Familial gigantism de Herder WW known in France as ‘‘les Ge´ants des Alpes’’ (‘‘the Giants of the Alps’’) (Figure 1), were two famous giants who traveled the world and appeared at fairs and circuses at the end of the 19th century and the beginning of the 20th century. Battista Ugo (in French: Baptiste Hugo, 1876–1916) attained a height of 2.30 m (7 ft, 7 in) and Paolo Antonio Ugo (in French: Antoine Hugo, 1887–1914) attained a height of 2.25 m (7 ft, 5 in) (39–41). Their parents, three brothers and two sisters were of average size. The postmortem examina- tion of Baptiste Hugo was performed and published by Dr. D. Symmers at the William Parker Hospital in New York. The report describes a pituitary adenoma measuring 5 6 2.5 6 2.3 cm (2 6 1 6 0.9 in) and weighing 5.94 g with suprasellar expansion that compressed both optic nerves. Left parasellar and retrosellar expansion were also found. In his famous monograph, ‘‘The Pituitary Body and its Disorders’’, published in 1912, Dr. Harvey Cushing (42) hinted at ‘‘Mendelian tendencies’’ in two patients with Figure 1 - Familial gigantism in the two Hugo brothers. Top row: Battista Ugo (Baptiste Hugo), 1876–1916, reached a height of 2.30 m (7 ft, 7 in) and Paolo Antonio Ugo (Antoine Hugo), 1887– 1914, reached a height of 2.25 m (7 ft, 5 in). Bottom row: the parents of the Ugo brothers, Teresa Chiardola (1849–1905) and Antonio Ugo (1840–1917), and their sister, Maddalena Ugo (1885–1960). Picture from the collection of Dr. W. W. de Herder. 30 CLINICS 2012;67(S1):29-32 familial gigantism (case XIII, surgical No. 27784, pp. 8–92; case XXXI, surgical No. 27011K, pp. 158–162) (42). Since these initial reports, several authors have reported the coincidence of acromegaly and gigantism in first-degree relatives (43–55). Clinical relevance Growth hormone (GH)-secreting pituitary adenomas have an annual incidence of about 3 per 1,000,000 and a prevalence of about 60 per 1,000,000. The likelihood of multiple GH- secreting tumors presenting among first-degree relatives within a single family is, therefore, statistically very un- common, and their occurrence has prompted many research- ers to consider this an inheritable disorder (56). Familial GH-secreting tumors are seen in association with three separate hereditary clinical syndromes: (1) multiple endocrine neoplasia type 1 (MEN1), (2) Carney complex (CNC), and (3) familial isolated pituitary adenomas (FIPA). Multiple endocrine neoplasia type 1 (MEN1) Autosomal-dominant MEN1 syndrome is associated with a loss of heterozygosity (LOH) on chromosome locus 11q13 (57). The MEN1 gene tumor suppressor gene encodes a 610-amino acid protein known as menin. More than 550 mutations of the MEN1 gene have been identified. Pituitary tumors occur in approximately 30–50% of patients with MEN1 (58), but the frequency of GH-producing pituitary tumors in MEN1 patients is only about 10% (59). Carney complex (CNC) Pituitary adenomas occur in 10–20% of patients with the autosomal-dominant CNC, and these are invariably GH- secreting tumors (60). CNC is associated with a LOH on chromosomal locus 17q22–24. Germline mutations in the protein kinase A (PKA) regulatory subunit 1 (PRKAR1A) gene have been identified (61). Loss of function of this regulatory subunit results in constitutive activation of PKA that increases signaling through a pathway that enhances proliferation of the GH-producing cells in the pituitary. Familial isolated pituitary adenomas (FIPA) Inactivating germline mutations in the aryl hydrocarbon receptor that interacts with tumor suppressor protein (AIP) can be found in 40–50% of families that have a case of acromegaly occurring along with FIPA (62–66). To date, about 50 different AIP mutations have been identified. AIP mutation-positive acromegaly or gigantism is gen- erally diagnosed 10 years earlier than sporadic acromegaly. GH-producing tumors in AIP-positive patients (mostly males) more frequently display extrasellar growth, exhibit more aggressive characteristics, and have a tendency for higher accelerated growth than sporadic tumors. These tumors are also more frequently associated with onset in childhood and adolescence, thus presenting more frequently with gigantism (67,68). Furthermore, AIP muta- tion-positive GH-producing tumors appear to be less responsive to medical therapy with somatostatin analogs and dopamine agonists. In 2010, Chahal and co-workers extracted DNA from a tooth of the Irish giant, Charles Byrne (1761–1783; 2.31 m, [7 ft 7 in]), and identified a germline mutation in the AIP gene. Four contemporary Northern Irish families who