FHLH types 1, 2, 3, 4 and 5; FHL; HLH; HPLH; Familial Erythrophagocytic Lymphohistiocytosis; Erythrophagocytic Lymphohistiocytosis; Familial Histiocytic Retulosis; Familial Hemophagocytic Lymphohistiocytosis

Familial Hemophagocytic Lymphohistiocytosis (FHLH) is a rare, genetic disease that is caused by mutations in the perforin 1 (PRF1) gene. FHLH is characterized by uncontrolled activation of the immune system. The T cells, macrophages and overproduced inflammatory cytokines infiltrate the liver, spleen, bone marrow and central nervous system resulting in a multi-system disorder. The highly stimulated and ineffective immune response threatens the life of the individual and may lead to death unless appropriate and timely treatment is provided. It commonly appears in infants and during early childhood, although it can appear in all age groups. FHLH can be triggered by infections, viruses such as Epstein-Barr, rheumatic diseases and malignancies.

Diagnostic testing: A molecular diagnosis confirms the disease. Clinical evaluation of fever and splenomegaly, and blood tests which measure high triglycerides, ferritin, transaminases, bilirubin, coagulation time and decreased fibrinogen.

Physical findings: Children with FHLH present with:

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  Prolonged high fever;

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  Splenomegaly (enlarged spleen);

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  Liver abnormalities;

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  Cytopenia;

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  Hypofibrinogenemia or hypertriglyceridemia;

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  Hemophagocytosis;

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  Skin rashes on the scalp and behind the ears;

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  Swollen or hemorrhagic gums;

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  Abdominal pain;

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  Vomiting;

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  Diarrhea;

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  Weight loss;

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  Jaundice;

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  Engulfment and destruction of blood cells in the bone marrow and other tissues; and

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  Failure to thrive.

ICD-9: 288.4

FHLH is uniformly fatal if not treated. The prognosis is varied for those receiving treatment. The median survival time is 2-6 months after diagnosis without treatment, but survival time has dramatically improved with advent of recent treatment protocols. Even with treatment, approximately 21% of individuals with FHLH can be expected to survive 5 years but survival rates of up to 66% have been reported in those receiving bone marrow transplantation (versus 10% of patients receiving chemotherapy alone). Success or failure of an allogenic bone marrow transplant if the most important long-term prognostic factor. Without treatment, the uncontrolled inflammatory response leads to sustained neutropenia and death from bacterial or fungal infections as well as from cerebral dysfunction.

Individuals with FHLH may be classified into high-risk and low-risk groups. Patients who are at low risk may be treated effectively with cyclosporine, corticosteroids or IVIG. Those at high-risk may require chemotherapy. The first goal of treatment is to achieve clinical stability and then to cure with bone marrow transplant.

SUGGESTED PROGRAMMATIC ASSESSMENT*

Suggested MER for Evaluation:

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  Clinical history and examination that describes the diagnostic features of the impairment; and

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  Laboratory studies measuring high triglycerides, ferritin, transaminases, bilirubin, coagulation time and decreased fibrinogen.

Suggested Listings for Evaluation:

REMARKS

Need to differentiate Familial HLH from Acquired or Secondary HLH, which has a very good prognosis.