Tp63-Related Disorders
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.
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. 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.
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 multigene panel:
- Single-gene testing. Sequence analysis of TP63 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
- A multigene panel that includes TP63 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 2.
Molecular Genetic Testing Used in TP63 Related Disorders
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| TP63 | Sequence analysis 3 | 75%-100% 4 |
| Gene-targeted deletion/duplication analysis 5 | Rare 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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.
van Bokhoven et al [2001], Rinne et al [2009]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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