Familial hemophagocytic lymphohistiocytosis (FHL) and Langerhans cell histiocytosis (LCH) are histiocytic diseases that occur most commonly in young children. Improvements in recognition and treatment have been substantial for both diseases in the past decade, although early and late morbidity continue to be major concerns. These two diagnoses behave differently, although the clinical spectra for both diseases are diverse and can lead to confusion and delays in diagnosis and treatment. This article focuses on the clinical and genetic spectrum of FHL as well as the clinical and treatment variations of LCH.
Key points
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Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening autosomal recessive condition of young children caused by many different gene mutations that affect cytotoxic lymphocytes and lead to a variety of clinical presentations.
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FHL is treated with hematopoietic stem cell transplant and cure rates continue to improve, with overall survival rates ranging from 54% to 91%.
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Langerhans cell histiocytosis (LCH) is recognized as a myeloid-derived dendritic cell neoplasm with an inflammatory component and can affect almost any system of the body, with bone and skin being most common.
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Treatments and outcomes for LCH are as varied as its clinical presentations and new findings in LCH bring hope for the possibility of active targeted therapies.
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Both FHL and LCH may mimic several diseases, leading to delays in diagnosis and treatment. LCH and FHL should be considered as differential diagnoses for many unusual case presentations.
Familial hemophagocytic lymphohistiocytosis
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of uncontrolled inflammation and abnormal immune regulation. A spectrum of clinical presentations may occur depending on triggers and genetics. HLH can be broadly divided into primary HLH or familial HLH (FHLH) and secondary forms. This article focuses on FHLH that is caused by lymphocyte defects inherited in an autosomal recessive manner. FHLH is most common in the first year of life, with an incidence in infants less than 1 year old of 1.1 per 100,000 (median age of onset, 5.1 months). Most children are asymptomatic at birth, although a small subset may be symptomatic within the first weeks of life.
Case 1
A 2-month-old boy presented with 3 days of fever up to 39.2°C (102.6°F), sleepiness, and poor feeding. Past medical history was significant for a sibling stillborn at 37 weeks with fetal hydrops and neonatal hemochromatosis. The mother was treated with intravenous immunoglobulin (IVIG) during pregnancy to abrogate neonatal hemochromatosis. The infant was born at 36 weeks without signs of liver disease and was clinically well until admission. On admission, the patient had pancytopenia, hepatitis, hypoalbuminemia, coagulopathy, hyperferritinemia, hepatosplenomegaly, and respiratory failure requiring mechanical ventilation. Septic work-up and infectious studies were negative. MRI of the abdomen revealed low signal intensity in liver consistent with suspected primary hemochromatosis. Two attempts for biopsy of salivary gland tissue to evaluate for iron deposition were inadequate. However, because of this atypical presentation and continued clinical deterioration, further laboratory studies were obtained.
Further work-up revealed hemophagocytosis in his bone marrow, increased soluble interleukin-2 receptor (sIL-2R) level (38,872 U/mL) and CD8 lacking perforin. Genetic testing revealed a compound heterozygote MUNC13-4 gene mutation diagnostic for FHLH. He was started on dexamethasone, cyclosporine, and etoposide per the HLH-2004 protocol. He responded well to induction therapy and ultimately underwent myeloablative hematopoietic stem cell transplant (HSCT). He is currently well 4 years after transplant.
Further studies were performed on the stillborn infant’s genetic tissue, confirming a MUNC13-4 gene mutation and ruling out the previous diagnosis of neonatal hemochromatosis. This misdiagnosis led to delay in treatment of the current patient and shows that neonatal hemochromatosis may mimic FHLH.
Case 2
A 16-month-old boy presented with mild hepatomegaly and 3 months of generalized tremors, truncal ataxia, and generalized motor regression with loss of the ability to ambulate. Initial differential diagnosis included hereditary ataxias, inborn errors of metabolism (including lysosomal storage disorders and mitochondrial disorders), spinal muscular atrophy, as well as autoimmune and inflammatory conditions.
He was initially treated with high-dose steroids for presumed central nervous system (CNS) inflammatory disease and had improvement. However, when steroids were discontinued, his tremors, ataxia, and motor regression recurred. He ultimately had 3 prolonged hospitalizations involving multiple subspecialists over a 5-month period (summarized here).
| Admission 1 | Admission 2 | Admission 3 | |
|---|---|---|---|
| Signs and Symptoms on Admission | Truncal ataxia, regression of motor skills, papilledema, and mild hepatosplenomegaly | Increasing ataxia and generalized tremors, no hepatosplenomegaly | High fevers, vomiting, worsening ataxia, and motor regression |
| CBC | WBC 8.8 × 10 3 /μL Hb 10.1 g/dL Plt 259 × 10 3 /μL ANC 1056/μL | WBC 11.5 × 10 3 /μL Hb 11.9 g/dL Plt 475 × 10 3 /μL ANC 4900/μL | WBC 12.3 × 10 3 /μL Hb 11 g/dL Plt 221 × 10 3 /μL ANC 3000/μL |
| Coagulation Panel | PT 13.5 s PTT 27.4 s | PT 13.6 s PTT 28 s | PT 13.4s, PTT 34.8s, D-dimer 1.12 μg/mL, fibrinogen 291 mg/dL |
| CSF | No increase in cellularity, protein, and no hemophagocytosis | Moderate cellularity with inflammatory lymphocytes and macrophages, no hemophagocytosis | NA |
| Bone Marrow | Occasional hemophagocytosis | NA | NA |
| Ferritin | 180 ng/mL | NA | 83 ng/mL |
| Liver Enzymes | AST 348 iU/L, ALT 457 iU/L | AST 35 iU/L, ALT 63 iU/L | AST 73 iU/L, ALT 70 iU/L |
| MRI Brain | Cerebellitis and mild hydrocephalus | Worsening cerebellitis on left with new-onset frontal lobe and parieto-occipital lesions | Hyperintense periventricular white matter and increased enhancement of cerebellar lesions |
| Treatment in Hospital | Steroids and temporary external ventricular drain | Steroids and IVIG | Steroids, IVIG, and plasma exchange |
| Discharge | Diagnosis of CNS inflammatory disease, likely infectious. Home on steroid taper | Concern for inflammatory demyelinating disease. Home on steroid taper | Home on hydrocortisone wean because of adrenal suppression |
Because of the uncertainty of his diagnosis, he ultimately underwent whole-exome sequencing. Sequencing was positive for 2 heterozygous autosomal recessive mutations in the perforin gene (c.755A > G and c.1066C > T), diagnostic for FHLH. He began treatment with dexamethasone, cyclosporine, and etoposide and work-up for HSCT was initiated. He developed new language regression and had progression of disease noted on cranial MRI. At time of transplant he had no hemophagocytosis in his bone marrow but had occasional CNS hemophagocytosis in his CSF with stabilized motor symptoms. He received a matched unrelated donor with a reduced-intensity conditioning regimen. His post-HSCT course was complicated with 2 CNS reactivations noted by hemophagocytosis in the CSF and worsening tremors. Both of these CNS reactivations were treated successfully with oral dexamethasone. He is currently off steroids and clinically well 2 years after HSCT.
Pathogenesis of Familial Hemophagocytic Lymphohistiocytosis
Cytotoxic lymphocytes such as natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are important components of a working immune system. Normally, infected or abnormal cells are targeted and destroyed by NK cells and CTLs. In HLH, the infected or abnormal cells are overactive and are unable to undergo apoptosis. An impaired granule exocytosis cytotoxicity pathway incites a positive feedback loop in which antigen-presenting cells (APCs) overproduce proinflammatory cytokines, including tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, interleukin (IL) 1b, IL-6, IL-8, IL-12, and IL-18, which then further activate APCs ( Fig. 1 ). This process then leads to tissue necrosis, hemophagocytosis (mediated by CD163 heme-scavenging receptor), and ultimately multiorgan failure.
Genotype and Phenotype Correlations in Familial Hemophagocytic Lymphohistiocytosis
There are at least 12 genetic mutations currently associated with FHLH ( Table 1 ). The most common mutations are in the fHLH-2 and fHLH-3 genes. Mutations that render these proteins nonfunctional result in early disease onset, whereas missense mutations and splice-site sequence variants can have adult onset. Also, FHLH phenotypes in childhood can occur with bigenic heterozygous mutations in which 2 separate FHLH genes have mutations. Although patients with a single heterozygous mutation in genes of the granule exocytosis pathway can develop HLH, it is often considered secondary HLH, because patients often respond to immunosuppression alone.
| Disease | Gene | Protein | Percentage of FHLH | Immune Impairment | Unique Clinical Characteristics |
|---|---|---|---|---|---|
| fHLH-1 | Unknown 9q21.3–22 | Rare | |||
| fHLH-2 | PRF1 | Perforin | ∼20–37, 50delT mainly in African American/African descent | Cytotoxicity; forms pores in APCs | |
| fHLH-3 | UNC13D | Munc13–4 | 20–33 | Cytotoxicity; vesicle priming | Increased incidence of CNS HLH |
| fHLH-4 | STX11 | Syntaxin 11 | <5 | Cytotoxicity; vesicle fusion | Mild, recurrent HLH, and colitis |
| fHLH-5 | STXBP2 | Syntaxin binding protein 2 | 5–20 | Cytotoxicity; vesicle fusion | Colitis and hypogammaglobulinemia |
| Syndromes with Partial Oculocutaneous Albinism | |||||
| Griscelli syndrome | RAB27A | Rab27A | ∼5 | Cytotoxicity; vesicle docking | Partial albinism and silver-gray hair |
| Chédiak-Higashi syndrome | LYST | Lyst | ∼2 | Cytotoxicity; heterogeneous defects in NK cells | Partial albinism, bleeding tendency, and recurrent infections |
| Hermansky-Pudlak syndrome type II | AP3B1 | AP-3 complex subunit beta-1 | Rare | Cytotoxicity; vesicle trafficking | Partial albinism and bleeding tendency |
| EBV-driven and Rare Causes | |||||
| XLP1 | SH2D1A | SAP | ∼7 | Signaling in cytotoxic NK and T cells | Hypogammaglobulinemia and lymphoma |
| XLP2 | BIRC4 | XIAP | ∼2 | NK T-cell survival and NF-κB signaling | Mild, recurrent HLH and colitis |
| ITK deficiency | ITK | ITK | Rare | IL-2 signaling in T cells | Hypogammaglobulinemia, autoimmunity and Hodgkin lymphoma |
| CD27 deficiency | CD27 | CD27 | Rare | Signal transduction in lymphocytes | Combined immunodeficiency and lymphoma |
| XMEN syndrome | MAGT1 | MAGT1 | Rare | Magnesium transporter, induced by TCR stimulation | Lymphoma, recurrent infections, and CD4 T-cell lymphopenia |
The first genetic defect discovered in association with HLH was a perforin deficiency. Perforin is a cytolytic mediator produced by cytotoxic lymphocytes and released from cytoplasmic granules when the effector cells are activated. Perforin produces holes in the target cell membranes on activation. The effector molecule, granzyme B, a serine protease also found in cytolytic cells, is delivered into target cells (predominantly cancerous or pathogen-infected cells) via the porelike structures, which are generated on activation of NK cells and cytotoxic T cells. Granzyme B then induces programmed cell death in target cells. Decreased levels or absence of perforin or granzyme results in HLH.
Other HLH-related syndromes are associated with vesicle priming, fusion, docking, or trafficking (see Table 1 ). Three diseases that can lead to HLH-like reactions are X linked (see Table 1 ) and have a propensity to develop HLH-like symptoms after exposure to Epstein-Barr virus (EBV). Other symptoms frequently seen include immunodeficiency (most often hypogammaglobulinemia or dysgammaglobulinemia), colitis, and lymphoproliferative disorders. Recently described and rare disorders related to persistent or recurrent EBV infection include IL-2–inducible T-cell kinase (ITK) deficiency and CD27 deficiency.
Common Findings and Diagnosis of Familial Hemophagocytic Lymphohistiocytosis
Almost all patients with FHLH have findings of fever, bicytopenia/pancytopenia, and increased soluble CD25 levels. Other common findings include splenomegaly (95%), hepatomegaly (94%), hyperferritinemia (90%), hypertriglyceridemia (85%), hemophagocytosis (85%), ( Fig. 2 ) hypofibrinogenemia (79%), and CNS disease in 30% to 76% with CSF pleocytosis and/or neurologic symptoms such as seizures or coma. Not all signs and symptoms are present when a patient first encounters medical care, but with time FHLH progresses if untreated.
Diagnostic criteria for HLH have been created by consensus and last revised in 2004 by the Histiocyte Society ( Table 2 ). At presentation, FHLH is often diagnosed clinically but genetic testing alone is also sufficient and often used in siblings and diagnostic confirmation. Often young children are misdiagnosed with sepsis. If FHLH is unrecognized or untreated dismal outcomes occur, with an estimated survival of less than 10%.
| HLH can be Established if Either A or B is Fulfilled | |||
| A | A molecular diagnosis is consistent with HLH (see Table 1 ) | ||
| B | Diagnostic criteria (5 out of the 8 criteria below) | Cause | |
| 1 | Fever | Increased IL-1 and IL-6 levels | |
| 2 | Splenomegaly | Organ infiltration by lymphocytes and histiocytes | |
| 3 |
| Increased TNF-α and IFN-γ | |
| 4 |
| Increased TNF-α inhibits lipoprotein lipase Activated macrophages secrete plasminogen activator, which results in high plasmin levels and hyperfibrinolysis | |
| 5 | Hemophagocytosis in bone marrow or spleen or lymph nodes | Activated macrophages | |
| 6 | Low or absent NK-cell activity (using local laboratory reference) | ||
| 7 | Ferritin ≥500 mg/L a | Activated macrophages secrete ferritin | |
| 8 | Soluble CD25 (ie, soluble IL-2 receptor) ≥ 2400 U/mL | From activated lymphocytes (sIL-2R) | |
a A ferritin level of greater than 500 ng/mL is nonspecific and can be seen in a variety of diseases, including shock, chronic transfusions, immunodeficiency, liver disease, cystic fibrosis, malignancy, after transplant, and autoimmune diseases. Experts often use ferritin level of greater than 2000 ng/mL as concerning and greater than 10,000 ng/mL as highly suspicious for HLH. The sensitivity and specificity for HLH with a ferritin level greater than 10,000 ng/mL are ∼90% and greater than 95% respectively.
Central Nervous System Hemophagocytic Lymphohistiocytosis
CNS disease is noted clinically or by examination of the CSF or neuroradiologic imaging. It can occur at initial presentation or may develop later in the disease course and is associated with increased mortality. Suspicion of CNS disease should prompt MRI and diagnostic lumbar puncture. In a patient cohort from the HLH-94 trial of 193 patients, 70 patients had documented neurologic symptoms; irritability was found in 24 patients (34%); seizures (focal or generalized) in 23 patients (33%); meningeal findings, including neck stiffness, opisthotonus, bulging fontanel, and papilledema, were seen in 17 patients (24%); and altered levels of consciousness in 8 patients (11%). Furthermore, findings on brain MRI parallel the severity of neurologic impairment. About half of patients with CNS pleocytosis have abnormal MRI with white matter changes, whereas patients with neurologic symptoms often have necrotic lesions and cerebral atrophy.
Treatment
All patients with primary or secondary HLH are treated with 8 weeks of cytotoxic induction therapy (dexamethasone, etoposide with or without cyclosporine). Patients with FHLH require an HSCT for cure and correction of their genetic abnormality. Patients with presumed secondary HLH often do not require further therapy after induction unless they develop recurrence, for which HSCT is often needed.
In the HLH-2004 protocol, cyclosporine was moved to up-front treatment compared with the HLH-1994 protocol in which cyclosporine started in week 9 of continuation therapy. There is some concern that cyclosporine may increase neurotoxicity, including risk of posterior reversible encephalopathy syndrome. Other complications, including early morality before transplant, HSCT-related mortality, and neurologic late effects, are areas of difficulty and ongoing research. The HLH-94 trial reported a 5-year overall survival of 54% ± 6% for all patients, whereas those who underwent HSCT had a 5-year overall survival of 66% ± 8%. This trial also showed that patients with active HLH at the time of transplant have worse outcomes. Results for the HLH-2004 trial with early initiation of cyclosporine are not yet available.
Recently, reduced-intensity conditioning regimens with alemtuzumab, fludarabine, and melphalan have shown improvements in overall survival. One report in patients with XLP-1 showed an estimated 71% long-term survival, whereas other types of FHLH have shown 92% 3-year overall survival. Furthermore, promising results from a retrospective study using antithymocyte globulin during induction have led to a hybrid immunotherapy-HLH phase II clinical trial (NCT01104025). Ongoing HLH research and collaboration is needed for ongoing improvements in FHLH care and outcomes.
Familial hemophagocytic lymphohistiocytosis
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of uncontrolled inflammation and abnormal immune regulation. A spectrum of clinical presentations may occur depending on triggers and genetics. HLH can be broadly divided into primary HLH or familial HLH (FHLH) and secondary forms. This article focuses on FHLH that is caused by lymphocyte defects inherited in an autosomal recessive manner. FHLH is most common in the first year of life, with an incidence in infants less than 1 year old of 1.1 per 100,000 (median age of onset, 5.1 months). Most children are asymptomatic at birth, although a small subset may be symptomatic within the first weeks of life.
Case 1
A 2-month-old boy presented with 3 days of fever up to 39.2°C (102.6°F), sleepiness, and poor feeding. Past medical history was significant for a sibling stillborn at 37 weeks with fetal hydrops and neonatal hemochromatosis. The mother was treated with intravenous immunoglobulin (IVIG) during pregnancy to abrogate neonatal hemochromatosis. The infant was born at 36 weeks without signs of liver disease and was clinically well until admission. On admission, the patient had pancytopenia, hepatitis, hypoalbuminemia, coagulopathy, hyperferritinemia, hepatosplenomegaly, and respiratory failure requiring mechanical ventilation. Septic work-up and infectious studies were negative. MRI of the abdomen revealed low signal intensity in liver consistent with suspected primary hemochromatosis. Two attempts for biopsy of salivary gland tissue to evaluate for iron deposition were inadequate. However, because of this atypical presentation and continued clinical deterioration, further laboratory studies were obtained.
Further work-up revealed hemophagocytosis in his bone marrow, increased soluble interleukin-2 receptor (sIL-2R) level (38,872 U/mL) and CD8 lacking perforin. Genetic testing revealed a compound heterozygote MUNC13-4 gene mutation diagnostic for FHLH. He was started on dexamethasone, cyclosporine, and etoposide per the HLH-2004 protocol. He responded well to induction therapy and ultimately underwent myeloablative hematopoietic stem cell transplant (HSCT). He is currently well 4 years after transplant.
Further studies were performed on the stillborn infant’s genetic tissue, confirming a MUNC13-4 gene mutation and ruling out the previous diagnosis of neonatal hemochromatosis. This misdiagnosis led to delay in treatment of the current patient and shows that neonatal hemochromatosis may mimic FHLH.
Case 2
A 16-month-old boy presented with mild hepatomegaly and 3 months of generalized tremors, truncal ataxia, and generalized motor regression with loss of the ability to ambulate. Initial differential diagnosis included hereditary ataxias, inborn errors of metabolism (including lysosomal storage disorders and mitochondrial disorders), spinal muscular atrophy, as well as autoimmune and inflammatory conditions.
He was initially treated with high-dose steroids for presumed central nervous system (CNS) inflammatory disease and had improvement. However, when steroids were discontinued, his tremors, ataxia, and motor regression recurred. He ultimately had 3 prolonged hospitalizations involving multiple subspecialists over a 5-month period (summarized here).
| Admission 1 | Admission 2 | Admission 3 | |
|---|---|---|---|
| Signs and Symptoms on Admission | Truncal ataxia, regression of motor skills, papilledema, and mild hepatosplenomegaly | Increasing ataxia and generalized tremors, no hepatosplenomegaly | High fevers, vomiting, worsening ataxia, and motor regression |
| CBC | WBC 8.8 × 10 3 /μL Hb 10.1 g/dL Plt 259 × 10 3 /μL ANC 1056/μL | WBC 11.5 × 10 3 /μL Hb 11.9 g/dL Plt 475 × 10 3 /μL ANC 4900/μL | WBC 12.3 × 10 3 /μL Hb 11 g/dL Plt 221 × 10 3 /μL ANC 3000/μL |
| Coagulation Panel | PT 13.5 s PTT 27.4 s | PT 13.6 s PTT 28 s | PT 13.4s, PTT 34.8s, D-dimer 1.12 μg/mL, fibrinogen 291 mg/dL |
| CSF | No increase in cellularity, protein, and no hemophagocytosis | Moderate cellularity with inflammatory lymphocytes and macrophages, no hemophagocytosis | NA |
| Bone Marrow | Occasional hemophagocytosis | NA | NA |
| Ferritin | 180 ng/mL | NA | 83 ng/mL |
| Liver Enzymes | AST 348 iU/L, ALT 457 iU/L | AST 35 iU/L, ALT 63 iU/L | AST 73 iU/L, ALT 70 iU/L |
| MRI Brain | Cerebellitis and mild hydrocephalus | Worsening cerebellitis on left with new-onset frontal lobe and parieto-occipital lesions | Hyperintense periventricular white matter and increased enhancement of cerebellar lesions |
| Treatment in Hospital | Steroids and temporary external ventricular drain | Steroids and IVIG | Steroids, IVIG, and plasma exchange |
| Discharge | Diagnosis of CNS inflammatory disease, likely infectious. Home on steroid taper | Concern for inflammatory demyelinating disease. Home on steroid taper | Home on hydrocortisone wean because of adrenal suppression |
Because of the uncertainty of his diagnosis, he ultimately underwent whole-exome sequencing. Sequencing was positive for 2 heterozygous autosomal recessive mutations in the perforin gene (c.755A > G and c.1066C > T), diagnostic for FHLH. He began treatment with dexamethasone, cyclosporine, and etoposide and work-up for HSCT was initiated. He developed new language regression and had progression of disease noted on cranial MRI. At time of transplant he had no hemophagocytosis in his bone marrow but had occasional CNS hemophagocytosis in his CSF with stabilized motor symptoms. He received a matched unrelated donor with a reduced-intensity conditioning regimen. His post-HSCT course was complicated with 2 CNS reactivations noted by hemophagocytosis in the CSF and worsening tremors. Both of these CNS reactivations were treated successfully with oral dexamethasone. He is currently off steroids and clinically well 2 years after HSCT.
Pathogenesis of Familial Hemophagocytic Lymphohistiocytosis
Cytotoxic lymphocytes such as natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are important components of a working immune system. Normally, infected or abnormal cells are targeted and destroyed by NK cells and CTLs. In HLH, the infected or abnormal cells are overactive and are unable to undergo apoptosis. An impaired granule exocytosis cytotoxicity pathway incites a positive feedback loop in which antigen-presenting cells (APCs) overproduce proinflammatory cytokines, including tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, interleukin (IL) 1b, IL-6, IL-8, IL-12, and IL-18, which then further activate APCs ( Fig. 1 ). This process then leads to tissue necrosis, hemophagocytosis (mediated by CD163 heme-scavenging receptor), and ultimately multiorgan failure.
