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Pituitary Disorders
Familial Isolated Pituitary Adenomas
Harvinder S Chahal, MBBS, MRCP,
1
VK Ajith Kumar, MD, DCH, MRCP, MRCPCH
2
and Márta Korbonits, MD, PhD
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 20–40% 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. Tumors 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 recognized disease.
Keywords
Pituitary tumor, familial disease, AIP, tumor 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: April 25, 2009 Accepted: July 6, 2009
Correspondence: Márta Korbonits, MD, PhD, 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 tumors, and clinically large families with acromegaly and prolactinoma in northern Finland.
7
relevant pituitary adenomas have been estimated to occur in about Subsequent work focused on determining the prevalence of AIP
one in every 1,000 of the population.
1
The vast majority of these mutations in FIPA families and studying the relevance in sporadic
adenomas are sporadic; however, there is increasing recognition that pituitary tumors.
pituitary adenomas may also occur in a familial setting, and a
recent estimate suggests that 5% of pituitary adenomas are familial FIPA is an autosomal dominant disease with low or variable
in origin.
2
Familial pituitary adenomas can form part of the penetrance (see Figure 3) characterized by a heterogeneous genetic
classic syndromes of multiple endocrine neoplasia type 1 (MEN1) and background. FIPA has been identified in more than 170 families, with
Carney complex. over 400 individuals described in the literature, including 86 families
having familial acromegaly. Within FIPA families there is a
However, a number of families have been identified to have isolated heterogeneity of pituitary tumors (see Figure 4),
2,6,7,9–11
with somatotroph
familial pituitary tumors and show an autosomal dominant inheritance (growth-hormone-secreting) and lactotroph (prolactin-secreting)
with incomplete penetrance (the proportion of individuals with the adenomas being the most common, although other combinations
inherited mutation who develop the disease), without the clinical involving non-functioning adenomas, corticotroph (ACTH-secreting),
features or genetic abnormalities of the MEN1 syndrome and Carney and gonadotroph (gonadotropin-secreting) adenomas have also been
complex. Over the last decade, these individuals have been classified as reported.
2,12
Patients with familial disease are on average four to six
having isolated familial somatotropinoma (IFS),
3,4
familial isolated years younger at diagnosis than sporadic patients. Patients from later
pituitary adenoma (FIPA),
5,6
or pituitary adenoma predisposition (PAP),
7
generations tend to be significantly younger at diagnosis compared
covering overlapping entities. with earlier generations, probably because of increased pituitary
disease recognition and surveillance among later generations.
The first documented report of families with several members affected
by acromegaly occurred over 100 years ago (see Figure 1).
8
However, Clinical Characteristics of AIP Mutation
the genetic basis of this condition was unknown until 2006, when a Patients versus Those with No AIP Mutation
Finnish group identified germline mutations in a gene known as AIP (aryl About 20–40% of families with FIPA have a mutation in the AIP gene.
hydrocarbon receptor interacting protein; see Figure 2) while studying Some early-onset—often childhood-onset—acromegaly patients are
104 © TOUCH BRIEFINGS 2009
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