Carney Complex

Executive Summary

The Carney complex is a hereditary condition differentiated by spotty skin pigmentation forming benign connective tissue tumors and other tumors of the endocrine glands. The symptoms of the Carney complex are developed in the early stage of childhood. The initial signs of carney complex include skin pigmentation, heart myxomas or other heart problems. Other common symptoms include skin pigmentation on lips, outer and inner corners of the eyes, the conjunctiva of the eye, and around the genital, Cushing’s syndrome and multiple thyroid nodules (tumors). Symptoms are the combination of high blood pressure, weight gain, diabetes, and easy bruising caused by the overproduction of the cortisol hormone. Carney complex occurs due to genetic mutations. 

PRKAR1A is associated with the Carney complex through its role in regulating the body’s cell-signaling with protein kinase A. A second genetic cause linked with the Carney complex is described on chromosome 2 (2p16), but the genes responsible for this phenotype are unknown. The inheritance of the Carney complex evolved from the mother and the other from the father. It follows an autosomal dominant inheritance pattern, meaning a mutation in only one gene copy can lead to the Carney complex. It is diagnosed with several features mainly evolved from parent, sibling, or child. Genetic testing is usually done for its diagnosis. Types of cancer reported in people with the complex are adrenocortical carcinoma, thyroid, colorectal, liver and pancreatic cancers are more prone to risk. Yearly echocardiogram, annual blood tests, regular skin, endocrine system screening, thyroid gland examinations, and ultrasounds are used as screening methods for the Carney complex. 

What is Carney complex?

Carney complex is a hereditary condition distinguished by spotty skin pigmentation; myxomas, which are benign (noncancerous) connective tissue tumors; and several other tumors of the endocrine (hormone-producing) glands ^​1​. Tumors can be benign or cancerous. A benign tumor remains confined to its original location. A cancerous tumor can grow and spread to other parts of the body.

Symptoms

Symptoms of the Carney complex usually develop when a person is in childhood or their early twenties. Skin pigmentation, heart myxomas or other heart problems are typically the first signs of this condition ^​2​. The spotty skin pigmentation is seen on lips, outer and inner corners of the eyes, the conjunctiva of the eye, and around the genital area. Other standard features of the Carney complex are Cushing’s syndrome and multiple thyroid nodules (tumors). Cushing’s syndrome in the Carney complex is always due to primary pigmented nodular adrenocortical disease (PPNAD). Symptoms may be a combination of high blood pressure, weight gain, diabetes, and easy bruising caused by the overproduction of the cortisol hormone. Although people with Carney complex have a higher risk of cancer, most tumors are benign. This cancer includes liver, testicular, ovarian, and pancreatic cancers. A rare nervous system tumor called ‘schwannoma’ can occasionally be cancerous and very aggressive.

Carney complex is also known as –

• NAME syndrome – Nevi, meaning birthmarks or moles, Atrial myxoma, Ephelides (freckles) and Myxoid neurofibromas
• LAMB syndrome – Lentigines, Atrial Myxoma, and Blue nevi

Causes

The Carney complex is a hereditary genetic condition that may be inherited autosomal dominantly or sporadically. It means that the chances of developing cancer and other features of the Carney complex can be passed from generation to generation in a family through genetic mutations ^​3​. Notably, researchers have learned more about how the gene called PRKAR1A is associated with the Carney complex through its role in regulating the body’s cell-signaling with protein kinase A. Researchers believe around 70% of people have CC, 80% of patients with PPNAD have a mutation in the PRKAR1A gene, and up to 6% may have deletions in this gene or the chromosomal that contains it. To date, 130 or more different PRKAR1A mutations are known. Most of the mutations are unique, as they are seen in single families only. So far, no firm link between a particular genetic mutation type and specific symptoms of the Carney complex, like cancer, has been seen.

People without a PRKAR1A gene mutation usually show mild symptoms later in life. These people less frequently have any other family members affected by the Carney complex. The gene mutation in that person is believed to be sporadic (occurs by chance).

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

How is the Carney complex inherited?

Typically, every cell has two copies of the same gene: one inherited from the mother and the other from the father. The Carney complex follows an autosomal dominant inheritance pattern, meaning a mutation in only one gene copy can lead to the Carney complex ^​4​. This means that a parent with a mutation in a gene can pass along a copy of the normal gene or the mutated gene. It takes one copy of the gene with the mutation to have the disease. Therefore, a parent with a mutation has a 50% chance of passing it to their child each pregnancy. A sister, brother, or parent of a person who has the mutation also has a 50% chance of inheriting the same gene mutation. However, suppose the parents test negative for the mutation (meaning each person’s test results found no mutation). In that case, the risk to the siblings significantly decreases, but their risk may still be higher than the average risk.

Options exist for people desiring to have a child when a prospective parent has a gene mutation that increases the chances for this hereditary cancer syndrome. Preimplantation genetic diagnosis (PGD), a medical procedure with in-vitro fertilization, allows people who have a particular known genetic mutation to decrease the likelihood that their children will inherit the mutation. A woman’s eggs are fertilized in a laboratory. When the embryos reach a specific size (approximately eight cells), one cell is removed and is tested for the hereditary condition in question. The parents can then transfer embryos that don’t have the mutation. PGD has been used for over two decades and has been used for various hereditary cancer predisposition syndromes. But, it is a complex procedure with financial, emotional, and physical factors to consider before starting. 

How is the Carney complex diagnosed?

The Carney complex is diagnosed when at least 2 of the 12 significant features are listed below ^​5​. People who have a close family member that is a parent, sibling, or child already diagnosed with CC are affected if they have at least 1 of the features listed.

Major diagnostic features

• Spotty skin pigmentation with specific patterns and locations
• Myxoma (benign tumours)
• Heart myxoma
• Breast myxomatosis
• Breast ductal adenomas
• PPNAD or an abnormal result of urine test known as Liddle’s test, related to Cushing’s syndrome
• Acromegaly increased size of face, hands, and feet due to a pituitary tumour
• Testicular neoplasm knew as large cell calcifying Sertoli cell tumour (LCCST)
• Thyroid cancer
• Psammomatous melanotic schwannoma, meaning tumours that grow on nerves
• Blue nevi, which are blue-black moles
• Osteochondromyxoma (bone tumours)

Genetic testing for PRKAR1A gene mutations is there for people presumed to have Carney complex. If a person has a PRKAR1A mutation and one of the above tumors or other conditions, then that person is diagnosed with a Carney complex ^​6​. Genetic testing for the recently discovered genes, such as PRKACA, PRKACB, PDE11A, and PDE8B, is not yet commercially available.

Other physical symptoms are seen in people with the Carney complex. These physical signs suggest the complex but are not considered major diagnostic features. Research is going on to learn more about these symptoms and their link, if any, to the condition.

• Blue nevus, if multiple and confirmed by biopsy.
• Café-au-lait spots are light brown spots on the skin or other ‘birthmarks.’
• Significant freckling without darkly pigmented spots or typical pattern
• Abnormal blood test reports of high insulin-like growth factor 1 (IGF-I) levels, abnormal glucose tolerance test (GTT), or paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) testing when there is no clinical acromegaly. Also, high prolactin levels are in the blood known as hyperprolactinemia and are usually paired with acromegaly.
• Cardiomyopathy, a disease of the heart muscle.
• Pilonidal sinus, which is an abscess in the buttock cleft
• A single, noncancerous thyroid nodule in a young person, as well as multiple thyroid nodules in an older person
• Extended family history of Acromegaly, Cushing’s syndrome, or sudden death
• Polyps are benign growths in the colon, usually along with acromegaly.
• Multiple skin tags or other skin lesions are known as lipomas.
• Family history of cancer, particularly of the thyroid, colon, pancreas, and ovary

What are the estimated cancer risks linked with the Carney complex?

The risk of cancer increases in people who have a the complex ^​7​. Types of cancer reported in people with the complex are 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

Recommended screening includes –

• Yearly echocardiogram, beginning in infancy. Patients who already have myxoma should have an echocardiogram every six months.
• Annual blood tests to check serum levels of cortisol, prolactin, and IGF-1 beginning in adolescence
• Regular skin examinations by a health care professional and self-examinations
• General endocrine system screening
• Thyroid gland examinations can include ultrasound imaging. 
• Testicular examinations or ultrasound for men

Screening guidelines can change with time as new technologies are being developed and more is learned about the Carney complex.

Questions to ask the health care team

If you are worried about cancer risk, talk to your health care team. Consider asking your health care team the given questions-

• What are the chances of developing cancer?
• What can I do to decrease the risk of cancer?
• What are my alternatives for cancer screening?

If you are worried about the family history and doubt that you or other family members may have Carney complex, you can ask the below-mentioned questions –

• Does my family history increase my chances of developing cancer?
• Should I seek genetic testing or counseling?

References