Ehlers-Danlos syndromes and Marfan syndrome

Ehlers-Danlos syndromes (EDS) and Marfan syndrome (MFS) are multisystemic disorders that primarily affect the soft connective tissues. Both disorders have benefited from recent advances in clinical and molecular characterization, allowing improvements in clinical diagnosis and management. EDS are a heterogeneous group of conditions characterized by skin hyperextensibility, atrophic scarring, joint hypermobility and generalized tissue fragility. The current classification proposes six subtypes based on clinical, biochemical and molecular characteristics. However, examples of unclassified variants and ‘overlap phenotypes’ are becoming more common. Mutations in genes encoding fibrillar collagens or collagen-modifying enzymes have been identified in most forms of EDS, including the classic and vascular subtypes (collagen type V and III, respectively), and the rare arthrochalasis, kyphoscoliosis and dermatosparaxis variants (type I collagen defects). To date, the genetic background of the hypermobility type of EDS remains unclear, although some new insights have been gained recently.MFS is an autosomal-dominant disorder that affects the cardiovascular, ocular and skeletal system with aortic root dilation/dissection, ectopia lentis and bone overgrowth, respectively. Advances in therapeutic, mainly surgical, techniques have improved median survival significantly, yet severe morbidity and a substantial risk for premature mortality remain associated. The disorder is caused by mutations in the FBN1 gene, encoding the microfibrillar protein fibrillin-1. Recently, new insights in the pathogenesis changed the prevailing concept of this type 1 fibrillinopathy as a structural disorder of the connective tissue into a developmental abnormality manifesting perturbed cytokine signalling. These findings have opened new and unexpected targets for aetiologically directed drug treatments.