What is Carney Complex: Causes, Symptoms, Treatment, Prognosis, Pathophysiology

Carney complex is a rare hereditary disorder described by an increased risk of developing several types of noncancerous or cancerous tumors called myxoma in the heart and other parts of the body. Myxomas may also be seen on the skin and in different internal organs. Affected individuals may also develop tumors in endocrine glands including the thyroid, adrenal gland, ovaries, testes, and even in the pituitary gland. Some people also develop a rare benign or malignant tumor in the Schwann cells of nervous tissue called psammomatous melanotic schwannoma. Generally, people with Carney Complex experience unusual skin color or pigmentation in the form of brown spots called lentigines that appear on various parts of the body mainly around the eyes, lips, or genitalia.

Carney complex is a rare genetic, i.e., autosomal dominant condition characterized by spotty skin, hyperpigmentation or lentiginosis; myxomas (mostly benign) mainly in skin and heart, noncancerous connective tissue tumors; nerve sheath tumors or schwannomas and cancerous or benign tumors in the different endocrine glands of the body resulting in endocrine over activity. Carney complex also called multiple neoplasia syndromes and is distinct from Carney’s Triad disease.

Carney complex is also denoted by the following terms according to the symptoms manifested.

• LAMB syndrome, i.e. Lentigines, Atrial Myxoma, Blue nevi.
• NAME syndrome i.e., Nevi, Atrial Myxoma or Myxoid neurofibromas, Ephelides.

Signs and symptoms of carney complex commonly start around the 20 years or sometimes in the teenage.

• Multiple cardiac myxomas are seen in two-thirds of patients.
• Spotty skin pigmentation with the appearance of blue nevi or lentigines especially on the face, eyelids, inner and outer corners of the eyes, trunk, conjunctiva, lips, around the genital area, and sclera.

Multiple other features including extracardiac tumors are seen in the following.

• Breast
• Oral mucosa
• Skin
• Testis
• Thyroid
• Pancreas
• Testicular tumors mainly in the Sertoli cells
• Pituitary adenoma
• Impaired fertility is seen in males
• Nervous tissue resulting in psammomatous melanotic schwannoma
• Adrenal gland leading to primary pigmented nodular adrenocortical disease or PPNAD.

Carney Complex, although a worldwide ailment, affects the general population with a frequency of 7 cases per 10,000 individuals. Most patients who are affected with this condition belong to a white race, but the tendency of the occurrence of this disease is most common in blacks or other racial groups. The mean age of the patient diagnosed with Carney complex is about 10-20 years, and the disorder is seen in individuals of either sex and of any age. Sporadic myxomas usually affect middle-aged adults, especially females. This rare disorder has been identified in about fewer than 750 individuals till now.

Cardiac Myxomas recur in approximately 1-2% of sporadic cases and about 12-22% of familial cases and may require additional cardiac surgery to eradicate these tumors. The prognosis of Carney complex is usually good depending on the tendency of cardiac myxomas to recur.

Intracardiac myxomas may result in ball-valve obstructions that result in cardiac insufficiency, unexpected syncopal attacks, and sudden death in mostly healthy adults or young children.

Carney complex in women may create a high risk for recurring atrial myxomas that may result in multiple strokes. Early identification of Carney complex may lead to stroke prevention in female patients. Extra cardiac tumors may cause morbidity due to a local extension. Endocrine dysfunction is also seen as often symptomatic, but sometimes it may be subclinical.

The psammomatous melanotic schwannomas are usually benign and in 10% of cases, it becomes malignant. Although people with Carney complex have a high risk of cancer, most tumors are generally benign.

Mutations in the tumor-suppressor gene PRKAR1A gene on chromosome 17q23-q24 encoding the R1α regulatory subunit of protein kinase A (PKA) have been found to cause Carney complex. Inactivated germline mutations of this gene are seen in 70% of people with Carney complex. Researchers have shown that more than 60% of people with Carney complex have a mutation in the PRKAR1A gene and about 6% of people may have deletions in this gene. Most of these mutations are distinct as they are identified only in single families.

Basically, the molecular pathogenesis of Carney complex occurs due to a variety of genetic changes at chromosome 2p16. Both types of Carney complex are usually autosomal dominant. Despite dissimilar genetics, there is actually no phenotypic difference between PRKAR1A gene and chromosome 2p16 mutations. Some myxomas may occur due to the generation of the pro-inflammatory cytokine interleukin-6 by the myxoma. Findings suggest a role of PKA and perinatal myosin heavy chain in cardiac tumorigenesis.

Carney complex-related genes are associated with genomic instability and also the cell lines from Carney complex tumors may lead to various chromosomal changes, such as dicentric chromosomes and telomeric associations.

People without a mutation in PRKAR1A typically show mild symptoms mostly in the later stage of life. The gene mutation in such individual are considered sporadic, i.e., it occurs by chance.

• Prolonged family history of acromegaly, Cushing’s syndrome, or sudden death.
• Family history of cancer, particularly in pancreas, colon, testis, and ovary.
• Familial non-medullary thyroid cancer or FNMTC is most frequently associated with Carney Complex.

Complications associated with Carney Complex are mentioned in the following.

• Cardiac myxomas may lead to Arthralgia, fever, shortness of breath, joint pain, tumor plop, mitral regurgitation, signs of anemia, and diastolic rumble.
• Pulmonary hypertension
• Cerebellar ischemic stroke resulting from emboli of an atrial myxoma; ischemic stroke described as a presentation of recurrent cardiac myxoma.
• Peripheral embolization, such as in the retinal, coronary, celiac, renal, pulmonary, and femoral arteries.
• Congestive heart failure.
• Endocrine tumors may be characterized as disorders like over activity of the gland. The most common one is an ACTH-independent Cushing’s syndrome caused by PPNAD. Cushing’s syndrome features a combination of weight gain in the upper body and face, high blood pressure, diabetes, easy bruising due to the overproduction of the hormone cortisol, slowed growth in children, fatigue, fragile skin, and other health problems.
• A pituitary adenoma commonly result in the hyperactivity of growth hormone which may result in acromegaly, a disorder characterized by arthritis, enlarged hands and feet, and rough facial skin.

Genetic testing for mutations in the PRKAR1A gene is now available for people suspected to have Carney complex.

Other physical symptoms that are mentioned in the following have been seen in people with Carney Complex are:

• Significantly dark pigmented typical pattern or spots
• Blue nevus confirmed by biopsy
• Unusual light brown spots or any birthmarks on skin.
• Abnormal blood test results of high insulin-like growth factor 1 or IGF-I levels, urinary cortisol levels, blood glucose, glucose tolerance test or GTT, salivary circadian variations of cortisol, and paradoxical growth hormone or GH response to thyrotropin-releasing hormone or TRH testing when there is no clinical acromegaly. Also, test for high levels of prolactin hormone in the plasma.
• Polyps or benign growths in the colon, generally along with acromegaly.
• A noncancerous single thyroid nodule in a younger age or multiple thyroid nodules in an older age.

Suggested screening guidelines include:

• Annual echocardiogram at the beginning of infancy.
• Regular skin check-up by a health care professional or self-examinations.

Imaging investigations should include:

• Adrenal CT-scan (in cases of Cushing’s syndrome)
• Thyroid ultrasound (in cases of abnormal palpation)
• Testicular or ovarian ultrasound
• Pituitary and spine MRI when the clinical symptoms suggest schwannoma
• Complete blood count or CBC
• Erythrocyte sedimentation rate
• 24-hour dexamethasone stimulation test to evaluate PPNAD as a measure to detect Carney Complex.

Cardiac myxomas require surgical removal but can recur within the heart and also far away from the site of the initial tumor. Surgery is necessary to operate intracardiac myxomas and in order to prevent valvular obstruction or embolic stroke. Antibiotic prophylaxis is necessary if there is an existence of valvular insufficiency.

Treatment for the other manifestations may include surgery, or medical procedure depending on the size and location of the tumor together with the existence of clinical symptoms of hormonal excess, tumor mass, or, suspecting of malignancy. Malignancy in Carney Complex is usually observed in thyroid nodes and melanotic schwannoma. Bilateral adrenalectomy is the most popular treatment for Cushing’s syndrome caused by PPNAD.

In Carney Complex, medical care is restricted to the treatment of endocrine over activity. No specific drug is useful for the treatment of myxomas.

The mutation involved in Carney Complex occurs haphazardly for no apparent reason or can be inherited as an autosomal dominant trait. The specificity of symptoms and severity related to Carney Complex usually vary greatly from one individual to another. In very rare cases, manifestations of various syndrome overlap with those observed in Carney Complex.