Erdheim-Chester disease (ECD) is characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes, with 1500 known-cases since 1930. Mutations activating the MAPK pathway are found in more than 80% of ECD patients, mainly the BRAFV600E activating mutation in 57-70% of cases, followed by MAP2K1 in close to 20%. The discovery of BRAF mutations and of other MAP kinase pathway alterations, as well as the co-occurrence of ECD with LCH in 15% of ECD patients, led to the 2016 revision of the classification of histiocytoses in which LCH and ECD belong to the "L" group. Both conditions are considered inflammatory myeloid neoplasms. Ten percent of ECD cases are associated with myeloproliferative neoplasms and/or myelodysplastic syndromes. Some of the most striking signs of ECD are the long bone involvement (80-95%), as well as the 'hairy kidney' appearance on the CT-scan (63%), the "coated aorta" (40%), the right atrium pseudo-tumoral infiltration (36%). Central nervous system (CNS) involvement is a strong prognostic factor and independent predictor of death. Interferon-alpha seems to be the best initial treatment for ECD. Since 2012, more than 200 patients worldwide with multi-system or refractory ECD have benefitted from highly effective therapy with BRAF and MEK inhibitors. Targeted therapies have an overall, robust and reproducible efficacy in ECD, with no acquired resistance to date, but their use may be best reserved for the most severe manifestations of the disease, as they may be associated with serious side-effects and as yet unknown long-term consequences.

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