Carney Complex

Updated: May 05, 2016
  • Author: Craig T Basson, MD, PhD; Chief Editor: Richard A Lange, MD, MBA  more...
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Overview

Practice Essentials

Carney complex is an autosomal dominant syndrome associated with spotty pigmentation of the skin, endocrinopathy, and endocrine and nonendocrine tumors, including the following:

  • Myxomas of the skin, heart, breast, and other sites
  • Primary pigmented nodular adrenocortical disease
  • Psammomatous melanotic schwannomas
  • Growth hormone–producing pituitary adenomas
  • Possibly, other benign and malignant neoplasms and conditions, including tumors of the thyroid gland and ductal adenomas of the breast, as well as acromegaly due to somatomammotroph hyperplasia and adenomas not dependent on growth hormone–releasing hormone

Signs and symptoms

Skin:

  • Pigmentation, including blue nevi of the face, lips, sclera, trunk, or genital mucosa
  • Cutaneous myxomas
  • Generalized hyperpigmentation, obesity, striae, or cushingoid appearance

Masses:

  • Cutaneous
  • Thyroid
  • Breast
  • Testis mass/enlargement (secondary to myxoma)

Neurologic:

Patients may exhibit neurologic deficits secondary to tumor emboli.

Cardiac:

Upon physical examination, an accentuated first heart sound can be appreciated in patients with cardiac myxomas. Other symptoms include the following:

  • 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

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies used in the diagnosis of Carney complex include the following:

  • Complete blood count (CBC)
  • Glucose/electrolytes
  • Erythrocyte sedimentation rate
  • Thyroxine/thyroid-stimulating hormone
  • Adrenocorticotropic hormone
  • Growth hormone
  • Twenty-four–hour urinary cortisol excretion test and dexamethasone stimulation test: To evaluate for primary pigmented nodular adrenocortical disease (PPNAD) as part of Carney complex [1]

Echocardiography is the investigation of choice to define cardiac involvement in the Carney complex (see the image below). Occasionally, evidence of myxomas in more than 1 cavity is found. [2]

Transthoracic echocardiogram of a left atrial myxo Transthoracic echocardiogram of a left atrial myxoma in an individual with Carney complex. A 42-year-old woman with a history of spotty pigmentation on the face 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.

Mass lesions in Carney complex usually require biopsy/resection to provide a histopathologic diagnosis.

See Workup for more detail.

Management

In Carney complex, medical care is restricted to the treatment of endocrine overactivity, which is commonly present. No specific drug is useful in the management of myxomas.

Surgery is necessary to resect intracardiac myxomas and to prevent embolic stroke or valvular obstruction. [3]

Extracardiac myxomas and nonmyxomatous benign lesions should be resected if they produce symptoms via local extension. Large or symptomatic skin myxomas or other benign lesions also can be excised.

Rare malignant tumors require resection, as well as, possibly, adjunctive therapy and referral to an oncologist.

See Treatment for more detail.

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Background

Carney complex is an autosomal dominant syndrome associated with spotty pigmentation of the skin, endocrinopathy, and endocrine and nonendocrine tumors. (See Pathophysiology, Etiology, and Clinical Presentation.)

These tumors include myxomas of the skin, heart, breast, and other sites; primary pigmented nodular adrenocortical disease, psammomatous melanotic schwannomas; growth hormone–producing pituitary adenomas; testicular Sertoli-cell tumors; and, possibly, other benign and malignant neoplasms and conditions, including tumors of the thyroid gland and ductal adenomas of the breast, as well as acromegaly due to somatomammotroph hyperplasia and adenomas not dependent on growth hormone–releasing hormone (see the image below). (See Clinical Presentation and Workup.)

Transthoracic echocardiogram of a left atrial myxo Transthoracic echocardiogram of a left atrial myxoma in an individual with Carney complex. A 42-year-old woman with a history of spotty pigmentation on the face 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.

Carney complex accounts for 7% of all cardiac myxomas. Although primary tumors of the heart are rare in all age groups, 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. (See Epidemiology and DDx.)

While myxomas are usually sporadic, several familial, autosomal dominant 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. (See Workup.)

Although the existence of the complex as an unrecognized inherited syndrome was first suggested in 1985, combinations of several components of the syndrome and their familial occurrence were reported earlier. [4] The Carney complex gene 1 was later identified as the regulatory subunit 1A of protein kinase A (PRKAR1A) located at 17q22-24. [5, 6] An inactivating heterozygous germ-line mutation of PRKAR1A has been documented in about two thirds of individuals with Carney complex. (See Pathophysiology and Etiology.)

Endocrine overactivity is one of the characteristics of this syndrome. [7] In fact, corticotropin hormone–independent Cushing syndrome due to primary pigmented nodular adrenocortical disease is an important characteristic of Carney complex. (See Workup and Treatment.)

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.

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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.

Mutations in the PRKAR1A gene encoding the R1α regulatory subunit of protein kinase A have been shown to cause Carney complex. [8, 5, 6, 9] In an analysis of 51 unrelated patients with Carney complex, 65% were shown to have mutations in the PRKAR1A gene. PRKAR1A may act as a tumor suppressor gene by regulating protein kinase A activity, which in turn can suppress or stimulate cell growth and differentiation. [10]

Carney complex genes are associated with genomic instability; cell lines established from Carney complex tumors accumulate chromosomal changes, including telomeric associations and dicentric chromosomes.

A variant form of Carney complex associated with distal arthrogryposis has been 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. [11] Further studies of families with similar phenotypes revealed that this missense mutation was a common founder mutation. These findings suggest a role for 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. 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. [12, 13] Subsequent linkage analysis in several families affected by the Carney complex, including some of the families initially proposed to be linked to chromosome 2, mapped a disease locus to band 17q2. [14]

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, and adrenal gland. (See the image below.) Nonmyxomatous tumors, such as pituitary adenomas, psammomatous melanotic schwannomas, and Sertoli cell tumors of the testis, also may be observed. Impaired fertility has been observed in males with Carney complex.

A pedunculated, flesh-colored cutaneous myxoma tha A pedunculated, flesh-colored cutaneous myxoma that is 1.5 cm in diameter on trunk. Courtesy of Dermatology, NYU, and Ann Stoecker, medical photographer.

Patients can also exhibit a spectrum of endocrine overactivity, including Cushing syndrome secondary to primary pigmented nodular adrenocortical hyperplasia. Thyroid and pituitary dysfunction may be observed as well. [15, 16]

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Etiology

Because family members with the same mutation can show distinct phenotypes, Carney complex may be viewed as a multifactorial disorder arising from various genetic and environmental factors. [17]

In a study of families with Carney complex, Casey et al identified mutations in the PRKAR1A gene. [10] In addition, Kirschner and colleagues detected a loss of heterozygosity in the vicinity of the PRKAR1A gene. [18] This gene encodes the protein kinase A regulatory subunit 1-alpha (R1α), on chromosome 17q. The investigators subsequently identified 3 unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analyses of PRKAR1A activity have inconsistently demonstrated altered PKA activity in Carney complex tumors compared with non–Carney complex tumors.

Kirschner et al [19] also screened the mutations present in 54 Carney complex kindreds. In 14 of the mutations that were mapped to the PRKAR1A locus, they found a premature stop codon; one altered the initiator ATG codon. The messenger ribonucleic acids (mRNAs) resulting from this mutation were unstable, and they rapidly decayed. In addition, the PRKAR1A products were absent in the affected cells. Casey et al and Veugelers et al demonstrated that in fact loss of heterozygosity and nonsense-mediated decay occurred during the pathogenesis of some Carney complex cases but not all. [10, 11]

The role of PDE11A as a possible gene modifier of the phenotype was evaluated in a series of 150 patients with Carney complex, with the high frequency of PDE11A variants identified. It remains unknown if this gene is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation. [20]

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Epidemiology

Occurrence in the United States

Cardiac myxomas are the most common primary cardiac tumor in the general population, occurring with a frequency of 7 cases per 10,000 individuals. Myxomas occurring as part of Carney complex account for 7% of all cardiac myxomas.

International occurrence

More than 150 patients have been identified as having Carney complex since its recognition in 1985. Cases in persons with only limited involvement may not be reported. The syndrome is distributed worldwide.

Race-, sex-, and age-related demographics

Most patients who are affected with Carney complex are white, although the disease has been described in blacks and other racial groups.

The mean patient age at diagnosis of Carney complex is 10-20 years, although the condition may arise in persons of any age and either sex. Sporadic myxomas generally affect middle-aged adults, particularly females.

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Prognosis

Complications associated with Carney complex include the following:

  • Recurrent myxoma growth: Myxomas recur in approximately 12-22% of familial cases and in about 1-2% of sporadic cases; individuals with recurrent cardiac myxomas may require additional cardiac surgery to resect these tumors; the prognosis in Carney complex, which is generally good, depends on the proclivity of cardiac myxomas to recur
  • Congestive heart failure
  • Stroke: Cerebellar ischemic stroke can result from emboli from an atrial myxoma; ischemic stroke has been described as a presentation of recurrent cardiac myxoma in Carney complex [21]
  • Peripheral embolization, including in the coronary, retinal, renal, celiac, femoral, and pulmonary arteries
  • Pulmonary hypertension

Intracardiac myxomas may create ball-valve obstructions that cause unexpected syncopal attacks, cardiac insufficiency, and sudden death in apparently healthy young children and adults.

Women with Carney complex may be at a high risk for recurrent atrial myxomas that lead to multiple strokes. [22] Early identification of a female patient with Carney complex may facilitate stroke prevention.

Extracardiac tumors may produce morbidity by local extension. Endocrine dysfunction also often is symptomatic, but it may be subclinical.

The psammomatous melanotic schwannomas are typically benign; they metastasize, however, in as many as 10% of cases.

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Mortality

Cardiac myxomas account for a mortality rate of 25% in patients with this syndrome. Cardiac myxomas are a silent killer, causing major disability with its embolic capacity and even sudden death.

Although the mortality rate is less than 2% during excisions of primary cardiac tumors, the risks associated with open-heart surgery increase with each successive operation.

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