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

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 45 |

Medical Terms	Other Names	Learn More: HPO ID
5%-29% of people have these symptoms
Generalized hypotonia	Decreased muscle tone Low muscle tone [ more ]	0001290
Global developmental delay		0001263
Seizures	Seizure	0001250
1%-4% of people have these symptoms
Anemia	Low number of red blood cells or hemoglobin	0001903
Granulocytopenia		0001913
Hepatomegaly	Enlarged liver	0002240
Hypofibrinogenemia		0011900
Neutropenia	Low blood neutrophil count Low neutrophil count [ more ]	0001875
Reduced natural killer cell activity		0012178
Splenomegaly	Increased spleen size	0001744
Thrombocytopenia	Low platelet count	0001873
Percent of people who have these symptoms is not available through HPO
Abnormal natural killer cell physiology		0012177
Ataxia		0001251
Autosomal recessive inheritance		0000007
Coma		0001259
CSF pleocytosis		0012229
Decreased HDL cholesterol concentration	Decreased circulating high-density lipoprotein cholesterol Decreased HDL cholesterol Low HDL-cholesterol [ more ]	0003233
Encephalitis	Brain inflammation	0002383
Episodic fever	Increased body temperature, episodic Intermittent fever [ more ]	0001954
Failure to thrive	Faltering weight Weight faltering [ more ]	0001508
Fever		0001945
Generalized edema		0007430
Hemiplegia		0002301
Hemophagocytosis		0012156
Hepatosplenomegaly	Enlarged liver and spleen	0001433
Hypertonia		0001276
Hypertriglyceridemia	Increased plasma triglycerides Increased serum triglycerides Increased triglycerides [ more ]	0002155
Hypoalbuminemia	Low blood albumin	0003073
Hyponatremia	Low blood sodium levels	0002902
Hypoproteinemia		0003075
Increased CSF protein		0002922
Increased intracranial pressure	Rise in pressure inside skull	0002516
Increased LDL cholesterol concentration	Increased circulating LDL level Increased LDL cholesterol [ more ]	0003141
Increased serum ferritin	Elevated serum ferritin High ferritin level Increased ferritin Increased serum ferritin level [ more ]	0003281
Increased total bilirubin	High bili total	0003573
Increased VLDL cholesterol concentration		0003362
Irritability	Irritable	0000737
Jaundice	Yellow skin Yellowing of the skin [ more ]	0000952
Leukopenia	Decreased blood leukocyte number Low white blood cell count [ more ]	0001882
Lymphadenopathy	Swollen lymph nodes	0002716
Meningitis		0001287
Muscular hypotonia	Low or weak muscle tone	0001252
Prolonged partial thromboplastin time		0003645
Prolonged prothrombin time		0008151
Tetraplegia	Paralysis of all four limbs	0002445

Showing of 45 |

Do you have more information about symptoms of this disease? We want to hear from you.

Last updated: 12/1/2018

Do you have updated information on this disease? We want to hear from you.

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

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Emapalumab (Brand name: Gamifant) - Manufactured by NovImmune S.A.
FDA-approved indication: November 2018, emapalumab (Gamifant) was approved for the treatment of adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance of conventional HLH therapy.

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

Find a Specialist Find a Specialist

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare 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 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.

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 related to 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

Histio UK
United Kingdom
Telephone: 01733 309619
Website: https://www.histiouk.org/
Histiocytosis Association
332 North Broadway
Pitman, NJ 08071
Toll-free: 800-548-2758
Telephone: 856-589-6606
Fax: 856-589-6614
E-mail: info@histio.org
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? We want to hear from you.

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.

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

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.
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.

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.