Genetics of Cutis Laxa

Abstract

Cutis laxa syndromes are a heterogeneous group of multisystem disorders with prominent connective tissue features including loose redundant skin folds, a clinical hallmark shared among all subtypes. The skin laxity results from severe dermal elastic fibre fragmentation. The molecular defects underlying congenital forms of cutis laxa may affect any step in elastic fibre assembly, as illustrated by the identification of pathogenic variants in different extracellular matrix proteins, including elastin, latent transforming growth factor β proteins and fibulins ( ELN , LTBP4 , FBLN4 , FBLN5, LOX, EMILIN1, LTPB1 ), cellular trafficking ( ATP6V0A2, ATP6V1E1, ATP6V1A and ATP7A ) and metabolic processes ( ALDH18A1, PYCR1) . The latter two groups have been referred to as neurometabolic cutis laxa and may present with skeletal and neurological phenotypes in addition to connective tissue manifestations. Key Concepts Elastic fibres (EF) provide resilience and elasticity to the connective tissue and contribute to tissue homeostasis by regulating cytokine signalling and cell–matrix interactions. Elastic fibre synthesis or elastogenesis is a complex spatiotemporally regulated multistep process. Cutis laxa syndromes are a heterogeneous group of multisystem connective tissue disorders that share loose redundant skin folds, that vary significantly in severity and spectrum of the associated clinical manifestations. The molecular defects underlying congenital forms of cutis laxa involve all steps in EF synthesis, affecting different extracellular matrix proteins ( ELN, LTBP4, FBLN4, FBLN5, LOX, EMILIN1, LTBP1 ), cellular trafficking ( ATP6V0A2, ATP6V1E1, ATP6V1A, SCYL1BP1 and ATP7A ) and metabolism ( ALDH18A1, PYCR1 ). Cutis laxa caused by defects in extracellular matrix proteins present with prominent arterial and/or pulmonary abnormalities. Cutis laxa caused by intracellular trafficking disorders and/or metabolic disorders may present with intellectual deficiency, skeletal and/or ocular defects.