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      Carney complex with multiple breast tumours including breast cancer: a case report

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          Abstract

          Carney complex (CNC) is a rare multiple tumour syndrome characterized by cutaneous pigmented lesions, myxoma and endocrine tumours, among others, and is inherited as an autosomal dominant trait. Protein kinase cAMP-dependent type I regulatory subunit alpha ( PRKAR1A) is known to be the responsible gene. Breast myxomatosis and ductal adenoma, which are regarded as benign, are well-known mammary lesions of CNC and are included in the main diagnostic criteria. In this case, a 59-year-old woman with repeated cardiac myxoma was diagnosed with CNC with PRKAR1A mutation. She also had three multiple breast tumours bilaterally: breast cancer, adenomyoepithelioma and intraductal papilloma. In mammary lesions of CNC, attention should be paid to benign lesions, such as breast myxomatosis or ductal adenomas, and the development of breast cancer or breast tumours with malignant potential. Mammary lesions should be aggressively scrutinized and considered for resection, as required.

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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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            Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes.

            The "complex of myxomas, spotty skin pigmentation, and endocrine overactivity," or "Carney complex" (CNC), is caused by inactivating mutations of the regulatory subunit type 1A of the cAMP-dependent protein kinase (PRKAR1A) gene and as yet unknown defect(s) in other gene(s). Delineation of a genotype-phenotype correlation for CNC patients is essential for understanding PRKAR1A function and providing counseling and preventive care. A transatlantic consortium studied the molecular genotype and clinical phenotype of 353 patients (221 females and 132 males, age 34 +/- 19 yr) who carried a germline PRKAR1A mutation or were diagnosed with CNC and/or primary pigmented nodular adrenocortical disease. A total of 258 patients (73%) carried 80 different PRKAR1A mutations; 114 (62%) of the index cases had a PRKAR1A mutation. Most PRKAR1A mutations (82%) led to lack of detectable mutant protein (nonexpressed mutations) because of nonsense mRNA mediated decay. Patients with a PRKAR1A mutation were more likely to have pigmented skin lesions, myxomas, and thyroid and gonadal tumors; they also presented earlier with these tumors. Primary pigmented nodular adrenocortical disease occurred earlier, was more frequent in females, and was the only manifestation of CNC with a gender predilection. Mutations located in exons were more often associated with acromegaly, myxomas, lentigines, and schwannomas, whereas the frequent c.491-492delTG mutation was commonly associated with lentigines, cardiac myxomas, and thyroid tumors. Overall, nonexpressed PRKAR1A mutations were associated with less severe disease. CNC is genetically and clinically heterogeneous. Certain tumors are more frequent, with specific mutations providing some genotype-phenotype correlation for PRKAR1A mutations.
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              Carney Complex

              Carney complex is a rare, autosomal dominant, multiple endocrine neoplasia and lentiginosis syndrome, caused in most patients by defects in the PRKAR1A gene, which encodes the regulatory subunit type 1α of protein kinase A. Inactivating defects of PRKAR1A lead to aberrant cyclic-AMP-protein kinase A signaling. Patients may develop multiple skin abnormalities and a variety of endocrine and non-endocrine tumors. Endocrine manifestations include primary pigmented nodular adrenocortical disease, that may cause Cushing syndrome, growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia which can result in acromegaly, as well as gonadal and thyroid tumors. Non-endocrine tumors associated with Carney complex include myxomas of the heart, breast, and other sites, psamommatous melanotic schwannomas, breast ductal adenomas, osteochondromyxomas, and a predisposition to a number of malignancies from adrenal to pancreatic and liver cancer.
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                Author and article information

                Contributors
                Journal
                Oxf Med Case Reports
                Oxf Med Case Reports
                omcr
                Oxford Medical Case Reports
                Oxford University Press
                2053-8855
                June 2022
                23 June 2022
                23 June 2022
                : 2022
                : 6
                : omac063
                Affiliations
                Breast Oncology Service , Saitama Medical University International Medical Center, Hidaka, Saitama JP 350-1298, Japan
                Breast Oncology Service , Saitama Medical University International Medical Center, Hidaka, Saitama JP 350-1298, Japan
                Department of Digestive Surgery , IMS Miyoshi General Hospital, Miyoshi, Saitama JP 354-0041, Japan
                Breast Oncology Service , Saitama Medical University International Medical Center, Hidaka, Saitama JP 350-1298, Japan
                Department of Pathology , Saitama Medical University International Medical Center, Hidaka, Saitama JP 350-1298, Japan
                Breast Oncology Service , Saitama Medical University International Medical Center, Hidaka, Saitama JP 350-1298, Japan
                Breast Oncology Service , Saitama Medical University International Medical Center, Hidaka, Saitama JP 350-1298, Japan
                Author notes
                Correspondence address. Breast Oncology Service, Saitama Medical University International Medical Center, Hidaka, Saitama JP 350-1298, Japan. Tel.: +81429844111; E-mail: afujimot@ 123456saitama-med.ac.jp ; ORCID ID: 0000-0003-4261-7984
                Author information
                https://orcid.org/0000-0003-4261-7984
                Article
                omac063
                10.1093/omcr/omac063
                9235021
                35769184
                2fd1aa23-2693-4994-883f-88e32588a67a
                © The Author(s) 2022. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 March 2022
                : 6 May 2022
                : 9 May 2022
                Page count
                Pages: 4
                Categories
                Case Report
                AcademicSubjects/MED00010
                omcrep/1500

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