A giant? Think of genetics: growth hormone-producing adenomas in the young are almost always the result of genetic defects

Giants (from the Greek ‘‘Ci 9camse1’’) are known from ancient times in all societies and cultures (Fig. 1). In Greek mythology, the giants challenged the Olympian Gods for supremacy in the world in a battle known as gigantomachy. In Hebrew, the nephilim were giants that existed before the flooding that occurred at Noah’s time; Goliath was a giant Philistine warrior who was defeated by David, the man who was to become king of Israel. Both gigantes and nephilim were related to the divine but seen as different, even vile; they had to be eliminated: in fact, one of the reasons for Noah’s flooding was to get rid of the nephilim. To this day, Enceladus (9Ecje9kado1), a giant who was buried under Aetna, is one of the Greek words for earthquake. Thus, humans of large size were always around: the Irish giants were famous in the 1700s; the Alton giant (Robert Pershing Wadlow, 1918–1940) was the tallest man of his time and of international fame, just like today every move of a 2.51-m-tall Turkish man makes world news. Although unusually large size in humans always existed, it was most likely the result of de novo mutations that were apparently never selected for, at least not in Homo Sapiens. Not favoring the large size as a trait was seen by the old texts as nemesis to the hubris of oversize and was most likely the result of disease conferred by the excess growth hormone (GH) but also perhaps due to other coexisting morbidities in the context of genetic, syndromic associations. Nevertheless, the existence of multiple affected members of a clan or family (there were many Giants and Nephilim, and Goliath had both a large brother and three giant sons) [1] pointed to not only de novo defects but also some that could be inherited, at least for some generations. The evidence for occasional inheritance aside, why was gigantism not favored as a trait? Not only the size of the known affected families was small but the life span of sporadic giants was also short (Mr. Wadlow died at the age of 22 years). Today, we know that at least part of the answer to this question is that almost every gene involved in the genetics of predisposition to gigantism or acromegaly or in somatic mutations in GH-producing pituitary adenomas (GHPAs) is a potent oncogene or tumor suppressor gene that is regulating a major signaling pathway [2]. GNAS defects (activating mutations of the G-protein stimulatory subunit alpha, Gsa) are not even compatible with life in the germline; somatic GNAS defects lead to gigantism in McCune–Albright syndrome (MAS) and in acromegaly when confined to sporadic GHPAs [3]. PRKAR1A mutations that lead to increased cAMP signaling, just like GNAS mutations, are responsible for gigantism or acromegaly in the context of Carney complex (CNC) but have never been found in sporadic GHPAs [4]. MEN1 (menin) gene mutations lead to gigantism and/or acromegaly in the context of multiple endocrine neoplasia (MEN) type 1 (MEN 1) but only rarely in sporadic acromegaly [5]. Mutations in the cyclin-dependent kinase (CDKN) 1B (CDKN1B) are found in MEN type 4 (MEN 4) [6]; other CDKNs, all essential molecules in the regulation of cell cycle, growth, and proliferation, are mutated, rarely, in MEN 1/MEN 4-like syndromic gigantism and/or acromegaly but not in sporadic GHPAs [7]. Most of the patients with gigantism before puberty have defects on the & Constantine A. Stratakis stratakc@mail.nih.gov