Estudios clínicos y genéticos en tres miembros de una familia afectados con adenomas hipofisarios aislados con prolactinomas homogéneos / Clinical and genetic studies of a three-member familial isolated pituitary adenoma with homogeneous prolactinomas

La mayoría de los adenomas hipofisarios son esporádicos, pero un 3-5% puede ocurrir en un contexto familiar y hereditario. Este es el caso de la neoplasia endocrina múltiple de tipo 1 (NEM1), complejo de Carney (CNC) y adenomas hipofisarios aislados familiares (FIPA). El FIPA es una condición infrecuente, que ocurre en un contexto familiar, no asociada a NEM t ipo1 ni CNC. Los FIPA pueden ser homogéneos (todos los adenomas tienen el mismo fenotipo) o heterogéneos (diferente fenotipo tumoral). Describimos una familia congolesa en la que dos hermanas y una prima fueron diagnosticadas a los 29, 32 y 40 años, respectivamente, con un prolactinoma (FIPA homogéneo). Las pacientes presentaron macroadenomas no invasivos al momento del diagnóstico, con buena respuesta biológica y tumoral al tratamiento con cabergolina hasta una dosis máxima de 1.5 mg/semanal. De las dos hermanas, una cursó un embarazo sin complicaciones. Durante el seguimiento de 12 años, ninguna de ellas presentó elementos clínicos o biológicos compatibles con NEM1 o CNC, por lo que dichos genes no se estudiaron. El análisis genético en dos de las pacientes permitió descartar la posibilidad de una mutación germinal del gen aryl hydrocarbon receptor interacting protein (AIP). Se considera que el 80% de los pacientes con FIPA no presentan mutación del gen AIP, por lo que se requieren futuros estudios en este tipo de familias, para poder determinar otros genes afectados involucrados en su fisiopatología.

Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology.

Clinical and genetic aspects of familial isolated pituitary adenomas

Pituitary adenomas represent a group of functionally diverse neoplasms with relatively high prevalence in the general population. Most occur sporadically, but inherited genetic predisposing factors are increasingly recognized. Familial isolated pituitary adenoma is a recently defined clinical entity, and is characterized by hereditary presentation of pituitary adenomas in the absence of clinical and genetic features of syndromic disease such as multiple endocrine neoplasia type 1 and Carney complex. Familial isolated pituitary adenoma is inherited in an autosomal dominant manner and accounted for approximately 2-3% of pituitary tumors in some series. Germline mutations in the aryl-hydrocarbon interacting protein gene are identified in around 25% of familial isolated pituitary adenoma kindreds. Pituitary adenomas with mutations of the aryl-hydrocarbon interacting protein gene are predominantly somatotropinomas and prolactinomas, but non-functioning adenomas, Cushing disease, and thyrotropinoma may also occur. These tumors may present as macroadenomas in young patients and are often relatively difficult to control. Furthermore, recent evidence indicates that aryl-hydrocarbon interacting protein gene mutations occur in >10% of patients with sporadic macroadenomas that occur before 30 years of age, and in >20% of children with macroadenomas. Genetic screening for aryl-hydrocarbon interacting protein gene mutations is warranted in selected high-risk patients who may benefit from early recognition and follow-up.

Aggressive prolactinoma in a child related to germline mutation in the ARYL hydrocarbon receptor interacting protein (AIP) gene / Prolactinoma agressivo na infância relacionado à mutação no gene da proteína Aryl hidrocarbono (AIP)

The 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 (50th 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.

O 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.