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Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome, which is also known as Hay-Wells syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate, ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome, Hay-Wells syndrome, Rapp-Hodgkin syndrome is a rare genetic disease with an autosomal dominant transmission with ectodermal dysplasia forms 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 (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 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.
Causes
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 in an autosomal dominant pattern. 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 is 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.
Diagnosis
A diagnosis of AEC syndrome is based upon the 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 of having a baby with AEC syndrome.
Genetic Testing. Informed parental consent was obtained. DNA was extracted from peripheral blood collected from the affected child and his parents. According to the approach described in the literature, we performed sequence analysis of TP63 gene focusing on exons 13 and 14, which include the SAM domain [rx]. TP63 mutations were identified by bi-directional sequencing of genomic DNA. Alamut interface with Polyphen2 and SIFT software was used to perform bioinformatic predictions of mutation effects.
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 systematically and comprehensively plan an affected child’s treatment.
Small ankyloblepharon may break down or disintegrate autolyze) 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 underdevean loped 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 the also important.
Individuals with chronic skin erosions are at risk of developing a secondary infection, which can be treated with topical or oral antibiotics. Anti-fungal medications can also be used in some cases.
Myringotomy is 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.
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