Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune–Albright syndrome, familial acromegaly and genetic defects in sporadic tumors

Abstract

Pituitary tumors are among the most common neoplasms in man; they account for approximately 15% of all primary intracranial lesions (Jagannathan et al., Neurosurg Focus, 19:E4, 2005). Although almost never malignant and rarely clinically expressed, pituitary tumors may cause significant morbidity in affected patients. First, given the critical location of the gland, large tumors may lead to mass effects, and, second, proliferation of hormone-secreting pituitary cells leads to endocrine syndromes. Acromegaly results from oversecretion of growth hormone (GH) by the proliferating somatotrophs. Despite the significant efforts made over the last decade, still little is known about the genetic causes of common pituitary tumors and even less is applied from this knowledge therapeutically. In this review, we present an update on the genetic syndromes associated with pituitary adenomas and discuss the related genetic defects. We next review findings on sporadic, non-genetic, pituitary tumors with an emphasis on pathways and animal models of pituitary disease. In conclusion, we attempt to present an overall, integrative approach to the human molecular genetics of both familiar and sporadic pituitary tumors.

Pituitary tumors in childhood: update of diagnosis, treatment and molecular genetics

“…Typical histological findings in pituitary glands of MAS patients are GH-and PRLproducing cell hyperplasia [32,106,112], similar to what one sees in CNC pituitaries. Hypersomatotropinemia in MAS can be associated with significant morbidity due to exacerbation of polyostotic fibrous dysplasia in the presence of elevated GH levels [106,113].…”

“…GH-and/or PRL-producing are the second most frequently found functional pituitary tumors in early childhood; these tumors in children almost always occur in the familial setting or in the context of known genetic defects: GNAS, menin, PRKAR1A, AIP and p27 (CDKN1B) mutations [21,[32][33][34][35][36]; somato-and/or mammotropinomas become significantly more frequent than corticotropinomas in late childhood, adolescence and adulthood [37].…”

“…Somatic mutations on the adenylate cyclase-stimulating G alpha protein (GNAS complex locus, GNAS) are found in McCune-Albright syndrome [102]. Familial growth hormone secreting pituitary adenomas may occur as an isolated autosomal dominant disorder (familial somatotropinoma,) [103,104] or as part of MEN 1 and Carney complex [32,105]. McCuneAlbright syndrome (MAS) is a genetic, but not inherited, disorder [106].…”

Possible association between Carney complex and multiple endocrine neoplasia type 1 phenotypes

“…Another possibility for this case is an occurrence of the clinical condition termed FIPA (familial isolated pituitary adenomas) that refers to relatives with two or more pituitary adenomas that are genetically negative for mutations in MEN1 or PRKAR1A (30). All pituitary tumor phenotypes are reported in heterogeneous FIPA, however, almost invariably at least one prolactinoma or GH-secreting adenoma is seen per family.…”

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

“…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].…”