or familial tendencies. Diagnosis Diagnosing Letterer-Siwe disease requires a complete work-up and examination because its symptoms are often non-specific and appear like other benign conditions. A diagnosis of LSD can be made with positive biochemical findings suggestive of LSD in addition to evidence of multi-organ involvement. The diagnosis is established by biopsy. Pathology then uses immunohistochemical characteristics, such as cell surface markers CD1a, CD207, and S-100, to help identify the Langerhans cells. Because of the link LCH has to BRAFV600E and other MAPK pathway mutations, tumor tissue should be tested for associated mutations. Electron microscopy will show racket-like Langerhans cell granules within the specific infiltrating cells. The demonstration of these organelles allows the unequivocal diagnosis in cases with uncharacteristic clinical or histopathological appearance. The same structures are characteristic of Hand-Schüller-Christian disease and of eosinophilic granuloma. The electron microscopic findings confirm the grouping of these three diseases together as "histiocytosis X". In order to evaluate the degree of organ involvement in these patients, physicians may conduct a variety of diagnostic tests, such as In addition, a work-up for congenital and acquired immunodeficiency syndromes should be completed. In addition, a work-up should be done on potential infectious etiologies. LSD may easily be missed for other conditions causing anemia, thrombocytopenia, and hepatosplenomegaly, but should be considered especially if the patient's disease course has been refractory to antibiotics. Prognosis The disease is often rapidly fatal, with a five-year survival rate of 50%. Poor prognostic indicators include disseminated disease, age < 2 years, and the development of thrombocytopenia. The involvement of risk organs, which include the liver, spleen, and organs of the hematopoietic system, also suggests a worse prognosis and significantly higher mortality rate. The most significant prognostic factor is a response to initial (6-12 weeks) therapy with vinblastine and steroids. This factor outweighs even age as a prognostic indicator. For infants, LSD is nearly always a fatal illness. Death may occur in-utero or within a few weeks of birth. Treatment Chemotherapy is indicated for patients with multisystem involvement. Patients who do not respond to even aggressive chemotherapy may consider reduced-intensity hematopoietic stem cell transplantation, experimental chemotherapy, or immunomodulatory therapy specific to any identified mutation. Patients with BRAFV600E mutations, for example, may be candidates for BRAF inhibitors such as vemurafenib. Early consultation with a dermatologist in patients with skin manifestations is key, as early diagnosis and treatment can be life-saving to patients with this often