Defining Neuro-EDS: A Neuro-Predominant Phenotype in hEDS/HSD and Related Heritable Connective Tissue Disorders

A subgroup of patients with hypermobile Ehlers–Danlos syndrome (hEDS), hypermobility spectrum disorders (HSD), and related heritable connective tissue disorders develop complex neurological manifestations that extend beyond generalized joint hypermobility and musculoskeletal involvement. Although individual craniospinal, autonomic, neurovascular, inflammatory, and neuropathic disorders have been increasingly recognized, they continue to be evaluated largely as isolated diagnoses, leaving a clinically meaningful subgroup embedded within broad and heterogeneous hEDS/HSD populations. In this position paper, we propose Neuro-EDS as a clinically recognizable neuro-predominant phenotype within hEDS/HSD and related heritable connective tissue disorders. We synthesize evidence from multidisciplinary clinical experience, phenotypic clustering analyses, tertiary referral cohorts, population-based studies, dynamic physiologic assessment, and emerging molecular and cellular investigations supporting the recognition of this subgroup. We further discuss the clinical importance of standardized phenotypic characterization for improving patient stratification, multidisciplinary care, and systematic investigation, and propose a practical framework that organizes Neuro-EDS into two interconnected clinical manifestation domains: a Cranial and Spinal Domain and a Neuro-Autonomic-Inflammatory Domain. We propose that recognition of this phenotype will provide a foundation for multicenter collaboration, prospective registries, mechanism-informed investigation, and future integration of clinical phenotypes with biologically defined endotypes to advance precision diagnosis and care.