Pituitary Pathology in Carney Complex Patients

Abstract

Carney complex (CNC) is a familial multiple neoplasia syndrome with features overlapping those of McCune-Albright syndrome (MAS) and multiple endocrine neoplasia (MEN) type 1 (MEN 1). Like MAS and MEN 1 patients, patients with CNC develop growth hormone (GH)-producing pituitary tumors. Occasionally, these tumors are also prolactin-producing, but there are no isolated pro-lactinomas or other types of pituitary tumors. In at least some patients with CNC, the pituitary gland is characterized by hyperplastic areas; hyperplasia appears to involve somatomammotrophs only. Hyperplasia most likely precedes the formation of GH-producing adenomas in CNC, as has been suggested in MAS-related somatotropinomas, but has never been seen in MEN 1 patients. In at least one case of a patient with CNC and advanced acromegaly, a GH-producing macroadenoma showed extensive genetic changes at the chromosomal level. So far, half of the patients with CNC have germline inactivating mutations in the PRKAR1A gene; in their pituitary tumors, the normal allele of the PRKAR1A gene is lost. Loss-of-hererozygosity suggests that PRKAR1A, which codes for the regulatory subunit type 1α of the cAMP-dependent protein kinase A (PKA) may act as a tumor-suppressor gene in CNC somatomammotrophs. These data provide evidence for a PRKAR1A-induced somatomammotroph hyperpasia in the pituitary tissue of CNC patients; hyperplasia, in turn may lead to additional genetic changes at the somatic level, which then cause the formation of adenomas in some, but not all, patients.

Growth hormone-secreting adenomas: pathology and cell biology

“…11 The great majority of adenomas arise in a sporadic manner, and only a minority of adenomas are part of hereditary or familial syndromes. 14 Familial syndromes in which GH-secreting adenomas arise include the following: 1) MEN-1, linked to somatic mutations of the tumor suppressor gene MEN-1 located at the 11q13 locus; 8 2) CNC, linked to mutations of the tumor suppressor gene PRKAR1A located at 17q22-24; 49 and less commonly 3) McCune-Albright syndrome, linked to activating mutation of the gsp oncogene located at 20q13 55 (see below). Growth hormone-secreting adenomas linked to either MEN-1 or CNC are believed to correspond to about 3% of all GH-secreting tumors.…”

Mouse models of altered protein kinase A signaling

“…However, little is known about the precise environmental and genetic factors involved in pituitary tumorigenesis. In CNC, GH-producing pituitary adenomas are observed in w10% of patients (Stratakis et al 2001), and prolactinomas have also been reported in CNC kindreds (Stergiopoulos et al 2004). In both of the Prkar1a C/K mouse models described (Veugelers et al 2004, Kirschner et al 2005, pituitary pathology was not observed.…”

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

“…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].…”