Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome

Abstract

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

Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes

“…19,20 In line with this, EYFP expression was found in a small fraction of immunophenotypically defined hematopoietic stem and progenitor cells (HSPCs) and in all blood lineages (Gr1 + Mac1 + myeloid, Ter119 + erythroid and B220 + lymphoid) at varying frequencies (Table 1 and Figure 3A). The bone marrow of mice transplanted with Sbds f/f fetal liver cells was hypocellular, a common finding in SDS patients 7,25 ( Figure 3B Figure 3C and D). Of note, myelodysplastic features were not observed in Sbds f/f recipients in the current model, suggesting that hematopoietic cell-extrinsic factors may contribute to myelodysplasia in SDS.…”

“…43 The resulting left-shifted myelopoiesis in our model is reminiscent of that observed in vitro upon granulocytic differentiation of Sbds-knockdown hematopoietic cells, resulting in an accumulation of MC-MMs, 17 and of the maturation defect that characterizes a subset of SDS patients. 5,7,25,44 While our findings provide a basis for understanding the myeloid lineage specificity of ribosomal dysfunction in SDS, in translating these findings to human disease it is important to point out that pluripotent hematopoietic stem cells are incompletely targeted in this model. Cebpa-driven deletion of Sbds occurred in a small subset of immunophenotypically defined, multipotent HSCs, reflected in a modest decrease in erythroid and lymphoid cells in the EYFP + compartment of mutant mice.…”

“…[1][2][3] The hematologic hallmark of the disease is neutropenia, which affects 88%-98% of patients 4,5 and represents, together with leukemic evolution, the main cause of morbidity and mortality in SDS. 1,[6][7][8] Other less common manifestations are anemia, thrombocytopenia and pancytopenia. 6,7 The disease is caused by biallelic loss of function mutations in the Shwachman-Bodian-Diamond Syndrome gene (SBDS).…”

“…1,[6][7][8] Other less common manifestations are anemia, thrombocytopenia and pancytopenia. 6,7 The disease is caused by biallelic loss of function mutations in the Shwachman-Bodian-Diamond Syndrome gene (SBDS). 9 The two most common mutations, 258+2T→C and 183-184TA→CT, result in impaired splicing and a premature stop codon, respectively, and are associated with reduced protein levels of SBDS.…”

Association of isochromosome (7)(q10) in Shwachman–Diamond syndrome with the severity of cytopenia

“…PCR products were cleaned up using PCR purification kit (Qiagen) and sequenced with Dye Terminator method. All samples were analyzed by a ABI PRISM 310 Genetic Analyzer 4, 11, 12 (Fig. 1A).…”