Patient case: 57-year-old male with melanoma; genetic feature: BRAF (V600E), PTEN loss of function

Clinical trial: Clinical and Basic Investigations Into Erdheim Chester Disease

Summary: Background:
  - Erdheim Chester Disease (ECD) is a very rare disease in which abnormal white blood cells start growing and affect the bones, kidneys, skin, and brain. ECD can cause severe lung disease, kidney failure, heart disease, and other complications that lead to death. Because ECD is a rare disease, found mostly in men over 40 years of age, there is no standard treatment for it. More information is needed to find out what genes can cause ECD and how best to treat it.
  Objectives:
  - To collect study samples and medical information on people with Erdheim Chester Disease.
  Eligibility:
  - Individuals 2 to 80 year of age who have been diagnosed with Erdheim Chester Disease.
  Design:
  -  Participants will be screened with a physical exam and medical history.
  -  Participants will have a study visit to provide samples for study, including blood, urine, and skin tissue samples. Participants will also have lung, heart, and muscle function tests; imaging studies of the brain, chest, and whole body; a treadmill running stress test; an eye exam; and other tests as needed by the study doctors.
  -  Participants will be asked to return for a similar set of tests every 2 years, and to remain in contact for possible treatment options.

Detailed description: 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.

Eligibility: -  INCLUSION CRITERIA:
  -  ECD patients of any gender and ethnicity age 2-80 years are eligible to enroll in this protocol.
  -  Patients will be diagnosed as having ECD based upon pathologic evaluations of affected organs.
  -  Any child older than 2 years with confirmed ECD by pathology will be enrolled in our study since childhood cases are so rare. The child must be clinically stable prior to visiting the NIHCC.
  -  Patients that agree to be part of this research study are expected to undergo the evaluations and testing of this protocol.
  EXCLUSION CRITERIA:
  -  Patients will be excluded if they have a suspected diagnosis of ECD not confirmed by biopsy or another form of histiocytosis.
  --If the patient cannot travel to the NIH because of their medical condition, they can still participate in our study by submitting tissue and blood for research purposes after consent has been obtained and diagnosis of ECD has been confirmed through tissue-biopsy evaluation. This exception applies to all patients aged 2-80 years.
  -  Children under age two year are excluded because there is no urgency for a very early diagnosis and care is more readily provided to older children at the Clinical Center.
  -  Pregnant women will not be able to be part of this study because of the risks that can be harmful to the fetus, unless they will be participating by only submitting samples of already available affected tissue while they are pregnant. By any means we will not encourage pregnant women to undergo affected organ surgery or biopsy in order to participate in this study unless clinically indicated and recommended by their primary care provider.

Relevance to patient case: not relevant