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This version published online on February 7, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2708
A more recent version of this article appeared on May 1, 2006
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Submitted on December 13, 2005
Accepted on February 1, 2006

A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds

Lionel Groussin, Anelia Horvath, Eric Jullian, Sosipatros Boikos, Fernande Rene-Corail, Herve Lefebvre, Fritz-Line Cephise-Velayoudom, Marie-Christine Vantyghem, Philippe Chanson, Bernard Conte-Devolx, Miguel Lucas, Alfonso Gentil, Carl D. Malchoff, Xavier Bertagna, Constantine A Stratakis, and Jérôme Bertherat*

INSERM U 567, CNRS UMR 8104, Institut Cochin, Université René-Descartes Paris 5, Paris, France, 75014; Centre de référence maladies rares de la surrénale, Endocrinology, Hôpital Cochin, Paris, France; Section on Endocrinology & Genetics (SEGEN), DEB, NICHD, National Institutes of Health (NIH), Bethesda, USA; Endocrinology, CHU de Rouen, Rouen, France; Endocrinology, Clinique Marc Linquette-CHU, Lille, France; Endocrinology, Kremlin Bicetre, France; Endocrinology, Hôpital de la Timone, Marseille, France; Molecular Biology, Hospital Universitario Virgen Macarena; Endocrinology, Hospital Universitario Virgen Macarena, Seville, Spain and Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut, USA

* To whom correspondence should be addressed. E-mail: jerome.bertherat{at}cch.ap-hop-paris.fr.

Context: Primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of corticotropin-independent Cushing syndrome (CS), can be part of Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac myxomas and endocrine tumors or be isolated (i). Germline PRKAR1A-inactivating mutations have been observed in both CNC and iPPNAD, but with no apparent genotype-phenotype correlation.

Objective: detailed phenotyping for CNC manifestations in twelve kindreds bearing the same PRKAR1A mutation and to study the consequences of the mutation and study a potential founder effect.

Design: The study consisted of descriptive case reports.

Setting: The study was conducted at two referral centers.

Patients : The patients described in this study were referred for PRKAR1A gene mutation analysis because of a diagnosis of apparently isolated PPNAD.

Results : We describe a 6 bp polypyrimidine tract deletion [exon 7 IVS del (-7->-2)] in 12 unrelated kindreds that were referred for CS due to PPNAD. Nine of the patients had no family history; in two, there was a family history of iPPNAD. Only one patient met the criteria for CNC. Relatives carrying the same mutation had no manifestations of CNC or PPNAD, suggesting a low penetrance of this PRKAR1A defect. A founder effect was excluded by extensive genotyping of chromosome 17 markers.

Conclusions : In conclusion, a small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly iPPNAD; it is the first PRKAR1A genetic defect to have an association with a specific phenotype.
Key words: Carney complex • Primary Pigmented Nodular Adrenocortical Disease • Cushing's syndrome • PRKAR1A




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