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Hemophagocytic Lymphohistiocytosis, Familial.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2006 Mar 22 [updated 2013 Jan 17].

Author information

1
Associate Professor of Pediatrics, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
2
Professor, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
3
Genetic Counselor and Project Manager, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
4
Assistant Professor, Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
5
Research and Development Coordinator, Immunodeficiency and Histiocytosis Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

Excerpt

CLINICAL CHARACTERISTICS:

Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.

DIAGNOSIS/TESTING:

The diagnosis of FHL is made based on the presence of clinical criteria and is confirmed by molecular genetic testing. Five disease subtypes (FHL1, FHL2, FHL3, FHL4, and FHL5) are described. Four genes in which pathogenic variants are causative have been identified: PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5).

MANAGEMENT:

Treatment of manifestations: Antibiotics or antiviral agents are used to treat or prevent infections that may have triggered the exaggerated inflammatory response. Individuals suspected of having FHL or diagnosed with FHL are treated with chemotherapy and immunotherapy to achieve clinical stability prior to allogeneic hematopoietic cell transplantation (HCT). Prevention of primary manifestations: Allogeneic HCT is the only curative therapy and is undertaken as early in life as feasible in children with confirmed FHL. Surveillance: Following HCT, annual neuropsychological evaluation and regular follow up by a transplant specialist to monitor for late complications related to growth and hormone function is recommended. Agents/circumstances to avoid: Live vaccines; exposure to infections. Evaluation of relatives at risk: Molecular genetic testing of at-risk sibs for the familial pathogenic variants enables consideration of presymptomatic bone marrow transplantation and timely treatment.

GENETIC COUNSELING:

FHL is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the two pathogenic variants in the family are known.

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