Efforts on recognition, diagnosis and management of the presumed, most common connective tissue disorder, Hypermobile Ehlers Danlos syndrome have been an ongoing challenge, decades after the description of this condition. The recent international consortium proposed a revised Ehlers Danlos syndrome classification, an update much needed since Villefranche nosology, in 1998. Hypermobile Ehlers Danlos is the only subtype in these groups of syndromes with no known genetic cause(s). This effort brought significant attention to this often underappreciated condition. This review provides an update in clinical and genetics aspects of hypermobile Ehlers Danlos syndrome for clinicians and researchers.

Background/Objectives: Hypermobile Ehlers–Danlos syndrome (hEDS) is the most common subtype of Ehlers–Danlos syndromes (EDS), a heterogeneous group of hereditary connective tissue disorders. The hallmark features of hEDS include generalized joint hypermobility (GJH), soft or velvety skin, and persistent joint pain. The molecular etiology of hEDS remains unknown, and diagnosis is primarily clinical. The updated diagnostic criteria for hEDS requires the fulfillment of three criteria: (1) GJH, (2) a combination of musculoskeletal and systemic manifestations consistent with a connective tissue disorder, and (3) the exclusion of alternative diagnoses. However, the exclusion process and the role of genetic testing have not yet been fully refined. Methods: This retrospective review utilized data from the Hereditary Connective Tissue Disorders (HCTD) patient registry at the University of Miami, which includes individuals evaluated at the HCTD Clinic using a standardized internal clinical and genetic protocol. We analyzed data from 907 patients referred for hEDS evaluation between June 2019 and December 2022. Results: Among these patients, 178 met the 2017 diagnostic criteria for hEDS. Genetic testing identified an alternative or additional diagnosis in 47 of these individuals (26.4%), with clinical implications requiring distinct management strategies. Conclusions: These findings underscore the importance of criterion three—exclusion of alternative diagnoses—and highlight the critical yet underutilized role of genetic testing in the assessment of joint hypermobility. Furthermore, the results suggest that hypermobility may present a shared phenotype across a spectrum of disorders, including inflammatory diseases, monogenic syndromes, and chromosomal abnormalities.