Clinical and Basic Investigations Into Erdheim Chester Disease

Erdheim-Chester Diseases (ECD) is a very rare non-Langerhans cell histiocytosis of unknown origin and pathogenesis. It has been reported mainly in adult males over the age of 40 years, although cases have been reported in females as well. Children are rarely affected by this condition. Mutation of the BRAF gene has been recently identified in 50% of Erdheim Chester lesions in a French cohort18; family studies have not been performed due to the rarity and sporadic nature of the disease. The clinical characteristics of ECD range from asymptomatic to multisystemic involvement; longitudinal progression and natural history have not been well documented. ECD commonly affects the bones, kidneys, retroperitoneal space, skin and brain. After diagnosis, the disease progresses rapidly, causing fatal outcomes due to severe lung disease, chronic renal failure, cardiomyopathy and other complications. The diagnosis of ECD relies upon imaging studies and specific pathologic findings in biopsies of affected organs, i.e., fibrosis and infiltration of the affected tissues with foamy histiocytes, lymphocytes, and plasma cells. Immunohistochemistry reveals cells positive for CD68, CD 163 and negative for CD1a and S-100; although a 20% positivity has been reported for the S-100 marker. There is no standard treatment for ECD, although chemotherapy with cladribine, radiation, stem cell transplantation, alpha-interferon, anakinra, imatinib, steroids and sirolimus have been proposed. Symptomatic improvement has been reported with some of these therapies, but death within a few years after diagnosis remains the expected outcome. For patients where the BRAF V600E mutation has been detected, the use of BRAF Inhibitors such as vemurafenib is currently under study. We are currently studying the use of Dabrafnib and Trametinib in patients with the BRAF V600E mutation. In this protocol, we will clinically evaluate ECD patients, obtain cells, plasma, and urine, search for genes that can be responsible for ECD, and perform other studies dictated by each patient s presentation.