Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate
Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate
National Organization for Rare Disorders, Inc.
It is possible that the main title of the report Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.
- ectrodactyly-ectodermal dysplasia-clefting syndrome
- ectrodactyly-ectodermal dysplasia-orofacial clefts
- EEC syndrome
Related Disorders List
Information on the following diseases can be found in the Related Disorders section of this report:
Ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome is a rare genetic disorder. Symptoms can vary greatly from one person to another. Affected individuals often have abnormalities affecting the limbs including ectrodactyly, a condition in which part or all of the central digits (fingers or toes) are missing. Ectrodactyly often affects the middle fingers or toes, but can present differently in different people (or be absent altogether). A groove or gap in the upper lip (cleft lip) and a groove or gap in the roof of the mouth (cleft palate) may also occur. The ectodermal dysplasia component refers to abnormalities to structures that arise from the outermost layer of the embryo (ectoderm). In EEC syndrome, this generally affects the hair, teeth, nails, skin and sweat glands. Individuals with EEC syndrome can also develop a variety of additional symptoms including abnormalities of the genitourinary system and the eyes. Intelligence does not seem to be affected. Most cases of EEC syndrome are caused by mutations of the p63 gene and are either new (spontaneous) mutations or are inherited as autosomal dominant disorders.
There are at least four other syndromes caused by mutations of the p63 gene including AEC/Hay-wells syndrome, Rapp-Hodgkin syndrome, limb-mammary syndrome, and ADULT syndrome. In addition, p63 mutations have also been reported as the cause of nonsyndromic split hand/foot malformation and nonsyndromic cleft lip/palate (CL/P). 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.
The symptoms of EEC 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). Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Ectrodactyly, which is also known as split hand/foot malformation (SHFM), is a condition characterized by absence or malformation of one or more of the fingers or toes. Usually, the middle fingers or toes are affected. All four hands and feet may be affected in some individuals. However, some individuals have only mild malformation or are unaffected. Individuals with EEC may also exhibit webbing or fusion (syndactyly) of some of the fingers and/or toes. In some cases, syndactyly is the only limb defect that occurs.
Affected individuals have cleft lip with or without cleft palate. Additional distinctive facial features can occur including an undeveloped upper jaw (maxillary hypoplasia), a broad nasal tip, an abnormally long groove (philtrum) between the nose and the upper lip, and narrowing or blockage of the nasal airways (choanal atresia).
The type and severity of ectodermal dysplasia in individuals with EEC syndrome is highly variable. The skin, hair, teeth, and sweat glands are commonly affected. Affected individuals may have dry, discolored (hypopigmented) skin. The skin may also be itchy. In some cases, mildly thickened, scaly patches of skin (hyperkeratosis) may also develop. Individuals tend to be fair skinned and have sparse, coarse, slow-growing scalp hair. Eyelashes or eyebrows may be sparse or absent.
Additional symptoms can include slow-growing, thin, malformed (dysplastic) nails and missing, malformed or underdeveloped teeth (hypodontia). Tooth decay (dental caries) is common and often severe. Tooth enamel may be abnormal. Some individuals experience reduced activity or absence of certain exocrine glands (glands that secrete into ducts) including the sweat, salivary, and small oil-producing (sebaceous) glands. Abnormality of the sweat glands can lead to a reduced ability to sweat (hypohidrosis), which can be associated with heat intolerance and fever. Abnormality of the salivary glands can lead to dry mouth (xerostomia).
Some individuals have eye issues including abnormalities of the tear (lacrimal) ducts that can cause frequent tearing, increased susceptibility to eye infections and chronic inflammation of the delicate membranes that line the inside of the eyes (conjunctivitis), potentially causing vision impairment. Additional abnormalities affecting the eyes can occur including sensitivity to light (photophobia), corneal ulcerations, inflammation of the cornea (keratitis), and inflammation of the eyelashes and eyelids (blepharitis).
In some cases, affected individuals may have genitourinary anomalies. Virtually any part of the genitourinary tract can be involved. Symptoms can include absence of the kidneys (renal agenesis), narrowing of the tubes that carry urine out of the body from the bladder (urethral atresia), and obstruction of the tubes (ureters) that carry urine from the kidney to the bladder, resulting in the accumulation of urine in the pelvis and kidney duct (hydronephrosis). An extremely uncommon genitourinary complication known as atrophic/dysplastic bladder epithelium has been reported in individuals with EEC syndrome. Epithelium refers to specific tissue that lines many of the cavities and structures within the body such as the bladder. In affected individuals, abnormal thinning of this lining within the bladder results in painful urination (dysuria), increased urgency to urinate and an increased frequency to urinate.
Additional abnormalities have been reported in some cases including underdeveloped (hypoplastic) nipples. Some individuals with EEC syndrome have developed hearing loss. The ears can be abnormally small and the outer part of the ears (auricles) malformed. Some individuals may develop glandular abnormalities such as an underdeveloped thymus and reduced activity of the pituitary gland (hypopituitarism). Glandular abnormalities can result in growth hormone deficiency.
Intelligence is usually unaffected in children with EEC syndrome. Language development, however, may be delayed due to certain associated abnormalities such as cleft lip/palate or hearing impairment.
Most cases of EEC syndrome are caused by mutations of the TP63 gene. The official gene name is TP63; the protein product of the gene is known as p63. A small percentage of cases with features resembling EEC syndrome are caused by chromosomal abnormalities. EEC syndrome is inherited as an autosomal dominant trait. Some cases occur sporadically with no previous family history of the disorder (i.e., new mutations).
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 that is essential for the proper development of the limbs and structures derived from the ectoderm. Mutations of this gene lead to a reduction of functional levels of normally functioning p63 protein, which hinders the proper development of these structures.
In rare cases, individuals with EEC syndrome carry chromosomal disruptions (deletions, translocations) on the long arm of chromosome 7 (7q11.2-q21.3).
When EEC syndrome is caused by mutations of the TP63 gene it is sometimes referred to EEC syndrome type 3 (EEC3); when it caused by chromosomal abnormalities of chromosome 7 it is referred to as EEC syndrome type 1 (EEC1). A disorder formerly designated EEC syndrome type 2 no longer exists.
In some cases EEC syndrome may be due to gonadal mosaicism, a condition in which some of a parent's reproductive cells (germ cells) carry the p63 or mutation, while others contain a normal cell line (mosaicism). The other cells (non-reproductive or somatic cells) in a parent's body do not have the mutation. As a result, one or more of the parent's children may inherit the gene mutation, potentially leading to development of EEC syndrome, while the parent does not have the disorder (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parent's have more than one child with the same genetic abnormality. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent's germ cells that carry the mutation versus the percentage that do not. There is no test for germline mosaicism before pregnancy. Testing during pregnancy may be available and is best discussed with a genetic specialist.
The symptoms and physical findings of EEC syndrome can vary greatly in severity from one person to another (variable expressivity). In addition, individuals who inherited a defective gene for EEC syndrome will not develop all of the symptoms discussed above (reduced penetrance). Researchers have noted that specific features of EEC syndrome are more likely or only associated with specific mutations of the p63 genes. 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 EEC syndrome.
EEC syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown.
Symptoms of the following disorders can be similar to those of EEC syndrome. Comparisons may be useful for a differential diagnosis.
Several disorders in addition to EEC 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 (nonsyndrommic) 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.)
Lacrimo-auriculo-dento-digital (LADD) syndrome is an extremely rare genetic disorder characterized by abnormalities affecting the lacrimal and salivary glands and ducts, ears, teeth and fingers and toes. The most common findings involve malformations in the network of structures of the eye that secrete tears and drain them from the eyes (lacrimal apparatus) and abnormalities of the forearms and fingers. Specific symptoms may vary greatly from case to case. LADD syndrome may occur sporadically or be inherited as an autosomal dominant trait. (For more information on this disorder, choose "LADD" 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.)
A diagnosis of EEC syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.
Clinical Testing and Work-Up
A variety of tests may be used to evaluate individuals with EEC syndrome. Imaging techniques may include traditional x-rays can be used assess abnormalities of the limbs and face. A complete ophthalmological exam will be performed to detect potential eye complications associated with the disorder such as lacrimal duct obstruction. A kidney (renal) ultrasound will be performed to detect potential kidney complications. An ultrasound uses reflected sound waves to create an image of the organ(s) in question.
Molecular examination of the small samples of skin tissue (skin biopsy) may reveal abnormal thinning of the outer layer of the skin (epidermis) and the absence of certain specialized structures normally located within the skin (e.g., sweat glands).
Molecular genetic testing can confirm a diagnosis of EEC syndrome. Molecular genetic testing can detect mutations in the TP63 gene or chromosomal abnormalities that account for the phenotype. In clinically diagnosed EEC syndrome patients, mutation analysis of the TP63 gene is the first test to perform; if negative, testing for chromosomal abnormalities can be considered. Testing is available only on a clinical basis.
Prenatal diagnosis of EEC syndrome can be suspected based upon identification of ectrodactyly, cleft lip/palate or other associated anomalies, which can be detected during a routine fetal ultrasound.
Prenatal diagnosis is available for families with a known risk for having a baby with EEC syndrome. Molecular genetic testing can be performed on cells obtained from the fluid that surrounds the developing fetus (amniotic fluid). A test known as chorionic villi sampling can also be used to obtain a prenatal diagnosis of EEC syndrome in these cases. Chorionic villi are thin, hair-like structures found on the placenta. Molecular genetic testing can also be performed on these cells.
The treatment of EEC 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, pediatric surgeons, plastic surgeons, orthopedic surgeons, orthopedists, dentists, speech therapists, specialists that are trained to deal with abnormalities of the eyes (ophthalmologists), ears (audiologists), and skin (dermatologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.
Reconstructive surgery may be beneficial for individuals with all defects causing functional disability such as ectrodactyly, syndactyly, cleft lip or palate and other associated facial anomalies (e.g., underdeveloped jaw, malformed ears). Dental surgery and corrective devices may be used to treat misshapen teeth. If teeth are missing, dentures may be necessary. Affected individuals should pay particular attention to dental health to prevent tooth decay.
Artificial tears may be necessary for individuals with lacrimal duct obstruction. Surgery may also be necessary for blocked lacrimal ducts. Emollients may be used to treat dry skin. If hearing impairment is present, hearing aids may be beneficial. Children with hypohidrosis should be monitored closely for signs of hyperthermia, particularly during periods of prolonged activity and or during summer months.
When hydronephrosis is present, temporary drainage of the urine may be necessary. Surgery may be indicated when pain or infection is present or when kidney function is compromised.
Genetic counseling may be of benefit for affected individuals and their families.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Bamshad MJ. p63 and the Ectodermal Dysplasia, Ectrodactyly, and Cleft Lip and/or Palate (EEC), Limb-Mammary (LMS), Ankyloblepharon, Ectrodactyly, and Cleft Lip/Palate (AEC, Hay-Wells), and Acro-Dermato-Ungual-Lacrimal-Digit (ADULT) Syndromes and Ectrodactyly (Split Hand/Foot Malformation). In: Inborn Errors of Development: the Molecular Basis of Clinical Disorders of Morphogenesis. Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. New York, NY: Oxford University Press; 2004:1017-1026.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. New York, NY: Oxford University Press; 2001:878-882.
Clements SE, Techanukul T, Coman D, Mellerio JE, McGrath JA. Molecular basis of EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome: fiver new mutations in the DNA-binding domain of the TP63 gene and genotype-phenotype correlation. Br J Dermatol. 2010;162:201-207. http://www.ncbi.nlm.nih.gov/pubmed/19903181
Rinne T, Brunner HG, van Bokhoven H. p63-associated disorders. Cell Cycle. 2007;6:262-268. http://www.landesbioscience.com/journals/cc/rinneCC6-3.pdf
Ray AK, Marazita ML, Pathak R, et al. TP63 mutation and clefting modifier genes in an EEC syndrome family. Clin Genet. 2004;66:217-222. http://www.ncbi.nlm.nih.gov/pubmed/15324320
Barrow LL, van Bokhoven H, Daack-Hirsch S, et al. Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. J Med Genet. 2002;39:559-566. http://jmg.bmj.com/content/39/8/559.full.pdf+html
Brunner HG, van Bokhoven H, Hamel BCJ. The p63 gene in EEC and other syndromes. J Med Genet. 2002;39:377-381. http://jmg.bmj.com/content/39/6/377.full
Van Bokhoven H, Hamel BCJ, Bamshad M, et al. p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Med Genet. 2001;69:481-492. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1235479/
Rinne T, Hamel B, van Bockhoven H, Brunner HG. Pattern of p63 mutations and their phenotypes – update. Am J Med Genet A. 2006;140:1396-1406. http://www.ncbi.nlm.nih.gov/pubmed/16691622
Lacombe D. EEC Syndrome. Orphanet encyclopedia, March 2011. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=1896. Accessed January 12, 2012.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:129900; Last Update:05/07/2009. Available at: http://omim.org/entry/129900. Accessed January 27, 2012.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:604292; Last Update:01/11/2012. Available at: http://omim.org/entry/604292. Accessed January 27, 2012.
Reid Sutton V, Bree AF, van Bokhoven H. Updated:06/08/2010. Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.
National Foundation for Ectodermal Dysplasias
6 Executive Drive
Fairview Hiights, IL 62208-1360
March of Dimes Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, NY 10605
Cleft Palate Foundation
1504 East Franklin Street
Chapel Hill, NC 27514-2820
NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
One AMS Circle
Bethesda, MD 20892-3675
Craniofacial Foundation of America
975 East Third Street
Chattanooga, TN 37403
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Ectodermal Dysplasia Society
Unit 1 Maida Vale Business Centre
England, GL53 7ER
For a Complete Report
This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.
The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only. NORD recommends that affected individuals seek the advice or counsel of their own personal physicians.
It is possible that the title of this topic is not the name you selected. Please check the Synonyms listing to find the alternate name(s) and Disorder Subdivision(s) covered by this report
This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.
For additional information and assistance about rare disorders, please contact the National Organization for Rare Disorders at P.O. Box 1968, Danbury, CT 06813-1968; phone (203) 744-0100; web site www.rarediseases.org or email email@example.com
Last Updated: 5/22/2012
Copyright 1993, 2000, 2012 National Organization for Rare Disorders, Inc.
Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.