Clinical characteristics.

Familial hemophagocytic lymphohistiocytosis (fHLH), defined as the presence of biallelic pathogenic variants in one of four genes (PRF1, STX11, STXBP2, or UNC13D), is an immune deficiency characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs including the bone marrow, liver, spleen, and brain. Familial HLH usually presents as an acute illness with prolonged and high fever, cytopenias, and hepatosplenomegaly. Rash and lymphadenopathy are less common. Individuals with fHLH may also exhibit liver dysfunction and neurologic abnormalities. Although manifestations of fHLH are usually evident within the first months or years of life and may develop in utero, symptomatic presentation can occur throughout childhood and into adulthood. Median survival in untreated infants with fHLH who develop active disease is less than two months after onset of manifestations; progressive manifestations of fHLH, organ dysfunction, invasive infection, and bleeding account for the majority of deaths. Use of etoposide-containing regimens such as the HLH-94 and HLH-2004 protocols followed by allogeneic hematopoietic stem cell transplantation (HSCT) has improved survival.

Diagnosis/testing.

The diagnosis of fHLH is established in a proband with suggestive findings by identification of either biallelic pathogenic variants in one of four genes (PRF1, STX11, STXBP2, or UNC13D) or (rarely) a gain-of-function heterozygous variant in STXBP2.

Management.

Treatment of manifestations: Management should be coordinated by or in consultation with a multidisciplinary team with expertise in fHLH, including specialists in hematology/oncology, bone marrow and stem cell transplantation, immunology, rheumatology, infectious diseases, critical care, neurology, nephrology, pathology, and medical genetics. Treatment regimens focus on use of chemoimmunotherapy to treat active disease followed by allogeneic HSCT, the only curative therapy. Supportive care that should accompany treatment with chemoimmunotherapy and allogenic HSCT includes antibiotics or antiviral agents to treat or prevent infections, and antipyretics, intravenous fluids, electrolyte replacement, transfusion of packed red blood cells and platelets, infusions of immunoglobulin, fresh frozen plasma, and/or cryoprecipitate.

Surveillance: Individuals responding to treatment and HSCT are technically not at risk for other organ system involvement; thus, surveillance focuses on potential complications of fHLH while fHLH is active, such as bleeding, hypotension, respiratory distress, neurologic complications, malnutrition, infection, liver, or other organ failure.

Agents/circumstances to avoid: Live vaccines; exposure to infections; acetaminophen in persons with liver failure; nonsteroidal anti-inflammatory drugs in persons with thrombocytopenia; areas of construction or soil manipulation (which increase the risk for fungal infection in individuals with neutropenia); transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT.

Evaluation of relatives at risk: It is appropriate to identify – before symptoms occur –those at-risk sibs who have the family-specific pathogenic variants so that they can be monitored and preemptive HSCT considered (particularly during febrile episodes) for development of manifestations of active disease. Any manifestations of possible active disease should prompt more detailed evaluation and referral to a clinician with expertise in fHLH.

Genetic counseling.

Familial HLH is inherited in an autosomal recessive manner. (Autosomal dominant inheritance of STXBP2-fHLH is suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants. Autosomal dominant inheritance will not be discussed further in this section.)

If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants. Once the fHLH-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Familial HLH (fHLH) should be suspected in young children with the following clinical findings, supportive laboratory findings, and suggestive family history.

Establishing the Diagnosis

The diagnosis of fHLH is established in a proband with Suggestive Findings by identification of either biallelic pathogenic (or likely pathogenic) variants in one of the following genes: PRF1, STX11, STXBP2, UNC13D (see Table 2), or (rarely) a gain-of-function heterozygous variant in STXBP2 (see Molecular Genetics).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (VUS) in one of the four genes in Table 2 (or identification of one pathogenic variant and one VUS in the same gene) itself does not establish or rule out the diagnosis. Correlation with clinical and functional data is needed to support the genetic diagnosis.

The options for molecular genetic testing include use of a multigene panel or genomic testing.

• A multigene panel that includes PRF1, STX11, STXBP2, UNC13D, and other genes of interest as outlined in Differential Diagnosis can be used. Note: (1) Use of a multigene panel limits identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Familial hemophagocytic lymphohistiocytosis (fHLH) is an immune deficiency characterized by the overactivation and excessive proliferation of T lymphocytes and macrophages, leading to infiltration and damage of organs including bone marrow, liver, spleen, and brain [Zhang et al 2011]. Familial HLH usually presents as an acute illness with prolonged and high fever, cytopenias, and hepatosplenomegaly. Rash and lymphadenopathy are less common. Affected individuals may also exhibit liver dysfunction and neurologic abnormalities.

Often fHLH-associated inflammation is triggered by infection, especially with herpes viruses, but it can manifest after infection with many other pathogens, or it can occur in the absence of any detectable infection [Canna & Marsh 2020].

Although manifestations of fHLH are usually evident within the first months or years of life and may develop in utero [Malloy et al 2004], symptomatic presentation throughout childhood and into adulthood has been observed [Zhang et al 2011, Sieni et al 2012].

Except for individuals with STXBP2-fHLH, the manifestations and general treatment options do not differ by the associated fHLH gene (see Genotype-Phenotype Correlations).

Familial HLH has not been well studied in adults. The disease may present with acute onset of full-blown HLH manifestations or as a more insidious illness with recurrent bouts of nonspecific features. HLH in adults is often triggered by infection or malignancy [Birndt et al 2020]. The course of disease and life expectancy are not well studied in adults with fHLH. A systematic review of mortality in critically ill adults with HLH (not genetically verified as fHLH) reported an overall mortality of 57.8% [Knaak et al 2020].

Common Signs and Symptoms

Fever may be high and protracted. In a few children, it may develop later in the disease course.

Splenomegaly and hepatomegaly are usually pronounced and progressive. It is difficult to know if splenomegaly affects splenic function, as low platelet counts could also result from bone marrow involvement from the disease process itself.

Liver involvement. Affected individuals often present with elevated transaminases (AST, ALT, and GGT), lactate dehydrogenase, and bilirubin with or without hepatomegaly. Hepatic dysfunction may manifest with abnormal markers of coagulation, such as elevated PT/PTT and D-dimers. Liver involvement can range in severity from mild involvement to acute liver failure.

Skin rash may be seen, often in association with high fever. It is often nonspecific and takes the form of pruritic morbilliform eruptions, although erythroderma has also been described [Morrell et al 2002, Griffin et al 2020].

Lymph node enlargement may be seen in some individuals.

Neurologic abnormalities may be an initial manifestation or – in many instances – may develop later in the disease course. 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 [Horne et al 2008b].

Other organ system involvement. In severe cases, affected individuals may present with or progress to multisystem organ failure manifesting with hypotension, pulmonary dysfunction often requiring intubation, and renal dysfunction leading to fluid overload.

Individuals with STXBP2-fHLH may present with colitis, which can manifest as abdominal pain, vomiting, chronic diarrhea, failure to thrive, and inflammation of the lips and oral mucosa [Meeths et al 2010].

Life expectancy. Median survival in untreated infants with fHLH who develop active disease is less than two months after onset of manifestations. In these infants, progressive manifestations of fHLH, organ dysfunction, invasive infection, and bleeding account for the majority of deaths.

Use of etoposide-containing regimens such as the HLH-94 and HLH-2004 protocols followed by allogeneic hematopoietic stem cell transplantation (HSCT) has improved survival (see Management). Bergsten et al [2017] reported a 59% five-year probability of survival of children with fHLH who were treated with the HLH-2004 protocol and HSCT.

Phenotype Correlations by Gene

PRF1. Individuals with PRF1-fHLH appear to have an earlier age of onset than individuals with UNC13D-fHLH [Sieni et al 2011].

STX11. Individuals with STX11-fHLH appear to have a later onset of manifestations and a milder disease course than those with PRF1-fHLH and UNC13D-fHLH [Horne et al 2008a, Kram et al 2019].

STXBP2. Approximately one third of individuals have additional clinical findings including colitis, bleeding disorders, and hypogammaglobulinemia [Meeths et al 2010].

Although the age of onset in individuals with STXBP2-fHLH tends to be later than in individuals with PRF1-fHLH or UNC13D-fHLH, age of onset is variable even within the same family [Meeths et al 2010].

UNC13D. CNS involvement may be more common in individuals with UNC13D-fHLH than those with PRF1-fHLH [Sieni et al 2011].

Genotype-Phenotype Correlations

Hypomorphic pathogenic variants in PRF1, MUNC13-4, and STXBP2 have been associated with mild and late-onset (i.e., adult) fHLH [Zhang et al 2011].

PRF1. The PRF1 c.272C>T (p.Ala91Var) variant has been reported in individuals with late-onset adult fHLH [Carvelli et al 2020, Miller et al 2020].

Nonsense variants are associated with younger age at onset than missense variants [Trizzino et al 2008].

UNC13D. Biallelic truncating variants are associated with younger age at onset than missense variants [Sieni et al 2011].

Nomenclature

Prior to discovery of the genes associated with fHLH, a locus-based naming system was used to identify the distinct genetic causes of this disorder (Table 3). Following discovery of the associated genes, a gene-based naming system was adopted.

Prevalence

The estimated prevalence of familial HLH (fHLH) is 1.8 per 100,000 births in Sweden with equal male/female distribution [Meeths et al 2015].

The estimated prevalence of the HLH phenotype in Texas has been calculated as 1:100,000 children younger than age 18 years [Niece et al 2010].

Ethnic groups with gene-specific pathogenic variants include the following:

• PRF1. The following pathogenic variants have been reported in particular ethnic groups:
  • c.50delT (p.Leu17ArgfsTer34) has been observed at a high frequency in individuals with fHLH in the African American population. There appears to be a founder effect for this variant: extent of haplotype sharing and variability of microsatellite alleles in chromosomes with this variant suggest that the variant arose approximately 1,000 to 4,000 years ago and is mostly restricted to individuals of African descent due to a founder effect [Lee et al 2006].
  • c.1090-1091delCT (p.Leu364fsTer) has been identified only in individuals of Japanese descent [Trizzino et al 2008].
  • c.1122G>A (p.Trp374Ter) has a high prevalence in Turkish individuals [Zur Stadt et al 2006].
• STX11. Initially, most individuals with STX11 variants were from Middle Eastern regions and of Turkish, Kurdish, or Pakistani descent. Since these initial reports, individuals from other regions and ethnicities have been reported [Marsh et al 2010].
• UNC13D. The following pathogenic variants have been reported in particular ethnic groups:
  • c.118-308C>T, the most frequent cause of disease in Koreans, is also common in affected individuals of northern European descent [Meeths et al 2011, Seo et al 2013, Qian et al 2014].
  • c.754-1G>C is predominantly found in Korean individuals [Seo et al 2013].
  • c.1596+1G>C is described as the most common UNC13D variant in Japan [Yamamoto et al 2004].
  • A 253-kb inversion with a high prevalence in Scandinavia is also commonly found in North America [Meeths et al 2011, Qian et al 2014].

STXBP2 pathogenic variants do not appear to be restricted to a specific geographic region.

Evaluations Following Initial Diagnosis

To establish the extent of disease and treatment needs in an individual diagnosed with fHLH, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Individuals responding to treatment and HSCT are technically not at risk for other organ system involvement. Surveillance focuses on potential complications of HSCT.

Surveillance for changes in neurologic manifestations, respiratory function, GI tract manifestations, renal function, and other systems is per standard of care by primary care health care providers or specialty clinicians.

Agents/Circumstances to Avoid

The following should be avoided:

• Live vaccines
• Exposure to infections
• Acetaminophen in individuals with liver failure
• Nonsteroidal anti-inflammatory drugs in individuals with thrombocytopenia
• Areas of construction or soil manipulation, which increase the risk for fungal infection for individuals with neutropenia
• Transfusion of non-irradiated blood products in individuals undergoing chemoimmunotherapy and/or allogeneic HSCT, per institutional guidelines

Evaluation of Relatives at Risk

For early diagnosis and treatment. Molecular genetic testing of at-risk sibs for the family-specific pathogenic variants is appropriate to identify those who are affected before symptoms occur. (Note: Such testing is not useful in accurately predicting the age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.)

Sibs found to have biallelic fHLH-causing pathogenic variants should be carefully monitored for the development of manifestations of active disease (i.e., expectant/watchful waiting), particularly during febrile episodes. Any manifestations of possible active disease should prompt evaluation for splenomegaly, anemia, leukopenia, thrombocytopenia, transaminitis, hypofibrinogenemia/coagulopathy, hypertriglyceridemia, and elevated blood levels of ferritin and soluble IL-2r. If any parameters are abnormal, consultation with a clinician with expertise in fHLH should be initiated.

For matched sib donor HSCT. Potential sib donors should be tested for the presence of the family-specific pathogenic variants to ensure that only those without biallelic fHLH-causing pathogenic variants are evaluated further.

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

Pregnancy Management

If a pregnant woman is diagnosed with fHLH, treatment should be tailored and if possible, incorporate non-cytotoxic drugs such as steroids [Dunn et al 2012]. Because etoposide is thought to interfere with mitosis, thus inhibiting DNA synthesis, and has been used to terminate ectopic pregnancies, it has only rarely been used to treat HLH during pregnancy [Parrott et al 2019]. There have been reports of infants exposed to etoposide in the second and third trimesters of pregnancy who have had a normal outcome and others who have experienced anemia, thrombocytopenia, leukopenia, and neutropenia.

Underlying triggers, such as infection, malignancy, and autoimmune disease, should be sought and treated as appropriate.

See MotherToBaby for more information about medication use in pregnancy.

Therapies Under Investigation

Emapalumab (NI-0501) – an anti-interferon gamma antibody – was approved by the FDA in 2018 for children and adults with fHLH who have refractory, recurrent, or progressive disease or intolerance of conventional HLH therapy [Locatelli et al 2020]. The drug is under investigation for individuals with newly diagnosed fHLH as well as individuals with nonfamilial HLH.

Ruxolitinib – a janus kinase (JAK) 1 and 2 inhibitor – was shown to sensitize immune cells to glucocorticoid-induced apoptosis in vitro and dampen hyperinflammation in a mouse fHLH model [Albeituni et al 2019, Meyer et al 2020]. Several case reports and small case series have described its use in children and adults with active disease (of whom ~6/200 had fHLH) [Keenan et al 2021]; additional larger studies are ongoing.

Alemtuzumab – an anti-CD52 monoclonal antibody – in a pilot trial has shown promising results as frontline treatment for children with fHLH [Moshous et al 2019]. It is under investigation in France.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Familial hemophagocytic lymphohistiocytosis (fHLH) caused by loss-of-function variants in PRF1, STXBP2, STX11, or UNC13D is inherited in an autosomal recessive manner.

Note: Autosomal dominant inheritance of STXBP2-fHLH is suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants (see Molecular Genetics, Gene-specific laboratory technical considerations). Autosomal dominant inheritance will not be discussed further in this section.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one fHLH-causing pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an fHLH-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an fHLH-causing pathogenic variant, each sib of an affected individual has a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial fHLH-causing pathogenic variants.
• Sibs who inherit biallelic fHLH-causing pathogenic variants are at risk of developing fHLH; however, intrafamilial clinical variability may be observed and the age of onset, severity, type of symptoms, and rate of progression in asymptomatic sibs cannot be predicted.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with fHLH are obligate heterozygotes (carriers) for an fHLH-causing pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an fHLH-causing pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the fHLH-causing pathogenic variants in the family.

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 and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the fHLH-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression; however, expectant management is warranted for newborns with the same genotype as the symptomatic proband, as hematopoietic stem cell transplantation prior to onset of symptoms may improve outcome.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The result of biallelic pathogenic variants in PRF1, UNC13D (formerly MUNC13-4), STX11, and STXBP2 is defective perforin-mediated killing of target cells, also known as lymphocyte cytotoxicity [de Saint Basile et al 2010]. Lymphocyte cytotoxicity is important for killing of infected and malignant cells, as well as maintenance of immune homeostasis.

PRF1 encodes perforin, which is predominately expressed by lymphocytes of the CD8⁺ T-cell and NK-cell lineages [Stepp et al 1999]. Perforin is essential for cell-mediated cytotoxicity. Perforin is stored in specialized secretory lysosomal vesicles commonly termed cytotoxic granules. Besides perforin, cytotoxic granules contain granzymes and other proteins that promote target cell death. Upon recognition of a susceptible target cell, cytotoxic lymphocytes release granule contents toward the target cells in a regulated manner, whereupon perforin subunits rapidly form pores in the target cell membrane that serve as conduits for entry of granzymes into the target cell [Lopez et al 2013]. Granzymes are serine proteases that induce apoptosis (cell death) of the target cells. The process of granzyme-mediated lymphocyte cytotoxicity is important for control of infection, protection against cancer, and downregulation of the immune response. Failure to carry out this process can lead to overactivation of the immune response resulting in the signs and symptoms of familial hemophagocytic lymphohistiocytosis (fHLH).

UNC13D, STX11, and STXBP2 encode the cytoplasmic proteins Munc13-4, syntaxin-11, and Munc18-2, respectively. They are expressed in most hematopoietic cells. Deficiency in any one of these proteins results in defective exocytosis of secretory lysosome contents, a prerequisite for lymphocyte cytotoxicity. Deficiencies in these proteins also result in defective exocytosis from other hematopoietic cells, including platelets, neutrophils, and mast cells. Nonetheless, the phenotypes of individuals harboring biallelic pathogenic variants in UNC13D, STX11, and STXBP2 are largely the same as that associated with pathogenic variants in PRF1.

At the cellular level, syntaxin-11 is a membrane-associated SNARE protein that interacts with other SNARE proteins to drive membrane fusion. Signals from activating receptors recruit syntaxin-11 from recycling endosomes to the plasma membrane in a VAMP-8 dependent manner [Marshall et al 2015]. Munc18-2 regulates syntaxin-11 trafficking and function, whereas Munc13-4 primes vesicle exocytosis, in part by sensing elevated intracellular Ca²⁺ concentrations required for cytotoxic granule exocytosis [Boswell et al 2012]. Notably, cytokine activation of lymphocytes can bypass a requirement for syntaxin-11 in exocytosis, explaining a typically later onset and somewhat milder course of disease in individuals with syntaxin-11 deficiency [Bryceson et al 2007, Sepulveda et al 2013].

Marsh et al [2010] noted that pathogenic missense variants in STX11 are associated with preserved NK cell function compared to nonsense variants, which resulted in abrogation of NK cell function.

Mechanism of disease causation. The vast majority of fHLH is associated with autosomal recessive loss-of-function pathogenic variants in the four well-described fHLH genes (PRF1, STXBP2, STX11, and UNC13D).

However, two reports provide evidence for three STXBP2 variants with gain of function: p.Arg65Trp, p.Arg65Gln [Spessott et al 2015], and p.Arg190Cys [Benavides et al 2020], which impair lymphocyte cytotoxicity and act in dominant-negative manner. The variants reported by Spessott et al [2015] are associated with late-onset fHLH.

Gene-specific laboratory technical considerations: UNC13D. Two deep intronic variants (c.118-308C>T and c.118-307G>A) and one large gene inversion have been identified as causative of early-onset fHLH [Meeths et al 2011, Entesarian et al 2013].

A large 253-kb inversion straddles the UNC13D 3' end and adjacent sequences, abolishing protein expression; the breakpoints have been mapped and the inversion is detectable by targeted analysis for pathogenic variants (see Table 2).

The deep intronic variants lie within an intron 1 region that is typically not sequenced; detection will require specific primers. The c.118-308C>T and c.118-307G>A variants disrupt a lymphocyte-specific enhancer and alternative transcriptional start site, specifically impairing gene transcription in lymphocytes [Cichocki et al 2014].

The deep intronic (c.117+143A>G) variant disrupts an enhancer and has been associated with reduced gene transcription and macrophage activation in a single individual [Schulert et al 2018].

Author Notes

The authors of this chapter are members of The North American Consortium for Histiocytosis or The European Consortium for Histiocytosis, multi-institutional consortia in North America and Europe aimed at developing and implementing clinical and translational studies and biological research on histiocytic diseases including fHLH.

North American Consortium for Histiocytosis
Memphis, Tennessee
Phone: 901-595-6042
Fax: 901-595-5319
Email: gro.edujts@OHCAN
Website: www.nacho-consortium.org

European Consortium for Histiocytosis
Paris, France
Phone: 33 1 44 73 74 75
Website: www.echo-histio.net

Acknowledgments

We respectfully acknowledge all the patients, their families, and our medical colleagues from the Histiocyte Society and elsewhere, who have contributed to our understanding of HLH over the years.

Author History

Itziar Astigarraga, MD, PhD (2021-present)
Yenan Bryceson, PhD (2021-present)
Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2006-2021)
Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2006-2021)
Kai Lehmberg, MD (2021-present)
Rafal Machowicz, MD (2021-present)
Rebecca Marsh, MD (2006-present)
Kim E Nichols, MD (2021-present)
Elena Sieni, MD (2021-present)
Joyce Villanueva, MT, MBA; Cincinnati Children's Hospital Medical Center (2006-2021)
Zhao Wang, MD (2021-present)
Kejian Zhang, MD, MBA (2006-present)

Revision History

• 30 September 2021 (bp) Comprehensive update posted live
• 17 January 2013 (me) Comprehensive update posted live
• 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 live
• 21 April 2005 (jj, af, rw) Original submission

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