Case studies of two related Chinese patients with Carney complex presenting with extensive cardiac myxomas and PRKAR1A gene mutation of c.491_492delTG

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Abstract

Carney complex is an autosomal dominant disease that is clinically characterized by cardiac myxomas, spotty skin pigmentation, and endocrine overactivity. Carney complex is most commonly caused by mutations in the PRKAR1A gene on chromosome 17q22-24. Currently, there are at least 117 pathogenic mutations in PRKAR1A that have been identified. Herein, we report on two cases of Carney complex in related Chinese patients with a c.491_492delTG mutation that presented with multiple and extensive cardiac myxomas and skin pigmentation.

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Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.

C Stratakis, L S Kirschner, J Carney (2001)

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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Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update.

Marine Guillaud-Bataille, Jérôme Bertherat, Fabio Rueda Faucz … (2010)

PRKAR1A encodes the regulatory subunit type 1-alpha (RIalpha) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA). Inactivating PRKAR1A mutations are known to be responsible for the multiple neoplasia and lentiginosis syndrome Carney complex (CNC). To date, at least 117 pathogenic variants in PRKAR1A have been identified (online database: http://prkar1a.nichd.nih.gov). The majority are subject to nonsense mediated mRNA decay (NMD), leading to RIalpha haploinsufficiency and, as a result, activated cAMP signaling. Recently, it became apparent that CNC may be caused not only by RIalpha haploinsufficiency, but also by the expression of altered RIalpha protein, as proven by analysis of expressed mutations in the gene, consisting of amino acid substitutions and in-frame genetic alterations. In addition, a new subgroup of mutations that potentially escape NMD and result in CNC through altered (rather than missing) protein has been analyzed-these are frame-shifts in the 3' end of the coding sequence that shift the stop codon downstream of the normal one. The mutation detection rate in CNC patients is recently estimated at above 60%; PRKAR1A mutation-negative CNC patients are characterized by significant phenotypic heterogeneity. In this report, we present a comprehensive analysis of all presently known PRKAR1A sequence variations and discuss their molecular context and clinical phenotype. Published 2010 Wiley-Liss, Inc.

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Carney complex (CNC)

Jérôme Bertherat (2006)

The Carney complex (CNC) is a dominantly inherited syndrome characterized by spotty skin pigmentation, endocrine overactivity and myxomas. Skin pigmentation anomalies include lentigines and blue naevi. The most common endocrine gland manifestations are acromegaly, thyroid and testicular tumors, and adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). PPNAD, a rare cause of Cushing's syndrome, is due to primary bilateral adrenal defect that can be also observed in some patients without other CNC manifestations or familial history of the disease. Myxomas can be observed in the heart, skin and breast. Cardiac myxomas can develop in any cardiac chamber and may be multiple. One of the putative CNC genes located on 17q22-24, (PRKAR1A), has been identified to encode the regulatory subunit (R1A) of protein kinase A. Heterozygous inactivating mutations of PRKAR1A were reported initially in 45 to 65 % of CNC index cases, and may be present in about 80 % of the CNC families presenting mainly with Cushing's syndrome. PRKAR1A is a key component of the cAMP signaling pathway that has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumor suppressor gene. Genetic analysis should be proposed to all CNC index cases. Patients with CNC or with a genetic predisposition to CNC should have regular screening for manifestations of the disease. Clinical work-up for all the manifestations of CNC should be performed at least once a year in all patients and should start in infancy. Cardiac myxomas require surgical removal. Treatment of the other manifestations of CNC should be discussed and may include follow-up, surgery, or medical treatment depending on the location of the tumor, its size, the existence of clinical signs of tumor mass or hormonal excess, and the suspicion of malignancy. Bilateral adrenalectomy is the most common treatment for Cushing's syndrome due to PPNAD.

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Author and article information

Contributors

Hongwei Guo: ghwdr@sina.com

Jianping Xu: xujianpingmedsci@163.com

Hui Xiong: xionghuidr@sina.com

Shengshou Hu: hushengshoudr@sina.com

Journal

Journal ID (nlm-ta): World J Surg Oncol

Journal ID (iso-abbrev): World J Surg Oncol

Title: World Journal of Surgical Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-7819

Publication date (Electronic): 27 February 2015

Publication date PMC-release: 27 February 2015

Publication date Collection: 2015

Volume: 13

Electronic Location Identifier: 83

Affiliations

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037 China

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Publisher ID: 470

DOI: 10.1186/s12957-015-0470-4

PMC ID: 4349715

PubMed ID: 25890363

SO-VID: 5d0d75ca-20ff-46b1-afc4-5490b2d49b56

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 July 2014

Date accepted : 17 January 2015

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ScienceOpen disciplines: Surgery

Keywords: carney complex,prkar1a,mutation,myxomas

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ScienceOpen disciplines: Surgery

Keywords: carney complex, prkar1a, mutation, myxomas

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Case studies of two related Chinese patients with Carney complex presenting with extensive cardiac myxomas and PRKAR1A gene mutation of c.491_492delTG

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Most cited references 7

Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.

Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update.

Carney complex (CNC)

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Cited by 1

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