Hematopoietic stem cell transplantation in a patient with type 1 mosaic variegated aneuploidy syndrome

Abstract Background Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal instability disorder that leads to aneuploidies of different chromosomes in various tissues. Type 1 MVA (MVA1) is caused by mutations in the budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) gene. The main clinical features of MVA1 syndrome are growth and mental retardation, central nervous system anomalies, microcephaly, and predisposition to cancers. There have been no reports of hematopoietic stem cell transplantation (HSCT) in MVA patients. Results We report an 11-year old boy diagnosed with MVA1 syndrome. The BUB1B gene mutations c.498_505delAAACTTTA and c.1288 + 5G > A were detected using the next generation sequencing (NGS) method. The patient presented with cytopenia soon after birth, but remained stable until 9 years of age, when he developed myelodysplastic syndrome associated with monosomy of chromosome 7. Due to severe dependence on blood transfusions, a TCRαβ+/CD19+ depleted HSCT was performed from a matched unrelated donor (MUD) using a treosulfan-based reduced intensity conditioning (RIC) regimen. The engraftment occurred, and no severe toxicity was observed soon after the HSCT, but on day + 47, graft rejection was detected. It was followed by prolonged pancytopenia and sepsis with multi-organ Enterococcus faecium infection, which led to the patient’s death on day + 156 after HSCT. Conclusions In conclusion, we demonstrate that RIC HSCT with TCRαβ+/CD19+ depletion was well tolerated and resulted in complete hematologic recovery in our MVA1 patient, but, unfortunately, it was followed by rapid graft rejection. This fact needs to be taken into consideration for HSCT in other MVA patients

Genetic and Clinical Features of Shwachman-Diamond Syndrome in Russian Population: Prospective Study

Background. Shwachman-Diamond syndrome (SDS) is the rare genetic autosomal recessive disorder with pathogenic variants in SBDS gene. The spectrum of SBDS gene variants in patients with SDS and features of disease course have not been studied before in Russian population.Objective. The aim of the study was to describe all the variants of SBDS gene and clinical and laboratory abnormalities in children with SDS. Methods. In this prospective study exocrine pancreatic function was estimated by amylase and lipase activity in blood, steatorrhea presence and stool elastase levels during the initial hospitalization. Haematological disorders were analysed by complete blood count. Bone abnormalities were diagnosed via X-ray imaging. Growth delay was established due to anthropometry indicators and percentile curves. Molecular genetic testing was performed with using next generation sequencing and Senger sequencing.Results. Pathogenic variants in SBDS gene (8 in general) were revealed in 25 (89%) out of 28 children with SDS. The most common variant (in 23 patients, 82%) was с.258+2T>C, and in 18 cases it was in compound heterozygous state with c.183_184delTAinsCT. Two patients had с.653G>A (p.Arg218Gln) variant and for one patient for every of the following variants: c.258+1G>A, c.107delT, с.356G>A, c.297_300delAAGA, c.338C>T. All children with SDS had growth delay, in 11 (39%) cases we revealed bone abnormalities. In blood samples of 24 (86%) children we revealed neutropenia and less frequently anemia and thrombocytopenia. The stool elastase I decreased activity (< 200 pg/g) was revealed in 26 (92%) patients. 21 (75%) children had cytolysis syndrome.Conclusion. Pathogenic variants of SBDS gene were revealed in majority of Russian children with SDS. The most frequent are c.258+2T>C and c.183_184delTAinsCT variants. Clinical signs of Shwachman-Diamond syndrome manifest since birth with growth delay, steatorrhea and haematological disorders