Hemophagocytic lymphohistiocytosis

Información en español Title

Other Names:

Familial hemophagocytic lymphohistiocytosis; Familial erythrophagocytic lymphohistiocytosis; Familial histiocytic reticulosis; Familial hemophagocytic lymphohistiocytosis; Familial erythrophagocytic lymphohistiocytosis; Familial histiocytic reticulosis; FHL; HLH See More

Categories:

Congenital and Genetic Diseases; Immune System Diseases; Nervous System Diseases

Summary Summary

Hemophagocytic lymphohistiocytosis (HLH) is a condition in which the body makes too many activated immune cells (macrophages and lymphocytes).^[1] People with HLH usually develop symptoms within the first months or years of life. Symptoms may include fever, enlarged liver or spleen, cytopenia (decreased number of blood cells), and neurological abnormalities.^[2]^[3] HLH may be inherited in an autosomal recessive manner or it can have non-genetic causes in which case it is called acquired HLH. There are five subtypes of inherited HLH which are designated as familial HLH, types 1-5. Each subtype is caused by a change (mutation) in a different gene. The genetic cause of type 1 is currently unknown. Types 2-5 are caused by mutations in the PRF1 gene, the UNC13D gene, the STX11 gene and the STXBP2 gene, respectively.^[4] Treatment depends on a number of factors, including the severity of symptoms, the age of onset, and the underlying cause of the condition.^[4]^[5]

When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.^[6]

Last updated: 9/11/2017

Symptoms Symptoms

The signs and symptoms of hemophagocytic lymphohistiocytosis typically develop during the first months or years of life. However, in rare cases, affected people may not show symptoms until later in childhood or even into adulthood. The features of this condition may include:^[1]^[2]^[3]^[4]

Fever
Enlarged liver and/or spleen
Skin rash
Lymph node enlargement
Breathing problems
Easy bruising and/or abnormal bleeding
Kidney abnormalities
Heart problems
Increased risk for certain cancers (leukemia, lymphoma)

Many people with this condition also develop neurologic abnormalities. The neurological symptoms vary but may include irritability, fatigue, abnormal muscle tone, seizures, neck stiffness, mental status changes, ataxia, blindness, paralysis, and/or coma.^[1]^[4]

Last updated: 9/11/2017

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Granulocytopenia	Very rare (present in 1%-4% of cases)
Neutropenia	Very rare (present in 1%-4% of cases)
Reduced natural killer cell activity	Very rare (present in 1%-4% of cases)
Abnormal natural killer cell physiology	-
Anemia	-
Ataxia	-
Autosomal recessive inheritance	-
Coma	-
CSF pleocytosis	-
Encephalitis	-
Episodic fever	-
Failure to thrive	-
Fever	-
Generalized edema	-
Hemiplegia	-
Hemophagocytosis	-
Hepatomegaly	-
Hepatosplenomegaly	-
Hyperbetalipoproteinemia	-
Hypertonia	-
Hypertriglyceridemia	-
Hypoalbuminemia	-
Hypoalphalipoproteinemia	-
Hypofibrinogenemia	-
Hyponatremia	-
Hypoproteinemia	-
Increased circulating very-low-density lipoprotein cholesterol	-
Increased CSF protein	-
Increased intracranial pressure	-
Increased serum ferritin	-
Increased total bilirubin	-
Irritability	-
Jaundice	-
Leukopenia	-
Lymphadenopathy	-
Meningitis	-
Muscular hypotonia	-
Prolonged partial thromboplastin time	-
Prolonged prothrombin time	-
Seizures	-
Splenomegaly	-
Tetraplegia	-
Thrombocytopenia	-

Last updated: 9/1/2017

Cause Cause

There are inherited and non-inherited (acquired) causes of hemophagocytic lymphohistiocytosis (HLH).^[3]^[7]

There are five subtypes of inherited (or familial) HLH which are designated familial HLH, types 1-5. Each subtype is caused by a change (mutation) in a different gene that helps regulate the immune system. Type 1 is due to a gene defect on chromosome 9. Familial HLH, type 2 is caused by mutations in the PRF1 gene. Familial HLH, type 3 is caused by mutations in the UNC13D gene. Familial HLH, type 4 is caused by mutations in the STX11 gene. Familial HLH, type 5 is caused by mutations in the STXBP2 gene.^[4]

All of the genes involved with HLH normally provide instructions for proteins that help destroy or turn off activated immune cells when they are no longer needed. Changes in these genes lead to an overproduction of immune cells which results in an excessive immune response and the many signs and symptoms of familial HLH.^[1]^[3]^[7]

The acquired causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases.^[3]^[7]

When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.^[6]

Last updated: 9/11/2017

Inheritance Inheritance

Hemophagocytic lymphohistiocytosis (HLH) may be inherited or acquired (due to non-genetic factors).

Familial HLH is inherited in an autosomal recessive manner.^[4] This means that to be affected, a person must have a change (mutation) in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Acquired HLH is not inherited. The non-genetic causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases.^[3]^[7]

When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.^[6]

Last updated: 9/11/2017

Diagnosis Diagnosis

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) can be established if 1 and/or 2 below is fullfilled:^[4]^[8]

1. A genetic test identifying a mutation in one of the genes involved with this condition

2. At least five out of the following 8 signs or symptoms:

Fever
Enlarged spleen
Cytopenia (lower-than-normal number of blood cells)
Elevated levels of triglycerides or low levels of fibrinogen in the blood
Hemophagocytosis (the destruction of certain types of blood cells by histiocytes) on bone marrow, spleen or lymph node biopsy
Decreased or absent NK cell activity
High levels of ferritin in the blood
Elevated blood levels of CD25 (a measure of prolonged immune cell activation).

Clinical genetic testing is available for the four genes known to cause familial hemophagocytic lymphohistiocytosis, types 2-5. The Genetic Testing Registry (GTR) is a centralized online resource for information about genetic tests. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Last updated: 9/11/2017

Treatment Treatment

The best treatment options for hemophagocytic lymphohistiocytosis (HLH) are determined by a number of factors, including the severity of symptoms, the age of onset, and the underlying cause of the condition.

In acquired HLH, it is often necessary to treat the underlying condition. For example, antiobiotics or antiviral medications can be used to treat or prevent infections that may have triggered the exaggerated immune response.

Allogeneic hematopoietic cell transplantation is considered a cure for familial HLH. It is often recommended that people with confirmed or suspected familial HLH undergo this treatment as early in life as possible. Prior to hematopoietic cell transplanation, people with HLH are usually treated with chemotherapy and/or immunotherapy to destroy excess immune cells which can lead to life-threatening inflammation.^[4]^[5]^[3]^[7]

Please visit the Histiocyte Society to learn more about the treatment guidelines for HLH.

Last updated: 9/11/2017

Management Guidelines

GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.

Prognosis Prognosis

All forms of HLH, including cases treated adequately, may have a high mortality rate. The long-term outlook (prognosis) of familial forms without treatment is poor, with a median survival of less than 2 months to 6 months after diagnosis.^[4]^[9] Even with treatment, only 21-26% are expected to survive 5 years.^[9] The course of the disease and life expectancy are not well studied in adults with familial HLH.^[4]

The prognosis for people with acquired HLH varies.^[9] For example, the mortality rate reportedly is lower when HLH is associated with autoimmune diseases (8–22%), and greater when it is associated with tumors (especially T-cell lymphoma).^[9]

Because affected people are being diagnosed earlier and treatment options are improving, the prognosis for people with HLH is likely to get better over time.^[5]^[8]

Last updated: 9/11/2017

Do you have updated information on this condition? Let us know.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

The Centers for Mendelian Genomics program is working to discover the causes of rare genetic disorders. For more information about applying to the research study, please visit their website.
ClinicalTrials.gov lists trials that are studying or have studied Hemophagocytic lymphohistiocytosis. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.
The Research Portfolio Online Reporting Tool (RePORT) provides access to reports, data, and analyses of research activities at the National Institutes of Health (NIH), including information on NIH expenditures and the results of NIH-supported research. Although these projects may not conduct studies on humans, you may want to contact the investigators to learn more. To search for studies, enter the disease name in the "Text Search" box. Then click "Submit Query".

Organizations 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 Supporting this Disease

Histiocytosis Association of America
332 North Broadway
Pitman, NJ 08071
Toll-free: 800-548-2758
Telephone: 856-589-6606
Fax: 856-589-6614
Website: http://www.histio.org/
Histiocytosis Association of Canada
Box 29095
Okanagan Mission RPO
Kelowna, B.C.
V1W 4A7
Canada
Telephone: 250-764-6104
E-mail: histio.canada@shaw.ca
Website: http://www.histiocytosis.ca

Do you know of an organization? Send us your suggestions.

Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by GeneTests, the American College of Medical Genetics, and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Financial Resources

The Social Security Administration has included this condition in their Compassionate Allowances Initiative. This initiative speeds up the processing of disability claims for applicants with certain medical conditions that cause severe disability. More information about Compassionate Allowances and applying for Social Security disability is available online.

Learn More 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

The Cincinnati Children's Hospital has an information page on Hemophagocytic lymphohistiocytosis. Click on the link to view this information page.
Genetics Home Reference (GHR) contains information on Hemophagocytic lymphohistiocytosis. This website is maintained by the National Library of Medicine.
The Histiocytosis Association of America has an information page on hemophagocytic syndromes. Click on Histiocytosis Association to view the information page.

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.
Familial hemophagocytic lymphohistiocytosis, type 1
Familial hemophagocytic lymphohistiocytosis, type 2
Familial hemophagocytic lymphohistiocytosis, type 3
Familial hemophagocytic lymphohistiocytosis, type 4
Familial hemophagocytic lymphohistiocytosis, type 5
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 Hemophagocytic lymphohistiocytosis. Click on the link to view a sample search on this topic.

Selected Full-Text Journal Articles

Fisman DN. Hemophagocytic Syndromes and Infection. Emerging Infectious Diseases. 2000; 6(6): 601-608.

News & Events News & Events

News

Don’t Miss the NCATS Toolkit for Patient-Focused Therapy Development Event
August 31, 2017
Funding Opportunities Now Available for the Undiagnosed Diseases Network (UDN) Phase II
August 30, 2017
IRDiRC Goals 2017-2027: New Rare Disease Research Goals for the Next Decade
August 10, 2017

GARD Answers GARD Answers

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

My daughter has HLH. Can HLH cause a brain injury? How does HLH relate to these types of injuries? If you could send me information on how HLH affects the brain, and is there chance of recovery when this happens. Thank you for your time. See answer
Can you elaborate on some the causes of this disease in adults? Specifically, what triggers HLH and what is the general mortality rate? See answer
My granddaughter had familial hemophagocytic lymphohistiocytosis when she was 8 months old. Can her brothers also develop this disease? I have noticed that both of the boys have had skin problems but the older one, now 13, has developed asthma and unexplained headaches. My granddaughter received a BMT from the 2nd born who is now 11 years old. Is there any testing we can have done to check the boys for the presence or absence of the disease? See answer
What is HLH and what are the symptoms of this condition? See answer

Have a question? Contact a GARD Information Specialist.

References References

Familial hemophagocytic lymphohistiocytosis. Genetics Home Reference. November 2014; http://ghr.nlm.nih.gov/condition/familial-hemophagocytic-lymphohistiocytosis.
Kenneth L McClain, MD, PhD. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. UpToDate. July 29, 2015;
George MR.. Hemophagocytic lymphohistiocytosis: review of etiologies and management.. J Blood Med. June 2014; 5:69-86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062561/.
Kejian Zhang, MD, MBA, Alexandra H Filipovich, MD, Judith Johnson, MS, Rebecca A Marsh, MD, and Joyce Villanueva, MT, MBA.. Hemophagocytic Lymphohistiocytosis, Familial. GeneReviews. January 17, 2013; http://www.ncbi.nlm.nih.gov/books/NBK1444/.
Kenneth L McClain, MD, PhD. Treatment and prognosis of hemophagocytic lymphohistiocytosis. UpToDate. October 15, 2015;
Zhang K, Wakefield E, and Marsh R. Lymphoproliferative Disease, X-Linked. GeneReviews. June 30, 2016; https://www.ncbi.nlm.nih.gov/books/NBK1406/.
Janka GE, Lehmberg K.. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment.. Hematology Am Soc Hematol Educ Program. 2013; 2013:605-611. https://www.ncbi.nlm.nih.gov/pubmed/24319239.
Zhang L, Zhou J & Sokol L. Hereditary and acquired hemophagocytic lymphohistiocytosis. Cancer Control. October 2014; 21(4):301-312.
Schwartz RA. Lymphohistiocytosis (Hemophagocytic Lymphohistiocytosis). Medscape. 2016; http://emedicine.medscape.com/article/986458-overview.