Pituitary pathology in patients with Carney Complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities

Abstract

First described in the mid 80's, Carney Complex (CNC) is a rare, dominantly heritable disorder with features overlapping those of McCune-Albright syndrome (MAS) and other multiple endocrine neoplasia (MEN) syndromes like MEN type 1 (MEN 1). Pituitary tumors have been described in a number of patients with CNC; they present with elevated growth hormone (GH) levels and mild hyperprolactinemia. However, most patients with CNC have mild hypersomatomammotropinemia starting in adolescence; this is similar to the situation in MAS patients: in both disorders, pituitary hyperplasia appears to precede tumor development. Familial pituitary tumor syndromes such as CNC provide an important insight into the genetics and molecular pathology of pituitary and other endocrine tumors. Our understanding of these conditions is expanding rapidly due to the identification of the causative genes and the availability of murine disease models. The present report reviews the clinical findings related to pituitary tumor development among patients with CNC and provides an update on murine models of the complex.

Hyperplasia–adenoma sequence in pituitary tumorigenesis related to aryl hydrocarbon receptor interacting protein gene mutation

“…Pituitary hyperplasia is, however, characteristic of patients with CNC and acromegaly (Pack et al 2000), although the tumor multicentricity seen in CNC has not been seen to date in the setting of AIP mutations. In contrast to the tumors in this study where the hyperplastic areas were immunoreactive for GH only, pituitary hyperplasia in CNC is characterized by GH and prolactin immunoreactivity (Boikos & Stratakis 2006). McCune-Albright syndrome (MAS) is also associated with acromegaly and disorders of both GH and prolactin secretion in which diffuse somatomammotrope hyperplasia accompanying the adenoma has been described (Kovacs et al 1984, Dumitrescu & Collins 2008.…”

“…Owing to this lack of suggestive symptoms or signs in advance of emergency presentation, the standard hormonal workup (including dynamic pituitary function tests) was not available before surgery. For this reason, although the current patients were unlikely to have the very elevated GH levels and concomitant symptoms typical of AIP-mutation-related somatotropinomas , more subtle abnormalities in the somatotrope axis such as those commonly seen in CNC cannot be ruled out (Boikos & Stratakis 2006). The pathological designation is suggested by the presence of scattered GH-positive cells ( Figs 3C and 4C) and immunoreactivity for Pit-1 (Figs 3E and 4E).…”

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

“…Recently, a mutation in the CDKN1B gene (also known as p27/ KIP1) was reported to be associated with a MEN 1-like syndrome in a rat model and few humans [99]. Genetic defects in one of the regulatory subunits of protein kinase A (PKA) (regulatory subunit type 1 alpha, PRKAR1A) causes Carney complex [100]. Vierimaa (2006) reported that inactivating mutations of the gene encoding aryl hydrocarbon receptor-interacting protein (AIP) were found in patients with pituitary tumors (predominantly acromegaly) in both sporadic and familial settings [101].…”

“…This change in clinical phenotype in patients with concurrent Cushings syndrome and acromegaly is not surprising given the known relationship between cortisol and growth hormone metabolism, but as phenomenon deserves further investigation in patients affected with CNC or similar conditions, such as McCune Albright syndrome [34] For patients with CNC who have elevated GH and/or IGF-1, it is important to identify clinically significant acromegaly as defined by generally applied criteria [69]. Most CNC patients will have some abnormality of GH secretion due to the underlying pituitary hyperplasia, but almost all of them will have negative imaging studies [100,108]. It is common practice to treat CNC patients with elevated IGF-1 levels with somatostatin analogues with the goal of normalizing IGF-1 [100,109].…”

“…Most CNC patients will have some abnormality of GH secretion due to the underlying pituitary hyperplasia, but almost all of them will have negative imaging studies [100,108]. It is common practice to treat CNC patients with elevated IGF-1 levels with somatostatin analogues with the goal of normalizing IGF-1 [100,109]. For CNC patients with abnormal response to oral glucose tolerance tests but normal IGF-1 levels and normal pituitary imaging, evaluations should be performed annually to assess for changes that may require treatment.…”