eMedicine Specialties > Cardiology > Cancer and the Heart

Carney Complex

Author: Craig T Basson, MD, PhD, FAHA, FACC, Director, Cardiovascular Research, The New York Presbyterian Hospital; Professor, Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University
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
Contributor Information and Disclosures

Updated: Mar 18, 2009

Introduction

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/yr. Initial genetic analyses suggested that a gene defect may map to arm 2p.^1,2 More recent linkage analysis in several families affected by the Carney complex has also mapped a disease locus to band 17q2.³ Mutations in the PRKAR1A gene encoding the R1 α regulatory subunit of protein kinase A have been shown to cause Carney complex.⁴

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.⁵ 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.

Clinical

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.

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