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AEC Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1992, 1997, 1998, 2005, 2013

NORD is very grateful to Timothy J. Fete MD, MPH, Children’s Miracle Network Distinguished Professor and Chair, Department of Child Health University of Missouri School of Medicine, for assistance in the preparation of this report.

Synonyms of AEC Syndrome

Disorder Subdivisions

General Discussion

Summary
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 arms and legs. 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 including malformation of the nails, abnormalities in skin color, limb malformations, and dental changes can also be present. Specific symptoms may vary greatly from one individual to another. AEC syndrome is caused by mutations in the p63 gene and most cases are either new (spontaneous) mutations or are inherited as autosomal dominant disorders. Another disorder that is caused by mutations in the p63 gene, Rapp Hodgkin syndrome, is now considered to be part of the one disease spectrum that also includes AEC syndrome.

Introduction
There are at least three other syndromes caused by mutations of the p63 gene including limb-mammary syndrome, ADULT syndrome, and EEC syndrome. In addition, p63 mutations have also been reported as the cause of nonsyndromic split hand/foot malformation and nonsyndromic cleft lip/palate. There is considerable overlap among these disorders and some researchers consider them different expressions of one disease process. Despite the overlap, the p63-associated syndromes have their own characteristic physical findings related, in part, to the specific mutation of the p63 gene present. These syndromes are further classified as forms of ectodermal dysplasia, a group of disorders characterized by abnormalities that occur during early embryonic development. Ectodermal dysplasias typically affect the hair, teeth, nails, and/or skin.

Symptoms

The symptoms of AEC syndrome are highly variable, even among members of the same family. The variability is due, in part, to different mutations of the p63 gene (e.g. certain mutations are more likely to be associated with certain symptoms). 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 p63-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 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 symptoms of 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 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. One report noted that affected adults have on average 4.75 permanent (secondary) 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 abnormally 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), fingers that are stuck in a bent or flexed position (camptodactyly), and a condition in which part or all of the central digits (fingers or toes) are missing (ectrodactyly or split hand-foot malformation).

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).

Causes

AEC syndrome is caused by a mutation in the p63 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 gene name in AEC syndrome is transcription factor 63 (TP63); the protein product of the gene is known as p63. AEC syndrome is inherited as an autosomal dominant trait. Some 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 regardless of the sex of the resulting child.

Investigators have determined that the TP63 gene is located on the long arm (q) of chromosome 3 (3q27). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q27” refers to band 27 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The TP63 gene contains instructions for synthesizing (encoding) a protein (p63) that is essential for the proper development of the limbs and structures derived from the ectoderm. The ectoderm is outermost germ layer of the developing embryo from which numerous structures of the body are derived including the hair, nails, glands of the skin, mucous membranes of the mouth, etc. Mutations of this gene lead to a reduction of functional levels of normal p63 protein, which hinders the proper development of these structures.

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 (reduced penetrance). Researchers have noted that specific features of AEC syndrome are more likely or only associated with specific mutations of the TP63 gene. In addition, 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.

Affected Populations

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 cases have been described in the medical literature.

Related Disorders

Symptoms of the following disorders can be similar to those of AEC syndrome. Comparisons may be useful for a differential diagnosis.

Several disorders in addition to AEC syndrome are caused by mutations of the p63 gene. These disorders are allelic, caused by different mutations to the same disease gene. Some researchers consider these disorders different expressions of the same disease process. However, other researchers have noted that associated symptoms tend to vary based upon the specific mutation present (genotype-phenotype correlation), resulting in distinct yet overlapping syndromes. These disorders include AEC/Hay-Wells syndrome/Rapp Hodgkin syndrome, ADULT syndrome, limb-mammary syndrome, and nonsyndromic split hand/foot malformation. Some individuals with isolated (nonsyndromic) cleft lip also have mutations of the p63 gene. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Epidermolysis bullosa (EB) is a genetic skin disorder characterized clinically by blister formation from mechanical trauma. There are three main types with additional sub-types identified. There is a spectrum of severity, and within each type, one may be either mildly or severely affected. EB ranges from being a minor inconvenience requiring modification of some activities, to being completely disabling and, in some cases, fatal. Friction causes blister formation. Blisters can form anywhere on the surface of the skin, within the oral cavity and in more severe forms may also involve the external surface of the eye, as well as the respiratory, gastrointestinal and genitourinary tracts. In some forms of the disease, disfiguring scars and disabling musculoskeletal deformities occur. Currently, there is no cure for EB. Supportive care includes daily wound care, bandaging, and pain management as needed. (For more information on this disorder, choose “epidermolysis bullosa” as your search term in the Rare Disease Database.)

Ectodermal dysplasias (EDs) are a group of rare genetic multisystem disorders that typically affect structures that arise from the outermost layer of the embryo (ectoderm). EDs typically affect the hair, teeth, nails, and/or skin. Several other ectodermal dysplasia disorders may be characterized by sparse or absent hair, absence or improper functioning of sweat glands, skin abnormalities, malformations of the nose, and/or other abnormalities similar to those associated with EEC syndrome. (For more information on these disorders, choose the specific disorder name or “ectodermal dysplasias” as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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 or help assess the severity of the disorder. 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.

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, orthopedists, orthopedic surgeons, dermatologists, dentists, audiologists, otolaryngologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.

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 in made in the eardrum and small tubes are placed inside to relieve pressure and drain fluid to treat hearing loss and ear infections. Artificial tears may be necessary for individuals with lacrimal duct obstruction and dry eyes. Hypohidrosis is mild and usually does not require treatment.

A child’s weight should be monitored and proper caloric intake provided. If growth still fails to improve, the insertion of a gastrostomy tube can be considered. A gastrostomy tube delivers nutrients directly into the stomach through an incision made in the abdominal wall.

Investigational Therapies

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: prpl@cc.nih.gov

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/

Organizations related to AEC Syndrome

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., cleft palate, etc.)

References

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, Bree AF, van Bokhoven H. Updated:06/08/2010. Ankyloblepharon-Ectodermal Defects-Cleft Palate/Lip Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:106260; Last Update:07/15/2011. Available at: http://omim.org/entry/106260 Accessed on: May 24, 2013.

Report last updated: 2013/10/25 00:00:00 GMT+0