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Familial HLH type 2
This rare condition occurs when genetic changes prevent immune cells from properly controlling their response to infection. Without treatment, the resulting uncontrolled immune activation can damage multiple organs. It typically presents in infancy or early childhood, though some individuals develop symptoms later.
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Overview
Familial haemophagocytic lymphohistiocytosis type 2 (familial HLH type 2) is a severe inherited disorder affecting immune system regulation. The condition arises when specialised immune cells called cytotoxic lymphocytes cannot properly terminate their response after fighting infection. Instead of switching off once a threat is cleared, these cells remain active and release excessive amounts of inflammatory molecules called cytokines. This cytokine storm triggers widespread inflammation throughout the body, affecting multiple organ systems simultaneously.
The condition affects approximately 1 in 50,000 individuals, making it a rare but serious diagnosis within paediatric immunology services. Most affected children present during the first two years of life, often triggered by a viral infection such as Epstein-Barr virus, though the underlying genetic vulnerability is present from birth. Without prompt recognition and treatment, the uncontrolled immune activation can progress rapidly to multi-organ failure. Early diagnosis through genetic testing enables timely intervention and appropriate management planning.
Symptoms & clinical features
Children with familial HLH type 2 typically present with prolonged high fever that does not respond to antibiotics, often accompanied by marked enlargement of the liver and spleen. Many affected individuals develop neurological symptoms including seizures, altered consciousness, or progressive irritability. Skin rashes may appear, and bleeding problems can occur due to reduced platelet counts and impaired blood clotting mechanisms.
Laboratory investigations reveal characteristic abnormalities including very low blood cell counts across multiple lineages, markedly elevated ferritin levels, and raised triglycerides. Under the microscope, bone marrow examination may show haemophagocytosis, where activated immune cells engulf other blood cells. The severity and combination of features vary between individuals, but the constellation of persistent fever, organ enlargement, blood count abnormalities, and hyperinflammation should prompt consideration of HLH.
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Affected organs
The immune dysregulation in familial HLH type 2 affects multiple organ systems, though the liver, spleen, and bone marrow bear the most consistent impact. The liver often becomes significantly enlarged and may show impaired function with rising liver enzymes and bilirubin. The spleen enlarges due to accumulation of activated immune cells, sometimes becoming massively distended.
The central nervous system is frequently involved, with inflammation affecting the brain and spinal cord. This can manifest as seizures, developmental regression, or progressive neurological decline. The bone marrow becomes infiltrated with activated lymphocytes and macrophages, disrupting normal blood cell production and leading to anaemia, low white cell counts, and reduced platelets. The lungs, heart, and kidneys may also be affected as the systemic inflammation progresses.
Risks & severity
Familial HLH type 2 represents a medical emergency when it presents. Without treatment, the condition can be rapidly fatal. The uncontrolled immune activation leads to progressive multi-organ dysfunction, with neurological involvement often determining long-term outcomes even in those who survive the acute episode.
The age of onset varies, though most affected individuals present before age two years. A smaller proportion develop symptoms in later childhood or even adolescence, particularly following specific viral triggers. Even with modern immunosuppressive therapy and haematopoietic stem cell transplantation, the condition carries significant mortality and morbidity. Neurological sequelae affect many survivors, emphasising the importance of early diagnosis and prompt treatment initiation. Given the autosomal recessive inheritance pattern, family genetic counselling is essential for understanding recurrence risks.
Genetic causes
Familial HLH type 2 arises from pathogenic variants in PRF1, which encodes the protein perforin. Perforin plays a critical role in how cytotoxic lymphocytes eliminate infected or abnormal cells. When a cytotoxic T cell or natural killer cell recognises a target cell requiring destruction, perforin molecules insert into the target cell membrane, forming pores that allow entry of enzymes triggering cell death [PMID:11907092].
When PRF1 variants impair perforin function, cytotoxic lymphocytes cannot efficiently eliminate their targets. This defect prevents proper termination of the immune response, as infected cells persist and continue stimulating immune activation. The inability to complete the normal cycle of target cell elimination leads to sustained lymphocyte activation, excessive cytokine release, and the clinical picture of HLH [PMID:15195087]. Different PRF1 variants affect protein function to varying degrees, which may partly explain differences in age of onset and disease severity between families.
- PRF1 perforin 1
Inheritance pattern
Familial HLH type 2 follows an autosomal recessive inheritance pattern. This means an affected individual has inherited a pathogenic variant in PRF1 from both parents. Each parent carries one altered copy and one working copy of the gene, which typically allows their own immune systems to function normally without symptoms.
When both parents are carriers, each of their children has a 25% chance of inheriting both altered copies and developing the condition, a 50% chance of being an unaffected carrier like the parents, and a 25% chance of inheriting two working copies. Carrier testing is available for at-risk family members, and prenatal or preimplantation genetic diagnosis may be discussed with families who have had an affected child. Genetic counselling helps families understand these inheritance patterns and reproductive options.
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
Diagnosis of familial HLH type 2 requires a combination of clinical features, laboratory findings, and genetic confirmation. The HLH-2004 diagnostic criteria include specific thresholds for fever, spleen size, blood counts, ferritin, and other markers. However, genetic testing confirming pathogenic variants in PRF1 provides definitive diagnosis and distinguishes familial HLH type 2 from other forms of HLH [PMID:17146469].
Within the NHS, suspected HLH typically prompts urgent referral to paediatric immunology or haematology services. Functional testing of natural killer cell activity and perforin expression in lymphocytes can support the diagnosis whilst genetic results are awaited. Gene panel testing through the NHS Genomic Medicine Service examines PRF1 alongside other genes associated with familial HLH subtypes. The relevant PanelApp panel covers primary haemophagocytic lymphohistiocytosis, enabling comprehensive genetic investigation of suspected cases.
Management & lifestyle
Management of familial HLH type 2 requires specialist immunology input and typically follows established treatment protocols combining immunosuppressive medications and chemotherapy agents to control the hyperinflammation. Initial therapy aims to suppress the excessive immune activation and prevent organ damage whilst preparing for definitive treatment. Haematopoietic stem cell transplantation represents the only curative option, replacing the defective immune system with donor cells capable of normal immune regulation.
Ongoing surveillance during and after treatment monitors for disease reactivation, infection complications, and treatment-related effects. Neurological assessment remains important given the risk of central nervous system involvement. Families require access to specialist centres with experience managing this rare condition, and genetic counselling supports family planning decisions. The NHS care pathway involves close collaboration between immunology, haematology, and bone marrow transplant teams to optimise outcomes.
UK care pathway
Families affected by familial HLH type 2 access care through the NHS Genomic Medicine Service and specialist immunology centres. Genetic testing is arranged through clinical genetics services following referral from paediatrics, immunology, or haematology. The PanelApp gene panel for primary haemophagocytic lymphohistiocytosis includes PRF1 and is used for diagnostic testing.
Genetic counsellors provide essential support to families, explaining test results, inheritance patterns, and implications for relatives. Specialist immunology centres coordinate acute treatment and long-term management, including transplant planning where appropriate. Carrier testing for family members and reproductive genetic counselling are available through regional genetics services.
Frequently asked questions
Can infections trigger familial HLH type 2 even if someone has the genetic variants from birth?
Yes, individuals with PRF1 variants affecting both gene copies are born with the genetic predisposition, but symptoms often only appear when triggered by infection, particularly viral infections like Epstein-Barr virus. The infection challenges the already impaired immune system, unmasking the underlying defect.
If my child has been diagnosed with familial HLH type 2, what does this mean for my other children?
Each of your other children has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting two working gene copies. Genetic testing can determine their status, and your genetics team can discuss testing options and timing.
Is stem cell transplantation always necessary for familial HLH type 2?
Haematopoietic stem cell transplantation is generally considered the only curative treatment, as it replaces the defective immune system. The decision about transplant timing and approach depends on disease control, donor availability, and individual clinical circumstances, which your specialist team will discuss with you.
Could I be a carrier of a PRF1 variant without knowing it?
Yes, carriers have one working and one altered PRF1 copy and typically have no symptoms. Carrier status usually only becomes known through family genetic testing after a child is diagnosed, or occasionally through population carrier screening programmes where available.
What support is available for families affected by familial HLH type 2?
NHS genetics services provide genetic counselling to help families understand the condition and inheritance. Specialist immunology centres coordinate medical care, and patient support organisations can connect families with others who have experience with HLH.
References
- Dou L, Zhang J, Wu L. Clinical and prognostic significance of whole blood Epstein-Barr virus DNA in patients with primary hemophagocytic lymphohistiocytosis: a retrospective observational study from China. Annals of hematology. 2025. PMID: 40536720
- Alfaraidi AT, Alqarni AA, Aqeel MT. Familial Hemophagocytic Lymphohistiocytosis Secondary to PRF1 Mutation. Case reports in hematology. 2021. PMID: 35003815
- Tesi B, Chiang SC, El-Ghoneimy D. Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations. Pediatric blood & cancer. 2015. PMID: 26184781
- Lu G, Xie ZD, Shen KL. Mutations in the perforin gene in children with hemophagocytic lymphohistiocytosis. Chinese medical journal. 2009. PMID: 20092789
- Shokripour M, Pakniat Jahromi B, Monabati A. The Role of Perforin Gene Mutation in Patients Suspected of Hemophagocytic Lymphohistiocytosis. Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2026. PMID: 42333146
- Wada T, Sakakibara Y, Nishimura R. Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations. Human immunology. 2013. PMID: 24051121