Histiocytic disorders of childhood represent a wide spectrum of conditions that share the common histologic feature of activated or transformed “histiocytes.” Langerhans cell histiocytosis (LCH) is the most common, with an incidence of approximately 5 per million children. LCH may be difficult to distinguish from more ubiquitous causes of skin rashes, bone pain, or fever. Current chemotherapy fails to cure more than 50 of children with multifocal disease, and treatment failure is associated with increased risks of long-term sequelae. Somatic activating mitogen-activated protein kinase (MAPK) pathway-activating mutations (most often BRAFV600E) have been identified in hematopoietic precursors in patients with LCH. Opportunities to improve outcomes with targeted therapies are under investigation. Juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are less common than LCH and are distinguished by specific histologic and clinical features. Recurrent MAPK pathway gene mutations are also identified in JXG and RDD. In many cases, these conditions spontaneously resolve, but disseminated disease can be fatal. Although there has been historic debate regarding the nature of these conditions as inflammatory versus neoplastic, LCH, JXG, and RDD are now considered myeloid neoplastic disorders. In contrast, hemophagocytic lymphohistiocytosis (HLH) is clearly a disorder of immune dysregulation. HLH is characterized by extreme immune activation driven by hyperactivated T cells. HLH arises in approximately 1 child per million and is nearly universally fatal without prompt recognition and immune suppression. Outcomes of treated children are poor, with approximately 60 survival. Emapalumab, which targets interferon-γ signaling, was recently approved for patients with recurrent or refractory HLH, and additional cytokine-directed therapies are under investigation.
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