Letterer–Siwe disease, (LSD) or Abt-Letterer-Siwe disease, is one of the four recognized clinical syndromes of Langerhans cell histiocytosis (LCH) and is the most severe form, involving multiple organ systems such as the skin, bone marrow, spleen, liver, and lung. Oral cavity and gastrointestinal involvement may also be seen. LCH and all its subtypes are characterized by monoclonal migration and proliferation of specific dendritic cells. The subcategorization of Letterer-Siwe disease is a historical eponym. Designating the four subtypes of LCH as separate entities are mostly of historical significance, because they are varied manifestations of the same underlying disease process, and patients also often exhibit symptoms from more than one of the four syndromes. Letterer-Siwe causes approximately 10% of LCH disease. Prevalence is estimated at 1:500,000 and the disease almost exclusively occurs in children less than three years old. It is more common among Caucasian patients than in African American patients. Children with LCH with single organ involvement tend to have a better prognosis than patients with the multi-system involvement seen in Letter-Siwe disease. The name is derived from the names of Erich Letterer and Sture Siwe. Presentation Letterer-Siwe typically presents in children less than 2 years old, and the clinical manifestations may include: In a more severe course or in later phases of the disease, patients may present with hemorrhage and sepsis secondary to hepatic failure and severe pancytopenia. A purpuric rash or bruise may be apparent right before death in a patient who has a hemorrhagic tendency. Cause In general, the cause of Langerhans Cell Histiocytosis is unknown. Regardless of the subtype of Langerhans cell histiocytosis, the pathologic hallmark for all subtypes of LCH is the abnormal proliferation and accumulation of immature Langerhans cells, macrophages, lymphocytes, and eosinophils. The collection of these cells is what forms granulomatous lesions. Histiocytes, a type of white blood cell, are part of the body's immune system. When produced in excess, like in LCH and LSD, they attack the body's systems and cause the physical manifestations that are seen in these patients. There have been associated gene mutations linked to Abt-Letterer-Siwe disease. LSD, in addition to all forms of LCH, is an oncogene-driven cancer of myeloid lineage. Activation of the RAS-RAF-MEK-ERK signaling pathway is seen in all patients with LCH. In 50-60% of patients with LCH, oncogenic mutations of BRAFV600E are identified. 10-15% of patients have MAP2K1 mutations. LSD has no clear association with hereditary