CLINICAL QUESTION Familial pituitary adenomas – who should be tested for AIP mutations? Ma ´ rta Korbonits*, Helen Storr* and Ajith V. Kumar† *Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London and †North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK Summary Familial Isolated Pituitary Adenomas (FIPA), an autosomal dominant disease with low penetrance is being increasingly recognized. FIPA families can be divided into two distinct groups based on genetic and phenotypic features. Patients with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are characterized by young-onset somatotroph or lactotroph macroadenomas, while in the other, larger group of FIPA patients with typically adult-onset disease and more varied adenoma types, no causative gene(s) has been identified. Young- onset macroadenoma patients can also be identified with germ- line AIP mutation without an apparent family history. Further data and longer follow-up are necessary to establish formal guidelines, but the current data suggest genetic screening of the AIP gene in patients with a pituitary adenoma and no other associated features who have (i) a family history of pituitary adenoma, (ii) childhood-onset pituitary adenoma or (iii) a pitu- itary somatotroph or lactotroph macroadenoma diagnosed before the age of 30 years. (Received 17 October 2011; returned for revision 6 November 2011; finally revised 16 April 2012; accepted 17 May 2012) Introduction The vast majority of pituitary adenomas occur in adult patients with no family history of pituitary disease. However, patients with a family history are being recognized more frequently, 1,2 and these patients, together with childhood-onset cases, raise the possibility of the presence of an inherited disorder. Pituitary tumours may be a manifestation of a genetic condition such as multiple endocrine neoplasia (MEN) type 1 or type 4, Carney complex, McCune–Albright syndrome and the recently estab- lished syndrome of familial isolated pituitary adenoma (FIPA) 2 (Fig. 1). MEN1, MEN4, Carney complex and the FIPA syn- drome are dominantly inherited, whereas McCune–Albright syn- drome is attributed to a mosaic somatic mutation (see detailed review 3 ). In addition, infant-onset ACTH-secreting pituitary blastoma has been recently described with germline DICER1 mutation, 4 and case reports of familial paraganglioma-associated SDH mutations have been described with familial pituitary ade- noma, either prolactinoma (SDHB, 5 SDHC 6 , SDHD 7 ), non-func- tioning pituitary adenoma (SDHB 6 ) or acromegaly (SDHD). 8 Familial isolated pituitary adenoma is a clinical diagnosis characterized by the presence of a pituitary adenoma in more than one family member without other associated features. 9–12 Typically, the penetrance is incomplete. The commonly occur- ring adenomas are growth hormone (GH)-secreting, prolactin- secreting and GH and prolactin co-secreting adenomas, followed by nonfunctioning pituitary adenomas (NFPA) (Fig. 2). Rarely TSH- or ACTH-secreting adenomas are observed. Family mem- bers with FIPA can have similar or different types of pituitary adenomas within a particular family. Patients with FIPA can be divided to two groups based on their phenotypic and genotypic features. AIP mutation–positive cases Approximately 20% of families with FIPA have a heterozygous germline mutation in the aryl hydrocarbon receptor-interacting pro- tein (AIP) gene. 9–11,13 The majority of AIP mutation–positive patients show an onset of symptoms in childhood or young adult- hood (mean age of diagnosis around 20–24 years, ranging from 6 years to 74 years). 13,14 A third of all individuals with an AIP mutation and 40–50% of AIP mutation–positive patients with so- matotroph adenomas present in childhood, often leading to pitui- tary gigantism, compared with only 4% of AIP mutation–negative sporadic adenoma patients. 14 AIP mutation–positive patients usually have invasive GH, mixed GH and prolactin or prolactin- secreting macroadenomas (Fig. 2). Occasionally, NFPA and ACTH- or TSH-secreting adenomas have been described. 15,16 Typically, somatotroph adenomas belong to the sparsely granulated subtype and respond poorly to somatostatin analogue therapy. 12–14,17 In Correspondence: Ma ´rta Korbonits, Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1A 6BQ, UK. Tel.: +44 20 7882 6238; Fax: +44 20 7882 6197; E-mail: m.korbonits@qmul.ac.uk © 2012 Blackwell Publishing Ltd 351 Clinical Endocrinology (2012) 77, 351–356 doi: 10.1111/j.1365-2265.2012.04445.x