To study the prevalence of the Val617Phe JAK2 mutation in familial cases of myeloproliferative disorder (MPD) and its possible implication as a predisposing genetic factor, we analyzed 72 families including 174 patients (
The online version of this article has a Supplementary Appendix. BackgroundPatients 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 MethodsOne hundred and two patients with Shwachman-Diamond syndrome, with a median followup 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. ResultsSevere 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 nonmalignant 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. ConclusionsPatients 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.Key words: Shwachman-Diamond syndrome, genotype, aplastic anemia, secondary leukemia, cytopenia, myelodysplasia, monosomy 7.Citation: Donadieu J, Fenneteau O, Beaupain B, Beaufils S, Bellanger F, Mahlaoui N, Lambilliotte A, Aladjidi N, Bertrand Y, Mialou V, Perot C, Michel G, Fouyssac F, Paillard C, Gandemer V, Boutard P, Schmitz J, Morali A, Leblanc T, Bellanné-Chantelot C, and Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome
Common variable immunodeficiency (CVID) is characterized by abnormally low levels of antibodies in the blood and dysfunctional immune cells called CD4+ T cells. Perreau et al. now show evidence that bacteria-fighting CD4+ T cells in these patients are in a state of exhaustion due to a constant leakage of normal gut bacteria into the bloodstream, possibly due to insufficient antibody levels.
Expression of co-inhibitory molecules is generally associated with T-cell dysfunction in chronic viral infections such as HIV or HCV. However, their relative contribution in the T-cell impairment remains unclear. In the present study, we have evaluated the impact of the expression of co-inhibitory molecules such as 2B4, PD-1 and CD160 on the functions of CD8 T-cells specific to influenza, EBV and CMV. We show that CD8 T-cell populations expressing CD160, but not PD-1, had reduced proliferation capacity and perforin expression, thus indicating that the functional impairment in CD160+ CD8 T cells may be independent of PD-1 expression. The blockade of CD160/CD160-ligand interaction restored CD8 T-cell proliferation capacity, and the extent of restoration directly correlated with the ex vivo proportion of CD160+ CD8 T cells suggesting that CD160 negatively regulates TCR-mediated signaling. Furthermore, CD160 expression was not up-regulated upon T-cell activation or proliferation as compared to PD-1. Taken together, these results provide evidence that CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression.
BackgroundThe purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry.MethodsAmong 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations.ResultsMedian age at the last visit was 22.4 years. All patients had developed various comordibities, including prominent veins (n = 12), cardiac malformations (n = 12), intellectual disability (n = 7), and myopathic syndrome with recurrent painful cramps (n = 1). Three patients developed Crohn’s disease, and five had chronic diarrhea with steatorrhea. Neutropenia was profound (<0.5 × 109/l) in almost all cases at diagnosis and could marginally fluctuate. The bone marrow smears exhibited mild late-stage granulopoeitic defects. One patient developed myelodysplasia followed by acute myelogenous leukemia with translocation (18, 21) at age 14 years, cured by chemotherapy and hematopoietic stem cell transplantation. Four deaths occurred, including one from sepsis at age 5, one from pulmonary late-stage insufficiency at age 19, and two from sudden death, both at age 30 years. A new homozygous mutation (c.249G > A /p.Trp83*) was detected in one pedigree.ConclusionsSevere congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. This series includes the first described case of malignancy in this neutropenia.
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