Why hEDS, POTS, and MCAS Almost Always Come Together: The Mechanistic Triad and the Upstream Lesion Standard Medicine Doesn't Treat — Why the Three Diagnoses Cluster

The clustering of hEDS, POTS, and MCAS is well documented in patient cohorts. Multiple studies have shown that patients with hEDS are several times more likely to have POTS or MCAS than the general population, and that patients with MCAS frequently have signs of both hypermobility and orthostatic intolerance. The clinical observation has been called the "trifecta" or the "triad," and the patient community has been aware of it for longer than the academic literature has properly engaged with it. The standard explanations for why the three cluster are several. The connective tissue laxity is structural, and the structural laxity has downstream consequences for vascular tone (POTS) and for tissue compartmentalization (MCAS). Mast cells live in connective tissue, and connective tissue that is structurally abnormal may have abnormal mast cell distribution or activation thresholds. The autonomic nervous system regulates both vascular tone and mast cell activation, so disruption at the autonomic layer can produce signs of both POTS and MCAS. These explanations are partially correct. They are also incomplete. The deeper explanation is that all three diagnoses describe failure modes of systems that share the same bioenergetic dependency. Connective tissue maintenance requires energy. Autonomic regulation requires energy. Mast cell threshold regulation requires energy. When the bioenerge