Molecular Genetics in Acromegaly

Abstract Pituitary tumours are the most frequent intracranial neoplasms, affecting 1/1000 of the worldwide population. Growth hormone (GH)‐secreting adenomas, also known as somatotropinomas, comprise about 20% of all pituitary tumours. Acromegaly is the clinical syndrome that results from high levels of GH in patients after the end of their growing years, whereas gigantism occurs when high GH acts on a skeleton that is still growing. Most cases of acromegaly/gigantism occur as a result of sporadic GH‐secreting pituitary adenomas. However, in 5% of cases (and significantly more frequently in the young ages), they can occur as a result of a genetic defect, most of the time in association with other endocrine abnormalities or as an isolated disorder. These familial syndromes include multiple endocrine neoplasia (MEN) type 1 (MEN1), Carney complex (CNC), MEN type 4 (MEN4). McCune–Albright syndrome (MAS), familial isolated pituitary adenoma (FIPA), the 3Ps association (pheochromocytoma/paraganglioma and pituitary adenoma syndrome or 3PAs) and X‐linked acrogigantism (X‐LAG). Key Concepts About 5% of acromegaly may be caused by a genetic mutation; this may be significantly higher in the young ages. The frequency of GH‐producing pituitary tumours in MEN1 syndrome is only about 10%, with a mean age at diagnosis comparable to the sporadic GH‐secreting adenomas (40–45 years) but with a more aggressive behaviour. The incidence of GH‐producing pituitary tumours in Carney complex (CNC) has been estimated to be less than 15%; however, insulin‐like growth factor 1 (IGF‐1) elevation may be present in up to 80% of affected patients who have no detectable tumours due to somatomammotrophic hyperplasia, which may precede clinically evident acromegaly. GH excess is found in up to 20% of patients with McCune–Albright syndrome mainly due to GH‐producing cell hyperplasia rather than due to pituitary tumours, which are identified in only a few patients. Somatotropinomas are the most common tumour type in both AIP mutation‐positive and ‐negative familial isolated pituitary adenoma (FIPA) families. AIP mutation‐positive FIPA patients are more likely to have larger tumours, more likely to invade the extrasellar region and more resistant to medication treatment GH‐secreting pituitary adenomas in 3PAs due to SDHx mutations display more aggressive phenotype, are more resistant to somatostatin analogues, and most often require surgery X‐linked acrogigantism (X‐LAG) caused by an Xq26.3 genomic duplication is a paediatric disorder characterised by early onset gigantism resulting from an excess of growth hormone as early as in infancy. The GPR101 gene duplication most likely causes X‐LAG.