Carney complex

Carney complex is a hereditary condition associated with spotty skin pigmentation; myxomas, which are benign (noncancerous) connective tissue tumors; and a number of other tumors of the endocrine (hormone-producing) glands. Tumors can be benign or cancerous. A benign tumor means the tumor can grow but will not spread. A cancerous tumor is malignant, meaning it can grow and spread to other parts of the body.

Symptoms of Carney complex typically develop when a person is in childhood or their early 20s. Skin pigmentation and heart myxomas or other heart problems are usually the first signs of the condition. The spotty skin pigmentation is found on lips, inner and outer corners of the eyes, the conjunctiva (membrane lining) of the eye, and around the genital area. Other common features of Carney complex are Cushing’s syndrome and multiple thyroid nodules (tumors). Cushing’s syndrome in Carney complex is always due to primary pigmented nodular adrenocortical disease (PPNAD), and symptoms may be a combination of weight gain, high blood pressure, diabetes, and easy bruising, caused by the overproduction of the hormone cortisol. Although people with Carney complex have an increased risk of cancer, most tumors are benign. Cancers associated with Carney complex include liver, ovarian, testicular, and pancreatic cancers. A rare tumor of the nervous system called “schwannoma” can sometimes be cancerous and very aggressive.

Carney complex is also referred to as:

NAME syndrome – Nevi, meaning birthmarks or moles, Atrial myxoma, Myxoid neurofibromas, and Ephelides (freckles)

LAMB syndrome – Lentigines, Atrial Myxoma, and Blue nevi

Signs & Symptoms

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. Some 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.

causes

Carney complex is a hereditary genetic condition that may be inherited in an autosomal dominant manner or occur sporadically. This means that the risk of developing cancer and other features of Carney complex can be passed from generation to generation in a family through gene(s) mutations (alterations). In particular, researchers have learned more about how the gene called PRKAR1A is associated with Carney complex, through its involvement with regulating the body’s cell signaling with protein kinase A (PKA). Researchers believe that more than 70% of people with Carney complex, and 80% of patients with PPNAD, have a mutation in the PRKAR1A gene (on chromosome 17q24.2), and up to 6% may have deletions in this gene or the chromosomal area that contains it. To date, more than 130 different PRKAR1A mutations have been found. Most of the mutations are unique, meaning they are identified in single families only. So far, no strong association between a particular genetic mutation type and certain symptoms of Carney complex, such as cancer, has been seen.

People without a mutation in the PRKAR1A gene typically start to show mild symptoms later in life. These people less frequently have other family members affected by Carney complex. The gene mutation in that person is considered sporadic, meaning it occurs by chance.

A second genetic cause associated with Carney complex has been described in a region on chromosome 2 (2p16), but the genes responsible for this phenotype are still unknown. Recently, mutations in the PRKACB gene were found in a single person with Carney complex and also in young children with Cushing syndrome that had no other symptoms of Carney complex. Mutations in the PDE11A and PDE8B genes have also been found in younger people with Cushing syndrome due to PPNAD, but their link to Carney complex remains in question. The search continues for other genes that might be associated with Carney complex. Mutations of another related gene (PRKACA) involved in PPNAD and other types of Cushing’s syndrome do not appear to cause Carney complex.

How is Carney complex inherited?

Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 inherited from the father. Carney complex follows an autosomal dominant inheritance pattern, in which a mutation happens in only 1 copy of the gene. This means that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation. However, if the parents test negative for the mutation (meaning each person’s test results found no mutation), the risk to the siblings significantly decreases but their risk may still be higher than an average risk.

Options exist for people interested in having a child when a prospective parent carries a gene mutation that increases the risk for this hereditary cancer syndrome. Preimplantation genetic diagnosis (PGD) is a medical procedure done in conjunction with in-vitro fertilization (IVF). It allows people who carry a specific known genetic mutation to reduce the likelihood that their children will inherit the condition. A woman’s eggs are removed and fertilized in a laboratory. When the embryos reach a certain size, 1 cell is removed and is tested for the hereditary condition in question. The parents can then choose to transfer embryos which do not have the mutation. PGD has been in use for over 2 decades and has been used for several hereditary cancer predisposition syndromes. However, this is a complex procedure with financial, physical, and emotional factors to consider before starting. For more information, talk with an assisted reproduction specialist at a fertility clinic.

How common is Carney complex?

Carney complex is rare. Several hundred cases have been reported worldwide. It is estimated that between 60% and 75% of cases of Carney complex run in families. The remaining 25% to 40% of cases appear to be sporadic and may be due to a de novo, meaning new, gene mutation.

How is Carney complex diagnosed?

Carney complex is diagnosed when a person has at least 2 of the 12 major features listed below. People who have a close family member, meaning a parent, sibling, or child, already diagnosed with Carney complex are considered to be affected if they have at least 1 of the features listed.

• Major diagnostic features for Carney Complex
• Spotty skin pigmentation with specific pattern and locations
• Myxoma (benign tumors)
• Heart myxoma
• Breast myxomatosis
• Breast ductal adenomas
• PPNAD or abnormal result of urine test called Liddle’s test, related to Cushing’s syndrome
• Acromegaly, an increased size of hands, feet, and face due to a pituitary tumor
• Testicular neoplasm called large cell calcifying Sertoli cell tumor (LCCST)

Thyroid cancer

• Psammomatous melanotic schwannoma, meaning tumors that grow on nerves
• Blue nevi, which are blue-black moles
• Osteochondromyxoma (bone tumors)

Genetic testing for mutations in the PRKAR1A gene is available for people suspected to have Carney complex. If a person has a PRKAR1A mutation and 1 of the above tumors or other conditions, then that person is diagnosed with Carney complex. Genetic testing for the genes discovered more recently, such as PRKACA, PRKACB, PDE11A, and PDE8B, is not yet commercially available.

In addition, other physical symptoms have been seen in people with Carney complex. These physical signs may suggest Carney complex, but they are not considered major diagnostic features. Research is ongoing to learn more about these symptoms and their link, if any, to the condition.

• Significant freckling without darkly pigmented spots or typical pattern
• Blue nevus, if multiple and confirmed by biopsy
• Café-au-lait spots, which are light brown spots on skin, or other ‘‘birthmarks’’

Abnormal blood test results of high insulin-like growth factor 1 (IGF-I) levels, abnormal glucose tolerance test (GTT), and/or paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) testing when there is no clinical acromegaly. Also, high levels of a hormone called prolactin in the blood. This is called hyperprolactinemia and is usually paired with acromegaly.

• Cardiomyopathy, meaning diseases of the heart muscle
• Pilonidal sinus, which is an abscess in the buttock cleft
• Extended family history of Cushing’s syndrome, acromegaly, or sudden death
• Multiple skin tags or other skin lesions called lipomas
• Polyps, meaning benign growths in the colon, usually along with acromegaly
• A single, noncancerous thyroid nodule in a younger person, as well as multiple thyroid nodules in an older person
• Family history of cancer, in particular of the thyroid, colon, pancreas, and ovary

What are the estimated cancer risks associated with Carney complex?

The risk of cancer is increased in people who have Carney complex. Types of cancer reported in people with Carney complex include adrenocortical carcinoma, thyroid, colorectal, liver and pancreatic cancers. Ovarian cancer in women and tumors of the testicles in men involving the Sertoli or Leydig cells have also been reported.

What are the screening options for Carney complex?

Suggested screening includes:

Yearly echocardiogram, beginning in infancy. Patients that have already had a myxoma should have an echocardiogram every 6 months.

Regular skin evaluations by a health care professional and self-examinations

Yearly blood tests to check serum levels of cortisol, prolactin, and IGF-1 beginning in adolescence

Thyroid gland examinations that may include ultrasound imaging. An ultrasound uses sound waves that create a picture of internal organs.

General endocrine system screening

Testicular examinations and/or ultrasound for men

Screening guidelines may change over time as new technologies are developed and more is learned about Carney complex. It is important to talk with your health care team about appropriate screening tests.

Learn more about what to expect when having common tests, procedures, and scans. 

Questions to ask the health care team

If you are concerned about your risk of cancer, talk with your health care team. It can be helpful to bring someone along to your appointments to take notes. Consider asking your health care team the following questions:

• What is my risk of developing cancer?
• What can I do to reduce my risk of cancer?
• What are my options for cancer screening?
• If you are concerned about your family history and think you or other family members may have Carney complex, consider asking the following questions:
• Does my family history increase my risk of developing cancer?
• Should I meet with a genetic counselor?
• Should I consider genetic testing?