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

Abstract

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.

Mast Cell Involvement in the Pathogenesis of Selected Musculoskeletal Diseases

“…Hypermobile EDS is no longer perceived as a musculoskeletal disease affecting only connective tissue. It is a multisystem, heterogeneous disease, which—just like MCADs—produces symptoms also related to the digestive system, skin, pain sensation, chronic fatigue, as well as autonomic dysfunction [ 99 , 100 , 101 ]. Some of these symptoms are difficult to exclusively attribute to abnormal connective tissue, which justifies suspicions of additional factors contributing to the nature of hEDS.…”

“…Regarding the disproportion in patients’ sex, the vast majority of patients in both conditions are female. Also, hEDS and MCAS are associated with a recently recognized condition, hereditary alpha-tryptasemia, characterized by overexpression of tryptase [ 99 ]. The MCAD and hEDS connection may be rooted in the release of MC mediators.…”

“…MCs release corresponding mediators based on a combination of detected factors [ 94 ]. Because of all of the information mentioned above, a concept emerged that in hEDS and HSD, mediators from at least MCs, whether primary to one of the MCADs, or other disorders, lead to the production of abnormal connective tissue [ 99 ]. However, even if this hypothesis is true, it would not clarify if MCs initiate this disorder or if they only intensify it.…”

Central Role of Mast Cells in Mastocytosis, Hereditary α-Tryptasemia, Mast Cell Activation Syndrome, Urticaria, and Angioedema

“…65 Mast Cell Activation Syndrome Clinically, mast cell activation syndrome is an extremely heterogeneous disease, with aetiology and pathology that is still not fully understood, making the diagnostic process more difficult. 66 Current evidence suggests that mast cell activation syndrome is associated with a number of mutations in signal transduction proteins that pathologically stimulate activated mast cells, kinases, and receptors in different organ systems. 67 KIT D816V point mutation is typical in systemic mastocytosis, but is not present in mast cell activation syndrome.…”