TP63 – Acro-Dermato-Ungual-Lacrimal-Tooth (ADULT) Syndrome

TP63 encodes the p63 transcription factor, a p53 family member essential for limb and ectodermal development. ADULT syndrome (MONDO:0007072) is an autosomal dominant ectodermal dysplasia characterized by ectrodactyly or syndactyly, dysplastic nails, tooth anomalies, lacrimal duct defects, hypohidrosis, and facial freckling. Diagnosis relies on clinical recognition of these hallmark features and confirmatory TP63 sequencing.

Genetic evidence for TP63 in ADULT syndrome derives from >30 unrelated individuals reported to date (PMID:16724007), including 16 patients across five unrelated families (PMID:16724007) and additional segregation in multigenerational pedigrees (PMID:22607287; PMID:27469932). Segregation has been demonstrated in three-generation families (PMID:22607287) and in father–daughter–son trios (PMID:27469932), consistent with dominant inheritance. De novo events have also been described (PMID:28293528), supporting pathogenicity in sporadic cases.

The variant spectrum is dominated by heterozygous missense substitutions in the DNA-binding domain, with recurrent alleles including c.728G>A (p.Arg243Gln) and c.893G>A (p.Arg298Gln). c.728G>A (p.Arg243Gln) has been identified in multiple families from diverse ancestries (PMID:19781362). Other reported changes include c.445C>T (p.Arg149Trp), c.446G>A (p.Arg149Gln), c.518G>T (p.Gly173Val), c.401G>T (p.Gly134Val), and c.674G>A (p.Arg225His), all co-segregating with ADULT features.

Functional studies reveal a gain-of-function mechanism: the R298Q mutation does not impair DNA binding but confers novel transactivation capacity on the ΔNp63γ isoform, unmasking a second activation domain (PMID:11929852). This aligns with unique ADULT-syndrome phenotype distinct from loss-of-function EEC mutations.

No studies to date have refuted this association or identified benign missense variation at the key arginine residues in control cohorts. Phenotypic overlap with EEC, LMS, and the proposed ELA umbrella highlights intrafamilial variability but does not detract from the core ADULT features.

In summary, TP63 missense variants in the DNA-binding domain cause ADULT syndrome via dominant gain-of-function. Clinical genetic testing of TP63 is recommended for individuals with the characteristic combination of limb malformations, ectodermal dysplasia signs, and lacrimal duct anomalies. This association is strong and clinically actionable for diagnosis and genetic counseling.

Key Take-home: Dominant TP63 missense mutations underlie ADULT syndrome through a gain-of-function mechanism, enabling accurate molecular diagnosis and management.

References

• European Journal of Human Genetics | 2006 | Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene PMID:16724007
• International Journal of Dermatology | 2012 | ADULT syndrome due to an R243W mutation in TP63 PMID:22607287
• Pediatric Dermatology | 2016 | Acro-Dermato-Ungual-Lacrimal-Tooth Syndrome: An Uncommon Member of the Ectodermal Dysplasias. PMID:27469932
• Plastic and Reconstructive Surgery. Global Open | 2016 | Intermediate Phenotype between ADULT Syndrome and EEC Syndrome Caused by R243Q Mutation in TP63 PMID:28293528
• Human Molecular Genetics | 2002 | Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63 PMID:11929852

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