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Summary: Patients with Langerhans cell histiocytosis (LCH) may develop progressive neurodegeneration in the central nervous system (ND‐CNS‐LCH). Neurofilament light protein (NFL) in cerebrospinal fluid (CSF) is a promising biomarker to detect and monitor ND‐CNS‐LCH. We compared paired samples of NFL in plasma (p‐NFL) and CSF in 10 patients (19 samples). Nine samples had abnormal CSF‐NFL (defined as ≥380 ng/l) with corresponding p‐NFL ≥ 2 ng/l. Ten samples had CSF‐NFL < 380 ng/l; eight (80%) with p‐NFL < 2 ng/l (p < 0.001; Fisher's exact test). Thus, our results suggest that p‐NFL may be used to screen for ND‐CNS‐LCH. Further studies are encouraged, including the role of p‐NFL for monitoring of ND‐CNS‐LCH. [ABSTRACT FROM AUTHOR]

Response to mitogen-activated protein kinase inhibition of neurodegeneration in Langerhans cell histiocytosis monitored by cerebrospinal fluid neurofilament light as a biomarker: a pilot study Keywords: Langerhans cell histiocytosis; central nervous system; neurodegeneration; mitogen-activated protein kinase inhibition; neurofilament light chain protein EN Langerhans cell histiocytosis central nervous system neurodegeneration mitogen-activated protein kinase inhibition neurofilament light chain protein 248 254 7 12/27/21 20220101 NES 220101 Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with highly variable clinical presentation.1 Granulomatous lesions of bone, skin, and lungs (particularly in adults) are most common, but the liver, spleen, bone marrow, and central nervous system (CNS) may also be affected.1 CNS involvement (CNS LCH) often causes endocrinopathies, most commonly diabetes insipidus (DI), but may also cause a debilitating slowly-progressive neurodegeneration.1,2 Notably, a population-based study reported that at least 24% of all children with LCH develop signs of neurodegenerative CNS LCH (ND-CNS-LCH) on magnetic resonance imaging (MRI).3 Thus, a strategy for early detection, treatment, and monitoring of ND-CNS-LCH is imperative. Central nervous system, neurodegeneration, Langerhans cell histiocytosis, mitogen-activated protein kinase inhibition, neurofilament light chain protein GLO:1XW/01jan22:bjh17781-fig-0001.jpg PHOTO (COLOR): 1 Neurofilament (NFL) levels in the cerebrospinal fluid (CSF) in the five children with central nervous system (CNS) affection of Langerhans cell histiocytosis (LCH) before and after initiation of treatment with mitogen-activated protein kinase pathway inhibitors (MAPKi). [Extracted from the article]

Background: Experimental models have demonstrated that immune surveillance by cytotoxic lymphocytes can protect from spontaneous neoplasms and cancer. In humans, defective lymphocyte cytotoxicity is associated with the development of hemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome. However, to the best of the authors' knowledge, the degree to which human lymphocyte cytotoxicity protects from cancer remains unclear. In the current study, the authors examined the risk of lymphoma attributable to haploinsufficiency in a gene required for lymphocyte cytotoxicity.Methods: The authors exploited a founder effect of an UNC13D inversion, which abolishes Munc13-4 expression and causes hemophagocytic lymphohistiocytosis in an autosomal recessive manner. Within 2 epidemiological screening programs in northern Sweden, an area demonstrating a founder effect of this specific UNC13D mutation, all individuals with a diagnosis of lymphoma (487 patients) and matched controls (1844 controls) were assessed using polymerase chain reaction for carrier status.Results: Among 487 individuals with lymphoma, 15 (3.1%) were heterozygous carriers of the UNC13D inversion, compared with 18 controls (1.0%) (odds ratio, 3.0; P = .002). It is interesting to note that a higher risk of lymphoma was attributed to female carriers (odds ratio, 3.7; P = .004).Conclusions: Establishing a high regional prevalence of the UNC13D inversion, the authors have reported an overrepresentation of this mutation in individuals with lymphoma. Therefore, the results of the current study indicate that haploinsufficiency of a gene required for lymphocyte cytotoxicity can predispose patients to lymphoma, suggesting the importance of cytotoxic lymphocyte-mediated surveillance of cancer. Furthermore, the results of the current study suggest that female carriers are more susceptible to lymphoma. [ABSTRACT FROM AUTHOR]

Aim: To present the first case series of patients with Langerhans cell histiocytosis (LCH) also affected by Crohn's disease (CD), both of which are granulomatous diseases, and in LCH investigate the role of interleukin (IL)‐23, which is a well‐described disease mediator in CD. Methods: A case series of three patients with LCH and CD were described; a cohort of LCH patients (n = 55) as well as controls (n = 55) were analysed for circulating IL‐23 levels; and the relation between the percentage of LCH cells in lesions and circulating IL‐23 levels was analysed in seven LCH patients. Results: Differential diagnostic challenges for these two granulomatous diseases were highlighted in the case series, and it took up to 3 years to diagnose CD. Elevated IL‐23 levels were found in LCH patients. The amount of lesional LCH cells correlated with the levels of circulating IL‐23. Conclusion: Both CD and LCH should be considered in patients with inflammatory gastrointestinal involvement. The IL‐23 pathway is a common immunological trait between these two granulomatous diseases. [ABSTRACT FROM AUTHOR]

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non‐oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH‐associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below −3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non‐oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage‐bone stem cell population. [ABSTRACT FROM AUTHOR]

Summary: Severe congenital neutropenia (SCN) of autosomal recessive inheritance, also known as Kostmann disease, is characterised by a lack of neutrophils and a propensity for life‐threatening infections. Using whole‐exome sequencing, we identified homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) in three patients with Kostmann‐like SCN, thus confirming the recent attribution of JAGN1 mutations to SCN. Using the human promyelocytic cell line HL‐60 as a model, we found that overexpression of patient‐derived JAGN1 mutants, but not silencing of JAGN1, augmented cell death in response to the pro‐apoptotic stimuli, etoposide, staurosporine, and thapsigargin. Furthermore, cells expressing mutant JAGN1 were remarkably susceptible to agonists that normally trigger degranulation and succumbed to a calcium‐dependent cell death programme. This mode of cell death was completely prevented by pharmacological inhibition of calpain but unaffected by caspase inhibition. In conclusion, our results confirmed the association between JAGN1 mutations and SCN and showed that SCN‐associated JAGN1 mutations unleash a calcium‐ and calpain‐dependent cell death in myeloid cells. [ABSTRACT FROM AUTHOR]

Aim: One in five children diagnosed with cancer will die from the disease. The aim of the study was to explore how children with cancer want to receive bad news about their disease, such as when no more treatment options are available.Methods: We conducted individual interviews with ten children with cancer, aged seven to 17 years, at a single paediatric oncology unit in central Sweden. Interviews were audio-taped and analysed with systematic text condensation. Bad news was defined as information about a potentially fatal outcome, such as a disease relapse, or information that the treatment administered was no longer working and that there was no more treatment possible.Results: All children expressed that they wanted truthful information and they did not want to be excluded from bad news regarding their illness. They wanted to be informed as positively as possible, allowing them to maintain hope, and in words that they could understand. They also wanted to receive any bad news at the same time as their parents.Conclusion: Children with cancer want to be fully informed about their disease, but they also wanted it to be relayed as positively as possible so that they could stay hopeful. [ABSTRACT FROM AUTHOR]

Objective To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). Methods A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Results Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76). Conclusion We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies. [ABSTRACT FROM AUTHOR]

Key Clinical Message We report a case of several autoimmune disorders eventually presenting as severe multi organ dysfunction syndrome caused by adult hemophagocytic lymphohistiocytosis ( HLH). Clinical and laboratory tests might lead to fatal misinterpretation without awareness of its diagnostic evaluation, as HLH shares common features with sepsis and immune-mediated systemic inflammatory response syndromes. [ABSTRACT FROM AUTHOR]

Skeletal involvement is generally, but not universally, characteristic of Langerhans cell histiocytosis ( LCH). We investigated whether the presence of bone lesions at diagnosis is a prognostic factor for survival in LCH. Nine hundred and thirty-eight children with multisystem ( MS) LCH, both high (386 RO+) and low ( RO−) risk, were evaluated for bone lesions at diagnosis. Risk organ ( RO+) involvement was defined as: haematopoietic system (haemoglobin <100 g/l, and/or white blood cell count <4·0 × 109/l and/or platelet count <100 × 109/l), spleen (>2 cm below the costal margin), liver (>3 cm and/or hypoproteinaemia, hypoalbuminaemia, hyperbilirubinaemia, and/or increased aspartate transaminase/alanine transaminase). Given the general view that prognosis in LCH worsens with increasing extent of disease, the surprising finding was that in MS+ RO+ LCH the probability of survival with bone involvement 74 ± 3% ( n = 230, 56 events) was reduced to 62 ± 4% ( n = 156, 55 events) if this was absent ( P = 0·007). An even greater difference was seen in the subgroup of patients with both liver and either haematopoiesis or spleen involvement: 61 ± 5% survival ( n = 105; 52 events) if patients had bony lesions, versus 47 ± 5% ( n = 111; 39 events) if they did not ( P = 0·014). This difference was retained in multivariate analysis ( P = 0·048). Although as yet unexplained, we conclude that bone involvement at diagnosis is a previously unrecognized favourable prognostic factor in MS+ RO+ LCH. [ABSTRACT FROM AUTHOR]

The article presents a case study of an 8-year old boy with haemorphagocytic lymphohistiocytosis (HLH) representing a case of familial haemophagocytic lymphohistiocytosis (FHL). It states that the oldest brother of the patient was wild-type for exon 15 mutation and carried intron 1 mutation. It also mentions that the defective cytotoxic lymphocyte functions of the two brothers were caused by reduced protein stability encoded by allele.

Aim To estimate whether and when children dying from a malignancy are recognized as being beyond cure and to study patterns of care the last weeks of life. Methods A nationwide retrospective medical record review was conducted. Medical records of 95 children (60% of eligible children) who died from a malignancy 2007-2009 in Sweden were studied. Results Eighty-three children (87%) were treated without curative intent at the time of death. Children with haematological malignancies were less likely to be recognized as being beyond cure than children with brain tumours [relative risks ( RR) 0.7; 95% confidence interval ( CI) 0.6-0.9] or solid tumours ( RR 0.8; 0.6-1.0). The transition to noncurative care varied from the last day of life to over four years prior to death (median 60 days). Children with haematological malignancies were treated with a curative intent closer to death and were also given chemotherapy ( RR 5.5; 1.3-22.9), transfusions ( RR 2.0; 1.0-4.0) and antibiotics ( RR 5.3; 1.8-15.5) more frequently than children with brain tumours the last weeks of life. Conclusion The majority of children dying from a malignancy were treated with noncurative intent at the time of death. The timing of a transition in care varied with the diagnoses, being closer to death in children with haematological malignancies. [ABSTRACT FROM AUTHOR]

Aim Severe congenital neutropenia ( SCN) is a rare disorder of myelopoiesis characterized by neutropenia, recurrent bacterial infections and a maturation arrest of the myelopoiesis in the bone marrow. Homozygous mutations in the HAX1 gene were described in patients with autosomal recessive SCN or Kostmann disease. Some of these patients display neurological disease. We noted, during the course of clinical management of patients with Kostmann disease, insufficient pubertal development in female patients, but not in our male patients. The study objective was to provide a detailed account of this phenotype and its possible relation to HAX1 mutations. Methods Detailed clinical histories and laboratory investigations of three patients with Kostmann disease belonging to the original kindred in northern Sweden described by Rolf Kostmann are reported. Results We report one male patient with normal puberty and two female patients with insufficient pubertal development. Elevated levels of LH and FSH were recorded in both patients. All three patients harbour the same p. Glu190 X mutation in the HAX1 gene. Conclusions We show for the first time that female patients with Kostmann disease display primary gonadal insufficiency. This suggests a possible role for HAX1 in the development and/or function of the human ovary. [ABSTRACT FROM AUTHOR]

Severe congenital neutropenia ( SCN) is characterized by low blood neutrophil counts, early bacterial infections, and risk of leukaemia development. As yet, no population-based incidence estimates of SCN have been reported. Children less than 16 years of age with SCN were sought in Sweden during the 20-year period 1987-2006 by a questionnaire to all Swedish Departments of Paediatrics and by reviewing the Swedish Health and Welfare Statistical Databases. Thirty-two patients were diagnosed with congenital neutropenia during this period. All received treatment with recombinant granulocyte-colony stimulating factor (G- CSF). Twenty-one patients were diagnosed as SCN or probable SCN, corresponding to 1·0 per 100 000 live births. Nine (43%) had ELANE mutations, four (19%) HAX1 mutations and eight (38%) were children with disease of unknown genetic aetiology. Four out of 21 patients (19%) developed myelodysplastic syndrome/leukaemia and three (14%) died, all with leukaemia. The cumulative incidence of myelodysplastic syndrome/leukaemia was 31%. The observed incidence of SCN in this population-based study was higher than previously estimated, possibly because genetic testing now can identify SCN cases previously thought to be idiopathic or benign neutropenia. The risk of developing myelodysplastic syndrome/leukaemia is considerable. ELANE mutations are the most commonly identified genetic defects. [ABSTRACT FROM AUTHOR]

Aim: To describe the clinical course, morbidity and platelet recovery in an unselected Nordic cohort of children with chronic Immune Thrombocytopenic Purpura (ITP). Methods: Prospective 5-year follow-up of 96 children with ITP lasting more than 6 months, with reporting of hospital admissions, severity of bleeding episodes and stabilization of platelet counts above 20, 50 and 150 × 109/L. Results: The estimated 5-year recovery rate was 52%; exclusion of 12 splenectomized children did not change the estimate. Events eliciting admission to hospital occurred in 39 (41%). Major haemorrhages occurred in eight children (8%), including a nonfatal intracranial haemorrhage in one child (1%). The overall admission rate was 0.4/year of thrombocytopenia, decreasing during follow-up as thrombocytopenia converted to milder degrees. Early recovery within 2 years of diagnosis occurred in 35%, was associated with low morbidity and was more likely in young children with abrupt onset of symptoms. Conclusion: In a Nordic cohort of children with chronic ITP, one half had recovered 5 years after diagnosis, more than half never required hospitalization and <10% experienced serious bleeding episodes, always with a platelet count <20 × 109/L. Aggressive management can be restricted to the minority of children with continuing severe thrombocytopenia and frequent, clinically significant bleeding events. [ABSTRACT FROM AUTHOR]

ABSTRACT Epstein-Barr virus associated hemophagocytic lymphohistiocytosis (EBV-HLH) has a high mortality rate among children. The pathogenesis of, and underlying predisposing factors for, EBV-HLH are as yet unclear; however, natural killer cells may play a key role in progression of the disease. This study attempted to determine whether killer cell immunoglobulin-like receptor (KIR) gene polymorphisms are responsible for susceptibility to EBV-HLH. Of the 125 children with EBV infection studied, 59 had EBV-HLH and 66 patients had EBV associated infectious mononucleosis (IM) without HLH. The control group was 146 normal children without immune deficiency. KIR polymorphisms were determined by polymerase chain reaction with sequence-specific primers. KIR polymorphism data were analyzed using the X2 test or Fisher's exact test. The overall observed carrier frequency (OF) of KIR2DS5 was significantly higher in EBV-HLH patients than in IM patients and normal controls (49.2% versus 31.8%, P = 0.048; 49.2% versus 31.5%, P = 0.018, respectively), and the odds ratios (95% confidence interval) were 2.071 (1.001-4.286) and 2.101(1.132-3.900) respectively. The OF of KIR3DS1 was significantly higher in the EBV-HLH patients than in the IM patients (47.4% versus 24.6%, P = 0.012), but not different from normal controls. In summary, KIR polymorphisms may be involved in the development of EBV-HLH, with KIR2DS5 promoting susceptibility to this disease. The obtained KIR data will enrich the understanding of genetic relationships among diseases associated with EBV infection in children. [ABSTRACT FROM AUTHOR]

The syntaxin 11 (STX11) gene is mutated in a proportion of patients with familial haemophagocytic lymphohistiocytosis (FHL) and exocytosis of cytotoxic granules is impaired in STX11-deficient NK cells. However, the subcellular localization, regulation of expression and molecular function of STX11 in NK cells and other cytotoxic lymphocytes remain unknown. Here we demonstrate that STX11 expression is strictly controlled by several mechanisms in a cell-type-specific manner and that the enzymatic activity of the proteasome is required for STX11 expression in NK cells. In resting NKL cells, STX11 was localized in the cation-dependent mannose-6-phosphate receptor (CD-M6PR)-containing compartment, which was clearly distinct from cytotoxic granules or Rab27a-expressing vesicles. These subcellular structures appeared to fuse at the contact area with NK-sensitive target cells as demonstrated by partial colocalization of STX11 with perforin and Rab27a. Although STX11-deficent allo-specific cytotoxic T-lymphocytes efficiently lysed target cells and released cytotoxic granules, they exhibited a significantly lower extent of spontaneous association of perforin with Rab27a as compared with STX11-expressing T cells. Thus, our results suggest that STX11 promotes the fusion of Rab27a-expressing vesicles with cytotoxic granules and reveal an additional level of complexity in the spatial/temporal segregation of subcellular structures participating in the process of granule-mediated cytotoxicity. [ABSTRACT FROM AUTHOR]

There is currently no well-accepted therapy for central nervous system Langerhans cell histiocytosis (CNS-LCH), a neuroinflammatory disease clinically characterized by often progressive, neurological symptoms including ataxia, dysarthria, dysphagia, hypertonicity, intellectual impairment and behavioural abnormalities. We applied immunomodulative/anti-inflammatory treatment on a patient with progressive CNS-LCH disease. Intravenous immunoglobulin (IVIG) was administered monthly for 15 years to a patient with severe, image-verified neurodegenerative CNS-LCH. During the IVIG treatment, the neurological deterioration initially appeared to be haltered, but over time there was still some deterioration. IVIG may be beneficial in partly haltering CNS-LCH neurodegeneration, but further studies are needed. [ABSTRACT FROM AUTHOR]

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease-causing genes ( PRF1, UNC13D, STX11) have been identified. We performed a genotype-phenotype study in a large, multi-ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in PRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%) and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed for all three genes, no molecular diagnosis was established. STX11 mutations were most common in Turkish families (7/28, 25%), whereas in Middle East families, PRF1 mutations were most frequent (6/13, 46%). No biallelic mutation was identified in most families of Nordic origin (13/14, 93%). Patients carrying PRF1 mutations had higher risk of early onset (age <6 months) compared to patients carrying STX11 mutations [adjusted odds ratio 8·23 (95% confidence interval [CI] = 1·20–56·40), P = 0·032]. Moreover, patients without identified mutations had increased risk of pathological cerebrospinal fluid (CSF) at diagnosis compared to patients with STX11 mutations [adjusted odds ratio 26·37 (CI = 1·90–366·82), P = 0·015]. These results indicate that the disease-causing mutations in FHL have different phenotypes with regard to ethnic origin, age at onset, and pathological CSF at diagnosis. [ABSTRACT FROM AUTHOR]

Syntaxin-11 is a member of a family of membrane-trafficking proteins referred to as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Recent studies have shown that syntaxin-11 is expressed in natural killer cells and cytotoxic T cells and is likely to play a role in the granule exocytosis pathway. However, the biological role of syntaxin-11 in other immune cells has remained elusive. This study found that stimulation with interferon-γ upregulated syntaxin-11 expression in primary monocytes. Experiments using monocytes from patients with familial haemophagocytic lymphohistiocytosis harbouring mutations in the gene encoding syntaxin-11 ( STX11), or monocytes from healthy individuals in which syntaxin-11 was downregulated using specific short-interfering RNA, demonstrated that syntaxin-11 was not required for antibody-dependent cellular cytotoxicity. On the other hand, silencing of syntaxin-11 expression in primary macrophages enhanced the phagocytosis of apoptotic target cells with a concomitant increase in macrophage secretion of tumour necrosis factor-α. Moreover, Fcγ-receptor-mediated uptake of target cells was also enhanced following silencing of syntaxin-11 expression in macrophages. In addition, syntaxin-11 localized to the plasma membrane in macrophages ingesting apoptotic cell corpses. Syntaxin-11 thus appears to act as a negative regulator of human macrophage engulfment of apoptotic cells and IgG-opsonized red blood cells. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) may cause meningoencephalitis and significant neurological sequelae. We examined the relationship between neurological symptoms and cerebrospinal fluid (CSF) at diagnosis, and long-term outcome, in all children enroled in the HLH-94-study prior to July 1, 2003, for whom information on CSF at diagnosis was available ( n = 193). Patients were divided into four groups: (i) normal CSF (cells/protein) and no neurological symptoms ( n = 71); (ii) normal CSF but neurological symptoms ( n = 21); (iii) abnormal CSF but no symptoms ( n = 50); and (iv) abnormal CSF with neurological symptoms ( n = 51). At diagnosis, neurological symptoms were reported in 72/193 (37%) (seizures = 23); abnormal CSF in 101/193 (52%), and either or both in 122/193 (63%). Altogether 16/107 (15%) survivors had neurological sequelae at follow-up (median 5·3 years). Multivariate hazard ratios (HR) for mortality were 0·98 [95% confidence interval (CI) = 0·42–2·31], 1·52 (0·82–2·82) and 2·05 (1·13–3·72) for groups 2–4, compared with group 1. Moreover, sequelae were more frequent in group 4 (7/21, 33%) compared to groups 1–3 (9/86, 10%) ( P = 0·015). Patients with abnormal CSF at diagnosis had significantly increased mortality [HR = 1·78 (95% CI = 1·08–2·92), P = 0·023]. Thus, a substantial proportion of HLH survivors suffer neurological sequelae, and children with abnormal CSF have increased risk of mortality and neurological sequelae. Prompt treatment of HLH at onset or relapse may reduce these complications. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition with high mortality. We report an extremely premature girl, born in the 24th gestational week (BW 732 g), that during her second month developed a severe HLH subsequent to a Serratia marcescens septicemia, with hepatosplenomegaly, cytopenias, hyperbilirubinemia (mostly conjugated, total bilirubin 916 μmol/L), hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia (21266 μg/L), and elevated sIL-2 receptor levels. Genetic analysis revealed no PRF1, STX11 or UNC13D gene mutations. Treatment was provided according to the HLH-2004 protocol with etoposide, dexamethasone, and immunoglobulin, but no cyclosporin because of immature kidneys. She recovered fully from the HLH but developed a severe retinopathy as well as green teeth secondary to the hyperbilirubinemia. We conclude that secondary, bacteria-associated HLH can develop in premature infants, and that HLH can be treated with cytotoxic therapy also in premature infants. It is important to be aware of HLH in premature infants, since it is treatable. [ABSTRACT FROM AUTHOR]

Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term ‘infantile genetic agranulocytosis’ for this condition, which is now known as Kostmann syndrome. Recent studies have revealed mutations in ELA-2, encoding the neutrophil granule protease, neutrophil elastase, in autosomal dominant neutropenia, and mutations in HAX-1, encoding an anti-apoptotic protein, in autosomal recessive neutropenia. Conclusion: Future studies should aim to clarify the mechanisms underlying the evolution of secondary malignancies in these patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Antibodies with anti-M specificity are detected in 10 percent of pregnant women with a positive antibody screen, but anti-M is only rarely associated with hemolytic anemia in the fetus. STUDY DESIGN AND METHODS: This study reports on three pregnancies in one family that all resulted in severe fetal anemia. The first fetus died in utero with hydrops fetalis during the 20th gestational week and the second child was delivered after 28 weeks of gestation with hydrops fetalis and a hemoglobin level of 16 g per L whereas the third affected child was treated with intrauterine red cell (RBC) transfusions before delivery at 28 weeks of gestation. RESULTS: The direct antiglobulin test was negative but anti-M in a low titer was detected through the three pregnancies, and its clinical relevance, which initially was uncertain, was confirmed by pronounced in vivo hemolysis in maternal blood of chromate (51Cr)-labeled M+ RBCs and normal survival of 51Cr labeled M– RBCs. CONCLUSION: It is concluded that anti-M immunization in a few cases may cause severe fetal hemolytic anemia and intrauterine death. It remains to be elucidated why a normally clinically insignificant antibody is this aggressive in a small proportion of cases. Because the condition is treatable, anti-M must be considered as a possible cause of fetal anemia and intrauterine death. [ABSTRACT FROM AUTHOR]

Chronic neutropenia comprises several different diseases that vary in degree of severity and management. We analysed the levels of the neutrophil-derived protein pro-LL-37 in plasma of patients with chronic neutropenia to assess whether it could be used to differentiate different categories of chronic neutropenia. All patients with severe congenital neutropenia were pro-LL-37 deficient. This was in contrast to patients with autoimmune or idiopathic neutropenia, who exhibited normal pro-LL-37 levels while patients with cyclic neutropenia displayed an oscillation of pro-LL-37 in plasma. Plasma levels of pro-LL-37 may thus prove useful for differential diagnosis of chronic neutropenia. [ABSTRACT FROM AUTHOR]

Unlabelled: Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term "infantile genetic agranulocytosis" for this condition, which is now known as Kostmann syndrome. Recent studies have demonstrated a lack of antibacterial peptides and severe periodontitis in these patients despite recombinant growth factor treatment. Moreover, an increased degree of apoptosis of myeloid progenitor cells in the bone marrow has been shown.Conclusion: Future studies should aim to clarify the underlying molecular genetic defect in Kostmann syndrome. [ABSTRACT FROM AUTHOR]

Background: Patients with Kostmann syndrome (severe congenital neutropenia [SCN]) typically normalize their absolute neutrophil count (ANC) upon granulocyte colony-stimulating factor (G-CSF) therapy. However, although they no longer experience life-threatening bacterial infections, they frequently still have recurrent gingivitis and even severe periodontitis, often starting in early childhood.Methods: We studied the periodontal disease in the four surviving patients belonging to the family originally described by Kostmann. Their odontological records, x-rays, color photos, bacterial cultures, serum antibodies to oral bacteria, and histopathological examinations were reviewed. The data were also correlated to previous investigations on their antibacterial peptides and molecular biology.Results: Three patients had periodontal disease, despite normal ANC and professional dental care, and had neutrophils deficient in antibacterial peptides. One of these patients also had a heterozygous mutation in the neutrophil elastase gene, had severe periodontal disease and overgrowth of the periodontal pathogen Actinobacillus actinomycetemcomitans in the dental flora, and 15 permanent teeth had been extracted by the age of 27. One bone marrow-transplanted patient had no periodontal disease.Conclusions: Normalized ANC levels are not sufficient to maintain normal oral health in SCN patients, and because neutrophils are important for first-line defense and innate immunity, the deficiency of the antibacterial peptide LL-37 probably explains their chronic periodontal disease. Professional dental care is still important for SCN patients, despite treatment with G-CSF and normal ANC levels. Whether antibacterial peptides play a role in the pathogenesis of periodontitis in other patients remains to be elucidated. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the long-term outcome of Langerhans cell histiocytosis (LCH) in children.Methods: We re-evaluated all children (<15 y old at diagnosis) treated at our unit in 1962-1989. Histopathology specimens were reviewed and verified for 49 patients. Forty patients underwent physical examination and laboratory tests, and 38 were subjected to imaging, at a median time of 16 y (range 5.5-33.5) after diagnosis.Results: Altogether, 5/49 (10%) children died, all with multi-system disease and age <2 y at diagnosis. Age at diagnosis (p=0.001) and survival (p=0.014) for the 22 children with multi-system disease was significantly lower compared with the 27 children with single-system disease. The term "maximal extent of disease" was introduced since reactivation of LCH often tends to involve additional organs not previously affected by the disease. At follow-up, late sequelae had developed in 17/40 (42%) patients, including diabetes insipidus in 6/40 (15%), CNS complications in at least 4/40 (10%) (3/16, 19%, of multi-system patients) and late-stage pulmonary disease in 4/38 (11%). Seven out of 21 (33%) of the patients with multi-system disease were alive and healthy without sequelae at follow-up, as compared to 16/24 (67%) of those with single-system disease (p=0.026). Of 14 individuals 25 y at follow-up, senior high school had been completed in 7/9 (78%) with single-system and 1/5 (20%) with multi-system disease (at maximal disease extent) (p=0.091).Conclusion: Multi-system LCH is associated not only with increased mortality but also pronounced propensity for severe late sequelae; 51% of the patients (multi-system=33%, single-system=67%) were alive without sequelae at follow-up. Among multi-system patients, at least 19% suffered CNS sequelae. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) poses major therapeutic challenges, and the primary inherited form, familial haemophagocytic lymphohistiocytosis (FHL), is usually fatal. We evaluated, including Cox regression analysis, survival in 86 children (29 familial) that received HLH-94-therapy (etoposide, dexamethasone, ciclosporin) followed by allogeneic stem cell transplantation (SCT) between 1995 and 2000. The overall estimated 3-year-survival post-SCT was 64% [confidence interval (CI) = ±10%] (n = 86); 71 ± 18% in those patients with a matched related donor (MRD,n = 24), 70 ± 16% with a matched unrelated donor (MUD,n = 33), 50 ± 24% with a family haploidentical donor (haploidentical,n = 16), and 54 ± 27% with a mismatched unrelated donor (MMUD,n = 13). After adjustment for potential confounding factors, estimated odds ratios (OR) for mortality were 1·93 (CI =0·61–6·19) for MUD, 3·31 (1·02–10·76) for haploidentical, and 3·01 (0·91–9·97) for MMUD, compared with MRD. In children with active disease after 2-months of therapy (n = 43) the OR was 2·75 (1·26–5·99), compared with inactive disease (n = 43). In children with active disease at SCT (n = 37), the OR was 1·80 (0·80–4·06) compared with inactive disease (n = 49), after adjustment for disease activity at 2-months. Mortality was predominantly transplant-related. Most HLH patients survived SCT using MRD or MUD, and survival with partially mismatched donors was also acceptable. Patients that responded well to initial pretransplant-induction therapy fared best, but some persisting HLH activity should not automatically preclude performing SCT. [ABSTRACT FROM AUTHOR]

The familial form of haemophagocytic lymphohistiocytosis (HLH) is a fatal disease, with allogeneic stem cell transplantation (SCT) being the only curative treatment. In contrast, patients with secondary (infection-associated) HLH usually do not require SCT. Since it often is difficult to distinguish primary and secondary HLH, we wanted to identify a tool that provides guidance on whether SCT is required. The clinical outcome of 65 HLH patients was analysed in relation to the recently reported four types of defects in natural killer (NK)-cell cytotoxicity in HLH. None (0%) of the 36 patients with NK-cell deficiency type 3 attained a sustained (1-year) remission after stopping therapy without receiving SCT, in contrast to 45% (13/29) non-type 3 patients (P < 0·001). Most type 3 patients (22/36) underwent SCT (14/22, 64% are alive), whereas 11 of 14 that did not receive SCT died, and the three others had received HLH-therapy during the last year of follow-up. Of 54 patients analysed for perforin expression and/or mutation, the five with perforin deficiency were all type 3 patients. The data suggests that HLH patients with NK-cell deficiency type 3 will probably require SCT to survive. Thus, NK-cell deficiency classification may provide valuable guidance in judging whether an HLH-patient needs SCT. [ABSTRACT FROM AUTHOR]