Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive inherited bone marrow failure syndrome (IBMFS) characterized by a triad of skeletal abnormalities, exocrine pancreatic dysfunction, and hematopoietic dysfunction, with an increased predisposition to myeloid malignancies (Huang and Shimamura, 2011; Myers et al., 2020). As one of the most common IBMFS subtypes, SDS exhibits significant clinical heterogeneity and is primarily caused by biallelic mutations in the SBDS gene (Nelson and Myers, 2018). Less than 10% of patients with SDS possess mutations in other genes, such as DNAJC21 (Tummala et al., 2016; Dhanraj et al., 2017), SRP54 (Carapito et al., 2017), and EFL1 (Stepensky et al., 2017; Tan et al., 2018; Tan et al., 2019; Revy and Donadieu, 2021). Despite its clinical significance, the epidemiology of SDS remains poorly defined, with population-based studies estimating the incidence of biallelic SBDS mutations at approximately 1 in 153,000 to 1 in 168,000 live births (Minelli et al., 2012). In the Chinese population, the disease demonstrates a male predominance, with a male-to-female ratio of approximately 1.3:1 (Han et al., 2023).

Current understanding of SDS has been largely established through well-characterized cohort studies from Western populations, including investigations on IBMFS, myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), and hematopoietic stem cell transplantation in North America (Muramatsu et al., 2017; Link, 2019; Myers et al., 2020), and French (Donadieu et al., 2012), Italian (Cesaro et al., 2020; Pegoraro et al., 2024), and European Severe Chronic Neutropenia International Registry (SCNIR) (Mellor-Heineke et al., 2025) studies. While these multinational efforts have significantly advanced SDS research, comprehensive data from Asian populations remain markedly limited. This knowledge gap significantly hinders the development of population-specific diagnostic criteria and management strategies.

This study presents a comprehensive retrospective analysis of 18 genetically confirmed SDS cases from a single Chinese medical center, with the following objectives: (1) to characterize the clinical spectrum and genetic landscape of SDS in Chinese pediatric patients; (2) to evaluate the pathogenicity of identified genetic variants; and (3) to establish a foundation for improved early diagnosis and therapeutic intervention. By addressing these critical aspects, these findings enhance the global understanding of SDS pathogenesis while providing population-specific insights that may inform clinical practice and guide future research directions in this rare but clinically significant disorder.

SDS is a rare genetic disorder characterized by impaired ribosome biogenesis, affecting multiple systems and organs throughout the body. Due to its rarity and highly variable clinical manifestations, SDS poses significant diagnostic challenges. This study retrospectively analyzed the clinical and genetic features of 18 patients with SDS, revealing that neutropenia (94%), PEI (100%), and growth retardation liver function abnormalities (83%) were the most common clinical manifestations. Compared with domestic and international studies, our case series demonstrated higher incidence rates of developmental anomalies, growth retardation, and neurocognitive impairments. This discrepancy may be attributed to the following factors:

1. Insufficient clinical recognition: Some symptoms might have been underestimated or overlooked by clinicians, failing to establish timely association with SDS.

SDS exhibits significant clinical heterogeneity involving multiple systems. Below, we highlight the key diagnostic findings from our cohort and compare them with previous studies:

1. EPI: Although direct gold-standard tests such as fecal elastase-1 (FE-1), 72-h fecal fat quantification, or trypsinogen assays were unavailable at our center due to technical limitations, the diagnosis of EPI was strongly supported by clinical manifestations (diarrhea, steatorrhea [fecal fat globule positivity]), reduced serum pancreatic enzyme levels (amylase, pancreatic amylase, lipase), and imaging features (pancreatic hyperechogenicity/fatty infiltration).

In our cohort, the incidence of pancreatic enzyme deficiency (100%, 16/16) was significantly higher than that previously reported in domestic studies (50%) (Han et al., 2023), potentially due to case selection bias or methodological differences. Notably, the high prevalence of infantile diarrhea and steatorrhea (97%, 15/16) aligns with the compensatory characteristics of pancreatic function—clinically apparent steatorrhea typically occurs only when lipase secretion drops to critically low levels (<10% of normal) (Chinese Society of Gastrointestinal Surgery, 2024).Spontaneous symptom resolution was observed in some children with age.

Pancreatic imaging abnormalities were prominent in our study (65%, 11/17), exceeding the domestic reported rate of 41.7% (15/36) (Han et al., 2023), further corroborating EPI diagnosis. Future incorporation of precise functional tests (e.g., FE-1) could improve early EPI detection and refine assessment of disease progression and therapeutic response. Nevertheless, this study provides a practical diagnostic strategy for EPI evaluation in resource-limited settings.

2. Hematologic Abnormalities: Neutropenia was observed in 94% (17/18) of our cases, consistent with previously reported rates of 80%–100% in international studies (Donadieu et al., 2012; Myers et al., 2013; Myers et al., 2014; Thompson et al., 2022; Mellor-Heineke et al., 2025). Anemia was observed in 50% (9/18) of cases, a notably higher prevalence compared to reported rates in international cohorts (12.7%–27%) (Donadieu et al., 2012; Myers et al., 2014; Delaporta et al., 2017; Cesaro et al., 2020; Thompson et al., 2022). Pancytopenia was present in 44% (8/18) of cases, exceeding the previously reported domestic rate of 27.3% (12/44) (Han et al., 2023), Comparative international cohort data remain unavailable. Bone marrow hypoplasia was noted in 50% (7/14) of cases, a frequency comparable to European SDS cohorts with severe chronic neutropenia (47%) (Mellor-Heineke et al., 2025) but higher than that in domestic reports 26.7% (8/30). However, this rate remained lower than tha in the IBMFS cohort (66.6%, 20/30) (Thompson et al., 2022) and North American SDS cohort (100%, 32/32) (Myers et al., 2014). Notably, the degree of bone marrow hypoplasia does not always correlate with cytopenia. A North American SDS cohort reported that bone marrow cellularity is independent of blood cell counts with increasing age (Furutani et al., 2022). Severe bone marrow failure typically occurs within the first decade of life, while hematologic malignancies are more common thereafter (Donadieu et al., 2012; Kennedy et al., 2021). Therefore, we recommend blood evaluations every 3–6 months and bone marrow assessments every 1–3 years following an SDS diagnosis (Nelson and Myers, 2018).

The novelty of this study lies in its comprehensive analysis of multisystem involvement in patients with SDS, particularly cardiac, renal, and neurological abnormalities, which may vary across different age groups. These findings provide valuable insights for the early diagnosis and multidisciplinary management of SDS.

Pathogenic biallelic mutations in the SBDS gene were identified in 90% of patients (Boocock et al., 2003; Thompson et al., 2022), with the most common mutation sites being c.258+2T>C and c.183_184TA>CT (Shimamura, 2006; Minelli et al., 2009),which is consistent with the findings in our cohort (Figure 3). However, significant phenotypic variability was noted among these patients, with differences becoming more pronounced with age, even within the same individual. No significant correlation was found between clinical phenotypes and genotypes (P > 0.05) (Supplementary Table S2), consistent with previous reports (Donadieu et al., 2012; Alter et al., 2018; Furutani et al., 2022; Han et al., 2023).

The c.258+2T>C mutation is a known hotspot pathogenic mutation. This splicing mutation leads to premature termination of SBDS translation, although in vitro and in vivo studies have shown that it can produce a small amount of normal protein (Peretto et al., 2023). Clinically, Cases 1 and 2 were identified as homozygous carriers of this mutation. In Case 14, the father carried both c.258+2T>C and c.183_184TA>CT mutations on one allele, which were inherited by the patient, while the mother carried the c.258+2T>C mutation, which was also inherited by the patient. The c.183_184TA>CT mutation results in a nonsense truncation (p.K62X) (Boocock et al., 2003; Zhang et al., 2006; Parikh et al., 2012), and this patient eventually progressed to MDS.

Studies by Kennedy et al. (2021) and Reilly and Shimamura (2023) provide molecular mechanisms supporting this clinical phenotype:

1. Homozygous c.258+2T>C mutations lead to gene deletion, preventing the release of the anti-association factor eIF6 from the 60S ribosomal subunit, resulting in impaired ribosome maturation and reduced translation efficiency.

Therefore, we hypothesize that the combined effects of these two mutations may lead to more severe clinical manifestations, such as bone marrow failure, pancreatic insufficiency, and MDS transformation. Further cytogenetic analysis revealed a highly complex karyotype in this patient, including add (5), add (7), −17, −20, and +mar1∼6. Complex karyotypes are known risk factors (Xia et al., 2018) for bone marrow failure and hematologic malignant transformation (Cada et al., 2015; Furutani et al., 2022). Additionally, the presence of TP53 mutations, an early initiating event in MDS/AML transformation in patients with SDS (Xia et al., 2018; Kennedy et al., 2021), suggests that a “dual-hit” mechanism drives clonal evolution, leading to MDS progression.

In summary, our retrospective analysis of patients with SDS at our center highlights the significant clinical heterogeneity of the disease, which poses challenges for both diagnosis and treatment. This study further refines the clinical phenotype of SDS, enhancing diagnostic accuracy and therapeutic approaches while also providing valuable data for epidemiological research and policy-making in rare diseases. The identification of novel mutations, c.185A>C and c.41A>T, enriches the mutational spectrum of SDS. However, this study primarily relied on bioinformatics analysis, lacking functional validation of these mutations at the protein and cellular levels. Future research should employ cell-based assays and animal models to elucidate the impact of SBDS mutations on protein function and cellular behavior.

The observed differences in clinical features compared to other SDS cohorts may stem from genetic, epigenetic, environmental, and methodological variations, as well as differences in diagnostic criteria and inflammatory modifiers, which are difficult to quantify. Larger collaborative studies are essential to comprehensively characterize the clinical spectrum and disease progression of SDS. Additionally, comprehensive monitoring programs, genetic counseling, and multidisciplinary collaboration are crucial for improving patient quality of life and maximizing survival outcomes.