A Multi-Hit Model for Dercum's Disease: Infection-Triggered Adipose Progenitor Dysfunction

This document presents a comprehensive four-tier hypothesis for Dercum's disease (Adiposis Dolorosa) pathogenesis based on multi-generational familial clustering and detailed case analysis. The model integrates genetic susceptibility, immune suppression, chronic infection (particularly mycobacterial), and failed adipose progenitor cell differentiation through kinase pathway dysfunction. The hypothesis proposes that chronic granuloma-forming infections trigger epigenetic reprogramming of c-kit+ adipose progenitor cells in genetically susceptible individuals, leading to failed brown adipocyte differentiation and pathological lipoma formation. Family data demonstrates dose-response correlation between infection burden and disease severity across five members spanning two generations. The document includes detailed mechanistic pathways, testable predictions, and a reversibility hypothesis suggesting that clearing persistent biofilm infections may allow disease regression. This work extends published observations of infection-triggered Dercum's disease and proposes kinase-targeted therapeutic approaches.