Clinical characteristics.

The TP63-related disorders comprise six overlapping phenotypes:

• Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome)
• Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome
• Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3)
• Limb-mammary syndrome
• Split-hand/foot malformation type 4 (SHFM4)
• Isolated cleft lip/cleft palate (orofacial cleft 8)

Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

Diagnosis/testing.

The diagnosis of a TP63-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in TP63 identified by molecular genetic testing.

Management.

Treatment of manifestations: A multidisciplinary team of specialists in clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, nutrition/gastroenterology, and psychology is recommended. Skin erosions are treated with gentle wound care and periodic, dilute bleach soaks to prevent secondary infection, and infants with severe skin erosions are monitored and treated aggressively for dehydration, electrolyte imbalances, malnutrition, and infection. Wigs can be used for sparse hair and alopecia; dentures may be considered in early childhood and dental implants in the teens or early adulthood. Cleft lip/palate is managed per routine protocols; limb malformations are treated with occupational therapy and surgery as needed to optimize function.

Surveillance: Regular attention to dental needs and possible hearing loss.

Genetic counseling.

The TP63-related disorders are inherited in an autosomal dominant manner. Approximately 30% of individuals diagnosed with a TP63-related disorder have an affected parent. The proportion of individuals with a TP63-related disorder caused by a de novo TP63 pathogenic variant is approximately 70%. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Once the TP63 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

A TP63-related disorder should be suspected/considered in individuals with a combination of the following findings.

Clinical findings

• Ankyloblepharon filiforme adnatum
• Dermal erosions
• Signs of ectodermal dysplasia
  • Hypohidrosis
  • Nail dysplasia
  • Sparse hair
  • Tooth abnormalities
• Freckles in sun-exposed areas
• Cleft lip/palate
• Split-hand/foot malformation and/or syndactyly
• Lacrimal duct obstruction
• Hypopigmentation
• Hypospadias
• Hypoplastic nipples/breasts

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Note: The TP63-related disorders include five overlapping phenotypes as well as isolated cleft lip/palate (see Clinical Description and Table 2 for details on the phenotypes).

Establishing the Diagnosis

The diagnosis of a TP63-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in TP63 identified by molecular genetic testing (see Table 1). Identification of a heterozygous TP63 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with ectodermal dysplasia, cleft lip/palate, or split-hand/foot malformation are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The TP63-related disorders include the overlapping phenotypes summarized in Table 2 and fully described in the text that follows.

Genotype-Phenotype Correlations

Note: Pathogenic variants have been described on two TP63 isoforms: the TAp63α isoform, encoded by NM_003722.4, and the ΔNp63α isoform, encoded by NM_001114982.1, which is 39 amino acids shorter and has an alternate N-terminal TA domain. See Figure 1 for details.

Figure 1.

Typical and common TP63 pathogenic variants identified in various disorders as indicated by color key. Pathogenic variants indicated by * are specific for the ΔNp63α isoform and their numbering is based on the respective reference sequences (more...)

AEC syndrome. All pathogenic variants associated with AEC syndrome occur in either the sterile alpha motif (SAM) domain (82%) or the ΔNp63-specific N-terminal domain (18%). Pathogenic variants in the N-terminal domain that introduce premature termination codons lead to the use of an alternative start codon [Rinne et al 2008] and to the consequent production of ΔNp63α isoforms lacking the N-terminal domain, which are specifically associated with AEC syndrome. This isoform of p63 is the predominant isoform in mature epidermis, and it has been shown to repress ZNF750, leading to impaired epidermal differentiation [Zarnegar et al 2012].

ADULT syndrome is typically associated with pathogenic variants in the DNA binding domain. Other pathogenic variants have been reported in isolated individuals with features reminiscent of ADULT syndrome, but also of other TP63-associated syndromes in ΔNp63α (an alternative TA domain), in TAp63α between the TA and DNA binding domains [Rinne et al 2006b, Rinne et al 2007], and at other locations in TAp63α [van Zelst-Stams & van Steensel 2009].

EEC3. All EEC3-causing pathogenic variants are missense variants in the DNA binding domain and have been demonstrated to disrupt DNA binding [Rinne et al 2006b]. Splice changes and frameshifts associated with EEC3 have been reported [Celli et al 1999, van Bokhoven et al 2001, Barrow et al 2002, Monti et al 2013].

Limb-mammary syndrome is caused by pathogenic missense variants that are located between the transactivation domain and the DNA binding domain (p.Gly115, p.Ser129, and p.Gly173 residues in TAp63α) or by truncating variants in the SAM domain of TP63 [van Bokhoven et al 2001, Rinne et al 2007].

SHFM4. Pathogenic missense variants in the TA and DNA binding domains have been associated with SHFM4 [Rinne et al 2007].

Orofacial cleft 8 has been associated with a TP63 variant in the DNA binding domain [Leoyklang et al 2006, Basha et al 2018].

Penetrance

Reduced penetrance or possible germline mosaicism has been documented in a small number of individuals and families.

• Reduced penetrance for SHFM4 [Spranger & Schapera 1988] and ADULT syndrome [Amiel et al 2001] has been reported.
• 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 the result of somatic and germline mosaicism in one parent.
  In one family, the TP63 pathogenic variant present in affected fraternal twins was also present in the phenotypically normal mother. The data suggested somatic mosaicism in the mother [van Bokhoven, unpublished data] with presumed germline mosaicism.

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 pathogenic variants in the two conditions [Cambiaghi et al 1994, McGrath et al 2001].

EEC3 is thought to be genetically unrelated to EEC1 (which has been mapped to chromosome 7q11q21). An entity called EEC2 was initially mapped to chromosome 19 [O'Quinn et al 1998]; however, pathogenic variants in TP63 were ultimately identified [Celli et al 1999].

Prevalence

TP63-related disorders are rare. The prevalence of disorders individually or collectively is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a TP63 -related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management by multidisciplinary specialists, including clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, nutrition/gastroenterology, and psychology, is recommended.

Surveillance

Agents/Circumstances to Avoid

Prolonged exposure to sunlight should be avoided to:

• Prevent sunburn of hypopigmented areas and increase in contrast between the patchy areas of hyper- and hypopigmentation seen in AEC syndrome;
• Minimize freckling of skin in individuals with ADULT syndrome.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from regular evaluation for disease manifestations with attention to dental needs and possible hearing loss.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

TP63-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 30% of individuals diagnosed with AEC have an affected parent. This appears to be true for the other TP63-related disorders as well [H van Bokhoven, AF Bree, VR Sutton, unpublished data].
• The proportion of individuals with AEC caused by a de novo TP63 pathogenic variant is approximately 70%. This appears to be true for the other TP63-related disorders as well [H van Bokhoven, AF Bree, VR Sutton, unpublished data].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism * [Enriquez et al 2016; van Bokhoven, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
    * A parent with somatic and germline mosaicism for a TP63 pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with a TP63-related disorder may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the TP63 pathogenic variant identified in the proband.

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 and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. There can be a significant range of clinical variability in affected family members.
• If the TP63 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Enriquez et al 2016; van Bokhoven, unpublished data].
• If the parents have not been tested for the TP63 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a TP63-related disorder because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

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

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the TP63 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the TP63 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Transcription factor p63 encoded by TP63 is a key regulator in epithelial commitment and development. TP63 encodes a large number of p63 isoforms, which are engaged in dimeric and tetrameric complexes regulating a network of genes important for development of ectodermal structures [Khandelwal et al 2019]. Different p63 isoforms have been shown to play roles in various cells and tissues, such as the epidermis, oocytes, muscles, and cochlea. TP63 is a master regulator of the embryonic development and differentiation of ectodermal cells [Shalom-Feuerstein et al 2013]. Additionally, it plays a critical role in the development of the apical ectodermal ridge of the limb bud in collaboration with the signaling molecule FGF8 [Restelli et al 2014]. The ΔN promoter is the only active promoter and the 3′ exon is the first expressed exon detected in epidermal cells throughout epidermal stratification in many epithelial cells, such as those from skin, oral tissues, and the mammary gland [Sethi et al 2015, Soares & Zhou 2018]. In contrast, the TA isoform is generally expressed at a low level in a range of nonepithelial cells. Thus, TAp63 is expressed in oocytes and plays an important role in controlling apoptosis in response to DNA damage [Deutsch et al 2011]. In the cochlea, the TA isoform is also expressed and regulates the Notch signaling pathway, which is required for proper cochlea development [Terrinoni et al 2013]. Additionally, TAp63 has been found to be expressed in late-stage myogenesis [Cefalù et al 2015] and in cardiomyocyte development [Rouleau et al 2011].

Mechanism of disease causation. Variants in TP63 lead to three major phenotypes: ectodermal dysplasia, orofacial clefting (OFC), and split-hand/foot malformation (SHFM) [Celli et al 1999]. Heterozygous TP63 variants have been associated with five different syndromes with overlapping phenotypic features: ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome (EEC), ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, Rapp-Hodgkin syndrome (RHS), acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome, and limb-mammary syndrome (LMS). Rare TP63 variants are causative for OFC with variable mild ectodermal features (OFC8) [Leoyklang et al 2006], and for nonsyndromic SHFM4.

A broad spectrum of different heterozygous variants has been reported in TP63, leading to the developmental disorders stated above. The vast majority of variants give rise to amino acid substitutions. A striking genotype-phenotype correlation for TP63 missense variants is apparent in EEC and AEC syndrome / RHS [Rinne et al 2006a, Figure 1]. Variants underlying EEC and AEC syndrome / RHS exert dominant-negative effects by interfering with normal p63 proteins in dimeric and tetrameric complexes. Variants in LMS affect yet another region of the p63 protein, and probably have dominant-negative effects. Causative variants in ADULT syndrome typically give rise to amino acid substitution of arginine 337 in the DNA-binding domain (DBD) but appear to exert gain-of-function effects, in contrast to dominant-negative DBD missense variants seen in EEC syndrome. Deletions encompassing large parts of TP63 generating loss-of-function alleles are associated with OFC8 [Khandelwal et al 2019].

Notable TP63 variants. Figure 1 demonstrates typical and common TP63 pathogenic variants identified with the various phenotypes.

Author Notes

Dr Sutton's web page

Dr van Bokhoven's web page

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.

Author History

Alanna F Bree, MD; Dermatology Specialists of Houston (2010-2015)
V Reid Sutton, MD (2010-present)
Hans van Bokhoven, PhD (2010-present)

Revision History

• 1 April 2021 (ha) Comprehensive update posted live
• 5 December 2019 (vrs) Revision: correction to SHFM4
• 6 August 2015 (me) Comprehensive update posted live
• 8 June 2010 (me) Review posted live
• 2 February 2010 (vrs) Original submission

Literature Cited

• Amiel J, Bougeard G, Francannet C, Raclin V, Munnich A, Lyonnet S, Frebourg T. TP63 gene mutation in ADULT syndrome. Eur J Hum Genet. 2001;9:642–5. [PubMed: 11528512]
• Aradhya S, Lewis R, Bonaga T, Nwokekeh N, Stafford A, Boggs B, Hruska K, Smaoul N, Compton JG, Richard G, Suchy S. Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders. Genet Med. 2012;14:594–603. [PubMed: 22382802]
• Barrow LL, van Bokhoven H, Daack-Hirsch S, Andersen T, van Beersum SE, Gorlin R, Murray JC. Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. J Med Genet. 2002;39:559–66. [PMC free article: PMC1735218] [PubMed: 12161593]
• Basha M, Demeer B, Revencu N, Helaers R, Theys S, Bou Saba S, Boute O, Devauchelle B, Francois G, Bayet B, Vikkula M. Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes. J Med Genet. 2018;55:449–58. [PubMed: 29500247]
• Buss PW, Hughes HE, Clarke A. Twenty-four cases of the EEC syndrome: clinical presentation and management. J Med Genet. 1995;32:716–23. [PMC free article: PMC1051673] [PubMed: 8544192]
• Cadieux-Dion M, Safina NP, Engleman K, Saunders C, Repnikova E, Raje N, Canty K, Farrow E, Miller N, Zellmer L, Thiffault I. Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion syndrome: a case report. BMC Med Genet. 2018;19:41. [PMC free article: PMC5845372] [PubMed: 29523099]
• Cambiaghi S, Tadini G, Barbareschi M, Menni S, Caputo R. Rapp-Hodgkin syndrome and AEC syndrome: Are they the same entity? Br J Dermatol. 1994;130:97–101. [PubMed: 8305327]
• Cefalù S, Lena AM, Vojtesek B, Musarò A, Rossi A, Melino G, Candi E. Tap63gamma is required for the late stages of myogenesis. Cell Cycle. 2015;14:894–901. [PMC free article: PMC4615066] [PubMed: 25790093]
• Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, Newbury-Ecob R, Hennekam RC, Van Buggenhout G, van Haeringen A, Woods CG, van Essen AJ, de Waal R, Vriend G, Haber DA, Yang A, McKeon F, Brunner HG, van Bokhoven H. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell. 1999;99:143–53. [PubMed: 10535733]
• Cole P, Hatef DA, Kaufman Y, Magruder A, Bree A, Friedman E, Sindwani R, Hollier LH Jr. Facial clefting and oroauditory pathway manifestations in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome. Am J Med Genet. 2009;149A:1910–5. [PubMed: 19697430]
• de Mollerat XJ, Gurrieri F, Morgan CT, Sangiorgi E, Everman DB, Gaspari P, Amiel J, Bamshad MJ, Lyle R, Blouin JL, Allanson JE, Le Marec B, Wilson M, Braverman NE, Radhakrishna U, Delozier-Blanchet C, Abbott A, Elghouzzi V, Antonarakis S, Stevenson RE, Munnich A, Neri G, Schwartz CE. A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24. Hum Mol Genet. 2003;12:1959–71. [PubMed: 12913067]
• Deutsch GB, Zielonka EM, Coutandin D, Weber TA, Schäfer B, Hannewald J, Luh LM, Durst FG, Ibrahim M, Hoffmann J, Niesen FH, Sentürk A, Kunkel H, Brutschy B, Schleiff E, Knapp S, Acker-Palmer A, Grez M, McKeon F, Dötsch V. DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer. Cell. 2011;144:566–76. [PMC free article: PMC3087504] [PubMed: 21335238]
• Dishop MK, Bree AF, Hicks MJ. Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet. 2009;149A:1935–41. [PubMed: 19697429]
• Elliott AM, Evans JA. Genotype-phenotype correlations in mapped split hand foot malformation (SHFM) patients. Am J Med Genet A. 2006;140:1419–27. [PubMed: 16688749]
• Enriquez A, Krivanek M, Flöttmann R, Peters H, Wilson M. Recurrence of split hand/foot malformation, cleft lip/palate, and severe urogenital abnormalities due to germline mosaicism for TP63 mutation. Am J Med Genet A. 2016;170:2372–6. [PubMed: 27351625]
• Farrington F, Lausten L. Oral findings in ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome. Am J Med Genet. 2009;149A:1907–9. [PubMed: 19681142]
• Ferstl P, Wohlfart S, Schneider H. Sweating ability of patients with P63-associated syndromes. Eur J Pediatr. 2018;177:1727–31. [PubMed: 30088137]
• Julapalli MR, Scher RK, Sybert VP, Siegfried EC, Bree AF. Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet A. 2009;149A:1900–6. [PubMed: 19681128]
• Khandelwal KD, van den Boogaard MH, Mehrem SL, Gebel J, Fagerberg C, van Beusekom E, van Binsbergen E, Topaloglu O, Steehouwer M, Gilissen C, Ishorst N, van Rooij IALM, Roeleveld N, Christensen K, Schoenaers J, Bergé S, Murray JC, Hens G, Devriendt K, Ludwig KU, Mangold E, Hoischen A, Zhou H, Dötsch V, Carels CEL, van Bokhoven H. Deletions and loss-of-function variants in TP63 associated with orofacial clefting. Eur J Hum Genet. 2019;27:1101–12. [PMC free article: PMC6777535] [PubMed: 30850703]
• Lane MM, Dalton WT 3rd, Sherman SA, Bree AF, Czyzewski DI. Psychosocial functioning and quality of life in children and families affected by AEC syndrome. Am J Med Genet A. 2009;149A:1926–34. [PubMed: 19504609]
• Leoyklang P, Siriwan P, Shotelersuk V. A mutation of the p63 gene in non-syndromic cleft lip. J Med Genet. 2006;43:e28. [PMC free article: PMC2564545] [PubMed: 16740912]
• McGrath JA, Duijf PH, Doetsch V, Irvine AD, de Waal R, Vanmolkot KR, Wessagowit V, Kelly A, Atherton DJ, Griffiths WA, Orlow SJ, van Haeringen A, Ausems MG, Yang A, McKeon F, Bamshad MA, Brunner HG, Hamel BC, van Bokhoven H. Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of TP63. Hum Mol Genet. 2001;10:221–9. [PubMed: 11159940]
• Monti P, Russo D, Bocciardi R, Foggetti G, Menichini P, Divizia MT, Lerone M, Graziano C, Wischmeijer A, Viadiu H, Ravazzolo R, Inga A, Fronza G. EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences. Hum Mutat. 2013;34:894–904. [PubMed: 23463580]
• Motil KJ, Fete TJ. Growth, nutritional, and gastrointestinal aspects of ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC) syndrome. Am J Med Genet A. 2009;149A:1922–5. [PubMed: 19676058]
• O'Quinn JR, Hennekam RC, Jorde LB, Bamshad M. Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19. Am J Hum Genet. 1998;62:130–5. [PMC free article: PMC1376811] [PubMed: 9443880]
• Pashayan HM, Pruzansky S, Solomon L. The EEC syndrome. Report of six patients. Birth Defects Orig Artic Ser. 1974;10:105–27. [PubMed: 4425508]
• Restelli M, Lopardo T, Lo Iacono N, Garaffo G, Conte D, Rustighi A, Napoli M, Del Sal G, Perez-Morga D, Costanzo A, Merlo GR, Guerrini L. DLX5, FGF8 and Pin1 isomerase control ΔNp63α protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations. Hum Mol Genet. 2014;23:3830–42. [PMC free article: PMC4065156] [PubMed: 24569166]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rinne T, Brunner HG, van Bokhoven H. p63-associated disorders. Cell Cycle. 2007;6:262–8. [PubMed: 17224651]
• Rinne T, Clements SE, Lamme E, Duijf PH, Bolat E, Meijer R, Scheffer H, Rosser E, Tan TY, McGrath JA, Schalkwijk J, Brunner HG, Zhou H, van Bokhoven H. A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes. Hum Mol Genet. 2008;17:1968–77. [PubMed: 18364388]
• Rinne T, Hamel B, van Bokhoven H, Brunner HG. Pattern of p63 mutations and their phenotypes--update. Am J Med Genet A. 2006a;140:1396–406. [PubMed: 16691622]
• Rinne T, Spadoni E, Kjaer KW, Danesino C, Larizza D, Kock M, Huoponen K, Savontaus M-L, Aaltonen M, Duijf P, Brunner HG, Penttinen M, van Bokhoven H. Delineation of the ADULT syndrome phenotype due to arginine 298 mutgations of the p63 gene. Eur J Hum Genet. 2006b;14:904–10. [PubMed: 16724007]
• Rouleau M, Medawar A, Hamon L, Shivtiel S, Wolchinsky Z, Zhou H, De Rosa L, Candi E, de la Forest Divonne S, Mikkola ML, van Bokhoven H, Missero C, Melino G, Pucéat M, Aberdam D. TAp63 is important for cardiac differentiation of embryonic stem cells and heart development. Stem Cells. 2011;29:1672–83. [PubMed: 21898690]
• Sethi I, Romano R-A, Gluck C, Smalley K, Vojtesek B, Buck MJ, Sinha S. A global analysis of the complex landscape of isoforms and regulatory networks of p63 in human cells and tissues. BMC Genomics. 2015;16:584. [PMC free article: PMC4528692] [PubMed: 26251276]
• Shalom-Feuerstein R, Serror L, Aberdam E, Müller FJ, van Bokhoven H, Wiman KG, Zhou H, Aberdam D, Petit I. Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET. Proc Natl Acad Sci U S A. 2013;110:2152–6. [PMC free article: PMC3568301] [PubMed: 23355677]
• Siegfried E, Bree A, Fete M, Sybert V. Skin erosions and wound healing in ankyloblepharon-ectodermal defect – cleft lip and/or palate. Arch Dermatol. 2005;141:1591–4. [PubMed: 16365264]
• Soares E, Zhou H. Master regulatory role of p63 in epidermal development and disease. Cell Mol Life Sci. 2018;75:1179–90. [PMC free article: PMC5843667] [PubMed: 29103147]
• Spranger M, Schapera J. Anomalous inheritance in a kindred with split hand, split foot malformation. Eur J Pediatr. 1988;147:202–5. [PubMed: 3366140]
• Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
• Sutton VR, Plunkett K, Dang DX, Lewis RA, Bree AF, Bacino CA. Craniofacial and anthropometric phenotype in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (Hay-Wells syndrome) in a cohort of 17 patients. Am J Med Genet A. 2009;149A:1916–21. [PubMed: 19676059]
• Terrinoni A, Serra V, Bruno E, Strasser A, Valente E, Flores ER, van Bokhoven H, Lu X, Knight RA, Melino G. Role of p63 and the Notch pathway in cochlea development and sensorineural deafness. Proc Natl Acad Sci USA. 2013;110:7300–5. [PMC free article: PMC3645580] [PubMed: 23589895]
• Ugur SA, Tolun A. Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation. Hum Mol Genet. 2008;17:2644–53. [PubMed: 18515319]
• van Bokhoven H, Hamel BC, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PH, Vanmolkot KR, van Beusekom E, van Beersum SE, Celli J, Merkx GF, Tenconi R, Fryns JP, Verloes A, Newbury-Ecob RA, Raas-Rotschild A, Majewski F, Beemer FA, Janecke A, Chitayat D, Crisponi G, Kayserili H, Yates JR, Neri G, Brunner HG. p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet. 2001;69:481–92. [PMC free article: PMC1235479] [PubMed: 11462173]
• van Bokhoven H, Jung M, Smits AP, van Beersum S, Rüschendorf F, van Steensel M, Veenstra M, Tuerlings JH, Mariman EC, Brunner HG, Wienker TF, Reis A, Ropers HH, Hamel BC. Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other Hand/Foot anomalies maps to human chromosome 3q27. Am J Hum Genet. 1999;64:538–46. [PMC free article: PMC1377763] [PubMed: 9973291]
• van Zelst-Stams WA, van Steensel MA. A novel TP63 mutation in family with ADULT syndrome presenting with eczema and hypothelia. Am J Med Genet A. 2009;149A:1558–60. [PubMed: 19530185]
• Zarnegar BJ, Webster DE, Lopez-Pajares V, Vander Stoep Hunt B, Qu K, Yan KJ, Berk DR, Sen GL, Khavari PA. Genomic profiling of a human organotypic model of AEC syndrome reveals ZNF750 as an essential downstream target of mutant TP63. Am J Hum Genet. 2012;91:435–43. [PMC free article: PMC3511987] [PubMed: 22922031]