NORD gratefully acknowledges Maranke I. Koster, PhD, Associate Professor, Department of Dermatology, University of Colorado, Timothy J. Fete MD, MPH, Children’s Miracle Network Distinguished Professor and Chair, Department of Child Health University of Missouri School of Medicine, and the National Foundation for Ectodermal Dysplasias, for assistance in the preparation of this report.
Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome, which is also known as Hay-Wells syndrome, is a rare disorder characterized by a wide variety of symptoms that can affect the skin, hair, nails, teeth, certain glands, and the hands and feet. Common symptoms include abnormal fibrous strands of tissue that can partially or completely fuse the upper and lower eyelids (ankyloblepharon), mild to severe skin erosions, abnormal hair, and cleft palate and/or cleft lip. Additional symptoms include malformation of the nails, abnormalities in skin color, limb malformations, and dental changes. Specific symptoms may vary greatly from one individual to another. AEC syndrome is caused by mutations in the TP63 gene and most cases are either new (spontaneous) mutations or are inherited in an autosomal dominant fashion. Another disorder that is caused by mutations in the TP63 gene, Rapp Hodgkin syndrome, is now considered to be part of the one disease spectrum that also includes AEC syndrome.
There are at least three other syndromes caused by mutations in the TP63 gene including limb-mammary syndrome, ADULT syndrome, and ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome. In addition, TP63 mutations have also been reported as the cause of nonsyndromic split hand/foot malformation. There is considerable overlap among these disorders. Despite the overlap, the TP63-associated syndromes have their own characteristic physical findings, related in part, to the specific mutation in the TP63 gene present. These syndromes are further classified as forms of ectodermal dysplasia, a group of disorders characterized by abnormalities that occur during embryonic development. Ectodermal dysplasias typically affect the hair, teeth, nails, and/or skin.
The symptoms of AEC syndrome are highly variable, even among members of the same family. In addition, the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder prevent physicians from developing a completely accurate picture of associated symptoms and prognosis. Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Many of the symptoms associated with AEC syndrome are present at birth (congenital). Many infants will have abnormal strands of tissue that connect the upper eyelids with the lower eyelids causing them to be fused together, a condition known as ankyloblepharon filiforme adnatum. Ankyloblepharon affects approximately 70% of individuals with AEC syndrome and is generally not seen in other TP63-related disorders.
Most infants will have some degree of skin erosion, ranging from mild involvement of a specific area to severe, even life-threatening, involvement of the whole body. The scalp is commonly involved and is usually affected more severely than other areas. Severe scalp erosions can cause a generalized loss of hair (hypotrichosis) as well as patchy areas where hair loss is followed by the formation of scar tissue (scarring alopecia). Skin erosions may recur periodically throughout childhood and sometimes adulthood. The head and neck, palms and soles, and skin folds are most often affected. Skin erosions can be slow to heal and a considerable source of discomfort, pain and disability. In severe cases, these persistent skin erosions can lead to frequent infection and potentially life-threatening complications such as sepsis.
Additional skin abnormalities may also be present. The characteristic skin erosions may be associated with a widespread (diffuse) reddish discoloration (erythroderma). The affected skin can also appear shiny and waxy (collodion membrane). Affected individuals may also develop areas of darkened or faded skin color (hyper- or hypo-pigmentation). Dry, scaly patches of skin may form on the palms and soles (palmar-plantar hyperkeratosis) as well as tiny, hardened bumps (punctate keratoderma). Increased numbers and depth of skin lines on the palms may also occur (hyperlinearity). Hyperkeratosis may also affect the knees and elbows.
All affected individuals have oral clefting abnormalities. Some have only a cleft or groove on the roof of the mouth (palate), some have only a cleft lip, and others have both. A cleft palate or lip is usually obvious at birth. However, a cleft palate can vary in size and location and some small clefts can go unnoticed or undetected until later in life. Cleft palate occurs more frequently than cleft lip.
AEC syndrome also causes decreased sweat production (hypohidrosis), which causes some affected individuals to be uncomfortable or feel “overheated” when the temperature rises (heat intolerance). Hypohidrosis is due, in part, to reduced number or absence of sweat glands.
Additional common findings in AEC syndrome include sparse, wiry, brittle hair that is usually light colored. In some cases, flattened, twisted hair shafts (pili torti) may be present. Eyebrows and eyelashes are also sparse. Nail changes may also occur and can vary greatly among individuals. Such changes include misshapen or malformed fingernails and toenails, abnormally small nail plates (micronychia), frayed edges of the nails, and absent nails. Hair and nail abnormalities become more apparent as affected individuals grow older.
Dental abnormalities are also common and can include one or more missing teeth (hypodontia), widely spaced teeth, and malformed or underdeveloped (hypoplastic) teeth. The lower jaw may also be small and underdeveloped (maxillary hypoplasia).
Affected individuals may also have narrowing (atresia) or absence of the opening in the edge of each eyelid that is linked to the tear duct (lacrimal punctata). This can lead to obstruction of the tear ducts and predispose to recurrent eye crusting and conjunctivitis. Many individuals with AEC report chronic dry eyes. Chronic inflammation of the eyelids (blepharitis) has also been reported.
Less often, certain limb anomalies have been associated with AEC syndrome including webbing of certain fingers or toes (syndactyly) and fingers that are stuck in a bent or flexed position (camptodactyly).
Some children experience chronic middle ear infections (otitis media) and approximately 90% develop hearing loss due to the failure of sound waves to be sent (conducted) through the middle ear (conductive hearing loss). Hearing loss can cause delays in speech development.
Poor weight gain, growth deficiencies and short stature can also occur. Additional findings that have been reported in individuals with AEC syndrome include abnormally small ears, a broad bridge of the nose, an abnormally short groove that runs from the top of the upper lip to the nose (philtrum), an abnormally small mouth (microstomia), and the inability to completely open the mouth (trismus). In affected males, the opening of the small tube that carries urine from the bladder to outside of the body (urethra) may be abnormally located on the underside of the penis (hypospadias).
AEC syndrome is caused by a mutation in the TP63 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The official name of the gene mutated in AEC syndrome is tumor protein 63 (TP63).
The TP63 gene contains instructions for synthesizing (encoding) a protein (p63) that is essential for the proper development of structures derived from the ectoderm. The ectoderm is the outermost germ layer of the developing embryo from which numerous structures of the body are derived, including the skin, hair, nails, glands of the skin, mucous membranes of the mouth, etc. Mutations in this gene lead to abnormal p63 protein function, which hinders the proper development of these structures.
AEC syndrome is inherited as an autosomal dominant trait. Seventy percent of cases of AEC syndrome occur sporadically with no previous family history (i.e., new or “de novo” mutation).
Genetic diseases are determined by the combination of 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% for each pregnancy. The risk is the same for males and females.
The symptoms and physical findings of AEC syndrome can vary greatly in severity from one person to another (variable expressivity). In addition, individuals who inherited a defective gene for AEC syndrome may not develop all of the symptoms discussed above. Other factors such as additional genes that modify the expression of a disorder (modifier genes) may play a role in the variable findings of AEC syndrome.
AEC syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown. AEC syndrome is a rare disorder and fewer than 100 affected individuals have been described in the medical literature.
A diagnosis of AEC syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A variety of specialized tests can aid in a diagnosis. For example, molecular examination of small samples of skin tissue (skin biopsy) may reveal specific features such as thinning (atrophy) of the outer layer of the skin (epidermis).
Molecular genetic testing can confirm a diagnosis of AEC syndrome. Molecular genetic testing can detect mutations in the TP63 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
Prenatal diagnosis is available for families with a known risk for having a baby with AEC syndrome.
The treatment of AEC syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, ophthalmologists, orthopedic surgeons, dermatologists, dentists, audiologists, otolaryngologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.
Small ankyloblepharon may breakdown or disintegrate (autolyse) on their own without any treatment. Larger ones may require surgical removal. Surgery may also be necessary for cleft lip, cleft palate, limb malformations, and certain facial anomalies such as underdeveloped jaw.
Dental surgery and corrective devices may be used to treat misshapen teeth. If teeth are missing, dentures may be necessary or dental implants may be considered during the teen-aged or early adult years. Affected individuals should pay particular attention to dental health to prevent tooth decay.
Skin erosions are often difficult to treat and often do not respond to standard wound care options. Aggressive techniques such as debridement are not recommended and can worsen the condition. Gentle wound care options and periodic treatment with dilute bleach soaks are recommended. A dilute bleach soak involves using an antiseptic solution, such as the Dakins solution, to kill off germs that can grow in a wound. Limiting further trauma to the affected areas of skin is also important.
Individuals with chronic skin erosions are at risk of developing secondary infection, which can be treated with topical or oral antibiotics. Anti-fungal medications can also be used in some cases.
Myringotomy, a procedure in which a tiny incision is made in the eardrum and a small tube is placed to relieve pressure and drain fluid to treat hearing loss and ear infections. Artificial tears may be necessary for individuals with dry eyes. Hypohidrosis is mild and usually does not require treatment.
A child’s weight should be monitored and proper caloric intake provided. If a child is failing to grow properly, consultation with the nutrition team is warranted.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., cleft palate, etc.)
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