Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene

Abstract

Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with pituitary adenomas.

Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences

“…These larger adenomas appearing at a younger age may indicate more aggressive tumor behavior. One reason for this increased growth might be molecular genetic factors, as this profile of larger adenomas in young patients is shared with AIP-mutation-related adenomas (Beckers et al 2013). In terms of somatic DNA alterations, GSP oncogeneactivating mutations are the most frequently encountered (Landis et al 1990).…”

Prospective, long-term study of the effect of cabergoline on valvular status in patients with prolactinoma and idiopathic hyperprolactinemia

“…At doses within the indicated range of about 2 mg per week, resistance to cabergoline treatment is rare. A recent multicenter study in 92 resistant prolactinomas reported that they comprised only about 3.4 % of prolactinomas overall, although this rate rose to 13 % in those with a genetic component to their tumorigenesis [21], such as AIP mutation [22,23]. Cabergoline has a long half-life and its potent D2 receptor affinity leads to a rapid and effective control of many prolactinomas.…”

15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas

“…Phaeo/PGL have not been reported in patients with mutations in AIP (Beckers et al 2013, Hernández-Ramírez et al 2015. No pheo/PGL or mutations in pheo/PGLpredisposing genes have been identified in 23 families with AIP mutation negative familial isolated pituitary adenomas (Dénes et al 2015).…”