Erdheim–Chester disease

Overview

Erdheim–Chester disease (ECD) is a rare, progressive form of non-Langerhans cell histiocytosis characterized by the abnormal overproduction and accumulation of histiocytes (a type of white blood cell) in multiple organs and tissues. These histiocytes cause inflammation and fibrosis, leading to damage and dysfunction in affected systems. First described in 1930, ECD primarily affects adults between the ages of 40 and 70 and can involve the bones, heart, lungs, kidneys, central nervous system, and other organs. ECD is considered a systemic inflammatory neoplasm and has features of both autoimmune and neoplastic diseases.

Causes

The exact cause of Erdheim–Chester disease is not fully understood, but it is now recognized as a clonal disorder, meaning it originates from a single abnormal cell that proliferates. Genetic mutations play a key role in driving the disease. Common findings include:

• BRAF V600E mutation: Found in over 50% of cases; leads to uncontrolled cell growth

• MAPK/ERK pathway mutations: Including NRAS, KRAS, and ARAF

These mutations contribute to abnormal histiocyte activation and proliferation. ECD is classified as an inflammatory myeloid neoplasm, placing it in the spectrum of histiocytic disorders.

Symptoms

Symptoms of ECD vary widely depending on which organs are involved. Common manifestations include:

Bone involvement (up to 95% of cases):

• Bilateral, symmetric pain in the legs, especially the long bones (femur, tibia)

• Bone thickening and sclerosis visible on imaging

Cardiovascular system:

• Pericardial effusion (fluid around the heart)

• Infiltration of the heart tissue, valves, or large vessels like the aorta

Central nervous system (CNS):

• Diabetes insipidus (due to pituitary involvement)

• Ataxia, seizures, cognitive impairment

Other possible symptoms:

• Exophthalmos (bulging eyes)

• Shortness of breath (lung involvement)

• Renal dysfunction or obstruction due to retroperitoneal fibrosis

• Fatigue, fever, weight loss

Diagnosis

Diagnosis of Erdheim–Chester disease involves a combination of clinical evaluation, imaging, histopathology, and genetic testing. Key diagnostic steps include:

• Imaging studies:

  • Bone scintigraphy or PET scan shows symmetric uptake in long bones

  • MRI or CT scans for organ involvement

• Tissue biopsy:

  • Shows infiltration by foamy histiocytes that are CD68-positive and CD1a-negative (distinguishing ECD from Langerhans cell histiocytosis)

• Genetic testing:

  • Identification of mutations in BRAF or other MAPK pathway genes to confirm clonality and guide treatment

• Hormonal testing: For suspected pituitary involvement

Treatment

There is no universal cure for ECD, but targeted therapies have significantly improved outcomes. Treatment is personalized based on organ involvement and mutation status:

• Targeted therapies:

  • BRAF inhibitors (e.g., vemurafenib, dabrafenib) for patients with BRAF V600E mutations

  • MEK inhibitors (e.g., cobimetinib, trametinib) for non-BRAF mutations in the MAPK pathway

• Immunosuppressive therapy:

  • Interferon-alpha has been used historically with variable success

• Corticosteroids: For acute inflammation and symptom control

• Radiation or surgery: In select cases for symptom relief or mass reduction

• Hormone replacement therapy: For endocrine dysfunction like diabetes insipidus

Prognosis

Prognosis in Erdheim–Chester disease has improved with the development of targeted therapies. While ECD was once considered highly fatal, many patients now experience disease stabilization or regression with appropriate treatment. Prognosis depends on:

• Extent and severity of organ involvement

• Presence of CNS or cardiovascular disease

• Response to therapy

With early diagnosis and modern treatment, 5-year survival rates have significantly increased. Lifelong monitoring is essential, as ECD is a chronic condition with potential for relapse or progression.