Version May 2024
INTRODUCTION — Tumor protein p63 (TP63) is a transcription factor encoded by TP63 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, TP63 is required for epidermal lineage commitment, epidermal differentiation, cell adhesion, and basement membrane formation [1]. Postnatally, the p63 protein 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]. Pathogenic variants in different domains of TP63 result in different ectodermal dysplasia syndromes with considerable overlapping features [1,5,6]:
●ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome (MIM #103285)
●EEC (ectrodactyly, ectodermal dysplasia, and cleft lip/palate) type 3 (EEC3) syndrome (MIM #604292)
●AEC (ankyloblepharon-ectodermal defects-cleft lip/palate) 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)
TP63 variants have been implicated in the pathogenesis of primary ovarian insufficiency [6-9], in which patients experience infertility associated with early arrest of menstruation and high follicle-stimulating hormone before the age of 40. TP63 has also been shown to play a role in the pathogenesis of nonsyndromic cleft lip and palate [10].
The following sections will expand on EEC3 syndrome and AEC syndrome as representative examples of this group of ectodermal dysplasias. Classic ectodermal dysplasias are discussed separately. Focal dermal hypoplasia (Goltz syndrome) is also discussed separately. (See "Ectodermal dysplasias" and "Focal dermal hypoplasia (Goltz syndrome)".)
EEC3 SYNDROME — EEC (ectrodactyly, ectodermal dysplasia, and cleft lip/palate) type 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 [11].
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 [12].
Extracutaneous — Extracutaneous manifestations include:
●Dental anomalies – Hypodontia is common, and teeth can be conical in shape, with poor enamel and an increased risk of caries.
●Facial features – 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 anomalies – Limb anomalies include split-hand/foot, syndactyly, oligodactyly, and digital duplication (picture 1A-B) [5,13]. Any combination of one to four extremities can be involved.
●Absent lacrimal puncta – 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 [14].
●Genitourinary anomalies – Genitourinary tract malformations occur in at least 50 percent of individuals with EEC3 syndrome, including hydroureter, hydronephrosis, renal agenesis, urethral stenosis, micropenis, hypospadias, and cryptorchidism [15].
●Endocrine abnormalities – Endocrine abnormalities may include growth hormone deficiency, hypogonadotropic hypogonadism, and arginine vasopressin deficiency (previously called central diabetes insipidus) [16].
Choanal atresia and rectal stenosis have also been reported in association with EEC3 syndrome [17].
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 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 — Prenatal testing is available. Preimplantation genetic testing is possible if the familial TP63 variant has been identified.
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, EEC (ectrodactyly, ectodermal dysplasia, and cleft lip/palate) type 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; ophthalmologist; speech-language therapist; nutritionist; orthopedic surgeon; urologist; 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 therapists 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 and referral, as necessary, to a pediatric urologist.
●Children who are not growing as expected should be evaluated for feeding difficulties related to cleft lip and/or palate and may need to be followed by a pediatric feeding team. Referral to a pediatric endocrinologist may also be needed to test for hormonal abnormalities, such as growth hormone deficiency.
Prognosis — The prognosis is overall good for general health and life expectancy.
AEC SYNDROME — AEC (ankyloblepharon-ectodermal defects-cleft lip/palate) 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 [18].
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) [19,20]. 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 [12].
Extracutaneous — Extracutaneous manifestations include:
●Ankyloblepharon – Approximately 70 percent of individuals with AEC syndrome 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.
●Facial features – Cleft lip and/or palate occurs in nearly all cases. Other facial features include maxillary hypoplasia, micrognathia, underdeveloped alae nasi, and short philtrum.
●Dental anomalies – Dental anomalies include significant hypodontia and conical teeth.
●Hypospadia – Hypospadias is common in males [21].
●Poor growth – Height and weight deficits, requiring nutritional supplementation, are common and may persist through childhood [22].
●Limb anomalies – Limb anomalies have been reported, including syndactyly and ectrodactyly [21].
Skin and hair 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 of the hair include pili torti, pili trianguli et canaliculi, irregular indentation, and shallow grooves [23].
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 via sequencing and deletion/duplication analysis. Most of the AEC syndrome variants occur in exons 13 and 14, which encode the SAM and transactivation domains.
Prenatal diagnosis — Prenatal and preimplantation genetic testing are options for future pregnancies if a pathogenic variant in TP63 has been identified in an affected family member.
Differential diagnosis — Rapp-Hodgkin syndrome is an allelic disorder with AEC, and many experts now consider it to be a variant of AEC syndrome [24]. 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.
CHAND (curly hair-ankyloblepharon-nail dysplasia) syndrome has overlapping features with AEC syndrome but lacks skin erosions and cleft lip/palate [25,26].
Management — As in EEC3 (ectrodactyly, ectodermal dysplasia, and cleft lip/palate type 3) 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.
Research investigating the use of induced pluripotent stem cells to build patient-derived skin to treat skin erosions is ongoing [27]. An initial trial of 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 [28].
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
●Genetics and phenotypes – Pathogenic variants in different domains of the TP63 gene, which encodes 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. These include (see 'Introduction' above):
•ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome
•EEC (ectrodactyly, ectodermal dysplasia, and cleft lip/palate) type 3 (EEC3) syndrome
•AEC (ankyloblepharon-ectodermal defects-cleft lip/palate) syndrome
•Limb-mammary syndrome
•Orofacial cleft 8
•Split-hand/foot malformation 4
●EEC3 syndrome – 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 may occur. (See 'EEC3 syndrome' above.)
●AEC syndrome – AEC syndrome is an autosomal dominant disorder characterized by ankyloblepharon filiforme adnatum (partial or complete fusion of 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 'AEC syndrome' above.)
●Management – Patients with EEC3 syndrome and AEC syndrome require management by a multidisciplinary team that includes a primary care clinician; dermatologist; geneticist; plastic surgeon; ear, nose, and throat (ENT) specialist; ophthalmologist; speech-language therapist; nutritionist; orthopedic surgeon; urologist; and pediatric dentist, orthodontist, and prosthodontist. (See 'Management' above and 'Management' above.)
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