Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation

Abstract

Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.

The ribosome-related protein, SBDS, is critical for normal erythropoiesis

“…Approximately 85% of the patients have hypomorphic mutations in the Shwachman Bodian Diamond syndrome gene, SBDS. 3,4 Knockdown of the SBDS homolog in murine myeloid 32Dcl3 cells resulted in normal neutrophil maturation but reduced viability of granulocyte precursors. 5 These studies provide evidence that SBDS is critical for normal granulopoiesis.…”

“…In addition, 60% of the patients have high erythrocyte mean corpuscular volume, and 70% have high fetal hemoglobin blood levels. 4,6,7 Despite these erythrocyte abnormalities, SDS has frequently been classified as an inherited neutropenia disorder. 8,9 The underlying mechanism of anemia and the degree to which it can be attributed to erythropoietic failure, nutritional deficiencies, and/or recurrent infection have not been studied.…”

The impact of category, cytopathology and cytogenetics on development and progression of clonal and malignant myeloid transformation in inherited bone marrow failure syndromes

“…21 Although the various IBMFS share many clinical and morphological phenotypes, their respective IBMFS genes play roles in several different biochemical pathways. It is, therefore, reasonable to hypothesize that mutations in different IBMFS genes may have different impacts on the malignant potential and behavior of bone marrow cells.…”

Molecular Diagnosis of Shwachman-Diamond Syndrome Presenting with Pancytopenia at an Early Age: The First Report from Turkey

“…The most common described mutations are splice site mutation; 258?2T-C in one allele, followed by 183-184TA-CT mutation in the other one. SBDS-negative SDS patients may have more severe hematological involvement but milder exocrine pancreatic disease [7].…”