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(Circulation. 1998;98:2560-2566.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Identification of a Novel Genetic Locus for Familial Cardiac Myxomas and Carney Complex

Mairead Casey, BSc; Caroline Mah, BA; Andrew D. Merliss, MD; Lawrence S. Kirschner, MD, PhD; Susan E. Taymans, PhD; Alfred E. Denio, MD; Bruce Korf, MD, PhD; Alan D. Irvine, MRCP; Anne Hughes, PhD; J. Aidan Carney, MD, PhD; Constantine A. Stratakis, MD, PhD; Craig T. Basson, MD, PhD

From the Cardiology Division, Department of Medicine and Department of Cell Biology and Anatomy, Cornell University Medical College, The New York Hospital, New York, NY (M.C., C.M., C.T.B.); Pacing and Electrophysiology, MeritCare Heart Services, Fargo, ND (A.D.M.); National Institutes of Health, National Institute of Child Health and Human Development, Bethesda, Md (L.S.K., S.E.T., C.A.S.); Center for Arthritis and Rheumatic Diseases, Virginia Beach, Va (A.E.D.); Department of Genetics, Harvard Medical School, Children's Hospital, Boston, Mass (B.K.); Department of Dermatology, Royal Victoria Hospital (A.D.I.) and Department of Medical Genetics, Queen's University (A.H.), Belfast, Northern Ireland, UK; and Department of Pathology, Mayo Clinic, Rochester, Minn (J.A.C.).

Correspondence to Craig T. Basson, MD, PhD, Cardiology Division, Department of Medicine, Cornell University Medical College, The New York Hospital, Starr 4, 525 E 68th St, New York, NY 10021. E-mail ctbasson{at}mail.med.cornell.edu

	Abstract

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Background—Intracardiac myxomas are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. In the autosomal dominant syndrome Carney complex, intracardiac myxomas arise in the setting of lentiginosis and other lesions associated with cutaneous hyperpigmentation, extracardiac myxomas, and nonmyxomatous tumors. Genetic factors that regulate cardiac tumor growth remain unknown.

Methods and Results—We used the molecular genetic techniques of linkage analysis to study 4 kindreds affected by Carney complex to determine the genetic basis of this syndrome. Our investigation confirmed genetic heterogeneity of Carney complex. Moreover, genetic linkage analysis with polymorphic short tandem repeats on the long arm of chromosome 17 revealed maximal pairwise LOD scores of 5.9, 1.5, 1.8, and 2.9 for families YA, YB, YC01, and YC11, respectively. Haplotype analysis excluded a founder effect at this locus. These data identify a major 17 cM locus on chromosome 17q2 that contains the Carney complex disease gene.

Conclusions—The ultimate identification and analysis of the Carney complex disease gene at this human chromosome 17q2 locus will facilitate diagnosis and treatment of cardiac myxomas and will foster new concepts in regulation of cardiac cell growth and differentiation.

Key Words: genetics • cardiovascular diseases • growth substances • genes • myxoma

	Introduction

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Primary intracardiac tumors, such as myxomas, occur in at least 7 of 10 000 individuals¹ and are an important clinical problem whose pathogenesis is poorly understood. Cardiac myxomas may occur as isolated findings or as components of heritable multisystem disease. Several inherited syndromes that relate lentiginosis to myxomas have been reported,^{2 3} and the most commonly associated myxomas are intracardiac, particularly atrial. Multiple acronyms have been proposed for such lentiginosis: atrial myxoma syndromes, including LAMB (Lentigines, Atrial myxomas, Mucocutaneous myxomas, and Blue nevi) syndrome and NAME (Nevi, Atrial myxoma, Myxoid neurofibroma, and Ephelides) syndrome. However, recent nosology^{3 4} aggregates them under the broader category of Carney complex.

In the autosomal dominant syndrome Carney complex,^{3 4 5 6 7 8} affected individuals variably express the disease phenotype but typically exhibit cutaneous disease (lentigines, ephelides, and blue nevi) in the setting of intracardiac myxomas. Cutaneous hyperpigmentation most commonly occurs on the face and trunk as well as on the lips, sclera, and mucosal surfaces of oral and genital regions and is present in 95% of individuals affected by Carney complex.⁵ Lentiginosis is present at birth, intensifies during puberty, and may fade with aging during adulthood. Associated intracardiac myxomas are often atrial, but ventricular tumors also occur. Familial syndromic atrial myxomas are estimated¹ to account for 7% of all atrial myxomas and may be particularly refractory to therapy. Whereas sporadic atrial myxomas occur most commonly as isolated left atrial lesions in middle-aged women, familial atrial myxomas⁶ occur in individuals of all ages without sex preference and are often bilateral and/or multicentric. Although sporadic atrial myxomas are usually highly amenable to curative surgical resection, familial lesions frequently recur, often at locations distant from the initial site of surgery.^{6 8}

Extracardiac myxomas^{4 5 6} occasionally occur in Carney complex. Such extracardiac myxomas are usually mucocutaneous, but less often, myxomas of the breast, testis, adrenal gland, thyroid gland, and brain are seen. Nonmyxomatous tumors such as pituitary adenoma, breast fibroadenoma, and psammomatous melanotic schwannoma are also observed. Cutaneous and neoplastic disease in the Carney complex may be associated with nonneoplastic endocrine abnormalities, most commonly Cushing syndrome secondary to primary pigmented nodular adrenocortical hyperplasia. Pituitary and thyroid dysfunction have also been noted. A variety of hematological, immunological, and rheumatic disorders (eg, anemia, polycythemia, fever, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and Raynaud's phenomenon) have all been associated with atrial myxomas. Such systemic abnormalities have been suggested^{9 10 11} to be secondary to myxoma secretion of the cytokine interleukin 6 and frequently resolve with tumor resection. Histopathological studies of Carney complex lentigines and cardiac myxomas have not demonstrated features unique to this syndrome to differentiate them from their sporadic counterparts.

The gene defect that produces cardiovascular and cutaneous disease in Carney complex remains unknown, and no cytogenetic abnormalities have consistently been associated with the Carney complex. Because of the known proto-oncogene functions of GTP binding proteins, DeMarco et al¹² hypothesized that defects in G_s might explain Carney complex, but they were unable to identify any such mutations. Telomeric rearrangements in sporadic atrial myxomas have occasionally been noted^{13 14 15} to involve chromosomes 2, 12, and 17. Stratakis et al⁷ used linkage analysis to propose a chromosomal locus in a 6.4-cM interval on chromosome 2p, but we have recently proved that Carney complex is genetically heterogeneous.¹⁶ In this study, we now show that a genetic defect on chromosome 17q causes Carney complex in at least 4 unrelated families.

	Methods

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Clinical Status
Informed consent was obtained from all participants in accordance with approval by the respective review boards of participating institutions. All family members were evaluated by a thorough history and physical examination without knowledge of genotype status. If there was any evidence of dermatologic, cardiac, or endocrine disease suggestive of Carney complex, patients were further evaluated by electrocardiography, transthoracic echocardiography, serum chemistry, and hematology.

Genotype Analyses
Peripheral blood was obtained from each family member, and lymphoblastoid lines were established by transformation with the Epstein-Barr virus.¹⁷ Genomic DNA was isolated from either cell lines or peripheral lymphocytes.^{16 17} Polymorphic short tandem repeats (also called microsatellites) were amplified by polymerase chain reaction with published nucleotide primer sequences,¹⁸ analyzed on denaturing polyacrylamide gels^{16 17} and visualized by autoradiography.

Linkage Analyses
Two-point logarithm of the odds (LOD) scores were calculated with LINKAGE software (version 5.1; Reference 19¹⁹ ). Multipoint LOD scores were calculated with LINKMAP software.²⁰ The LOD score indicates the statistical likelihood that 2 genetic loci are linked. A LOD score 3.0 indicates a significant likelihood of linkage (odds in favor of linkage, 1000:1) to a novel locus. A LOD score 1.3 (odds in favor of linkage, 20:1) is sufficient (in Reference 21²¹ , see Equation 4.10) to establish significant linkage (P0.05) to a locus identified in other kindreds with a LOD score 3.0. A LOD score -2.0 is generally accepted as evidence against linkage between loci.^{16 17 19} Penetrance of Carney complex was set at a level of P=0.95 for all analyses, and the disease gene frequency was set at 0.001. Allele frequencies were taken from published data,^{18 22} and all LOD scores reported were confirmed not to be significantly altered by changes in allele frequencies. The HOMOG program was used to test for genetic heterogeneity.²¹

Statistical Analyses
Incidence of specific Carney complex clinical manifestations among adults was defined as the percentage of individuals 16 years old with a given finding. To compare frequencies of Carney complex manifestations among all 4 families affected by this syndrome, Kruskall-Wallis nonparametric analysis was performed with CRUNCH software. To further contrast manifestations between pairs of families, a 2-tailed Fisher exact nonparametric test was performed. By use of a Bonferroni correction for multiple comparisons, a limit was established for statistical significance at P<0.00083.

	Results

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Clinical Evaluations
Families YA, YB, YC01, and YC11 (Figure 1) are unrelated Caucasian kindreds, with typical clinical findings (Figure 2) of Carney complex. All affected individuals in these 4 families exhibited cutaneous manifestations of Carney complex, including mucocutaneous hyperpigmentation (ie, lentiginosis, ephelides, and/or blue nevi). Most adults exhibited or had histories of intracardiac myxomas, and some individuals had experienced as many as 3 recurrences despite adequate surgical resection.

View larger version (16K): [in this window] [in a new window]   Figure 1. Pedigrees of families (YA, YB, YC01, and YC11) affected by Carney complex. Subject number and disease status of each family member analyzed are indicated. Squares denote male family members; circles, females. Affected and unaffected individuals are represented by solid and open symbols, respectively, and indeterminate or unknown diagnoses by gray symbols. Slashes denote deceased family members. Carney complex is transmitted in these families in an autosomal dominant fashion.

View larger version (46K): [in this window] [in a new window]   Figure 2. Typical clinical features of Carney complex. Examples of cutaneous (A) and cardiac (B through D) manifestations of Carney complex in 3 individuals from family YA. A, Individual IV-11 exhibits typical spotty pigmentation and lentiginosis of Carney complex. Note hyperpigmentation of lips as well as large nevus on right temple (arrowhead). Later in life, this individual also developed recurrent intracardiac myxomas. B, Echocardiographic view of left atrium (LA) of individual IV-1 bordered by mitral valve (mv) below left ventricle (LV) and interatrial septum (s). Note large mass (atrial myxoma; arrow) arising from interatrial septum. Individual IV-1 also exhibits lentiginosis similar to that in her cousin (A) and has also required resection of a cutaneous myxoma. C, Individual III-5, who also has typical hyperpigmentation and lentiginosis, required resection of this left atrial intracardiac mass after developing symptoms of an embolic stroke. D, Histopathological analysis (hematoxylin-eosin stain) of mass shown in C reveals typical stellate myxoma cells (arrows) surrounded by abundant extracellular matrix and a capillary (c) coursing through field. Bar=30 µm.

Family YA has 16 affected individuals (Table 1). Eleven affected individuals in family YA were 16 years old, and all but 2 had evidence of current or previous intracardiac myxomas. Extracardiac myxomas were noted to occur in the breast and skin. Endocrinologic disorders were noted to involve the adrenal and thyroid glands in affected individuals in family YA. Two individuals had primary pigmented nodular adrenocortical disease with resultant Cushing syndrome requiring adrenalectomy. One individual has been diagnosed with several thoracic and lumbar spine psammomatous melanotic schwannomas.

View this table: [in this window] [in a new window]   Table 1. Clinical Manifestations of Carney Complex in 4 Families

Clinical features of affected individuals in family YB (Table 1) were similar. Five individuals were affected by Carney complex, and preliminary descriptions of these individuals have previously been described.²³ All were adults, and 4 had been found to have intracardiac tumors. Three individuals had mucocutaneous myxomas, and the remaining 2 individuals had lesions on physical examination that were most consistent with mucocutaneous myxomas, although biopsy was not available. Two individuals also had histories of nonmyxomatous tumors (spleen, thyroid). Other than the individual who had required thyroid resection for malignancy, no other affected individual in family YB had clinical evidence of endocrinologic abnormalities. One individual (II-6) was considered to have an indeterminate diagnosis for initial linkage analyses because complete clinical data were not available.

Six individuals in family YC01 (previously referred to as CAR01⁷ ) were affected by Carney complex (Table 1). Two were affected by intracardiac myxomas, but all had mucocutaneous myxomas. Four individuals had breast myxoid tumors. Nonmyxomatous tumor diagnoses included follicular thyroid carcinoma and pituitary adenoma. All affected individuals in family YC01 had acromegaly and/or primary pigmented nodular adrenocortical disease.

Clinical features of the 8 affected family members in family YC11 (Table 1) have been described previously.²⁴ In brief, all individuals were known to exhibit typical lentiginosis. Although the eldest affected individual (I-1) was deceased and therefore was not available for further clinical evaluation, all other individuals were affected by mucocutaneous myxomas, but none had cardiac myxomas. Three individuals required surgical intervention for pilonidal sinuses. One individual was affected by a gastric carcinoma, and 2 were diagnosed with breast fibroadenomas. Elevated prolactin levels were detected in 2 women, although no source for this endocrinopathy has yet been identified.

Adults (age >16 years) in families YA, YB, YC01, and YC11 who were affected by Carney complex shared many similar clinical features. No significant differences were noted in the incidence of cutaneous abnormalities (lentiginosis/hyperpigmentation), the incidence of all myxomas (cardiac and extracardiac), or the incidence of endocrinopathy. However, by Kruskall-Wallis analysis, statistically significant differences were seen in the frequency of cardiac myxomas among the 4 families (P=0.003). By 2-tailed Fisher exact test, the incidence of cardiac myxomas was significantly lower (P=0.007) in family YC11 (0%) than in family YA (82%) or YB (80%). Similarly, Kruskall-Wallis analysis demonstrated statistically significant differences in the frequencies of extracardiac myxomas among the 4 families (P=0.02), with lowest incidence rate in family YA (45%) compared with families YB (100%), YC01 (100%), and YC11 (88%). Finally, the incidence of nonmyxomatous tumors in affected adults among the 4 families differed significantly (P=0.007). Although the 2-tailed Fisher exact test failed to identify significant differences between all pairs of families analyzed, the nonmyxomatous tumor frequency in family YA (9%) was significantly different from the frequency in family YC01 (100%).

Confirmation of Carney Complex Genetic Heterogeneity
We have previously demonstrated that family YA is not linked to the proposed Carney complex locus on chromosome 2p.¹⁶ In this investigation, we now show that family YB is also not linked to the chromosome 2p locus (Table 2), because LOD scores of greater magnitude than -2.0 were obtained over the 2p interval. Thus, we are able to confirm genetic heterogeneity of Carney complex. With similar analysis of families YC01 and YC11 (Table 2), some LOD scores were noted to be between -1.0 and 1.0, and thus, neither linkage nor nonlinkage to chromosome 2 could be definitively established for these families. Therefore, exploration of other loci to explain Carney complex in families YA, YB, YC01, and YC11 was warranted.

View this table: [in this window] [in a new window]   Table 2. Pairwise LOD Scores Between Chromosome 2p Loci and the Carney Complex

Demonstration of a Novel Carney Complex Locus on Chromosome 17q
Highly polymorphic short tandem repeat sequences dispersed throughout the genome were analyzed for linkage to the Carney complex disease gene in family YA. Because telomeric rearrangements had been reported^{13 15} to occur on the short arm of chromosome 17 in Carney complex myxomas, our initial efforts focused on this chromosome. No linkage was demonstrated with microsatellites on chromosome 17p (not shown), and analysis with random microsatellites excluded <1% of the human genome. However, linkage was then detected between microsatellite D17S807 on the long arm of chromosome 17 and the Carney complex in family YA (LOD score, 5.9; =0). Therefore, several additional polymorphic short tandem repeats (D17S944, D17S942, D17S795, and D17S789) on 17q2 were used to analyze family YA further. Linkage was confirmed between the Carney complex in family YA (Table 3) and these chromosome 17q polymorphisms; maximal 2-point LOD scores achieved demonstrated with odds of 10^5.9:1 that the gene responsible for Carney complex is located on chromosome 17q2. Moreover, multipoint analysis of Carney complex in family YA revealed a maximal multipoint LOD score at this locus of 6.16 (Figure 3).

View this table: [in this window] [in a new window]   Table 3. Pairwise LOD Scores Between Chromosome 17q Loci and the Carney Complex

View larger version (19K): [in this window] [in a new window]   Figure 3. Multipoint LOD score analysis of CAR locus in family YA. Family YA genotypes at polymorphisms D17S787, D17S944, D17S789, and D17S802 were used in multipoint LOD score analysis to assess linkage of Carney complex in family YA to chromosome 17q2. D17S944 is arbitrarily plotted at 0 cM on abscissa. Other markers in vicinity of Carney complex locus (CAR) are indicated along abscissa from centromere to telomere of chromosome 17q.

To determine whether the gene responsible for Carney complex in family YA could also be mutated to produce the various clinical features found in affected members of families YB, YC01, and YC11, linkage studies in these families were performed (Table 3). Two-point LOD scores were calculated between polymorphic loci now established to be linked to Carney complex in family YA and the disease gene in families YB, YC01, and YC11. Linkage was observed between these chromosome 17q loci and the Carney complex disease gene with odds of 10^1.5:1 in family YB, 10^1.8:1 in family YC01, and 10^2.9:1 in family YC11. HOMOG analyses of data from all 4 families (YA, YB, YC01, and YC11) revealed no evidence of genetic heterogeneity. Genetic homogeneity was evident (P<0.001), and the likelihood of linkage of Carney complex in all 4 families to the D17S789 locus on chromosome 17q2 was calculated by HOMOG to be 1.259x10^1.2:1. Thus, these data demonstrate that the gene defect that causes Carney complex in families YA, YB, YC01, and YC11 resides on the long arm of chromosome 17 (Figure 4).

View larger version (20K): [in this window] [in a new window]   Figure 4. Ideogram of chromosome 17 with Giemsa banding pattern and localization of Carney complex locus. Positive bands are black, and pericentromeric region is gray. Numbers indicate cytogenetic designations for bands. Genetic map locations of polymorphic loci analyzed from 17q are given. Bar indicates 1 cM. Linkage data suggest that the gene responsible for Carney complex (CAR) is located in the 17 cM interval between D17S807 and D17S785.

Genotyping analyses revealed that disease haplotypes of affected individuals are different in each family evaluated. Therefore, families YA, YB, YC01, and YC11 are genetically unrelated, and the Carney complex in these 4 families is not secondary to a common founder effect but rather is the result of independent mutation events.

Data from these haplotype analyses (Table 4) permitted the identification of recombination events to define the Carney complex locus (CAR) genetic interval (Figure 4). The genotypes of individual II-3 in family YB and of individual II-8 in family YC01 suggested that a recombination event had occurred between locus D17S807 and the Carney complex disease gene. Analyses also identified recombination between the D17S785 locus and the disease gene in individual II-4 (family YB), individual II-7 (family YC01), and individuals II-4 and II-8 (family YC11). Collectively, these data mapped the gene responsible for Carney complex to a 17 cM region between D17S807 and D17S785 that is localized at chromosome 17q2.

View this table: [in this window] [in a new window]   Table 4. Haplotype Analysis of Individuals in Families Affected by Carney Complex

Two known tumor suppressor genes map to chromosome 17q: BRCA1 and neurofibromin (NF1). However, their known genetic map location^{3 22} outside of the interval between D17S807 and D17S785 excludes them as candidate genes and positions them centromeric to the CAR locus. Moreover, exclusion of NF1 as a Carney complex candidate gene is confirmed by linkage analysis performed in family YA, with a microsatellite (NF1CA) contained within the neurofibromin gene (LOD score, -2.8 at =0.05).

	Discussion

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Our analyses demonstrate that a gene defect located on the long arm of chromosome 17 causes autosomal dominant syndrome Carney complex. In 3 of the families studied, this chromosome 17q2 gene defect is associated with intracardiac myxoma formation. Moreover, although Carney complex in these families is associated with different frequencies of cardiac myxoma, extracardiac myxoma, and nonmyxomatous tumor formation, genetic linkage analysis demonstrates that mutations at chromosome 17q2 can produce the range of diverse clinical features observed in Carney complex. We hypothesize that different mutations in the as yet unidentified CAR disease gene may have different pathological consequences and thus may account for the variable phenotypes among families affected by Carney complex. Tissue/organ specificity in other multiple neoplasia syndromes has been shown to relate to the intragenic location of the mutation, eg, mutations²⁵ in the RET proto-oncogene in multiple endocrine neoplasia type II.

In addition to the chromosome 17q locus reported here, Stratakis and colleagues⁷ proposed that a gene defect at chromosome 2p may cause Carney complex. The possibility of still more Carney complex loci still exists, and the relative contributions of mutations at the 17q2 and the 2p loci remain to be determined. Although analyses of previously reported families⁷ suggested the existence of the chromosome 2p locus, the limited size of the families available in that study precluded assessment of linkage to chromosome 2p on an individual family basis. Therefore, it is unknown how many of these families actually transmit Carney complex as a result of a chromosome 2p gene defect. It is noteworthy that YC01 was one of the families included in the prior investigation⁷ of the putative chromosome 2p locus, but yet it is now shown to be affected by Carney complex on the basis of the chromosome 17q2 gene defect. Moreover, LOD scores for each of the 4 families (YA, YB, YC01, and YC11) reported here demonstrate that in each case, Carney complex is clearly secondary to genetic abnormality at the chromosome 17q2 locus. Thus, we conclude that the CAR locus on chromosome 17q2 is a major genetic cause of familial myxomas and the Carney complex.

Positional cloning studies are currently under way to identify the CAR disease gene. Genes encoding for a wide variety of protein classes may cause Carney complex, and some that have been mapped^{3 22} to chromosome 17q2 include growth hormone, platelet–endothelial cell adhesion molecule I, intercellular adhesion molecule 2, TBX2 transcription factor, and several enzymes for DNA and protein structural modification. Oncogenes and tumor suppressor genes are likely candidates, and several have also been mapped^{3 22} to chromosome 17. Notably, the genetic mapping studies reported here already exclude from the CAR locus, and therefore as candidate Carney complex disease genes, neurofibromin and BRCA1, the chromosome 17q tumor suppressor genes that cause neurofibromatosis and breast cancer, respectively. Refinement of the CAR locus genetic map will facilitate analysis of other candidate genes, and such refinement is feasible given the presence of recombination events in several individuals between the CAR disease gene and the current short tandem repeats (D17S807 and D17S805) flanking the CAR locus.

Investigation of the Carney complex disease gene on chromosome 17q2 will enhance our diagnosis and management of cardiac and extracardiac myxomas. Moreover, in both heritable and acquired cardiac disorders, such as cardiomyopathy and ischemic heart disease, the inability of the terminally differentiated myocyte to proliferate thwarts definitive therapeutics. Cardiac myxomas are thought to arise from rests of subendocardial primitive mesenchymal cells with the capacity to proliferate and to differentiate into multiple cell types.^{26 27 28 29} Identification of the Carney complex disease gene will elucidate basic mechanisms that regulate cardiac cell growth and will ultimately suggest modalities to promote cardiac remodeling.

	Acknowledgments

 
Dr Basson was supported by NIH grant HL-03468. We are grateful to family members and their physicians for their participation in this study. We thank Dr Peter Okin for assistance with statistical analyses and acknowledge technical assistance by Mohammed Miri and Barbara McDonough and computing services sponsored by the UK Human Genome Mapping Project Resource Center. We are indebted to Drs Christine Seidman, Jonathan Seidman, and Bruce Lerman for their advice and consultation.

Received June 8, 1998; revision received August 11, 1998; accepted August 21, 1998.

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29. Burke AP, Virmani R. Cardiac myxomas: a clinicopathologic study. Am J Clin Pathol. 1993;100:671–680.Intracardiac myxomas are significant causes of cardiovascular morbidity and mortality. In the autosomal dominant syndrome Carney complex, intracardiac myxomas arise in the setting of lentiginosis, extracardiac myxomas, and nonmyxomatous tumors. Genetic linkage analysis of 4 kindreds affected by Carney complex demonstrates that a major locus on the long arm of chromosome 17 contains the Carney complex disease gene. Future identification and analysis of this gene will facilitate management of cardiac myxomas and will improve understanding of cardiac cell growth and differentiation.[Medline] [Order article via Infotrieve]
    

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