Clinical features and gene mutations of children with Shwachman-Diamond syndrome and malignant myeloid transformation
AN Wen-Bin1,2,3, LIU Chao1,2,3, WAN Yang1,2,3, CHANG Li-Xian1,2,3, CHEN Xiao-Yan1,2,3, ZHU Xiao-Fan1,2,3
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
Abstract Objective To study the clinical features and genetic mutations of children with Shwachman-Diamond syndrome (SDS) and malignant myeloid transformation. Methods Next-generation sequencing was used to analyze the gene mutations in 11 SDS children with malignant myeloid transformation, and their clinical features and genetic mutations were analyzed. Results Of the 11 children with SDS, 9 (82%) presented with refractory cytopenia of childhood (RCC), 1 (9%) had myelodysplastic syndrome with excess blasts (MDS-EB), and 1 (9%) had acute myeloid leukemia with myelodysplasia-related changes (AML-MRC). The median age of onset of malignant myeloid transformation was 48 months (ranged 7 months to 14 years). Of the 11 children, 45% had abnormalities in the hematological system alone. Mutations of the SBDS gene were detected in all 11 children, among whom 5 (45%) had c.258+2T > C homozygous mutation and 3 (27%) had c.184A > T+c.258+2T > C compound heterozygous mutation. The new mutations of the SBDS gene, c.634_635insAACATACCTGT+c.637_638delGA and c.8T > C, were rated as "pathogenic" and "possibly pathogenic" respectively. The 3-year predicted overall survival rates of children transformed to RCC and MDS-EB/AML-MRC were 100% and 0% respectively (P=0.001). Conclusions SDS children may have hematological system symptoms as the only manifestation, which needs to be taken seriously in clinical practice. The type of malignant transformation is associated with prognosis.
AN Wen-Bin,LIU Chao,WAN Yang et al. Clinical features and gene mutations of children with Shwachman-Diamond syndrome and malignant myeloid transformation[J]. CJCP, 2020, 22(5): 460-465.
AN Wen-Bin,LIU Chao,WAN Yang et al. Clinical features and gene mutations of children with Shwachman-Diamond syndrome and malignant myeloid transformation[J]. CJCP, 2020, 22(5): 460-465.
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia[J]. Blood, 2016, 127(20):2391-2405.
[5]
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
[6]
Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation[J]. N Engl J Med, 2017, 376(6):536-547.
[7]
Kuijpers TW, Alders M, Tool AT, et al. Hematologic abnormalities in Shwachman Diamond syndrome:lack of genotype-phenotype relationship[J]. Blood, 2005, 106(1):356-361.
[8]
Dhanraj S, Matveev A, Li H, et al. Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome[J]. Blood, 2017, 129(11):1557-1562.
[9]
Morini J, Nacci L, Babini G, et al. Whole exome sequencing discloses heterozygous variants in the DNAJC21 and EFL1 genes but not in SRP54 in 6 out of 16 patients with Shwachman-Diamond syndrome carrying biallelic SBDS mutations[J]. Br J Haematol, 2019, 185(3):627-630.
[10]
Stepensky P, Chacón-Flores M, Kim KH, et al. Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome[J]. J Med Genet, 2017, 54(8):558-566.
[11]
Carapito R, Konantz M, Paillard C, et al. Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features[J]. J Clin Invest, 2017, 127(11):4090-4103.
[12]
Mourad S, Bilodeau M, Roussy M, et al. IDH1 as a cooperating mutation in AML arising in the context of Shwachman-Diamond syndrome[J]. Front Oncol, 2019, 9:772.
[13]
Myers KC, Furutani E, Weller E, et al. Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia:a multicentre, retrospective, cohort study[J]. Lancet Haematol, 2020, 7(3):e238-e246.
[14]
Donadieu J, Fenneteau O, Beaupain B, et al. Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome[J]. Haematologica, 2012, 97(9):1312-1319.
[15]
Alter BP, Giri N, Savage SA, et al. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up[J]. Haematologica, 2018, 103(1):30-39.
[16]
Rosenberg PS, Alter BP, Bolyard AA, et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy[J]. Blood, 2006, 107(12):4628-4635.
[17]
Myers KC, Davies SM, Shimamura A. Clinical and molecular pathophysiology of Shwachman-Diamond syndrome:an update[J]. Hematol Oncol Clin North Am, 2013, 27(1):117-128.
[18]
Cada M, Segbefia CI, Klaassen R, et al. The impact of category, cytopathology and cytogenetics on development and progression of clonal and malignant myeloid transformation in inherited bone marrow failure syndromes[J]. Haematologica, 2015, 100(5):633-642.
