Histiocytosis with STEAP3-Associated Anemia and Type 4 Hemochromatosis

Introduction: Langerhans cell histiocytosis (LCH) is a rare clonal myeloid disorder characterized by tissue infiltration with pathological antigen-presenting cells morphologically and phenotypically similar to Langerhans cells. Activating mutations in the MAPK/ERK signaling pathway play a key role in the pathogenesis of LCH. The aim of this study was to characterize the morphological and molecular features of the neoplastic process. Materials and Methods: This study presents a clinical case of a 34-year-old patient with a rare mixed form of LCH combined with Erdheim-Chester disease (ECD), involving multiple organs including kidneys, skin, bones, ENT organs, eyes, and the central nervous system. The patient also had diabetes insipidus, chronic external otitis, and presumptive hereditary forms of anemia and hemochromatosis. A comprehensive histopathological evaluation was performed, including histochemical, immunohistochemical, and immunofluorescent analyses, alongside molecular genetic testing using whole exome sequencing (WES) of blood and skin samples. The patient demonstrated a partial clinical and laboratory response to targeted therapy with trametinib and desmopressin. Results: Comparison of WES data from blood and skin revealed 71,953 shared variants consistent with likely germline changes, as well as 3,081 unique somatic variants in skin and 2,633 unique variants in blood. Low-level mosaic BRAF V600E mutation (VAF = 1%) was detected in the skin, alongside pathogenic germline variants in the STEAP3 (c.523-2A>T, NM_182915.3) and SLC40A1 (c.332T>A, p.Met111Lys, NM_014585.6) genes. Immunofluorescence analysis of the trephine biopsy revealed diverse cellular populations, including sparse tryptase-positive mast cells, which showed minimal contact with each other or other labeled cells. The populations of Vimentin+CD11b–CD34+ and Vimentin+CD11b+CD34– cells (excluding endothelial cells) accounted for median values of 0.68% and 7.78%, respectively, of the total Vimentin+ cells. Regarding CD68 and S100 expression, CD68+ cells predominated (median = 55.61%), S100+ cells constituted a median of 43.02%, whereas CD68+S100+ cells were the rarest (median = 2.174%), reflecting the transition of Langerhans cells to LCH cells, encompassing up to 4.81% of the cellular population. This hybrid microenvironment paralleled the patient’s systemic inflammatory activity (elevated acute-phase reactants), multi-organ involvement, and renal interstitial fibrosis/tubular atrophy with reduced kidney function, without serological or histological evidence of vasculitis. Conclusion: This case illustrates the histological heterogeneity and hybrid pathology of mixed histiocytosis, where canonical dendritic LCH cells coexist with macrophage-rich ECD-like stroma. An integrated approach involving a multidisciplinary clinical team, thorough molecular genetic testing, and the application of targeted therapy is essential for improving prognosis and quality of life in young patients.