Familial Occurrence of Systemic Mast Cell Activation Disease
Open accessAbstract
Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by accumulation of dysfunctional mast cells. Demonstration of familial clustering would be an important step towards defining the genetic contribution to the risk of systemic MCAD. The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT) among affected family members in three selected pedigrees. Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population. The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p<0.0001). In three families with a high familial loading of MCAD, the subtype of MCAD and the severity of mediator-related symptoms varied between family members. In addition, genetic alterations detected in KIT were variable, and included mutations at position 816 of the amino acid sequence. In conclusion, our data provide evidence for common familial occurrence of MCAD. Our findings observed in the three pedigrees together with recent reports in the literature suggest that, in familial cases (i.e., in the majority of MCAD), mutated disease-related operator and/or regulator genes could be responsible for the development of somatic mutations in KIT and other proteins important for the regulation of mast cell activity. Accordingly, the immunohistochemically different subtypes of MCAD (i.e. mast cell activation syndrome and systemic mastocytosis) should be more accurately regarded as varying presentations of a common generic root process of mast cell dysfunction, than as distinct diseases.
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MCAS is prevalent, with estimates ranging up to 17% of the general population.
“increasing appreciation that MCAS is prevalent (up to 17% of the general population)”
From Diagnosis of mast cell activation syndrome: a global "consensus-2" (2021) · cites this paper as [11]
The Discussion reports approximately 17% *suspected MCAD* in a German general-population control group and says this is probably due to the common MCAS subtype. It does not establish 17% as an MCAS-specific prevalence estimate; the Discussion also cautions that self-report and response bias may have inflated the MCAD estimate. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe known prevalence of allergy is congruent with higher estimates of MCAS prevalence and with estimates for prevalence of the spectrum of chronic inflammatory diseases.
“This figure unsurprisingly is congruent with not only some of the higher estimates of prevalence for MCAS [11,44,45] but also (given that chronic multisystem inflammation is, more than any other clinical feature, the sine qua non of MCAS) estimates for prevalence of the spectrum of chronic inflammatory diseases [43,46,47].”
From Diagnosis of mast cell activation syndrome: a global "consensus-2" (2021) · cites this paper as [11]
MCAS likely is prevalent.
“MCAS likely is prevalent [11].”
From Diagnosis of mast cell activation syndrome: a global "consensus-2" (2021) · cites this paper as [11]
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References 30 · Cited by 94
Research works printed but not linked: 21
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- Authors
- Molderings, G. J., Haenisch, B., Bogdanow, M., Fimmers, R., & Nöthen, M. M.
- Affiliations
- University Hospital Bonn (DE)
- Federal Institute for Drugs and Medical Devices (DE)
- Corresponding author
- Molderings, Gerhard J.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-09-30
- Volume
- 8
- Issue
- 9
- Pages
- e76241
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3787002
- OpenAlex
- W2094906508
- Cited by
- 94
- References
- 30
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 7 · 2022: 10 · 2021: 10 · 2020: 7 · 2019: 7 · 2018: 2 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 11 · 2013: 2
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal Tumor Research and Treatment
- Keywords
- familial aggregation, mast cell activation syndrome, systemic mastocytosis, KIT mutations, somatic mutations, genetic susceptibility, first-degree relatives, disease heterogeneity
- MeSH terms
- Adult, Female, Germany, Humans, Immunohistochemistry, Male, Middle Aged, Pedigree, Prevalence, DNA Primers, Proto-Oncogene Proteins c-kit, Protein Isoforms, Mutation, Missense, Mastocytosis, Systemic, Inheritance Patterns, Self Report
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