Endocrine Abstracts

The clinical and genetic characteristics of patients with familial isolated pituitary adenoma

H Chahal¹, S Igreja¹, M Gueorguiev¹, R Quinton², J Wass³, V Popovic⁴, A Ribeiro-Oliveira Jr⁵, J Monson¹, S Akker¹, P Gallego⁶, S Orme⁷, A Goldstone⁸, J Bevan⁹, T Cheetam¹⁰, J Davis¹¹, R Clayton¹², D Flanagan¹³, L Frohman¹⁴, A Grossman¹ & M Korbonits¹

¹Barts and the London Medical School, Centre for Endocrinology, London, UK; ²Department of Endocrinology, Royal Victoria Infirmary and University of Newcastle-upon-Tyne, Newcastle-Upon-Tyne, UK; ³Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK; ⁴Department of Endocrinology, University Clinical Center, Belgrade, Serbia; ⁵Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil; ⁶Department of Endocrinology, Perth, Australia; ⁷Department of Endocrinology, Leeds, UK; ⁸Department of Endocrinology, Hammersmith Hospital, London, UK; ⁹Department of Endocrinology, Aberdeen, UK; ¹⁰Department of Endocrinology, Newcastle-Upon-Tyne, UK; ¹¹Department of Endocrinology, University of Manchester, Manchester, UK; ¹²Department of Endocrinology, University Hospital of North Staffordshire, Stoke-On-Trent, UK; ¹³Department of Endocrinology, Derriford Hospital, Plymouth, UK; ¹⁴Section of Endocrinology, Metabolism and Diabetes, University of Illinois at Chicago, Chicago, UK.

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Background: Familial pituitary adenomas can occur in the classic syndromes of MEN-1 and Carney complex. Recently an autosomal dominant disease with incomplete penetrance has been described as ‘familial-isolated-pituitary-adenoma’ (FIPA). Previous studies of familial acromegaly and gigantism disclosed germline mutations in the AIP gene located in the previously suspected chromosome 11q13 region.

Aims: To analyse the prevalence of AIP-mutations in our large FIPA cohort and to evaluate the clinical characteristics of FIPA patients with or without AIP-mutations.

Methods: We studied 39 FIPA families and identified 97 pituitary tumour patients.

Results: Our FIPA cohort had 52 (54%) males and 45 (46%) females with the mean (±S.D.) age at diagnosis 33.3±15.1 year. Eleven families had a germline AIP-mutation with missense, nonsense, splice-site and the first known promoter mutation. While mutations resulting in complete disruption of the AIP-protein were scattered over the whole gene, point mutations only affected the C-terminal-protein-binding domain. Fifty-three individuals had a heterozygote germline AIP-mutation, with 36 (68%) having clinical disease, although not all family members were available for genotyping. Patients with AIP-mutations had a mean age of diagnosis significantly lower than those without AIP-mutations: 24.5±10.9 vs 40.0±14.9 year (P<0.001). Macroadenomas occurred in 93% patients with AIP-mutations versus 84% patients without AIP-mutations. A poor biochemical response to somatostatin analogues (<50% reduction in GH/IGF-I) occurred in 8/15 families with acromegaly. Non-pituitary tumours were observed in 7 families containing affected patients or obligate AIP-mutation carriers:lipomas, ependymoma, anaplastic astrocytoma, breast, thyroid, testicular and bone marrow tumours. Out the FIPA cohort, there were 23 families containing 22 patients with gigantism, of which 17 (77%) had AIP-mutations.

Conclusions: AIP-mutations were identified in 11 families of our FIPA cohort occurring in families with somatotroph adenomas. Patients with AIP-mutations have clinical disease significantly earlier than those patients without AIP-mutations, and may respond less well than other patients to somatostatin analogues.

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Endocrine Abstracts (2009) 19 OC40