Abstract
Background and objectives
Shwachman Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) associated with pancreatic insufficiency, neutropenia, and skeletal dysplasia. Biallelic pathogenic variants (PV) in SBDS account for >90% of SDS. We hypothesized that the SDS phenotype varies based on genotype and conducted a genotype-phenotype correlation study to better understand these complexities.
Methods
We reviewed records of all patients with SDS or SDS-like syndromes in the National Cancer Institute’s (NCI) IBMFS study. Additional published SDS cohorts were reviewed and compared with the NCI cohort.
Results
PVs in SBDS were present in 32/47 (68.1%) participants. Biallelic inheritance of SBDS c.258 + 2T > C and c.183_184TA > CT was the most common genotype in our study (25/32, 78.1%) and published cohorts. Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%). Developmental delay was common (20/34, 58.8%). Increased risk of hematologic malignancies at young ages and the rarity of solid malignancies was observed in both the NCI cohort and published studies.
Conclusions
SDS is a complex childhood illness with a narrow genotypic spectrum. Patients may first present to primary care, gastroenterology, orthopedic, and/or hematology clinics. Coordinated multidisciplinary care is important for diagnosis and patient management.
Clinical trial registration
ClinicalTrials.gov Identifier: NCT00027274.
Impact
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The clinical and genetic spectrum of Shwachman Diamond Syndrome was comprehensively evaluated, and the findings illustrate the importance of a multidisciplinary approach for these complex patients.
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Our work reveals:
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a narrow genotypic spectrum in SDS;
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a low risk of solid tumors in patients with SDS;
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patients with SDS have clinical manifestations in multiple organ systems
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Acknowledgements
We are grateful to the study participants, their families, and referring clinicians for their valuable contributions to this study. The authors thank Lisa Leathwood, RN, BSN, Maureen Risch, RN, BSN and Ann Carr, MS, CGC for assistance with the National Cancer Institute Inherited Bone Marrow Failure syndrome cohort patient data management. The authors thank members of the Cancer Genomics Research Laboratory for assistance with DNA sequencing and bioinformatics. This research was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute and supported by contract HHSN261201700004C with Westat, Inc.
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A.S.T. was responsible for data acquisition, medical record review, data analysis and interpretation, and wrote the first draft of the manuscript. N.G. evaluated patients, performed data analysis, and interpretation in addition to assisting the manuscript revision. D.M.G. assisted with data analysis and interpretation. S.A.S. contributed to study design, data analysis and interpretation, and manuscript revisions. B.P.A. is responsible for study design and patient recruitment to the NCI Inherited Bone Marrow Failure syndrome cohort and assisted with manuscript development. L.J.M. supervised the study and was responsible for study design, data analysis and interpretation, and manuscript drafting and revisions.
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Thompson, A.S., Giri, N., Gianferante, D.M. et al. Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features. Pediatr Res 92, 1671–1680 (2022). https://doi.org/10.1038/s41390-022-02009-8
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DOI: https://doi.org/10.1038/s41390-022-02009-8
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