Key Points• Germline GATA2 mutations account for 15% of advanced and 7% of all primary pediatric MDS and do not influence overall survival. • The majority (72%) of adolescents with MDS and monosomy 7 carry an underlying GATA2 deficiency.Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely

Key points † Monitoring whole-blood coagulation using viscoelasticity assays is useful in managing perioperative bleeding. † This observational study compared thromboelastometry [ROTEM w ] assays with standard coagulation tests in 359 children in six age groups. † Age-dependent differences identified in both standard and ROTEM w assays provide important reference ranges for monitoring paediatric surgical patients.Background. The small sample volume needed and the prompt availability of results make viscoelastic methods like rotational thromboelastometry (ROTEM w ) attractive for monitoring coagulation in small children. However, data on reference ranges for ROTEM w parameters in children are scarce.Methods. Four hundred and seven children (ASA I and II) undergoing elective surgery were recruited for this prospective, two-centre, observational study. Subjects were grouped as follows: 0-3, 4 -12, 13 -24 months, 2-5, 6-10, and 11-16 yr. Study objectives were to establish age-dependent reference ranges for ROTEM w assays, analyse age dependence of parameters, and compare ROTEM w data with standard coagulation tests.Results. Data from 359 subjects remained for final analysis. Except for extrinsically activated clot strength and lysis, parameters for ROTEM w assays were significantly different among all age groups. The most striking finding was that subjects aged 0-3 months exhibited accelerated initiation (ExTEM coagulation time: median 48 s, Q1-Q3 38 -65 s; P¼0.001) and propagation of coagulation (a angle: median 78 o , Q1-Q3 69-84 o ; P,0.001) and maximum clot firmness (median 62 mm, Q1-Q3 54-74 mm), although standard plasma coagulation test results were prolonged (prothrombin time: median 13.2 s, Q1-Q3 12.6 -13.6 s; activated partial thromboplastin time: median 42 s, Q1-Q3 40-46 s). Lysis indices of ,85% were observed in nearly one-third of all children without increased bleeding tendency. Platelet count and fibrinogen levels correlated significantly with clot strength, and fibrinogen levels correlated with fibrin polymerization.Conclusions. Reference ranges for ROTEM w assays were determined for all paediatric age groups. These values will be helpful when monitoring paediatric patients and in studies of perioperative coagulation in children.Viscoelastic coagulation tests have gained a renewed interest in the safe management of surgery-or trauma-induced coagulopathy in adult and paediatric patients. 1 -4 Viscoelastic whole-blood analyses, such as thromboelastography (TEG w ) and thromboelastometry (ROTEM w ), reflect initiation and propagation of coagulation, fibrinogen/fibrin -platelet interaction, and clot lysis. In 1997, the ROTEM w device was introduced into clinical routine at our institution. A multicentre study published by Lang and colleagues 5 presented reference ranges for ROTEM w assays for adults aged 17-85 yr. With the exception of some data referring to preterm neonates, newborns, and children exhibiting cardiac failure, reference data are scarce for paediatric patients. 6 -10 The main objective of ...

PT and aPTT cannot be interchangeably used with ROTEM(®) CT. Based on the results of ROTEM(®), recommended thresholds for PT and aPTT might overestimate the need for coagulation therapy. A good correlation was found between the fibrinogen level and the FibTEM assay. In addition, ROTEM(®) offered faster turnaround times.

Sterile alpha motif domain protein 9 (SAMD9) and its paralogue SAMD9-like (SAMD9L) are cytoplasmic proteins encoded by two juxtaposed single-exon genes on chromosome 7q21. They share a 60% amino acid sequence identity and likely originated from a duplication of a common ancestral gene 1 . Their function remains enigmatic; they have been linked to tumor suppression 2 , inflammation 3 , stress response 4 , development 4 , endosomal fusion 5,6 and protein translation 7,8 . Both proteins were also shown to function as restriction factors forming a cross-species barrier for poxvirus infection [9][10][11][12] . Structural analysis of these large proteins has been limited to homology modeling, which predicted identical domains in either protein (SAM, ALBA2, SIR2, P-loop/ NTPase and OB-fold) 13 . Moreover, these genes exhibit tight regulation during embryonic development and transition to ubiquitous expression levels in adult tissues 14,15 .Notably, Samd9l-haploinsufficient mice develop myeloid neoplasia mimicking human MDS with monosomy 7 5 . Several groups reported germline SAMD9 or SAMD9L mutations (SAMD9/9L mut ) underlying new human syndromes with a propensity for cytopenia, bone marrow failure (BMF) and MDS with non-random monosomy 7 or deletion of 7q 6,16-28 . SAMD9 mutations (SAMD9 mut ) were initially linked to a fatal, early-onset MIRAGE syndrome (myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) 6,29 . In contrast, SAMD9L mutations (SAMD9L mut ) were originally described in families with a progressive neurological phenotype, multi-lineage cytopenia and bone marrow hypoplasia (ataxia-pancytopenia syndrome) 16,17 . Recent reports broadened this spectrum and found missense SAMD9/9L mut in non-syndromic familial MDS [30][31][32][33] , truncating SAMD9L mut in children with autoinflammatory panniculitis resembling CANDLE

We report on the outcome of children with advanced primary myelodysplastic syndrome (MDS) transplanted from an HLAmatched sibling (MSD) or an unrelated donor (UD) following a preparative regimen with busulfan, cyclophosphamide and melphalan. Ninety-seven patients with refractory anemia with excess blasts (RAEB, n ¼ 53), RAEB in transformation (RAEB-T, n ¼ 29) and myelodysplasia-related acute myeloid leukemia (MDR-AML, n ¼ 15) enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) 98 study and given hematopoietic stem cell transplantation (HSCT) were analyzed. Median age at HSCT was 11.1 years (range 1.4-19.0). Thirty-nine children were transplanted from an MSD, whereas 58 were given the allograft from a UD (n ¼ 57) or alternative family donor (n ¼ 1). Stem cell source was bone marrow (n ¼ 69) or peripheral blood (n ¼ 28). With a median follow-up of 3.9 years (range 0.1-10.9), the 5-year probability of overall survival is 63%, while the 5-year cumulative incidence of transplantation-related mortality (TRM) and relapse is 21% each. Age at HSCT greater than 12 years, interval between diagnosis and HSCT longer than 4 months, and occurrence of acute or extensive chronic graft-versus-host disease were associated with increased TRM. The risk of relapse increased with more advanced disease. This study indicates that HSCT following a myeloablative preparative regimen offers a high probability of survival for children with advanced MDS.