Carney complex is a rare genetic disorder characterized by multiple benign tumors (multiple neoplasia) most often affecting the heart, skin and endocrine system and abnormalities in skin coloring (pigment) resulting in a spotty appearance to the skin of affected areas. Benign tumors of connective tissue (myxomas) are common in individuals with Carney complex and, most often, are found in the heart where they can potentially cause serious, life-threatening complications including stroke, valvular obstruction or heart failure. A wide variety of endocrine abnormalities potentially can occur in Carney complex affecting a variety of glands. Additional tumors include myxomas affecting the skin and nerve sheath tumors (schwannomas). Skin pigment abnormalities include tiny flat (freckle-like) black or brown spots (multiple lentigines) and small, blue or bluish-black spots (blue nevi). The specific symptoms and severity of Carney complex can vary greatly from one person to another. In many cases, Carney complex is due to mutations of the PRKAR1A gene. The mutation can occur randomly for no apparent reason (i.e., new mutation) or be inherited as an autosomal dominant trait.
Carney complex is a different disorder from Carney triad. Carney triad encompasses three types of tumors: a gastric stromal sarcoma; functioning extra-adrenal paragangliomas; and pulmonary chondromas. Although these two disorders are completely unrelated, both have sometimes been referred to as Carney syndrome, causing confusion. This report deals solely with Carney complex.
The symptoms and severity of Carney complex can vary greatly from one person to another, even among members of the same family. The disorder may be evident at birth, but the median age of diagnosis is 20. Many of the signs and symptoms of Carney complex become apparent during the teen-age years or during early adulthood.
It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
The presenting sign of Carney complex is often numerous tiny (freckle-like) black or brown spots on the skin (multiple lentigines). Although these tiny, flat discolorations resemble freckles, they tend to be darker and usually range between 2 and 10 millimeters in size. Lentigines are most often found around the upper and lower lips (pink part), on the eyelids, the membrane lining the eyes and the inside of the eyelids (conjunctiva), the ears and the genital area. Lentigines can be apparent at birth. In most cases, lentigines increase in number around puberty. Lentigines tend to fade in the 40s.
Another type of skin abnormality associated with Carney complex are blue nevi. Blue nevi are raised, small, blue or bluish-black spots on the skin. Less frequently, affected individuals may develop areas of light brown discoloration with irregular or jagged borders (café au lait spots) and white patches of skin due to loss of pigment (depigmented lesions).
Individuals with Carney complex are prone to developing a type of tumor known as a myxoma. Myxomas are small benign tumors consisting of connective tissue. Myxomas can affect any area of the body except the hands and feet and, in Carney complex, are most commonly seen in the heart (cardiac myxomas). One myxoma or multiple myxomas may be present. Myxomas may develop in any or all of the chambers of the heart. The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta).
Cardiac myxomas can potentially cause serious life-threatening complications usually due to the obstruction of blood flow. Specific complications can include stroke due to blockage of an artery (embolism) in the brain by a piece of detached cardiac myxoma or the inability of the heart to pump blood to the rest of the body, causing fluid buildup in the heart, lungs and various body tissues (congestive heart failure). Complete blockage (occlusion) of a valvular opening potentially can cause sudden death. Additional heart abnormalities that may occur in individuals with Carney complex include palpitations, diastolic heart murmurs and “tumor plop”, which is a distinctive sound related to the movement of a tumor within the heart. Cardiac myxomas may also cause general, nonspecific symptoms including fatigue, fever, muscle pain (myalgia), difficulty breathing (dyspnea) and unintended weight loss.
Less often, myxomas can be found in other areas of the body in addition to or instead of the heart. These areas include the eyelids, nipples and the external ear canal. Any area of the body can be affected except the hands and feet. Cutaneous myxomas may present as white, pink or flesh-colored papules or small nodules just under the surface of the skin. They generally do not cause any symptoms and can appear at any time from birth through the fourth decade. They are generally 1 cm or less in diameter. Myxomas may also occur in the oropharynx area, which encompasses the tongue, hard palate and the back wall of the throat (pharynx). In women, myxomas can also occur in the breasts after puberty. In addition, women may develop myxomas in the genital tract including the vagina, uterus and cervix. In rare cases, affected individuals may develop an osteochondromyxoma, a rare bone tumor predominantly affecting the nasal sinuses or the long bones of the arms and legs.
Individuals with Carney complex can develop a wide variety of abnormalities affecting the endocrine system including the development of multiple benign tumors. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes.
The most common endocrine tumor associated with Carney complex is known as primary pigmented nodular adrenocortical disease (PPNAD). PPNAD affects approximately 25 percent of individuals with Carney complex. The condition is characterized by multiple tiny nodules affecting the adrenal glands. The adrenal glands are situated atop the kidneys and produce cortisol, which is a hormone that is involved in certain metabolic and cardiovascular processes and helps the body respond to stress. PPNAD is a rare disorder that predominantly occurs in individuals with Carney complex. Elevated cortisol levels due to PPNAD can cause a disorder known as Cushing’s syndrome.
Cushing’s syndrome is a disorder that occurs because of abnormally high levels of cortisol in the body. The symptoms develop slowly over time. Affected children may experience weight gain and growth delays. Adults may experience progressive weight gain resulting in extra fat in the midsection, between the shoulder blades, around the neck and in the face, giving the face a rounded appearance. Additional symptoms include high blood pressure (hypertension), fatigue, purple or red stretch marks (striae) on the abdomen, excessive thirst, weakness of the muscles closest to the body (proximal muscle weakness) and psychological disturbances. Some affected women may experience disturbances of their menstrual cycles and a male pattern of hair growth (hirsutism). Some affected individuals may have progressive thinning and loss of protein of bones (osteoporosis) because of prolonged mild elevation of cortisol.
Some individuals with Carney complex may have a benign tumor (adenoma) of the pituitary gland. The pituitary gland is a small gland located near the base of the skull that produces several hormones and releases them into the bloodstream as needed by the body. Infrequently, individuals with Carney complex can develop a condition known as acromegaly. Acromegaly occurs when a pituitary adenoma causes increased production of growth hormone. Symptoms include abnormal enlargement of the bones of the arms, legs and head. The bones in the jaws and in the front of the skull are typically most often affected. Consequently, affected individuals may exhibit abnormal enlargement of the hands, feet, jaws and face. Acromegaly may also cause thickening of the soft tissues of the body, particularly the heart and accelerated growth leading to tall stature. Acromegaly is a slowly progressive condition.
Some individuals with Carney complex may have multiple tumors (nodules) affecting the thyroid. The thyroid is a butterfly-shaped gland at the base of the neck that secretes hormones that help to regulate growth and development in the body. In most cases, these nodules are benign nonfunctioning adenomas. Nonfunctioning means that the adenoma does not produce excess hormones. In some cases, affected individuals may have papillary or follicular thyroid carcinoma. In rare cases, thyroid carcinoma has developed in individuals with a longstanding history of multiple thyroid nodules.
In males, an endocrine tumor known as a large-cell calcifying Sertoli cell tumor (LCCSCT) may develop. This tumor is found in the testes as tiny areas of calcification and sometimes can be associated with early development of secondary sexual characteristics (precocious puberty). This tumor can potentially cause breast development in males (gynecomastia). LCCSCTs are almost always benign; only one case has ever been reported of malignant transformation. Approximately one-third of males with Carney complex have these tumors present when first diagnosed with the disorder, usually during the first decade of life. Virtually all adult males develop LCCSCTs at some point. Less frequently, two other testicular tumors can also occur in males with Carney complex, specifically Leydig cell tumors and pigmented nodular adrenocortical rest tumors. Leydig cell tumors potentially can become malignant. Pigmented nodular adrenocortical rest tumors are benign, but can cause Cushing’s syndrome.
In some cases, testicular tumors can affect fertility due to replacement and obstruction of the tiny tubes in which sperm is formed (seminiferous tubules) and decreased sperm motility (oligoasthenospermia). The presence of these tumors can cause the testes to become abnormally large (macroorchidism) as well.
Although not a frequent finding, some females with Carney complex have developed ovarian cysts. In approximately 10 percent of cases, individuals with Carney complex may develop a psammomatous melanotic schwannoma, which is a rare tumor of the peripheral nerve sheath. They can occur anywhere along the central and peripheral nervous system, but most often affect the gastrointestinal tract (including the esophagus) or the network of nerves adjacent to the spine (paraspinal sympathetic chain). Depending upon their location psammomatous melanotic schwannomas can cause pain or discomfort as well as damage to one or more nerves (radiculopathy). In rare cases, these tumors can become malignant.
Some cases of Carney complex occur due to mutations of the PRKAR1A gene. This mutation may occur randomly for no apparent reason (i.e., new mutation) with no family history or be inherited as an autosomal dominant trait. The majority of cases of Carney complex have occurred in individuals with a family history of the disorder.
Genetic diseases are determined by the combination of abnormal genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Some individuals with Carney complex do not have an identifiable mutation of the PRKAR1A gene. Researchers believe that additional, as yet unidentified, genes may cause the disorder in these cases (genetic heterogeneity). Investigators have determined that an as yet unidentified gene on the short arm (p) of chromosome 2 is involved in some cases of Carney complex. These cases are sometimes referred to as Carney complex type II. More research is necessary to determine the gene on this region of chromosome 2 that causes certain cases of Carney complex.
Investigators have determined that the PRKAR1A gene is located on the long arm (q) of chromosome 17 (17q22-q24). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13″ refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The PRKAR1A gene is believed to be a tumor suppressor gene. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. The PRKAR1A gene creates (encodes) a protein known as protein kinase A (PKA) R1alpha regulatory subunit. A mutation of the PRKAR1A gene leads to increased PKA signaling in affected tissues. It is believed that PKA can suppress or stimulate cell growth and proliferation. However, the exact function of this protein and how mutations of the PRKAR1A gene ultimately lead to the symptoms of Carney complex are not fully understood.
Carney complex affects males and females in equal numbers. Approximately 600 cases have been reported since the disorder was first described in the medical literature in 1985. The disorder can present at any age, but the mean age at diagnosis is 20.
A diagnosis of Carney complex is made based upon a detailed patient history, a thorough clinical evaluation, a variety of specialized tests and identification of characteristic symptoms. According to the medical literature, identification of two or more of the following symptoms in typical fashion is indicative of Carney complex: cardiac myxoma: skin myxoma; lentiginosis; multiple blue nevi; primary pigmented nodular adrenocortical disease (PPNAD); testicular tumors; acromegaly; thyroid tumors, melanotic schwannoma; or an osteochondromyxoma.
Tests that may performed to help obtain a diagnosis of Carney complex include surgical removal and microscopic study of affected skin (skin biopsy), urine analysis to detect elevated levels of cortisol (indicative of Cushing's disease), an echocardiogram to detect the presence of cardiac myxomas, and blood tests to detect abnormal high levels of certain hormones such as insulin-like growth factor, cortisol and prolactin due to the presence of endocrine tumors.
A diagnosis of Carney complex can be confirmed in some cases through molecular genetic testing, which can reveal the characteristic mutation of the PRKAR1A gene that causes the disorder in many cases. Molecular genetic testing is available on a clinical basis.
The treatment of Carney complex is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, cardiothoracic surgeons, endocrinologists, dermatologists and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.
Affected individuals should receive regular screening for the various potential symptoms associated with Carney complex. No specific guidelines have been agreed upon in the medical literature, but most sources recommend yearly screening for cardiac myxoma.
The specific therapeutic procedures and interventions for individuals with Carney complex will vary, depending upon numerous factors including the specific symptoms present, the extent of the disorder, an individual's age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Cardiac myxomas require open-heart surgical removal. Despite surgery, cardiac myxomas can recur. Cutaneous and mammary myxomas also require surgical removal. Surgical removal of the adrenal glands (adrenalectomy) may be required in individuals who develop Cushing's syndrome.
A pituitary adenoma may be treated by transsphenoidal surgery; a procedure in which all or part of a pituitary tumor is removed. In some cases, surgery results in a rapid therapeutic response, and lowering growth hormone levels.
Although rare, cancerous tumors may occur in Carney complex including thyroid carcinoma and malignant psammomatous melanotic schwannoma. Surgical removal of the primary tumor and any metastatic lesions is necessary. Individuals who have their thyroid removed will require lifelong supplementation of the hormones normally produced by the thyroid.
Surgical removal of one or both testes (orchiectomy) may be recommended to avoid or cope with the adverse effects (e.g., gynecomastia) of excessive hormone production that can occur in males with LCCSCT. However, because these tumors are benign, some physicians prefer surgery that spares fertility. In some cases, surgery that spares the testicles combined with strict monitoring of growth and puberty milestones has been performed. The administration of antiestrogen drugs may be necessary in the case of recurrence. Leydig cell tumors, because of the potential of malignant transformation, are usually treated by orchiectomy.
Genetic counseling should be offered to affected individuals and their families. Other treatment is symptomatic and supportive.
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