Erdheim-Chester Disease

Erdheim-Chester disease (ECD), a non-Langerhans form of histiocytosis, is a multisystemic disease characterized by various manifestations such as skeletal involvement with bone pain, exophthalmos, diabetes insipidus, renal impairment and central nervous system (CNS) and/or cardiovascular involvement.

Epidemiology

Prevalence is unknown. More than 500 cases (<15 pediatric) have been reported since 1930.

Clinical description

ECD usually presents in adults aged 40-60 with a 3:1 male to female ratio. Clinical course varies from asymptomatic to multisystemic, life-threatening forms. The pathognomonic feature of ECD is osteosclerosis of the long bones manifesting as bone pain, mainly affecting the distal lowerlimbs (50% of cases). Pituitary gland infiltration leads to diabetes insipidus and rarely hyperprolactinemia and gonadotropin insufficiency. Constitutional symptoms include fever, weakness and weight loss. Infiltrations in other organs can lead to intracranial hypertension, exophthalmos, papilledema, adrenal insufficiency, xanthelasmas and papulonodular skin lesions. CNS involvement can cause cerebellar and pyramidal syndromes, headaches, seizures, cognitive impairment, cranial nerve palsies and sensory disturbances. A frequent cardiovascular involvement is the ''coated aorta''. Renal arteries can also be involved, leading to reno-vascular hypertension. Pericardial involvement may be complicated by a tamponade. Pseudo-tumoral infiltration of the right atrium is also seen. Dyspnea, due to lung infiltration, has been reported. Pseudo retroperitoneal fibrosis is sometimes complicated by bilateral hydronephrosis.

Etiology

Etiology is unknown but it is thought to be either a reactive or neoplastic disorder. Elevated levels of interferon-alpha (IFN-alpha), interleukin (IL)-7, IL-12, monocyte chemoattractant protein-1 and decreased levels of IL-4 found in ECD patients support an associated systemic immune Th-1 oriented perturbation. Recent findings of mutations in the BRAF proto-oncogene in > 50% of ECD cases clearly add further complexity to the pathophysiology of ECD.

Diagnostic methods

The hallmark histological finding is the xanthogranulomatous or xanthomatous infiltration of tissues with spumous histiocytes. Immunohistochemical staining of a biopsy sample is CD68-positive and CD1a-negative. Bone x-rays usually display bilateral and symmetric cortical osteosclerosis of the long bones, while technetium 99m bone scintigraphy shows almost constantly evidence of symmetric and abnormally strong labeling of the distal ends of the long bones of the lower limbs (and sometimes the upper limbs). Abdominal CT scan may show a ''hairy kidney'' appearance (in 50%) which can be biopsied.

Differential diagnosis

Differential diagnosis includes Langerhans' cell histiocytosis, Rosai-Dorfman disease, Takayasu arteritis, Wegener's granulomatosis, primary hypophysitis, chronic recurrent multifocal osteomyelitis (see these terms), malignancies, neurosarcoidosis, mycobacterial infections and metabolic disorders.

Management and treatment

First line treatment is the administration of standard or pegylated IFN-alpha for all forms of ECD with higher doses (9 million units, 3 times per week) required on a long-term basis for those with CNS and cardiac localizations (if well tolerated). Bisphosphonates may be given to alleviate bone pain. Cladribine can be given to those with orbital involvement that have been resistant to other forms of treatment. Anakinra can improve symptoms of mild forms of ECD in patients where IFN-alpha was ineffective. Recently, infliximab and vemurafenib have been used with some success, this latter drug seeming very promising for patients with a BRAFV600 mutation. PET scans are recommended for the assessment of disease activity.

Prognosis

ECD has a variable prognosis but is overall poorer in those with CNS involvement. Before IFN-alpha, the mean survival after diagnosis was 19.2 months. Nowadays, with IFN-alpha treatments, the mortality rate is only 26%, and 5-year survival is 68%.