Last updated:
2/14/2024
Years published: 1992, 1997, 1998, 2005, 2013, 2017, 2020, 2024
NORD gratefully acknowledges Maranke I. Koster, PhD, Professor, Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Timothy J. Fete, MD, MPH, Professor Emeritus, 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.
Summary
Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome, formerly 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 changes (variants or mutations) in the TP63 gene, and most cases are due to either new (do novo) variants or are inherited in an autosomal dominant fashion.
Introduction
There are at least three other syndromes caused by variants in the TP63 gene including limb-mammary syndrome, ADULT syndrome and ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome. In addition, TP63 variants 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 variant in the TP63 gene present. These syndromes are further classified as forms of ectodermal dysplasia, a large group of disorders characterized by abnormalities that occur during embryonic development. Tissues that are typically affected in ectodermal dysplasias include hair, teeth, nails, certain glands and/or skin. Another disorder that is caused by variants in the TP63 gene, Rapp Hodgkin syndrome, is now considered to be part of one disease spectrum that also includes AEC syndrome.
The symptoms of AEC syndrome are highly variable, even among members of the same family. In addition, the small number of identified patients, 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). Hair loss can also occur in individuals without a history of scalp erosions. 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 are generally slow to heal and a considerable source of discomfort, pain and disability. In severe cases, these persistent skin erosions can lead to frequent infections 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 hypopigmentation). 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 can also cause decreased sweat production (hypohidrosis), which causes some affected individuals to be uncomfortable or feel “overheated” when the temperature rises (heat intolerance).
Additional common findings in AEC syndrome include sparse, wiry, brittle hair that is usually light colored. In some patients, 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 transmitted (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 variant in the TP63 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the protein, this can affect many tissues and organs of the body.
The TP63 gene contains instructions for synthesizing (encoding) a protein (TP63) 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, several glands, teeth, mucous membranes of the mouth, etc. Variants in this gene lead to abnormal TP63 protein function, which interferes with the proper development of these structures.
AEC syndrome follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary for the disease to occur. The gene variant can be inherited from either parent or can be the result of a new (de novo) variant in the affected individual. Seventy percent of cases of AEC syndrome occur sporadically with no previous family history (i.e., new or “de novo” variant). The risk of passing the gene variant from affected parent to a child 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 gene variant 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.
Molecular genetic testing can confirm a diagnosis of AEC syndrome. Molecular genetic testing can detect variants in the TP63 gene known to cause the disorder but is available as a diagnostic service only at specialized laboratories.
Treatment
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 plan an affected child’s treatment systematically and comprehensively.
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 Dakin’s solution, to kill 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, can be used 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.
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For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
TEXTBOOKS
McGrath JA, Irvine AD. Hay-Wells syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:116-117.
JOURNAL ARTICLES
Tadini G, Santagada F, Brena M, Pezzani L Nannini P. Ectodermal dysplasias: the p63 tail. G Ital Dermatol Venereol. 2013;148:53-58. http://www.ncbi.nlm.nih.gov/pubmed/23407076
Clements SE, Techanukul T, Lai-Cheong JE, et al. Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology. Br J Dermatol. 2012;167:134-144. http://www.ncbi.nlm.nih.gov/pubmed/22329826
Clements SE, Techanukul T, Holden ST, et al. Rapp-Hodgkin and Hay-Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder. Br J Dermatol. 2010;624-629. http://www.ncbi.nlm.nih.gov/pubmed/20491771#
Fete M, van Bokhoven H, Clements SE, et al. International research symposium on ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet A. 2009;149A:1885-1893. http://www.ncbi.nlm.nih.gov/pubmed/19353643
Rinne T, Bolat E, Meijer R, Scheffer H, van Bokhoven H. Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC). Am J Med Genet A. 2009;149A:1948-1951. http://www.ncbi.nlm.nih.gov/pubmed/19676060
Farrington F, Lausten L. Oral findings in ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome. Am J Med Genet A. 2009;149A:1907-1909. http://www.ncbi.nlm.nih.gov/pubmed/19681142
Bree AF. Clinical lessons learned from the International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome. Am J Med Genet A. 2009;149A:1894-1899. http://www.ncbi.nlm.nih.gov/pubmed/19676057
Sutton VR, Plunkett K, Dang DX, et al. Craniofacial and anthropometric phenotype in ankyloblepharon-ectodermal defects-clef lip/palate syndrome (Hay-Wells syndrome) in a cohort of 17 patients. Am J Med Genet A. 2009;149A:1916-1921. http://www.ncbi.nlm.nih.gov/pubmed/19676059
Julapalli MR, Scher RK, Sybert VP, Siegfried EC, Bree AF. Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet A. 2009;149A:1900-1906. http://www.ncbi.nlm.nih.gov/pubmed/19681128
Rinne T, Brunner HG, van Bokhoven H. p63-associated disorder. Cell Cycle. 2007;6:262-268. http://www.ncbi.nlm.nih.gov/pubmed/17224651
Siegfried E, Bree A, Fete M, Sybert VP. Skin erosions and wound healing in ankyloblepharon-ectodermal defect-cleft lip and/or palate. Arch Dermatol. 2005;141:1591-1594. http://www.ncbi.nlm.nih.gov/pubmed/16365264
McGrath JA, Duijf PH, Doetsch V, et al. Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet. 2001;10:221-229. http://www.ncbi.nlm.nih.gov/pubmed/11159940
INTERNET
Sutton VR, van Bokhoven H. TP63-Related Disorders. 2010 Jun 8 [Updated 2021 Apr 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK43797/ Accessed Feb 6, 2024.
AEC Syndrome. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:106260; Last Update: 12/15/2022. Available at: http://omim.org/entry/106260 Accessed Feb 6, 2024.
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