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Tumor protein p63-related disorders

Authors: Timothy J Fete, MD, MPH, Dorothy K Grange, MD
Section Editor: Jennifer L Hand, MD
Deputy Editor: Rosamaria Corona, MD, DSc

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2020. | This topic last updated: Aug 19, 2020.

INTRODUCTION

Tumor protein p63 is a transcription factor that plays a vital role in the development and maintenance of
the skin and other ectodermal tissues, as well as orofacial structures and limbs. During embryogenesis,
p63 is required for epidermal lineage commitment, epidermal differentiation, cell adhesion, and
basement membrane formation [1]. Postnatally, p63 is localized to the nuclei of basal cells in the
stratified epithelium, including the skin, oral mucosa, cervical and vaginal epithelium, urothelium, and
breast [2,3]. TP63 maps to chromosome 3q28 and produces six isoforms [4]. Mutations in different
domains of TP63 result in different ectodermal dysplasia syndromes with considerable overlapping
features [1,5]:

● Acro-dermato-ungual-lacrimal-tooth syndrome (ADULT syndrome, MIM #103285)

● Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3 syndrome, MIM #604292)

● Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC syndrome), also known as Hay-

Wells syndrome (MIM #106260)

● Limb-mammary syndrome (MIM #603543)

● Orofacial cleft 8 (MIM #129400)

● Split-hand/foot malformation 4 (MIM #605289)

The following sections will expand upon EEC3 syndrome and AEC syndrome as representative
examples of this group of ectodermal dysplasias.

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ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE

SYNDROME 3

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

dominant disorder characterized by split hands and/or feet; abnormalities of the hair, skin, and teeth; and
cleft lip and palate. EEC3 syndrome is caused by missense mutations in the DNA-binding protein domain
of TP63 [6].

Clinical manifestations

Cutaneous — Individuals with EEC3 syndrome tend to have light-colored hair that is coarse and dry,
and it may be sparse. Eyebrows and eyelashes are sparse. Nails are thin, brittle, and occasionally have
pits. Skin is dry. Sweating is variable. In one study of 14 patients with EEC3, 9 patients (64 percent) had
a normal number of sweat glands and produced sufficient sweat in response to pilocarpine. All others
had clearly reduced sweating ability and fewer sweat glands but not anhidrosis [7].

Extracutaneous — Hypodontia is common and teeth can be conical in shape, with poor enamel and
an increased risk of caries. Facial features include midface hypoplasia, a broad nasal tip, and a short
philtrum. Cleft lip and/or palate is present in 60 to 75 percent of individuals with EEC3 syndrome. Limb
abnormalities include split-hand/foot, syndactyly, oligodactyly, and digital duplication (picture 1A-B) [5,8].
Any combination of one to four extremities can be involved. Absent lacrimal puncta occur in most
patients, with secondary tearing, dacryocystitis, blepharitis, keratoconjunctivitis, corneal ulceration, and
scarring. Research studies are ongoing to create stem cells to potentially treat the corneal damage [9].
Genitourinary tract anomalies occur in at least 50 percent of individuals with EEC3 syndrome, including
hydroureter, hydronephrosis, renal agenesis, urethral stenosis, micropenis, hypospadias, and
cryptorchidism [10]. Growth hormone deficiency, hypogonadotropic hypogonadism, and central diabetes
insipidus have been reported.

Diagnosis — Suspicion for EEC3 syndrome should occur in a child with any combination of ectodermal
defects associated with cleft lip/palate and/or with limb anomalies. Molecular genetic confirmation can be
achieved by single-gene testing (sequence analysis of TP63 first, followed by gene-targeted
deletion/duplication analysis if sequence analysis is normal) or by using a multigene panel that includes
TP63 (multigene panels vary by laboratory). Prenatal diagnosis is available.

Differential diagnosis — There is considerable clinical overlap and variability in the TP63-related
disorders. Consideration of other syndromes within this family is always prudent. Ectrodactyly,
ectodermal defects, and cleft lip/palate have been found in nearly 100 percent of classic EEC3 syndrome
cases. However, similar findings have been noted to be linked to other chromosomes. As an example,
ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 1 (EEC1 syndrome, MIM #129900) has
been mapped to chromosome 7q21, but the involved gene has not been identified.

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Management — Patients with EEC3 syndrome generally require management by a multidisciplinary

team that may include a primary care clinician; dermatologist; geneticist; plastic surgeon; ear, nose, and
throat (ENT) specialist; speech-language therapist; nutritionist; orthopedic surgeon; and pediatric dentist,
orthodontist, and prosthodontist:

● Evaluation and management of cleft lip/palate, including surgical repair and treatment of associated
morbidities, is needed as early as possible. Affected individuals will need close surveillance for
recurrent otitis media and otitis media with effusion. Speech and language therapy should be
actively involved. A nutritionist should follow children for early feeding difficulties.

● In children with hypodontia, early involvement with a pediatric dentist is advised for consideration of
early dentures and later team care with orthodontist and prosthodontist as needed.

● Hand and foot anomalies may require evaluation by a plastic surgery team/orthopedic surgery team,
including occupational therapy and physical therapy.

● Early evaluation by a pediatric ophthalmologist is recommended to assess lacrimal puncta and

follow closely for complications.

● All individuals with EEC3 syndrome should have evaluation for genitourinary tract anomalies.

● Children who are not growing as expected should be referred to a pediatric endocrinologist and
nutritionist.

Prognosis — The prognosis is overall good for general health and life expectancy.

ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE SYNDROME

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC syndrome, MIM #106260), also

known as Hay-Wells syndrome, is an autosomal dominant disorder characterized by ankyloblepharon
filiforme adnatum that partially or completely fuses the upper and lower eyelids; abnormalities of hair,
skin, teeth and nails; and cleft lip and/or palate [11].

AEC syndrome is caused by mutations in the sterile alpha motif (SAM) domain or the N-terminal domain
of TP63. Approximately 70 percent of individuals have a de novo mutation, with only 30 percent having
an affected parent [5].

Clinical manifestations

Cutaneous — Newborns with AEC syndrome usually present with congenital erythroderma,
sometimes appearing as a red, shiny collodion membrane (picture 2). Superficial skin erosions, most
often involving the scalp, are also present at birth (picture 3) [12,13]. They can be few and scattered or

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can be diffuse and potentially life threatening, due to fluid and electrolyte disturbance and risk of
infection. The scalp erosions can lead to severe scarring and alopecia. The skin erosions can be
recurrent throughout childhood, often involving the head and neck, palms, soles, and skin folds. Both
hyperpigmentation and hypopigmentation are noted in nearly all individuals with AEC syndrome.

Hair is light-colored, coarse, wiry, and brittle. Eyelashes and eyebrows are sparse to absent. Nails are
absent or dystrophic (picture 4A-B). Sweating is variable. In one study of nine patients with AEC
syndrome, three subjects had normal numbers of sweat glands and produced sufficient sweat in
response to pilocarpine. All other subjects had clearly reduced sweating ability and fewer sweat glands
but not anhidrosis [7].

Extracutaneous — Approximately 70 percent of individuals with AEC syndrome will have

ankyloblepharon filiforme adnatum (fusion of the eyelids) (picture 2), which can be partial or nearly
complete. Lacrimal puncta are often absent, leading to chronic conjunctivitis, blepharitis, and keratitis.
Cleft lip and/or palate is universal. Other facial features include maxillary hypoplasia, micrognathia,
underdeveloped alae nasi, and short philtrum. Dental anomalies include significant hypodontia and
conical teeth. Hypospadias is common in males. Height and weight deficits, requiring nutritional
supplementation, are common and may persist through childhood [14]. Limb anomalies have been
reported, including syndactyly and ectrodactyly [15].

Pathology — Biopsy samples from clinically unaffected skin shows mild atrophy, focal orthokeratosis,
and mild perivascular lymphocytic dermatitis. Scattered melanophages in the superficial and deep
dermis likely represent postinflammatory change. Examination of the hair shafts reveals atrophy and loss
of melanin. Structural anomalies include pili torti, pili trianguli et canaliculi, irregular indentation, and
shallow grooves [16].

Diagnosis — The combination of ankyloblepharon, ectodermal defects, skin erosions (particularly

scalp), and cleft lip and/or palate should suggest the diagnosis of AEC syndrome. Molecular testing of
TP63 is available. Experts suggest sequencing of exons 13 and 14 initially, since these exons encode
the SAM and transactivation domains where most of the AEC syndrome mutations occur. If no mutation
is found in exons 13 and 14, the rest of the TP63 gene should be sequenced. If a TP63 mutation is
identified in a family member, prenatal testing and preimplantation genetic diagnosis are possible
options.

Differential diagnosis — Rapp-Hodgkin syndrome is an allelic disorder with AEC, and many experts
now consider it to be a variant of AEC syndrome [17]. The lack of ankyloblepharon in Rapp-Hodgkin
syndrome is the only significant difference.

Scalp erosions differentiate AEC syndrome from the other p63 disorders. Although skin erosions at birth
could raise the question of epidermolysis bullosa, other manifestations of AEC syndrome should be
apparent.

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Curly hair-ankyloblepharon-nail dysplasia syndrome (CHAND syndrome) has overlapping features with
AEC syndrome but lacks skin erosions and cleft lip/palate [18,19].

Treatment — There is active research in using induced pluripotent stem cells to build patient-derived
skin to treat skin erosions [20]. An initial trial of a topical application of an experimental p53-reactivating
compound to skin erosions on two patients allowed for re-epithelialization of the eroded skin and
significant decrease in pain [21]. As in ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome
(EEC syndrome), a multidisciplinary team including primary care, nutrition, genetics, dermatology, plastic
surgery, ophthalmology, speech and language therapy, audiology, pediatric dentistry, orthodontics,
prosthodontists, and potentially others will be required to treat and follow patients with AEC syndrome.

Skin erosions should be managed in neonatal intensive care settings with careful attention to risk for fluid
and electrolyte imbalance, anemia, secondary infection, and sepsis. Erosions should be treated with
gentle cleansing and application of skin emollients, whereas aggressive debridement should be avoided.

Ophthalmologic consultation is recommended if eyelid fusion has not resolved spontaneously and for
lacrimal duct atresia.

Prognosis — Prognosis is dependent upon early and aggressive management of potentially life-
threatening skin erosions, careful management of fluids and nutrition, and ongoing management of the
multiple clinical manifestations noted in AEC syndrome.

SUMMARY AND RECOMMENDATIONS

● Mutations in different domains of the gene encoding tumor protein p63 (TP63), a transcription factor
involved in the development of the skin, orofacial structures, and limbs, result in different ectodermal
dysplasia syndromes with considerable overlapping features. Examples include ectrodactyly,
ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3 syndrome) and ankyloblepharon-
ectodermal defects-cleft lip/palate syndrome (AEC syndrome). (See 'Introduction' above.)

● EEC3 syndrome is an autosomal dominant disorder characterized by split hands and/or feet;
abnormalities of the hair, skin, and teeth; and cleft lip/palate. Individuals with EEC3 syndrome
present with sparse, coarse, and dry hair; hypodontia; cleft lip/palate; and limb anomalies, including
split-hand/foot, syndactyly, and oligodactyly (picture 1A-B). Genitourinary anomalies and endocrine
disorders are also common. (See 'Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome
3' above.)

● AEC syndrome is an autosomal dominant disorder characterized by ankyloblepharon filiforme

adnatum that partially or completely fuses the upper and lower eyelids; abnormalities of hair, skin,
teeth, and nails; and cleft lip and/or palate. Newborns with AEC syndrome usually present with

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congenital erythroderma and superficial skin erosions, most often involving the scalp (picture 2 and
picture 3). (See 'Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome' above.)

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REFERENCES

1. Koster MI. p63 in skin development and ectodermal dysplasias. J Invest Dermatol 2010; 130:2352.

2. Barbieri CE, Pietenpol JA. p63 and epithelial biology. Exp Cell Res 2006; 312:695.

3. Casasco M, Icaro Cornaglia A, Riva F, et al. Expression of p63 transcription factor in ectoderm-
derived oral tissues. Ital J Anat Embryol 2006; 111:125.

4. Di Iorio E, Barbaro V, Ruzza A, et al. Isoforms of DeltaNp63 and the migration of ocular limbal cells
in human corneal regeneration. Proc Natl Acad Sci U S A 2005; 102:9523.

5. Sutton VR, van Bokhoven H. TP63-related disorders. In: GeneReviews, Adam MP, Ardinger HH, P
agon RA, et al (Eds), University of Washington, Seattle, Seattle (WA) 1993.

6. Rinne T, Bolat E, Meijer R, et al. Spectrum of p63 mutations in a selected patient cohort affected
with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC). Am J Med Genet A
2009; 149A:1948.

7. Ferstl P, Wohlfart S, Schneider H. Sweating ability of patients with p63-associated syndromes. Eur
J Pediatr 2018; 177:1727.

8. Buss PW, Hughes HE, Clarke A. Twenty-four cases of the EEC syndrome: clinical presentation and
management. J Med Genet 1995; 32:716.

9. Barbaro V, Nasti AA, Raffa P, et al. Personalized Stem Cell Therapy to Correct Corneal Defects
Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-
Clefting Syndrome. Stem Cells Transl Med 2016; 5:1098.

10. Hyder Z, Beale V, O'Connor R, Clayton-Smith J. Genitourinary malformations: an under-recognized

feature of ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome. Clin Dysmorphol 2017;
26:78.

11. Fete M, vanBokhoven H, Clements SE, et al. International Research Symposium on

Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome. Am J Med Genet A 2009;
149A:1885.

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12. Julapalli MR, Scher RK, Sybert VP, et al. Dermatologic findings of ankyloblepharon-ectodermal
defects-cleft lip/palate (AEC) syndrome. Am J Med Genet A 2009; 149A:1900.

13. Maillard A, Alby C, Gabison E, et al. P63-related disorders: Dermatological characteristics in 22

patients. Exp Dermatol 2019; 28:1190.

14. 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.

15. Sutton VR, Plunkett K, Dang DX, et al. 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.

16. 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 A 2009; 149A:1935.

17. Bertola DR, Kim CA, Albano LM, et al. Molecular evidence that AEC syndrome and Rapp-Hodgkin
syndrome are variable expression of a single genetic disorder. Clin Genet 2004; 66:79.

18. Busa T, Jeraiby M, Clémenson A, et al. Confirmation that RIPK4 mutations cause not only
Bartsocas-Papas syndrome but also CHAND syndrome. Am J Med Genet A 2017; 173:3114.

19. Bertola DR, Kim CA, Sugayama SM, et al. AEC syndrome and CHAND syndrome: further evidence
of clinical overlapping in the ectodermal dysplasias. Pediatr Dermatol 2000; 17:218.

20. Koch PJ, Dinella J, Fete M, et al. Modeling AEC-New approaches to study rare genetic disorders.
Am J Med Genet A 2014; 164A:2443.

21. Aberdam E, Roux LN, Secrétan PH, et al. Improvement of epidermal covering on AEC patients with
severe skin erosions by PRIMA-1MET/APR-246. Cell Death Dis 2020; 11:30.

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GRAPHICS

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

Hand abnormalities in an individual with EEC3 syndrome.

Reproduced with permission from the National Foundation for Ectodermal Dysplasias. Copyright © 2018.

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

Foot deformities in an individual with EEC3 syndrome.

Reproduced with permission from the National Foundation for Ectodermal Dysplasias. Copyright © 2018.

Graphic 117088 Version 2.0

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

Diffuse erythema in newborn with AEC syndrome. Note ankyloblepharon of medial aspect of left eyelids.

Reproduced with permission from the National Foundation for Ectodermal Dysplasias. Copyright © 2018.

Graphic 117093 Version 2.0

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

syndrome)

Diffuse scalp erosions in a newborn with AEC syndrome.

Reproduced with permission from the National Foundation for Ectodermal Dysplasias. Copyright © 2018.

Graphic 117092 Version 2.0

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

Thin, ridged, chipped fingernails in a child with AEC syndrome.

Reproduced with permission from the National Foundation for Ectodermal Dysplasias. Copyright © 2018.

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

Small, thin, chipped toenails in a child with AEC syndrome.

Reproduced with permission from the National Foundation for Ectodermal Dysplasias. Copyright © 2018.

Graphic 117095 Version 2.0

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Contributor Disclosures
Timothy J Fete, MD, MPH Employment (Spouse): National Foundation for Ectodermal Dysplasia [Ectodermal
dysplasia]. Consultant/Advisory Boards: National Foundation for Ectodermal Dysplasia [Ectodermal
dysplasia]. Dorothy K Grange, MD Consultant/Advisory Boards: National Foundation for Ectodermal Dysplasia
[Ectodermal dysplasia]. Jennifer L Hand, MD Nothing to disclose Rosamaria Corona, MD, DSc Nothing to
disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support
the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.

Conflict of interest policy

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