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J Clin Endocrinol Metab. 2014 Apr;99(4):1122-31. doi: 10.1210/jc.2013-2868. Epub 2013 Jan 1.

Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation.

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Regional Center for Endocrinology and Diabetes (F.W., S.H., A.B.A.), Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland, United Kingdom; Department of Medical Genetics (L.B., P.J.M.), Belfast Health and Social Care Trust, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Endocrinology (H.S.C., H.L.S., S.A.A., M.K.), Barts and London School of Medicine, Queen Mary University of London, London EC1A 6BQ, United Kingdom; North East Thames Regional Genetics Service (A.V.K.), Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; Department of Endocrinology (S.M.O.), St James University Hospital, Leeds LS9 7TF, United Kingdom; Department of Radiology (J.E.), St Bartholomew Hospital, London EC1A 7BE, United Kingdom; and Department of Endocrinology (N.A.), Royal Belfast Hospital for Sick Children, Belfast, BT12 6BA, United Kingdom.



Germline AIP mutations usually cause young-onset acromegaly with low penetrance in a subset of familial isolated pituitary adenoma families. We describe our experience with a large family with R304* AIP mutation and discuss some of the diagnostic dilemmas and management issues.


The aim of the study was to identify and screen mutation carriers in the family.


Forty-three family members participated in the study.


The study was performed in university hospitals.


We conducted genetic and endocrine screening of family members.


We identified 18 carriers of the R304* mutation, three family members with an AIP-variant A299V, and two family members who harbored both changes. One of the two index cases presented with gigantism and pituitary apoplexy, the other presented with young-onset acromegaly, and both had surgery and radiotherapy. After genetic and clinical screening of the family, two R304* carriers were diagnosed with acromegaly. They underwent transsphenoidal surgery after a short period of somatostatin analog treatment. One of these two patients is in remission; the other achieved successful pregnancy despite suboptimal control of acromegaly. One of the A299V carrier family members was previously diagnosed with a microprolactinoma; we consider this case to be a phenocopy. Height of the unaffected R304* carrier family members is not different compared to noncarrier relatives.


Families with AIP mutations present particular problems such as the occurrence of large invasive tumors, poor response to medical treatment, difficulties with fertility and management of pregnancy, and the finding of AIP sequence variants of unknown significance. Because disease mostly develops at a younger age and penetrance is low, the timing and duration of the follow-up of carriers without overt disease requires further study. The psychological and financial impact of prolonged clinical screening must be considered. Excellent relationships between the family, endocrinologists, and geneticists are essential, and ideally these families should be managed in centers with specialist expertise.

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