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      Novel Mutation in PRKAR1A in Carney Complex

      case-report

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          Abstract

          A case of Carney complex in a Korean patient is presented. The patient had the characteristics of Carney complex including skin lesions, positive family history, and multiple myxomas including a superficial angiomyxoma in the perianal area. An extensive genetic analysis revealed a novel mutation in the protein kinase A type I-a regulatory subunit ( PRKAR1A) gene, but not in the phosphodiesterase type 11A ( PDE11A) gene. This is the first case wherein extensive genetic studies were performed in a patient with Carney complex in Korea.

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          Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.

          Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas. CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6, 7). Because of its similarities to the McCune-Albright syndrome and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.
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            The complex of myxomas, spotty pigmentation, and endocrine overactivity.

            Of 40 patients (16 males and 24 females), 29 had cardiac myxoma(s), 14 had skin pigmentation (lentigo and several types of nevi) which also commonly affected the lips, 6 had skin myxoma(s), and 12 had both pigmentation and myxoma(s); 18 had primary pigmented nodular adrenocortical disease (Cushing syndrome was present in 11); 10 had myxoid mammary fibroadenomas; 9 had testicular tumor(s) (large-cell calcifying Sertoli cell tumor, Leydig cell tumor, or adrenocortical rest tumor, or a combination); and 4 had pituitary adenoma with gigantism or acromegaly. The maximum number of conditions present together was five, occurring in two patients; each of the remaining patients had at least two of the conditions. The overlap, in this sizeable number of patients, of various combinations of the same rare or very rare conditions unlikely to occur together by chance with any degree of frequency is striking evidence for a unique syndrome. The patients were young (mean age at diagnosis of the first component, 18 years). Pathologic involvement tended to be multicentric (heart and skin) and bilateral in paired organs (adrenal, breast, and testis). Thirteen patients (32%) are alive and well. Twelve patients are alive but with complications of cardiac myxoma (in 8), testicular tumors (in 2), residual Cushing syndrome (in 1), or bilateral pulmonary nodules (in 1). Twelve patients are dead: 9 of cardiac myxoma, 1 of intracranial (nonpituitary) tumor, and 2 postoperatively. The status of three is unknown.
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              Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.

              Carney complex is a multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous, and neural tumors, as well as a variety of pigmented lesions of the skin and mucosae. Carney complex is inherited as an autosomal dominant trait and may simultaneously involve multiple endocrine glands, as in the classic multiple endocrine neoplasia syndromes 1 and 2. Carney complex also has some similarities to McCuneAlbright syndrome, a sporadic condition that is also characterized by multiple endocrine and nonendocrine tumors. Carney complex shares skin abnormalities and some nonendocrine tumors with the lentiginoses and certain of the hamartomatoses, particularly Peutz-Jeghers syndrome, with which it shares mucosal lentiginosis and an unusual gonadal tumor, large-cell calcifying Sertoli cell tumor. Careful clinical analysis has enabled positional cloning efforts to identify two chromosomal loci harboring potential candidate genes for Carney complex. Most recently, at the 17q22-24 locus, the tumor suppressor gene PRKAR1A, coding for the type 1alpha regulatory subunit of PKA, was found to be mutated in approximately half of the known Carney complex kindreds. PRKAR1A acts a classic tumor suppressor gene as demonstrated by loss of heterozygosity at the 17q22-24 locus in tumors associated with the complex. The second locus, at chromosome 2p16, to which most (but not all) of the remaining kindreds map, is also involved in the molecular pathogenesis of Carney complex tumors, as demonstrated by multiple genetic changes at this locus, including loss of heterozygosity and copy number gain. Despite the known genetic heterogeneity in the disease, clinical analysis has not detected any corresponding phenotypic differences between patients with PRKAR1A mutations and those without. This article summarizes the clinical manifestations of Carney complex from a worldwide collection of affected patients and also presents revised diagnostic criteria for Carney complex. In light of the recent identification of mutations in the PRKAR1A gene, an estimate of penetrance and recommendations for genetic screening are provided.
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                Author and article information

                Journal
                Korean J Pathol
                Korean J Pathol
                KJP
                Korean Journal of Pathology
                The Korean Society of Pathologists and The Korean Society for Cytopathology
                1738-1843
                2092-8920
                December 2012
                26 December 2012
                : 46
                : 6
                : 595-600
                Affiliations
                Indiana University School of Medicine, Indianapolis, IN, USA.
                [1 ]Department of Biomedical Science, College of Health Science, Korea University, Seoul, Korea.
                [2 ]Research Institute of Health Science, College of Health Science, Korea University, Seoul, Korea.
                [3 ]Department of Pathology, Kyung Hee University School of Medicine, Seoul, Korea.
                Author notes
                Corresponding Author: Yong-Koo Park, M.D. Department of Pathology, Kyung Hee University Hospital, Kyung Hee University School of Medicine, 23 Kyunghee-daero, Dongdaemun-gu, Seoul 130-872, Korea. Tel: +82-2-958-8742, Fax: +82-2-957-0489, ykpark@ 123456khmc.or.kr
                Article
                10.4132/KoreanJPathol.2012.46.6.595
                3540340
                23323113
                224736e0-5ceb-40ec-a62f-bd2030e268c3
                © 2012 The Korean Society of Pathologists/The Korean Society for Cytopathology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 03 February 2012
                : 17 April 2012
                : 07 May 2012
                Categories
                Case Report

                Pathology
                carney complex,prkar1a,pde11a,superficial angiomyxoma
                Pathology
                carney complex, prkar1a, pde11a, superficial angiomyxoma

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