Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes

Am J Med Genet A. 2015 Nov;167A(11):2555-62. doi: 10.1002/ajmg.a.37233. Epub 2015 Jun 30.


Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas-Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging.

Keywords: Bartsocas-Papas syndrome; CHAND syndrome; RIPK4; TP63; ectodermal dysplasia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cleft Lip / complications*
  • Cleft Lip / genetics*
  • Cleft Palate / complications*
  • Cleft Palate / genetics*
  • Conserved Sequence
  • DNA Mutational Analysis
  • Evolution, Molecular
  • Exome / genetics
  • Eye Abnormalities / complications*
  • Eye Abnormalities / genetics*
  • Eyelid Diseases / complications*
  • Eyelid Diseases / genetics*
  • Female
  • Hair Diseases / complications*
  • Hair Diseases / genetics*
  • Humans
  • Knee / abnormalities*
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nails, Malformed / complications*
  • Nails, Malformed / genetics*
  • Pedigree
  • Phenotype
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics*
  • Structural Homology, Protein
  • Syndactyly / complications*
  • Syndactyly / genetics*
  • Syndrome
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins / genetics


  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • RIPK4 protein, human
  • Protein Serine-Threonine Kinases

Supplementary concepts

  • Curly hair-ankyloblepharon-nail dysplasia syndrome
  • Popliteal Pterygium Syndrome, Lethal Type