Blandine Beaupain

Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis

Neutropenia in mice and humans results in the generation of NK cells with an immature and hyporesponsive phenotype.

High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia

UNLABELLED Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reportedGATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. KEY POINTS Mutations of key transcription factor in myeloid malignancies.

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

Background 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 <20×109/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.

Natural history of Barth syndrome: a national cohort study of 22 patients

BackgroundThis study describes the natural history of Barth syndrome (BTHS).MethodsThe medical records of all patients with BTHS living in France were identified in multiple sources and reviewed.ResultsWe identified 16 BTHS pedigrees that included 22 patients. TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2–2.3). The median age at presentation was 3.1 weeks (range, 0–1.4 years), and the median age at last follow-up was 4.75 years (range, 3–15 years). Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients ≥3 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 × 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000.ConclusionsThis survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation.

Is pegfilgrastim safe and effective in congenital neutropenia? An analysis of the French Severe Chronic Neutropenia registry.

To examine the efficacy and safety of pegfilgrastim in patients with congenital neutropenia (CN).

Epidemiology of Congenital Neutropenia

Epidemiologic investigations of congenital neutropenia aim to determine several important indicators related to the disease, such as incidence at birth, prevalence, and outcome in the population, including the rate of severe infections, leukemia, and survival. Genetic diagnosis is an important criterion for classifying patients and reliably determining the epidemiologic indicators. Patient registries were developed in the 1990s. The prevalence today is probably more than 10 cases per million inhabitants. The rate of infection and leukemia risk can now be calculated. Risk factors for leukemia seem to depend on both the genetic background and cumulative dose of granulocyte colony stimulating factor.

Occurrence of myelodysplastic syndrome in 2 patients with reticular dysgenesis

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Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations

To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so‐called Kostmann syndrome, in France.

Respiratory distress and sudden death of a patient with GSDIb chronic neutropenia: possible role of pegfilgrastim

The advent of commercial G-CSF preparations has considerably improved the survival and quality of life of patients with chronic neutropenia,[1][1] including patients with glycogenosis Ib.[2][2] Pegylated G-CSF was authorized in the early 2000s for chemotherapy-induced neutropenia,[3][3] allowing

Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history

This review focuses on the classification, diagnosis and natural history of congenital neutropenia (CN). CN encompasses a number of genetic disorders with chronic neutropenia and, for some, affecting other organ systems, such as the pancreas, central nervous system, heart, bone and skin. To date, 24 distinct genes have been associated with CN. The number of genes involved makes gene screening difficult. This can be solved by next‐generation sequencing (NGS) of targeted gene panels. One of the major complications of CN is spontaneous leukaemia, which is preceded by clonal somatic evolution, and can be screened by a targeted NGS panel focused on somatic events.