Haemophagocytic lymphohistiocytosis type 5

Overview

Haemophagocytic lymphohistiocytosis type 5 (HLH5) is an inherited condition that causes the immune system to become dysregulated. This means certain immune cells, particularly T-lymphocytes and macrophages, become overactive and fail to switch off appropriately. Instead of clearing infections and damaged cells, these overactive cells attack healthy tissues and organs, leading to significant inflammation and damage throughout the body [PMID:33671239].

HLH5 is one of several types of familial haemophagocytic lymphohistiocytosis (FHL), which are primary immunodeficiencies. These conditions are rare and can be life-threatening if not diagnosed and treated promptly. HLH5 typically manifests in early life, often within the first year, but can sometimes appear later [PMID:28795589].

Symptoms & clinical features

The symptoms of HLH5 arise from widespread inflammation and can vary, though some features are commonly observed. Persistent fever that does not respond to antibiotics is often one of the first signs. Other typical symptoms include an enlarged spleen (splenomegaly) and an enlarged liver (hepatomegaly). Lymph nodes may also become swollen.

Neurological symptoms are also common in HLH5, which can include irritability, seizures, or problems with movement and coordination. As the disease progresses, individuals may develop skin rashes, jaundice (yellowing of the skin and eyes), and problems with blood clotting. Repeated infections can also occur due to the underlying immune dysfunction, even as the immune system appears overactive.

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Affected organs

HLH5 can affect multiple organs due to the uncontrolled immune response. The liver and spleen are almost always involved, becoming enlarged. The central nervous system, including the brain and spinal cord, is frequently affected, leading to neurological symptoms. Bone marrow, where blood cells are produced, can also be impacted, resulting in low blood cell counts (cytopenias).

Other organs that may be affected include the lungs, kidneys, and skin. The widespread inflammation can lead to organ damage and dysfunction if not managed effectively, making HLH5 a complex condition that requires careful monitoring of various body systems.

Immune cells

Immune system dysfunction

Cellular impact

Mechanism at cellular level

Risks & severity

HLH5 is a severe condition with a significant risk of complications if left untreated. The severity can vary between individuals, even within the same family, but it generally follows a progressive course. Without appropriate treatment, the uncontrolled immune activation can lead to multi-organ failure, which can be life-threatening [PMID:33671239].

The onset of symptoms typically occurs in infancy or early childhood, often triggered by an infection. However, some individuals may experience a later onset or a more chronic course. Early diagnosis and intervention are crucial to improve outcomes and manage the severe inflammatory response associated with HLH5.

Genetic causes

HLH5 is caused by pathogenic variants in the STXBP2 gene. This gene provides instructions for making a protein called syntaxin binding protein 2 (also known as Munc18-2). This protein plays a critical role in the proper functioning of certain immune cells, specifically natural killer (NK) cells and cytotoxic T-lymphocytes [PMID:28795589].

These immune cells are responsible for destroying infected cells and cancer cells by releasing toxic substances. STXBP2 is essential for the regulated release of these substances. When there are pathogenic variants in STXBP2, the protein is either non-functional or missing, leading to impaired ability of NK cells and cytotoxic T-lymphocytes to perform their killing functions effectively. This defect contributes to the uncontrolled inflammation seen in HLH5, as the immune system cannot properly clear pathogens or regulate itself [PMID:22094248].

• STXBP2
  syntaxin binding protein 2

Inheritance pattern

HLH5 is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the STXBP2 gene - one from each parent - to develop the condition. People who have only one altered copy of the gene are known as carriers. Carriers typically do not show symptoms of HLH5 but can pass the altered gene to their children.

If both parents are carriers of a pathogenic variant in STXBP2, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered copies of the gene and develop HLH5. There is a 2 in 4 (50%) chance their child will be a carrier, and a 1 in 4 (25%) chance their child will inherit two unaffected copies of the gene.

Diagnosis & testing

Diagnosing HLH5 often begins with clinical suspicion based on a combination of symptoms such as prolonged fever, splenomegaly, and low blood cell counts. Blood tests may show elevated levels of specific markers of inflammation, such as ferritin, soluble CD25 (sCD25), and triglycerides, along with reduced NK cell activity.

Definitive diagnosis of HLH5 is confirmed through genetic testing, which identifies pathogenic variants in the STXBP2 gene. Referral to clinical genetics services is appropriate for individuals with suspected HLH, especially if there is a family history or presentation in early childhood. Genetic testing for HLH5 can be accessed through the NHS Genomic Medicine Service, often utilising R-codes such as R146 (Familial HLH) or broader immunodeficiency panels.

Management & lifestyle

Management of HLH5 typically involves a multi-disciplinary approach overseen by specialist immunology and haematology teams. The primary goal is to control the hyperinflammation and replace the defective immune system. Initial treatment often involves immunosuppressive medications, such as corticosteroids and etoposide, to suppress the overactive immune response.

Ultimately, for many individuals with HLH5, haematopoietic stem cell transplantation (HSCT) is considered the only curative treatment option. This procedure replaces the affected bone marrow with healthy stem cells from a donor. Genetic counsellors play a vital role in supporting families, explaining inheritance patterns, and discussing reproductive options. Ongoing monitoring for complications and supportive care are also essential components of managing HLH5 within the NHS care pathway.

UK care pathway

In the UK, individuals suspected of having HLH5 are typically referred to specialist immunology or haematology centres, often linked to paediatric hospitals. Diagnosis and management are guided by the NHS Genomic Medicine Service (GMS) pathways. Genetic testing for HLH5 falls under specific R-codes, such as R146 for Familial HLH, enabling access to comprehensive genomic analysis.

Following a diagnosis, patients and their families will have access to clinical geneticists and genetic counsellors who can provide detailed information about the condition, its inheritance, and implications for family planning. The care pathway involves close collaboration between various specialists to ensure integrated and holistic management.

Related conditions

HLH5 is one of several conditions within the spectrum of familial haemophagocytic lymphohistiocytosis (FHL). Other types, such as FHL1, FHL2, FHL3, and FHL4, are caused by pathogenic variants in different genes (e.g., PRF1, UNC13D, STX11). These conditions share many clinical features but have distinct genetic causes.

There are also secondary forms of HLH, which can be triggered by severe infections, autoimmune diseases, or malignancies, without an underlying genetic predisposition. Differentiating between primary (familial) and secondary HLH is crucial for appropriate treatment planning. Furthermore, other primary immunodeficiencies can present with overlapping symptoms, making accurate genetic diagnosis essential.

Frequently asked questions