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

Abstract

SUMMARYThe objective of this study was to describe a familial screening for AIP mutations in the context of aggressive prolactinoma in childhood. A 12-year-old boy, presented headaches and bilateral hemianopsia. He had adequate height and weight for his age (50 th percentile), Tanner stage G1 P1. His bone age was 10 years. Prolactin was 10.560 ng/mL (3-25), FSH and LH were undetectable, IGF-1, TSH, Free T4, ACTH, and cortisol were within normal ranges. MRI showed a pituitary macroadenoma, 5.3 X 4.0 X 3.5 cm with compression of the optic chiasm, bilateral cavernous sinus invasion, encasement of carotids, and extension to clivus. Surgical debulking was performed. Resistance to cabergoline was characterized and he was submitted to two surgeries and radiotherapy. Immunohistochemical evaluation included prolactin, ACTH, GH, FSH, LH,AIP, c-erb B2, Ki-67, and p53. Genomic DNA was isolated from the index case and 48 relatives, PCR and sequencing were performed. A germline A195V mutation in AIP was identified in the index case and in five asymptomatic relatives. Germline mutations in the AIP gene may be involved in the predisposition to pituitary adenoma formation, as cause or co-factor in pathogenesis of aggressive tumors in young patients. Arq Bras Endocrinol Metab. 2010;54(8):761-7 SUMÁRIOO objetivo deste estudo foi descrever o rastreamento familiar para mutações AIP em paciente portador de prolactinoma agressivo e resistente na infância. Um menino de 12 anos foi avaliado com queixa de cefaleia e hemianopsia bitemporal. Apresentava peso e altura adequados para a idade (percentil 50), estádio puberal Tanner G1 P1 e idade óssea de 10 anos. Prolactina 10.560 ng/mL (3-25), FSH e LH indetectáveis, IGF-1, TSH, T4 livre, ACTH, e cortisol normais. A ressonância magnética de sela evidenciou macroadenoma hipofisário, 53 X 40 X 35 mm com compressão de quiasma ótico, invasão de seios cavernosos, envolvimento de carótidas internas e extensão para o clivus. Foi realizada descompressão cirúrgica por via transesfenoidal e caracterizada resistência a doses máximas de cabergolina, sendo o paciente operado por mais duas vezes e submetido à radioterapia. Realizou-se imuno-histoquímica para prolactina, ACTH, GH, FSH, LH, AIP, c-erb B2, Ki-67 e p53. O DNA genômico foi extraído do caso índice e de 48 familiares, e PCR e sequenciamento. Uma mutação A195V na AIP foi detectada no paciente e em cinco parentes assintomáticos. As mutações no gene da AIP podem estar envolvidas na predisposição à formação de adenomas, como causa ou cofator na patogênese de tumores agressivos em jovens. Arq Bras Endocrinol Metab. 2010;54(8):761-7

Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients

“…Excluding the intronic variant of uncertain significance, AIP mutations were found in 1/3 FIPA patients and in 3/22 sporadic patients (13.6%). Such data are in agreement with AIP mutations associated with aggressive prolactinomas in FIPA and in young sporadic patients, with a male predominance (15,16,17). Further studies are necessary to better evaluate the prevalence of AIP mutations in sporadic-resistant prolactinomas.…”

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.…”

Prognostic Value of Invasion, Markers of Proliferation, and Classification of Giant Pituitary Tumors, in a Georeferred Cohort in Brazil of 50 Patients, with a Long-Term Postoperative Follow-Up

“…Some of these patients were in isolated familial pituitary adenoma (FIPA) setting. Several studies have described the aggressive behavior of pituitary adenomas in younger ages that might be related to genetic syndromes, as MEN-1, AIP mutations, or X-Lag Syndrome [39–41]. …”