Erdheim-Chester Disease
Erdheim-Chester disease is a rare blood cancer that occurs when the body produces too many immune cells called histiocytes, which then accumulate in organs and tissues throughout the body. This condition can range from causing no symptoms at all to life-threatening complications, depending on which organs are affected.
Erdheim-Chester syndrome, Polyostotic sclerosing histiocytosis, Lipid granulomatosis
Table of contents
- What is Erdheim-Chester disease?
- How common is this disease?
- Signs and symptoms
- What causes Erdheim-Chester disease?
- Diagnosis
- Treatment approaches
What is Erdheim-Chester disease?
Erdheim-Chester disease (ECD) is a rare type of blood cancer classified as a histiocytic neoplasm, which is a disease involving abnormal growth of certain immune cells. The condition belongs to a group of rare disorders called histiocytosis, where there is an abnormal increase in certain immune cells called histiocytes[1].
Histiocytes are normally an important part of the immune system. They are found in many parts of the body, including the bone marrow, bloodstream, skin, lungs, spleen, and liver. Their job is to help destroy foreign substances and protect the body from infection[1][3].
In Erdheim-Chester disease, histiocytes grow out of control. The excess histiocytes may travel to different parts of the body where they are not usually found and cause tumors. These invading histiocytes damage tissues and can lead to inflammation that causes organs to become thickened, dense, and scarred. This tissue damage may eventually lead to organ failure[1][3].
The disease was first identified in 1930 when scientists Jakob Erdheim and William Chester reported the first two cases. In 2016, the World Health Organization officially recognized ECD as a slow-growing blood cancer, following the discovery of cancer-causing genetic changes in biopsy samples from most patients[4].
How common is this disease?
Erdheim-Chester disease is extremely rare. Since the condition was discovered in 1930, approximately 800 to 1,500 cases have been reported worldwide[1][4]. The disease is likely underdiagnosed because it can mimic other conditions and there are no general reporting guidelines that nations use to keep track of diagnoses[1][4].
Erdheim-Chester disease most commonly affects middle-aged adults, with an average age at diagnosis around 46 to 50 years in the United States. While the disease primarily affects adults, children have been diagnosed in rare instances[1][4].
The condition is more common in men, who account for 60% to 75% of diagnosed cases[1][3].
Signs and symptoms
Erdheim-Chester disease affects people differently. The signs and symptoms vary greatly depending on which parts of the body have excess histiocytes and which body systems are affected. Some people with ECD have few or no symptoms, while others develop severe complications. In cases without symptoms, doctors may discover evidence of ECD during imaging or lab tests performed for other reasons[1][3].
The severity of the condition varies widely. Some affected individuals experience minor health problems, while others have severe complications that can be life-threatening[3].
Bone involvement
More than 90% of people with ECD have bone involvement, making it the most frequently affected body system. The disease can cause abnormal hardening of the bones, a condition called osteosclerosis. This hardening most commonly affects the long bones of the legs around the knees, but it can affect any bone in the body[1][4].
Bone pain in both legs is the most common symptom of ECD. The pain typically affects the legs, knees, shins, and ankles, and is usually mild but constant, occurring close to the joints. Less commonly, pain may occur in the lower jaw, facial bones, and spinal column[1][6].
Kidney and abdominal involvement
Between 50% and 60% of cases involve the kidneys and the tissue surrounding the kidneys and large blood vessels. This area, called the retroperitoneum, is the tissue in the body cavity that contains the kidneys and other abdominal organs[4].
When viewed on CT scans, the disease can create distinctive appearances such as “hairy kidney” or “coated aorta” due to tissue growth around these organs. Symptoms may include abdominal pain, lower back pain, painful or difficult urination, and reduced kidney function. The invading histiocytes may cause kidney swelling, kidney atrophy, and in severe cases, kidney failure[1][4].
Hormonal problems
Invading histiocytes can damage glands that release hormones, which help regulate important processes in the body. This is known as endocrine system involvement. Depending on which gland is damaged, people may experience too little of various hormones produced by the pituitary gland, thyroid gland, or adrenal gland. They may also experience too few sex hormones like testosterone or estrogen[1].
Damage to the pituitary gland, a structure at the base of the brain that produces several hormones, is particularly common. This can cause a condition called diabetes insipidus, which leads to excessive urination and thirst. Up to half of people with ECD also have diabetes insipidus. This is different from the more common diabetes mellitus[1][3].
Brain and nervous system
Between 40% and 50% of cases involve the nervous system, including the brain. Histiocytes can damage tissue in the brain and nervous system, leading to various problems[4].
Symptoms may include problems with coordination and balance, a condition called ataxia. People may have a staggering gait or difficulty walking. They may also experience slurred speech due to poor control over speaking muscles, a condition called dysarthria. Other symptoms include trouble thinking, concentrating, or remembering, as well as headaches. Some people may have behavior disorders or rapid, involuntary eye movements[1][6].
Abnormally high pressure of the fluid within the skull may result from accumulation of histiocytes in the brain, potentially causing headaches, seizures, cognitive impairment, or problems with movement or sensation[3].
Eye involvement
Approximately 25% of patients develop eye problems. ECD may affect one or both eyes. When tissues around the eyes are affected, people may develop soft, fatty, yellow bumps on the eyelids, a condition called xanthelasma. They may also experience bulging eyeballs, known as proptosis or exophthalmos, along with eye pain and vision loss, including double vision[1][2][5].
Lung and breathing problems
Excess histiocytes affecting the lungs often appear on imaging tests but do not cause symptoms. When symptoms do occur, they may include cough and shortness of breath, especially with exercise. Left untreated, ECD can cause serious, long-term lung scarring called pulmonary fibrosis, which can lead to severe complications[1][5].
Heart and blood vessel problems
The cardiovascular system is the second most affected organ system, involved in more than half of reported cases. While the buildup of tissue around arteries usually has minimal impact, it can cause increased blood pressure if it affects the arteries to the kidneys[2].
More serious complications can include tissue buildup around the heart’s outer covering causing fluid accumulation, infiltration of the heart muscle itself, problems with heart valves that may require replacement, and tissue growth around the coronary arteries that can lead to heart attacks[2].
General symptoms
People with Erdheim-Chester disease may also experience non-specific symptoms including weight loss, fever, night sweats, fatigue, weakness, muscle and joint aches, and a general feeling of being unwell[5].
What causes Erdheim-Chester disease?
The exact cause of developing Erdheim-Chester disease is not fully understood. However, more than half of people with ECD have a specific change in the BRAF gene. Changes in other genes are also thought to be involved in this disorder[3][4].
The BRAF gene provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell’s nucleus. This protein is part of a signaling pathway that controls several important cell functions, including how cells grow and divide, how they mature to carry out specific functions, how they move, and when they self-destruct[3].
The BRAF gene mutation that causes Erdheim-Chester disease is what doctors call a somatic mutation, which means it occurs during a person’s lifetime and is present only in certain cells. The mutation occurs in histiocytes or in immature cells that will develop into histiocytes. This mutation leads to production of an abnormally active BRAF protein, which disrupts the normal regulation of cell growth and division. The unregulated overproduction of histiocytes results in their accumulation in the body’s tissues and organs, leading to the signs and symptoms of the disease[3].
Erdheim-Chester disease is not considered a hereditary condition, meaning it is not passed down from parents to children. It is also not contagious[4].
Diagnosis
Diagnosing Erdheim-Chester disease can be challenging for several reasons. The rarity of ECD cases, unclear findings from biopsies, and the need to distinguish it from similar conditions all make diagnosis difficult[2].
The disease is diagnosed based on a combination of symptoms, tissue samples examined under a microscope, and specialized tests. These tests may include blood tests and imaging studies such as X-rays, CT scans, MRIs, and bone scans[5].
Under the microscope, tissue samples from people with ECD show an infiltrate of lipid-laden foamy cells (the excess histiocytes), scattered giant cells, chronic inflammatory cells, and fibrosis. The foamy histiocytes can be distinguished from another type of immune cell by using special staining techniques. Specifically, the histiocytes in ECD test negative for certain markers called S-100 protein and CD1a[9].
Bone involvement, particularly symmetrical hardening of the long bones around the knees, is considered a hallmark sign of the disease when seen on imaging tests[9].
Treatment approaches
It is important that patients be diagnosed and treated early before Erdheim-Chester disease progresses, as it may lead to organ failure[6].
Current treatments for ECD include targeted therapy, immunotherapy, and chemotherapy[1]. The discovery of BRAF and other gene mutations has revolutionized the care of patients with ECD, resulting in targeted treatments that have the ability to improve patient survival[4].
Treatment of the disease has historically been on an individual basis, and no single treatment approach has been shown to be clearly superior for all patients[9].
Langerhans cell histiocytosis, Rosai-Dorfman disease, and Takayasu arteritis are among the conditions that doctors must consider when diagnosing Erdheim-Chester disease[2].
