Models of LCH pathogenesis. (A) Ontogeny of physiologic epidermal LCs and microglia may inform mechanisms of LCH pathogenesis. Physiologic epidermal LCs arise from yolk sac and fetal liver; microglia arise from yolk sac (blue arrows). Subsequently, epidermal LC and microglia may be replace monocytes derived from bone marrow after activation or injury (orange arrows). (B) The variant allele frequency (BRAFV600E or other MAPK mutation) is found in very rare population in myeloid precursors in bone marrow and peripheral blood in patients with HR LCH and some with LR multifocal LCH. The Misguided Model of LCH Pathogenesis proposes that extent of disease is defined by the state of differentiation at which an activating somatic MAPK pathway gene mutation arises (red). (C) Lack of detectable PBMCs with BRAFV600E and self-resolving course support potential fetal liver origin, where identification of PBMCs with BRAFV600E and perivascular BRAF-V600E⁺ cells at sites of neurodegeneration support potential for hematopoietic clone (red) in LCH-ND. HSC, hematopoietic stem cell; HR, high risk; LR, low risk; mDC, myeloid dendritic cell.