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Background

Carney first described patients with the association of myxomas, spotty pigmentation of skin and mucous membranes, and endocrine overactivity. This syndrome belongs to a group of genetic disorders, the lentiginoses, which include Peutz-Jeghers, LEOPARD, and Laugier-Hunziker syndromes. The most serious manifestation of the Carney complex are cardiac myxomas, which can occur in approximately one third of patients

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

PATHOGENESIS CHARACTERIZATION
CHROMOSOMAL ABNORMALITIES  
LINKAGE TO LOCI ON 2p16 AND 17q22-24  
Carney complex, a familial multiple neoplasia and lentiginosis syndrome: analysis of 11 kindreds and linkage to the short arm of chromosome 2 J Clin Invest 1996;97:699-705
Circulation 1998;98:2560-6.
Identification of a novel genetic locus for familial cardiac myxomas and Carney complex

Circulation 1998;98:2560-6.

Long arm chromosome 17

PRKAR1A GENE  


Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex.

Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA.

Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, Building 10, Room 10N262, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, MSC1862, Bethesda, MD 20892, USA.

Hum Mol Genet 2000 Dec 12;9(20):3037-46 Abstract quote

Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome, which has been linked to loci on 2p16 and 17q22-24. We recently reported that PRKAR1A, which codes for the type 1A regulatory subunit of protein kinase A (PKA), is a tumor suppressor gene on chromosome 17 that is mutated in some CNC families.

To evaluate the spectrum of PRKAR1A mutations, we identified its genomic structure and screened for mutations in 54 CNC kindreds (34 families and 20 patients with sporadic disease). Fourteen families were informative for linkage analysis: four of four families that mapped to 17q had PRKAR1A mutations, whereas there were no mutations found in seven families exhibiting at least one recombination with 17q. In six of the latter, CNC mapped to 2p16. PRKAR1A mutations were also found in 12 of 20 non-informative families and 7 of 20 sporadic cases. Altogether, 15 distinct PRKAR1A mutations were identified in 22 of 54 kindreds (40.7%). In 14 mutations, the sequence change was predicted to lead to a premature stop codon; one altered the initiator ATG codon. Mutant mRNAs containing a premature stop codon were unstable, as a result of nonsense-mediated mRNA decay. Accordingly, the predicted truncated PRKAR1A protein products were absent in these cells.

We conclude that (i) genetic heterogeneity exists in CNC; and (ii) all of the CNC alleles on 17q are functionally null mutations of PRKAR1A. CNC is the first human disease recognized to be caused by mutations of the PKA holoenzyme, a critical component of cellular signaling.

Molecular Analysis of the Cyclic AMP-Dependent Protein Kinase A (PKA) Regulatory Subunit 1A (PRKAR1A) Gene in Patients with Carney Complex and Primary Pigmented Nodular Adrenocortical Disease (PPNAD) Reveals Novel Mutations and Clues For Pathophysiology: Augmented PKA Signaling is Associated with Adrenal Tumorigenesis in PPNAD.

Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, Bertherat J.

Departments of Endocrinology, Institut Cochin, INSERM U576, CNRS UMR 8104 IFR116, Rene Descartes-Paris V University, and Endocrinology, Hopital Cochin, Paris; and COMETE Network, France.

Am J Hum Genet 2002 Dec;71(6):1433-42 Abstract quote

We studied 11 new kindreds with primary pigmented nodular adrenocortical disease (PPNAD) or Carney complex (CNC) and found that 82% of the kindreds had PRKAR1A gene defects (including seven novel inactivating mutations), most of which led to nonsense mRNA and, thus, were not expressed in patients' cells. However, a previously undescribed base substitution in intron 6 (exon 6 IVS +1G-->T) led to exon 6 skipping and an expressed shorter PRKAR1A protein.

The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent protein kinase A (PKA) signaling at the nuclear level. This is the first demonstration of an inactivating PRKAR1A mutation being expressed at the protein level and leading to stimulation of the PKA pathway in CNC patients.

Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggest that alteration of PRKAR1A function (not only its complete loss) is sufficient for augmenting PKA activity leading to tumorigenesis in tissues affected by CNC.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  


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

Stratakis CA, Kirschner LS, Carney JA.

Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862, USA.

J Clin Endocrinol Metab 2001 Sep;86(9):4041-6 Abstract quote

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.

VARIANTS  
ENDOCRINE Adrenal or testicular tumors (or both) are present in approximately one third of patients, with pituitary tumors being present in about one tenth of patients
HEART  


Carney's syndrome: complex myxomas. Report of four cases and review of the literature.

Edwards A, Bermudez C, Piwonka G, Berr ML, Zamorano J, Larrain E, Franck R, Gonzalez M, Alvarez E, Maiers E.

Centro Cardiovascular, Hospital Clinico Universidad de Chile, Av. Santos Dumont 999, Santiago, Chile.

Cardiovasc Surg 2002 Jun;10(3):264-75 Abstract quote

Cardiac myxomas are rare tumors. They usually appear as a sporadic isolated condition in the left atrium of middle-aged women with no other coincidental pathology. Carney and others have described in young people a special complex group of cardiac myxomas associated to a distinctive complex pathology, giving identity to the "Syndrome Myxoma" or "Carney's Syndrome". Four additional cases of this syndrome, treated from 1977 to 1999 at the Hospital Clinico de la Universidad de Chile are presented here with a comprehensive review of the literature, accumulating 100 cases.

The main features of our cases include the presence of malignant non cardiac tumors, a familial trend, follow-up of 23 years and an iterative recurrence in the elder case. To date all patients are tumor free. Reviewing the literature, patients with Carney's Syndrome were younger, with a mean age of 26 years and female predominance (62%). Cardiac myxomas affected the four chambers of the heart: 64% the left atrium; 44% the right atrium; 14% the left ventricle and 12% the right ventricle. They were multiple tumors in 41% and involved more than one chamber in 31%, being synchronous or metachronous.

There was a marked familial trend (52%), a high incidence of recurrence (20%), with more than one occurring in half the cases. Extra-cardiac involvement consisted of: 68% pigmented skin lesions, 40% cutaneous myxomas, 37% adrenal cortical disease, 27% myxoid mammary fibroadenoma and 34% male patients with testes tumors. A low percentage had pituitary adenoma, melanotic schwannomas and thyroid disease. The diagnosis is made when two or more of these criteria are present. In agreement with these findings the four chambers of the heart should be examined at surgery for atypical myxoma locations, right atriotomy and combined superior-transseptal approach improve exposure of the cavities, careful screening of the first degree family members should be conducted, and closed short and long term follow up controls are important.

Complex myxoma appears as a multi-systemic disorder, occasionally having an ominous prognosis and malignant potentiality, and is still undergoing investigation for better understanding and identification.

SKIN  
Cutaneous myxomas One third of patients
Pink shiny papules which may be larger and pedunculated
Cutaneous lentigines

Majority of patients

Most commonly seen on the face, especially in the periocular and the perioral regions
May also occur on the ears, trunk, neck, lips (commonly on the vermilion border), conjunctiva, sclera, vulva, or glans penis

TESTIS  


Testicular tumors in Carney's complex.

Washecka R, Dresner MI, Honda SA.

Department of Urology, Hawaii Kaiser Permanente Medical Center, Honolulu, Hawaii, USA.

 

J Urol 2002 Mar;167(3):1299-302 Abstract quote

PURPOSE: Bilateral sex cord stromal testicular tumors are common in the syndrome of myxoma, spotty pigmentation and endocrine overactivity (Carney's complex). Large cell calcifying Sertoli cell tumor is the particular testicular tumor found in Carney's complex. A clinicopathological review of 26 patients is presented.

MATERIALS AND METHODS: We report 2 cases of Carney's complex with testicular tumors. An additional 24 patients with Carney's complex and testicular tumors were identified by MEDLINE search and review of the literature.

RESULTS: Bilateral testicular tumors were found in 16 patients (61%) with a familial occurrence in 10 (38%). A testicular mass was the most common presentation. The associated findings of Carney's complex included cardiac myxoma in 16 patients, skin myxoma in 16, skin pigmentation in 15, Cushing's syndrome in 8, acromegaly in 3 and schwannoma in 3. Excisional biopsy, surveillance, bilateral orchiectomy and unilateral orchiectomy were performed in 7, 4, 7 and 8 patients, respectively.

CONCLUSIONS: No local tumor recurrence or metastasis has developed in patients with bilateral and/or multifocal testicular tumors. Excisional biopsy or surveillance only are treatment options for bilateral testicular tumors in Carney's complex.

 

HISTOLOGICAL TYPES CHARACTERIZATION
General  
VARIANTS  
BONE  



Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders.

Carney JA, Boccon-Gibod L, Jarka DE, Tanaka Y, Swee RG, Unni KK, Stratakis CA.

Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.

Am J Surg Pathol 2001 Feb;25(2):164-76 Abstract quote

This article describes the clinical and pathologic features of four unusual bone tumors. Three were congenital or most likely so; the fourth, detected at age 1 year, was probably of considerable duration. The patients, three boys and one girl, each presented with a painless mass. Two had the Carney complex, a familial lentiginous and multiorgan tumorous syndrome; another probably had this disorder; the fourth did not show it, but his mother did. The tumors occurred in the nasal region (n = 2) and the diaphysis of the tibia and radius (n = 1 each). Roentgenographically, three had benign characteristics; the fourth, malignant features.

Grossly, the tumors were gelatinous, cartilaginous. and bony. Microscopically, they featured benign-appearing polymorphic cells with few division figures arranged in sheets and lobules set in a myxomatous, cartilaginous, osseous, and hyaline fibrous matrix. Cellularity was low to moderate. The tumors eroded bone, one infiltrated between bony trabeculae, and three had soft tissue extension.

Complete resection of one tumor was curative; incomplete excision of two tumors resulted in local recurrence (intracranial and fatal) in one and persistence in the other; the fourth tumor remains under observation after biopsy. No tumor metastasized.

BREAST  
Breast imaging findings

Radiology 1997;205:221-7.

Myxoid mammary tumors or ductal adenomas, may be seen in about one fourth of patients

EYE  
Pigmented lesions of the conjunctiva in Carney's complex J Am Acad Dermatol 2000;42:145.
SKIN  
Epithelioid blue nevi

Am J Surg Pathol 1996;19:25972

Larger, somewhat raised lesions that are consistent with blue nevi

SOFT TISSUE  
Psammomatous melanotic schwannoma

Am J Surg Pathol 1990;14:206-22

Up to 10% of patients they are malignant and can metastasize

OVARY  


Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy.

Stratakis CA, Papageorgiou T, Premkumar A, Pack S, Kirschner LS, Taymans SE, Zhuang Z, Oelkers WH, Carney JA.

Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862, USA.

J Clin Endocrinol Metab 2000 Nov;85(11):4359-66 Abstract quote

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome (OMIM 160980, http://www.ncbi.nlm.nih.gov/omim) with features overlapping those of other multiple endocrine neoplasias and hamartomatoses, Peutz-Jeghers syndrome (PJS) in particular. Although a number of patients with CNC and ovarian tumors have been described in individual patient reports, it is unclear whether ovarian lesions constitute a component of the syndrome or are coincidental events. We investigated 18 women with CNC [age at first evaluation, 31.3+/-12.1 yr (mean +/- SD)] prospectively for the development of ovarian tumors over a period of 35.7+/-30.6 months by physical examination and pelvic ultrasonography. They were compared with 11 women (age at first evaluation, 32.9+/-17 yr) who were enrolled under the same protocol (follow up, 32.3+/-25.1 months) and served as a control group. In addition, a registry of 178 women from among a total of 309 patients with CNC was searched retrospectively for any having ovarian tumors. Seven available histological specimens were rereviewed. None of the CNC patients had ovarian tumors analogous to those of PJS. Two patients with CNC in the prospective group developed ovarian tumors and were operated upon. One had bilateral oophorectomy for asynchronous serous cystadenomas. The second patient had a unilateral serous cystadenoma. Resected tumor tissue from both patients was tested for genetic abnormalities of the chromosomal regions to which CNC genetic loci have been mapped. Both showed genomic amplification of chromosomal region 2p16. An additional 10 patients had at least 1 sonogram positive for ovarian cysts. Only 1 of the patients in the control group was found to have a persistent, simple ovarian cyst by ultrasonography. The registry of 178 CNC patients included 4 who had undergone surgery for ovarian tumors.

The diagnoses included endometrioid adenocarcinoma (1 patient) and metastatic mucinous adenocarcinoma (the primary site was probably ovarian; 1 patient). In addition, 7 of 12 patients (58%) with CNC, who died of other causes, had ovarian lesions at autopsy. In conclusion, although the same stromal tumor, large-cell calcifying Sertoli cell tumor, affects the testes in CNC and PJS, we did not find such tumors in a small population of CNC patients that was studied prospectively or a larger group of CNC patients that was studied retrospectively. The results of our study also suggested that women with CNC commonly develop ovarian cysts and may be at risk for ovarian carcinoma. The chromosome 2p16 CNC locus was involved in ovarian pathology with apparent copy number gain, suggesting that at least molecularly there is some involvement of the CNC gene(s) in these lesions.

Although ovarian tumors do not seem to be a major manifestation of CNC, sonography of the ovaries may be part of the initial evaluation for this genetic syndrome in women with CNC; follow-up of any identified lesion is recommended because of the possible risk for malignancy.

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