Distal limb malformations: underlying mechanisms and clinical associations

Congenital malformations of the extremities are conspicuous and have been d escribed 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 in volved in the initiation and maintenance of the apical ectodermal ridge (AE R) as well as the molecular markers defining the three axes of the developi ng limb. Studies of abnormal murine phenotypes have uncovered the role play ed by genes such as p63 and Dactylin in the maintenance of AER activity. Th ese phenotypes resemble human malformations and in this review we describe the underlying mechanisms and clinical associations of split hand/foot malf ormation and ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome, w hich have both been associated with mutations in the p63 gene.