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Tumor protein p63-related disorders

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
Literature review current through: Feb 2022. | 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.

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.

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 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.

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 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.)

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, Pagon 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.
  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.
Topic 117131 Version 2.0

References

1 : p63 in skin development and ectodermal dysplasias.

2 : p63 and epithelial biology.

3 : Expression of p63 transcription factor in ectoderm-derived oral tissues.

4 : Isoforms of DeltaNp63 and the migration of ocular limbal cells in human corneal regeneration.

5 : Isoforms of DeltaNp63 and the migration of ocular limbal cells in human corneal regeneration.

6 : Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC).

7 : Sweating ability of patients with p63-associated syndromes.

8 : Twenty-four cases of the EEC syndrome: clinical presentation and management.

9 : Personalized Stem Cell Therapy to Correct Corneal Defects Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome.

10 : Genitourinary malformations: an under-recognized feature of ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome.

11 : International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome.

12 : Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome.

13 : P63-related disorders: Dermatological characteristics in 22 patients.

14 : Growth, nutritional, and gastrointestinal aspects of ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC) syndrome.

15 : Craniofacial and anthropometric phenotype in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (Hay-Wells syndrome) in a cohort of 17 patients.

16 : Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome.

17 : Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable expression of a single genetic disorder.

18 : Confirmation that RIPK4 mutations cause not only Bartsocas-Papas syndrome but also CHAND syndrome.

19 : AEC syndrome and CHAND syndrome: further evidence of clinical overlapping in the ectodermal dysplasias.

20 : Modeling AEC-New approaches to study rare genetic disorders.

21 : Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET/APR-246.