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Conditions

Familial haemophagocytic lymphohistiocytosis

Familial haemophagocytic lymphohistiocytosis is the name for a group of genetic immune dysregulatory conditions characterised by excessive activation and proliferation of immune cells, leading to potentially fatal organ damage.

Overview

Familial (primary) haemophagocytic lymphohistiocytosis (FHL) is caused by deleterious variants in several genes, including PRF1, UNC13D, STX11 and STXBP2. The genes encode regulatory proteins that, when deficient, result in excessive activation and proliferation. Patients with FHL may be asymptomatic up until they develop haemophagocytic lymphohistiocytosis (HLH), a multi-system, inflammatory condition that can be life-threatening.

Clinical features

FHL typically presents during infancy or early childhood. The clinical features of HLH may be variable, which can make diagnosis challenging. Symptoms may be triggered by infections, typically viral, though in many cases no specific precipitant infection is found. Untreated, mortality is high.

The main features of HLH are:

  • prolonged, unremitting fever;
  • hepatosplenomegaly;
  • pancytopenia;
  • skin rashes, including maculopapular rash, bruising and petechiae;
  • neurological symptoms such as confusion, seizures and ataxia; and
  • liver failure.

Laboratory tests may show:

  • low ferritin;
  • raised triglycerides;
  • low fibrinogen; and
  • evidence of haemophagocytosis in bone marrow.

Features specific to PRF1 deficiency include:

  • increased susceptibility to non-Hodgkin lymphoma, particularly in patients with perforin dysfunction rather than complete loss of function; and
  • juvenile idiopathic arthritis.

Features specific to UNC13D deficiency include:

  • a predominant neurological presentation; and
  • a tendency to present later than other familial HLH cases.

Features specific to STX11 deficiency include:

  • neurological involvement, with some patients having significant leukoencephalopathy.

Features specific to STXBP2 deficiency include:

  • inflammatory bowel disease/chronic colitis; and
  • failure to thrive.

Genomics

Four subtypes of familial autosomal recessive HLH are described (see table 1 below).

Table 1: The four subtypes of familial autosomal recessive HLH

Subtype Gene Protein
FHL2 PRF1 Perforin
FHL3 UNC13D Munc13-4
FHL4 STX11 Syntaxin-11
FHL5 STXBP2 Munc18-2

In PRF1, UNC13D and STXBP2 deficiency, complete biallelic loss-of-function variants present earlier with more severe phenotypes, while hypomorphic variants retaining some level of protein production tend to present later and atypically with variable features.

The biallelic and monoallelic PRF1 c.272C>T, p.Ala91Var variants have been reported in patients with adult-onset HLH. Monoallelic PRF1 variants have been described in association with late-onset HLH or atypical presentations, such as lymphoma with atypical histiocytosis.

Founder effects are found in UNC13D c.1122G>A, p.W374X in Turkish populations, and the intronic variants in UNC13D c.118-308C>T, c754-1G>C in South Korea.

The monoallelic variant STXBP2 c.568C>T, p.R190C has been associated with HLH by interfering with wild-type Munc18-2 in a dominant negative mechanism.

Diagnosis

Diagnosis of FHL is confirmed by reduced natural killer (NK) and/or cytotoxic T-cell (CTL) cytotoxicity. Perforin expression may also be analysed by flow cytometry.

The European Society for Immunodeficiencies diagnostic criteria are outlined below.

  • At least one of the following:
  • at least one of the following:
    • recurrent disease (>4 weeks after initiating treatment for first episode);
    • persistent disease (no full remission can be achieved);
    • partial albinism;
    • absent or significantly decreased perforin expression in flow cytometry;
    • at least one assay with absent degranulation (NK or CTL) or two assays with reduced degranulation; and/or
    • at least two assays with absent NK cell cytotoxicity.

Genomic testing confirms the diagnosis and differentiates FHL subtypes.

For information about testing, see ‘Infant or child with severe, recurrent, persistent and/or unusual infections‘.

For individuals with low or absent perforin expression, consider more targeted testing. For more information, see ‘Child with haemophagocytic lymphohistiocytosis syndrome with absent perforin expression‘.

FHL may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

All four FHL subtypes are caused by biallelic pathogenic genetic variants in PRF1, UNC13D, STX11 and STXBP2 genes respectively (see table 1 above). All are inherited in an autosomal recessive pattern, and the prevalence is 1–2 in 1,000,000. FHL is also described in monoallelic variants in PRF1 and STXBP2.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise.

  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of the child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of the child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of the child inheriting both normal copies and being neither affected nor a carrier.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

FHL can present variably, and the presentation will determine management options.

Patients with HLH should be managed using standard HLH treatment based on current protocols. Initial therapy consists of etoposide and dexamethasone for eight weeks in varying doses. Patients with central nervous system involvement may require intrathecal methotrexate. In some cases, emapalumab targeting interferon-γ has been used successfully.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications. Patients require long-term monitoring following HSCT to assess immune reconstitution and monitor for potential complications.

Supportive care or immunosuppression may be required for patients with neurological features of HLH, or if there are other complications as a result of organ involvement.

FHL may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 27/08/2025
  • Next review due: 27/08/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay