Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a form of ectodermal dysplasia, a group of about 180 conditions characterized by abnormal development of ectodermal tissues including the skin, hair, nails, teeth, eyes, ears, and sweat glands.

Among the most common features of AEC syndrome are missing patches of skin (erosion). In affected infants, skin erosion most commonly occurs on the scalp. It tends to recur throughout childhood and into adulthood, frequently affecting the scalp, neck, hands, and feet. Skin erosion ranges from mild to severe and can lead to life-threatening infection in infancy, scarring, and hair loss. Other ectodermal abnormalities in AEC syndrome include changes in skin coloring; brittle, sparse, or missing hair; misshapen or absent fingernails and toenails; and malformed or missing teeth. Affected individuals may also have an inability to control their body temperature because of missing or nonfunctioning sweat glands causing overheating or hypothermia.

Many infants with AEC syndrome are born with an eyelid condition known as ankyloblepharon filiforme adnatum, in which strands of tissue partially or completely fuse the upper and lower eyelids. Most people with AEC syndrome are also born with an opening in the roof of the mouth (a cleft palate), a split in the lip (a cleft lip), or both. Cleft lip or cleft palate can make it difficult for affected infants to suck, so these infants often have trouble feeding and do not grow and gain weight at the expected rate (failure to thrive).

Additional features of AEC syndrome can include limb abnormalities, most commonly fused fingers and toes (syndactyly). Less often, affected individuals have permanently bent fingers and toes (camptodactyly) or a deep split in the hands or feet with missing fingers or toes and fusion of the remaining digits (ectrodactyly). Hearing loss is common, occurring in more than 90 percent of children with AEC syndrome. Some affected individuals have distinctive facial features, such as small jaws that cannot open fully and a narrow space between the upper lip and nose (philtrum). Other signs and symptoms can include the opening of the urethra on the underside of the penis (hypospadias) in affected males, digestive problems, absent tear duct openings in the eyes, and chronic sinus or ear infections.

A condition known as Rapp-Hodgkin syndrome has signs and symptoms that overlap considerably with those of AEC syndrome. These two syndromes were classified as separate disorders until it was discovered that they both result from mutations in the same part of the same gene. Most researchers now consider Rapp-Hodgkin syndrome and AEC syndrome to be part of the same disease spectrum.

AEC syndrome is caused by variants (also known as mutations) in the TP63 gene. This gene provides instructions for making a protein known as p63, which plays an essential role in early development. The p63 protein is a transcription factor, which means that it attaches (binds) to DNA and controls the activity of particular genes. The p63 protein turns many different genes on and off during development. It appears to be especially critical for the development of ectodermal structures, such as the skin, hair, teeth, and nails. Studies suggest that it also plays important roles in the development of the limbs, facial features, urinary system, and other organs and tissues.

The TP63 gene variants responsible for AEC syndrome interfere with the ability of p63 to turn target genes on and off at the right times. It is unclear how these changes lead to abnormal ectodermal development and the specific features of AEC syndrome.

Normal Function

The TP63 gene provides instructions for making a protein called tumor protein p63 (also known simply as p63). The p63 protein functions as a transcription factor, which means it attaches (binds) to certain regions of DNA and controls the activity of particular genes.

The p63 protein interacts with other proteins to turn many different genes on and off at different times. The action of p63 helps regulate numerous cell activities, including cell growth and division (proliferation), cell maintenance, the process by which cells mature to carry out specific functions (differentiation), the ability of cells to stick to one another (cell adhesion), and the orderly self-destruction of cells (apoptosis).

The p63 protein plays a critical role in early development. It is especially important for the normal development of ectodermal structures, such as the skin, hair, teeth, and nails. Studies suggest that it also plays essential roles in the development of the limbs, facial features, urinary system, and other organs and tissues. In addition to its roles in development, the p63 protein appears to be necessary for the maintenance of various cells and tissues later in life.

Health Conditions Related to Genetic Changes

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

At least 40 mutations in the TP63 gene have been identified in people with ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. This condition is a form of ectodermal dysplasia, which is a group of disorders characterized by abnormal development of the skin, hair, nails, teeth, and sweat glands. Other characteristic features of AEC syndrome include partial or complete fusion of the upper and lower eyelids (ankyloblepharon filiforme adnatum) and an opening in the roof of the mouth (a cleft palate), a split in the lip (a cleft lip), or both.

Most of the TP63 gene mutations responsible for AEC syndrome occur in regions of the p63 protein known as the sterile alpha motif (SAM) domain and the transactivation inhibitory (TI) domain. Mutations in these regions interfere with the ability of p63 to turn target genes on and off at the right times. However, it is unclear how these changes lead to abnormal ectodermal development and the specific features of AEC syndrome.

Other disorders

Mutations in the TP63 gene cause several additional ectodermal dysplasias with features that overlap those of AEC syndrome. These conditions include ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome; acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome; and limb-mammary syndrome (LMS). This group of disorders is characterized by varying combinations of ectodermal abnormalities (which affect the skin, hair, nails, teeth, and sweat glands), cleft lip and/or cleft palate, and malformations of the hands and feet.

Mutations in the TP63 gene have also been found to cause split hand/foot malformation type 4 (SHFM4), a condition involving hand and foot malformations without any other signs or symptoms. Additionally, TP63 gene mutations are a rare cause of cleft lip and/or cleft palate that occur without features affecting other parts of the body.

The TP63 gene mutations responsible for these conditions occur in various regions of the TP63 gene and affect the function of the p63 protein in different ways. Some of the known mutations may give the p63 protein a new, abnormal function (described as "gain-of-function" mutations) or lead to a version of the p63 protein that interferes with normal cell activities (described as "dominant-negative" mutations). These changes alter the ability of p63 to interact with other proteins, to turn target genes on and off at the right times, or both. It is unclear how abnormal p63 activity disrupts ectodermal development and leads to the specific features of the TP63-related conditions.

Other Names for This Gene

• AIS
• amplified in squamous cell carcinoma
• chronic ulcerative stomatitis protein
• CUSP
• KET
• NBP
• p40
• p51
• p51A
• p51B
• p53CP
• p63
• P63_HUMAN
• p73L
• TP53CP
• TP53L
• TP73L
• transformation-related protein 63
• tumor protein 63
• tumor protein p53-competing protein

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.

AEC syndrome is a rare condition; its prevalence is unknown. All forms of ectodermal dysplasia together occur in about 1 in 70,000 newborns worldwide.