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Haemophagocytic lymphohistiocytosis type 3
HLH3 is a life-threatening condition where certain immune cells become overactive, causing widespread tissue damage. It typically affects infants and young children, often triggered by infection.
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Overview
Haemophagocytic lymphohistiocytosis type 3 (HLH3), also known as familial haemophagocytic lymphohistiocytosis type 3 (FHL3), is a rare genetic disorder affecting the immune system. It belongs to a group of conditions called haemophagocytic lymphohistiocytoses (HLH), which are characterised by an overactive and ineffective immune response [PMID:33675079]. In HLH3, immune cells, particularly T-lymphocytes and natural killer (NK) cells, fail to function correctly. This leads to an uncontrolled inflammatory response throughout the body.
Normally, after fighting off an infection, these immune cells are programmed to calm down. In HLH3, this 'off switch' does not work, resulting in continuous activation and proliferation of immune cells. These overactive cells then damage healthy tissues and organs, leading to the diverse symptoms observed in affected individuals. HLH3 is considered a primary or familial form of HLH, meaning it is inherited.
Symptoms & clinical features
The symptoms of HLH3 are diverse and can vary in severity, but they often appear rapidly and are severe. Common initial signs include prolonged fever that does not respond to antibiotics, an enlarged liver and spleen (hepatosplenomegaly), and low blood counts affecting red blood cells (anaemia), white blood cells, and platelets (thrombocytopenia) [PMID:33675079].
Other symptoms may include skin rashes, jaundice (yellowing of the skin and eyes), and neurological issues such as irritability, seizures, or developmental regression. Some individuals may experience swollen lymph nodes. The severity of these symptoms is often linked to the degree of uncontrolled inflammation and organ damage, which can be life-threatening if not promptly managed.
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Affected organs
HLH3 can affect many different organs and body systems due to the widespread inflammation. The most commonly affected organs include the bone marrow, spleen, and liver. The bone marrow, where blood cells are produced, is often infiltrated by immune cells, leading to low blood cell counts. The spleen and liver become enlarged as they try to process the excess immune cells and damaged blood cells.
The central nervous system (brain and spinal cord) can also be affected, leading to neurological symptoms. Other organs that may experience damage include the lungs, kidneys, and skin. The widespread nature of the inflammation means that almost any organ can potentially be impacted, leading to a complex clinical picture.
Risks & severity
HLH3 is a severe and potentially life-threatening condition. Without appropriate intervention, it can be fatal. The condition typically manifests in infancy or early childhood, often triggered by infections, which can be viral (e.g., Epstein-Barr virus), bacterial, or fungal [PMID:28751556]. In some cases, symptoms may appear later in childhood or even in adulthood, though this is less common.
The severity of HLH3 can vary, but most individuals experience a rapidly progressive and severe course. Early diagnosis and prompt treatment are crucial for improving outcomes. The condition involves a high risk of multi-organ failure due to the uncontrolled immune activation and inflammation. The exact prevalence of HLH3 is not well established, but familial HLH forms are rare disorders.
Genetic causes
HLH3 is caused by pathogenic variants in the UNC13D gene. The UNC13D gene provides instructions for making a protein called Munc13-4, which plays a critical role in the function of certain immune cells, specifically cytotoxic T-lymphocytes and natural killer (NK) cells [PMID:28751556]. These cells are essential for eliminating infected or cancerous cells in the body.
Munc13-4 is involved in the process by which these immune cells release cytotoxic (cell-killing) molecules, such as perforin and granzymes, into target cells. When pathogenic variants occur in the UNC13D gene, the Munc13-4 protein may be absent or not function correctly. This impairs the ability of cytotoxic T-lymphocytes and NK cells to kill target cells effectively. As a result, the immune system cannot properly clear infections or regulate its own response, leading to the uncontrolled inflammation characteristic of HLH3.
- UNC13D unc-13 homolog D
Inheritance pattern
HLH3 is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the pathogenic UNC13D gene variant - one from each parent - to develop the condition. If a person inherits only one copy of the pathogenic variant, they are considered a carrier and typically do not show symptoms of HLH3.
When both parents are carriers of a pathogenic UNC13D variant, there is a 25% chance with each pregnancy that their child will inherit two copies of the variant and develop HLH3. There is also a 50% chance that the child will be a carrier (inheriting one variant copy) and a 25% chance that the child will inherit no variant copies and therefore not be affected and not be a carrier. Family members of an affected individual may be offered genetic counselling to understand their own carrier status and reproductive risks.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
A diagnosis of HLH3 is typically suspected based on a combination of clinical symptoms, such as persistent fever, enlarged liver and spleen, and abnormal blood counts. Laboratory tests are then performed to support the diagnosis, including measures of inflammation (e.g., ferritin, C-reactive protein), markers of immune activation, and assessment of the cytotoxic function of immune cells.
Confirmation of HLH3 specifically involves genetic testing to identify pathogenic variants in the UNC13D gene. This testing is crucial for distinguishing HLH3 from other forms of HLH or other conditions with similar symptoms. In the UK, genetic testing for HLH is available through the NHS Genomic Medicine Service, often initiated following referral to a clinical genetics service or specialist immunology centre. The relevant R-code for familial haemophagocytic lymphohistiocytosis gene panel testing would be R140, covering genes like UNC13D.
Management & lifestyle
Management of HLH3 focuses on suppressing the overactive immune response and addressing the underlying genetic defect. Initial treatment often involves immunosuppressive medications, such as corticosteroids and chemotherapy agents, to control the severe inflammation and organ damage. This aims to bring the disease into remission.
Once the acute phase is managed, the definitive treatment for familial forms of HLH, including HLH3, is generally a haematopoietic stem cell transplant (HSCT). This procedure replaces the faulty immune system with healthy stem cells, providing a long-term cure. Patients are typically managed by a multidisciplinary team including immunologists, haematologists, and neurologists. Genetic counsellors play a vital role in providing information and support to families regarding the genetic basis of the condition and inheritance patterns.
UK care pathway
In the UK, individuals suspected of having HLH3 typically enter a diagnostic pathway through specialist paediatric or immunology services. If HLH is suspected, referral to a clinical genetics service or a specialist centre for inherited immune disorders is usually made. Genetic testing, often guided by NHS National Genomic Test Directory R-codes such as R140 for familial HLH gene panel testing, will be performed to identify causative genetic variants. Genetic counsellors are available to provide support, explain the inheritance patterns, and discuss implications for family members.
Frequently asked questions
Can HLH3 be cured?
While treatments can manage the acute symptoms and bring the disease into remission, the only known long-term cure for HLH3 is typically a haematopoietic stem cell transplant (HSCT). This procedure replaces the affected immune system with healthy cells, addressing the underlying genetic defect.
How common is HLH3?
HLH3 is considered a rare disorder. As part of the familial haemophagocytic lymphohistiocytoses group, exact prevalence figures for HLH3 specifically are not well established, but these conditions collectively are uncommon.
If I am a carrier for HLH3, will I develop symptoms?
No, if you are a carrier for HLH3, meaning you have one copy of the pathogenic UNC13D gene variant, you typically will not develop symptoms of the condition. HLH3 follows an autosomal recessive inheritance pattern, requiring two copies of the variant for the disease to manifest.
What kind of doctors treat HLH3?
HLH3 is managed by a team of specialists due to its complex nature. This team often includes paediatric immunologists, haematologists, oncologists, and neurologists. Genetic counsellors also play an important role in supporting families.
References
- Sieni E, Cetica V, Santoro A. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3. Journal of medical genetics. 2011. PMID: 21248318
- Entesarian M, Chiang SC, Schlums H. Novel deep intronic and missense UNC13D mutations in familial haemophagocytic lymphohistiocytosis type 3. British journal of haematology. 2013. PMID: 23672263
- Elstak E, de Jong A, van der Sluijs P. A platform for complementation and characterization of familial haemophagocytic lymphohistiocytosis 3 mutations. Journal of immunological methods. 2011. PMID: 21182842