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.

Isolated familial somatotropinoma: 11Q13-LOH and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis

OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.

Adenomas hipofisários familiares isolados: nova condição clínica a ser considerada na investigação de tumores endócrinos / Isolated familial pituitary adenomas: a new clinical condition to be considered in the investigation of endocrine tumors

Os adenomas hipofisários familiares são condição rara, cuja descrição inicial foi em neoplasia endócrina múltipla tipo 1 e em complexo de Carney, doenças provocadas por mutações nos genes MEN1 e PRKAR1A respectivamente. O somatotropinoma familiar isolado é também uma síndrome clínica bem descrita, relacionada exclusivamente em pacientes com acrogigantismo. Os adenomas hipofisários de todos os tipos - não limitados aos somatotropinomas - podem ocorrer em cenário familiar na ausência do MEN1 e do complexo de Carney. Este fenótipo é denominado adenomas hipofisários familiares isolados. Nesses adenomas, os fenótipos do adenoma da hipófise, seja homogêneo ou heterogêneo, podem ocorrer em famílias. Os casos de adenomas hipofisários familiares isolados diferem do MEN1 em termos de baixa proporção de prolactinomas e maior frequência de somatotropinomas no coorte desses adenomas. Pacientes com esta doença são mais jovens e têm prolactinomas com maiores dimensões que aqueles portadores de adenoma hipofisário esporádico. A minoria das famílias com esses adenomas hipofisários (15%) trazem mutação no gene que codifica a proteína interatuante-receptora do aril-hidrocarboneto (aryl hydrocarbon receptor interacting protein AIP). Mutações nessa proteína estão presentes em somente metade dos casos de somatotropinoma familiar isolado, ocorrendo como parte dos coortes de adenomas hipofisários familiares isolados. Em famílias com mutações no gene da AIP, os adenomas hipofisários estão em fase invasiva em mais de 50% dos casos. Tais mutações são extremamente raras em pacientes com adenoma hipofisário esporádico. Esta revisão trata de adenomas hipofisários de origem familiar, em que se descrevem em detalhes os achados clínicos, patológicos e genéticos dessa afecção e direciona aspectos da abordagem clínica das famílias com a anomalia, portadoras ou não de mutações no gene AIP.

Familial pituitary adenomas are a rare condition and was firstly described in multiple endocrine neoplasia type 1(MEN1) and Carney's complex, which occur due to mutations in the genes MEN1 and PRKAR1A, respectively. Isolated familial somatotropinoma is also a well-described clinical syndrome related only to patients with acrogigantism. Pituitary adenomas of all types - not limited to isolated familial somatotropinoma - can occur in a familial setting in the absence of MEN1 and Carney's complex; this phenotype is termed familial isolated pituitary adenomas (FIPA). In these adenomas both homogeneous and heterogeneous pituitary adenoma phenotypes can occur within families. These adenomas differs from MEN1 in terms of a lower proportion of prolactinomas and more frequent somatotropinomas in the FIPA cohort. Patients with familial isolated pituitary adenomas are significantly younger at diagnosis and have significantly larger pituitary adenomas than matched sporadic pituitary adenoma counterparts. A minority of FIPA families overall (15%) exhibit mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene; AIP mutations are present in only half of isolated familial somatotropinoma kindreds occurring as part of the FIPA cohort. In families with AIP mutations, pituitary adenomas have a penetrance of over 50%. AIP mutations are extremely rare in patients with sporadic pituitary adenomas. This review deals with pituitary adenomas that occur in a familial setting, describes in detail the clinical, pathological and genetic features of familial isolated pituitary adenomas and addresses aspects of the clinical approach to FIPA families with and without AIP mutations.