The Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity

Carney, J. Aidan; Gordon, Hymie; Carpenter, Paul C.; Shenoy, B V; Go, Vay Liang W.

doi:10.1097/00005792-198507000-00007

Cited by 998 publications

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“…I n the autosomal dominant multiple neoplasia syndrome Carney complex (CNC, Online Mendelian Inheritance in Man 160980), recurrent heart, skin, and͞or visceral myxomas are associated with spotty skin pigmentation, adrenal gland dysplasia, and schwannomas and pituitary, Sertoli, bone, ovarian, and breast tumors (1)(2)(3)(4)(5)(6). Mutations in the chromosome 17q24 PRKAR1A gene encoding the R1␣ regulatory subunit of cAMP-dependent protein kinase A (PKA) cause CNC in some kindreds (7,8).…”

mentioning

confidence: 99%

Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Veugelers

Wilkes

Burton

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

146

122

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Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1α of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a +/– mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a +/– mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a +/– mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.

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mentioning

confidence: 99%

Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Veugelers

Wilkes

Burton

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

146

122

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“…Each sample was given a two-digit number that reflected the order of its collection (for example, CAR107.03 represents the third specimen collected from the CAR.107 family). Clinical information for most of these families has been reported before (5,10,16,(47)(48)(49)(50)(51)(52)(53)(54).…”

Section: Methodsmentioning

confidence: 99%

“…The latter include myxomas of the skin (2), heart (3-5), breast (6), and other sites (7)(8)(9)(10), psammomatous melanotic schwannoma (11,12), growth hormone-producing pituitary adenoma (13), testicular Sertoli cell tumor (14), and possibly other benign and malignant neoplasms, including tumors of the thyroid gland and ductal adenoma of the breast (1,15). Although the existence of the complex as an unrecognized, inherited syndrome was first suggested in 1985 (16,17), combinations of several components of the syndrome, and their familial occurrence had been reported earlier. Thus, the pathologic findings of the adrenal glands, multiple, small, pigmented, adrenocortical nodules and internodular cortical atrophy, were described in children and young adults with Cushing syndrome as early as in 1949 (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the pathologic findings of the adrenal glands, multiple, small, pigmented, adrenocortical nodules and internodular cortical atrophy, were described in children and young adults with Cushing syndrome as early as in 1949 (18)(19)(20)(21)(22). Similarly, by then, several familial cases of cutaneous and cardiac myxomas associated with lentigines (lentigo simplex) or ephelides and blue nevi of the skin and mucosae had been described under the acronyms, NAME (for nevi, atrial myxoma, myxoid neurofibromata, and ephelides) and LAMB (for lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) syndromes (16,17,(23)(24)(25)(26)(27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

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Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.

Stratakis

Carney²,

Lin³

et al. 1996

J. Clin. Invest.

431

217

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Carney complex is an autosomal dominant syndrome characterized by multiple neoplasias, including myxomas at various sites and endocrine tumors, and lentiginosis. The genetic defect(s) responsible for the complex remain(s) unknown. We studied 101 subjects, including 51 affected members, from 11 North American kindreds with Carney complex. Blood samples were collected from patients and their family members. Hospital records, photographs, and tissue specimens of deceased individuals were reviewed. DNA was extracted from blood samples, patient-derived cell lines, and/ or paraffin-embedded tissues. Linkage analysis was performed with highly polymorphic microsatellite markers, distributed over areas of the human genome harboring the most likely candidate genes. The most prevalent clinical manifestation in patients with Carney complex was spotty skin pigmentation, similar to that observed in Peutz-Jeghers and other lentiginosis syndromes. Skin and cardiac myxomas, Cushing syndrome, and acromegaly were present in 62, 30, 31, and 8 percent of the patients, respectively. Linkage was obtained for three markers on the short arm of chromosome 2 (2p16), with a maximum two-point lod score of 5.97 at ϭ 0.03 for the marker CA-2 (odds in favor of linkage 10 6 :1). The flanking markers CA7 and D2S378 defined a region of ‫ف‬ 6.4 cM that is likely to contain the gene(s) associated with Carney complex. Candidate genes in the proximity, including the propiomelanocortin and the DNA-mismatch repair hMSH2 genes, were excluded. We conclude that the genetic defect(s) responsible for Carney complex map(s) to the short arm of chromosome 2 (2p16). This region has exhibited cytogenetic aberrations in atrial myxomas associated with the complex, and has been characterized by microsatellite instability in human neoplasias.

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“…The complex of 'spotty-skin pigmentation, myxomas, endocrine overactivity, and schwannomas' or Carney complex (CNC) (MIM 160980) is an autosomal dominant multiple neoplasia syndrome (1). CNC is an inherited predisposition to tumors associated with primary pigmented nodular adrenocortical disease (PPNAD), GHand/or PRL-producing pituitary adenoma, myxomas of heart or skin, psammomatous melanotic schwannoma, and breast ductal adenoma (2).…”

Section: Introductionmentioning

confidence: 99%

Germline deletion and a somatic mutation of the PRKAR1A gene in a Carney complex-related pituitary adenoma

Iwata

Tamanaha

Koezuka

et al. 2015

European Journal of Endocrinology

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Objective: The objective was to assess involvement of loss of the PRKAR1A gene encoding a type 1a regulatory subunit of cAMP-dependent protein kinase A located on 17q24 in a Carney complex (CNC)-related pituitary adenoma. Design: We investigated aberrations of the PRKAR1A gene in a CNC patient with a GH-producing pituitary adenoma, whose family has three other members with probable CNC. Methods: A gene mutation was identified by a standard DNA sequencing method based on PCR. DNA copy number was measured to evaluate allelic loss on 17q24 by quantitative PCR. The breakpoints of deletion were determined by cloning a rearranged region in the deleted allele. Results: A PRKAR1A mutation of c.751_758del8 (p.S251LfsX16) was found in genomic DNA obtained from a pituitary adenoma, but not leukocytes from the patient. Reduced DNA copy number at loci including the PRKAR1A gene on 17q24 was detected in both the tumor and leukocytes, suggesting a deletion at the loci at the germline level. The deletion size was determined to be w0.5 Mb and this large deletion was also found in two other family members. Conclusion: This is the first case showing a CNC-related pituitary adenoma with the combination of somatic mutation and a large inherited deletion of the PRKAR1A gene. Biallelic inactivation of PRKAR1A appears to be necessary for the development of CNC-related pituitary adenoma.

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The Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity

Cited by 998 publications

References 0 publications

Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.

Germline deletion and a somatic mutation of the PRKAR1A gene in a Carney complex-related pituitary adenoma

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