Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations.

BACKGROUND: Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a transcriptional regulator mediating histone deubiquitination. Its role in human immunity and hematopoiesis is poorly understood. OBJECTIVES: We sought to investigate the clinical, cellular, and molecular features in 2 siblings presenting with progressive bone marrow failure (BMF), immunodeficiency, and developmental aberrations. METHODS: We performed genome-wide homozygosity mapping, whole-exome and Sanger sequencing, immunophenotyping studies, and analysis of genotoxic stress responses. p38 activation, reactive oxygen species levels, rate of apoptosis and clonogenic survival, and growth in immune and nonimmune cells were assessed. The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) was monitored. RESULTS: We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts. Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1. MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein, increased reactive oxygen species production, and decreased survival following UV light-induced DNA damage. Both patients were successfully treated with allogeneic HSCT with sustained reconstitution of hematopoietic defects. CONCLUSIONS: Here we show that MYSM1 deficiency is associated with developmental aberrations, progressive BMF with myelodysplastic features, and increased susceptibility to genotoxic stress. HSCT represents a curative therapy for patients with MYSM1 deficiency.

Evidence-based interventions for children and adolescents with fetal alcohol spectrum disorders - A systematic review.

INTRODUCTION: Brain function deficits cause strong negative impacts for the everyday lives of children and adolescents with fetal alcohol spectrum disorders (FASD). Therefore, evidence-based intervention programs that are specifically designed for patients with FASD are needed but still scarce. The aim of the presented article is a systematic literature review of evidence-based intervention strategies for children and adolescents with FASD. MATERIALS AND METHODS: A comprehensive systematic literature search was conducted in several relevant databases to identify randomized-controlled intervention studies for children and adolescents with FASD. RESULTS: We identified 25 randomized-controlled studies regarding interventions in FASD. Overall, evidence indicating that some therapeutic interventions are effective in children and adolescents with FASD was found. Even though evidence-based interventions rarely lead to improvements of performance into a "normal range", those measures can alleviate negative consequences of prenatal alcohol exposure and relieve daily burdens. CONCLUSION: There are only a few randomized-controlled trials regarding therapy research for children and adolescents with FASD. Their results indicate that especially the combination of parent and child sessions present a promising approach for the treatment of FASD. Positive treatment effects of interventions seem to be domain specific, except for interventions regarding self-regulation or social interaction.