Rare Immunology News

Disease Profile

Langerhans cell histiocytosis

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 100 000

3,310 - 29,790

US Estimated

1-9 / 100 000

5,135 - 46,215

Europe Estimated

Age of onset

All ages

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ICD-10

C96.0 C96.5 C96.6

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

LCH; Histiocytosis X

Categories

Endocrine Diseases; Hereditary Cancer Syndromes

Summary

Langerhans cell histiocytosis (LCH) is a disorder that primarily affects children, but is also found in adults of all ages. People with LCH produce too many Langerhans cells or histiocytes, a form of white blood cell found in healthy people that is supposed to protect the body from infection. In people with LCH, these cells multiply excessively and build up in certain areas of the body, causing tumors called granulomas to form.[1] The symptoms of LCH vary from person to person, depending on the areas of the body affected. LCH may be found in many areas of the body, including but not limited to the skin and nails, mouth, bones, lymph nodes, pituitary gland, and thyroid gland. When it is found in multiple areas of the body, it is known as multisystem disease.[1][2] The cause of this disease is unknown, although most data suggest that it is characterized by a growth of immature Langerhans cells that appear to have mutations of the BRAF gene in about half the cases. LCH is not caused by a known infection, is not contagious, nor is it believed to be inherited. There remain differing opinions among experts as to whether it is definitively a cancer or not.[1][3] Treatment for LCH varies and may include surgery, chemotherapy, radiation therapy, and use of certain medications.[3][2]

LHC includes four variants, with different degrees of severity:[1][2][3]

  • Hashimoto-Pritzker disease, a congenital self-healing form
  • Letterer-Siwe disease, a severe, acute and disseminate form 
  • Hand-Schüller-Christian disease, an intermediate chronic form with multiple lesions characterized by diabetes insipidus, bulging of the eye and localized lesions in the bone
  • Eosinophilic granuloma, a less severe form, characterized by solitary or few, and chronic lesions of bone or other organs

Because all the variants have many common symptoms it is thought that they may be manifestations of LCH and not separate syndromes.[1][2][3]

Symptoms

Symptoms of Langerhans cell histiocytosis (LCH) can vary greatly from person to person depending on how much of the body is involved and what part(s) are affected. The disease can affect virtually every organ, including skin, bones, lymph nodes, bone marrow, liver, spleen, lungs, gastrointestinal tract, thymus, central nervous system, and hormone glands. The symptoms may range from localized bone lesions or skin disease to multiple organ involvement and severe dysfunction.[4]

Below are the organs that may be affected as well as the symptoms that might be observed:[4]

  • Skin Red, scaly papules in areas where opposing skin surfaces touch or rub (e.g. skin folds) are commonly seen in LCH. Infants with the skin presentation on the scalp are often misdiagnosed with cradle cap. The skin symptoms usually improve without treatment.
  • Bone Lesions that cause bone destruction are common, with the skull, lower limbs, ribs, pelvis, and vertebrae usually being affected. Symptoms may include pain, swelling, limited motion, and inability to bear weight.
  • Lymph node Lymph node involvement may be limited or associated with a skin or bone lesion or disseminated disease. Although any of the lymph nodes may be affected, the cervical lymph nodes are where the disease commonly occurs. Individuals usually only present with pain of the lymph node affected. If only one lymph node is affected, prognosis is normally good and treatment is unnecessary.
  • Liver Liver involvement at the time of diagnosis is generally associated with more severe disease. Symptoms may include ascites, jaundice, low levels of protein, and prolonged clotting time.
  • Central nervous system (CNS) and hormone CNS involvement is rare and may be devastating. The most common result of CNS involvement is the altering of hormonal function, with some individuals developing diabetes insipidus.

More detailed information about the symptoms of LCH can be accessed through the Histiocytosis Association's website.

In adults with LCH, the lung is the most frequently involved organ system, and solitary lung lesions may be the only symptom. Chronic cough, dyspnea (breathing difficulty) dyspnea), chest pain, and recurrent pneumothorax (abnormal presence of air in the pleural space between the lung and the chest wall) are the usual signs and symptoms of lung disease.[5]

Cause

The cause of Langerhans cell histiocytosis (LCH) is unknown in many cases.[6][3] However, somatic mutations in the BRAF gene have been identified in the Langerhans cells of about half of people with LCH. Somatic gene mutations are acquired during a person's lifetime, which means they are acquired after conception and are only present in certain cells. Because they are not present in the germ cells (egg and sperm), they are not passed on to the next generation (are not inherited).[7] 

The BRAF gene provides instructions for making a protein that is normally switched on and off in response to signals that control cell growth and development. Somatic mutations cause the BRAF protein in affected cells to be continuously on and to transmit messages to the nucleus even in the absence of these chemical signals. The overactive protein may contribute to the development of LCH by allowing the Langerhans cells to grow and divide uncontrollably.[7]

The protein produced by the BRAF gene is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth.[8][7]

The BRAF gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. Changes in other genes such as the MAP2K gene (20% of the cases), and other rarer genes (also involved in the RAS/MAPK pathway), have also been identified in the Langerhans cells of some people with LCH. Some researchers believe that additional factors, such as viral infections and environmental toxins, may also influence the development of this complex disorder.[7] 

Family members of LCH patients have a higher incidence of thyroid disease. Smoking is strongly associated with lung LCH.[6]

Diagnosis

Testing for Langerhans cell histiocytosis (LCH) may include bronchoscopy with biopsyx-ray, skin biopsy, bone marrow biopsy, complete blood count, skeletal X-rays survey, pulmonary function tests and liver funcion tests, as well as MRI and CT scanning of the head to evaluate possible abnormalities of the hypothalamus and the pituitary gland. A fluorodeoxyglucose (FDG) positron-emission tomography (PET) scanning may also be used when evaluating patients for LCH, specially bone lesions.[4][11][5]

Additional information about the diagnosis of LCH can be viewed on the Histiocytosis Association's website.

Treatment

Treatment for Langerhans cell histiocytosis (LCH) depends upon the individual patient; it may differ depending on the type and severity of the condition as well as what part(s) of the body are affected. In some cases, the disease will go away without any treatment at all. In other cases, depending on the extent of the disease, limited surgery and small doses of radiation therapy or chemotherapy may be needed. Treatment is planned after complete evaluation of the patient, with the goal of using as little treatment as possible to keep the disease under control.[1]

No consensus exists for the best therapy for LCH, especially when multiple organs are involved. However, the Histiocyte Society has done many clinical trials to evaluate the effect of several treatments, which have resulted in recommendations by the Histiocyte Society.

Generally, the choice of treatment is based on disease severity. The International LCH Study of the Histiocyte Society proposes classifying LCH cases by the number of systems involved and by the number of sites within that system (e.g., involving one or more bones, involving one or multiple lymph nodes). Although most of the trials are in children, the recommendations can also be used for adults.[5]

Detailed information about the treatment of LCH can be viewed on Medscape Reference's Web site.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Providing General Support

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
    • Genetics Home Reference (GHR) contains information on Langerhans cell histiocytosis. This website is maintained by the National Library of Medicine.
    • The Merck Manuals Online Medical Library provides information on this condition for patients and caregivers.
    • The National Cancer Institute provides the most current information on cancer for patients, health professionals, and the general public.
    • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

      In-Depth Information

      • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Langerhans cell histiocytosis. Click on the link to view a sample search on this topic.

        Selected Full-Text Journal Articles

          References

          1. LCH in Children. Histiocytosis Association of America. https://www.histio.org/page.aspx?pid=379.
          2. Langerhans Cell Histiocytosis Treatment (PDQ®)–Health Professional Version. National Cancer Institute. November 30, 2016; https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq.
          3. Shea CR, Boos MD. Langerhans Cell Histiocytosis. Medscape. February 8, 2016; https://emedicine.medscape.com/article/1100579-overview.
          4. Grifo AH. Langerhans Cell Histiocytosis in Children. Association of Pediatric Hematology/Oncology Nurses.
          5. Shea CR. Langerhans Cell Histiocytosis. Medscape Reference. March 7, 2017; https://emedicine.medscape.com/article/1100579-overview.
          6. LCH in Children. Histiocytosis Association of America. 2007; https://www.histio.org/site/c.kiKTL4PQLvF/b.1764433/k.8BCD/LCH_in_Children.htm. Accessed 2/18/2010.
          7. Langerhans cell histiocytosis. Genetics Home Reference. 2017; https://ghr.nlm.nih.gov/condition/langerhans-cell-histiocytosis#genes.
          8. BRAF gene. Genetics Home Reference. 2017; https://ghr.nlm.nih.gov/gene/BRAF.
          9. Langerhans Cell Histiocytosis. Online Mendelian Inheritance in Man (OMIM). 2009; https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604856. Accessed 2/18/2010.
          10. Arico M, Nichols K, Whitlock JA, Arceci R, Haupt R, Mittler U, Kuhne T, Lombardi A, Ishii E, Egeler RM, Danesino C. Br J Haematol. 1999; https://www.ncbi.nlm.nih.gov/pubmed/10606898?dopt=Abstract. Accessed 2/18/2010.
          11. Satter EK, High WA. Langerhans Cell Histiocytosis: A Review of the Current Recommendations of the Histiocyte Society. Pediatric Dermatology. 2008;

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