Characteristics of Familial Isolated Pituitary Adenomas

Adrian F Daly; Jean-François Vanbellinghen; Albert Beckers

Disclosures

Expert Rev Endocrinol Metab. 2007;2(6):725-733. 

In This Article

Abstract and Introduction

The familial occurrence of pituitary adenomas has been recognized for many years and currently accounts for approximately 5% of all cases. Molecular, genetic and clinical features of familial pituitary adenomas have been well characterized in multiple endocrine neoplasia type 1 (MEN-1) and Carney's complex (CNC), which account for the majority of familial pituitary tumor cases. These conditions are caused by MEN1 and PRKAR1A gene mutations, respectively, and the clinical and pathological features of pituitary pathology in these diseases differ from those of sporadic pituitary tumors. Familial acromegaly has been recognized for many years and, more recently, the clinical features of this clinical phenotype, referred to as isolated familial somatotropinoma, have been clarified. Over the past decade, the concept of non-MEN-1/CNC familial pituitary tumors has been expanded significantly to include all phenotypes, a condition known as familial isolated pituitary adenomas (FIPA). In FIPA, tumors can present homogeneously (same phenotype) or heterogeneously (different tumor phenotypes) within the same family. Compared with sporadic pituitary adenomas, patients with FIPA have a younger age at diagnosis and have larger tumors. The clinical features of FIPA differ from those of MEN-1 in terms of a higher frequency of somatotropinomas and a lower frequency of prolactinomas. The recent discovery of the involvement of mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in association with pituitary tumors has provided new information regarding potential mechanisms of tumorigenesis in FIPA patients. While very infrequent in sporadic pituitary tumors, approximately 15% of FIPA patients have AIP mutations, rising to half of patients with familial acromegaly. In this review, we detail the clinical features of FIPA and discuss tumor pathology and genetic findings in this increasingly recognized clinical condition.

Pituitary adenomas occur frequently, with data from autopsy and radiological series of unselected subjects suggesting that they may be present in as many as one in six people.[1] Of these adenomas, the majority are clinically silent and termed 'incidentalomas'. For many years it was believed that clinically active pituitary adenomas were rare;[2] however, recent data suggest that the true prevalence of clinically apparent pituitary adenomas is approximately one in 1000 of the population.[3] Anatomic pathology and molecular genetic studies of pituitary adenomas have revealed many molecular defects in adenomatous cells compared with normal pituitary tissue.[4] However, germline gene mutations that lead to hereditary or familial pituitary tumors are few in number,[5] and overall pituitary adenomas that occur in families comprise up to 5% of the total number.[5,6]

Most familial pituitary adenomas occur in the setting of multiple endocrine neoplasia-type 1 (MEN-1), Carney complex (CNC) or isolated familial somatotropinomas (IFS).[4] In the last decade, we have described familial isolated pituitary adenomas (FIPA), which comprises the occurrence of pituitary adenomas of all types (not limited to acromegaly) in families in the absence of MEN-1 and CNC.[7] Recent genetic advances have highlighted the association of specific genes such as the aryl hydrocarbon receptor interacting protein (AIP) gene in the etiology of a minority of FIPA cases.[8,9] The clinical, pathological and genetic features of FIPA have been clarified and this review describes the clinically relevant aspects of this condition as they relate to diagnosis, management and future research.

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