The propositions the PMCHS model rests on — from pillars established by the published preprints to leads still exploratory.
The starting point of the whole research effort: mast cells, via a terrain inherited mainly along the maternal line, could be a common risk factor across conditions currently considered separately — including sudden infant death syndrome (SIDS).
Starting point · February 2026 🔶 PMCHS predictionThe terrain is preferentially transmitted along the maternal line, consistent with an epigenetic mechanism. Ratio of 5.4:1 observed in survey data (N=423).
Established · Preprint 1 ✅ Established (survey data)ERα/GPR30 → mast cell activation → histamine + LTC4 → endothelial HMGB1 → reactivation via RAGE. Specifically concerns the role of estrogen in tissue inflammation, notably in the pathogenesis of lipedema and obesity. See the loop diagram.
Established · Preprint 1 🟡 Mechanistic inferenceEarly stress and childhood trauma durably lower the mast cell reactivity threshold by acting on the HPA axis.
Established · Preprint 1 🟡 Mechanistic inferenceChronic desensitization of hypothalamic H1 receptors reduces the ability to perceive internal homeostatic signals (thirst, satiety, fatigue, pain, thyroid, affect). See the GIH detail.
Established · Original hypothesis, E. Silva 2026 🔶 PMCHS predictionThe origin of the terrain is now positioned on the side of an early rupture of safety and attachment, rather than generic perinatal trauma. See Model evolution for this change.
Current model · Summer 2026 🔶 PMCHS predictionThe hyperactivated locus coeruleus becomes the central upstream relay, from which four branches of observable consequences flow. See Proposed mechanisms.
Current model · Summer 2026 🟡 Mechanistic inferenceNon-integrated archaic reflexes (Moro, Galant, ATNR, TLR…) are no longer considered the terrain's starting point — nor a simple downstream consequence of the LC. LC-NE dysregulation and the persistence of archaic reflexes are now treated as parallel manifestations of the same atypical neurodevelopmental trajectory. See Primitive reflexes.
Current model · October 2026 🟡 Mechanistic inferenceMechanical pelvic venous congestion (May-Thurner syndrome) could act as a regional trigger for mast cell activation in lipedema.
Exploratory · Not formalized 🔶 PMCHS predictionA mechanism involving folate receptor autoantibodies (FRAA) as a contributing pathway in some cases of autism spectrum disorder, to be linked to the PMCHS terrain.
Exploratory · Not formalized 🔶 PMCHS predictionThe connective tissue fragility observed in some PMCHS phenotypes could be a consequence of chronic mast cell activity, rather than a primary structural defect (an alternative hypothesis to classic hEDS frameworks).
Exploratory · Not formalized 🔶 PMCHS predictionDistinct from the estrogenic amplification loop (hypothesis 3, a local mechanism), the worsening of the PMCHS terrain from generation to generation may result from the accumulation of four factors: maternal mitochondrial transmission (5.4:1 ratio), epigenetic amplification (NR3C1/KITLG methylation), combined parental load, and fetal microchimerism (residual semi-allogeneic cells programming the next child's terrain). See Proposed mechanisms.
Exploratory · Synthesis of personal research notes, not formalized 🟡 Mechanistic inference