Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome.

International audienceBACKGROUND: 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. DESIGN AND METHODS: 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. RESULTS: 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

Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches

EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.Medical Research Council, Bloodwise, Wellcome Trust, Ted’s Gang, The Connor Wright Shwachman Diamond Projec

Evaluation du microscope automatisé DM8 en pédiatrie

PARIS-BIUP (751062107) / SudocSudocFranceF

Congenital neutropenia: diagnosis, molecular bases and patient management

<p>Abstract</p> <p>The term congenital neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, severe (<0.5 G/l) or mild (between 0.5-1.5 G/l), which may also affect other organ systems such as the pancreas, central nervous system, heart, muscle and skin. Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae. The risk of infection is roughly inversely proportional to the circulating polymorphonuclear neutrophil count and is particularly high at counts below 0.2 G/l.</p> <p>When neutropenia is detected, an attempt should be made to establish the etiology, distinguishing between acquired forms (the most frequent, including post viral neutropenia and auto immune neutropenia) and congenital forms that may either be isolated or part of a complex genetic disease.</p> <p>Except for ethnic neutropenia, which is a frequent but mild congenital form, probably with polygenic inheritance, all other forms of congenital neutropenia are extremely rare and have monogenic inheritance, which may be X-linked or autosomal, recessive or dominant.</p> <p>About half the forms of congenital neutropenia with no extra-hematopoetic manifestations and normal adaptive immunity are due to neutrophil elastase (<it>ELANE</it>) mutations. Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia.</p> <p>Congenital neutropenia may also be associated with a wide range of organ dysfunctions, as for example in Shwachman-Diamond syndrome (associated with pancreatic insufficiency) and glycogen storage disease type Ib (associated with a glycogen storage syndrome). So far, the molecular bases of 12 neutropenic disorders have been identified.</p> <p>Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte-colony-stimulating factor (G-CSF). G-CSF has considerably improved these patients' outlook. It is usually well tolerated, but potential adverse effects include thrombocytopenia, glomerulonephritis, vasculitis and osteoporosis. Long-term treatment with G-CSF, especially at high doses, augments the spontaneous risk of leukemia in patients with congenital neutropenia.</p

When Ring Sideroblasts on Bone Marrow Smears Are Inconsistent with the Diagnosis of Myelodysplastic Neoplasms

Ring sideroblasts are commonly seen in myelodysplastic neoplasms and are a key condition for identifying distinct entities of myelodysplastic neoplasms according to the WHO classification. However, the presence of ring sideroblasts is not exclusive to myelodysplastic neoplasms. Ring sideroblasts are as well either encountered in non-clonal secondary acquired disorders, such as exposure to toxic substances, drug/medicine, copper deficiency, zinc overload, lead poison, or hereditary sideroblastic anemias related to X-linked, autosomal, or mitochondrial mutations. This review article will discuss diseases associated with ring sideroblasts outside the context of myelodysplastic neoplasms. Knowledge of the differential diagnoses characterized by the presence of ring sideroblasts in bone marrow is essential to prevent any misdiagnosis, which leads to delayed diagnosis and subsequent management of patients that differ in the different forms of sideroblastic anemia

Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity

Infant acute myeloid leukemia (AML) is a rare subgroup of AML of children <2 years of age. It is as frequent as infant acute lymphoblastic leukemia (ALL) but not clearly distinguished by study groups. However, infant AML demonstrates peculiar clinical and biological characteristics, and its prognosis differs from AML in older children. Acute megakaryoblastic leukemia (AMKL) is very frequent in this age group and has raised growing interest. Thus, AMKL is a dominant topic in this review. Recent genomic sequencing has contributed to our understanding of infant AML. These data demonstrated striking features of infant AML: fusion genes are able to induce AML transformation without additional cooperation, and unlike AML in older age groups there is a paucity of associated mutations. Mice modeling of these fusions showed the essential role of ontogeny in the infant leukemia phenotype compared to older children and adults. Understanding leukemogenesis may help in developing new targeted treatments to improve outcomes that are often very poor in this age group. A specific diagnostic and therapeutic approach for this age group should be investigated

Recommendations for cerebrospinal fluid examination in acute leukemia

Cytological identification of blasts in cerebrospinal fluid in acute leukemia, lymphoid or myeloid, in adult and child, at diagnosis or during follow up lead to the diagnosis of leukemic meningitidis. Suitable CNS therapy based on a defined "CNS status" following an international standardized classification, lead to decrease cerebrospinal relapses. Established in 1993, this classification allows to treat patients based on their CNS status. Based on the red blood cells count, nucleated cells count and presence of blasts, it requires a standard technical procedure that guarantees the comparability of results coming from different medical laboratory. To improve the quality of cerebrospinal fluid analysis, in acute leukemias, preanalytical guidelines (turn around time), analytical guidelines (cytocentrifugation, adding serum protein, speed and duration of cytocentrifugation) and postanalytical guidelines (duration of conservation) are set by the Groupe francophone d'hématologie cellulaire

Platelet morphology analysis

Platelets are very small blood cells (1.5-3 μm), which play a major role in primary haemostasis and in coagulation mechanisms. Platelet characterization requires their counting (see Chapter 15 ) associated with accurate morphology analysis. We describe the major steps in order to correctly obtain stained blood films, which can be analyzed by optical microscope. Platelet morphology abnormalities are found in acquired malignant hematological diseases such myeloproliferative or myelodysplastic syndromes and acute megakaryoblastic leukemia. A careful analysis of the platelet size and morphology, by detecting either normal platelets with or without excessive anisocytosis, microplatelets, or large/giant platelets, will contribute to inherited thrombocytopenia diagnosis and gather substantial data when looking for an acquired platelet disorders