Distal limb malformations: underlying mechanisms and clinical associations

Clin Genet. 2001 Sep;60(3):165-72. doi: 10.1034/j.1399-0004.2001.600301.x.


Congenital malformations of the extremities are conspicuous and have been described through the ages. Over the past decade, a wealth of knowledge has been generated regarding the genetic regulation of limb development and the underlying molecular mechanisms. Recent studies have identified several of the signaling molecules, growth factors, and transcriptional regulators involved in the initiation and maintenance of the apical ectodermal ridge (AER) as well as the molecular markers defining the three axes of the developing limb. Studies of abnormal murine phenotypes have uncovered the role played by genes such as p63 and Dactylin in the maintenance of AER activity. These phenotypes resemble human malformations and in this review we describe the underlying mechanisms and clinical associations of split hand/foot malformation and ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome, which have both been associated with mutations in the p63 gene.

Publication types

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

MeSH terms

  • Animals
  • DNA-Binding Proteins
  • F-Box Proteins
  • Genes, Tumor Suppressor
  • Humans
  • Limb Deformities, Congenital / diagnosis*
  • Limb Deformities, Congenital / genetics*
  • Membrane Proteins*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Models, Genetic
  • Mutation
  • Phenotype
  • Phosphoproteins / genetics
  • Proteins / genetics
  • Signal Transduction
  • Trans-Activators / genetics
  • Transcription Factors
  • Tumor Suppressor Proteins


  • CKAP4 protein, human
  • DNA-Binding Proteins
  • F-Box Proteins
  • FBXW4 protein, human
  • Fbxw4 protein, mouse
  • Membrane Proteins
  • Phosphoproteins
  • Proteins
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Trp63 protein, mouse
  • Tumor Suppressor Proteins