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

Am J Med Genet C Semin Med Genet. 2021 Dec;187(4):473-481. doi: 10.1002/ajmg.c.31940. Epub 2021 Nov 7.


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.

Keywords: Ehlers-Danlos syndrome; hypermobility; hypogammaglobulinemia; immunoglobulin deficiency; mast cell.

MeSH terms

  • Ehlers-Danlos Syndrome*
  • Female
  • Humans
  • Joint Instability*
  • Mast Cell Activation Disorders*
  • Mast Cell Activation Syndrome*
  • Primary Immunodeficiency Diseases*