Form Of Hemophagocytic Lymphohistiocytosis Research Articles

A novelPRF1gene mutation in a fatal neonate case with type 2 familial hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) occurs in the primary form (genetic or familial) or secondary form (acquired). The familial form of HLH (FHL) is a potentially fatal autosomal recessive disorder that occurs because of constitutional defects in cell-mediated cytotoxicity. Here, we report a fatal neonatal case of type 2 FHL (FHL2) that involved a novel frameshift mutation. Clinically, the newborn presented with severe sepsis-like features and required mechanical ventilation and continuous venovenous hemodiafiltration. Flow cytometry analysis showed marked HLH and complete absence of intracytoplasmic perforin expression in cytotoxic cells; therefore, we performed molecular genetic analyses for PRF1 mutations, which showed that the patient had a compound heterozygous mutation in PRF1, that is, c.65delC (p.Pro22Argfs*2) and c.1090_1091delCT (p.Leu364Glufs*93). Clinical and genetic assessments for FHL are required for neonates with refractory fever and progressive multiple organ failure, particularly when there is no evidence of microbiological or metabolic cause.

PReS-FINAL-2186: Monoallelic mutations of familial hlh-related genes associated to macrophage activation syndrome

Macrophage Activation Syndrome (MAS) is a severe complication of rheumatic diseases, frequently associated with systemic juvenile idiopathic arthritis (sJIA), but also described in others pediatric inflammatory disorders including Juvenile Systemic Lupus Erythematosus (SLE) and Kawasaki disease. Due to the close resemblance to a group of histiocytic disorders collectively known as hemophagocytic lymphohistiocytosis (HLH) it is currently classified among the secondary or acquired forms of HLH, and the term rheu-HLH has been proposed.

Reactive haemophagocytic syndrome in a patient with adult-onset Still’s disease: beta-lactams as trigger?

Reactive haemophagocytic syndrome (RHS) is a severe and acquired form of haemophagocytic lymphohistiocytosis that may overlap with adult-onset Still’s disease (AOSD) [1]. The diagnosis of RHS, particularly in its early phase, may be confused with other clinical conditions, such as sepsis, malignancy and rheumatological flare. In November 2012, a 27-year-old woman presented to our hospital with a 3-day history of alternating fever and low back pain. Neurological examination was normal. Tenderness of the lumbar spine on percussion was reported. Blood tests showed a white cell count of 24,130/lL with a normal C-reactive protein (CRP \1.00 mg/L) and erythrocyte sedimentation rate (ESR; 10 mm/h). Hepatic and renal function were normal. Examination of the blood smear did not reveal blasts, and the platelet count and coagulation indices were normal. Urinalysis showed no abnormalities. Procalcitonin (PCT) was 5.7 ng/mL. Fever persisted ([39 C) for 2 days following presentation, and the patient developed signs of haemodynamic instability. Empirical oxacillin was begun awaiting the results of the blood cultures. Emergency imaging scans were performed. A symmetrical oligoarthritis and an intermittent macular–papular rash that extended to the trunk and extremities were detected (Fig. 1). Concomitantly, the levels of CRP (247.6 mg/L), ferritin (up to 15,000 lg/L), lactate dehydrognase (LDH; 2,670 U/L), triglycerides (403 mg/dL), aspartate transaminase (AST; 474 U/L), alanine transaminase (ALT; 171 U/L) started to increase, as did the prothrombin time (12.7 s) and activated partial thromboplastin time (32.4 s). Pancytopenia and reduced fibrinogen levels were also detected. A magnetic resonance imaging (MRI) scan of the spine ruled out epidural abscess and vertebral osteomyelitis. Transthoracic echocardiography did not reveal any valvular vegetations. Positron emission tomography–computed tomography imaging showed no abscess or solid malignancy. Blood and urine cultures grew no bacterial and mycobacterial pathogens. Autoimmunity screening was negative, and radiographs of all involved joints did not reveal marginal erosions. At this point a presumptive diagnosis of AOSD (5/8 criteria) [1] with RHS (4/8 criteria) [1] was strongly considered, and we ruled out infective triggers. Examination of the bone marrow confirmed haemophagocytosis. After the suspension of betalactam treatment, PCT (and other blood tests) progressively normalized. A literature search revealed 34 reported cases of RHS in AOSD in which an active infection was clearly not identified as a potential trigger [1–7]. The authors of these studies proposed that anti-tuberculosis, nonsteroidal antiinflammatory drugs (NSAIDS), sulfasalazine, hydroxychloroquine, gold salts, etanercept and adalimumab, respectively, could have elicited the RHS. In our patient, oxacillin was suspected of acting as the RHS trigger. She received penicillinase-resistant penicillin as a unique medication; moreover, the ‘‘switch-off’’ began just with its suspension. Takeshita [8] and Motegi [9] are the only two authors who advocated treatment with beta-lactams (penicillin G) as the triggering factor for RHS, but in these two F. Mearelli, P. Vinci and M. Gigli were the clinicians involved in the management of the patient.

SP0103 Treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) comes in two forms, a primary, genetic form and a secondary form. The primary form is caused by mutations in genes encoding proteins required for lymphocyte cytotoxicity...

Une encéphalite limbique révélée par un état de mal épileptique

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.

SAP and XIAP deficiency in hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a multisystem inflammatory disorder due to cytokine overproduction from excessively activated lymphocytes and macrophages. HLH has been divided into two subgroups: primary HLH and secondary HLH. Primary HLH includes PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST, SH2D1A and XIAP gene mutations; and secondary HLH is associated with infections, malignancies and autoimmune diseases. Among primary HLH-related genes, SH2D1A and XIAP are genetically responsible for X-linked lymphoproliferative syndrome (XLP) due to signaling-lymphocytic-activation-molecule-associated protein (SAP) and XIAP deficiencies, respectively. XLP is characterized by extreme vulnerability to Epstein-Barr virus infection. The major clinical manifestations of XLP consist of HLH (60%), lymphoproliferative disorder (30%) and dysgammaglobulinemia (30%). Analysis of clinical phenotypes of XLP patients suggests that XLP predominantly shows familial HLH phenotypes, whereas some XLP patients present sporadic HLH. For many decades, clinicians and investigators have been concerned with possible XLP in young boys presenting with Epstein-Barr-virus-associated HLH. This review aims to describe the new knowledge about XLP and to draw the attention of the pediatrician to XLP, which should be differentiated from other forms of HLH.

Familial and Acquired Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which an uncontrolled and ineffective immune response, triggered in most cases by infectious agents, leads to severe hyperinflammation. Familial forms of HLH (FHL), which are increasingly found also in adolescents and adults, are due to genetic defects leading to impaired function of natural killer cells and cytotoxic T cells. These mutations occur either in the perforin gene or in genes important for the exocytosis of cytotoxic granules. Cytotoxic granules contain perforin and granzymes, which induce apoptosis upon entering (infected) target cells. Additionally, perforin is important for the downregulation of the immune response. Acquired forms of HLH are encountered in association with (usually) viral infections, autoinflammatory/autoimmune diseases, malignant diseases, and acquired immune deficiency states (e.g., after organ transplantation). Treatment of HLH includes immune-suppressive and immune-modulatory agents, cytostatic drugs, and biological response modifiers. For patients with FHL, stem cell transplantation is indicated and can be curative.

Treatment of Hemophagocytic Lymphohistiocytosis with Cop Chemotherapy Protocol: A Retrospective Clinical Analysis of Fifteen Cases

Abstract 1121Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyper-inflammatory syndrome with prolonged high fever, hepatosplenomegaly, pancytopenia, hepatic dysfunction, low fibrinogen level, hypertriglyceridemia and hemophagocytosis in the bone marrow, liver, spleen, or lymph nodes. Broadly, HLH can be classified into either primary or secondary HLH. The familial HLH (FHL) is an autosomal recessive disorder with a median survival of less than two months after diagnosis if untreated, and that typically has its onset during infancy or early childhood. Secondary HLH (sHLH) may occur in association with severe infections, malignancies or autoimmune diseases, although it may subside spontaneously, it may also be associated with pronounced mortality. The most present therapeutic regimes such as HLH-2004 protocol and allogene hemopoietic stem cell transplantation (allo-HSCT) have been designed for the primary, inherited disease FHL, in patients aged <18 years, as well as any severe form of HLH. Reports on the treatment of sHLH are rare, and no standard treatment protocol is as yet established. We implemented prednisone, vincristine, cyclophosphamide (COP) combined chemotherapy in treating adult hemophagocytic lymphohistiocytosis (HLH) and observed the therapeutic efficacy. Fifteen patients, among whom 7 were infection-associated HLH (IHLH), 4 had no apprent underlying causes, lymphoma-associated HLH (LHLH) and autoimmune disease-associated HLH took up of 2 respectively, were enrolled in our study. The initial therapy of COP protocol included cyclophosphamide (CTX) 0.3 g/m2 i.v. and vincristine (VCR) 1.4 mg/m2 i.v., once weekly for the first eight weeks, prednisone (PRED) 60 mg/m2/d p.o., for the first 2 weeks, and reduced by 50% of the previous dose every 2 weeks until the end of the 7th week, then progressively tapered it for 1 week. A continuation therapy of COP was CTX 0.3 g/m2 i.v., on day 1, day 8; VCR 1.4 mg/m2 i.v., on day 1, day 8; PRED 20 mg/m2 p.o. for 14 days and it was repeated every 4 weeks for a total of 4 to 6 cycles in responding. Patients were given COP protocol individually depending on their different etiologies and responses to therapy. With a mean follow-up of 72.5 weeks, the median overall survival (OS) was 43 weeks and the one-year probability of overall survival (OS) was 10/15(66.7%). The overall response rate was 80.0%, consisting of seven (46.7%) complete response (CR) and five (33.3%) partial response (PR). Different etiology induced HLH had different sensitivity and response rate to COP chemotherapy. Hematological and non-hematological toxicities were predominantly grade I or II and most patients could well tolerate without requiring a dose reduction of full-dose COP. In conclusion, as a mild and cost-effective chemotherapy, COP protocol showed a relatively favorable effect for adult patients with sHLH. In the following situations, like some with bacteria infection, some arose from an autoimmune disease, or else some who can not endure an intensive chemotherapy due to an old age or disease severity, the COP protocol may be the first choice. Disclosures:No relevant conflicts of interest to declare.

Hemophagocytic Lymphohistiocytosis: A Potentially Underrecognized Association With Systemic Inflammatory Response Syndrome, Severe Sepsis, and Septic Shock in Adults

Hemophagocytic lymphohistiocytosis (HLH) was originally described as a genetic disorder of immune regulation, presenting in neonates with protracted fever, hepatosplenomegaly, and cytopenia. A secondary form of HLH, triggered by serious infections, was subsequently described in adults. We report three adult patients who presented with systemic inflammatory response syndrome and features consistent with severe sepsis and septic shock, who subsequently received a diagnosis of secondary HLH. We reviewed the relationship between infection-triggered HLH and septic shock from the perspective of the adult intensivist. The hyperinflammatory pathophysiologic characteristics of HLH and septic shock are closely intertwined. Clinical and laboratory features of HLH and septic shock overlap in some patients, making the syndromes difficult to distinguish. In our experience and review, progressive pancytopenia was the feature most likely to suggest secondary HLH in the adult patient with presumed (or definite) septic shock. Use of other HLH-2004 diagnostic criteria is hindered by the poor operating characteristics of these tests in critically ill adults. Bone marrow aspiration is the most useful diagnostic test, but may yield an initial false-negative result. The HLH-2004 treatment protocol is not of proven benefit in critically ill adults, but observational data suggest that aggressive immunosuppressive therapy should not be delayed. Further study of HLH in the critical care setting might provide important insights into the pathogenesis and clinical treatment of sepsis.

Fulminant hemophagocytic lymphohistiocytosis induced by pandemic A (H1N1) influenza: a case report

IntroductionHemophagocytic lymphohistiocytosis induced by viral diseases is a well recognized entity. Severe forms of H5N1 influenza are known to be associated with symptoms very similar to a reactive hemophagocytic syndrome. We report a case of fulminant lymphohistiocytosis associated with the pandemic A (H1N1) variant.Case presentationA 42-year-old Caucasian woman developed a syndrome of fatal hemophagocytic lymphohistiocytosis shortly after H1N1 influenza. Initial symptoms of the viral disease were unusual, with acute abdominal involvement. Our patient's course was complicated by diffuse skin rash and ileal ischemia. Our patient died of refractory shock and multi-organ failure. Skin, ileum and colon histology was consistent with an acute apoptosis combined with an increased cellular regeneration.ConclusionsInfluenza may be complicated by severe forms of hemophagocytic lymphohistiocytosis. To ensure early recognition and treatment, physicians should be aware of the possible induction of the syndrome by the novel H1N1 variant. The rapid occurrence of a multi-organ involvement with evocative biological features of macrophage activation should alert clinicians.

Reduced‐intensity conditioning haematopoietic cell transplantation for haemophagocytic lymphohistiocytosis: an important step forward

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunodeficiency characterized by severe systemic hyper-inflammatory responses to infectious or other triggers of the immune system. In many patients, the underlying cause of HLH is a genetic defect leading to defective CD8(+) T cell and natural killer cell granule-mediated cytotoxicity. The treatment of HLH consists principally of immune suppression followed by allogeneic haematopoietic cell transplantation (HCT) to cure the underlying defect and prevent relapse of HLH. Initial treatment regimens consist of steroids coupled with either etoposide or antithymocyte globulin, ± ciclosporin. Complete responses are observed in only 50-75% of patients and even after a complete response, relapse and death still occur. The only definitive, long-term cure for patients with genetic forms of HLH is allogeneic HCT. Unfortunately, allogeneic HCT for patients with HLH is often complicated by critical illness, extensive organ involvement, active infections, or refractory HLH. For these reasons, patients are unusually prone to developing transplant-related toxicities and complications. In recent years, great strides have been made with regard to the care and transplantation of patients with HLH. Here we review the current state of the treatment of patients with HLH with allogeneic HCT, highlighting the important steps forward that have been made with reduced-intensity conditioning.

Successful treatment of recurrent malignancy-associated hemophagocytic lymphohistiocytosis with a modified HLH-94 immunochemotherapy and allogeneic stem cell transplantation

Acquired hemophagocytic lymphohistiocytosis (HLH) triggered by a known or still to be recognized malignancy is a life-threatening hyperinflammatory syndrome due to massive cytokine release from activated lymphocytes and macrophages. Malignancy-associated HLH (M-HLH) often impedes adequate treatment of malignancy and has the worst outcome compared with any other form of HLH. The incidence of M-HLH is unknown, and there are no published treatment recommendations addressed to this HLH form. Here, we report the case of a young woman with recurrent ALK1-positive anaplastic large T-cell lymphoma and M-HLH successfully treated with a modified HLH-94 protocol, allogeneic stem cell transplantation (alloSCT) and donor lymphocyte infusion (DLI). More than 3 years after DLI, the patient is alive, in complete remission from her malignancy and HLH-free, although suffering from extensive chronic graft-versus-host disease. AlloSCT and, if needed, DLI performed to consolidate remission of malignancy and HLH may have a curative impact on both entities. We propose that when discussing possible treatment options for patients with M-HLH, alloSCT should be considered in eligible individuals.

What Intensivists Need to Know About Hemophagocytic Syndrome

Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a rare and frequently fatal disorder caused by an uncontrollable and ineffective systemic immune response. Patients initially present with fever, cytopenia, and hepatosplenomegaly, and subsequently develop multiorgan failure (MOF). Hemophagocytosis can be found on biopsy specimen but is not required. Acquired forms of HLH can occur in apparently healthy adults, while children present more often with an inherited form of the disease. Since HLH often presents with sepsis-like symptoms and organ dysfunction, patients are usually treated for presumed sepsis, which inevitably leads to delayed diagnosis and treatment. Intensivists need to have a low threshold for suspecting this disorder when previously healthy individuals present with a fulminant sepsis-like syndrome, which are unresponsive to conventional treatment. We present 3 patients with HLH who were admitted to our adult medical intensive care unit (MICU) over a 2-year period with fatal outcomes and emphasize the diagnostic importance of markedly elevated serum ferritin levels and the need for tissue biopsy in making an accurate diagnosis in a timely manner.

Advances in Hemophagocytic Lymphohistiocytosis: Pathogenesis, Early Diagnosis/Differential Diagnosis, and Treatment

Hemophagocytic lymphohistiocytosis (HLH) is a histiocytic disorder characterized by a highly stimulated, but ineffective, immune response to antigens, which results in life-threatening cytokine storm and inflammatory reaction. Considerable progress has been made during the past 2 decades. Detection of molecular genetic abnormalities in genes involved in immune response pathways, such as PRF1, STX11, UNC13D, STXBP2, RAB27A, LYST, AP3B1, SH2D1A, and BIRC4, is confirmatory for the diagnosis. Clinical diagnosis is largely made according to HLH-2004 criteria. However, a new finding of the Th1/Th2 cytokine pattern (significant increase of IFN-γ and IL-10 with slightly increased or normal level of IL-6) is a useful biomarker for the early diagnosis, differential diagnosis, and the monitoring of the disease. Intensive immunosuppressive therapy is generally accepted as treatment for the relief of clinical symptoms/signs, while allogeneic hematopoietic stem cell transplantation is currently the only potentially curative therapy option for severe familial forms of HLH.

1115 Hemophagocytic Lymphohistiocytosis in Two Romanian Young Infants

Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder of early infancy, resulting from abnormal proliferation of histiocytes in tissues and organs, but potentially fatal disease. Diagnosing this disease may be difficult and is often delayed because the clinical presentation mimics other conditions like severe sepsis, hepatic failure and malignancies. HLH is characterized by fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia with hemophagocytosis in the bone marrow, spleen or lymph nodes, which represent the diagnostic criteria. We report two cases of HLH in infants within the first 10 weeks of life. Diagnosis of HLH was made relatively early after symptoms started, one of them - a rare case of primary HLH form (familial form), and other - the secondary form of HLH (associated infection with EBV virus) indicating that not all cases of HLH in very young infants are familial. Both patients had typical presentations with fever, anemia and thrombocytopenia, enlarged liver and spleen, hyperferritinemia, hypertriglyceridemia and hypofibrinogenemia, initially without the finding of hemophagocytosis in bone marrow. Awareness of the clinical symptoms and of the diagnostic criteria of HLH is important to start life-saving therapy with immunosuppressive/immunomodulatory agents in time. Diagnostic must be rapidly made, because the familial form is always fatal without treatment. In the absence of a specific marker, differential diagnosis may be difficult, especially in patients without familial recurrence. When there is strong clinical suspicion of HLH, chemotherapy and immunosuppressor treatment should be started early.

Hemophagocytic Lymphohistiocytosis in B-Cell Lymphoproliferative Disorder: Report of a Rare Association

Hemophagocytic Lymphohistiocytosis in B-Cell Lymphoproliferative Disorder: Report of a Rare Association

Inherited Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal immune disorder characterized by uncontrolled lymphocyte- and macrophage-activation. The resulting hypercytokinemia and cell infiltration of organs lead to the clinical and laboratory features of HLH. Viral infections and other triggers can induce both, inherited and acquired forms of HLH. Disease-causing mutations in the genes encoding perforin (PRF1, FHL2), munc13-4 (UNC13D, FHL3), syntaxin 11 (STX11, FHL4), and munc18-2 (UNC18-2/STXBP2, FHL5) have been previously identified in Familial Hemophagocyic Lymphohistiocytosis (FHL), whereas mutation in RAB27A and LYST account for Griscelli syndome type 2 and Chediak-Higashi syndrome, respectively. These genes all encode proteins which are involved in the cytotoxic activity of lymphocytes. The inability of activated cytotoxic cells to clear antigen-presenting targets results in sustained immune stimulation, likely accounting for the unremitting polyclonal CD8 T-cell activation and hyperimmune reaction which characterizes FHL. Treatment of HLH consists of elimination of the trigger and immunosuppressive treatment in order to induce remission from the uncontrolled inflammation. Allogeneic hematopoietic stem cell transplantation can be indicated in the inherited forms of HLH.

Hemophagocytic Lymphohistiocytosis: When the Immune System Runs Amok

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which an exaggerated but ineffective immune response leads to severe hyperinflammation. Key players in HLH are activated lymphocytes and histiocytes which infiltrate all organs and secrete large amounts of cytokines. Cardinal symptoms are prolonged fever, hepatosplenomegaly, cytopenias, and hemophagocytosis. Biochemical markers include elevated ferritin, triglycerides, and low fibrinogen. HLH occurs on the basis of various inherited and acquired immune defects. Impaired function of natural killer cells and cytotoxic T cells is shared by all forms of HLH. Nearly all genetic defects identified in inherited cases of HLH are either mutations in the perforin gene or in genes important for the exocytosis of cytotoxic granules. Cytotoxic granules contain perforin and granzymes which induce apoptosis upon entering the target cell. Additionally perforin is important for the down-regulation of the immune response. Acquired forms of HLH are found in association with infectious agents, in patients with autoimmune diseases, in malignant diseases, and in patients receiving immune suppression or after organ transplantation. - HLH is still difficult to diagnose and may be overlooked since initially it may masquerade as a normal infection. HLH should be considered when symptoms are more pronounced than usual and in case of progression. Suppression of the severe hyperinflammation can be achieved with immunosuppressive and immunomodulatory agents and cytostatic drugs. Patients with genetic HLH have to undergo stem cell transplantation for cure.

Prolonged hemophagocytic lymphohistiocytosis syndrome as an initial presentation of Hodgkin lymphoma: a case report

IntroductionHemophagocytic lymphohistiocytosis is an immune-mediated syndrome that typically has a rapidly progressive course that can result in pancytopenia, coagulopathy, multi-system organ failure and death.Case presentationA 57-year-old Caucasian woman was referred in fulminant hemophagocytic lymphohistiocytosis, with fever, pancytopenia, splenomegaly, mental status changes and respiratory failure. She was found to have stage IV classical Hodgkin lymphoma, in addition to Epstein-Barr virus and cytomegalovirus viremia. Her presentation was preceded by a 3-year prodrome consisting of cytopenia and fever that were partially controlled by steroids and azathioprine.ConclusionFulminant hemophagocytic lymphohistiocytosis may follow a prodromal phase that possesses features suggestive of a chronic form of hemophagocytic lymphohistiocytosis, but which may also resemble immune cytopenias of other causes. A diagnosis of hemophagocytic lymphohistiocytosis should be considered in the setting of chronic pancytopenia.

The role of BMT in childhood histiocytoses

Childhood histiocytoses comprise two main diseases, Langerhans cell histiocytosis (LCH) and hemophagocytic lymphohistiocytosis (HLH). LCH is a rare disorder with obscure pathogenesis. Data on clonality suggested neoplastic origin, yet were not convincing. Dysregulation of cytokines and of DC trafficking and cross-talk are documented. Clinical manifestations and course are highly variable, ranging from self-healing solitary bone lesion to disseminated, multi-organ involvement with 20% fatality rate despite standard chemotherapy. HSCT has been applied in less than 50 cases, outside any trial, with good disease control but elevated early toxicity. The familial form of HLH (FHL) has been recognized as congenital immune deficiency, with mutations of PRF1, Munc13-4, syntaxin11 genes resulting in defective cellular cytotoxicity machinery. Chemo-immunotherapy allows temporary disease control, but HSCT holds as the only procedure with potential for cure. Rapid identification of genetic defects allows differential diagnosis from transient, virus-associated HLH, thus indicating early HSCT. The role of HSCT in childhood histiocytoses is thus very important. Better understanding of the pathogenesis, in particular of genetic and immune function defects, will help to tailor indications and, possibly less toxic, conditioning regimens, reducing treatment-related mortality, and thus disclosing the way to final cure.