BRAF Mutations in Erdheim-Chester Disease

Erdheim-Chester disease (ECD) is a xanthogranulomatous disease with variable manifestations that can also severely involve the orbit. In their recent article, “Adult orbital xanthogranulomatous disease: a review with emphasis on etiology, systemic associations, diagnostic tools, and treatment,” published in Dermatologic Clinics , Justin Kerstetter and Jun Wang portray a global picture of the various conditions that may present as orbital xanthogranulomatous disease, with a particular focus on systemic diseases. Recent and crucial discoveries in the field of ECD are not included in their review and should be addressed. First of all, the BRAF mutation V600E has been identified by several groups in most of the patients with ECD. BRAF is a serine/threonine protein kinase, with a crucial role in the regulation of cell proliferation and survival, as it contributes to the RAS-RAF-MEK-ERK protein kinase pathway. More recently, other more sporadic mutations in genes associated with a chronic activation of this pathway have been described in ECD patients. The oncogenic activation of the MAP kinase pathway has also been associated with oncogene-induced senescence, a protective mechanism against oncogenic events, whose activation leads to cell-cycle arrest and induction of pro-inflammatory molecules, events that are characteristically seen in ECD. These important insights in the pathogenesis of ECD have fundamental therapeutic implications, since BRAFV600E is a drug-targetable mutation. It has indeed been shown that ECD patients treated with vemurafenib, a selective BRAF V600E inhibitor, encounter a dramatic clinical and radiographic improvement. These results have made vemurafenib one of the main cornerstones of the recently published guidelines on the management of ECD, particularly when the disease is advanced, diffuse, or severe.

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