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AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Craig T Basson, MD, PhD, Director, Cardiovascular Research, Professor, Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University
Craig T Basson is a member of the following medical societies: American College of Cardiology and American Heart Association
Coauthor(s):
Luke K Kim, MD, Fellow, Department of Internal Medicine, Division of Cardiology, New York Presbyterian Hospital, Weill Cornell Medical Center;
Carl J Vaughan, MD, MRCPI, Adjunct Assistant Professor, Department of Internal Medicine, Division of Cardiology, Weill Medical College of Cornell University; Consulting Cardiologist, Mercy University Hospital, Ireland
Editors: Justin D Pearlman, MD, PhD, ME, MA, Director of Dartmouth Advanced Imaging Center, Professor of Medicine, Professor of Radiology, Adjunct Professor, Thayer Bioengineering and Computer Science, Dartmouth-Hitchcock Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Frank M Sheridan, MD, Cardiology, Providence Everett Medical Center; Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital; Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice
Author and Editor Disclosure
Synonyms and related keywords:
Carney complex, lentigines, atrial myxomas, mucocutaneous myxomas, blue nevi, LAMB syndrome, nevi, atrial myxoma, myxoid neurofibroma, ephelides, NAME syndrome, rhabdomyoma, myxoma, cardiac myxomas, cardiac tumor, heart tumor, cutaneous myxoma, spotty pigmentation of the skin, endocrinopathy, endocrine tumor, nonendocrine tumor
Background
Primary tumors of the heart are rare in all age groups. However, they are still important to consider in differential diagnoses of valvular disease, congestive heart failure, and arrhythmia. Although myxomas are the most common cardiac tumors in adults, they are relatively rare in infants and children. While myxomas are usually sporadic, several autosomal dominant familial conditions that combine lentiginosis and cardiac myxomas have been described. Previously termed syndromes, such as LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi) syndrome and NAME (nevi, atrial myxoma, myxoid neurofibroma, and ephelides) syndrome, now are grouped under the broader category of Carney complex, an autosomal dominant syndrome that accounts for 7% of all cardiac myxomas. Carney complex findings include cardiac myxomas, cutaneous myxomas, spotty pigmentation of the skin, endocrinopathy, and both endocrine and nonendocrine tumors.
Pathophysiology
Carney complex is inherited as an autosomal dominant trait with variable penetrance. Cardiac myxomas are thought to arise from primitive subendocardial mesenchymal multipotent precursor cells. However, these cells have not been specifically identified yet. The systemic symptoms (eg, fever, arthralgia, elevated sedimentation rate, lupuslike rashes) that accompany some myxomas may be due to the production of the proinflammatory cytokine interleukin-6 by the myxoma.
Cardiac myxomas occurring as part of Carney complex may recur at sites distant from the resection. These tumors may grow in diameter by as much as 1.8 cm/y. Initial genetic analyses suggested that a gene defect may map to arm 2p. More recent linkage analysis in several families affected by the Carney complex has also mapped a disease locus to band 17q2. Mutations in the PRKAR1A gene encoding the R1a regulatory subunit of protein kinase A have been shown to cause Carney complex.
In an analysis of 51 unrelated patients with Carney complex, 65% of the patients were shown to have mutations in the PRKAR1A gene. PRKAR1A may act as a tumor suppressor gene by regulating PKA activity, which in turn can suppress or stimulate the cell growth and differentiation. Furthermore, a variant form of Carney complex associated with distal arthrogryposis has been recently identified. Analysis of a large family with cardiac myxomas and other typical findings of Carney complex, as well as trismus-pseudocamptodactyly, revealed a missense mutation in the MYH8 gene that encodes perinatal myosin heavy chain. Further studies of the families with similar phenotypes revealed that this missense mutation was a common founder mutation. These findings suggest a role of protein kinase A and perinatal myosin heavy chain in cardiac tumorigenesis.
Cardiac involvement
Cardiac myxomas in the Carney complex often are multiple, can occur in any cardiac chamber, and have a predilection to recur at distant intracardiac and extracardiac sites after initial surgical resection. Although they usually are benign, cardiac myxomas are associated with significant cardiac morbidity due to stroke from tumor embolization and heart failure from intracardiac valvular obstruction.
Extracardiac involvement
In addition to cardiac myxomas, individuals with Carney complex exhibit spotty pigmentation of the skin, particularly on the face, trunk, lips, and sclera. Pigmentation also may affect the mucosal surfaces of the oral or genital regions. Extracardiac myxomas may also occur in the breast, testis, thyroid, brain, or adrenal gland. Nonmyxomatous tumors, such as pituitary adenoma, psammomatous melanotic schwannoma, and Sertoli cell tumors of the testis, also may be observed. Impaired fertility has been observed in males with Carney complex. Patients can also exhibit a spectrum of endocrine overactivity, including Cushing syndrome secondary to primary pigmented nodular adrenocortical hyperplasia. Thyroid and pituitary dysfunction may also be observed.
Frequency
United States
Cardiac myxomas are the most common primary cardiac tumor in the general population and occur with a frequency of 7 cases per 10,000 individuals. Myxomas occurring as part of Carney complex account for 7% of all cardiac myxomas.
Mortality/Morbidity
Morbidity and mortality from stroke and heart failure arise from cardiac involvement, and individuals with recurrent intracardiac myxomas may require additional cardiac surgery to resect such myxomas. Other extracardiac tumors may produce morbidity by local extension. Endocrine dysfunction also often is symptomatic but may be subclinical.
Sex
Sporadic myxomas occur with a greater frequency among middle-aged women. Myxomas that occur as part of the Carney complex affect both sexes with equal frequency.
Age
Although sporadic myxomas generally affect middle-aged adults (incidence higher in females than in males), myxomas arising in the setting of Carney complex may arise in persons of any age and either sex.
History
- Patients may have a family history of cardiac myxomas and/or spotty pigmentation.
- Patients may present with symptoms of congestive heart failure, transient ischemic attack, or stroke. Additionally, patients may present with clinical signs of Cushing syndrome or be referred during the evaluation of hyperpigmentation or the investigation of a cutaneous tumor (myxoma).
Physical
- Skin
- Pigmentation, including blue nevi of face, lips, sclera, trunk, or genital mucosa
- Cutaneous myxomas
- Generalized hyperpigmentation, obesity, striae, or cushingoid appearance
- Masses - Thyroid, breast, or testis mass/enlargement (secondary to myxoma)
- Neurologic - Neurologic deficit (secondary to tumor emboli)
- Cardiac
- Accentuated first heart sound and opening snap
- Diastolic apical rumbling murmur (mimicking mitral stenosis)
- Holosystolic murmur best heard at apex and radiating to axilla (mitral regurgitation)
- Tumor "plop"
- Systemic
- Fever
- Clinical signs of anemia
- Weight loss
- Arthralgia
Causes
Carney complex is mostly due to mutations in the gene PRKAR1A encoding the R1a regulatory subunit of protein kinase A. Apparently, about 65% of Carney complex cases are due to mutations in the PRKAR1A gene. In a variant form of Carney complex associated with distal arthrogryposis, a mutation in the gene MYH8 encoding perinatal myosin heavy chain has been described to play a role.
Adrenal Adenoma
Adrenal Carcinoma
Breast Cancer
Cardiac Neoplasms, Primary
Rhabdomyomas
Other Problems to be Considered
Intracardiac thrombus
Metastatic neoplasm to the heart
Breast adenoma/carcinoma
Testicular adenoma/carcinoma
Lab Studies
- Complete blood count
- Glucose/electrolytes
- Erythrocyte sedimentation rate
- Thyroxine/thyroid stimulating hormone
- Adrenocorticotropic hormone
- Growth hormone
Imaging Studies
- Echocardiography is the investigation of choice to define cardiac involvement in the Carney complex.
- Occasionally, evidence of myxomas may be in more than one cavity.
- Echocardiography also defines the presence of associated valvular involvement.
- Left atrial myxomas may prolapse through the mitral valve orifice, creating functional mitral stenosis, or may produce progressive valve leaflet damage, leading to mitral insufficiency.
- Echocardiography is useful for follow-up of patients after surgical removal of the tumor to detect recurrence of myxomas.
- Transesophageal echocardiography reaches a sensitivity of 100%. It is useful to define the precise anatomical relationships of small tumors or to detect the presence of multiple cardiac myxomas.
- Body computed tomography scan or MRI may be appropriate to exclude extracardiac thoracic, abdominal, or paraspinal tumors.
- Testicular ultrasonography may be used to exclude testicular tumors.
Other Tests
- ECG: No specific electrocardiographic features of the Carney complex exist. The ECG findings may reflect the presence of left atrial enlargement or pulmonary hypertension.
- Genetic evaluation: Patients thought to have Carney complex should be evaluated by a cardiologist/geneticist with experience in the management of inherited cardiovascular disease.
- Referral to an endocrinologist may be appropriate if endocrinological problems are suggested by symptoms or laboratory studies
- The initial step in the workup of these patients is the ascertainment of a detailed family history to establish if the patient's disease represents a new mutation or is part of a familial syndrome. Recent studies have shown that linkage analysis of extended families can provide diagnostic information for individuals with equivocal findings; however, these techniques remain research tools that generally are not available clinically. Furthermore, mutational analysis of the PRKAR1A gene may be a useful adjunctive diagnostic test. In the presence of a family history of arthrogryposis, testing for mutation of MYH8 may be appropriate as well. However, such DNA-based testing currently remains the province of research laboratories (see GeneTests).
Procedures
- Cardiac catheterization may be indicated on an individual basis prior to surgical resection if coexisting coronary artery disease is a possibility.
Histologic Findings
Myxomas have a typical histologic appearance of small stellate cells against a bland proteoglycan background.
Medical Care
- Evaluation usually can be performed in an outpatient setting.
- No specific drug is useful in the management of myxomas. Anticoagulation is not indicated in patients with myxomas and does not reduce the risk of emboli. Emboli arising from intracardiac myxomas are due to fragments of the tumor that break off and embolize.
- Medical treatment of endocrine overactivity may be required.
Surgical Care
- Mass lesions usually require biopsy/resection to provide a histopathologic diagnosis.
- Surgery is necessary to resect intracardiac myxomas and to prevent embolic stroke or valvular obstruction.
- Recognize that even in the presence of resections with adequate surgical margins, intracardiac myxomas may recur at sites distant from the initial operative site. These recurrences do not reflect a failure of the initial surgical treatment but, rather, a genetic predisposition to recurrent tumor formation.
- Although recurrence of cardiac myxomas (and similarly extracardiac myxomas) is a feature of Carney complex, it is not a feature of typical nonsyndromic sporadic atrial myxomas.
- Resect extracardiac myxomas and nonmyxomatous benign lesions if they produce symptoms by local extension of the space-occupying lesion.
- Rare malignant tumors require resection and may require other adjunctive therapy and referral to an oncologist.
Consultations
- Cardiologist
- Geneticist
- Cardiothoracic surgeon
- Endocrinologist
- Oncologist
Diet
No special diet is required.
Activity
In the absence of heart failure or persistent cardiac sequelae, no activity limitation is required.
No medications are effective in treating patients with Carney complex.
Further Inpatient Care
- Admit the patient for testing and surgical intervention.
Further Outpatient Care
- Monitor patients annually with echocardiography to detect the occurrence of new cardiac myxomas.
- Annual history and physical examination also is required to detect the development of extracardiac myxomas, other tumors, and signs and symptoms of endocrine dysfunction.
In/Out Patient Meds
- No specific medications are indicated for this condition.
- Antibiotic prophylaxis is required if an associated valvular insufficiency exists.
- Medical management of endocrine dysfunction may be appropriate.
Transfer
- Transfer of the patient may be required for further diagnostic evaluation and surgical intervention.
Deterrence/Prevention
- No particular deterrent is available.
Complications
- Recurrent myxoma growth
- Congestive heart failure
- Stroke
- Peripheral embolization including coronary, retinal, renal, celiac, and femoral and pulmonary arteries
- Arrhythmia
- Pulmonary hypertension
Prognosis
- Prognosis generally is good and depends on the proclivity of cardiac myxomas to recur. The risks associated with open-heart surgery increase with each successive surgery.
Patient Education
- The family should be aware that this is an autosomal dominant disorder with a 50% chance that the offspring of an affected individual will have the disorder.
Medical/Legal Pitfalls
- Failure to perform echocardiography to rule out an intracardiac source of emboli in patients presenting with stroke or transient ischemic attack (particularly at a young age)
- Failure to recognize the potential for myxoma formation in family members of an individual affected by Carney complex
- Failure to recognize the potential for recurrent myxoma formation in individuals with prior myxoma resection
- Failure to recognize rare malignant tumors
- Failure to provide appropriate genetic counseling and properly inform the patient of the heritable nature of the disorder
- Failure to recognize endocrine dysfunction in a patient with Carney complex
| Media file 1:
Transthoracic echocardiogram of a left atrial myxoma in an individual with Carney complex. A 42-year-old woman with a history of facial spotty pigmentation and cutaneous myxomas presented for annual surveillance echocardiography. Findings from previous echocardiograms were normal. Echocardiography now revealed a 1.0 X 1.3 cm mass (arrow) in the left atrium (LA) arising from the interatrial septum above the mitral valve. No prolapse was seen into the left ventricle (LV). Histopathology upon surgical excision demonstrated that the lesion was a myxoma. |
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- Basson CT, MacRae CA, Korf B, Merliss A. Genetic heterogeneity of familial atrial myxoma syndromes (Carney complex). Am J Cardiol. Apr 1 1997;79(7):994-5. [Medline].
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- Casey M, Mah C, Merliss AD, et al. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation. Dec 8 1998;98(23):2560-6. [Medline].
- Casey M, Vaughan CJ, He J, et al. Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest. Sep 2000;106(5):R31-8. [Medline].
- Goldstein MM, Casey M, Carney JA, Basson CT. Molecular genetic diagnosis of the familial myxoma syndrome (Carney complex). Am J Med Genet. Sep 3 1999;86(1):62-5. [Medline].
- Kanda T, Umeyama S, Sasaki A, et al. Interleukin-6 and cardiac myxoma. Am J Cardiol. Nov 1 1994;74(9):965-7. [Medline].
- Reynen K. Cardiac myxomas. N Engl J Med. Dec 14 1995;333(24):1610-7. [Medline].
- Stratakis CA, Carney JA, Lin JP, et al. 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. Feb 1 1996;97(3):699-705. [Medline].
- Veugelers M, Wilkes D, Burton K, et al. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci U S A. Sep 28 2004;101(39):14222-7.
- Veugelers M, Bressan M, McDermott DA, et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med. Jul 29 2004;351(5):460-9.
Carney Complex excerpt Article Last Updated: May 26, 2006
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