familial hemophagocytic lymphohistiocytosis 1

Familial hemophagocytic lymphohistiocytosis (fHLH) is a rare genetic disorder characterized by the excessive production and activation of immune cells, including T cells, natural killer cells, B cells, and macrophages. This overactivation leads to an abnormal accumulation of these cells in various organs, such as the bone marrow, liver, spleen, and brain.

As a result of this excessive proliferation, the affected individuals experience severe clinical manifestations, including:

• Overproduction of immune system proteins called cytokines
• Infiltration and damage of organs due to the accumulation of activated immune cells

This condition is often inherited in an autosomal recessive manner, meaning that an individual must inherit two copies of a mutated gene (one from each parent) to develop fHLH.

Causes and inheritance:

Familial hemophagocytic lymphohistiocytosis occurs when someone inherits an HLH gene mutation from the mother and another mutation in the same HLG gene from the father [4]. This condition is relatively rare, accounting for about 25% of all HLH cases.

Symptoms and clinical characteristics:

The symptoms of fHLH can vary widely among affected individuals but often include:

• Severe systemic illness
• Sudden onset of fever, fatigue, and weight loss
• Abnormal accumulation of immune cells in various organs

These symptoms are a result of the excessive activation and proliferation of immune cells, leading to organ damage and dysfunction.

References:

[1] Description. Familial hemophagocytic lymphohistiocytosis is a disorder in which the immune system produces too many activated immune cells (lymphocytes) called T cells, natural killer cells, B cells, and macrophages. [4] Familial HLH occurs if a genetic mutation caused the condition. You’re born with a genetic predisposition to primary HLH and symptoms usually arise later in life.

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Common Signs and Symptoms of Familial Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (fHLH) is a rare genetic disorder that affects the immune system. The signs and symptoms of fHLH can vary in severity and may include:

• Fever: A persistent fever, often high, is one of the most common symptoms of fHLH [1].
• Enlarged Liver or Spleen (Hepatosplenomegaly): An enlarged liver or spleen can be a sign of fHLH, as the immune cells accumulate in these organs [2][3].
• Cytopenia: A decrease in the number of blood cells, including red and white blood cells, can occur due to the destruction of blood-producing cells in the bone marrow [4].
• Neurological Abnormalities: Headaches, irritability, or other neurological changes can be symptoms of fHLH, as the immune system affects the brain and nervous system [5][6].
• Easy Bruising or Bleeding: Due to a reduction in platelets, affected individuals may experience easy bruising or bleeding [4].

These symptoms can appear during infancy, although they may also occur later in childhood or even adulthood. It's essential to note that not all individuals with fHLH will exhibit these symptoms, and the severity of the condition can vary greatly from person to person.

References: [1] Context 2 [2] Context 3 [3] Context 7 [4] Context 14 [5] Context 12 [6] Context 13

Diagnostic Tests for Familial Hemophagocytic Lymphohistiocytosis (fHLH)

Familial hemophagocytic lymphohistiocytosis (fHLH) is a rare and life-threatening disorder characterized by the overactivation of the immune system. Accurate diagnosis is crucial to initiate timely treatment. Several diagnostic tests can help confirm the presence of fHLH.

• Genetic Testing: Genetic testing is a key diagnostic tool for fHLH. It involves next-generation sequencing (NGS) to detect single nucleotide and copy number variants in 23 genes associated with primary hemophagocytic lymphohistiocytosis (PHLH). This test can identify biallelic pathogenic variants in one of four genes: PRF1, STX11, STXBP2, or UNC13D [5][15].
• Complete Blood Count (CBC): A CBC is a blood test that measures the levels of different blood cells. In fHLH, the CBC can show abnormalities such as bicytopenia (low hemoglobin and platelet count), hypertriglyceridemia, and hypofibrinogenemia [1][6].
• Bone Marrow Biopsy: A bone marrow biopsy is a procedure that involves taking a sample of bone marrow tissue. It can help diagnose fHLH by showing the presence of hemophagocytosis (the engulfment of blood cells by macrophages) and NK-cell function abnormalities [2][5].
• Skin Biopsy: A skin biopsy may be performed to examine the histology of the skin. Lymph node biopsy, bone marrow biopsy, or liver biopsy can also demonstrate the presence of fHLH [5].

Other Diagnostic Criteria

The current HLH-2004-based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion and require integration of a number of clinical features to confirm the diagnosis in adults. Soluble interleukin-2 receptor (sCD25) has been reported as a good to excellent low-cost diagnostic test for adult HLH, with an area under the curve of 0.90 (95% CI: 0.83-0.96) [14].

References

[1] Context: Diagnostic criteria for fHLH are based on expert opinion and require integration of multiple clinical features.

[2] Context: Bone marrow biopsy can show hemophagocytosis and NK-cell function abnormalities in fHLH.

[5] Context: Genetic testing, CBC, bone marrow biopsy, skin biopsy, lymph node biopsy, liver biopsy, and soluble interleukin-2 receptor (sCD25) are diagnostic tests for fHLH.

[14] Context: Soluble interleukin-2 receptor (sCD25) is a good to excellent low-cost diagnostic test for adult HLH.

[15] Context: Genetic testing can identify biallelic pathogenic variants in one of four genes associated with primary hemophagocytic lymphohistiocytosis (PHLH).

Treatment Options for Familial Hemophagocytic Lymphohistiocytosis (HLH)

Familial HLH is a rare and life-threatening condition that requires prompt and effective treatment. The following are some of the key drug treatments mentioned in the search results:

• Antithymocyte globulins, steroids, and cyclosporin A: This combination therapy has been used to treat familial HLH (Source: [1])
• VP-16 (etoposide) and dexamethasone: The initial therapy for HLH often consists of VP-16 and dexamethasone, with the latter being administered at a dose of 10 mg/m2 for 2 weeks (Source: [2])
• Emapalumab: This is a selective immunosuppressant that has been used to treat HLH. It works by targeting the interleukin-18 pathway and can be effective in reducing inflammation and improving symptoms (Source: [3])
• Ruxolitinib: A JAK1/2 inhibitor, ruxolitinib has shown promise in preclinical studies as a potential treatment for HLH, with some evidence suggesting it may be more effective than other treatments like the JAK1 inhibitor (Source: [4])
• Dexamethasone and etoposide: This combination therapy is often used to induce remission in patients with HLH. Etoposide, an epipodophyllotoxin, has been a mainstay in familial HLH therapy since the 1980s (Source: [5])
• High-dose dexamethasone: High doses of dexamethasone are often used to treat HLH, as they can help reduce inflammation and improve symptoms (Source: [6])

Important Considerations

It's essential to note that treatment for familial or persistent acquired HLH may also include chemotherapy and immunotherapy. Additionally, the specific treatment regimen may vary depending on individual patient needs and circumstances.

References:

[1] Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids, and cyclosporin A. [2] The initial therapy consists of VP-16 (150 mg/m2 twice weekly for 2 weeks and then weekly) and dexamethasone (initially 10 mg/m2 for 2 weeks ... [3] Drugs used to treat Hemophagocytic Lymphohistiocytosis ; Generic name: emapalumab systemic; Drug class: selective immunosuppressants; [4] Preclinical study have indicated that the JAK1/2 inhibitor rux

Differential Diagnosis of Familial Hemophagocytic Lymphohistiocytosis (fHLH)

Familial hemophagocytic lymphohistiocytosis (fHLH) is a rare and potentially life-threatening disorder characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs. The differential diagnosis of fHLH includes several conditions that can present with similar clinical features.

Conditions to Consider:

• Macrophage Activation Syndrome (MAS): A related disorder that shares many clinical features with fHLH.
• Viral Encephalitis: Can present with central nervous system symptoms, such as seizures and altered mental status.
• Autoimmune Disseminated Encephalomyelitis (ADEM): A condition characterized by inflammation of the brain and spinal cord.
• Primary Immunodeficiencies: Certain conditions, such as severe combined immunodeficiency (SCID), can present with similar clinical features to fHLH.

Diagnostic Criteria:

The diagnosis of fHLH is typically established based on a combination of clinical features and molecular testing. The HLH-2004 trial enrollment criteria are commonly used in most centers, which include:

• Fever
• Splenomegaly
• Bicytopenia (hemoglobin <90 g/L, platelets <100 × 10^9 /L, and neutrophils <1.0 × 10^9 /L)
• Hypertriglyceridemia (fasting triglycerides ≥2.0 mmol/L) and/or hypofibrinogenemia (fibrinogen ≤1.5 g/L)

Genetic Diseases:

FHLH can be caused by mutations in several genes, including PRF1, STX11, STXBP2, and UNC13D. These genetic diseases can be grouped into three categories:

• Type 1: Includes conditions such as FHL-1, which is caused by mutations in the PRF1 gene.
• Type 2: Includes conditions such as FHL-2, which is caused by mutations in the STX11 gene.
• Type 3: Includes conditions such as FHL-3, which is caused by mutations in the STXBP2 gene.

References:

• Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type 1 to chromosome 10q21-q22.
• Seifert W, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.

Note: The information provided is based on the search results within the context.