Disability in children diagnosed with hypermobility syndrome (HMS) and Ehlers-Danlos (hypermobility type: EDS-HT) can vary from mild to very severe. This disability can be of temporary nature but for some may persist and become chronic, eventually leading to disablement. Historically it is believed that the origin of disability in HMS/EDS-HT arises from dysfunctions in joint biomechanics. Generalized connective tissue laxity (expressed in generalized joint hypermobility (GJH)) causes joint instability, musculoskeletal injury due to biomechanical overloading. In turn, these biomechanical dysfunctions render a child more vulnerable for musculoskeletal injury. This view is widely accepted as a potential mechanism for chronic pain and disability, still the evidence is limited. This rationality is the bases for most non-pharmacological interventions however the effectiveness is variable. In this thesis, it was observed in professional dancers that the presence of GJH was associated with decreased physical fitness, pain, fatigue and increased anxiety. Although joint laxity/instability was shown as an important determinant for the severity of pain, it was not the largest contributor to disability in children with HMS/EDS-HT. On the bases of observations on the natural course of disability, it was shown that a hyper-sensitized central nervous system and multi-systemic complaints were the largest contributors to disability. In addition, the natural course can follow different trajectories, in which children with a more progressive course of disability are characterized by the presence of dysautonomia, skin issues and gastro-intestinal complaints. These findings were integrated in a new theoretical framework on which new treatment modalities may be developed.