Clinical Diagnosis

The diagnosis of familial hemophagocytic lymphohistiocytosis (FHL), a cellular immunologic disorder resulting from genetic defects in cytotoxic cell function that lead to hyperactivation, proliferation, and infiltration of macrophages and T-lymphocytes, can be established if 1 and/or 2 is present:

1. A disease-causing mutation in PRF1, UNC13D (known previously as MUNC13-4), STX11, or STXBP2

2. At least five of the eight following criteria based on the guidelines of the Histiocyte Society [Henter et al 2007]:

• Prolonged fever (>7 days)

• Cytopenias affecting two or three of the three lineages in the peripheral blood:

  • Hemoglobin <90 g/L (for infants age <4 weeks: Hgb <100 g/L)

  • Platelets <100x109/L

  • Neutrophils <1.0x109/L

• Splenomegaly

• Hypertriglyceridemia and/or hypofibrinogenemia

  • Fasting triglycerides ≥2.0 mmol/L or >3 SD of the normal value for age

  • Fibrinogen ≤1.5 g/L

• Hemophagocytosis. Non-malignant, mixed lymphohistiocytic accumulation in the reticuloendothelial system; the spleen, liver, lymph nodes, bone marrow, and CNS are most frequently involved.
  
  Note: (1) Hemophagocytosis may not be apparent early in the course of the disease. (2) Hemophagocytosis is seen less often in the liver, where lymphocytic infiltration of the portal areas is typical [Kapelari et al 2005].

• Low or absent natural killer (NK) cell activity. This is common prior to and during active disease, as well as after remission following chemotherapy in a significant proportion of individuals with FHL. Normal or raised NK cell activity has also been observed in some patients, including those with UNC13D mutations [Yamamoto et al 2004, Ishii et al 2005].
  
  Note: (1) NK cell activity norms are per local laboratory reference. (2) The number of circulating NK cells (CD56+/16+) is generally within normal limits. (3) In secondary (acquired or reactive) hemophagocytic lymphohistiocytosis (HLH), NK cell activity has been reported to normalize during remission [Horne et al 2005b, Ishii et al 2005].

• Hyperferritinemia. Serum ferritin concentration ≥500 µg/L (normal 10-290 µg/L)

• High plasma concentrations of soluble CD25 (soluble IL2Rα); ≥2400 U/mL
  
  Note: (1) Normal range depends on test methodology used. (2) Results must be compared to age-matched controls.

In addition, a positive family history of affected sibs and/or parental consanguinity strongly suggests the diagnosis of FHL.

Testing

Protein analysis

• Perforin (the protein product of PRF1) analysis by flow cytometry:

  • In general, absent or markedly decreased perforin protein expression is highly likely to be associated with homozygous or compound heterozygous mutations in PRF1.

  • Of note, normal perforin protein expression may be associated with PRF1 mutations because some missense mutations alter perforin protein function without significantly changing protein expression.

  • If perforin protein expression is normal or increased, UNC13D molecular genetic testing should be considered first.
    
    Note: UNC13D protein expression by western blot analysis from lymphocytes or platelets is available on a research basis only.

• Natural killer (NK) cell activity analysis:

  • Low or absent NK cell activity is an important biomarker in persons with FHL.

  • Low or absent NK cell activity is frequently observed in persons with confirmed biallelic mutations in PRF1, UNC13D, or STX.

  • Normal or raised NK cell activity has also been observed in persons with UNC13D mutations [Yamamoto et al 2004, Ishii et al 2005].

  • In secondary (acquired or reactive) hemophagocytic lymphohistiocytosis (HLH), NK cell activity may fluctuate over time [Horne et al 2005b, Ishii et al 2005].

• NK cell degranulation (CD107a) analysis:

  • NK cell degranulation can be quantified by measurement of upregulation of surface CD107a [Bryceson et al 2007].

  • Defective CD107a surface expression in NK cells is a frequent finding in persons with UNC13D mutations (FHL3) and STX11 mutations (FHL4), in contrast to healthy controls or persons with PRF1 mutations (FHL2) [Marcenaro et al 2006]. Individuals with mutations in STXBP2 (FHL5) also have defective CD107a expression [zur Stadt et al 2009].

• Granzyme B initiates caspase-dependent and caspase-independent apoptotic killing of target cells.

  • In most types of HLH, including perforin deficiency and UNC13D mutations as well as secondary HLH, granzyme B is increased to markedly increased.

  • Increased amounts of granzyme B in persons with HLH do not necessarily indicate normal killing, but most likely indicate that the granules housing the granzymes are not able to mobilize and dock at the cell surface or that the granzyme B lacks sufficient perforin to enter the target cell.

• Soluble IL2R is an indicator of prolonged activation of T cells.

  • As the IL-2 receptor (CD25) forms on the surface of T cells during activation, increasing density of the receptor causes shedding into the plasma.

  • This soluble form of the receptor is useful as a diagnostic criterion of any of the forms of HLH and for monitoring reoccurrence of the disease.

  • It is expected for children to have different expression of CD25 and thus the soluble form of the IL2R in plasma at different ages. Therefore, when interpreting results in children, age-based reference ranges should be used.

• Serum ferritin concentration is a marker for generalized inflammation.

  • It is, however, markedly elevated in the majority of persons with HLH and is a very sensitive indicator of HLH when serum concentrations are markedly increased.

  • Increased serum ferritin concentrations make no distinction between genetic and secondary HLH.

Molecular Genetic Testing

Genes/loci. Five loci (FHL1, FHL2, FHL3, FHL4, FHL5) are associated with familial hemophagocytic lymphohistiocytosis; the five disease subtypes are based on these loci (Table 1). Four genes have been identified and characterized: PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5).

Table 1. Locus Names, Genes, and Mutations Associated with Familial Hemophagocytic Lymphohistiocytosis

View in own window

Locus Name	Gene Symbol	% of FHL	Mutations Identified
FHL1	N/A	Four inbred Pakistani families 1	N/A
FHL2	PRF1	20%-30% 2, 3 worldwide >50% in African-American families 4	Multiple distinctive mutations throughout the entire coding region
FHL3	UNC13D (MUNC13-4)	~20%-30% 3, 5 worldwide	Multiple distinctive mutations throughout the entire coding region and splicing sites
FHL4	STX11	~20% of Turkish/Kurdish families 5, 6 Biallelic mutations identified in other ethnic groups, albeit at a low frequency 7	Three recurrent mutations identified in Turkish/Kurdish families Additional mutations identified in other populations
FHL5	STXBP2	16% in Central Europeans, Turks, and Saudis 8 ~20% in North American patients with FHL 9	Multiple distinctive mutations throughout the entire coding region and splicing sites

1. Linkage analysis using homozygosity mapping in four inbred families of Pakistani descent with hemophagocytic lymphohistiocytosis (HLH) identified a locus (FHL1) on chromosome 9q21.3 22 [Ohadi et al 1999]. No gene in which mutation is causative has been identified at this locus.

2. Voskoboinik et al [2004]

3. Ishii et al [2005]

4. Molleran Lee et al [2004], Lee et al [2006]

5. Zur Stadt et al [2005]

6. Zur Stadt et al [2006]

7. Marsh et al [2010a], Weitzman [personal communication]

8. Zur Stadt et al [2009]

9. Johnson et al [2010]

Other loci. Approximately 30% of North Americans diagnosed with FHL do not have identified mutations in any of the four genes listed (see Table 1). Ménasché et al [2005] provide evidence that additional genetic loci that may be responsible for FHL.

Clinical testing

• Sequence analysis

  • PRF1 (FHL2). Mutations have been identified throughout the entire coding region of PRF1; the majority are missense and nonsense mutations. Sequence analysis detects more than 99% of nucleotide changes, small deletions, and insertions in this region. Mutations in PRF1 as a cause of FHL may be more common (~50%) in individuals of African-American and Hispanic descent [Molleran Lee et al 2004].

  • UNC13D (FHL3). Base substitutions, small insertions, and small deletions have been observed in the coding region and exon/intron boundaries of UNC13D. Sequence analysis detects about 99% of these mutations. Single UNC13D mutations are identified in more than half of individuals with hemophagocytic lymphohistiocytosis (HLH) and UNC13D mutations [Zur Stadt et al 2005], suggesting that a second mutation in (a) UNC13D not accessible by direct sequencing, or in (b) a different HLH-related gene may be responsible for a significant proportion of cases. Based on family studies, there is no evidence of a dominant model of disease in UNC13D.

  • STX11 (FHL4). Sequence analysis of the entire coding region of the STX11 gene detects about 99% of nucleotide changes and small deletions/ insertions in the regions analyzed. However, a whole-gene deletion in STX11 has been reported [Zur Stadt et al 2005] and would not be detected by this methodology.

  • STXBP2 (FHL5). Base substitutions and splice site mutations have been observed in the coding region and exon/intron boundaries of STXBP2. Sequence analysis detects approximately 99% of these mutations. Heterozygous STXBP2 mutations are identified in approximately 50% of individuals with hemophagocytic lymphohistiocytosis (HLH) and STXBP2 mutations [Zhang et al, unpublished data] suggesting that a second mutation in (a) STXBP2 not identifiable by direct sequencing or in (b) a different HLH-related gene may be responsible for a significant proportion of cases. Based on family studies, there is no evidence of a dominant model of disease in UNC13D.

Research testing may be available for:

• Linkage analysis. Of no practical use in individual families, linkage analysis is used as a research tool in evaluating multiple families; generation of a LOD score can direct research studies to the relevant gene for further analysis.

• Deletion/duplication analysis identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), semi-quantitative Southern blot analyses, and array CGH may be used.

Table 2. Summary of Molecular Genetic Testing Used in Familial Hemophagocytic Lymphohistiocytosis

View in own window

Locus Name / Gene Symbol	% of FHL Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
FHL2 / PRF1	20%-30% 2 >50% 3	Sequence analysis	Sequence variants 4	99%	Clinical
FHL3 / UNC13D	20%-30% 2	Sequence analysis	Sequence variants 4	99%	Clinical
FHL4 / STX11	~20% in Turks/Kurds 5 5% in Central Europeans and North Americans 5, 6	Sequence analysis	Sequence variants 4	Uncertain	Clinical
FHL5 / STXBP2	~20% in North Americans 7	Sequence analysis	Sequence variants 4	Uncertain	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Mutations in both PRF1 and UNC13D have been identified with almost equal frequency (~20%-30%) in individuals of Western European and Japanese descent [Göransdotter Ericson et al 2001, Molleran Lee et al 2004, Ishii et al 2005, Lee et al 2006]

3. For individuals of African American descent [Molleran Lee et al 2004]

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Rudd et al [2006], Zur Stadt et al [2006]

6. Marsh et al [2010a]

7. Johnson et al [2010]

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Sequence analysis typically does not detect gross deletions (one- or multiple-exon or whole-gene deletions), insertions, or some complex gene rearrangements. To date, no gross deletions (one- or multiple-exon deletion), insertions, or complex gene rearrangements have been found in either PRF1, UNC13D, or STXBP2. Gross deletions have been reported in STX11.

• Some individuals with FHL have only one abnormal PRF1 or UNC13D allele identified [Zur Stadt et al 2005]; it is possible that the second allele is mutated in the promoter region, deeper in the introns, or in other non-coding regions of the gene, and is thus undetectable by methods in current use. Alternately, a second mutation could be present in a different HLH-related gene for which clinical testing is not currently available.

• Approximately one third of all patients with presumed FHL do not have mutations in PRF1, UNC13D, STX11 or STXBP2; therefore, normal test results do not exclude the diagnosis of FHL.

Testing Strategy

To confirm/establish the diagnosis in a proband

• No unique clinical findings distinguish between FHL2, FHL3, FHL4, and FHL5.

• The recommended genetic workup of a person with HLH is complex and depends on the individual’s race/ethnicity, immunologic test results , and clinical presentation, among other factors.

• Immunologic testing may be useful in directing the genetic workup of a person with HLH, if time is not of the essence.

• PRF1 molecular genetic testing is generally performed first, as more than 60% of African Americans and 20%-30% of whites with FHL have at least one PRF1 mutation.

• UNC13D mutations are rare in African Americans.

• STX11 mutations account for about 1% of the disease-causing mutations in North American patients with HLH and have been identified in most racial/ethnic groups [Marsh et al 2010a].

• STXBP2 mutations account for about 20% of mutations in North American persons with FHL and have been identified in all ethnic/racial groups tested to date. Therefore, testing for STXBP2 is appropriate in any person with suspected FHL and for whom PRF1 and is normal.

• Sequencing of RAB27A should be considered in any individual who presents with HLH in the absence of identified mutations in PRF1, UNC13-D, STX11, or STXBP2. In a preliminary study, about 10% of people with FHL had identified mutations in RAB27A [Johnson et al, unpublished]. These individuals did not show evidence of partial albinism or other pigmentary abnormalities typically reported with Griscelli syndrome type 2. .

• XIAP (formerly BIRC4) and SH2D1A testing should be considered for any male who presents with HLH in the absence of identified mutations in PRF1, UNC13-D, STX11, STXBP2, or RAB27A.

Carrier testing for at-risk relatives requires prior identification of two disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic sibs of a proband requires prior identification of two disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of two disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

PRF1. There are reports of other phenotypes associated with mutations in PRF1; the pathologic consequences are not well defined.

• Clementi et al [2005] reported PRF1 sequence variants in a proportion of persons with lymphoma:

  • Two of four individuals with lymphoma had two PRF1 sequence variants, one of which is c.272C>T (p.Ala91Val), found in about 3% of controls [Molleran Lee et al 2004] and for which the understanding of the pathogenic effect is still controversial (see Molecular Genetics).

  • One person with a PRF1 variant also had a pathogenic mutation in FAS, the classic finding in autoimmune lymphoproliferative syndrome (ALPS).

• Solomou reported an association between PRF1 mutations and acquired aplastic anemia [Solomou et al 2007]. Three of five reported individuals had the c.272 C>T variant described above; a fourth had the c.11G>A (p.Arg4His) variant, a common benign variant in African Americans [Molleran Lee et al 2004]; the fifth had a novel sequence variant. All affected individuals were reported to have absent or markedly reduced perforin expression and absent perforin staining on microscopy; four of the five had hemophagocytosis in bone marrow.

• Chia et al [2009] examined temperature-sensitive PRF1 missense mutations in a subset of individuals with biallelic PRF1 mutations who did not develop hemophagocytic lymphohistiocytosis (HLH) by age ten years. 50% developed at least one hematologic malignancy by adulthood.

• Orilieri et al [2008] reported an association between the p.Asn252Ser (NM_001083116.1:c.755A>G) variant in PRF1 and type 1 diabetes mellitus.

• Cannella et al [2007] described 44 persons with childhood anaplastic large-cell lymphoma, 27.3% of whom had sequence variants in PRF1 compared to 10.2% in the general population (p<.01)

UNC13D. Although other phenotypes have been associated with UNC13D mutations, the disease pathogenic effects are not well studied.

• Hazen et al [2008] reported an African American girl with systemic juvenile idiopathic arthritis (sJIA) who was found to have biallelic mutations in UNC13D.

• Zhang et al [2008] also reported an association between UNC13D mutations and a specific haplotype with sJIA with macrophage activation syndrome (MAS).

• Donn et al [2008] failed to confirm an association between systemic onset sJIA/MAS and sequence variants or specific haplotypes in PRF1, GZMB, UNC13D, or RAB27A

STX11. No other phenotypes are known to be associated with mutations in STX11.

STXBP2. No other phenotypes are known to be associated with mutations in STXBP2.

Natural History

Symptoms of familial hemophagocytic lymphohistiocytosis (FHL) are usually evident within the first few months of life [Aricò et al 1996] and may even develop in utero [Malloy et al 2004]. However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases [Aricò et al 1996, Allen et al 2001, Clementi et al 2002].

FHL usually presents in childhood as an acute illness with prolonged fever (>7 days) and hepatosplenomegaly. Rash and lymphadenopathy are less frequently observed. Cytopenias (anemia, thrombocytopenia, neutropenia, and leukopenia), liver dysfunction (elevated serum aminotransferase and bilirubin), neurologic dysfunction (irritability or lethargy, hypotonia or hypertonia, seizures, ataxia, and cranial nerve involvement presenting as nerve palsy and blindness), and bone marrow hemophagocytosis complete the typical presentation of the disorder.

Oftentimes FHL is associated with documented infection, especially herpes viral infections [Imashuku et al 2005].

Common signs and symptoms

• Fever is frequently indolent and protracted but may decline spontaneously. In a few children, it may develop late in the course of the disease.

• Splenomegaly and hepatomegaly are usually pronounced and progressive.

• Skin rash is uncharacteristic, transient, and often associated with high fever.

• Lymph node enlargement develops in fewer than 50% of individuals but may occasionally be significant.

• Neurologic abnormalities may be present at initial clinical presentation or in many instances may develop later in the course of the disease. The presentation may include irritability, bulging fontanel in infants, neck stiffness, hypotonia, hypertonia, and convulsions. Cranial nerve VI and/or VII palsy, ataxia, hemiplegia, quadriplegia, blindness, and coma may occur, as well as nonspecific signs of increased intracranial pressure.
  
  On examination of CSF, elevated protein, increased number of mononuclear cells, and occasionally hemaphagocytosis are characteristic findings.
  
  MRI may show gross demyelination or failure of normal myelination during the first year of life. MRI may also show multifocal inflammation involving gray and white matter. Bleeding, generalized atrophy, and brain edema may be observed. Hyperdense areas on CT may be falsely interpreted as calcifications.

• Life expectancy. Median survival in typical FHL, without treatment, is less than two months. Progressive hemophagocytic lymphohistiocytosis (HLH) and invasive infection account for the majority of deaths in untreated children [Sung et al 2002]. Although children can survive without hematopoietic stem cell transplantation (HSCT) [Henter et al 2002], the five-year survival of children treated with chemotherapy alone was only 10.1% in one large series. Allogeneic hematopoietic stem cell transplantation is potentially curative (see Management).

Genotype-Phenotype Correlations

Both Feldmann and Molleran Lee documented poor correlation between phenotype and genotype in FHL2 with different classes of PRF1 mutations [Feldmann et al 2002, Molleran Lee et al 2004]. However, the number of cases in any one series is too limited to draw definitive conclusions.

In general, age of onset tends to be younger in those with nonsense versus missense PRF1 mutations [Clementi et al 2002, Feldmann et al 2002, Zur Stadt et al 2006, Trizzino et al 2008]. In particular, homozygosity for the PRF1 p.Leu17ArgfsX34 mutation, commonly seen in affected individuals of African descent, is associated with an earlier onset (median age 3 months; range 1.5-10 months) compared to other PRF1 missense mutations [Lee et al 2006]. However, affected individuals within the same family may develop evidence of disease at different ages [Allen et al 2001].

In a study of 35 Japanese patients, Ishii concluded that persons with PRF1 mutations had earlier disease onset than those with UNC13D mutations or FHL for whom no genetic basis was established.

Deficient NK cell activity persisted after chemotherapy in all persons with FHL2, whereas some individuals with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of NK cell activity during remission.

Alloantigen-specific CTL-mediated cytotoxicity was deficient in individuals with FHL2 with PRF1 nonsense mutations and very low in individuals with FHL3, but was only moderately reduced in individuals with FHL2 with PRF1 missense mutations [Ishii et al 2005].

Ueda found that the incidence of deficient NK cell activity was higher in those with PRF1 mutations than in those with UNC13D or uncharacterized disease-causing mutations. In addition, nonsense mutations in PRF1 were associated with significantly higher levels of ferritin and soluble Il2Ra than observed in other subtypes of FHL [Ueda et al 2006].

Horne et al [2008] concluded that persons with mutations in PRF1 had earlier onset of symptoms than those with STX11 mutations and that those with STX11 mutations had a somewhat milder disease course than those with PRF1 mutations, UNC13D mutations, or uncharacterized mutations. Rudd et al [2006] reported long remissions without specific treatments in some individuals with STX11 mutations. They also reported a higher than expected incidence of psychomotor retardation and myelodysplastic syndrome or acute myelogenous leukemia in their small group with STX11 mutations. Marsh et al [2010b] noted that missense mutations in STX11 were associated with later onset and preserved NK cell function compared to nonsense mutation in STX11, which resulted in abrogation of NK cell function.

Zur Stadt et al [2009] reported later age at onset in persons with the common c.1247-1G>C mutation in STXBP2 both in the homozygous and compound heterozygous states and an earlier age at onset in individuals with various missense mutations. In contrast, the authors have observed onset in infancy in several children with the c.1247-1G>C mutation [Author, unpublished data] as well as considerable discordance in phenotype and age at onset between siblings with the same genotype [Author, unpublished data].

Nomenclature

Classification. The widely used modern classification of histiocytic disorders was proposed by the Histiocyte Society in 1987 and refined in 1998.

The Writing Group of the Histiocyte Society recommended a division of the histiocytic disorders into three classes:

• Dendritic cell-related disorders, of which Langerhan's cell histiocytosis (LCH) is by far the most common

• Macrophage-related disorders (including hemophagocytic lymphohistiocytosis [HLH])

• Malignant disorders

Naming

• FHL was once called familial erythrophagocytic lymphohistiocytosis (FEL).

• FHL occurring in conjunction with identified viral infections was termed VAHS (virus-associated hemophagocytic syndrome); however, it is now recognized that FHL may be triggered by viral infection.

• The general term hemophagocytic lymphohistiocytosis (HLH) encompasses all forms of the disorder.

Prevalence

The estimated prevalence of FHL is 1:50,000 births [Henter et al 1998] with equal gender distribution.

A common PRF1 mutation, p.Leu17ArgfsX34, has been observed at a high frequency in individuals with FHL in the African American population [Lee et al 2006].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with familial hemophagocytic lymphohistiocytosis (FHL), the following evaluations are recommended:

• Physical examination to evaluate for rashes, lymphadenopathy, hepatosplenomegaly, and neurologic dysfunction

• Evaluation of blood and bone marrow compartments (CBC and BM biopsy)

• Determination of the extent of liver involvement by measuring serum concentration of transaminases, bilirubin, triglycerides, sodium, and lactate dehydrogenase

• Identification of potential infectious co-factors, especially viral infection or reactivation, which would require specific treatment

• Establishing the presence or extent of CNS involvement by evaluating the CSF and performing neuroimaging and neuropsychological assessment

• Testing of NK cell activity, intracellular perforin and granzyme B expression, and CD107a mobilization if these tests are available

• Evaluation of inflammatory factors such as serum concentrations of ferritin, sIL2Rα, and other cytokines

• Evaluation and monitoring of PT, PTT, and fibrinogen

• Genetic testing for PRF1, UNC13D, STX11 and STXBP2 mutations

• Consideration of testing for RAB27A mutations in any individual with HLH, even with no evidence of depigmentation

• Consideration of testing for XIAP (formerly BIRC4) and SH2D1A mutations in any male with HLH

• Collection of materials for future characterization of underlying genetic defects, most significantly in individuals with terminal disease

Treatment of Manifestations

HLH-1994. To improve survival, in 1994 the Histiocyte Society initiated a prospective international collaborative therapeutic study. It combined chemotherapy and immunotherapy (etoposide, corticosteroids, cyclosporine A, and intrathecal methotrexate for individuals with CNS diseases), followed by HSCT in persistent, recurring, and/or familial disease. Although HLH-94 was primarily designed for the treatment of FHL, it was also open to all individuals with non-familial HLH.

HLH-2004. The HLH-2004 protocol was opened on January 1, 2004, and was designed for individuals with FHL and non-familial HLH. This protocol was based on the HLH-94 protocol with minor therapeutic modifications such as initiation of cyclosporine from onset of induction therapy.

The two protocols developed by the Histiocyte Society are available from the Histiocyte Society Web site.

Given the poor prognosis of individuals with HLH without prompt and effective treatment, it is recommended that treatment be initiated when clinical suspicion is high, even if all recommended studies are incomplete. Treatment involves:

• Chemotherapy and immunotherapy to achieve a clinically stable resolution prior to HSCT

• Antibiotics or antiviral agents to treat or prevent infections that may have triggered the exaggerated inflammatory response

• Allogeneic HSCT, the only curative therapy, which should be undertaken in children with confirmed FHL as early in life as feasible: (a) presymptomatically if status is confirmed by family history of clinical HLH or (b) in simplex cases (i.e., a single occurrence in a family) after achievement of clinical remission.
  
  Use of HSCT has improved survival significantly [Henter et al 2002]. Three-year-survival in children who received HLH-94 therapy was approximately 64% [Horne et al 2005a]. Long-term follow-up reveals that following HSCT most children treated early in the disease course return to a normal or near-normal quality of life. Brain atrophy secondary to steroid therapy often identified on neuroimaging studies during the acute phase of HLH gradually resolves after HSCT [Shuper et al 1998]. However, children who experienced serious CNS involvement may have irreversible neurologic problems and learning disabilities despite adequate disease control following HSCT.

Prevention of Primary Manifestations

HSCT is the only curative therapy and should be undertaken in children with confirmed familial HLH as early in life as possible.

Surveillance

The following are recommended annually after HSCT:

• Neuropsychological evaluation

• Regular follow-up by transplant specialists to monitor for late complications relating to growth and hormone function

Evaluation of Relatives at Risk

Molecular genetic testing of at-risk sibs for the family-specific mutations is appropriate to identify those who are affected before symptoms occur for the purpose of early medical management and consideration of presymptomatic bone marrow transplantation.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

The treatment of FHL is also the most effective treatment for secondary HLH and the hemophagocytic syndrome associated with other inherited immunodeficiencies.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Familial hemophagocytic lymphohistiocytosis (FHL) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with FHL are obligate heterozygotes (carriers).

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible if the two disease-causing mutations in the family are known.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for FHL2, FHL3, and FHL4 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis at 16 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Allen M, De Fusco C, Legrand F, Clementi R, Conter V, Danesino C, Janka G, Aricò M. Familial hemophagocytic lymphohistiocytosis: how late can the onset be? Haematologica. 2001;86:499–503. [PubMed: 11410413]
2. Aricò M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, Martinetti M, Rusca MP. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10:197–203. [PubMed: 8637226]
3. Arneson LN, Brickshawana A, Segovis CM, Schoon RA, Dick CJ, Leibson PJ. Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J Immunol. 2007;179:3397–401. [PubMed: 17785771]
4. Bryceson YT, Rudd E, Zheng C, Edner J, Ma D, Wood SM, Bechensteen AG, Boelens JJ, Celkan T, Farah RA, Hultenby K, Winiarski J, Roche PA, Nordenskjöld M, Henter JI, Long EO, Ljunggren HG. Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood. 2007;110:1906–15. [PMC free article: PMC1976360] [PubMed: 17525286]
5. Busiello R, Fimiani G, Miano MG, Aricò M, Santoro A, Ursini MV, Pignata C. A91V perforin variation in healthy subjects and FHLH patients. Int J Immunogenet. 2006;33:123–5. [PubMed: 16611257]
6. Cannella S, Santoro A, Bruno G, Pillon M, Mussolin L, Mangili G, Rosolen A, Aricò M. Germline mutations of the perforin gene are a frequent occurrence in childhood anaplastic large cell lymphoma. Cancer. 2007;109:2566–71. [PubMed: 17477373]
7. Chia J, Yeo KP, Whisstock JC, Dunstone MA, Trapani JA, Voskoboinik I. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc Natl Acad Sci U S A. 2009;106:9809–14. [PMC free article: PMC2701033] [PubMed: 19487666]
8. Clementi R, Emmi L, Maccario R, Liotta F, Moretta L, Danesino C, Aricó M. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002;100:2266–7. [PubMed: 12229880]
9. Clementi R, Locatelli F, Dupré L, Garaventa A, Emmi L, Bregni M, Cefalo G, Moretta A, Danesino C, Comis M, Pession A, Ramenghi U, Maccario R, Aricò M, Roncarolo MG. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood. 2005;105:4424–8. [PubMed: 15728124]
10. Clementi R, zur Stadt U, Savoldi G, Varoitto S, Conter V, De Fusco C, Notarangelo LD, Schneider M, Klersy C, Janka G, Danesino C, Aricò M. Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis. J Med Genet. 2001;38:643–6. [PMC free article: PMC1734943] [PubMed: 11565555]
11. Côte M, Ménager MM, Burgess A, Mahlaoui N, Picard C, Schaffner C, Al-Manjomi F, Al-Harbi M, Alangari A, Le Deist F, Gennery AR, Prince N, Cariou A, Nitschke P, Blank U, El-Ghazali G, Ménasché G, Latour S, Fischer A, de Saint Basile G. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest. 2009;119:3765–73. [PMC free article: PMC2786810] [PubMed: 19884660]
12. Donn R, Ellison S, Lamb R, Day T, Baildam E, Ramanan AV. Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2008;58:869–74. [PMC free article: PMC2675009] [PubMed: 18311812]
13. Feldmann J, Le Deist F, Ouachée-Chardin M, Certain S, Alexander S, Quartier P, Haddad E, Wulffraat N, Casanova JL, Blanche S, Fischer A, de Saint Basile G. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. 2002;117:965–72. [PubMed: 12060139]
14. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis. 2000;6:601–8. [PMC free article: PMC2640913] [PubMed: 11076718]
15. Göransdotter Ericson K, Fadeel B, Nilsson-Ardnor S, Söderhäll C, Samuelsson A, Janka G, Schneider M, Gürgey A, Yalman N, Révész T, Egeler R, Jahnukainen K, Storm-Mathiesen I, Haraldsson A, Poole J, de Saint Basile G, Nordenskjöld M, Henter J. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am J Hum Genet. 2001;68:590–7. [PMC free article: PMC1274472] [PubMed: 11179007]
16. Hadchouel M, Prieur AM, Griscelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection. J Pediatr. 1985;106:561–6. [PubMed: 3981309]
17. Hazen MM, Woodward AL, Hofmann I, Degar BA, Grom A, Filipovich AH, Binstadt BA. Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2008;58:567–70. [PubMed: 18240215]
18. Henter JI, Aricò M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12:417–33. [PubMed: 9561910]
19. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31. [PubMed: 16937360]
20. Henter JI, Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S, Webb D, Janka G. Histocyte Society; Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367–73. [PubMed: 12239144]
21. Horne A, Janka G, Maarten Egeler R, Gadner H, Imashuku S, Ladisch S, Locatelli F, Montgomery SM, Webb D, Winiarski J, Filipovich AH, Henter JI. Histiocyte Society; Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis. Br J Haematol. 2005a;129:622–30. [PubMed: 15916685]
22. Horne A, Ramme KG, Rudd E, Zheng C, Wali Y, al-Lamki Z, Gürgey A, Yalman N, Nordenskjöld M, Henter JI. Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J Haematol. 2008;143:75–83. [PubMed: 18710388]
23. Horne A, Zheng C, Lorenz I, Löfstedt M, Montgomery SM, Janka G, Henter JI, Marion Schneider E. Subtyping of natural killer cell cytotoxicity deficiencies in haemophagocytic lymphohistocytosis provides therapeutic guidance. Br J Haematol. 2005b;129:658–66. [PubMed: 15916689]
24. Imashuku S, Hibi S, Ohara T, Iwai A, Sako M, Kato M, Arakawa H, Sotomatsu M, Kataoka S, Asami K, Hasegawa D, Kosaka Y, Sano K, Igarashi N, Maruhashi K, Ichimi R, Kawasaki H, Maeda N, Tanizawa A, Arai K, Abe T, Hisakawa H, Miyashita H, Henter JI. Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society. Blood. 1999;93:1869–74. [PubMed: 10068659]
25. Imashuku S, Tabata Y, Teramura T, Hibi S. Treatment strategies for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Leuk Lymphoma. 2000;39:37–49. [PubMed: 10975382]
26. Imashuku S, Ueda I, Teramura T, Mori K, Morimoto A, Sako M, Ishii E. Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients. Eur J Pediatr. 2005;164:315–9. [PubMed: 15731905]
27. Ishii E, Ueda I, Shirakawa R, Yamamoto K, Horiuchi H, Ohga S, Furuno K, Morimoto A, Imayoshi M, Ogata Y, Zaitsu M, Sako M, Koike K, Sakata A, Takada H, Hara T, Imashuku S, Sasazuki T, Yasukawa M. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood. 2005;105:3442–8. [PubMed: 15632205]
28. Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998;12:435–44. [PubMed: 9561911]
29. Johnson J, Kissell D, Huizenga K, Filipovich A, Jordan M, Zur Stadt U, Zhang K. STXBP2 (Munc18) mutations in North American patients with familial hemophagocytic lymphohistiocytosis. Abstract. Montréal, Quebec, Canada: ASPHO 23rd Annual Meeting, 2010. Available at www.aspho.org.
30. Kapelari K, Fruehwirth M, Heitger A, Königsrainer A, Margreiter R, Simma B, Offner FA. Loss of intrahepatic bile ducts: an important feature of familial hemophagocytic lymphohistiocytosis. Virchows Arch. 2005;446:619–25. [PubMed: 15906086]
31. Katano H, Ali MA, Patera AC, Catalfamo M, Jaffe ES, Kimura H, Dale JK, Straus SE, Cohen JI. Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood. 2004;103:1244–52. [PubMed: 14576041]
32. Lee SM, Sumegi J, Villanueva J, Tabata Y, Zhang K, Chakraborty R, Sheng X, Clementi R, de Saint Basile G, Filipovich AH. Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation. J Pediatr. 2006;149:134–7. [PubMed: 16860143]
33. Ma X, Okamura A, Yosioka M, Ishiguro N, Kikuta H, Kobayashi K. No mutations of SAP/SH2D1A/DSHP and perforin genes in patients with Epstein-Barr virus-associated hemophagocytic syndrome in Japan. J Med Virol. 2001;65:358–61. [PubMed: 11536244]
34. Malloy CA, Polinski C, Alkan S, Manera R, Challapalli M. Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol. 2004;24:458–60. [PubMed: 15224121]
35. Marcenaro S, Gallo F, Martini S, Santoro A, Griffiths GM, Aricó M, Moretta L, Pende D. Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. Blood. 2006;108:2316–23. [PubMed: 16778144]
36. Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, Bleesing JJ, Zhang K, Filipovich AH. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. 2010a;116:1079–82. [PMC free article: PMC2938130] [PubMed: 20489057]
37. Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, Bleesing JJ, Filipovich AH, Zhang K. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer. 2010b;55:134–40. [PubMed: 20486178]
38. Meeths M, Bryceson YT, Rudd E, Zheng C, Wood SM, Ramme K, Beutel K, Hasle H, Heilmann C, Hultenby K, Ljunggren HG, Fadeel B, Nordenskjöld M, Henter JI. Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr Blood Cancer. 2010;54:563–72. [PubMed: 19953648]
39. Ménager M, de Saint Basile G. Secretory cytotoxic granule maturation is required to their lytic contents excretion. Med Sci (Paris). 2007;23:473–4. [PubMed: 17502060]
40. Ménager MM, Ménasché G, Romao M, Knapnougel P, Ho CH, Garfa M, Raposo G, Feldmann J, Fischer A, de Saint Basile G. Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nat Immunol. 2007;8:257–67. [PubMed: 17237785]
41. Ménasché G, Feldmann J, Fischer A, de Saint Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. 2005;203:165–79. [PubMed: 15661029]
42. Ménasché G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S, Wulffraat N, Bianchi D, Fischer A, Le Deist F, de Saint Basile G. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000;25:173–6. [PubMed: 10835631]
43. Molleran Lee S, Villanueva J, Sumegi J, Zhang K, Kogawa K, Davis J, Filipovich AH. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet. 2004;41:137–44. [PMC free article: PMC1735659] [PubMed: 14757862]
44. Muiesan P, Dhawan A, Wendon J, Mufti GJ, O'Grady J, Rela M, Heaton ND. Hemophagocytosis: a potential complication in small bowel transplantation. Transplantation. 1998;66:794–6. [PubMed: 9771844]
45. Neeft M, Wieffer M, de Jong AS, Negroiu G, Metz CH, van Loon A, Griffith J, Krijgsveld J, Wulffraat N, Koch H, Heck AJ, Brose N, Kleijmeer M, van der Sluijs P. Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. Mol Biol Cell. 2005;16:731–41. [PMC free article: PMC545907] [PubMed: 15548590]
46. Normand NJ, Lehman TJA, Elkon KB, Onel KB. Lower expression of perforin in CD8+ T cells of patients with systemic onset juvenile rheumatoid arthritis. Arthritis Rheum. 2000;43:5406.
47. Ohadi M, Lalloz MR, Sham P, Zhao J, Dearlove AM, Shiach C, Kinsey S, Rhodes M, Layton DM. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet. 1999;64:165–71. [PMC free article: PMC1377714] [PubMed: 9915955]
48. Orilieri E, Cappellano G, Clementi R, Cometa A, Ferretti M, Cerutti E, Cadario F, Martinetti M, Larizza D, Calcaterra V, D'Annunzio G, Lorini R, Cerutti F, Bruno G, Chiocchetti A, Dianzani U. Variations of the perforin gene in patients with type 1 diabetes. Diabetes. 2008;57:1078–83. [PubMed: 18198357]
49. Rigaud S, Fondanèche MC, Lambert N, Pasquier B, Mateo V, Soulas P, Galicier L, Le Deist F, Rieux-Laucat F, Revy P, Fischer A, de Saint Basile G, Latour S. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444:110–4. [PubMed: 17080092]
50. Rudd E, Göransdotter Ericson K, Zheng C, Uysal Z, Ozkan A, Gürgey A, Fadeel B, Nordenskjöld M, Henter JI. Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J Med Genet. 2006;43:e14. [PMC free article: PMC2563216] [PubMed: 16582076]
51. Shuper A, Attias D, Kornreich L, Zaizov R, Yaniv I. Familial hemophagocytic lymphohistiocytosis: improved neurodevelopmental outcome after bone marrow transplantation. J Pediatr. 1998;133:126–8. [PubMed: 9672524]
52. Solomou EE, Gibellini F, Stewart B, Malide D, Berg M, Visconte V, Green S, Childs R, Chanock SJ, Young NS. Perforin gene mutations in patients with acquired aplastic anemia. Blood. 2007;109:5234–7. [PMC free article: PMC1890825] [PubMed: 17311987]
53. Stéphan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur AM. Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases. Clin Exp Rheumatol. 1993;11:451–6. [PubMed: 8403593]
54. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint Basile G, Kumar V. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286:1957–9. [PubMed: 10583959]
55. Sung L, King SM, Carcao M, Trebo M, Weitzman SS. Adverse outcomes in primary hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2002;24:550–4. [PubMed: 12368693]
56. Trambas C, Gallo F, Pende D, Marcenaro S, Moretta L, De Fusco C, Santoro A, Notarangelo L, Aricò M, Griffiths GM. A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin. Blood. 2005;106:932–7. [PubMed: 15741215]
57. Trizzino A, zur Stadt U, Ueda I, Risma K, Janka G, Ishii E, Beutel K, Sumegi J, Cannella S, Pende D, Mian A, Henter JI, Griffiths G, Santoro A, Filipovich A, Aricò M. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations. J Med Genet. 2008;45:15–21. [PubMed: 17873118]
58. Ueda H, Kashiwamura S, Sekiyama A, Ogura T, Gamachi N, Okamura H. Production of IL-13 in spleen cells by IL-18 and IL-12 through generation of NK-like cells. Cytokine. 2006;33:179–87. [PubMed: 16549365]
59. Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A, Grom AA. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther. 2005;7:R30–7. [PMC free article: PMC1064882] [PubMed: 15642140]
60. Voskoboinik I, Sutton VR, Ciccone A, House CM, Chia J, Darcy PK, Yagita H, Trapani JA. Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood. 2007;110:1184–90. [PubMed: 17475905]
61. Voskoboinik I, Thia MC, De Bono A, Browne K, Cretney E, Jackson JT, Darcy PK, Jane SM, Smyth MJ, Trapani JA. The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J Exp Med. 2004;200:811–6. [PMC free article: PMC2211966] [PubMed: 15365097]
62. Voskoboinik I, Thia MC, Trapani JA. A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood. 2005;105:4700–6. [PubMed: 15755897]
63. Yamamoto K, Ishii E, Sako M, Ohga S, Furuno K, Suzuki N, Ueda I, Imayoshi M, Yamamoto S, Morimoto A, Takada H, Hara T, Imashuku S, Sasazuki T, Yasukawa M. Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes. J Med Genet. 2004;41:763–7. [PMC free article: PMC1735600] [PubMed: 15466010]
64. Zhang K, Biroschak J, Glass DN, Thompson SD, Finkel T, Passo MH, Binstadt BA, Filipovich A, Grom AA. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum. 2008;58:2892–6. [PMC free article: PMC2779064] [PubMed: 18759271]
65. Zhang K, Johnson JA, Biroschak J, Villanueva J, Lee SM, Bleesing JJ, Risma KA, Wenstrup RJ, Filipovich AH. Familial haemophagocytic lymphohistiocytosis in patients who are heterozygous for the A91V perforin variation is often associated with other genetic defects. Int J Immunogenet. 2007;34:231–3. [PubMed: 17627755]
66. Ziegler SF, Mortrud MT, Swartz AR, Baker E, Sutherland GR, Burmeister M, Mulligan JT. Molecular characterization of a nonneuronal human UNC18 homolog. Genomics. 1996;37:19–23. [PubMed: 8921365]
67. zur Stadt U, Beutel K, Kolberg S, Schneppenheim R, Kabisch H, Janka G, Hennies HC. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat. 2006;27:62–8. [PubMed: 16278825]
68. zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, Strauss J, Kasper B, Nürnberg G, Becker C, Maul-Pavicic A, Beutel K, Janka G, Griffiths G, Ehl S, Hennies HC. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85:482–92. [PMC free article: PMC2756548] [PubMed: 19804848]
69. Zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, Kabisch H, Schneppenheim R, Nürnberg P, Janka G, Hennies HC. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14:827–34. [PubMed: 15703195]

Revision History

• 7 September 2010 (cd) Revision: sequence analysis of STXBP2 for familial hemophagocytic lymphohistiocytosis 5 available clinically

• 11 March 2010 (me) Comprehensive update posted live

• 9 March 2007 (cd) Revision: clinical testing and prenatal diagnosis available for FHL4

• 22 March 2006 (me) Review posted to live Web site

• 21 April 2005 (jj, af, rw) Original Submission