Abstract

Background: Mast cell activation syndrome (MCAS) and related mast cell dysregulation conditions are increasingly recognized in clinical practice, yet their developmental origins and transgenerational transmission remain poorly understood. We propose a novel framework - Programmed Mast Cell Hyperreactivity Syndrome (PMCHS) - that conceptualizes chronic mast cell hyperreactivity as an epigenetically programmed terrain, expressed through four distinct degranulation phenotypes, originating in early adversity, transmissible across generations via the NR3C1/KITLG axis, and expressed across a broad spectrum of multisystem comorbidities.

Methods: We conducted an online cross-sectional survey targeting individuals with suspected or diagnosed mast cell activation disorders, histamine intolerance, and associated conditions (lipedema, hypermobile Ehlers-Danlos syndrome, neurodevelopmental conditions, chronic inflammatory disorders). The survey collected data on symptom profiles, diagnostic trajectories, family history, adverse childhood experiences (ACEs), and comorbidity patterns. A total of 423 adults completed the survey between March 1 and April 5, 2026 (French-language cohort: n=319; English-language cohort: n=104). Descriptive statistics and frequency analyses were performed. Maternal/paternal transmission ratios were calculated from family history data.

Results: 96.0% of respondents were female (n=406/423). 94.8% reported a difficult diagnostic journey (n=401/423), with 42.3% waiting more than 15 years before receiving a relevant diagnosis (n=173/409). A family history signal consistent with sudden infant death syndrome (SIDS) was reported by 9.7% of respondents (n=41/423). Among respondents reporting familial clustering of related conditions, transmission was predominantly maternal (178 cases) vs paternal (33 cases), yielding a ratio of 5.4:1, consistent with mitochondrial and epigenetic inheritance patterns. 79.3% reported adverse childhood experiences (ACEs) (n=291/367 respondents to this item). 79.9% reported at least one first-degree family member with similar conditions (confirmed or probable, n=338/423). Four distinct degranulation phenotypes were identified based on dominant mediator profiles: histaminergic, tryptase/chymase-dominant, leukotriene-dominant, and prostaglandin-dominant, each associated with specific neurological, immunological, and comorbidity signatures.

Conclusions: PMCHS represents a clinically coherent, mechanistically grounded framework bridging early trauma, epigenetic reprogramming, mast cell dysregulation, and chronic multisystem disease expression. The observed 5.4:1 maternal transmission bias is consistent with NR3C1 methylation inheritance and mitochondrial transmission mechanisms. The high prevalence of ACEs (79.3%) supports a developmental programming model. Perinatal adversity was also prevalent: 29.1% of respondents reported maternal stress or depression during pregnancy, 22.9% reported post-birth separation from their mother, and 42.1% reported notable health problems in their first year of life - together constituting a perinatal adversity signal consistent with early programming of the stress-immune axis. These findings have implications for diagnostic approaches, therapeutic protocols, and preventive strategies across a wide range of currently siloed conditions. The PMCHS framework offers a unifying mechanistic explanation for the convergence of neurodivergence, connective tissue vulnerability, and chronic multisystem disease recently documented in trans-diagnostic research.