The K
+
channel activated by the Ca
2+
, KCNN4, has been shown to contribute to red blood cell dehydration in the rare hereditary hemolytic anemia, the dehydrated hereditary stomatocytosis. We report ...two
de novo
mutations on
KCNN4
, We reported two
de novo
mutations on
KCNN4
, V222L and H340N, characterized at the molecular, cellular and clinical levels. Whereas both mutations were shown to increase the calcium sensitivity of the K
+
channel, leading to channel opening for lower calcium concentrations compared to WT KCNN4 channel, there was no obvious red blood cell dehydration in patients carrying one or the other mutation. The clinical phenotype was greatly different between carriers of the mutated gene ranging from severe anemia for one patient to a single episode of anemia for the other patient or no documented sign of anemia for the parents who also carried the mutation. These data compared to already published KCNN4 mutations question the role of KCNN4 gain-of-function mutations in hydration status and viability of red blood cells in bloodstream.
Oncogenic subtypes in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are used for risk stratification. However, a significant number of BCP-ALL patients are still genetically ...unassigned. Using array-comparative genomic hybridization in a selected BCP-ALL cohort, we characterized a recurrent V(D)J-mediated intragenic deletion of the ERG gene (ERG(del)). A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 897 children aged 1-17 years treated for BCP-ALL in the EORTC-CLG 58951 trial. ERG(del) was found in 29/897 patients (3.2%) and was mutually exclusive of known classifying genetic lesions, suggesting that it characterized a distinct leukemia entity. ERG(del) was associated with higher age (median 7.0 vs. 4.0 years, P=0.004), aberrant CD2 expression (43.5% vs. 3.7%, P<0.001) and frequent IKZF1 Δ4-7 deletions (37.9% vs. 5.3%, P<0.001). However, ERG(del) patients had a very good outcome, with an 8-year event-free survival (8-y EFS) and an 8-year overall survival of 86.4% and 95.6%, respectively, suggesting that the IKZF1 deletion had no impact on prognosis in this genetic subtype. Accordingly, within patients with an IKZF1 Δ4-7 deletion, those with ERG(del) had a better outcome (8-y EFS: 85.7% vs. 51.3%; hazard ratio: 0.16; 95% confidence interval: 0.02-1.20; P=0.04). These findings have implications for further stratification including IKZF1 status.
CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by ...excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types.
CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype.
A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.
Introduction
The automated XN‐1000 hematology analyzer enables to perform a blood cell count and a leukocyte differential. When abnormal cells were detected, a flag was generated by the analyzer and ...a manual microscopic examination of the corresponding blood film was performed.
Methods
We compared the white blood cell differentials provided by the automated hematology analyzer XN‐1000 in a pediatric population (n = 765) with those obtained through microscopic examination by cytologists and those obtained using a previous version of this analyzer, the XE‐2100. Leukocytes count as well as flags sensitivity and specificity was analyzed.
Results
The leukocytes count provided by the analyzer is in good accordance with the differential obtained by manual count in children older than 3 months. The sensitivity for blast detection is 99% and the detection of reactive cells is 63%. The flag specificity remains low (<35%) for blood samples collected from infants between 8 days and 2 years of age, but increases up to 67% thereafter. The results obtained with the XN‐1000 analyzer show an improvement in comparison with those obtained with the XE‐2100 analyzer.
Conclusion
The automated WBC differential provided by the XN‐1000 analyzer in the pediatric setting is accurate, but a meticulous microscopic examination of blood smears remains necessary for infants up to 3 months of age to validate the analyzer flags.
The clinical and biological characteristics of children under 2 years (infants) with acute myeloid leukemia (AML) are different from those of older children. We aimed to describe the specific ...characteristics of this population and the potential factors that influence the prognosis. We analyzed data concerning 438 children with newly‐diagnosed AML treated in the ELAM02 protocol between March 2005 and December 2011, of which 103 were under 2 years old at diagnosis. The evaluation criteria were overall survival (OS) and event‐free survival (EFS) of infants vs older children. The clinical and biological features were secondary criteria. Infants presented more frequent extra‐medullary presentation than older children. They had a significantly higher proportion of skin lesions and central nervous system involvement (15% vs 3%, p < 0.0001 and 26% vs 12%, p = 0.0005, respectively). The global incidence of KMT2A rearrangements was nearly 55% for infants vs 11% for older children (p < 0.0001). Median 5‐year OS was 70.4% for infants vs 71.4% for older children (p = 0.83). Five‐year EFS was 67% for infants vs 58% for older children (p = 0.27). Infants with AML represent a cohort of patients with specific clinical and biological features. These remarkable differences had no significant impact on their outcome in the ELAM02 protocol.
The DM is an automated microscope, which performs WBC differential counts and monitors red cell morphology. The user either validates the cell recognition if the DM has correctly identified the WBCs ...or reclassifies the WBCs in the good category in case of a DM mis-assignment. Morphological anomalies of leukocytes, red blood cells or platelets are analyzed and registered. We studied 521 newborns and infants sorted by age and pathology. The results correlated well with those using conventional microscopy except for samples containing blasts, in which the percentage of malignant cells was underestimated. Newborns had the lowest rates of overall accuracy and postclassification agreement. For red cell analysis, 10% of the selected areas were considered unreadable. However, the DM diagnosed faithfully all studied red cell pathologies. The DM was also very useful in analyzing samples of storage diseases. Timesavings ranging from 1 up to 10 min (for vacuolated lymphocyte screening) were observed when performing analysis with the DM. The DM represents a useful diagnostic and training tool. However, conventional microscopy remains essential, in particular when the image quality is poor, such as in the case of lymphoblasts, and in the screening of platelet clusters.
Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the ...hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications.
One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20 × 10(9)/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant.
Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%-38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. CONCLUSIONS Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value.
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