Some cases of hypermobile Ehlers-Danlos syndrome may be rooted in mast cell activation syndrome

Am J Med Genet C Semin Med Genet. 2021 Dec;187(4):466-472. doi: 10.1002/ajmg.c.31944. Epub 2021 Oct 31.


Hypermobile Ehlers-Danlos syndrome (hEDS) is the most common type of EDS, yet has remained steadfastly inscrutable vis-à-vis efforts to identify its cellular, molecular, and pathophysiologic roots. Once thought to principally affect just connective tissues, hEDS is now appreciated to be a multisystem disease of great heterogeneity with many symptoms and findings difficult to attribute solely to disordered connective tissue development. In the last decade, there has been growth in the appreciation of the existence of a wide range of disorders of chronic inappropriate mast cell (MC) activation (a large heterogeneous pool of MC activation syndromes [MCAS]) distinguishable from other MC disorders such as rare neoplastic mastocytosis. Via chronic aberrant release of the MC's vast repertoire of potent mediators, MCAS can drive extraordinary arrays of pathologies, most commonly of inflammatory, allergic, and dystrophic natures. Although hEDS is seen in only a minority of MCAS cases, limited studies have identified an association between hEDS and MCAS, fueling speculation that certain variants of MCAS may drive hEDS. No laboratory studies probing cellular or molecular linkages between hEDS and MCAS have been conducted yet, and research efforts to identify the genetic roots of hEDS should also consider those of MCAS.

Keywords: Ehlers-Danlos syndrome; hypermobility; mast cell activation disease; mast cell activation syndrome; medical hypothesis.

Publication types

  • Review

MeSH terms

  • Ehlers-Danlos Syndrome* / genetics
  • Humans
  • Mast Cell Activation Syndrome*