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Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome

Synonyms: AEC Syndrome, Hay-Wells Syndrome

, MD, , MD, and , PhD.

Author Information
, MD
Associate Professor, Department of Molecular and Human Genetics
Baylor College of Medicine & Texas Children's Hospital
Houston, Texas
, MD
Dermatology Specialists of Houston
Houston, Texas
, PhD
Head, Neurogenetics & Molecular Neurobiology
Department of Human Genetics
Raboud University
Nijmegen, The Netherlands

Initial Posting: .

Summary

Disease characteristics. Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, which includes the Rapp-Hodgkin syndrome, is characterized by ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids); ectodermal defects (sparse wiry hair; skin erosions and unique pigmentary changes; nail changes; dental changes; subjective decrease in sweating capacity); and cleft lip/palate. Nearly 100% of affected neonates have superficial skin erosions that range from very limited to severe, even life-threatening, full body involvement. Scalp erosions at birth and during infancy are typical and, when severe, can lead to scarring alopecia and hypotrichosis. Limb anomalies are common and can include syndactyly of fingers and toes, camptodactyly (permanent and irreducible flexion of the fingers), and ectrodactyly (split hand split foot malformation).

Diagnosis/testing. The diagnosis is based on clinical findings and molecular genetic testing of TP63, the only gene known to be associated with AEC syndrome.

Management. Treatment of manifestations: A multidisciplinary team of specialists in medical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, gastroenterology, and psychiatry is recommended. Wigs can be used for alopecia; dentures may be considered in early childhood and dental implants in the teens or early adulthood. Skin erosions are treated with gentle wound care and periodic, dilute bleach soaks to prevent secondary infection. Cleft lip/palate is managed as per routine protocols with attention to feeding in infancy, recurrent otitis media, and speech therapy.

Prevention of secondary complications: Infants with severe skin erosions need aggressive monitoring/treatment of dehydration, electrolyte imbalances, malnutrition, and secondary infection and sepsis.

Surveillance: Regular evaluation with a multidisciplinary team with attention to dental needs and possible hearing loss.

Genetic counseling. AEC syndrome is inherited in an autosomal dominant manner. Approximately 30% of individuals have an affected parent and approximately 70% have a de novo mutation. Each child of an individual with AEC syndrome has a 50% chance of inheriting the disease-causing mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

GeneReview Scope

Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome: Included Disorders
  • Rapp-Hodgkin syndrome

Diagnosis

Clinical 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].

Testing

Dermato-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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
TP63Sequence analysis 4Sequence variants75%-100%
Sequence analysis of select exonsSequence variants of select exons 575%-100%
Deletion/ duplication analysis 6Exonic and whole-gene deletions Unknown 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Exons 5-8, 13, 14. Selected exons for sequencing may vary by laboratory.

6. 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.

7. No exonic or whole-gene deletions or duplications involving TP63 have been reported as causative of TP63-related disorders. Therefore, the mutation detection frequency is unknown.

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.

Clinical Description

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].

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.

Penetrance

A few individuals who do not appear to be clinically affected have had more than one child with AEC syndrome. These occurrences may be the result of reduced penetrance, but are more likely caused by somatic or germline mosaicism in one parent.

  • In one family, the TP63 mutation present in fraternal twins was seen in the phenotypically normal mother; the mutation data suggested somatic mosaicism [van Bokhoven, unpublished data].
  • In another family, one phenotypically normal parent had normal molecular genetic studies, whereas the other parent, reported to have a normal phenotype, was not available for DNA testing [van Bokhoven, unpublished data].

In contrast, reduced penetrance in the allelic disorder split hand/foot malformation type 4 (SHFM type 4) has been reported [Spranger & Schapera 1988].

Nomenclature

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is also known as Hay-Wells syndrome after the physicians who first described the condition in 1976.

Rapp-Hodgkin syndrome (RHS), once considered 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 in the two conditions [Cambiaghi et al 1994, McGrath et al 2001].

Prevalence

AEC syndrome is rare. The prevalence is unknown.

Differential Diagnosis

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].

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.

Management

Evaluations 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 counseling
  • Dermatology to evaluate and treat related skin issues, especially erosions
  • Gastroenterology for growth and nutrition issues
  • Dietary if there are concerns about failure to thrive
  • Ophthalmology for evaluation and treatment of ocular issues including ankyloblepharon, lacrimal duct obstruction, dry eyes and blepharitis
  • Plastic surgery to evaluate and repair cleft lip and palate
  • Otolaryngology for evaluation and treatment of recurrent otitis media and speech issues
  • Audiology to evaluate for hearing loss
  • Dental to evaluate and address issues of hypodontia
  • Prostodontics to address potential need for dental implants
  • Psychology/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 life

Treatment of Manifestations

A 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 Complications

Infants with severe skin erosions should be monitored and treated aggressively for dehydration, electrolyte imbalances, malnutrition and secondary infection and sepsis.

Surveillance

Regular 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 Avoid

Prolonged 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

No 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.

Other

The 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 30% of individuals diagnosed with a AEC syndrome have an affected parent [van Bokhoven H, Bree AF, Sutton VR; unpublished data]
  • A proband with AEC syndrome may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is approximately 70% [van Bokhoven H, Bree AF, Sutton VR, unpublished data].
  • If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations are germline or somatic mosaicism in a parent or a de novo mutation in the proband. Two possible examples of somatic or germline mosaicism in a parent:
    • In one family, the TP63 mutation present in fraternal twins was seen in the phenotypically normal mother and the mutation data suggested somatic mosaicism [van Bokhoven, unpublished data].
    • In another family, one phenotypically normal parent had normal molecular genetic studies, whereas the other parent, reported to have a normal phenotype, was not available for DNA testing [van Bokhoven, unpublished data].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include targeted mutation analysis of leukocyte DNA and genetic counseling regarding the potential risk of recurrence as a result of germline mosaicism. Evaluation of parents has not determined that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected and/or the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, they could be at risk of having more children with AEC syndrome as a result of somatic or germline mosaicism.

Offspring of a proband. Each child of an individual with a TP63-related disorder has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome have been identified by GeneReviews staff.

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TP633q28Tumor protein 63TP63 @ LOVDTP63

Data 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)

106260ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE
603273TUMOR PROTEIN p63; TP63

Benign allelic variants. Many TP63 transcripts encoding different proteins have been reported but the biologic 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).

Pathogenic 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 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.16A>Cp.Asn45His
(Asn6His)
NM_001114982​.1
NP_001108454​.1
c.1846delCp.Leu616SerfsTer88
(Arg616fsTer655)
NM_003722​.4
NP_003713​.3
c.518G>Ap.Gly173Asp
(G134D) 2
c.1009C>Gp.Arg337Gly
(Arg298Gly) 2
c.1010G>Ap.Arg337Gln
(Arg298Gln) 2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. 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 pathogenic consequences of mutations in the SAM and TI domains are poorly understood.

References

Literature Cited

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Chapter Notes

Author Notes

Dr Sutton’s Web page

Dr van Bokhoven’s Web page

Dr Bree is a Scientific Advisory Board member (volunteer position) for the National Foundation for Ectodermal Dysplasias.

Acknowledgments

The authors would like to thank the National Foundation for Ectodermal Dysplasias and Executive Director Mary Fete, who organized the International Research Symposium on AEC syndrome, and all the individuals and families who participated in the research that contributed to this review. Additionally, we would like to express our gratitude to Dr John Carey and the American Journal of Medical Genetics for publishing these research results in a unified special issue of the journal.

Revision History

  • 8 June 2010 (me) Review posted live
  • 2 February 2010 (vrs) Original submission
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