Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene

Abstract

Background: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations occur in 15% of familial isolated pituitary adenoma (FIPA) cases. To date, studies have focused on the identification of such mutations in large international cohorts. Detailed genetic and clinical studies within AIP mutation-positive families have been limited. Aim: To undertake a comprehensive study of a large Brazilian FIPA kindred with an E174 frameshift (E174fs) AIP mutation to assess clinical, hormonal, and radiological features in mutation carriers. Methods: The kindred included 122 subjects across six generations; all underwent clinical examination. Genetic studies were performed to identify E174fs mutation carriers. E174fs-positive subjects underwent magnetic resonance imaging (MRI) and hormonal assessments. Results: Of the ten germline AIP mutation carriers, three had pituitary tumors, while seven were asymptomatic carriers. Three patients with pituitary tumors showed variability in terms of tumor phenotype (two with acromegaly, one with prolactinoma, or mixed prolactin/GH-secreting tumor) and age at diagnosis; both patients with acromegaly had poor responses to octreotide. Tumor AIP immunohistochemistry from the operated patient showed decreased expression when compared with normal tissue. Two adult subjects with normal MRI had elevated IGF-I in the absence of other causes. A 2-year-old child with the E174fs mutation and a normal MRI had premature thelarche, ovarian development, and advanced bone age in the absence of other underlying causes. Conclusions: The penetrance of pituitary tumors in AIP mutation-positive adult subjects was 33.3%, while clinical/hormonal features were variable. The features noted in AIP-mutation carriers in this kindred suggest that clinical characteristics of such carriers may extend beyond pituitary tumors.

Aggressive prolactinoma in a child related to germline mutation in the ARYL hydrocarbon receptor interacting protein (AIP) gene

“…agonists, specially cabergoline, may be related to dopamine-receptor expression in the adenomatous tissue (7)(8)(9)(10), although tumor aggressiveness may be related to AIP mutations in young patients (12,13). Mutations on AIP may be involved in cell proliferation in several ways: multiple protein-protein interactions may lead in particular to AHR stabilization in the cytoplasm, thereby enhancing its ligand-induced nuclear translocation, and modulation of specific phosphodiesterases in some pituitary cells (16,20,21).…”

“…Our group previously reported variable c-erbB2 immunoreactivity in somatotropic and lactotrophic tumors and it might have some influence on their evolution, considering the intimate relationship between c-erb B2 and the epidermal growth factor (EGF) (28,30). We recently described a strong c-erb staining in aggressive somatotropic adenoma in the context of Familial Isolated Pituitary Adenomas (FIPA) with a 174 frameshift AIP mutation (13). In this case, c-erb B2 was negative and had no relation to tumor aggressiveness.…”

“…Primers used for the analysis of the AIP exonic and flanking intronic sequences are as reported by Vierimaa and cols. and the PCR reaction/sequencing were performed as reported previously (11)(12)(13).…”

“…These tumors usually occur in the familial isolated pituitary adenomas (FIPA) setting (13,14) and sporadic pituitary tumors firstly appeared to be very rare (15)(16). Recently, AIP mutations related to sporadic tumors have been increasingly reported in young patients (17,18).…”

The clinical, pathological, and genetic features of familial isolated pituitary adenomas

“…These questions will be answered in part by the clinical phenotype exhibited by aip knockout mouse models now at an advanced stage of development. However, there is an important caveat in extrapolating murine data on AIP function to humans because the interactions of AIP with AhR in the mouse differ from that in the human in terms of AIP-cytoplasmic localization and AIP-induced shuttling to the nucleus (63,64). It may be that this inter-species divergent AIP/AhR function may lead to different disease risks and tumor expression in humans when compared with mice.…”