Mast cell activation disease and immunoglobulin deficiency in patients with hypermobile Ehlers‐Danlos syndrome/hypermobility spectrum disorder

Abstract

Mast cell activation disease (MCAD) includes single organ disease such as asthma, urticaria, and gastroenteritis, as well as multiorgan system involvement such as mast cell activation syndrome and anaphylaxis. Reports link MCAD with hypermobile Ehlers-Danlos syndrome (hEDS), hypermobility spectrum disorder (HSD), and with primary immune deficiencies such as complement and immunoglobulin deficiencies (Ig Def). This study assesses the concurrence of these syndromes. We undertook a cohort analysis of patients seen in a community-based Allergy/Immunology clinic from 2015 to 2019. We searched for diagnostic codes for Ig Def disorders, hypermobility syndrome, hypermobile/Ehlers-Danlos syndrome, and MCADs. Of 974 patients with suspected MCAD, 449 (46%) had a diagnosis of MCAD; 496 (51%) of cases had a combination of at least two of hEDS/HSD, MCAD, and Ig Def. Ig Def was present in 417 (43%) of patients; 188 (19.3%) had hEDS/HSD with an Ig Def with or without MCAD and accounted for 45% of all the cases with Ig Def. Of 974 cases, 101 (10%) had hEDS/HSD and MCAD; 207 (21%) had Ig Def and MCAD; 7 (0.7%) had Ig Def and hEDS/HSD; and 181 (19%) had a combination of all three syndromes. Most patients (74%) with these comorbidities were female. The presence of MCAD and Ig Def should be explored in patients with hEDS/HSD. Identifying underlying contributors to recurrent/chronic inflammation and tissue injury is needed to tailor and personalize therapies. This, in turn, can reduce tissue damage, iatrogenic intervention, and optimize health outcomes.

RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms

“…Albeit the new criteria were introduced with the expectation to improve phenotyping and clinical diagnoses and to create homogeneous patients’ cohorts for the discovery of the underpinning genetic etiology, several later clinical research emphasized that they are likely inappropriate to clinically differentiate these groups of patients [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] and, despite multiple attempts, no convincing molecular explanations have been found yet [ 1 , 28 ]. Lack of precision on inclusion criteria for diagnosis, locus heterogeneity, and improper application of the diagnosis in the current clinical scenario, are all contributing to this outward failure.…”

“…After the publication of the updated diagnostic criteria, several authors raised serious doubts about their limits, and it is still debated if hEDS and HSD are distinct clinical entities rather than part of a phenotypic spectrum that require a similar pattern of multidisciplinary intervention [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Considering the overlapping clinical presentation of hEDS and HSD patients and the absence of any objective and validated diagnostic biomarker, many researchers currently use the terms hEDS and HSD interchangeably and these two diagnostic labels are often grouped together as hEDS/HSD [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Removal of Polymer Clips From the Gallbladder Fossa in a Patient With Ehlers-Danlos Syndrome (EDS) to Treat Mast Cell Activation Syndrome (MCAS): A Case Report

“…The 95% confidence interval calculated for the MCAS in the POTS and EDS group did not overlap with 2%, which showed a statistically significant result. There was a marked percentage of MCAS among the patients with diagnoses of POTS and EDS [ 12 ].…”

Mast Cell Diseases in Practice and Research: Issues and Perspectives Raised by Patients and Their Recommendations to the Scientific Community and Beyond

“…Patients who fail to demonstrate an MC mediator rise, but meet the other MCAS criteria, 1,8 exist in diagnostic limbo. 14,69 Patient advocacy groups also support those patients. In some centers, care continues under a provisional diagnosis and/or using current ICD-10-CM codes.…”

“…1,[10][11][12] A potential relationship of MCAS and HaT to other conditions, such as dysautonomia, connective tissue diseases, or immunodeficiency, is under investigation. [11][12][13][14][15] These conditions should be considered in the differential diagnosis. Mast cell diseases can have unpredictable, disabling, episodic, or chronic symptoms, including anaphylaxis, resulting from trigger exposure and MC mediator release.…”