NORD gratefully acknowledges Robert D. Shamburek, MD, Lipid Service, Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, for assistance in the preparation of this report.
Erdheim-Chester disease (ECD) characteristically affects certain regions of the long bones of the legs, including the shafts (diaphyses) and the areas (i.e., metaphyses) where the shafts converge with the ends (epiphyses). The ends of the long bones are usually spared or may have mild changes. Infiltration by histiocytes typically leads to widespread or patchy increases in bone density as well as hardening (osteosclerosis) and thickening of bone. In some rare cases, there may also be involvement of other bones, such as the lower jaw bone (mandible) or certain bones of the spinal column (vertebrae). In many affected individuals, the initial symptom of the disorder is associated bone pain, usually affecting the knees and legs, that is similar on both sides of the body (symmetrical). In some cases, more generalized symptoms may also develop, including weight loss, fever, muscle and joint aches; and a general feeling of discomfort, weakness, and fatigue (malaise).
ECD may also be characterized by involvement of the skin, tissues behind the eyeballs (retrobulbar region); the lungs; the brain; the pituitary gland, the region containing organs at the back of the abdominal cavity (retroperitoneum), and/or other sites. Associated symptoms and disease course may vary from case to case, depending on the site and degree of involvement.
Some individuals with ECD may develop soft, yellowish, fatty plaques or nodules on the eyelids (xanthelasma) or skin (cutaneous xanthomas). In addition, involvement of the retrobulbar region may lead to marked protrusion of the eyeballs (exophthalmos) and other symptoms and findings.
In those with lung (pulmonary) involvement, progressive scarring and thickening of lung tissue (pulmonary fibrosis) may lead to a dry cough, increasingly labored breathing (dyspnea) with exertion, insufficient oxygenation of the blood, impaired ability of the heart to pump enough blood to the lungs and the rest of the body (heart failure), and potentially life-threatening complications.
In some affected individuals, there may also be infiltration of the pituitary gland, leading to diabetes insipidus. This is a metabolic condition in which insufficient secretion of antidiuretic hormone (ADH) by the pituitary gland leads to passing of large amounts of dilute urine (polyuria) and excessive thirst (polydipsia). (ADH normally reduces the amount of water lost in urine. The pituitary gland produces several hormones, including ADH; it is controlled by and connected to a region of the brain called the hypothalamus.)
In some rare cases, ECD may also be characterized by involvement of other brain regions, such as part of the lowest region of the brain (brainstem) and the cerebellum, which is involved in coordinating voluntary movement, balance, and posture. Associated neurologic symptoms may be variable from case to case. However, such abnormalities often include impaired muscular coordination (ataxia); an abnormal staggering manner of walking (gait); slurred speech (dysarthria); and/or involuntary, rhythmic, rapid eye movements (nystagmus).
ECD may also be characterized by infiltration and associated scarring of tissues within the retroperitoneal region (retroperitoneal fibrosis). In some cases, such changes may result in obstruction of the tubes (i.e., ureters) that carry urine from the kidneys into the bladder, causing abnormal swelling of the kidneys with urine (hydronephrosis), impaired kidney (renal) function, and possible renal failure. A few cases have also been described in which retroperitoneal fibrosis has involved the major artery of the body (aorta) and its branching blood vessels (periaortic fibrosis).
As noted above, the course of the disease is variable, depending on the extent of involvement occurring outside of bone (extraosseous involvement) and affecting internal organs (visceral involvement). In some cases, disease progression and associated organ system dysfunction may lead to potentially life-threatening complications, such as due to pulmonary fibrosis, heart failure, and/or renal failure.
The exact cause of Erdheim-Chester disease (ECD) is unknown. However, the disease is thought to represent an abnormal inflammatory process characterized by excessive proliferation and accumulation of certain cells, with associated scarring or overgrowth of fibrous connective tissue (fibrosis). There may be widespread infiltration of affected tissues by histiocytic cells that contain large amounts of fatty (lipid) material (xanthomatous histiocytes); certain lymphocytes; and distinctive, large cells with multiple nuclei (Touton giant cells). (Lymphocytes are an immune system cell type that originate in the bone marrow.) In those with ECD, these fatty, nodular (xanthogranulomatous) cell deposits may infiltrate multiple tissues and organs, leading to impaired organ functioning.
Erdheim-Chester disease (ECD) is a rare disorder of adulthood that most frequently becomes apparent in middle age, with an average age of onset in the mid-50s. More than 100 cases have been reported in the medical literature with a slight male preponderance. ECD is named for the two investigators who originally described the disease.
A diagnosis of Erdheim-Chester disease (ECD) is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests. Such studies may include plain x-rays; advanced imaging techniques, including computed tomography (CT) scanning, magnetic resonance imaging (MRI), and/or a bone scan (bone scintigraphy); and/or other tests. Plain x-rays of involved bones typically reveal symmetrical increased hardening and thickening, mainly in the metaphyses and diaphyses with sparing of the epiphyses, a finding that is considered distinctive of ECD. In addition, the diagnosis may be confirmed by removal (biopsy) and microscopic evaluation of tissue samples that demonstrate infiltration by fatty (lipid)-laden, foamy histiocytes with certain non-Langerhans cellular features and distinctive, large cells with multiple nuclei (Touton giant cells). (For more on Langerhans cell histiocytosis, please see the “Related Disorders” section above.)
Reports indicate that various treatments have been used with limited success. Such recommended measures may include administration of corticosteroid drugs (e.g., prednisone); certain chemotherapeutic drugs that may control or prevent the proliferation of abnormal cells (e.g., vinblastine); use of high-energy rays that may preferentially destroy or injure rapidly proliferating cells (radiation therapy); immunotherapy; and/or surgery. Further research is needed to determine optimal treatments for this disorder. Additional treatment for individuals with ECD is symptomatic and supportive.
In 2017, Zelboraf (vemurafenib) was approved by the FDA to treat certain adult patients with ECD. Zelboraf is manufactured by Hoffman-LaRoche, Inc.
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