A novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype

Cold Spring Harb Mol Case Stud. 2020 Jun 12;6(3):a005207. doi: 10.1101/mcs.a005207. Print 2020 Jun.


The transforming growth factor-β-activated kinase 1 (TAK1) encoded by mitogen-activated protein kinase kinase kinase 7 (MAP3K7) is widely expressed and participates in multiple molecular and cellular processes, including growth, differentiation, inflammation, and apoptosis. Pathogenic variants in MAP3K7 have recently been associated with two disorders: cardiospondylocarpofacial syndrome (CSCFS) and frontometaphyseal dysplasia 2 (FMD2). To date, all small in-frame deletions and splice variants in MAP3K7 have been associated with CSCFS, whereas missense variants have been reported in both CSCFS and FMD2. Here, we present a patient with a novel heterozygous likely pathogenic variant, c.125_127del, p.(Val42del), in MAP3K7, only the sixth variant associated with CSCFS to be described in the literature. Although this patient has a phenotype that is most consistent with that of CSCFS, including valvular heart disease, short stature, fusions of the spine and bones of the hands and feet, and certain facial dysmorphisms, he interestingly has some features reported previously in FMD2 but not CSCFS. These include flexion contractures of the elbow and widely spaced first and second toes, highlighting new points of overlap between these two syndromes. We additionally point out features in the patient presented here that are rare but recurrent among CSCFS patients previously reported in the literature, as well as a new distinctive cutaneous finding not previously reported.

Keywords: bicuspid aortic valve; bilateral cryptorchidism; dysplastic pulmonary valve; elbow flexion contracture; excessive wrinkled skin; joint laxity; mild global developmental delay; nasogastric tube feeding in infancy; recurrent infections in infancy and early childhood; short stature; synostosis involving bones of the hand.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis*
  • Abnormalities, Multiple / genetics*
  • Biomarkers
  • Facies
  • Genetic Association Studies*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Infant
  • MAP Kinase Kinase Kinases / genetics*
  • Male
  • Mutation*
  • Phenotype*
  • Radiography
  • Syndrome


  • Biomarkers
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7