Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in , a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either mutation, 3 developed MDS upon loss of the mutated allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34 hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in germ line missense loss-of-function variant, potentially counteracting the mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.

SummaryDespite continuously more successful treatment of childhood acute lymphoblastic leukaemia (ALL), 2-5% of children still die of other causes than relapse. The Nordic Society of Paediatric Haematology and Oncology-ALL92 protocol included 1652 patients £15 years of age with precursor Band T-cell ALL diagnosed between 1992 and 2001. Induction deaths and deaths in first complete remission (CR1) were included in the study. A total of 56 deaths (3%) were identified: 19 died during induction (1%) and 37 in CR1 (2%). Infection was the major cause of death in 38 cases. Five patients died of early death before initiation of cytotoxic therapy. Five patients died because of toxicity of inner organs and one of accidental procedure failures. Seven patients died of complications following allogenic haematopoietic stem cell transplantation (HSCT) in CR1. Girls were at higher risk of treatmentrelated death (TRD) [relative risk (RR) ¼ 2AE2; 95% confidence interval (CI 95% ): 1AE2-4AE0, P < 0AE01], mostly because of infections. Risk of TRD was also higher in children with Down syndrome (RR ¼ 4AE5; CI 95% : 2AE0-10AE2, P < 0AE00). In conclusion, 3% of children with ALL died of TRD, with bacterial infections as the most common cause of death. Girls and Down syndrome patients had a higher risk of TRD. Infections still remain a major challenge in childhood ALL.

Respiratory viruses are found commonly during febrile episodes in children with leukemia. The detection of viruses permits the use of available antiviral agents, may explain a poor response to antimicrobial agents, and minimizes the proportion of febrile episodes without possible etiologic agents in children with leukemia.

Effective prevention of infections is possible in child day-care centers, and this can benefit both the families and the personnel. Such a program is cost-effective even if a specialist nurse implements it.