Familial Isolated Pituitary Adenomas

VK Ajith Kumar, Márta Korbonits, Harvinder S Chahal
European Endocrinology, 2009;5(1):55-8

Abstract

Abstract
Over the last century several families have been described with familial isolated pituitary adenomas (FIPAs). Most commonly, family members have acromegaly or prolactinoma, but other types of pituitary adenomas can also occur. Recently, mutations in the AIP (aryl hydrocarbon receptor interacting protein) gene have been found to occur in 30–50% of FIPA patients, while for the rest of the patients the gene causing the disease is currently unknown and is a topic of intense research. Tumours in patients with AIP mutations are diagnosed at significantly younger ages and tend to be larger. Often the response to medical therapy in these patients is poor. This article discusses the clinical and genetic characteristics of this relatively recently recognised disease.

Keywords
Pituitary tumour, familial disease, AIP, tumour suppressor gene

Disclosure: The authors have no conflicts of interest to declare.
Acknowledgements: We are very grateful for the helpful advice on the manuscript from one of our patients with familial isolated pituitary adenoma.
Received: 25 April 2009 Accepted: 6 July 2009
Correspondence: Márta Korbonits, Department of Endocrinology, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK. E: m.korbonits@qmul.ac.uk

Citation European Endocrinology, 2009;5(1):55-8

Pituitary adenomas are common intracranial tumours, and clinically relevant pituitary adenomas have been estimated to occur in about one in every 1,000 of the population. The vast majority of these adenomas are sporadic; however, there is increasing recognition that pituitary adenomas may also occur in a familial setting, and a recent estimate suggests that 5% of pituitary adenomas are familial in origin. Familial pituitary adenomas can form part of the classic syndromes of multiple endocrine neoplasia type 1 (MEN1) and Carney complex. However, a number of families have been identified to have isolated familial pituitary tumours and show an autosomal dominant inheritance with incomplete penetrance (the proportion of individuals with the inherited mutation who develop the disease), without the clinical features or genetic abnormalities of the MEN1 syndrome and Carney complex. Over the last decade, these individuals have been classified as having isolated familial somatotropinoma (IFS),familial isolated pituitary adenoma (FIPA) or pituitary adenoma predisposition (PAP), covering overlapping entities.

The first documented report of families with several members affected by acromegaly occurred over 100 years ago (see Figure 1).8 However, the genetic basis of this condition was unknown until 2006, when a Finnish group identified germline mutations in a gene known as AIP (aryl hydrocarbon receptor interacting protein; see Figure 2) while studying large families with acromegaly and prolactinoma in northern Finland.7 Subsequent work focused on determining the prevalence of AIP mutations in FIPA families and studying the relevance in sporadic pituitary tumours.

FIPA is an autosomal dominant disease with low or variable penetrance (see Figure 3) characterized by a heterogeneous genetic background. FIPA has been identified in more than 170 families, with over 400 individuals described in the literature, including 86 families having familial acromegaly. Within FIPA families there is a heterogeneity of pituitary tumors (see Figure 4),2,6,7,9–11 with somatotroph (growth-hormone-secreting) and lactotroph (prolactin-secreting) adenomas being the most common, although other combinations involving non-functioning adenomas, corticotroph (ACTH-secreting), and gonadotroph (gonadotropin-secreting) adenomas have also been reported.2,12 Patients with familial disease are on average four to six years younger at diagnosis than sporadic patients. Patients from later generations tend to be significantly younger at diagnosis compared with earlier generations, probably because of increased pituitary disease recognition and surveillance among later generations.

Clinical Characteristics of AIP Mutation Patients versus Those with No AIP Mutation

About 20–40% of families with FIPA have a mutation in the AIP gene. Some early-onset—often childhood-onset—acromegaly patients are also positive for AIP mutations. Mutations of AIP have mainly been found in families with either pure somatotroph adenomas or families with mixed somatotroph and lactotroph adenomas. Interestingly, none of the pure prolactinoma families have AIP mutations, and no AIP mutation has been found in a known FIPA family with at least one member not having either a somatotroph or lactotroph adenoma. Pituitary adenoma tissue has also been studied for AIP mutations in cases where the DNA extracted from blood (germline) is negative, but has never revealed any AIP mutations.9,13

Tumors with AIP mutations are diagnosed in subjects at significantly younger ages, and are larger than those found in FIPA patients without AIP mutations, as well as those found in patients with sporadic tumors.9,10,12 Patients with an AIP mutation have a mean age of diagnosis of 25 years compared with 40 years for those without AIP mutations.9,10,12 The youngest patient described as having AIP mutations is six years old (unpublished data), and around two-thirds of patients with AIP mutations are diagnosed at 25 years of age or under.9,10,12 AIP mutation patients have larger pituitary tumors, suggesting more aggressive disease.10 In our cohort, a poor biochemical response to somatostatin analogs (<50% reduction in growth hormone [GH]/ insulin-like growth factor 1 [IGF-I]) occurred in eight of the 15 patients with familial acromegaly.

Due to limited genealogical data, the exact penetrance (proportion of individuals with the mutation who develop the disease) of pituitary tumors is difficult to calculate accurately. However, a best estimate emerges from the largest well-studied family with an AIP mutation: one-third of individuals (three of nine subjects with AIP mutations) developed pituitary tumors at the time of the study.14 We find similar penetrance in our largest family with AIP mutations.

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