Char syndrome is a condition that affects the development of the face, heart, and limbs. It is characterized by a combination of three major features: a distinctive facial appearance, a heart defect called patent ductus arteriosus, and hand abnormalities.

Most people with Char syndrome have a characteristic facial appearance that includes flattened cheek bones and a flat nasal bridge (the area of the nose between the eyes). The tip of the nose is also flat and broad. The eyes are wide-set with droopy eyelids (ptosis) and outside corners that point downward (down-slanting palpebral fissures). Additional facial differences include a shortened distance between the nose and upper lip (a short philtrum), a triangular-shaped mouth, and thick, prominent lips.

Patent ductus arteriosus is a common heart defect in newborns, and it occurs in most babies with Char syndrome. Before birth, the ductus arteriosus forms a connection between two major arteries (the aorta and the pulmonary artery). This connection normally closes shortly after birth, but it remains open in babies with patent ductus arteriosus. If untreated, this heart defect causes infants to breathe rapidly, feed poorly, and gain weight slowly. In severe cases, it can lead to heart failure. People with patent ductus arteriosus also have an increased risk of infection.

Hand abnormalities are another feature of Char syndrome. In most people with this condition, the middle section of the fifth (pinky) finger is shortened or absent. Other abnormalities of the hands and feet have been reported but are less common.

Variants (also known as mutations) in the TFAP2B gene cause Char syndrome. This gene provides instructions for making a protein known as transcription factor AP-2β. A transcription factor is a protein that attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Transcription factor AP-2β regulates genes that are involved in development before birth. In particular, this protein appears to play a role in the normal formation of structures in the face, heart, and limbs.

TFAP2B variants alter the structure of transcription factor AP-2β. Some of these variants prevent the protein from binding to DNA, while other variants render it unable to regulate the activity of other genes. A loss of this protein's function disrupts the normal development of several parts of the body before birth, resulting in the major features of Char syndrome.

Normal Function

The TFAP2B gene provides instructions for making a protein called transcription factor AP-2β. A transcription factor is a protein that attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Transcription factor AP-2β is one of a group of related proteins called AP-2 transcription factors. These proteins regulate genes that help control cell division and the self-destruction of cells that are no longer needed (apoptosis).

Transcription factor AP-2β is involved in development before birth. In particular, this protein is active in the neural crest, which is a group of cells in the early embryo that give rise to many tissues and organs. Neural crest cells migrate to form portions of the nervous system, glands that produce hormones (endocrine glands), pigment cells, smooth muscle and other tissues in the heart, and many tissues in the face and skull. Transcription factor AP-2β also appears to play an important role in the development of the limbs.

Health Conditions Related to Genetic Changes

Char syndrome

Several variants (also known as mutations) in the TFAP2B gene have been identified in people with Char syndrome. Most of these genetic changes alter the structure of transcription factor AP-2β. More than half of these known variants alter a region of the protein that is critical for DNA binding. Others occur in an area of the protein that is necessary for regulating gene activity. A few changes in the TFAP2B gene prevent the production of any transcription factor AP-2β. A loss of this protein's function disrupts the normal development of structures derived from the neural crest, including the heart and facial features. Abnormal development of these tissues leads to the major features of Char syndrome.

Other disorders

Studies suggest that several normal variations (polymorphisms) in the TFAP2B gene are associated with an increased risk of type 2 diabetes, the most common form of diabetes. People with this disease have high blood sugar levels because the body does not respond correctly to insulin, a hormone produced by the pancreas. This hormone controls how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. Researchers have proposed that polymorphisms in the TFAP2B gene alter cells' responsiveness to insulin, particularly fat-storing cells (adipocytes).

Although changes in the TFAP2B gene may be associated with type 2 diabetes, a combination of lifestyle, genetic, and environmental factors all play a part in determining the risk of this complex disorder.

Other Names for This Gene

• activating enhancer binding protein 2 beta
• AP-2B
• AP2-B
• AP2-beta
• AP2B_HUMAN
• MGC21381
• transcription factor AP-2 beta (activating enhancer binding protein 2 beta)

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the variant from one affected parent. Other cases may result from new variants in the gene and occur in people with no history of the disorder in their family.

Char syndrome is rare, although its exact incidence is unknown. Only a few families with this condition have been identified worldwide.