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Last updated: 6/15/2023
Years published: 1993, 1994, 2001, 2002, 2004, 2009, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Robert D. Shamburek, MD, Lipid Service, Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, for assistance in the preparation of this report.
Erdheim-Chester disease (ECD) is a rare multisystem disorder of adulthood. It is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. Histiocytes are large phagocytic cells (macrophages) that normally play a role in responding to infection and injury. (A phagocytic cell is any โscavenger cellโ that engulfs and destroys invading microorganisms or cellular debris.) In people with ECD, sites of involvement may include the long bones, skin, tissues behind the eyeballs, lungs, brain, pituitary gland and/or additional tissues and organs. Associated symptoms and findings and disease course depend on the specific location and extent of such involvement. The underlying cause of ECD is thought to be a malignancy of the myeloid progenitor cells.
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 jawbone (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 the 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 person to person. 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.
ECD 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). Somatic mutations in the BRAF-V600 gene and other mutations in the mitogen-activated protein kinase (MAPK) signaling and phosphatidylinositol 3-kinase (PI3K)-ART pathways have established ECD as a malignancy of myeloid progenitor cells. A BRAF V600 gene mutation has been found in about half of patients with ECD. 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 originates 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.
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 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), FDG-PET-CT 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). Molecular testing of biopsy specimens can identify specific somatic mutations that can direct specific treatments. (For more on Langerhans cell histiocytosis, please see the โRelated Disordersโ section above.)
Treatment
There is no cure for ECD. Asymptomatic patients will generally be followed until they develop specific symptoms. Treatment of symptomatic patients will be guided by the type of somatic mutations and by organ specific involvement such as the CNS. Reports indicate that various treatments have been used with variable success.
Zelboraf (vemurafenib) is the only therapy approved by the U.S. Food and Drug Administration (FDA) to treat certain adult patients with ECD who have the BRAF V6000 gene mutation. Targeted therapies are being tried including BRAF-inhibitors, MEK-inhibitors, interferon alfa, glucocorticoids, mTOR inhibitors or systemic therapies such as cytotoxic chemotherapy or cytokine-directed therapy. Radiation therapy is not used since ECD is not radiosensitive. Surgery has a limited role due to extensive disease.
Patients are encouraged to enroll in clinical trials for ECD as several trials are underway. Further research is needed to determine optimal treatments for this disorder. Additional treatment for individuals with ECD is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
Shamburek RD. Erdheim-Chester Disease. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins; 2003:441.
Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: W.B. Saunders Company; 2000:1570-71.
Fauci AS, et al., eds. Harrisonโs Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies, Inc.; 1998:1465.
JOURNAL ARTICLES
Goyal G, et al. Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era. Blood. 2020:1929-1945.
Goyal G, Young JR, Koster MJ, et al. The Mayo Clinic Histiocytosis Working Group Consensus Statement for the Diagnosis and Evaluation of Adult Patients With Histiocytic Neoplasms: Erdheim-Chester Disease, Langerhans Cell Histiocytosis, and Rosai-Dorfman Disease. Mayo Clin Proc. 2019;94(10):2054-2071.
Diamond EL, et al. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease. Blood. 2014,124:483-92.
Caramaschi P, et al. Erdheim-Chester disease. Recenti Prog Med. 2004;95:104-7.
Pereira Neto CC, et al. Positron emission tomography/computed tomography of a rare xanthogranulomatous process: Erdheim-Chester disease. Mol Imaging Biol. 2004;6:63-7.
Jendro MC, et al. Improvement of Erdheim-Chester disease in two patients by sequential treatment with vinblastine and mycophenolate mofetil. Clin Rheumatol. 2004;23:52-6.
Bourke SC, et al. Erdheim-Chester disease: pulmonary infiltration responding to cyclophosphamide and prednisolone. Thorax. 2003;58:1004-5.
Shamburek RD, et al. Erdheim-Chester disease: a rare multisystem histiocytic disorder associated with interstitial lung disease. Am J Med Sci. 2001;321:66-75.
Vasakova M, et al. Erdheim-Chester disease. A case report. Monaldi Arch Chest Dis. 2001;56:115-17.
Grothe C, et al. Cerebellar syndrome, exophthalmos and secondary hypogonadism in Erdheim-Chester disease. Nervenarzt. 2001;72:449-52.
Murray D, et al. Erdheim-chester disease. Clin Radiol. 2001;56:481-84.
Watermann DF, et al. Skin manifestations of Erdheim-Chester disease. Case report and review of the literature. Hautarzt. 2001;52:510-17.
Petrikowski CG, et al. Erdheim-Chester disease of the jaws: literature review and case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:389-98.
Nakano H, et al. Erdheim-Chester disease presenting with pulmonary lesion. Nihon Kokyuki Gakkai Zasshi. 2000;38:380-84.
Rush WL, et al. Pulmonary pathology of Erdheim-Chester disease. Mod Pathol. 2000;13:747-54.
Serratrice J, et al. โCoated aortaโ: a new sign of Erdheim-Chester disease. J Rheumatol. 2000;27:1550-53.
Kenn W, et al. Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis. Hum Pathol. 2000;31:734-39.
Wright RA, et al. Neurological manifestations of Erdheim-Chester disease. J Neurol Neurosurg Psychiatry. 1999;66:72-75.
Bancroft LW, et al. Erdheim-Chester disease: radiographic findings in five patients. Skeletal Radiol. 1998;27:127-32.
Bohlega S, et al. Cerebral manifestation of Erdheim-Chester disease: clinical and radiologic findings. Neurology. 1997;49:1702-05.
Veyssier-Belot C, et al. Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine (Baltimore). 1996;75:157-69.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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