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A PRKAR1A Mutation Associated with Primary Pigmented Nodular Adrenocortical Disease in 12 Kindreds

Institut National de la Santé et de la Recherche Médicale U 567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104 (L.G., E.J., F.R.-C., F.T., X.B., J.B.), Institut Cochin, Université René-Descartes, Paris 5, 75014 Paris, France; Department of Endocrinology (L.G., X.B., J.B.), Centre de Référence Maladies Rares de la Surrénale, Hôpital Cochin, 75014 Paris, France; Section on Endocrinology and Genetics (A.H., S.B., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20847; Department of Endocrinology (H.L.), Centre Hospitalier Universitaire de Rouen, 76031 Rouen, France; Department of Endocrinology (F.-L.C.-V., M.-C.V.), Clinique Marc Linquette-Centre Hospitalier Universitaire, F-59037 Lille, France; Department of Endocrinology (P.C.), 94270 Kremlin Bicetre, France; Department of Endocrinology (B.C.-D.), Hôpital de la Timone, 13385 Marseille, France; Departments of Molecular Biology (M.L.) and Endocrinology (A.G.), Hospital Universitario Virgen Macarena, 41009 Seville, Spain; Department of Medicine (C.D.M.), University of Connecticut Health Center, Farmington, Connecticut 06030; Department of Pathology (F.T.), Hôpital Cochin, 75014 Paris, France; and Emeritus Staff (J.A.C.), Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Professor Jérôme Bertherat, Service d’Endocrinologie, Hôpital Cochin, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France. 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, 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: The objectives of the study were a detailed phenotyping for CNC manifestations in 12 kindreds bearing the same PRKAR1A mutation and a study of the consequences of the mutation and 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 iPPNAD.

Results: We describe a 6-bp polypyrimidine tract deletion [exon 7 IVS del (–7–2)] in 12 unrelated kindreds that were referred for Cushing syndrome 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.

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