Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances

Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosome maturation due to deficiency of SBDS and inability to evict the anti-association factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for SDS patients who develop myeloid malignancies are extremely poor due to high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for SDS patients who undergo routine bone marrow surveillance and receive a HSCT prior to developing overt malignancy. However, the optimal approach to hematologic surveillance and timing of HSCT for SDS patients is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in SDS patients that either alleviate the ribosome defect by somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in SDS patients have biallelic loss-of-function TP53 mutations. Single cell DNA sequencing (scDNA-seq) of SDS bone marrow samples can detect pre-malignant biallelic TP53-mutated clones prior to clinical diagnosis, suggesting molecular surveillance may enhance detection of incipient myeloid malignancies when HSCT may be most effective. Here we review the clinical, genetic, and biologic features of SDS. Additionally, we present evidence supporting hematologic surveillance for SDS patients that incorporates clinical, pathologic, and molecular data to risk-stratify patients and prioritize transplant evaluation for SDS patients with high-risk features.