Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement.

Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.

Et barn med langvarig anemi.

Background: Anemia in children is common and finding the underlying cause is often uncomplicated. However, in some cases, the underlying diagnosis is rare and difficult to diagnose. Case presentation: A toddler presented with severe anemia with normal red cell indices and a low reticulocyte count. The remaining hematological parameters were normal, bar a slight thrombocytosis. At this point a diagnosis of transient erythroblastopenia of childhood (TEC) was made. The child continued to have slight anemia with intermittent macrocytosis and reticulocytopenia throughout childhood. Growth and development was normal, and there were no signs of congenital abnormalities in the heart or kidneys nor any craniofacial or phalangeal defects. Repeated bone marrow examinations showed no significant abnormal findings. As a teenager the patient was diagnosed with Diamond-Blackfan anemia through an exome-based gene panel which revealed a mutation in the RPL11 gene. Interpretation: Congenital bone marrow failure syndromes do not always present in the classical way, leading to a delayed diagnosis. The increasing availability of different gene panels for patients with persistent abnormal hematological laboratory parameters offers the possibility of a more accurate diagnostic pathway, which is important for adequate follow-up and genetic counselling.

[Sickle cell disease ­ clinical manifestations and diagnostics]. / Sigdcellesykdom ­ kliniske manifestasjoner og diagnostikk.

Sickle cell disease is a group of diseases presenting with a set of characteristic acute and chronic manifestations. Sickle cell disease has traditionally been uncommon in the Northern European population; however, due to demographic changes, it is increasingly also something that Norwegian clinicians should be cognisant of. In this clinical review article we wish to present a brief introduction to sickle cell disease, with an emphasis on its aetiology, pathophysiology, clinical manifestation and how the diagnosis is established based on laboratory testing.

Impact of Allogeneic Hematopoietic Stem Cell Transplantation on Nutritional Status and Intake in Children.

OBJECTIVES: This study aimed to describe the impact of allogeneic/haploidentical hematopoietic stem cell transplantation on nutritional status and intake in a group of children aged 2 to 18 years. METHODS: In an observational study, data were collected prospectively. Patients were prescribed individual nutritional support by hospital routines. Anthropometrics were measured pre-transplant at hospital admission and weekly from the day of transplant (day 0) until day +28. z scores for weight, height, and BMI were calculated using Norwegian growth references to assess nutritional status. Pre-transplant diet was assessed on the day of hospitalization. Nutrient provision from enteral nutrition (EN = oral and tube) and parenteral nutrition (PN) was assessed by daily records from day +1 until day +28, or previous discharge, and compared with recommendations (RI) from the Nordic Nutrition Recommendations and ESPGHAN guidelines. Total energy intake was presented as the percentage (%) of basal metabolic rate (BMR) calculated by the Schofield equation. Macro- and micronutrient provisions were presented as medians (interquartile range) and the % of RI. RESULTS: Twenty-eight patients, mean age 10.3 years (range 3.5-16.6), were included. Two-thirds (n = 18) had malignant diseases. At admission, mean weight Z-score was -0.3, height z scores -0.7, and BMI Z-score 0.1. Eighteen percent (n = 5) were stunted and 25% (n = 7) had overweight. At admission, 25% (n = 7) had established tube feeding, and 7% (n = 2) also had PN. No significant changes in weight z scores were detected during the studied weeks ( P = 0.454). The median daily energy provision was 115% (110-123) of BMR and proteins 1.5 (1.3-1.8) g/kg. EN was provided during a median of 93% of the studied days and provided 21% of the energy. PN was given on a median of 96% of the studied days and provided 79% of energy. RI for vitamins, magnesium, and zinc was met. Provision of copper, iodine, selenium, calcium, and phosphate was below RI. CONCLUSIONS: Combined EN and PN providing 115% of BMR and 1.5 g/kg protein ensured stable weight by day +28 and covered RI, except for trace elements and minerals.

Bone mineral density and nutrition in long-term survivors of childhood brain tumors.

BACKGROUND AND AIMS: Childhood cancer survivors are at risk of unwanted late effects. The primary aim of this study was to assess bone mineral density Z-scores (BMDz) in long-term survivors of childhood medulloblastoma (MB) or central nervous system supratentorial primitive neuroectodermal tumor (CNS-PNET). Secondary aims were to describe nutrient intake, vitamin D status, physical activity and explore potential risk factors for decreased BMDz. METHODS: All MB and CNS-PNET survivors treated at Oslo University Hospital from 1974 to 2013 were invited to participate in a cross-sectional study. Dual-energy x-ray absorptiometry (Lunar Prodigy) assessed BMDz lumbar spine, BMDz total body, and lean body mass. Decreased BMDz was defined as a combination of low BMDz -1 to -1.99 and very low BMDz ≤-2. Lean body mass index (LMI) was calculated by dividing lean body mass by the squared height. Nutrient intake was assessed by a 3-day food record. Serum 25(OH)D was analyzed. Physical activity was reported by a questionnaire. Descriptive statistics and multivariable Cox regression analyses were applied. RESULTS: Fifty survivors with a median age of 25.5 years (5.5-51.9) and a median follow-up time of 19.5 years (3.2-40.5) were included. Mean BMDz lumbar spine was -0.8 (SD 1.1, 95% CI: -1.1 to -0.4), and BMDz total body was -0.6 (SD 1.1, 95% CI: -0.9 to -0.3). Decreased BMDz was detected in 48% of the lumbar spine and 34% of the total body measurements. In all, 62% had low calcium, and 69% had low vitamin D intake. 26% of participants had serum 25(OH)D < 50 nmol/L, and 62% reported an inactive lifestyle. Male sex, higher age at diagnosis, and lower LMI were potential risk factors for decreased BMDz. CONCLUSIONS: Long-term survivors of childhood MB and CNS-PNET had decreased BMDz, and risk factors were male sex, higher age at diagnosis, and lower LMI. Inadequate calcium and vitamin D intake, an inactive lifestyle, and a high prevalence of 25(OH)D ≤ 50 nmol/L were detected.

Neuropsychological functioning in survivors of childhood medulloblastoma/CNS-PNET: The role of secondary medical complications.

Objective To investigate the long-term cognitive consequences of malignant pediatric brain tumor and its treatment, and factors explaining variability in cognitive functioning among survivors. Method: A geographical cohort of survivors of pediatric medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET), treated between 1974 and 2013, was invited to participate. Of the 63 surviving patients, 50 (79%) consented to participation. The participants were tested with a battery of neuropsychological tests covering a wide age range. Verbal cognition, nonverbal cognition, processing speed, attention, memory, executive functioning, and manual dexterity were assessed. The participants were between 5:5 and 51:11 years of age at time of assessment. Assessments took place on average 19 years after primary tumor resective surgery. Results: One participant had a severe intellectual disability. For the rest, IQ varied from 52 to 125, with a mean score of 88.0 (SD 19.7). Twenty-eight (56%) of the participants had full-scale IQ scores in the age-average range or above. Gender, age at operation, time since operation, the presence of secondary medical complications, and treatment variables explained 46% of the variability in IQ scores, F(4,44) = 9.5, p<.001. The presence of endocrine insufficiency in combination with either epilepsy and/or hydrocephalus was associated with lowered IQ, lowered processing speed, and memory impairments. Conclusion: Patients treated for childhood MB and CNS-PNET have a lifelong risk of medical sequelae, including impaired cognitive functioning. This study adds to the literature by demonstrating the importance of following neuropsychological functioning closely, especially processing speed, learning, and memory, in survivors who have multiple secondary medical complications.

Alloimmunization in transfused patients with constitutional anemias in Norway.

BACKGROUND AND OBJECTIVES: The status of red blood cell alloimmunization in patients with constitutional anemias including hemoglobinopathies is not known in Norway. The study objective was to investigate the impact of a strategy based on phenotype-matching for C, c, E, e, K, Jka, Jkb, Fya, Fyb, S and s on alloimmunization. MATERIALS AND METHODS: We reviewed transfusions of 40 patients retrospectively using the computerized blood bank management system and medical records; including diagnosis, age at start of transfusion therapy, gender, number and age of packed red blood cell units transfused, follow-up time, phenotypes of the donors and patients, antigen-negative patients exposed to antigen-positive packed red blood cell units, transfusion reactions and alloantibody specificities. RESULTS: Forty patients received 5402 packed red blood cell units. Alloimmunization frequency was 20 % for the whole group, being 7%, 25 % and 30 % in patients with sickle cell disease (n = 14), thalassemia (n = 16) and other conditions (n = 10), respectively. The alloantibodies detected were anti-E, -c, -C, -Cw, -K, -Jka and -Lua. CONCLUSION: Good communication between the clinicians and the transfusion services is essential for successful management of patients with constitutional anemias. Providing full phenotype-matched units was not always possible. Extended pheno-/genotyping before the first transfusion and providing antigen-negative units for antigen-negative patients for at least C, c, E and K in every red cell transfusion would probably have reduced the alloimmunization rate. Non-phenotype-matched transfusions seem to be the main reason for alloimmunization. Finding markers for identifying responders prone to alloimmunization will ensure targeted transfusion strategies.

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

Unmet rehabilitation needs in 86% of Norwegian paediatric embryonal brain tumour survivors.

AIM: To study incidence, types and degrees of late effects in a geographical cohort of paediatric medulloblastoma and central nervous system primitive neuroectodermal tumour (CNS-PNET) survivors, and identify the need for rehabilitation. METHODS: Between 1974 and 2013, 63 patients survived treatment for paediatric medulloblastoma and CNS-PNET at Oslo University Hospital, Norway. Of these, 50 accepted invitation and were included in this study. RESULTS: Median follow-up was 20 years (range 3.2-41), and 96% of participants had developed late effects. Cognitive impairment was found in 72%, reduced hearing in 68%, endocrine deficits in 66%, epilepsy in 32% and another 30% had been diagnosed with one or more second primary neoplasms. Radiotherapy significantly increased risk of secondary primary neoplasms and endocrinological deficits, chemotherapy risk of ototoxicity and endocrinological deficits, and epilepsy was found significantly more often in CNS-PNET than medulloblastoma patients. Epilepsy was the main cause of cognitive impairments (full-scale IQ) in our study. 86% of participants had an unmet rehabilitation need. CONCLUSION: Significant late effects and unmet rehabilitation needs were documented in the large majority of survivors after treatment for paediatric medulloblastoma and CNS-PNET.

Children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor in Norway from 1974 through 2013: Unexplainable regional differences in survival.

BACKGROUND: A previous study based on Norwegian Cancer Registry data suggested regional differences in overall survival (OS) after treatment for medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. The purpose of the present study was to confirm in an extended cohort whether there were regional differences in outcome or not, and if so try to identify possible explanations. MATERIAL AND METHODS: Data from patients aged 0-20 years diagnosed with and treated for MB/CNS-PNET at all four university hospitals in Norway from 1974 to 2013 were collected and compared. RESULTS: Of 266 identified patients, 251 fulfilled inclusion criteria. MB was diagnosed in 200 and CNS-PNET in 51 patients. Five-year OS and event-free survival (EFS) were 59% and 52%, respectively. There was a significant difference in five-year OS and EFS between MB and CNS-PNET patients; 62% versus 47% (P =  0.007) and 57% versus 35% (P < 0.001). In multivariable analysis, two factors were found to significantly contribute to improved five-year OS and EFS, whereas one factor contributed to improved five-year OS only. Gross total resection (GTR) versus non-GTR (hazard ratio [HR] 0.53, P =  0.003; HR 0.46, P < 0.001) and cerebrospinal irradiation (CSI) versus non-CSI (HR 0.24, P < 0.001; HR 0.28, P < 0.001) for both, and treatment outside Oslo University Hospital for OS only (HR 0.64, P =  0.048). CONCLUSION: Survival was comparable with data from other population-based studies, and the importance of GTR and CSI was confirmed. The cause for regional survival differences could not be identified.

Hb Oslo [ß42(CD1)Phe→Ile; HBB: c.127T>A]: A Novel Unstable Hemoglobin Variant Found in a Norwegian Patient.

Unstable hemoglobin (Hb) variants are the result of sequence variants in the globin genes causing precipitation of Hb molecules in red blood cells (RBCs). Intracellular inclusions derived from the unstable Hb reduce the life-span of the red cells and may cause hemolytic anemia. Here we describe a patient with a history of hemolytic anemia and low oxygen saturation. She was found to be carrier of a novel unstable Hb variant, Hb Oslo [ß42(CD1)Phe→Ile (TTT>ATT), HBB: c.127T>A] located in the heme pocket of the ß-globin chain. Three-dimensional modeling suggested that isoleucine at position 42 creates weaker interactions with distal histidine and with the heme itself, which may lead to altered stability and decreased oxygen affinity. At steady state, the patient was in good clinical condition with a Hb concentration of 8.0-9.0 g/dL. During virus infections, the Hb concentration fell and on six occasions during 4 years, the patient needed a blood transfusion.

Outcome for children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor (CNS-PNET) - a retrospective analysis spanning 40 years of treatment.

BACKGROUND: Medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor of the central nervous system (CNS-PNET) are among the most common pediatric brain tumors. The diagnosis, treatment, and outcome of MB/CNS-PNET patients treated during the last four decades at Oslo University Hospital (OUH) are described. MATERIAL AND METHODS: All patients younger than 20 years of age diagnosed and treated for MB/CNS-PNET at OUH between 1 January 1974 and 31 December 2013 were identified. RESULTS: We found 175 patients. In 13 of them, the diagnosis was changed upon histopathological review and in 4 patients part of the treatment was administered at other hospitals. Thus, 158 patients were included for further analysis. Eight patients did not receive adjuvant therapy because of a dismal clinical condition. The overall 5-year survival rate for MB and CNS-PNET was 54%, for MB 57%, and for CNS-PNET 41%. Gross total resection (GTR) was achieved in 118 patients and 5-year overall survival for patients with GTR versus those with non-GTR differed significantly with 64% versus 22%. Cytological examination of the cerebrospinal fluid was performed in 52 patients. A total of 126 patients received radiotherapy as part of the primary treatment and 24 did not due to young age. Median time from surgery to start of radiotherapy was 33 days. Duration of radiotherapy was more than 48 days in 22% of patients. At the time of analysis, 63 patients were alive and disease-free, one alive with disease, and 94 patients were deceased; 84 of these due to MB/CNS-PNET and 10 due to supposed late effects from the treatment. CONCLUSIONS: Survival was comparable to data from other population-based studies. The importance of GTR for survival was corroborated. Reporting real-world data remains crucial to know the true outcome of patients treated outside clinical trials.

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity.

PURPOSE: Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. METHODS: Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. RESULTS: The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 109/L, P = 0.01; median ANC 1.4 vs. 1.7 × 109/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses). CONCLUSION: For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.

Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer.

BACKGROUND: Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMT(LA)) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMT(WT)) when treated with 6 MP maintenance therapy starting doses of 75 mg/m(2)/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m(2)/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol. PROCEDURE: We explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype. RESULTS: The overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMT(LA) who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose <75 mg/m(2)/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMT(LA) was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6-33.3%) vs. 6.7% (2.9-15.5%), P = 0.03). CONCLUSION: This study indicates that reducing 6MP starting dose for patients with TPMT(LA) may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMT(WT).

Preserved function after angioembolisation of splenic injury in children and adolescents: a case control study.

BACKGROUND: Non-operative management for blunt splenic injuries was introduced to reduce the risk of overwhelming post splenectomy infection in children. To increase splenic preservation rates, splenic artery embolization (SAE) was added to our institutional treatment protocol in 2002. In the presence of clinical signs of ongoing bleeding, SAE was considered also in children. To our knowledge, the long term splenic function after SAE performed in the paediatric population has not been evaluated and constitutes the aim of the present study. METHODS: A total of 11 SAE patients less than 17 years of age at the time of injury were included with 11 healthy volunteers serving as matched controls. Clinical examination, medical history, general blood counts, immunoglobulin quantifications and flowcytometric analysis of lymphocyte phenotypes were performed. Peripheral blood smears were examined for Howell-Jolly bodies (H-J bodies) and abdominal ultrasound was performed in order to assess the size and perfusion of the spleen. RESULTS: On average 4.6 years after SAE (range 1-8 years), no significant differences could be detected between the SAE patients and their controls. Total and Pneumococcus serospecific immunoglobulins and H-J bodies did not differ between the study groups, nor did general blood counts and lymphocyte numbers, including memory B cell proportions. The ultrasound examinations revealed normal sized and well perfused spleens in the SAE patients when compared to their controls. CONCLUSION: This case control study indicates preserved splenic function after SAE for splenic injury in children. Mandatory immunization to prevent severe infections does not seem warranted.

Preserved splenic function after angioembolisation of high grade injury.

BACKGROUND: After introducing splenic artery embolisation (SAE) in the institutional treatment protocol for splenic injury, we wanted to evaluate the effects of SAE on splenic function and assess the need for immunisation in SAE treated patients. METHODS: 15 SAE patients and 14 splenectomised (SPL) patients were included and 29 healthy blood donors volunteered as controls. Clinical examination, medical history, general blood counts, immunoglobulin quantifications and flowcytometric analysis of lymphocyte phenotypes were performed. Peripheral blood smears from all patients and controls were examined for Howell-Jolly (H-J) bodies. Abdominal doppler, gray scale and contrast enhanced ultrasound (CEUS) were performed on all the SAE patients. RESULTS: Leukocyte and platelet counts were elevated in both SAE and SPL individuals compared to controls. The proportion of memory B-lymphocytes did not differ significantly from controls in either group. In the SAE group total IgA, IgM and IgG levels as well as pneumococcal serotype specific IgG and IgM antibody levels did not differ from the control group. In the SPL group total IgA and IgG Pneumovax(®) (PPV23) antibody levels were significantly increased, and 5 of 12 pneumococcal serotype specific IgGs and IgMs were significantly elevated. H-J bodies were only detected in the SPL group. CEUS confirmed normal sized and well perfused spleens in all SAE patients. CONCLUSION: In our study non-operative management (NOM) of high grade splenic injuries including SAE, was followed by an increase in total leukocyte and platelet counts. Normal levels of immunoglobulins and memory B cells, absence of H-J bodies and preserved splenic size and intraparenchymal blood flow suggest that SAE has only minor impact on splenic function and that immunisation probably is unnecessary.

Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity.

The autosomal recessive immunodeficiencies Griscelli syndrome type 2 (GS2) and familial hemophagocytic lymphohistiocytosis type 3 (FHL3) are associated with loss-of-function mutations in RAB27A (encoding Rab27a) and UNC13D (encoding Munc13-4). Munc13-4 deficiency abrogates NK-cell release of perforin-containing lytic granules induced by signals for natural and antibody-dependent cellular cytotoxicity. We demonstrate here that these signals fail to induce degranulation in resting NK cells from Rab27a-deficient patients. In resting NK cells from healthy subjects, endogenous Rab27a and Munc13-4 do not colocalize extensively with perforin. However, phorbol 12-myristate 13-acetate and ionomycin stimulation or conjugation to susceptible target cells induced myosin-dependent colocalization of Rab27a and Munc13-4 with perforin. Unexpectedly, individual engagement of receptors leukocyte functional antigen-1, NKG2D, or 2B4 induced colocalization of Rab27a, but not Munc13-4, with perforin. Conversely, engagement of antibody-dependent cellular cytotoxicity receptor CD16 induced colocalization of Munc13-4, but not Rab27a, with perforin. Furthermore, colocalization of Munc13-4 with perforin was Rab27a-dependent. In conclusion, Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. The data suggest Rab27a facilitates degranulation at an early step yet highlight a reciprocal relationship between Munc13-4 and Rab27a for degranulation.