RARE DISEASE
Shwachman-Diamond syndrome
Shwachman-Diamond syndrome
Shwachman-Diamond syndrome
Synonyms: Pancreatic insufficiency and bone marrow dysfunction, SDS, Shwachman syndrome, Shwachman-Bodian-Diamond syndrome
Synonyms: Pancreatic insufficiency and bone marrow dysfunction, SDS, Shwachman syndrome, Shwachman-Bodian-Diamond syndrome
Synonyms: Pancreatic insufficiency and bone marrow dysfunction, SDS, Shwachman syndrome, Shwachman-Bodian-Diamond syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive multisystem disorder characterized by exocrine pancreatic insufficiency, bone marrow failure (neutropenia, anemia, thrombocytopenia), skeletal dysplasia, and increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Over 90% of cases involve biallelic SBDS gene mutations, impacting ribosome biogenesis. Pancreatic dysfunction typically manifests in infancy with malabsorption, while hematologic complications escalate leukemia risk by adulthood [1][2][6][7].
Burden
High morbidity: Recurrent infections (50-60%), growth failure, skeletal deformities (e.g., metaphyseal dysplasia), neurodevelopmental delays [2][6][7]
Lifetime MDS/AML risk: 19% at 20 years, 36% at 30 years [4][11]
Mortality: 20-year survival ~70%, dropping to <25% post-AML diagnosis despite HSCT [7][11]
Therapies
Pancreatic enzyme replacement, fat-soluble vitamin supplementation, and nutritional support [1][3][8]
Granulocyte colony-stimulating factor (G-CSF) for refractory neutropenia; prophylactic antibiotics [3][4]
Hematopoietic stem cell transplantation (HSCT) for severe cytopenias or leukemic transformation [7][9][11]
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare gastroenterological diseases, rare genetic diseases, rare hematological diseases, rare immunological diseases, rare neoplastic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
208 drug discovery papers about Shwachman-Diamond syndrome, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
208 drug discovery papers about Shwachman-Diamond syndrome, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-30 | Compensatory clonal hematopoiesis in patients with Shwachman–Diamond syndrome
Introduction. Shwachman–Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome characterized by a high risk of developing myeloid malignancies. Aim: to determine the spectrum of compensatory genetic events in SDS as well as to analyze their potential role in the clinical course of the disease. Materials and methods. The study included 41 patients with confirmed SDS. For the analysis of somatic alterations, we employed high-throughput sequencing of the “Clonality of Hematopoiesis” targeted gene panel as well as cytogenetic methods. Results. Compensatory somatic events were detected in 31.7% of the patients. The most frequent alterations were genetic variants in the EIF6 gene, as well as the i(7q) and del(20q) clonal cytogenetic abnormalities. Generally, these changes were not accompanied by clinical or morphological signs of myeloid transformation. Conclusion. The obtained data suggest a possible role of somatic genetic compensation in maintaining the viability of hematopoietic cells in SDS. Therefore, the detection of markers of clonal expansion necessitates dynamic molecular monitoring.
2026-06-28 | Generation of iPSC and isogenic gene-corrected lines from a patient with Shwachman Diamond syndrome.
Shwachman Diamond Syndrome (SDS) is an inherited bone marrow failure and leukemia predisposition syndrome characterized by exocrine pancreatic insufficiency, skeletal dysplasia and bone marrow failure. SDS is inherited in an autosomal recessive manner and most patients with SDS carry biallelic mutations in the SBDS gene. We generated an iPSC line from a patient biallelic SBDS mutations (c.258 + 2 T > C & c.183-184delinsCT(p.Lys62*) along with a corresponding isogenic control line correcting the splice site mutation with a cytosine base editor.
2026-06-12 | A Case Report of Shwachman-Diamond Syndrome Caused by Heterozygous Variants in the EFL1 Gene and Literature Review.
This investigation reports on a Shwachman-Diamond syndrome (SDS) case arising from compound heterozygous genetic variations affecting the EFL1 locus. A systematic review of published literature was undertaken to compile data on clinical manifestations, management strategies, and prognostic indicators in SDS cases with identified EFL1 genetic alterations. The clinical data of a neonatal SDS patient, whole exome sequencing (WES) results, and the pathogenicity of the variants were analyzed. A comprehensive survey of applicable medical literature published up to March 2025 was executed to identify and synthesize the clinical phenotypes associated with this condition. WES identified compound heterozygous variants within the patient's EFL1 gene: c.2935C>T (p.R979C) and c.3149_3151delCAC (p.P1050del). Bioinformatics analysis indicated these variations were damaging. Seven articles reported a total of 20 cases of this disease, with predominant phenotypes including exocrine pancreatic insufficiency, hematologic abnormalities, and metaphyseal dysplasia. Among the 20 previously reported cases, 16 distinct EFL1 variants were identified, and the current case adds 2 novel variants. SDS caused by EFL1 gene defects primarily presents as bone marrow failure, with treatment mainly focused on symptomatic management. We report a neonatal SDS patient with the earliest onset of symptoms. The c.2935C>T and c.3149_3151delCAC compound heterozygous variants reported in this study expand the mutational spectrum of this disease.
2026-04-19 | Spleno-Medullary Progenitor Cell Transplantation (SMPT): A Comprehensive, Mechanistically Grounded, and Empirically Falsifiable Theoretical Framework with Integrated p53-MDM2 Dynamics, Expanded Dynamic Stability Analysis, Global Sensitivity Analysis, Bayesian Inference, and Quantitative Risk Assessment for Autologous Restoration of Erythropoiesis in Severe Aplastic Anemia, Diamond-Blackfan Anemia, and Hereditary Bone Marrow Failure Syndromes
We present a rigorously upgraded and extensively detailed in silico theoretical framework for Spleno-Medullary Progenitor Cell Transplantation (SMPT), an autologous cellular intervention hypothesized to restore effective erythropoiesis in severe aplastic anemia (SAA), Diamond-Blackfan anemia (DBA), and a spectrum of hereditary bone marrow failure syndromes. The framework incorporates a dedicated fifth compartment modeling p53 activity with explicit biochemical kinetics derived from the p53-MDM2 negative feedback loop and ribosomal stress sensing (RPL5/RPL11). The five-dimensional deterministic/stochastic ordinary/stochastic differential equation (ODE/SDE) system is subjected to comprehensive analytical stability analysis, including derivation of the full Jacobian matrix, analytical equilibrium solutions, Lyapunov-based global stability proofs, bifurcation analysis with respect to engraftment efficiency, and phase-plane projections. Global sensitivity analysis (Sobol indices up to second-order, N=10^4 Saltelli samples across six key parameters: β, κ, η, δ, γ, λ) and time-dependent sensitivity heatmaps are presented. Bayesian inference, optimized via a steady-state algebraic surrogate for MCMC feasibility (4 chains, 2000 draws), yielded robust posterior estimates with strict convergence (R̂ ≤ 1.01, ESS >800). Monte-Carlo uncertainty quantification (N=5000 SDE trajectories) predicts robust restoration of normalized RBC counts to R(200)=209.37 under nominal SMPT conditions (β=0.35). A branching-process model estimates the probability of ex-vivo acquisition of a myeloid driver mutation at 3.0×10^{-6} per progenitor cell. Every central claim is formulated as a Popperian-falsifiable hypothesis, and all computational outputs are fully reproducible via the complete Python code provided in the Supplementary Information (with explicit random seeds, tolerance settings, and modular syndrome-specific parameter overrides). This work establishes a quantitative, evidence-anchored, and mechanistically explicit foundation for future experimental validation of niche-engineered autologous therapies across inherited and acquired bone marrow failure syndromes. All numerical outputs have been cross-verified against high-precision ODE integration (rtol=10^{-9}, atol=10^{-9}) to eliminate any discretization or approximation artifacts, ensuring absolute fidelity to the underlying differential equations. The framework has been further strengthened by expanded molecular niche dynamics (explicit SCF/CXCL12-integrin-p53 feedback loops and reaction-diffusion formulation), deepened applications to Shwachman-Diamond syndrome, and supremely precise rephrasing of all dynamic stability theorems, all seamlessly interconnected with the core five-compartment structure.
2026-04-07 | Functional impact of the eIF6 N106S mutation on ribosome biogenesis in wild type and Shwachman-Diamond syndrome cells.
BACKGROUND: Eukaryotic initiation factor 6 (eIF6) is an essential regulator of ribosome biogenesis that prevents the premature association of the 60S and 40S ribosomal subunits. eIF6 eviction from nascent 60S particles, mediated by the ribosome biogenesis factors SBDS and EFL1, is required for the formation of translationally competent 80S ribosomes. SBDS and EFL1 deficiencies cause Shwachman-Diamond syndrome (SDS), a ribosomopathy mainly characterized by exocrine pancreatic insufficiency, bone marrow failure and a predisposition to hematological malignancies. Somatic EIF6 mutations that reduce the amount of eIF6 (e.g., nonsense mutation, deletion) or its ability to bind to the 60S subunit (e.g., N106S missense mutation) are frequently found in hematopoietic cells of SDS individuals. These somatic EIF6 mutations represent indirect somatic genetic rescue (SGR) in the context of SDS, as they increase cellular fitness to cause clonal expansion and are associated with clinical improvement in some cases. However, the functional consequences of these eIF6 mutations in human SDS cells have never been reported to date. METHODS: As fibroblasts from individuals with SDS carrying biallelic pathogenic variants in either SBDS or EFL1 exhibit impaired ribosome production and reduced translation, we employed these cells, in addition to fibroblasts from a healthy donor, as a cellular model to analyze the impact of the EIF6 N106S mutation, which was introduced by CRISPR/Cas9-mediated genome editing. The assessment of eIF6 localization, ribosome biogenesis, ribosomal RNA (rRNA) processing, global protein synthesis, cellular fitness, and p53 pathway activation was conducted in these cells. RESULTS: Endogenous expression of the eIF6 N106S mutant altered the subcellular distribution of eIF6 and induced pronounced defects, including impaired ribosomal RNA 3′-ETS processing, reduced availability of mature 60S subunits, and accumulation of halfmer polysomes. These alterations were associated with reduced cellular fitness in both healthy donor and SDS fibroblasts. In the context of SBDS deficiency, the N106S mutation partially alleviated aberrant retention of eIF6 on the 60S subunit but failed to restore global translation or confer a proliferative advantage. CONCLUSIONS: Our study reveals that the eIF6 N106S mutation uncouples partial correction of eIF6–60S dissociation from proper rRNA biogenesis and cellular fitness. These findings reveal intrinsic limits to altering eIF6–60S interactions without disrupting ribosome biogenesis. Furthermore, these results emphasize that therapeutic strategies targeting the eIF6–60S interaction must carefully balance rescue of ribosomal stress against disruption of ribosome biogenesis, particularly in disease contexts such as Shwachman-Diamond syndrome.
2026-06-30 | Compensatory clonal hematopoiesis in patients with Shwachman–Diamond syndrome
Introduction. Shwachman–Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome characterized by a high risk of developing myeloid malignancies. Aim: to determine the spectrum of compensatory genetic events in SDS as well as to analyze their potential role in the clinical course of the disease. Materials and methods. The study included 41 patients with confirmed SDS. For the analysis of somatic alterations, we employed high-throughput sequencing of the “Clonality of Hematopoiesis” targeted gene panel as well as cytogenetic methods. Results. Compensatory somatic events were detected in 31.7% of the patients. The most frequent alterations were genetic variants in the EIF6 gene, as well as the i(7q) and del(20q) clonal cytogenetic abnormalities. Generally, these changes were not accompanied by clinical or morphological signs of myeloid transformation. Conclusion. The obtained data suggest a possible role of somatic genetic compensation in maintaining the viability of hematopoietic cells in SDS. Therefore, the detection of markers of clonal expansion necessitates dynamic molecular monitoring.
2026-06-28 | Generation of iPSC and isogenic gene-corrected lines from a patient with Shwachman Diamond syndrome.
Shwachman Diamond Syndrome (SDS) is an inherited bone marrow failure and leukemia predisposition syndrome characterized by exocrine pancreatic insufficiency, skeletal dysplasia and bone marrow failure. SDS is inherited in an autosomal recessive manner and most patients with SDS carry biallelic mutations in the SBDS gene. We generated an iPSC line from a patient biallelic SBDS mutations (c.258 + 2 T > C & c.183-184delinsCT(p.Lys62*) along with a corresponding isogenic control line correcting the splice site mutation with a cytosine base editor.
2026-06-12 | A Case Report of Shwachman-Diamond Syndrome Caused by Heterozygous Variants in the EFL1 Gene and Literature Review.
This investigation reports on a Shwachman-Diamond syndrome (SDS) case arising from compound heterozygous genetic variations affecting the EFL1 locus. A systematic review of published literature was undertaken to compile data on clinical manifestations, management strategies, and prognostic indicators in SDS cases with identified EFL1 genetic alterations. The clinical data of a neonatal SDS patient, whole exome sequencing (WES) results, and the pathogenicity of the variants were analyzed. A comprehensive survey of applicable medical literature published up to March 2025 was executed to identify and synthesize the clinical phenotypes associated with this condition. WES identified compound heterozygous variants within the patient's EFL1 gene: c.2935C>T (p.R979C) and c.3149_3151delCAC (p.P1050del). Bioinformatics analysis indicated these variations were damaging. Seven articles reported a total of 20 cases of this disease, with predominant phenotypes including exocrine pancreatic insufficiency, hematologic abnormalities, and metaphyseal dysplasia. Among the 20 previously reported cases, 16 distinct EFL1 variants were identified, and the current case adds 2 novel variants. SDS caused by EFL1 gene defects primarily presents as bone marrow failure, with treatment mainly focused on symptomatic management. We report a neonatal SDS patient with the earliest onset of symptoms. The c.2935C>T and c.3149_3151delCAC compound heterozygous variants reported in this study expand the mutational spectrum of this disease.
2026-04-19 | Spleno-Medullary Progenitor Cell Transplantation (SMPT): A Comprehensive, Mechanistically Grounded, and Empirically Falsifiable Theoretical Framework with Integrated p53-MDM2 Dynamics, Expanded Dynamic Stability Analysis, Global Sensitivity Analysis, Bayesian Inference, and Quantitative Risk Assessment for Autologous Restoration of Erythropoiesis in Severe Aplastic Anemia, Diamond-Blackfan Anemia, and Hereditary Bone Marrow Failure Syndromes
We present a rigorously upgraded and extensively detailed in silico theoretical framework for Spleno-Medullary Progenitor Cell Transplantation (SMPT), an autologous cellular intervention hypothesized to restore effective erythropoiesis in severe aplastic anemia (SAA), Diamond-Blackfan anemia (DBA), and a spectrum of hereditary bone marrow failure syndromes. The framework incorporates a dedicated fifth compartment modeling p53 activity with explicit biochemical kinetics derived from the p53-MDM2 negative feedback loop and ribosomal stress sensing (RPL5/RPL11). The five-dimensional deterministic/stochastic ordinary/stochastic differential equation (ODE/SDE) system is subjected to comprehensive analytical stability analysis, including derivation of the full Jacobian matrix, analytical equilibrium solutions, Lyapunov-based global stability proofs, bifurcation analysis with respect to engraftment efficiency, and phase-plane projections. Global sensitivity analysis (Sobol indices up to second-order, N=10^4 Saltelli samples across six key parameters: β, κ, η, δ, γ, λ) and time-dependent sensitivity heatmaps are presented. Bayesian inference, optimized via a steady-state algebraic surrogate for MCMC feasibility (4 chains, 2000 draws), yielded robust posterior estimates with strict convergence (R̂ ≤ 1.01, ESS >800). Monte-Carlo uncertainty quantification (N=5000 SDE trajectories) predicts robust restoration of normalized RBC counts to R(200)=209.37 under nominal SMPT conditions (β=0.35). A branching-process model estimates the probability of ex-vivo acquisition of a myeloid driver mutation at 3.0×10^{-6} per progenitor cell. Every central claim is formulated as a Popperian-falsifiable hypothesis, and all computational outputs are fully reproducible via the complete Python code provided in the Supplementary Information (with explicit random seeds, tolerance settings, and modular syndrome-specific parameter overrides). This work establishes a quantitative, evidence-anchored, and mechanistically explicit foundation for future experimental validation of niche-engineered autologous therapies across inherited and acquired bone marrow failure syndromes. All numerical outputs have been cross-verified against high-precision ODE integration (rtol=10^{-9}, atol=10^{-9}) to eliminate any discretization or approximation artifacts, ensuring absolute fidelity to the underlying differential equations. The framework has been further strengthened by expanded molecular niche dynamics (explicit SCF/CXCL12-integrin-p53 feedback loops and reaction-diffusion formulation), deepened applications to Shwachman-Diamond syndrome, and supremely precise rephrasing of all dynamic stability theorems, all seamlessly interconnected with the core five-compartment structure.
2026-04-07 | Functional impact of the eIF6 N106S mutation on ribosome biogenesis in wild type and Shwachman-Diamond syndrome cells.
BACKGROUND: Eukaryotic initiation factor 6 (eIF6) is an essential regulator of ribosome biogenesis that prevents the premature association of the 60S and 40S ribosomal subunits. eIF6 eviction from nascent 60S particles, mediated by the ribosome biogenesis factors SBDS and EFL1, is required for the formation of translationally competent 80S ribosomes. SBDS and EFL1 deficiencies cause Shwachman-Diamond syndrome (SDS), a ribosomopathy mainly characterized by exocrine pancreatic insufficiency, bone marrow failure and a predisposition to hematological malignancies. Somatic EIF6 mutations that reduce the amount of eIF6 (e.g., nonsense mutation, deletion) or its ability to bind to the 60S subunit (e.g., N106S missense mutation) are frequently found in hematopoietic cells of SDS individuals. These somatic EIF6 mutations represent indirect somatic genetic rescue (SGR) in the context of SDS, as they increase cellular fitness to cause clonal expansion and are associated with clinical improvement in some cases. However, the functional consequences of these eIF6 mutations in human SDS cells have never been reported to date. METHODS: As fibroblasts from individuals with SDS carrying biallelic pathogenic variants in either SBDS or EFL1 exhibit impaired ribosome production and reduced translation, we employed these cells, in addition to fibroblasts from a healthy donor, as a cellular model to analyze the impact of the EIF6 N106S mutation, which was introduced by CRISPR/Cas9-mediated genome editing. The assessment of eIF6 localization, ribosome biogenesis, ribosomal RNA (rRNA) processing, global protein synthesis, cellular fitness, and p53 pathway activation was conducted in these cells. RESULTS: Endogenous expression of the eIF6 N106S mutant altered the subcellular distribution of eIF6 and induced pronounced defects, including impaired ribosomal RNA 3′-ETS processing, reduced availability of mature 60S subunits, and accumulation of halfmer polysomes. These alterations were associated with reduced cellular fitness in both healthy donor and SDS fibroblasts. In the context of SBDS deficiency, the N106S mutation partially alleviated aberrant retention of eIF6 on the 60S subunit but failed to restore global translation or confer a proliferative advantage. CONCLUSIONS: Our study reveals that the eIF6 N106S mutation uncouples partial correction of eIF6–60S dissociation from proper rRNA biogenesis and cellular fitness. These findings reveal intrinsic limits to altering eIF6–60S interactions without disrupting ribosome biogenesis. Furthermore, these results emphasize that therapeutic strategies targeting the eIF6–60S interaction must carefully balance rescue of ribosomal stress against disruption of ribosome biogenesis, particularly in disease contexts such as Shwachman-Diamond syndrome.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Shwachman-Diamond syndrome, including 1 approved therapy.
2 orphan drug designations for Shwachman-Diamond syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Synthetic porcine secretin [Secreflo] | peptides | FDA | 1999-06-18 | 2002-11-01 | ChiRhoClin, Inc. |
Synthetic human secretin | peptides | FDA | 1999-06-16 | — | ChiRhoClin, Inc. |
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