Shwachman Diamond Syndrome: Narrow Genotypic Spectrum and Variable Clinical Features

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.