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Pituitary Disorders
Familial Isolated Pituitary Adenomas
Harvinder S Chahal,
1
VK Ajith Kumar
2
and Márta Korbonits
3
1. Specialist Registrar in Endocrinology, Centre for Endocrinology, Barts and the London Medical School; 2. Consultant in Clinical Genetics, Clinical Genetics
Department, Great Ormond Street Hospital; 3. Professor of Endocrinology and Metabolism, Centre for Endocrinology, Barts and the London Medical School
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
Pituitary adenomas are common intracranial tumours, and clinically genetic background. FIPA has been identified in more than 170
relevant pituitary adenomas have been estimated to occur in about one families, with over 400 individuals described in the literature,
in every 1,000 of the population.
1
The vast majority of these adenomas including 86 families having familial acromegaly. Within FIPA
are sporadic; however, there is increasing recognition that pituitary families there is a heterogeneity of pituitary tumours (see Figure
adenomas may also occur in a familial setting, and a recent estimate 4),
2,6,7,9–11
with somatotroph (growth-hormone-secreting) and
suggests that 5% of pituitary adenomas are familial in origin.
2
Familial lactotroph (prolactin-secreting) adenomas being the most common,
pituitary adenomas can form part of the classic syndromes of multiple although other combinations involving non-functioning adenomas,
endocrine neoplasia type 1 (MEN1) and Carney complex. However, a corticotroph (ACTH-secreting) and gonadotroph (gonadotropin-
number of families have been identified to have isolated familial pituitary secreting) adenomas have also been reported.
2,12
Patients with
tumours and show an autosomal dominant inheritance with incomplete familial disease are on average four to six years younger at
penetrance (the proportion of individuals with the inherited mutation diagnosis than sporadic patients. Patients from later generations
who develop the disease), without the clinical features or genetic tend to be significantly younger at diagnosis compared with earlier
abnormalities of the MEN1 syndrome and Carney complex. Over the last generations, probably because of increased pituitary disease
decade, these individuals have been classified as having isolated familial recognition and surveillance among later generations.
somatotropinoma (IFS),
3,4
familial isolated pituitary adenoma (FIPA)
5,6
or
pituitary adenoma predisposition (PAP),
7
covering overlapping entities. Clinical Characteristics of AIP Mutation
Patients versus Those with No AIP Mutation
The first documented report of families with several members affected About 30–50% of families with FIPA have a mutation in the AIP
by acromegaly occurred over 100 years ago (see Figure 1).
8
However, gene. Some early-onset – often childhood-onset – acromegaly
the genetic basis of this condition was unknown until 2006, when a patients are also positive for AIP mutations. Mutations of AIP have
Finnish group identified germline mutations in a gene known as AIP mainly been found in families with either pure somatotroph
(aryl hydrocarbon receptor interacting protein; see Figure 2) while adenomas or families with mixed somatotroph and lactotroph
studying large families with acromegaly and prolactinoma in northern adenomas. Interestingly, none of the pure prolactinoma families
Finland.
7
Subsequent work focused on determining the prevalence of have AIP mutations, and no AIP mutation has been found in a
AIP mutations in FIPA families and studying the relevance in sporadic known FIPA family with at least one member not having either a
pituitary tumours. somatotroph or lactotroph adenoma. Pituitary adenoma tissue has
also been studied for AIP mutations in cases where the DNA
FIPA is an autosomal dominant disease with low or variable extracted from blood (germline) is negative, but has never revealed
penetrance (see Figure 3) characterised by a heterogeneous any AIP mutations.
9,13
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