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Large Genomic Deletions in AIP in Pituitary Adenoma Predisposition

Department of Medical Genetics (M.G., E.H., A.K., L.A.A.), 00014 University of Helsinki, Helsinki, Finland; Medical Department III (R.P.), Leipzig University, 04103 Leipzig, Germany; Clinical Genetics (A.V.K.K.), Great Ormond Street National Health Service Trust, London WC1N 3JH, United Kingdom; Departments of Human Genetics, Oncology, and Medicine (M.T.), McGill University, Sir Mortimer B. Davis Jewish General Hospital, H3T 1E2 Montreal, Quebec, Canada; Departments of Clinical Genetics (O.V.) and Internal Medicine (P.S.), Oulu University Hospital, 90029 Oulu, Finland; Department of Endocrinology (T.S.), Helsinki University Central Hospital, 00029 Helsinki, Finland; Department of Internal Medicine (E.D.M.), General Hospital, 31044 Montebelluna, Italy; Department of Medicine and Pharmacology (S.C.), Section of Endocrinology, University of Messina, 98125 Messina, Italy; Division of Endocrinology-Metabolism and Diabetes (S.G.), Cerrahpaçsa Medical Faculty, University of Istanbul, 34303 Istanbul, Turkey; Wessex Clinical Genetics Service (A.L.), Princess Anne Hospital, SO16 5YA Southampton, United Kingdom; Department of Clinical Genetics (L.I.), New Guy’s House, Guy’s Hospital, London SE1 9RT, United Kingdom; Department of Medicine (S.A.), King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom; Department of Endocrinology and Diabetes (G.B.), Thomas Addison Unit, London SW17 0QT, United Kingdom; Department of Clinical Genetics (S.H.), St. Georges, University of London, London SW17 ORE, United Kingdom; and Division of Endocrinology (C.A.K.), University of Mississippi Medical Center, Jackson, Mississippi 39216

Address all correspondence and requests for reprints to: Professor Lauri A. Aaltonen, Department of Medical Genetics, Biomedicum Helsinki, P.O. Box 63 (Haartmaninkatu 8), University of Helsinki, 00014 Helsinki, Finland. E-mail: lauri.aaltonen{at}helsinki.fi.

Context: Germline mutations in AIP have been recently shown to cause pituitary adenoma predisposition (PAP). Subsequently, many intragenic germline mutations have been reported, both in familial and in sporadic settings.

Objective: Our objective was to evaluate the possible contribution of large genomic germline AIP deletions, an important mutation type in tumor predisposition syndromes, in PAP.

Design: Here, we applied the multiplex ligation-dependent probe amplification assay to examine whether large genomic AIP or MEN1 alterations account for a subset of PAP cases.

Patients: The study was performed on familial and sporadic pituitary adenoma cases of European origin, which had previously tested negative for germline AIP and MEN1 mutations by sequencing.

Results: Two of 21 pituitary adenoma families (9.5%) were found to harbor an AIP deletion. No copy number changes were detected among 67 sporadic pituitary adenoma patients. No MEN1 deletions were found.

Conclusions: The present study shows that large genomic AIP deletions account for a subset of PAP. Therefore, in suspected PAP cases undergoing counseling and AIP genetic testing, multiplex ligation-dependent probe amplification could be considered if direct sequencing does not identify a mutation.