Frequently Asked Questions

Hemophagocytic Syndromes (HLH)

The questions below are regarding Hemophagocytic Syndromes (HLH) specifically. Please click on a question to view the answer.

  1. What causes HLH?
  2. Is there a cure for HLH?
  3. What are the different therapies/treatments commonly used to treat HLH?
  4. What are the side effects of methotrexate?
  5. Can infants be tested at birth for HLH?
  6. Why is routine newborn screening not available?
  7. How do I know if my child has primary HLH (inherited/FHL) or secondary HLH?
  8. How can I find out if my child’s siblings have HLH?
  9. How can I find out if future children are at risk for developing HLH?
  10. What is MAS (macrophage activating syndrome)?
  11. What is reduced-intensity conditioning (RIC)?

Histiocytic Disorders and Orphan Diseases

The questions below are regarding Histiocytic Disorders and Orphan Diseases in general. Please click on a question to view the answer.

  1. What are histiocytic disorders, and how are they classified?
  2. Why are all of these diseases with different names considered to be related to each other?
  3. Where can I find reliable information about histiocytosis?
  4. How can I explain histiocytosis to family and friends?
  5. What is an orphan disease?
  6. How many orphan diseases are there?
  7. Where can I learn more about rare diseases in general?

Hemophagocytic Syndromes (HLH)

  1. What causes HLH?
    HLH can either be acquired (secondary HLH) or inherited (FHL). Both forms of the disease can be triggered by infections, although it is not known why this happens. Secondary HLH may be triggered by vaccinations, viral infections such as Epstein-Barr, CMV (cytomegalovirus), herpes virus, or other underlying diseases such as cancer. In FHL, defective genes are inherited from one or both parents. Some other rare inherited immunodeficiencies may also be associated with HLH. The underlying immune defect and/or triggering events result in an abnormal immune response with activation of certain types of white blood cells (lymphocytes and macrophages) and the release of inflammatory proteins which then cause disease. The true cause of HLH/FHL is not known.

  2. Is there a cure for HLH?
    HLH patients with an underlying genetic defect can only be cured when the defective immune system is replaced by a healthy one which is what happens with a hematopoietic stem cell transplant. Secondary HLH cases can usually be cured by treating the underlying disease and sometimes additional immunosuppressive/immunomodulating therapy.

  3. What are the different therapies/treatments commonly used to treat HLH?
    Some cases of secondary HLH can resolve spontaneously or after treatment of the underlying disease. Other cases are treated with a combination of chemotherapy (VP-16, methotrexate), immunotherapy (ATG, cyclosporin), and steroids. Any triggering infection has to be treated with appropriate antimicrobial drugs. Patients with persistent or recurring HLH or those with FHL additionally require a hematopoietic stem-cell transplant for recovery.

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  4. What are the side effects of methotrexate?
    Side effects include:
    • Mouth sores/swollen, tender gums
    • Nausea/vomiting/diarrhea/decreased appetite
    • Low blood counts
    • Dizziness/drowsiness
    • Headache
    More unusual side effects may include:
    • Blurred vision or loss of vision
    • Seizures
    • Confusion
    • Weakness/difficulty moving one or both sides of the body
    • Loss of consciousness
    • Lung damage
    • Allergic reactions
  5. Can infants be tested at birth for HLH?
    If an infant is suspected to have HLH because of an affected sibling, and if the affected sibling has a known genetic defect, then genetic screening can be performed at birth.

  6. Why is routine newborn screening not available?
    Although HLH may occur more frequently than some of the diseases routinely tested for, genetic testing for this disease is very complicated and very expensive.

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  7. How do I know if my child has primary HLH (inherited/FHL) or secondary HLH?
    The clinical symptoms and laboratory findings do not differ in genetic or acquired HLH. Specific immunologic testing can raise the suspicion of genetic disease. In families with more than one affected child or in cases with disease reactivations there is a high probability of genetic disease. However, the identification of a genetic defect is necessary to prove it. Genetic testing is therefore recommended, regardless of age. Depending on the ethnic background up to 30% of patients with FHL have no identified gene defect, so negative test results do not necessarily rule out FHL.

  8. How can I find out if my child’s siblings have HLH?
    Each sibling of a child with FHL has a 25% chance of being affected. In related genetic disorders, including X-linked lymphoproliferative disease, each male child has a 50% chance of being affected. If a genetic defect is known in your family, genetic testing (before or after onset of symptoms) is available to identify siblings who may also be affected. There are several hospitals that provide information and perform genetic testing on a clinical basis, including:

    Cincinnati Children’s Hospital, Cincinnati, Ohio
    Lisa Filipovich, MD
    http://www.cincinnatichildrens.org/hlh/

    Karolinska University Hospital, Stockholm, Sweden
    Jan-Inge Henter, MD
    jan-inge.henter@ki.se

    University Medical Center, Hamburg, Germany
    Gritta Janka, MD
    janka@uke.uni-hamburg.de

    Gene Tests Clinic Directory
    http://www.ncbi.nlm.nih.gov/sites/GeneTests/clinic?db=GeneTests

  9. How can I find out if future children are at risk for developing HLH?
    If a genetic defect has been identified in your family, prenatal diagnosis is possible by performing either amniocentesis or chorionic villus sampling (CVS) to test if the fetus is affected.

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  10. What is MAS (macrophage activating syndrome)?
    Macrophage activating syndrome is a severe, life-threatening illness caused by the excessive production of types of white blood cells called T cells and macrophages. MAS has strong similarities with familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic lymphohistiocytosis (HLH). The exact relationship between MAS and HLH is yet to be determined, although some researchers believe that MAS is a secondary HLH disorder. The term is typically used for the HLH-like syndrome that can occur in patients with systemic onset juvenile arthritis.

  11. What is reduced-intensity conditioning (RIC)?
    Reduced-intensity conditioning is a less toxic pre-transplant therapy with the goal of suppressing the patient’s immune system enough so that it will accept donor stem cells while reducing the side effects of high dose chemotherapy The RIC may be used in some HLH patients, as well as some LCH patients with severe, resistant disease.

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Histiocytic Disorders and Orphan Diseases

  1. What are histiocytic disorders, and how are they classified?
    Histiocytic disorders are a diverse group of diseases caused by over-production of white blood cells known as histiocytes, which can lead to organ damage and tumor formation. They include a wide variety of conditions that can affect both children and adults.

    The disorders are classified into three groups based on the types of histiocyte cells involved.
    • The first group is called a dendritic cell disorder, and the most common disease in this group is Langerhans cell histiocytosis. Also included in this group are more rare diseases, juvenile xanthogranuloma (JXG) and Erdheim Chester.
    • The second group is called a macrophage cell disorder, and includes primarily hemophagocytic lymphohistiocytosis (HLH) and Rosai-Dorfman.
    • The third group is called malignant histiocytosis and includes certain kinds of leukemia and tumors.
  2. Why are all of these diseases with different names considered to be related to each other?
    All of the diseases are caused by the over-production of white blood cells called histiocytes. Their different classifications depend on the type of histiocyte involved.

  3. Where can I find reliable information about histiocytosis?
    The Histiocytosis Association’s online community provides a number of informational documents and articles, as well as links to medical articles about the histiocytic disorders. While the Internet does provide a significant volume of information about histiocytic disorders, some of this information is not accurate. It is important to look for documents that are current, are free of grammatical and spelling errors, appear to be objective, are free of advertisements, and clearly state their sources.

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  4. How can I explain histiocytosis to family and friends?
    Histiocytosis is a rare disease that is caused by the over-production of a type of white cell that can lead to organ damage and the formation of tumors. The Histiocytosis Association’s Disease Fact Sheets are also a great way to help explain these complicated diseases to family and friends.

  5. What is an orphan disease?
    According to the Rare Disease Act of 2002, an orphan disease, also known as a rare disease, affects less than 200,000 persons in the U.S., or less than 1 in 1500 people. The criteria may vary in other countries. For example in Europe, an orphan disease is defined to occur in less than 1 in 2000.

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  6. How many orphan diseases are there?
    According to the National Institutes of Health there are approximately 6800 such diseases. Combined, they affect nearly 30 million Americans.

  7. Where can I learn more about rare diseases in general?

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