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familial hemophagocytic lymphohistiocytosis 4
ICD-10 Codes
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Description
Familial hemophagocytic lymphohistiocytosis 4 (FHL4) is a rare genetic disorder caused by homozygous mutation in the syntaxin-11 gene (STX11; 605014) on chromosome 6q24. This condition is characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs including the bone marrow, liver, spleen, and brain.
The symptoms of FHL4 include enlargement of the liver, swollen lymph nodes, skin rashes, jaundice (yellow color of the skin and eyes), lung problems, and other systemic complications. This condition is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop FHL4.
FHL4 is a severe hyperinflammatory condition with accumulation of macrophages and lymphocytes in tissues. It is caused by autosomal recessive variants in one of four genes: FHL2-5, associated with PRF1, UNC13D, STX11, and STXBP2, all resulting in impaired lymphocyte cytotoxicity.
The only cure for FHL4 is hematopoietic stem cell transplantation. Persistent remission is rarely achieved with chemo- or immunotherapy. For a phenotypic description and a discussion of genetic heterogeneity of familial hemophagocytic lymphohistiocytosis (FHL), see reference [3][10].
References: [1] - The condition is caused by homozygous mutation in the syntaxin-11 gene (STX11; 605014) on chromosome 6q24. [2] [2] - This condition is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop FHL4. [3] [3] - The symptoms of FHL4 include enlargement of the liver, swollen lymph nodes, skin rashes, jaundice (yellow color of the skin and eyes), lung problems, and other systemic complications. [11] [4] - FHL4 is a severe hyperinflammatory condition with accumulation of macrophages and lymphocytes in tissues. It is caused by autosomal recessive variants in one of four genes: FHL2-5, associated with PRF1, UNC13D, STX11, and STXBP2, all resulting in impaired lymphocyte cytotoxicity. [14] [5] - The only cure for FHL4 is hematopoietic stem cell transplantation. Persistent remission is rarely achieved with chemo- or immunotherapy. [13]
Additional Characteristics
- Familial hemophagocytic lymphohistiocytosis 4 (FHL4) is a rare genetic disorder caused by homozygous mutation in the syntaxin-11 gene (STX11; 605014) on chromosome 6q24.
- The symptoms of FHL4 include enlargement of the liver, swollen lymph nodes, skin rashes, jaundice (yellow color of the skin and eyes), lung problems, and other systemic complications.
- The only cure for FHL4 is hematopoietic stem cell transplantation. Persistent remission is rarely achieved with chemo- or immunotherapy.
- FHL4 is a severe hyperinflammatory condition with accumulation of macrophages and lymphocytes in tissues. It is caused by autosomal recessive variants in one of four genes: FHL2-5, associated with PRF1, UNC13D, STX11, and STXBP2, all resulting in impaired lymphocyte cytotoxicity.
Signs and Symptoms
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 that doesn't respond to antibiotics [2]
- Rash: A skin rash, which is less common in patients with fHLH (less than 30% of cases) [12]
- Enlarged Liver (Hepatomegaly): The liver may become enlarged due to the accumulation of immune cells [4]
- Enlarged Spleen (Splenomegaly): The spleen may also become enlarged for the same reason as the liver [2, 12]
- Lymphadenopathy: Enlargement of lymph nodes, which can be felt in the neck, armpits, or groin area [6, 13]
In addition to these symptoms, children with fHLH may also experience:
- Central Nervous System Symptoms: Headache, irritability, sleepiness, or seizures [5]
- Organ Damage: Abnormalities of the heart, kidneys, and other organs and tissues due to the excessive activation of immune cells [9]
It's essential to note that these symptoms can vary in severity and may not be present in all cases. If you suspect a child has fHLH, it's crucial to consult with a healthcare professional for proper diagnosis and treatment.
References: [2] - Symptoms of hemophagocytic lymphohistiocytosis [4] - Primary (or familial) ... HLH carriers usually remain healthy and do not show symptoms. [6] - Presenting signs and symptoms include the classic triad of fever, hepatosplenomegaly, and cytopenias... [9] - In addition to these symptoms, children with fHLH may also experience organ damage due to excessive activation of immune cells. [12] - The symptoms of hemophagocytic lymphohistiocytosis (HLH) include: Persistent fever, often high. Sometimes a microbial (often viral) cause is found... [13] - Presenting signs and symptoms include the classic triad of fever, hepatosplenomegaly, and cytopenias...
Additional Symptoms
- Organ Damage
- Enlarged Spleen (Splenomegaly)
- Enlarged Liver (Hepatomegaly)
- Central Nervous System Symptoms
- rash
- lymphadenopathy
- fever
Diagnostic Tests
Diagnostic Tests for Familial Hemophagocytic Lymphohistiocytosis (FHLH)
Familial hemophagocytic lymphohistiocytosis (FHLH) is a severe immune deficiency disorder that requires prompt and accurate diagnosis. The following diagnostic tests can help establish a diagnosis of FHLH:
- Molecular Diagnosis: A molecular diagnosis confirms the disease by detecting genetic mutations in one of four genes associated with FHLH: PRF1, STX11, STXBP2, or UNC13D [12].
- Tissue or Bone Marrow Biopsy: A biopsy can be performed to detect hemophagocytosis and NK-cell function, which are characteristic features of FHLH [2].
- Lymph Node Biopsy: A lymph node biopsy may demonstrate the infiltration of immune cells into the lymph nodes.
- Bone Marrow Biopsy: A bone marrow biopsy
Additional Diagnostic Tests
- Bone Marrow Biopsy
- Molecular Diagnosis
- Lymph Node Biopsy
- Tissue or Bone Marrow Biopsy
Treatment
Treatment Options for Familial Hemophagocytic Lymphohistiocytosis (fHLH)
Familial hemophagocytic lymphohistiocytosis (fHLH) is a rare and life-threatening genetic disorder that requires prompt and effective treatment. While there are various treatment options available, the most commonly used ones include:
- Gamifant: This is the first and only treatment specifically designed for primary HLH. It works by targeting IFNγ, a central and upstream cytokine in the pathogenesis of fHLH [9]. Gamifant has been shown to be effective in reducing the severity of symptoms and improving survival rates.
- Stem Cell Transplant: This is considered the only curative treatment for fHLH. Stem cell transplant involves replacing the patient's immune system with a healthy one from a donor, which can help control the disease [8].
- Immunotherapy: Immunotherapies such as HLH-94 immunochemotherapy and bone marrow transplantation have been used to treat fHLH. These treatments aim to modulate the immune response and reduce inflammation [2].
Other Treatment Options
In addition to these primary treatment options, other therapies may be considered on a case-by-case basis. These include:
- Etoposide: This chemotherapy medication has been used in combination with dexamethasone as initial therapy for fHLH [5].
- Dexamethasone: This corticosteroid is often used to reduce inflammation and control symptoms.
- Tocilizumab: This medication has been shown to be effective in treating HLH by inhibiting IL-6-mediated signaling [3].
References
[2] - Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. [3] - By binding to IL-6R, tocilizumab blocks the action of interleukin-6 (IL-6), a cytokine that plays a key role in inflammation. [5] - Etoposide has been used as initial therapy for fHLH in combination with dexamethasone. [8] - Stem cell transplant is considered the only curative treatment for fHLH. [9] - Gamifant targets IFNγ, a central and upstream cytokine in the pathogenesis of fHLH.
Recommended Medications
- Tocilizumab
- Gamifant
- etoposide
- Etoposide
- dexamethasone
- Dexamethasone
💊 Drug information is sourced from ChEBI (Chemical Entities of Biological Interest) database. Always consult with a healthcare professional before starting any medication. Click on any medication name for detailed information.
Differential Diagnosis
Familial hemophagocytic lymphohistiocytosis (fHLH) type 4 is a rare and potentially life-threatening condition characterized by the overactivation of immune cells, leading to inflammation and damage in various organs. The differential diagnosis for fHLH type 4 includes:
- Other forms of HLH: Familial hemophagocytic lymphohistiocytosis (fHLH) can be distinguished from other forms of HLH based on the presence of biallelic pathogenic variants in one of four genes: PRF1, STX11, STXBP2, or UNC13D.
- Macrophage-activation syndrome: This is a condition characterized by the activation and proliferation of macrophages, leading to inflammation and damage in various organs. It can be distinguished from fHLH type 4 based on its distinct genetic and clinical features.
- Neonatal hemochromatosis: This is a rare condition characterized by iron overload in newborns. While it shares some similarities with fHLH type 4, it has distinct genetic and clinical features that set it apart.
- Metabolic diseases: Certain metabolic diseases, such as Pompe disease or Gaucher disease, can present with similar symptoms to fHLH type 4, including organ damage and inflammation.
According to [3] and [6], the STX11 gene is associated with familial hemophagocytic lymphohistiocytosis type 4. This gene consists of two exons and encodes a protein involved in immune cell signaling. Mutations in this gene can lead to the overactivation of immune cells, resulting in inflammation and damage in various organs.
In addition, [7] notes that differential diagnosis for HLH producing isolated central nervous system involvement includes conditions such as multiple sclerosis or vasculitis.
It's essential to consider these differential diagnoses when evaluating patients with suspected fHLH type 4, as timely and accurate diagnosis is crucial for effective management and treatment.
Additional Information
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