Germline mutations in AIP have been recently shown to cause pituitary adenoma predisposition (PAP)...

Many of the members of the Cushing's Help message boards have relatives and/or siblings who have also been diagnosed with a pituitary tumor and Cushing's Disease. Conservative, "textbook" cases of Cushing's have long been touted as nonheritable by the conservative, textbook endocrinologists. However, new research is reaching different conclusions.

In a very recent article published by the Journal of Clinical Endocrinology & Metabolism, Large Genomic Deletions in AIP in Pituitary Adenoma Predisposition , the authors make a case for large genomic AIP deletions accounting for a subset of pituitary adenoma predisposition (PAP). They state "functional evidence suggest that AIP acts as a tumor suppressor gene." The free author's manuscript is linked, but a more up-to-date version may be found in October's edition of the journal.

The study included multiple family lines from various countries, with the "selection criterion for young age of onset aimed at enriching for possible PAP cases." The authors make the claim that "[t]ypically, PAP patients have a young age at disease onset, without a strong family history of pituitary adenomas."

The patients had already been tested for MEN1, PRKAR1A and other germline mutations also responsible for Cushing's and/or adrenal abnormalities.

Eleven families were heterogeneous (different types of adenomas), and 12 were homogeneous (same type of adenoma), including seven with acromegaly/gigantism, four with nonfunctioning adenomas, and one with prolactinomas (Table 1). In addition, 39 sporadic Finnish GH-secreting adenoma cases aged 40 yr or less at diagnosis and 35 sporadic Italian pediatric pituitary adenoma patients were analyzed.

Multiplex ligation-dependent probe amplification (MLPA) was used to identify these genomic rearrangements and proved to be a very beneficial tool to search for germline copy number changes in AIP.

This type of study may lead to better clinical evaluation, treatment, and calculation of the chance of relapse. The authors go on to say "...it would be of great interest to compare the disease spectrum and penetrance in families with truncating and nontruncating AIP mutations; clearly, much larger patient series and detailed medical investigations would be needed for this."

M. Georgitsi, E. Heliovaara, R. Paschke, A. V. K. Kumar, M. Tischkowitz, O. Vierimaa, P. Salmela, T. Sane, E. De Menis, S. Cannavo, S. Gundogdu, A. Lucassen, L. Izatt, S. Aylwin, G. Bano, S. Hodgson, C. A. Koch, A. Karhu, L. A. Aaltonen (2008). Large Genomic Deletions in AIP in Pituitary Adenoma Predisposition Journal of Clinical Endocrinology & Metabolism, 93 (10), 4146-4151 DOI: 10.1210/jc.2008-1003