One hundred and twenty patients with RC, enrolled in the prospective study 98 of the European Working Group of Myelodysplastic Syndromes in Childhood (EWOGMDS), were screened for SBDS mutations. Patients included were diagnosed with primary hypocellular RC between 1 July 1998 and 31 December 2006 after central reference review of bone marrow biopsies. The diagnosis followed guidelines later adopted by the World Health Organization. 4 Children with an abnormal clonal karyotype or myelofibrosis were excluded from the analysis. Fanconi anemia had been ruled out in all cases by mitomycin C/diepoxybutane sensitivity testing. Patients' age ranged from 0.2 to 19.0 years (median 10.3 years). Three patients had short stature, 2 showed bone abnormalities. Kidney or urinary tract anomalies were present in 4 patients, and cognitive or behavioral problems were noted in 3 children. Further symptoms indicative of SDS were not reported in our cohort. Mutational analysis of the SBDS gene was performed through genomic DNA sequencing using peripheral blood or bone marrow, as described elsewhere. 5-8

We detected one male patient who carried a heterozygous c. 258+ 2T> C mutation. This change is predicted to disrupt the donor splice site of intron 2 and is therefore regarded pathogenic if present in homozygous or compound-heterozygous form. 2 The alteration was present in leukocytes and fibroblasts, demonstrating germline origin. The boy was diagnosed with RC at the age of 14 years. He initially presented with transfusion-dependent pancytopenia. The patient had no clinical history of pancreatic exocrine failure, skeletal abnormalities or other SDS symptoms. Both parents were healthy. Allogeneic hematopoietic stem cell transplantation (HSCT) was performed six months after diagnosis from an 1 HLA-mismatched donor, using a reduced intensity regimen with fludarabin and thiotepa. The boy developed acute and chronic GvHD of the skin. Severe adverse events were not observed and the boy remains in stable condition more than three years after HSCT without symptoms typical of SDS. It is likely that the heterozygous c. 258+ 2 T> C lesion encountered here represents the background allele frequency in the general population, which is estimated at 1/110. 1