TP63 – Rapp-Hodgkin Syndrome

Rapp-Hodgkin syndrome (RHS) is a rare autosomal dominant ectodermal dysplasia characterized by cleft lip/palate, sparse hair, nail dystrophy, and hyperkeratosis. RHS is allelic with other TP63-related disorders, and genotype-phenotype correlations center on mutations in the SAM and transactivation inhibitory domains of the p63 transcription factor. Clinical overlap with AEC (Hay-Wells) syndrome and EEC3 emphasizes the need for molecular diagnosis to guide patient management.

Genetic evidence for TP63 in RHS includes at least 10 unrelated probands harboring heterozygous TP63 variants across six families: missense changes such as c.1456T>C (p.Ser486Pro)[PMID:12766194], c.1622C>A (p.Ser541Tyr)[PMID:15807690], c.1517G>A (p.Gly506Asp)[PMID:16190990], c.746G>A (p.Arg249Gln)[PMID:26882220], and c.671G>A (p.Arg224His)[PMID:12939657], as well as loss-of-function alleles including c.1545del (p.Glu515fs)[PMID:12939657], c.46C>T (p.Gln16Ter)[PMID:18364388], and p.Gln9Ter[PMID:35595744].

Affected individuals exhibit a dominant inheritance pattern with de novo occurrences predominating. Familial segregation is documented in at least two pedigrees, including three additional affected relatives in a single family with c.1517G>A (p.Gly506Asp)[PMID:16190990] and two in a family with c.746G>A (p.Arg249Gln)[PMID:26882220].

The TP63 variant spectrum in RHS comprises six missense mutations clustered in the SAM and DNA-binding domains, two frameshift alleles disrupting the transactivation inhibitory domain, and two nonsense variants truncating the N-terminus. No founder mutations have been reported. Key clinical features include hyperkeratosis (HP:0000962), cleft palate (HP:0000175), bifid uvula (HP:0000193), epiphora (HP:0009926), thin upper lip vermilion (HP:0000219), coarse hair (HP:0002208), and submucous cleft hard palate (HP:0000176).

Functional studies reveal that RHS mutations commonly impair p63 oligomerization, transcriptional repression, and dominant-negative regulation of p53 target genes, consistent with gain-of-function and dominant-negative mechanisms. Mutant p63 isoforms show aberrant retention in the ER–Golgi network, altered DNA binding, and disrupted regulation of epithelial differentiation markers.

Integration of genetic and experimental data supports a Strong clinical validity classification: multiple AD families, segregation, and concordant functional assays underscore the role of TP63 in RHS. Additional variants and phenotypic data continue to emerge, but current evidence suffices for diagnostic genetic testing. Key take-home: Heterozygous TP63 mutations cause RHS through dominant-negative and gain-of-function effects, justifying inclusion of TP63 in ectodermal dysplasia gene panels.

References

• Journal of dental research • 2003 • Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia. PMID:12766194
• European journal of human genetics : EJHG • 2003 • The Rapp-Hodgkin syndrome results from mutations of the TP63 gene. PMID:12939657
• Clinical and experimental dermatology • 2005 • De novo missense mutation, S541Y, in the p63 gene underlying Rapp-Hodgkin ectodermal dysplasia syndrome. PMID:15807690
• Pediatric dermatology • 2005 • Spectrum of phenotypic manifestations from a single point mutation of the p63 gene, including new cutaneous and immunologic findings. PMID:16190990
• Clinical dysmorphology • 2016 • A recurrent TP63 mutation causing EEC3 and Rapp-Hodgkin syndromes. PMID:26882220
• Human molecular genetics • 2008 • A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes. PMID:18364388
• Human genome variation • 2022 • A novel TP63 variant in a patient with ankyloblepharon-ectodermal defect-cleft lip/palate syndrome and Rapp-Hodgkin syndrome-like ectodermal dysplasia. PMID:35595744

Evidence Based Scoring (AI generated)