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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.

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TP63-Related Disorders

, MD and , PhD.

Author Information

Initial Posting: ; Last Update: August 6, 2015.

Summary

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 (subjective hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. 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, hypospadias, trismus, and excessive freckling.

Diagnosis/testing.

The diagnosis is based on clinical findings and molecular genetic testing of TP63.

Management.

Treatment of manifestations: A multidisciplinary team of specialists in clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, gastroenterology, and psychiatry is recommended. 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. 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.

The TP63-related disorders are inherited in an autosomal dominant manner. Approximately 30% of individuals have an affected parent and approximately 70% have a de novo pathogenic variant. Each child of an individual with a TP63-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the TP63 pathogenic variant in the family is known.

GeneReview Scope

TP63-Related Disorders: Included Phenotypes 1
  • Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC syndrome)
    • Rapp-Hodgkin syndrome
  • Acro-dermo-ungual-lacrimal-tooth syndrome (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)

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes, see Differential Diagnosis.

Diagnosis

Suggestive Findings

The TP63-related disorders include the following overlapping phenotypes (summarized in Table 1).

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome

  • 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: (1) Starch iodide sweat testing of the palms is rarely helpful in documenting sweating ability. (2) Scalp erosions are characteristic of AEC syndrome and are NOT seen in other TP63-related disorders.
  • Cleft lip/palate presents 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 affected individuals: 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%).
  • Craniofacial findings include the following:
    • Maxillary hypoplasia (reported in 94%)
    • Small mandible (reported in 65%)
    • Broad nasal bridge (76%)
    • Hypoplastic alae nasi (94%)
    • Thin vermilion border of the upper lip (82%)
    • Microstomia (94%)
    • Trismus (44%)
  • Hypospadias has been reported in 80% of males.

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 pathogenic variants observed in the two conditions [Cambiaghi et al 1994, Bertola et al 2004].

Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome

  • Acromelic malformation is present in the form of split hand and/or split foot with or without syndactyly.
  • Dermatologic abnormalities include sparse fine hair; dry skin, and unique pigmentary skin changes.
    • Excessive freckling in sun-exposed areas is common and progresses with age and sun exposure. It is unique to ADULT syndrome and not characteristic of other TP63–related disorders.
    • There may be subjective decrease in sweating capacity. Note: Starch iodide sweat testing of the palms is rarely helpful in documenting sweating ability.
  • Ungual defects manifest as hypoplastic, dysplastic, absent, and/or ridged nails.
  • Lacrimal puncta absence is seen in many affected individuals.
  • Tooth abnormalities include hypodontia or oligodontia.
  • Breast and/or nipple hypoplasia that may be symmetric or asymmetric is typically seen in ADULT syndrome and limb-mammary syndrome and not in other TP63-related disorders.

Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3)

  • Ectrodactyly (now referred to as split-hand/foot malformation) with or without syndactyly is present in approximately 70% of all affected individuals and ranges widely in severity and location of the digital abnormalities [Rinne et al 2006a].
  • Ectodermal defects typically manifest as silvery-blond, sparse fine hair; dry skin and unique pigmentary skin changes; nail changes; dental changes including oligodontia and enamel defects; and xerostomia and subjective decrease in sweating capacity.
    Note: Starch iodide sweat testing of the palms is rarely helpful in documenting sweating ability.
  • Cleft lip/palate is present in approximately 40% of affected individuals [Rinne et al 2006a]; 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.
  • Other
    • Absent lacrimal puncta is seen in almost all affected individuals.
    • Blepharophimosis is seen occasionally.
    • Hypospadias has been reported often in males.

Limb-mammary syndrome

  • Limb abnormalities can include split-hand/foot malformation, oligodactyly, and syndactyly.
  • Breast and/or nipple hypoplasia has been reported in 90% of individuals with limb-mammary syndrome [van Bokhoven et al 1999]. It may be symmetric or asymmetric, and is typical for ADULT syndrome and limb-mammary syndrome and rarely seen in other TP63-related disorders.
  • Less common findings
    • Absent lacrimal puncta and lacrimal duct atresia is seen in half of all affected individuals.
    • Cleft lip/palate is present in one quarter to one third of affected individuals; 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.
    • Hypodontia and nail dysplasia is found in a small percentage of individuals; skin and hair abnormalities are NOT seen.

Split-hand/foot malformation type 4 (SHFM4)

  • Split hand/foot with or without syndactyly is present in all affected individuals and ranges widely in severity and location of renal abnormalities. Aplasia or hypoplasia of phalanges and metacarpals is seen.
  • Ectodermal abnormalities and cleft lip/palate are very rarely seen.

Isolated cleft lip/cleft palate (orofacial cleft 8)

  • Cleft lip/palate includes a wide spectrum ranging from submucous cleft palate only to cleft of the soft and/or the hard palate only, cleft lip only, and the combination of cleft lip and cleft palate.

Table 1.

Clinical Features of TP63-Related Disorders

FeatureTP63-Related Disorder
AECADULTEEC3Limb-MammarySHFM4Isolated CL/P
Ankyloblepharon filiforme adnatumX
Ectodermal dysplasiaXXXRare
  • Hypohidrosis (mostly subjective)
XXX
  • Nail dysplasia
XXMildX
  • Sparse hair
XXX
Tooth abnormalitiesXXXX
Cleft lip/palateXXXX
Split-hand/foot malformation/syndactylyXXXXX
Lacrimal duct obstructionXXXX
Dermal erosionsX
HypopigmentationXXX
HypospadiasXX
TrismusX
Excessive frecklingX
Hypoplastic breastsXX
Hypoplastic nipplesXX

ADULT = acro-dermato-ungual-lacrimal-tooth

EEC = ectrodactyly (split-hand/foot malformation), ectodermal dysplasia, clefting

SHFM4 = split-hand/foot malformation type 4

CL/P = cleft lip/cleft palate

Establishing the Diagnosis

The diagnosis of a TP63-related disorder is established by identification of a TP63 heterozygous pathogenic variant in a proband on molecular genetic testing (see Table 2).

Molecular testing approaches can include single-gene testing and use of a multi-gene panel.

Table 2.

Summary of Molecular Genetic Testing Used in TP63 Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
TP63Sequence analysis 375%-100% 4
Gene-targeted deletion/duplication analysis 5Rare 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

A single case report of a four-exon deletion of TP63 has been reported in an individual with EEC [Aradhya et al 2012].

Clinical Characteristics

Clinical Description

AEC Syndrome

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

  • Skin. Nearly 100% of affected neonates have superficial skin erosions that vary from very limited to severe, life-threatening full-body involvement. The erosions most typically affect the scalp at birth and during infancy. Severe scalp erosions often lead to scarring alopecia and hypotrichosis. This is NOT seen in other TP63-related disorders.

    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.

    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].
  • 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. Light and scanning microscopy may reveal structural and pigmentary alterations of the hair including kinking, grooves, and discontinuous pigmentation.
  • 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].
  • Dental anomalies. 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].
  • Sweating. 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 findings include the following:

  • Limb anomalies were initially not considered to be part of the syndrome, but syndactyly of fingers and toes and/or camptodactyly (permanent and irreducible flexion of the fingers) of hands have been seen. Split-hand/foot malformation 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].
  • Facial features become more distinctive with age. Findings commonly include maxillary hypoplasia, micrognathia, broad nasal root, underdeveloped alae nasi, thin vermilion of the upper lip, and short philtrum.
  • Trismus has been reported in 35% of individuals with AEC syndrome [Sutton et al 2009].
  • Hearing loss. More than 90% of children have conductive hearing loss, often with secondary speech delay [Cole et al 2009].
  • Growth. Poor weight gain and failure to thrive should be anticipated. When treated appropriately with nutritional supplementation poor weight gain improves with age.

    Linear growth abnormalities are observed in early childhood with a significantly lower height for age compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [Motil & Fete 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].

ADULT Syndrome

The manifestations of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome are typically present at birth (although they may become more prominent with age), with the exception of skin freckling.

Limb anomalies. Most commonly seen is syndactyly of fingers and toes.

Ectodermal defects

  • Skin tends to be dry but erosions are not present.
  • Hair changes are more obvious with age. Hair is typically light-colored and fine. Eyebrows and eyelashes are sparse.
  • Nail dysplasia is commonly reported.
  • Dental anomalies. Malformed teeth (conical shape with small occlusal tables) and hypodontia (reduced number of teeth) also become evident during childhood and adolescence.
  • Sweating. 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.

Lacrimal duct atresia is frequent and often leads to chronic conjunctivitis and blepharitis, which are often not recognized until early childhood [Sutton et al 2009].

Breast and/or nipple hypoplasia is seen commonly and most notably in females. This feature is characteristic of ADULT and limb-mammary syndrome and NOT typically seen in other TP63-related disorders.

Excessive freckling in sun exposed areas is seen in a subset of patients and progresses with age and sun exposure. This feature is NOT seen in other TP63-related disorders.

EEC3 Syndrome

The manifestations of ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) are typically present at birth.

Limb anomalies are seen in 68%-90% of individuals with 60% having tetramelic involvement. A wide variety of limb abnormalities are reported including syndactyly, oligodactyly, split-hand/foot malformation and digital duplication. A cohort of 152 EEC syndrome patients showed split-hand/foot malformation in 68% and syndactyly in 43% [Rinne et al 2006a].

Ectodermal defects

  • Skin tends to be dry but erosions are not present.
  • Hair changes become more obvious with age and are seen in 60%-80% of individuals with EEC syndrome [Rinne et al 2006a]. Hair is typically silvery-blond, coarse, and dry; 20% have sparse hair. Light microscopy has been reported to be normal in EEC syndrome [Pashayan et al 1974]. Eyebrows and eyelashes are sparse.
  • Nail dysplasia is commonly reported.
  • Dental anomalies. Malformed teeth (conical shape with small occlusal tables) and hypodontia (reduced number of teeth) also become evident during childhood and adolescence.
  • Sweating. Hypohidrosis is uncommon in EEC3 syndrome.

Cleft lip with or without cleft palate is present in 60%-75% and is bilateral in half of cases. 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 [Buss et al 1995].

Absent lacrimal puncta is reported in 90% of individuals and results in tearing, blepharitis, dacryocystitis, keratoconjunctivitis and photophobia and often lead to corneal ulceration and scaring [Buss et al 1995].

Genitourinary malformations are reported in 45% and may include hypospadias and developmental abnormalities of the kidneys and urinary collecting system.

Limb-Mammary Syndrome

The manifestations limb-mammary syndrome are typically present at birth.

Limb anomalies, including split-hand/foot malformation and syndactyly are reported in 75%-85% of individuals.

Breast and/or nipple hypoplasia is seen commonly with almost all individuals having nipple aplasia or hypoplasia and 90% of females having mammary gland aplasia or hypoplasia. This feature is characteristic of ADULT and limb-mammary syndrome and NOT typically seen in other TP63-related disorders.

Lacrimal duct atresia is seen in about half leading to chronic conjunctivitis and blepharitis, which are often not recognized until early childhood [van Bokhoven et al 1999].

Ectodermal defects

  • Nail dysplasia is reported in 30% of individuals.
  • Dental anomalies. Hypodontia (reduced number of teeth) also become evident during childhood and adolescence and is seen in 10%-15%.

Note: Skin and hair abnormalities are NOT typically seen, in contrast to other TP63-related disorders.

Cleft lip with or without cleft palate is present in 25%-30% and 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.

SHFM4

The manifestations of split-hand/foot malformation-4 (SHFM4) are typically present at birth.

Limb abnormalities include median clefts of the hands and feet; aplasia/hypoplasia of phalanges, metacarpals, and metatarsals; and some syndactyly.

Ectodermal abnormalities and cleft lip/palate are considered to be exclusion criteria for making the diagnosis SHFM4.

Orofacial Cleft 8

Leoyklang et al [2006] have investigated the occurrence of TP63 pathogenic variants in a cohort of 100 Thai patients with nonsyndromic CL/P. In total, 21 variant sites were identified. All were single nucleotide changes, with six in coding regions, including three novel nonsynonymous changes. No other features of TP63-related disorders were observed in these patients

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 Molecular Genetics and Figure 1 for details.

Figure 1. . Typical and common TP63 pathogenic variants identified in various disorders as indicated by color key.

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 at p.Arg337 (TAp63α; formerly known as p.Arg298), such as c.1009C>G (p.Arg337Gly) and c.1010G>A (p.Arg337Gln). Other pathogenic variants have been reported in isolated patients with features reminiscent of ADULT syndrome, but also of other TP63-associated syndromes. Examples include c.16A>C (p.Asn6His in ΔNp63α), which is in an alternative TA domain and c.518G>T (p.Gly173Asp in TAp63α) which is between the TA and DNA binding domains [Rinne et al 2006b, Rinne et al 2007], and c.497C>T (p.Pro166Leu in TAp63α) [van Zelst-Stams & van Steensel 2009].

EEC3. All EEC 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 EEC have been reported [Celli et al 1999, van Bokhoven et al 2001, Barrow et al 2002, Monti et al 2013].

Limb-mammary syndrome. 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].

Isolated cleft lip/cleft palate (orofacial cleft 8) has been associated with TP63 variants in the DNA binding domain [Leoyklang et al 2006]. Of these variants, p.Arg352Gly in TAp63α was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, its occurrence in a functionally important domain, its predicted damaging function, its de novo occurrence, and its absence in 500 control individuals.

See Figure 1.

Penetrance

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

Reduced penetrance for split-hand/foot malformation type 4 (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 caused by somatic and germline mosaicism in one parent.

In one family, the TP63 pathogenic variant present in affected fraternal twins was seen 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.

Differential Diagnosis

AEC Syndrome

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) (OMIM) 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.

EEC3

EEC1 (OMIM) is suspected to be caused by pathogenic variants in a gene on chromosome 7q21q22 based on a series of individuals with various cytogenetically visible chromosomal abnormalities.

Other EEC syndrome-like phenotypes that do not appear to involve the EEC1 and EEC3 loci have been described.

SHFM4

SHFM1 (OMIM) is caused by deletions of chromosome 7q21 involving DLX5 and DLX6 as well as homozygous pathogenic variants in DLX5 and is associated with a high incidence of hearing loss. Findings in this disorder are largely restricted to the limbs. Dental and lacrimal duct abnormalities are seen in fewer than 10% of individuals [Elliott & Evans 2006].

SHFM2 (OMIM) has been mapped to Xq26 and while both males and females are affected, males tend to have a more severe phenotype. Cleft lip/palate and ectodermal defects are not seen in this condition.

SHFM3 (OMIM) is caused by a contiguous gene duplication on chromosome 10q24 and does not have lacrimal, dental, or ectodermal abnormalities (beyond nail abnormalities associated with developmental defects of the digits) [de Mollerat et al 2003, Elliott & Evans 2006].

SHFM5 (OMIM) is caused by deletions of chromosome 2q31. Abnormally shaped teeth may be present, but neither oligodontia nor other ectodermal defects that may be seen in SHFM4 are reported. Dysmorphic facial features tend to be present [Elliott & Evans 2006].

SHFM6 (OMIM) has been attributed to homozygous pathogenic variants in WNT10B. Interestingly, all but one of the affected individuals in the initial pedigree also had promoter polymorphism in TP63 [Ugur & Tolun 2008].

TP63-Related Disorders Generally

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 and needs in an individual diagnosed with a TP63 related disorder, the following evaluations are recommended:

  • Clinical 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 atresia/obstruction, dry eyes and blepharitis
  • Plastic surgery to evaluate and repair cleft lip and palate or breast/nipple assymetry
  • 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
  • Prosthodontics 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 clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, gastroenterology, and psychiatry.

Ankyloblepharon filiforme adnatum. These strands of tissue between the upper and lower eyelids 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 sparse hair and alopecia.
  • There are no known therapies for the nail or skin pigment changes.
  • Dentures should be considered in early childhood and the possibility of dental implants should be considered in the teens or early adult years.
  • Sweating is not severely impaired and does not require special care.

Skin erosions. The skin erosions are difficult to treat and prone to excessive ineffective granulation response; they are at increased risk for secondary infection and are not responsive to most standard wound care regimens or antibiotic therapy [Julapalli et al 2009]. Skin erosions 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. Early referral to a craniofacial surgeon for planning for surgical cleft repair is indicated.

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 is indicated as needed for conductive hearing loss resulting from chronic otitis media.
  • Significant breast asymmetry in women may be corrected through plastic surgery.
  • 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 seen in AEC syndrome. Reduced sun exposure can 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 of an affected individual by molecular genetic testing of the TP63 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

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. An investigational product developed to activate mutated p53 in cancer therapy has been tested for its ability to activate mutated p63 protein carrying EEC3-associated amino acid substitutions. This compound, denoted APR-246/PRIMA-1MET, showed a beneficial effect on skin differentiation [Shalom-Feuerstein et al 2013, Shen et al 2013].

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

The 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 [van Bokhoven H, Bree AF, Sutton VR; unpublished data].
  • A proband with a TP63-related disorder may have the disorder as the result of a new pathogenic variant. 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 [van Bokhoven H, Bree AF, Sutton VR; unpublished data].

    If the TP63 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband.
    • In one family, the TP63 pathogenic variant present in fraternal twins was identified in the phenotypically normal mother. Further study of the mother suggested somatic and germline mosaicism [van Bokhoven, unpublished data].
  • 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (physical exam and molecular genetic testing) have been performed on the parents of the proband.

Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

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 TP63 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of 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 status of the proband’s parents: if a parent is affected, 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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with a TP63-related disorder has the pathogenic variant or clinical evidence of the disorder, the TP63 pathogenic variant is likely de novo. 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 and Preimplantation Genetic Diagnosis

Once the TP63 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for a TP63-related disorder are possible options.

Requests for prenatal testing for conditions which (like the TP63-related disorders) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • National Foundation for Ectodermal Dysplasias (NFED)
    410 East Main Street
    PO Box 114
    Mascoutah IL 62258-0114
    Phone: 618-566-2020
    Fax: 618-566-4718
    Email: info@nfed.org
  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Asociación de Afectados por Displasia Ectodérmica
    Consumer health-oriented organization for Spain.
    C Poet Andres Bolarín
    2-3º Dcha.
    Murcia 30011
    Spain
    Phone: 968 350 026
    Email: info@displasiaectodermica.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • Cleft Palate Foundation (CPF)
    1504 East Franklin Street
    Suite 102
    Chapel Hill NC 27514-2820
    Phone: 800-242-5338 (toll-free); 919-933-9044
    Fax: 919-933-9604
    Email: info@cleftline.org
  • Ectodermal Dysplasia Society
    108 Charlton Lane
    Cheltenham Gloucestershire GL53 9EA
    United Kingdom
    Phone: 01242 261332
    Email: diana@ectodermaldysplasia.org
  • National Library of Medicine Genetics Home Reference
  • Selbsthilfegruppe Ektodermale Dysplasie e.V.
    Consumer health-oriented organization for Germany, Austria, and Switzerland
    Landhausweg 3
    Aichtal D-72631
    Germany
    Phone: 0 71 27 96 96 91
    Fax: 0 71 27 96 96 92
    Email: Burk-Aichtal@t-online.de
  • Ectodermal Dysplasias International Registry
    National Foundation for Ectodermal Dysplasias
    410 East Main Street
    Mascoutah IL 62258
    Phone: 618-566-2020
    Fax: 618-566-4718
    Email: info@nfed.org

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.

TP63-Related Disorders: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
TP633q28Tumor protein 63TP63 @ LOVDTP63

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for TP63-Related Disorders (View All in OMIM)

103285ADULT SYNDROME
106260ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE
129400RAPP-HODGKIN SYNDROME; RHS
603273TUMOR PROTEIN p63; TP63
603543LIMB-MAMMARY SYNDROME; LMS
604292ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3; EEC3
605289SPLIT-HAND/FOOT MALFORMATION 4; SHFM4

Gene structure. 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 Gene for TP63 transcript variants. For a detailed summary of gene and protein information, see Table A, Gene.

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 TAp63α, 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 ΔNp63γ) is shorter and has distinct N- and C-termini, compared to isoform 1.

Note: The nomenclature for TP63 pathogenic variants is problematic. The reason for confusion is that the reference sequence for TP63 has been changed over the years. The original reference sequence for TAp63α 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 pathogenic variants 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 TAp63α. Taking this sequence as a reference, all previously reported pathogenic variants should also be renamed by adding 39 amino acids. For example, p.Arg298Gly would be p.Arg337Gly (Table 3).

Pathogenic allelic variants. Heterozygous pathogenic variants in TP63 cause AEC syndrome, ADULT syndrome, EEC3, Limb-mammary syndrome, and SHFM4 (see Genotype-Phenotype Correlations).

Table 3.

Selected TP63 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences
c.16A>Cp.Asn6HisNM_001114982​.1
NP_001108454​.1
c.497C>Tp.Pro166LeuNM_003722​.4
NP_003713​.3
c.518G>Ap.Gly173Asp
(Gly134Asp) 2
c.1009C>Gp.Arg337Gly
(Arg298Gly) 2
c.1010G>Ap.Arg337Gln
(Arg298Gln) 2
c.1054A>Gp.Arg342Gly
c.1963delCp.Arg655GlufsTer49

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 TAp63α, KET, and p51B). The transcript variant NM_001114982.1 encodes isoform 6, also known as ΔNp63γ (NP_001108454.1), which is shorter and has distinct N- and C-termini, compared to isoform 1.

Abnormal gene product. 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].

References

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Chapter Notes

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

  • 6 August 2015 (me) Comprehensive update posted live
  • 8 June 2010 (me) Review posted live
  • 2 February 2010 (vrs) Original submission
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