Ehlers–Danlos syndrome (EDS) is a group of related connective tissue disorders consisting of 13 subtypes, each with its own unique phenotypic and genetic variation. The overlap of symptoms and multitude of EDS variations makes it difficult for patients to achieve a diagnosis early in the course of their disease. The most common form, hypermobile type EDS (hEDS) and its variant, hypermobile spectrum disorder (HSD), are correlated with rheumatologic and inflammatory conditions. Evidence is still needed to determine the pathophysiology of hEDS; however, the association among these conditions and their prevalence in hEDS/HSD may be explained through consideration of persistent chronic inflammation contributing to a disruption of the connective tissue. Aberrant mast cell activation has been shown to play a role in disruption of connective tissue integrity through activity of its mediators including histamine and tryptase which affects multiple organ systems resulting in mast cell activation disorders (MCAD). The overlap of findings associated with MCAD and the immune-mediated and rheumatologic conditions in patients with hEDS/HSD may provide an explanation for the relationship among these conditions and the presence of chronic inflammatory processes in these patients. It is clear that a multidisciplinary approach is required for the treatment of patients with EDS. However, it is also important for clinicians to consider the summarized symptoms and MCAD-associated characteristics in patients with multiple complaints as possible manifestations of connective tissue disorders, in order to potentially aid in establishing an early diagnosis of EDS. Supplementary Information The online version contains supplementary material available at 10.1007/s12026-022-09280-1.

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Of the 13 subtypes of Ehlers-Danlos Syndromes (EDSs) identified in the 2017 international classification of EDSs, 12 have a recognized, associated genetic mutation. However, hypermobile EDS (hEDS) currently has no identifiable associated gene. Therefore, patients with hEDS are identified through a set of clinical diagnosis guidelines and criteria, which are meant to differentiate hEDS from other hypermobile joint conditions and other EDSs subtypes. In this article, the authors provide an overview of hEDS symptoms and comborbidities, current treatment options, and the clinical criteria currently guiding the standard of care.

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