Limb Development Anomalies: Genetics

Abstract Congenital limb malformations range from reduction defects to subtle digit anomalies (number/length/anatomy). Their prevalence is evaluated from 1.3‰ to 1.9‰ neonates. They can be classified as disruption anomalies and genetic malformations. The later are due to limb development gene function alteration and may be isolated or associated with other malformations. The genes implicated in the limb bud development are numerous. They work together to trigger limb bud growth (proximodistal axis), polarisation (antero‐posterior and dorsoventral) and patterning. They are often pleiotropic, explaining the frequent association of limb anomalies with other malformations. Furthermore, limb malformations are often genetically heterogeneous and various anomalies of one single gene can cause different diseases (allelic heterogeneity). Key Concepts: The limb bud development requires a constant equilibrium between cell mitotic activity and apoptosis. The limb bud growth, its antero‐posterior and dorsoventral polarisation as well as its patterning are very interlinked and imply precise space and time regulation of the implicated genes’ expression. Regulators/enhancers : Alterations of regulatory elements of key developmental genes play an important role in limb bud development. (For example the Zone of polarising activity Regulatory Sequence (ZRS) is a crucial regulator of SHH expression in the limb bud.)