controller" of human height. Rare deleterious gene mutations affecting height have been described throughout the growth hormone-releasing hormone (GHRH)- GH- insulin-like growth factor-1 (IGF-I) pathway (3), involving the GHRH receptor, pituitary-specific transcription factors, GH, the GH receptor (Laron syndrome), post-GH receptor JAK/STAT signaling (STAT5B), IGF-I, and the type 1 IGF (IGF-1) receptor. More recently, studies have concentrated on investigations of target tissue defects involving the endochondral growth plate and its hormonal regulators. The schema below (4) has been developed in which various growth plate-centered genes have been linked to severe and mild forms of short stature, as well as to tall stature, depending on whether mutations are homozygous or heterozygous, and whether they are inhibitors (red) or activators (green) of protein regulation. With increased identification of genes that regulate growth, the number of cases of "idiopathic short stature" will inevitably decrease. References 1. Durand C, Rappold GA. Height matters-from monogenic disorders to normal variation. Nat Rev Endocrinol 2013;9:171-177. Epub 2013 Jan 22 2. Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z, Amin N, Buchkovich ML, Croteau-Chonka DC,Day FR, Duan Y, Fall T, Fehrmann R, Ferreira T, Jackson AU, Karjalainen J, Lo KS, Locke AE, Mägi R, Mihailov E, Porcu E, Randall JC, Scherag A,Vinkhuyzen AA, Westra HJ, Winkler TW, Workalemahu T, Zhao JH, Absher D, Albrecht E, Anderson D, Baron J, Beekman M, Demirkan A, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Fraser RM, Goel A, Gong J, Justice AE, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Lui JC, Mangino M,Mateo Leach I, Medina-Gomez C, Nalls MA, Nyholt DR, Palmer CD, Pasko D, Pechlivanis S, Prokopenko I, Ried JS, Ripke S, Shungin D, Stancáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet-Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Afzal U, Arnlöv J, Arscott GM, Bandinelli S, Barrett A, Bellis C, Bennett AJ, Berne C, Blüher M, Bolton JL, Böttcher Y, Boyd HA, Bruinenberg M, Buckley BM, Buyske S, Caspersen IH, Ch