Hay and Wells (1976) described 7 individuals from 4 families with an uncommon disorder characterized by congenital ectodermal dysplasia with coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; and cleft ... Hay and Wells (1976) described 7 individuals from 4 families with an uncommon disorder characterized by congenital ectodermal dysplasia with coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; and cleft lip/palate. Speigel and Colton (1985) reported an affected mother and son who both had cleft lip and palate. The eyelashes were rudimentary, and in the son there was fusion of the right upper and lower eyelids at birth. Greene et al. (1987) described 2 isolated cases. Weiss et al. (1992) described an isolated case. They reported 2 other patients with ankyloblepharon filiforme adnatum who had chromosomal abnormalities and 1 patient who had the abnormality as an isolated finding. Seres-Santamaria et al. (1993) reported a family in which 2 sibs showed cleft palate, ankyloblepharon, and ectodermal defects and, in addition, had congenital adhesions between the upper and lower jaws (alveolar synechiae). Neither parent had any features of the syndrome, suggesting this is either a recessive form of Hay-Wells syndrome with additional features or should be viewed as a separate entity. It is possible, of course, that the family reported by Seres-Santamaria et al. (1993) represented an instance of germinal mosaicism for the dominant mutation in one of the normal parents. Bertola et al. (2000) described a 5-year-old Brazilian boy with ectodermal dysplasia, ankyloblepharon, and bilateral choanal atresia but without cleft palate. The authors noted that choanal atresia was present in 1 of the patients reported by Hay and Wells (1976). The patient's nonconsanguineous parents had no ectodermal abnormality, and there was no family history of the disorder. Fete et al. (2009) provided a conference report from the 2006 International Research Symposium on AEC Syndrome. They noted that features present in 100% of 12 AEC patients presented in a workshop included scalp/skin erosions, ankyloblepharon, dental abnormalities, recurrent otitis media, and nail abnormalities; in addition, 92% had cleft palate, and 83% had cleft lip. Nails were not characteristically 'hyperconvex' as previously described, but were more often thin, distorted, or absent. The most dramatic ophthalmologic abnormality was blepharitis. Scalp erosions were a major source of morbidity for affected infants, and tetracyclines, especially doxycycline, were recommended for dual antimicrobial and matrix metalloproteinase activity. Fete et al. (2009) noted that many children with AEC have nutritional issues, with a majority suffering failure to thrive that was out of proportion compared to other children with isolated cleft lip/palate; the reasons for this were not clear. Cole et al. (2009) evaluated 18 patients with a diagnosis of AEC, who all had a history of otitis externa or otitis media; 14 of 15 subjects tested had conductive hearing loss, and 8 had hoarseness or voice problems. The authors suggested that many oroauditory problems in AEC are likely related to palatal clefting, as well as associated disorders such as feeding difficulty, recurrent middle ear infection, and speech disarticulation. Cole et al. (2009) noted that persistent feeding difficulties following cleft closure indicated that additional factors might be involved, and suggested that increased tissue vulnerability associated with absent epidermal appendages might also play a role. Sutton et al. (2009) examined 17 AEC patients from 13 unrelated families and found that short stature and poor weight gain with preservation of head circumference were present in nearly all patients. Additional features included trismus in 35% and hypospadias in 85% of males. In contrast to previous reports of syndactyly limited to the soft tissue, 8 (47%) of 17 patients had bilateral complete 2-3 toe syndactyly, and 3 cases (18%) had 3-4 toe syndactyly that was noted to extend to the fifth toe in some cases. In 4 (24%) of 17 cases there was webbing and/or syndactyly of the hands involving the third and fourth digits. Other limb anomalies included hammertoe deformities in 8 (47%) of the 17 patients. Sutton et al. (2009) concluded that limb involvement in AEC is more significant than previously thought; they also noted that these patients confirmed the extreme clinical variability in AEC. Dishop et al. (2009) used light microscopy to examine biopsies of normal and lesional skin from 19 AEC patients; in addition, hair samples from 18 patients were examined by light and scanning electron microscopy. Histopathologic changes identified within the skin biopsies from clinically unaffected skin included mild atrophy, focal orthokeratosis, and mild superficial perivascular lymphocytic dermatitis. Scattered melanophages in the superficial and deep dermis were believed to reflect postinflammatory changes. Examination of hair shafts revealed atrophy and loss of melanin pigment in some patients; structural abnormalities included pili torti, pili triangli et caniculi, and irregular indentation and shallow grooves. No pathognomonic findings of skin or hair were identified.
Some phenotypic overlap can be recognized with Hay-Wells syndrome and other ectodermal dysplasia syndromes, including ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC; 604292). Celli et al. (1999) demonstrated that heterozygous mutations in the TP63 gene are the major cause of EEC ... Some phenotypic overlap can be recognized with Hay-Wells syndrome and other ectodermal dysplasia syndromes, including ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC; 604292). Celli et al. (1999) demonstrated that heterozygous mutations in the TP63 gene are the major cause of EEC syndrome. McGrath et al. (2001) analyzed the TP63 gene in AEC syndrome patients and identified missense mutations in 8 families. All mutations gave rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and were predicted to affect protein-protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. The authors suggested that a distinct genotype-phenotype correlation can be recognized for EEC and AEC syndromes. In 2 sibs and their mother who had been diagnosed with Rapp-Hodgkin syndrome (RHS; 129400), Dianzani et al. (2003) identified a 1-bp deletion in the TP63 gene (603273.0017). The mother had a slight ankyloblepharon on the right eye at birth which was surgically treated; Dianzani et al. (2003) suggested that AEC and RHS are the same clinical entity. In a patient with AEC previously described by Bertola et al. (2000), Bertola et al. (2004) identified an ile510-to-thr mutation in the TP63 gene (603273.0018). They identified the same mutation in a patient with RHS and concluded that AEC and RHS represent variable expression of a single genetic disorder. In an 11-year-old boy who displayed an overlapping phenotype with features of both AEC and RHS, Prontera et al. (2008) identified heterozygosity for an 11-bp duplication in the TP63 gene (603273.0027). The authors stated that their findings confirmed the hypothesis that AEC and RHS are variable expressions of a single genetic disorder, and suggested that intermediate phenotypes are possible.
Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is most often a clinical diagnosis, although in some instances molecular genetic testing of the causative gene, TP63, can be helpful in establishing the diagnosis. ...
DiagnosisClinical Diagnosis Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is most often a clinical diagnosis, although in some instances molecular genetic testing of the causative gene, TP63, can be helpful in establishing the diagnosis. The cardinal features are: Ankyloblepharon filiforme adnatum. Typically manifest as strands of tissue that completely or partially fuse the upper and lower eyelids. In the latter instance, they may be barely perceptible and lyse spontaneously. Although a definitive part of the syndrome, ankyloblepharon may not be present or detected in up to 50% of cases. Ectodermal defects. Typically manifest as sparse wiry hair; skin erosions and unique pigmentary skin changes; nail changes; dental changes; and subjective decrease in sweating capacity. Note: Starch iodide sweat testing of the palms is rarely helpful in documenting sweating ability. Cleft lip/palate. Present in nearly 100%; the spectrum includes submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, and the combination of cleft lip and cleft palate. In a series of 18 patients: 44% had cleft lip (~1/3 bilateral); 100% had some form of palatal cleft (cleft hard palate: 56%; cleft soft palate: 89%; submucous cleft palate: 17%).Note: Rapp-Hodgkin syndrome (RHS), once thought to be a separate entity, is now considered to be part of the spectrum of the AEC syndrome because of the overlap of clinical manifestations and TP63 mutations observed in the two conditions [Cambiaghi et al 1994, McGrath et al 2001]. TestingDermato-pathologic findings are rarely diagnostic.Hair. Light and scanning microscopy may reveal structural and pigmentary alterations of the hair including kinking, grooves, and discontinuous pigmentation. Skin. Histopathologic features of skin biopsies may reveal epidermal atrophy, pigment incontinence, and a prominent superficial perivascular plexus with limited lymphocytic infiltrate [Dishop et al 2009]. Molecular Genetic Testing Gene. TP63 is the only gene associated with AEC syndrome.Clinical testing Sequence analysis of TP63 reveals mutations in the majority of affected individuals. Approximately 82% of documented mutations are found in the sterile alpha motif (SAM) domain with the remaining 18% occurring in the transactivation inhibitory (TI) domain [Rinne et al 2009]. The vast majority of these are missense mutations. One single nucleotide deletion mutation has been reported (see Molecular Genetics). Previous studies had found mutations in approximately 75% of individuals [Rinne et al 2009], raising the possibility of either an incorrect diagnosis in those without a TP63 mutation or presence of a mutation not detectable by sequence analysis of the coding region (e.g., deletion of an exon[s] or a mutation in the regulatory region). Somatic mosaicism may also decrease the sensitivity of mutation detection.Sequence analysis of select exons. Sequence analysis of exons 13 and 14, encoding the SAM domain and the TI domain, should be sequenced first for optimal mutation detection.Deletion/duplication analysis. To date, no deletion or duplication of a TP63 exon(s) or of an entire allele associated with AEC syndrome has been reported. Table 1. Summary of Molecular Genetic Testing Used in TP63-Related Disorders View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTP63Sequence analysisSequence variants 275%-100%ClinicalSequence analysis of select exonsSequence variants of select exons 375%-100%Deletion/ duplication analysis 4Exonic and whole-gene deletions Unknown 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Exons 5-8, 13, 14. Selected exons for sequencing may vary by laboratory.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. 5. No exonic or whole-gene deletions or duplications have been reported involving TP63 as causative of TP63-related disorders. Therefore, the mutation detection frequency is unknown.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy Confirming/establishing the diagnosis in a proband. If TP63 molecular genetic testing is used to confirm the diagnosis of AEC syndrome, the following tiered approach can be considered: 1.Perform sequence analysis of exons 13 and 14, which encompass the sterile alpha motif (SAM) domain and the transactivation inhibitory (TI) domain.2.If no mutation is identified in step 1, perform sequence analysis of the alternative exon 3' since mutations have been identified in three individuals with a phenotype resembling AEC/Rapp-Hodgkin syndrome [Rinne et al 2008]. 3.If no mutation is identified in steps 1 and 2, sequence analysis of the entire gene may be considered as the clinical findings of AEC syndrome may overlap with its allelic disorders: ADULT syndrome; ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome; limb-mammary syndrome; and split-hand/foot malformation, type 4 (see Table 2).4.Deletion/duplication analysis may be appropriate in those rare instances in which a clinical diagnosis of AEC syndrome is secure but no mutations are found by sequence analysis of TP63. Although no TP63 deletions or duplications causing AEC syndrome have been identified to date, it is possible that on occasion such rearrangements cause AEC syndrome. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders The clinical findings in TP63-related disorders are summarized in (Table 2).Table 2. Clinical Features of AEC and Other TP63-Related Disorders View in own windowFeatureTP63-Related DisorderAECADULTEECLimb-mammarySHFM4Ankyloblepharon filiforme adnatumXEctodermal dysplasiaXXXRare • Hypohidrosis (mostly subjective)XXX • Nail dysplasiaXXMildX • Sparse hairXXX • Tooth abnormalitiesXXXXCleftingXXXOther FeaturesEctrodactyly/syndactylyXXXXXLacrimal duct obstructionXXXXDermal erosionsXHypopigmentationXXXHypospadiasXTrismusXExcessive frecklingXHypoplastic breastsXXHypoplastic nipplesXXGenitourinary abnormalitiesXBlepharophimosisXADULT = acro-dermato-ungual-lacrimal-toothEEC = ectrodactyly, ectodermal dysplasia, cleftingSHFM4 = split hand/foot malformation type 4ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome can be distinguished from AEC by presence of excessive freckling and breast abnormalities and absence of ankylobelpharon filiforme adnatum, clefting, and dermal erosions. ADULT syndrome is typically associated with missense mutations at Arg298. Only two other point mutations have been reported for ADULT syndrome: p.Asn6His and p.Gly173Asp [Rinne et al 2006, Rinne et al 2007]. For further explanation of issues regarding naming of TP63 mutations see Molecular Genetics, Normal allelic variants, Note.EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome can be distinguished from AEC syndrome by presence of renal abnormalities and absence of ankyloblepharon filiforme adnatum and dermal erosions. All EEC mutations are missense mutations in the DNA binding domain and have been demonstrated to disrupt DNA binding [Rinne et al 2006].Limb-mammary syndrome is distinguished from AEC syndrome by presence of hypoplastic breasts and nipples and absence of ankyloblepharon filiforme adnatum and dermal erosions. Limb-mammary syndrome is caused by missense mutations that are located between the transactivation domain and the DNA binding domain (Gly115, Ser129 and Gly173 residues) or by truncating mutations in the SAM domain of TP63 [van Bokhoven et al 2001, Rinne et al 2007].SHFM4 (split hand/foot malformation type 4) Nonsyndromic split hand/foot malformation type 4 (SHFM4) has no additional phenotypic manifestations in addition to the limb anomalies. Mutations associated with SHFM4 are not restricted to a specific protein domain [Rinne et al 2007].Note that rare cases of isolated cleft lip/cleft palate have been associated with TP63 mutations [Leoyklang et al 2006].
The manifestations of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome are typically present at birth. ...
Natural History The manifestations of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome are typically present at birth. Ankyloblepharon is present in 70% of neonates. While the upper- and lower-eyelid adhesions can be obvious, partial adhesion of the upper and lower eyelids can be subtle and these filiforme adhesions can spontaneously lyse before they are recognized as such. Lacrimal puncta are frequently absent, often leading to chronic conjunctivitis and blepharitis which is often not recognized in infancy but rather seen in early childhood [Sutton et al 2009]. Ectodermal defects. Nearly 100% of affected neonates have superficial skin erosions that vary from very limited to severe full-body involvement that is life-threatening. The erosions most typically affect the scalp at birth and during infancy. Severe scalp erosions often lead to scarring alopecia and hypotrichosis. The skin erosions tend to be recurrent and intermittent throughout childhood and into adulthood with frequent involvement of the head and neck, palms, soles, and skin folds. Congenital erythroderma (i.e. diffuse erythema with associated erosions) is observed in 70%-90% of infants. The skin can also appear shiny with a collodion membrane (red, shiny, membranous skin changes) [Siegfried et al 2005]. Children typically manifest cutaneous depigmentation and scarring, most likely due to postinflammatory pigmentary changes related to previous erythroderma and associated underlying erosions which may or may not be appreciated clinically. African American infants can have facial hypopigmentation in a mask pattern that improves with age. Affected individuals with fair skin typically have a reticulated hyperpigmentation on the neck and intertriginous areas that progresses with age to cribiform, reticulate, stellate, or punctate scarring most commonly on the shoulders, upper back, and chest. Hair changes become more obvious with age. Hair is typically light-colored and coarse, wiry, and brittle with a spun glass/gold or “uncombable” appearance. Eyebrows and eyelashes are sparse.Nail changes, present in all and more obvious with age, vary among individuals. Most affected individuals have nail dystrophy (abnormal nail plate texture) and hyperconvex nail plates. Micronychia (abnormally small nail plates), distal frayed edges with nail plate resorption, and absent nails are also frequent [Julapalli et al 2009]. Malformed teeth (conical shape with small occlusal tables) and hypodontia (reduced number of teeth) also become evident during childhood and adolescence. Affected adults have an average of 4.75 secondary teeth [Farrington & Lausten 2009]. Subjective decreased sweat production is universal and is reported as heat intolerance; however, this does not lead to hyperthermia or fevers as seen in hypohidrotic ectodermal dysplasia.Clefting is present in all. Clefting can include submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, or the combination of cleft lip and cleft palate [Cole et al 2009]. Other. Limb anomalies, reported in the majority of individuals, are most commonly syndactyly of fingers and toes, but camptodactyly (permanent and irreducible flexion of the fingers) of hands has been seen and ectrodactyly of the hands and feet was observed in 2/17 individuals (12%) with AEC syndrome [Sutton et al 2009].Hypospadias has been reported in 78% of males with AEC syndrome [Sutton et al 2009]. Trismus has been reported in 35% of individuals with AEC syndrome [Sutton et al 2009]. Poor weight gain and failure to thrive should be anticipated and treated appropriately with nutritional supplementation; in one study gastrostomy placement was required in 25% of affected infants as a result of unsuccessful attempts with increased oral caloric intake. Poor weight gain improves with age.Linear growth abnormalities are observed in early childhood with a significantly lower height for age as compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [Motil & Fete 2009].Facial features become more distinctive with age. Findings commonly include maxillary hypoplasia, small mandible, broad nasal root, hypoplastic alae nasi, thin vermillion border, and short philtrum. Over 90% of children have conductive hearing loss, often with secondary speech delay [Cole et al 2009]. Psychological impact related to the phenotypic features of the disease can include a reduced quality of life with negative impact on both child and family. In one study, a variable degree of psychological functioning was noted with some families reporting few ill effects from the disease while others reported significant impact [Lane et al 2009].
AEC syndrome. No genotype-phenotype correlations have been identified in AEC syndrome. Inter- and intrafamilial variability has been observed among individuals with the same mutation [Bree 2009]. ...
Genotype-Phenotype Correlations AEC syndrome. No genotype-phenotype correlations have been identified in AEC syndrome. Inter- and intrafamilial variability has been observed among individuals with the same mutation [Bree 2009]. TP63-related disorders. See Table 2 and discussion that follows.
Epidermolysis bullosa. Because of the presence of skin erosions at birth, many affected individuals are misdiagnosed with epidermolysis bullosa; however, the erosions of AEC syndrome are typically more superficial and not associated with formation of bullae. In addition to the non-dermatologic phenotypic differences, dermatopathology should distinguish epidermolysis bullosa from AEC syndrome. The presence of erythroderma with a collodion membrane can also lead to an initial misdiagnosis of ichthyosis in the newborn period [Siegfried et al 2005]. ...
Differential DiagnosisEpidermolysis bullosa. Because of the presence of skin erosions at birth, many affected individuals are misdiagnosed with epidermolysis bullosa; however, the erosions of AEC syndrome are typically more superficial and not associated with formation of bullae. In addition to the non-dermatologic phenotypic differences, dermatopathology should distinguish epidermolysis bullosa from AEC syndrome. The presence of erythroderma with a collodion membrane can also lead to an initial misdiagnosis of ichthyosis in the newborn period [Siegfried et al 2005]. Curly hair-ankyloblepharon-nail dysplasia syndrome (CHANDS) has the overlapping features of ankyloblepharon and hair changes, but it does not typically include the significant facial/oral clefting or skin erosions that are virtually universal in AEC syndrome.Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). In HED the hypohidrosis is severe enough to impair body temperature regulation, a problem not seen in AEC syndrome. Orofacial clefting, universal in AEC syndrome is not typically seen in HED.
To establish the extent of disease in an individual diagnosed with AEC syndrome, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with AEC syndrome, the following evaluations are recommended:Medical genetics to aid in diagnosis, coordination of health surveillance, and genetic testing and counselingDermatology to evaluate and treat related skin issues, especially erosionsGastroenterology for growth and nutrition issuesDietary if there are concerns about failure to thriveOphthalmology for evaluation and treatment of ocular issues including ankyloblepharon, lacrimal duct obstruction, dry eyes and blepharitisPlastic surgery to evaluate and repair cleft lip and palateOtolaryngology for evaluation and treatment of recurrent otitis media and speech issuesAudiology to evaluate for hearing lossDental to evaluate and address issues of hypodontiaProstodontics to address potential need for dental implantsPsychology/psychiatry to address developmental issues and provide support for the individual and family by assisting in dealing with the impact of the phenotype on a normal lifeTreatment of ManifestationsA multidisciplinary approach is recommended including regular evaluations with specialists in medical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, gastroenterology, and psychiatry.Ankyloblepharon filiforme adnatum. These are often small and autolyse shortly after birth; larger ones may require surgical separation by an ophthalmologist. Ectodermal defects. Wigs can be used, if desired, for the alopecia. There are no known therapies for the nail changes or skin pigmentary alternations.Dentures should be considered in early childhood and the possibility of dental implants should be considered in the teens or early adult years.Impaired sweating is not severe and doe not require special care.Skin erosions. The skin erosions are difficult to treat, are prone to excessive ineffective granulation response, are at risk for secondary infection, and are not responsive to most standard wound care regimens or antibiotic therapy [Julapalli et al 2009]. They should be treated with gentle wound care and periodic, dilute bleach soaks (Dakins solution) to prevent secondary infection. Occlusive dressings should not be used as they tend to stimulate granulation tissue. Secondary infections should be treated with topical or oral antibiotics or antifungal agents when appropriate. Empiric treatment (i.e., use of antibiotic without culture-proven infection) is not recommended. Cleft lip/palate. Clefting should be addressed as soon as developmentally possible. Typical feeding issues associated with clefting are seen and include: poor suck, difficulty coordinating feeding and breathing, and excessive air intake. A nurse, nutritionist, pediatrician, speech therapist or other specialist familiar with the management of feeding issues in children with cleft lip/palate should be consulted. Clefts are typically repaired between ages nine and 18 months depending on the severity of the defect, surgical technique, and need for a stated (multi-step) surgical repair. Other. Weight should be followed closely with assessment for signs of failure to thrive. If optimization of oral caloric intake fails to improve growth, gastrostomy tube placement may be considered. Myringotomy as needed for conductive hearing loss resulting from chronic otitis media.Psychological impact of the phenotypic features of the disorder on patient and family should also be considered and referrals made to psychiatry or psychology as appropriate.Prevention of Secondary ComplicationsInfants with severe skin erosions should be monitored and treated aggressively for dehydration, electrolyte imbalances, malnutrition and secondary infection and sepsis. SurveillanceRegular evaluation with a multidisciplinary team is recommended for evaluation and prompt treatment of disease manifestations. In particular: Dental findings over time may warrant use of dental prosthetics. Periodic hearing evaluations should be performed as conductive hearing loss is common.Agents/Circumstances to AvoidProlonged exposure to sunlight should be avoided to prevent sunburn of hypopigmented areas and to prevent increasing the contrast between the patchy areas of hyper- and hypopigmentation. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationNo specific trials for therapies are being conducted at this time, but protein therapy in mice models is a future possibility.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherThe National Foundation for Ectodermal Dysplasias (NFED) (www.nfed.org) is an excellent resource for affected individuals, their families and clinicians who care for these individuals.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTP633q28Tumor protein 63TP63 @ LOVDTP63Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome (View All in OMIM) View in own window 106260ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE 603273TUMOR PROTEIN p63; TP63Normal allelic variants. Many TP63 transcripts encoding different proteins have been reported but the biological validity and the full-length nature of these variants have not been determined [NCBI RefSeq]. See NCBI Entrez Gene for TP63 transcript variants.The transcript variant NM_003722.4 has 16 exons and is the longest TP63 transcript; it encodes the longest protein, isoform 1 (also known as TAp63alpha, KET, and p51B). The transcript variant (6), NM_001114982.1, differs in the 5' UTR and coding region, and in the 3' UTR and coding region, compared to variant 1. The resulting protein (isoform 6, also known as deltaNp63gamma) is shorter and has distinct N- and C-termini, compared to isoform 1. Note: The nomenclature for TP63 mutations is problematic. The reason for confusion is that the reference sequence for TP63 has been changed over the years. The original reference sequence for Tap63alpha was defined by the cDNA with accession number AF075430, which encodes a protein of 641 amino acids. This is the cDNA reported in Yang et al [1998]. The numbering of mutations is based on this clone (except for those that are specific for the ΔN 5' end, which are based on NM_001114982.1). Yang et al [1998] also reported a protein with an extended 5' end, which they denoted TA*p63alpha. This protein encodes an additional 39 amino acids at the N-terminal end, resulting in a protein with a total of 680 amino acids. Later, this cDNA/protein (accession NM_003722.4) became the reference sequence for Tap63alpha. Taking this sequence as a reference, all previously reported mutations should also be renamed by adding 39 amino acids. For example, p.Arg298Gly would be p.Arg337Gly (Table 3). Pathologic allelic variants. Affected individuals are heterozygous for mutations in the sterile alpha motif (SAM) or transactivation inhibitory (TI) domain of TP63. In rare cases, a mutation has been found in the ΔN-specific domain of the protein. Mutations are most often missense substitutions in the SAM domain. One single nucleotide deletion (c.1846delC) results in a frameshift at amino acid 616 followed by 87 incorrect amino acid residues and a stop codon. Table 3. Selected TP63 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change (Alias 1)Reference Sequencesc.16A>Cp.Asn45His (Asn6His)NM_001114982.1 NP_001108454.1c.1846delCp.Leu616Serfs*88 (Arg616fs*655)NM_003722.4 NP_003713.3c.518G>Ap.Gly173Asp (G134D) 2c.1009C>Gp.Arg337Gly (Arg298Gly) 2c.1010G>Ap.Arg337Gln (Arg298Gln) 2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. In these instances, alias nomenclature is based on sequence AF075430.Normal gene product. This gene encodes a member of the p53 family of transcription factors. The transcript variant NM_003722.4 is the longest TP63 transcript and encodes the longest protein of 680 amino acid residues (isoform 1, also known as TAp63alpha, KET and p51B). ). The transcript variant NM_001114982.1 encodes isoform 6, also known as deltaNp63gamma (NP_001108454.1), which is shorter and has distinct N- and C-termini, compared to isoform 1. Abnormal gene product. The pathologic consequences of mutations in the SAM and TI domains are poorly understood.