Erdheim Chester Disease

 Erdheim Chester Disease

DISEASE OVERVIEW

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 “scavenger cell” 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.

SIGNS & SYMPTOMS

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.

CAUSES

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.

DISORDERS WITH SIMILAR SYMPTOMS

Symptoms of the following disorders may be similar to those of Erdheim-Chester disease. Comparisons may be useful for a differential diagnosis:

Histiocytosis X, also known as Langerhans cell histiocytosis (LCH), is a group of diseases characterized by excessive production and accumulation of histiocytes in various tissues and organs. The lesions may include certain distinctive granule-containing cells (known as Langerhans’ cells) involved in certain immune responses as well as lymphocytes and other immune system cell types (e.g., monocytes, eosinophils). Associated symptoms and findings may vary from case to case, depending on the specific tissues and organs affected and the extent of involvement. Most affected individuals have single or multiple bone lesions characterized by degenerative changes and loss of the calcium of bone (osteolysis). Although the skull is most commonly affected, there may also be involvement of other bones, such as those of the spine (vertebrae) and long bones. Affected individuals may have no apparent symptoms (asymptomatic), experience associated pain and swelling, and/or develop certain complications, such as fractures or secondary compression of the spinal cord. In some cases, other tissues and organs may also be affected, including the skin, lungs, or other regions. In some individuals, LCH may be associated with involvement of the pituitary gland, leading to diabetes insipidus; this form of LCH is known as Hand-Schuller-Christian disease. Certain cellular tissue changes, symptoms, and findings seen in LCH may resemble those associated with ECD, causing some to suggest that the latter may represent a form of LCH. However, evidence suggests that it is a distinct disease entity that differs from LCH regarding age of onset, characteristic bone changes, and other features. LCH most commonly becomes apparent during childhood, while ECD primarily affects middle-aged adults. In addition, the bone changes in LCH are typically characterized by osteolysis and involve the axial skeleton (e.g., the skull and vertebrae); in contrast, as noted earlier, ECD is associated with symmetric hardening (osteosclerosis) and thickening of certain regions of the long bones. (For more information on LCH, choose “histiocytosis” as your search term in the Rare Disease Database.)

Cerebrotendinous xanthomatosis (CTX) is an extremely rare, inherited lipid storage disease that is present at birth. It is characterized by the accumulation of large amounts of cholesterol (xanthomatosis) in many tissues of the body. Excessive cholesterol cannot be eliminated from the body. When cholesterol accumulates in the brain, affected children may have difficulty walking, developmental delays, and/or intellectual disability. During young adulthood, some people with cerebrotendinous xanthomatosis may have severe heart problems due to the buildup of cholesterol in the major arteries that surround the heart. Symptoms develop due to a deficiency of an enzyme sterol 26-hydroxycholesterol. (For more information on LCH, choose “cerebrotendinous xanthomatosis” as your search term in the Rare Disease Database.)

There are several other disorders and conditions that may be characterized by certain symptoms and findings similar to those potentially associated with ECD. (For further information, choose the exact disease name in question as your search term in the Rare Disease Database.)

DIAGNOSIS

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 “Related Disorders” 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.

TYPE OF DOCTOR AND DEPARTMENT: pathogenesis SPECIALIST CAN DIAGNOSE THIS DISEASE.