Familial Isolated Pituitary Adenomas
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.
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: firstname.lastname@example.org
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.
- Daly AF, Rixhon M, Adam C, et al., High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium, J Clin Endocrinol Metab, 2006;91(12):4769–75.
- Beckers A, Daly AF, The clinical, pathological, and genetic features of familial isolated pituitary adenomas, Eur J Endocrinol, 2007;157(4):371–82.
- Gadelha MR, Prezant TR, Une KN, et al., Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene, J Clin Endocrinol Metab, 1999;84(1):249–56.
- Yamada S, Yoshimoto K, Sano T, et al., Inactivation of the tumor suppressor gene on 11q13 in brothers with familial acrogigantism without multiple endocrine neoplasia type 1, J Clin Endocrinol Metab, 1997;82(1):239–42.
- Valdes-Socin H, Betea V, Stevenaert A, Beckers A, Familial isolated pituitary adenomas not related to the MEN-1 syndrome: A study of 27 patients, 10th Meeting of the Belgian Endocrine Society, 2000.
- Daly AF, Jaffrain-Rea ML, Ciccarelli A, et al., Clinical characterization of familial isolated pituitary adenomas, J Clin Endocrinol Metab, 2006;91(9):3316–23.
- Vierimaa O, Georgitsi M, Lehtonen R, et al., Pituitary adenoma predisposition caused by germline mutations in the AIP gene, Science, 2006;312(5777):1228–30.
- Soares BS, Frohman LA, Isolated familial somatotropinoma, Pituitary, 2004;7(2):95–101.
- Leontiou CA, Gueorguiev M, van der Spuy SJ, et al., The role of the AIP gene in familial and sporadic pituitary adenomas, J Clin Endocrinol Metab, 2008;93(6):2390–2401.
- Daly AF, Vanbellinghen JF, Khoo SK, et al., Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families, J Clin Endocrinol Metab, 2007;92(5):1891–6.
- Georgitsi M, Raitila A, Karhu A, et al., Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations, Proc Natl Acad Sci U S A, 2007;104(10):4101–5.
- Chahal HS, Igreja SC, Gueorguiev M, et al., The clinical and genetic characteristics of patients with familial isolated pituitary adenomas. Hormones, 11th International Workshop of MEN meeting, Delphi 7, 2008.
- Barlier A, Vanbellinghen JF, Daly AF, et al., Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas, J Clin Endocrinol Metab, 2007;92(5):1952–5.
- Naves LA, Daly AF, Vanbellinghen JF, et al., Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptorinteracting protein gene, Eur J Endocrinol, 2007;157(4):383–91.
- Georgitsi M, Heliovaara E, Paschke R, et al., Large genomic deletions of aryl hydrocarbon receptor interacting protein (AIP) gene in pituitary adenoma predisposition, J Clin Endocrinol Metab, 2008;93(10):4146–51.
- Iwata T, Yamada S, Mizusawa N, Golam HM, et al., The aryl hydrocarbon receptor-interacting protein gene is rarely mutated in sporadic GH-secreting adenomas, Clin Endocrinol (Oxf), 2007;66(4):499–502.
- Cazabat L, Libe R, Perlemoine K, et al., Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas, Eur J Endocrinol, 2007;157(1):1–8.
- Montanana CF, Daly AF, Tichomirowa MA, et al., Occurrence of AIP mutations in sporadic pituitary adenomas and familial isolated pituitary adenomas kindreds in Valencia, Spain, Proceedings of the 90th Annual Meeting of the Endocrine Society, 2008;P3-775.
- Beckers A, Vanbellinghen JF, Boikos S, et al., Germline AIP, MEN1, PRKAR1A, CDKN1B (p27Kip1) and CDKN2C (p18INK4c) gene mutations in a large cohort of pediatric patients with pituitary adenomas occurring in isolation or with associated syndromic features, Proceedings of the 90th Annual Meeting of the Endocrine Society, 2008;OR38-1.
- Yaneva M, Daly AF, Tichomirowa MA, et al., Aryl hydrocarbon receptor interacting protein gene mutations in bulgarian FIPA and young sporadic pituitary adenoma patients, Proceedings of the 90th Annual Meeting of the Endocrine Society, 2008;P3-520.
- Raitila A, Georgitsi M, Karhu A, et al., No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia, Endocr Relat Cancer, 2007;14(3):901–6.
- Georgitsi M, De ME, Cannavo S, et al., Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas, Clin Endocrinol (Oxf), 2008;69(4):621–7.
- Buchbinder S, Bierhaus A, Zorn M, et al., Aryl hydrocarbon receptor interacting protein gene (AIP) mutations are rare in patients with hormone secreting or non-secreting pituitary adenomas, Exp Clin Endocrinol Diabetes, 2008; 116(10):625–8.
- Toledo RA, Jallad RS, Fragoso MC, et al., The role of AIP gene in Brazilian patients with sporadic and familial acromegaly, Proceedings of the 90th Annual Meeting of the Endocrine Society, 2008;P3-738.
- Luccio-Camelo DC, Une KN, Ferreira RE, et al., A meiotic recombination in a new isolated familial somatotropinoma kindred, Eur J Endocrinol, 2004;150(5):643–8.
- Toledo RA, Mendonca BB, Longuini VC, et al., Familial somatotropinoma and adrenocortical carcinoma due to a novel germline mutation and loss of the wild-type allele of the AIP gene, Proceedings of the 90th Annual Meeting of the Endocrine Society, 2008;P1-488.
- Georgitsi M, Karhu A, Winqvist R, et al., Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers, Br J Cancer, 2007;96(2):352–6.