Expanding the phenotypic spectrum of TP63-related disorders including the first set of monozygotic twins

Am J Med Genet A. 2018 Jan;176(1):75-81. doi: 10.1002/ajmg.a.38516. Epub 2017 Nov 12.


Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay-Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T-cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63-related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63-related disorders, as it was reported in one prior individual and two of the individuals in our case series.

Keywords: cleft lip; cleft palate; ectrodactyly; monozygotic twins; volar nail.

Publication types

  • Case Reports
  • Twin Study

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Amino Acid Substitution
  • Child
  • Child, Preschool
  • Facies
  • Female
  • Genetic Association Studies*
  • Genotype
  • Humans
  • Male
  • Mutation*
  • Pedigree
  • Phenotype*
  • Transcription Factors*
  • Tumor Suppressor Proteins*
  • Twins, Monozygotic*
  • Young Adult


  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins