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
210 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:
210 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:
categories:
Small molecules
proteins
2025-08-17 | Growth Patterns in Shwachman-Diamond Syndrome: Findings from the North American Shwachman-Diamond Syndrome Registry.
To characterize growth patterns in individuals with Shwachman-Diamond syndrome (SDS) in North America by generating SDS-specific growth curves and assessing the impact of hematopoietic stem cell transplant (HSCT) and growth hormone (GH) on growth. We conducted a retrospective cohort study of 127 subjects with confirmed biallelic Shwachman-Bodian-Diamond syndrome mutations enrolled on the North American SDS Registry. Height-for-age, weight-for-age, and body mass index (BMI)-for-age Z-scores were analyzed and compared with Centers for Disease Control and Prevention and World Health Organization reference populations. The effects of HSCT and GH therapy on growth velocity and final height outcomes were assessed. Individuals with SDS demonstrated significantly lower height-for-age Z-scores, with median adult height being approximately 7 cm shorter in females and 11 cm shorter in males compared with Centers for Disease Control and Prevention standards. Although weight-for-age was diminished, BMI-for-age trajectories were preserved. HSCT significantly reduced height-for-age Z-scores slope, and in a small subsample, GH therapy showed limited efficacy in improving final height. This study of SDS across a diverse North American sample extends available growth data for this rare condition, confirming persistent short stature but normal BMI for age in SDS. HSCT was associated with a reduction in growth. No significant change in height velocity was observed with GH therapy. These data will inform clinical growth evaluation in SDS patients.
2025-05-29 | Correction of nutrient deficiencies in children with Shwachman–Diamond syndrome
Shwachman–Diamond syndrome (SDS) is a rare genetic ribosomopathy caused by impaired hematopoiesis, exocrine pancreatic insufficiency, delayed puberty, and skeletal abnormalities. Objective. To evaluate the efficacy of correcting nutrient deficiencies in children with SDS using specialized therapeutic formulas and enzyme replacement therapy (ERT). Patients and methods. The study included 69 patients with a diagnosis of SDS confirmed by genetic testing. During the first hospitalization and one year after the start of treatment with specialized therapeutic formulas and ERT, anthropometric data of patients were evaluated using the WHO Anthro and WHO Anthro Plus programs. Laboratory markers of nutritional status included total protein, albumin, urea, creatinine, cholesterol, high-density lipoproteins, low-density lipoproteins, triglycerides, glucose, iron, calcium, phosphorus, and vitamin D in blood serum. Food specific IgE antibodies, IgA and IgG to gliadin and tissue transglutaminase were examined. Fecal elastase-1 levels were determined to assess the exocrine pancreatic function. According to the results of examination, correction of diet therapy with selection of specialized therapeutic formulas was performed considering the age, basal metabolic rate and concomitant pathology. ERT with pancreatin minimicrospheres was prescribed. Results. In patients with SDS during their first hospitalization, the height Z-score (median, 1st and 3rd quartiles (Me [Q1; Q3])) was -1.60 [-2.4; -0.8], the weight Z-score was -1.5 [-2.2; -0.7], and the body mass index (BMI) Z-score was -0.8 [-1.5; 0.2]. IgE-mediated food allergy was laboratory confirmed in 43 (62.3%) children, and non-celiac gluten sensitivity was detected in 35 (50.7%) children. Celiac disease was diagnosed in 1 child, as was diabetes. Exocrine pancreatic insufficiency was revealed in 98.7% of patients as decreased fecal elastase-1 levels (24 [15; 53.5] μg/g). All children were prescribed individually selected diet therapy and therapeutic formulas (Alfare, Peptamen), ERT with pancreatin minimicrospheres. Comprehensive treatment for 1 year showed a statistically significant improvement in weight/height and laboratory parameters in children with SDS. Conclusion. Children with SDS require nutritional support that includes individually selected diet therapy considering food allergies/intolerances, supplemental therapeutic formulas, and pancreatin minimicrospheres in an adequate dose. Key words: Shwachman–Diamond syndrome, children, physical development, protein-energy undernutrition, diet therapy, therapeutic formulas, pancreatin
2025-04-01 | Shwachman–Diamond Syndrome: A Rare Possibility in a Child with Failure to Thrive and Recurrent Infections - A Case Report
Abstract Background: Shwachman–Diamond Syndrome (SDS) is a rare inherited autosomal recessive multisystem disorder, with features of pancreatic exocrine insufficiency, skeletal malformations, immunodeficiency, and bone marrow failure having a high risk of myeloid malignancies at a young age. Clinical Description: A 6.5-year-old girl presented with recurrent episodes of loose stools, cough with fever, and ear discharge since the age of 1 year, requiring multiple hospitalizations and blood transfusions. On examination, she was malnourished and stunted and had pallor, clubbing, oral mucositis, pectus carinatum, and hepatomegaly with crepitations in bilateral lung fields. Management and Outcome: Investigations showed anemia and leukopenia with normal iron, vitamin B12, and folic acid stores but elevated Hemoglobin F. Chest X-ray showed bilateral bronchiectasis, and bronchoscopy showed left lower lobe bronchomalacia. Diagnostic tests revealed low fecal elastase levels, absence of CFTR gene mutation, normal immunoglobulin profile, and a hypocellular bone marrow without dysplasia. Whole-exome sequencing from blood and buccal swab revealed a homozygous pathogenic mutation in SBDS gene, thus confirming SDS. Granulocyte colony-stimulating factor and pancreatic enzyme replacement therapy were started, though the latter could not be continued, the former being continued in follow-up. Thrombocytopenia developed later, though malignancy was ruled out. The child was referred for stem-cell transplantation. Conclusion: A possibility of SDS is to be kept in a child presenting with failure to thrive with recurrent respiratory and gastrointestinal infections requiring repeated blood transfusions. After ruling out cystic fibrosis and immunodeficiency disorders, an evaluation of the hematological system and exocrine pancreatic function, followed by genetic analysis, can confirm the diagnosis.
2025-03-27 | Genetic and clinical characteristics of patients with Shwachman Diamond syndrome with special consideration of treatment with granulocyte-colony stimulating factor
Not available.
2025-02-26 | Shwachman–Diamond syndrome: characteristics of exocrine and endocrine functions of the pancreas in children
Shwachman–Diamond syndrome (SDS) is a rare genetic disorder that belongs to the group of ribosomopathies. It is characterized by impaired hematopoiesis, exocrine pancreatic insufficiency (EPI), delay in physical development, and bone anomalies. Objective. To study the characteristics of exocrine and endocrine functions of the pancreas in children with a genetically confirmed diagnosis of SDS. Patients and methods. The study included 74 patients with a genetically confirmed diagnosis of SDS. The levels of total and pancreatic amylase and lipase in blood, the results of coprological examination, and the levels of fecal elastase-1 were evaluated to study the exocrine function of the pancreas. The endocrine function of the pancreas was assessed by determining the levels of fasting glucose, C-peptide and insulin. All children underwent abdominal ultrasound examination. Results. A total of 68.9% of children with SDS had delay in physical development, and 66.2% had protein-energy undernutrition of varying severity. In 98.7% of patients, a pronounced EPI was revealed, manifested by low fecal elastase-1 levels, median: 24 [15; 53.5] μg/g. Patients with SDS commonly had low levels of pancreatic amylase (95.9%) and lipase (83.8%). Ultrasound signs of pancreatic steatosis were detected in 78.4% of SDS patients. The median of glucose levels in SDS patients was 4.5 mmol/L [4.1; 5.1]. In 42 (56.8%) children, insulin levels were within the reference range, and in 32 (43.2%) children, they were below age norms – 3.4 [2; 6.8 mIU/mL]. In 47 (63.5%) children, C-peptide levels were below age norms – 0.7 [0.48; 1.5] ng/mL. There was a positive tendency toward higher C-peptide and insulin levels with age. One child in the study group was diagnosed with diabetes, which required insulin therapy. Conclusion. Patients with SDS need careful monitoring of both exocrine and endocrine functions of the pancreas. Severe EPI in children with SDS requires administration of high-dose pancreatic enzyme replacement therapy using pancreatic enzymes encapsulated in mini-microspheres (Creon®). Key words: Shwachman–Diamond syndrome, SBDS gene, children, pancreas, exocrine pancreatic insufficiency, carbohydrate metabolism, diabetes
small molecules
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.
2026-03-18 | Hydroxyl radical footprinting modification reveals an intradomain communication pathway in EFL1 disrupted by a Shwachman-Diamond syndrome-associated mutation.
Shwachman-Diamond syndrome (SDS) is a rare genetic disorder characterized by pancreatic insufficiency and neutropenia. While most cases are linked to mutations in the SBDS gene, some involve mutations in the GTPase EFL1. This protein works with SBDS to release the anti-association factor eIF6 from the 60S ribosomal subunit during ribosome biogenesis. The pathogenic EFL1 R1095Q mutant (R1086Q in yeast) exhibits altered guanine nucleotide recognition and impaired eIF6 release, prompting an investigation into its structural consequences. Using the yeast Efl1 orthologue in X-ray hydroxyl radical footprinting experiments, we tracked changes in solvent accessibility caused by the mutation. Although the mutation is situated in domain IV, widespread conformational changes were observed across the protein, particularly in domain I, suggesting a long-range intramolecular communication. Strikingly, the growth defect caused by the pathogenic mutation was rescued by a second mutation located in a allosteric pathway that spans from the nucleotide-binding pocket to domain IV. This compensatory mutation restored proper nuclear localization of eIF6 (Tif6 in yeast). These findings reveal that the R1086Q mutation disrupts a structural communication network within Efl1, impairing the conformational dynamics required for its activity. The loss of this coordination likely underlies the ribosome maturation defects observed in SDS cases linked to EFL1, offering new insights into the molecular basis of the disease.
2026-02-13 | Hog1/p38 and ZAKα drive Shwachman-Diamond syndrome and provide targets to improve cell growth.
Shwachman-Diamond syndrome (SDS) is a ribosomopathy characterized by neutropenia, pancreatic insufficiency, skeletal defects, and predisposition to leukemia. Most cases result from biallelic SBDS mutations that impairing 80S ribosome and polysome assembly. In yeast lacking SDO1 (the SBDS ortholog), growth slows dramatically and the p38 ortholog Hog1 signaling is elevated by multiple types of stress. SBDS-deficient HeLa cells exhibited reduced proliferation and slowed cell cycling. The p38 kinase was constitutively activated in SBDS mutants and SDS patient-derived blood cells. Because ZAKα detects ribosome dysfunction, its activation links ribosomal defects to stress kinase pathways in SDS. Suppressing p38α or its upstream activator ZAKα restored cell growth and reduced stress signaling. These findings reveal an evolutionarily conserved-independent mechanism via p38 drives SDS pathophysiology and identifies stress kinases as potential therapeutic targets for ribosomal dysfunction.
2025-12-28 | Ribosomes: Engines of Protein Synthesis
Ribosomes are essential macromolecular complexes that translate genetic information from mRNA into proteins. Composed of rRNA and ribosomal proteins, they consist of two subunits, large and small, in both prokaryotic (70S) and eukaryotic (80S) cells, with structural differences reflecting their evolutionary adaptations. Ribosome biogenesis (Ribi) is a tightly regulated process initiated by rDNA transcription and subunit assembly in eukaryotes and involving factors like NusA and NusG in prokaryotes. Ribosomes drive protein synthesis through complex processes of initiation, elongation, termination, and recycling, facilitated by GTPases and elongation factors, ribosomopathies cause diseases such as Diamond-Blackfan Anemia and Shwachman-Diamond Syndrome, linked to mutations in ribosomal proteins. Ribosomal dysfuntion can lead to both hypo- and hyper-proliferation, increasing cancer risk. Recent advances in targeting ribosome-related pathways, such as mTORC1 inhibition, and techniques like ribosome profiling have provided insights into diseases like leukemia and medulloblastoma, revealing non-canonical ORF translation and novel therapeutic targets. These findings highlight the therapeutic potential of modulating ribosome function in disease treatment.
2025-10-01 | Management Of Dental Caries In Shwachman-Diamond Syndrome Children
Shwachman-Diamond syndrome (SDS), a rare autosomal recessive disorder caused by SBDS gene mutations (c.258+2T>C in homozygous state), presents significant challenges in dental care due to rapid caries progression and systemic complications. Three children with SDS under surveillance at a regional orphan disease center presented with rapidly progressing caries immediately after tooth eruption. Despite adherence to oral hygiene practices (500 ppm fluoride toothpaste) and therapeutic dietary modifications with enzyme replacement therapy (Creon), early restorative treatment of primary teeth using glass ionomer cement under general anesthesia failed. Further evaluations revealed Proteus spp. in the oral microbiota and neutral salivary pH. Radical treatment was implemented, involving restoration of posterior teeth with stainless steel crowns, anterior teeth with zirconia crowns, and extraction of teeth with poor prognosis. Home maintenance included 1450 ppm fluoride toothpaste twice a day and a probiotic with D3 (Streptococcus salivarius K12 + cholecalciferol 5mg—30-day courses biannually). Patients were monitored biannually for up to 2 years. Radical treatment stabilized the caries process, with restorations remaining in satisfactory condition. This approach highlights the limitations of conservative treatment in SDS patients and the need for personalized management addressing systemic and microbial factors. The findings align with the limited literature on SDS-related dental challenges, underscoring the importance of tailored care. This case series demonstrates the efficacy of radical treatment in managing aggressive caries in SDS patients, emphasizing its relevance in stabilizing complex dental conditions associated with rare disorders.
cell therapies
2026-09-23 | Cumulative Hematologic Morbidity and Outcomes in Shwachman–Diamond Syndrome
In an international cohort of 865 patients, Shwachman–Diamond syndrome was associated with a high risk of myeloid cancer and poor survival. Early hematopoietic stem-cell transplantation for high-risk features had a potential benefit.
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.
2025-11-05 | SUPERIOR SURVIVAL FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR HIGH-RISK MARROW FEATURES IN PATIENTS WITH SHWACHMAN-DIAMOND SYNDROME
Background: Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome with a high risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).Outcomes following allogeneic hematopoietic stem cell transplantation (HSCT) for SDS-associated MDS/AML are poor.The role of HSCT for bone marrow (BM) high-risk features (HRF) in the absence of overt malignancy remains undefined.Objective: To evaluate outcomes of HSCT for HRF compared to HSCT for MDS/AML in SDS patients.Methods: We retrospectively analyzed 254 patients enrolled in the North American SDS Registry.HRF was defined as the presence of a somatic mutation in TP53 or other high-risk genes with variant allele frequency 3.0% in at least two consecutive BM samples, with or without morphologic abnormalities.Survival was estimated using the Kaplan-Meier method and compared by log-rank testing, accounting for HSCT and death as competing risks.Results: MDS and AML were diagnosed in 21 (median age 18 years) and 14 (median age 28 years) patients, respectively.HRF was identified in 26 patients (median age 13 years), of whom 24 (92%) harbored somatic TP53 mutations.Morphologic abnormalities were present in nine patients (35%).Nineteen patients underwent HSCT for HRF (median age 20 years).The 2-year overall survival (OS, 95% CI) after HSCT was 35.0%(11.8-59.8)for MDS (n=15), 37.5% (8.7-67.4) for AML (n=9), and 87.7% (58.8-96.8)for HRF (n=19; p=0.035).Notably, all 14 patients transplanted for HRF at 25 years were alive at last follow-up, while OS for those >25 years was 60.0% (12.6-88.2).Conclusions: HSCT for HRF in SDS was associated with favorable outcomes, particularly in patients 25 years.These findings support early identification and consideration of HSCT prior to malignant transformation.The benefit of HSCT for HRF in older patients warrants further investigation.
2025-11-03 | Allogeneic hematopoietic stem cell transplantation in treatment of Shwachman- diamond syndrome: A Report of 25 Pediatric cases from a Single center
Abstract Objective: To explore the effectiveness of allogeneic hematopoietic stem cell transplantation(allo-HSCT) for Shwachman-Diamond Syndrome(SDS) complicated with severe hemocytopenia, myelodysplastic syndrome(MDS) and acute myeloid leukemia(AML). Methods: A total of 25 patients with SDS who underwent allo-HSCT in Beijing JingDu Children's Hospital from July 2015 to July 2025 were enrolled. The clinical manifestations and details about allo-HSCT were summarized. Results: There were 17 males and 8 females enrolled. The male/female ratio was 2.125. All the patients were clinically and genetically diagnosed as SDS. The median age at diagnosis was 8 months(ranging from 1 day to 158 months) old. The patients' median age at HSCT was 28 months (ranging from 7 to 162) old. The patients' median weight and height was 9.7kg (ranging from 5.2 to 38.2) and 80cm(ranging from 60 to 160). All cases had neutropenia, 9 cases complicated with anemia or thrombopenia, 9 cases had pancytopenia. 1 case was diagnosed with AML, 5 cases were diagnosed with myelodysplastic syndrome(MDS) with low balsts. 2 cases complicated with complex karyotypes. 5 cases had mutated Tp53. 6 girls had their ovaries frozen before HSCT. The donors consisted of 14 cases of unrelated cord blood(UCB), 6 cases of mismatched related donors(MMRD) and 5 cases of mismatched unrelated donors(MMUD). All patients used myeloablating conditioning.The regimen of the case with AML consisted of busulfan, fludarabine, cytarabine, cyclophosphamide and anti-thymocyte globulin(ATG). Other patients' regimens consisted of busulfan, fludarabine, ATG with or without cyclophosphamide. All were given cyclosporine and mycophenolate mofetil to prevent graft-versus- host disease(GVHD). Balliximab was given at +1 day to the patients whose donor was MMRD and methotrexate was given at +1,+4,+7,+11 days to the patients whose donor was MMUD or UCB. 24 cases achieved engraftment, the other case underwent haploid HSCT following failure of cord blood transplantation, currently at day +6 post-infusion, and the engraftment rate was 96%. The median time to neutrophil engraftment and platelet engraftment was 12 (ranging from 9 to 22)days and 16.5 (ranging from 11 to 66)days, respectively. There were 0/13, 3/6, 2/5 cases with acute GVHD (grades II to IV) and 1/13, 2/6, 1/5 mild chronic GVHD in UCB, MMRD and MMUD groups. There was no middle and severe chronic GVHD. Within the follow-up of 10.5(ranging from 0 to 119) months, 2 patients died and 1 patient with MDS relapsed. The patient with complex karyotype and Tp53 mutation experienced MDS recurrence with increased blasts after cord blood transplantation. Then he got chemotherapy and second transplantation(haploid), but failed to achieve negative MRD. Melphalan was administered before donor peripheral blood stem cell infusion, resulting in negative MRD. But he subsequently developed grade IV acute GVHD and thrombotic microangiopath. Finally, another relapse occurred at +29 months post-second transplant, and he is currently receiving palliative care. The OS and EFS rate was 92% and 88%. Conclusions: Allo-HSCT is an effective treatment for SDS complicated with severe hematological abnormalities.Compared with MMRD and MMUD HSCT, the incidence of GVHD in CBT is lower. MDS complicated with both complex karyotype and Tp53 mutation was associated with an extremely poor prognosis.
2025-01-02 | Outcomes of allogeneic hematopoietic stem cell transplantation in Shwachman-Diamond syndrome: a systematic review and meta-analysis.
We conducted a systematic review and meta-analysis to evaluate the outcomes of Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in the treatment of Shwachman-Diamond syndrome (SDS). A literature search was performed on PubMed, Embase, and Web of Science. After screening 397 articles, 10 studies were included. Data was extracted in accordance with the PRISMA guidelines and analyzed using the R 'meta' package. The pooled median 3 (1-5)-year overall survival (OS) after Allo-HSCT were 63.7% (95% CI 56.9-70.2%), 80.3% (95% CI 68.% 5-92.1%), 41.1% (95% CI 21.7-60.4%), 48.9% (95% CI 29.0-68.9%), and 8.7% (95% CI 0.0-60.8%) in SDS patients, SDS patients with bone marrow failure (BMF), SDS patients with myeloid neoplasms (MN), SDS patients with myelodysplastic syndrome (MDS), and SDS patients with acute myeloid leukemia (AML), respectively. Allo-HSCT is an efficacious approach for treating SDS patients with severe hematologic complications. However, poor outcomes were revealed in SDS patients with MN with a pooled 3 (1-5)-year relapse rate (RR) after Allo-HSCT of 25.8% (95% CI 12.5-39.0%), and a pooled 3-year non-relapse mortality (NRM) was 52.6% (95% CI 34.2-70.9%). These findings were consistent with the clinical findings that transplant-related complications are the main cause of the poor transplantation prognosis of SDS patients with MN. Efficacious bone marrow conditioning regimens, graft-versus-host disease (GVHD) prevention, and bridging treatment regimens are potential means to improve the transplantation prognosis of SDS patients.
gene therapies
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.
2026-02-02 | Liver stiffness in patients with Shwachman‐Diamond syndrome
Abstract Objective This case series aims to describe whether transient elastography (TE) as a marker of liver stiffness is associated with clinically important liver disease in children and young adults with Shwachman‐Diamond Syndrome (SDS). Methods All patients ≤25 years of age with genetically confirmed SDS seen in the Pediatric Gastroenterology Clinic at Boston Children's Hospital from 07/2017 to 11/2019 were included. Data collected included TE, hepatic transaminases, fecal elastase, and anthropometry. The correlation of liver stiffness measurements with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was assessed by Spearman rank correlation accompanied by 95% confidence intervals based on Fisher's Z transformation. Results Eight patients (six female) were identified with genetically confirmed SDS for whom the median age on the day of TE was 6years. Median (range) AST and ALT were 31 U/L (17–61) and 30 U/L (12–87), respectively, obtained within a median of 18 days (range 0–168) from liver stiffness measurement (LSM). All patients had exocrine pancreatic insufficiency as defined by fecal elastase <200 μg/g. Five patients had abdominal ultrasound within a median of 1.7 years (range 0.0–5.1), of whom four had normal results (one unknown). All eight patients underwent TE with median (range) LSM and controlled attenuation parameter (CAP) measurement ( n = 6) of 5.2 kPa (3.3–6.4) and 171 dB/m (113–250), respectively. LSM greater than METAVIR F0 was not associated with AST and ALT elevations. Conclusion In our case series of eight patients with SDS, LSM greater than METAVIR F0 was reported in three patients, two of whom had normal transaminases. This suggests that subclinical liver disease may exist in SDS patients with normal hepatic transaminases.
2025-12-12 | Beyond Cystic Fibrosis: Recognising Shwachman-Diamond Syndrome in the Respiratory Clinic.
Cystic fibrosis (CF) and Shwachman-Diamond Syndrome (SDS) share overlapping features, including recurrent respiratory infections and pancreatic insufficiency, which can complicate diagnosis. We report a case of a six-year-old girl who presented with productive cough, steatorrhea and recurrent infections. Initial evaluation showed abnormal liver enzymes, elevated immunoreactive trypsin, neutrophil dysfunction and skeletal anomalies. Sweat test was equivocal and CFTR genetic panel was negative. Further genomic analysis identified compound heterozygous mutations in the SBDS gene: c.258+2T>C (known pathogenic variant) and c.284T>A (novel variant), confirming SDS. Over a 42-year follow-up, she experienced intermittent neutropenia, recurrent respiratory infections and pregnancy-related complications. This case emphasises the importance of considering SDS in CF-like presentations with atypical features and equivocal CF testing. Milder SDS phenotypes can survive into adulthood. Further work is needed to refine genotype-phenotype correlations and guide long-term management.
other
2024-11-05 | Acute Lymphoblastic Leukemia in Shwachman-Diamond Syndrome: Challenges and Treatment Outcomes
Introduction Shwachman-Diamond Syndrome (SDS) is a rare multisystem disorder characterized by skeletal abnormalities, pancreatic exocrine insufficiency, and bone marrow dysfunction. Individuals affected by SDS are predisposed to severe cytopenia and have an increased susceptibility to myeloid malignancies. Methods We report our experience of a young girl diagnosed with SDS who developed Acute Lymphoblastic Leukemia (ALL) at the age of 15-years. Results At the age of 14 months, the patient was diagnosed with SDS. Hematological follow-up was initiated to monitor for myelodysplastic syndrome(MDS)/Acute Myeloid Leukemia (AML) progression, a long side treatment for gastroenterological and nutritional complications. In September 2020, the patient was diagnosed with B-Cell-ALL. A dose-reduced AIEOP-BFM ALL 2017 protocol, containing vincristine and daunorubicin and omitting asparaginase to prevent pancreatic toxicity was started. Due to prolonged cytopenia following the first course, following the administration of day +8 vincristine and daunorubicin, chemotherapy was discontinued and patient received two courses of Blinatumomab treatment achieving complete remission (CR) with undetectable minimal residual disease (MRD). Patient then received consolidation therapy with allogeneic-stem cell transplantation (SCT). The conditioning regimen consisted of 12 Gy- total body irradiation (TBI)plus etoposide and graft versus host disease (GVHD) prophylaxis was obtained with Cyclosporin A; no short-course methotrexate (MTX) was given in order to minimizing toxicities. In September 2021, the patient experienced a molecular relapse detected by two consecutive bone marrow evaluations. Treatment involved Blinatumomab (1 cycle) and 4 DLI, resulting in a second CR. The patient is currently in molecular CR with full donor chimerism, 41 months after HSCT. Conclusions SDS is associated with predisposition to develop MDS or AML. Children with SDS develop AML in 12-25% of cases. Lymphoid malignancies are rare in SDS patients, with four cases reported cases in the literature: two patients with a diagnosis of ALL and 2 patients affected by CNS and primary mediastinal B cell lymphoma respectively treated with standard chemo-or chemo-immunotherapy. To our knowledge, our patient represents the fifth reported lymphoid malignancy in SDS who achieved a CR in a relatively short time and is the only one alive and in CR after transplantation with a follow-up exceeding three years from diagnosis. Second ALL can be very aggressive disease with poor prognosis, particularly challenging to treat in patients with SDS where treatment experience is limited. The BFM-inspired protocols emphasize the importance of dose density and intensity for achieving CR, which is difficult to obtain due to the SDS features, such as long time to bone marrow recover and the pancreatic insufficiency which did not allow the use of a crucial drug of the chemotherapy protocol Blinatumomab emerged as the optimal treatment option for low toxicity and well tolerable profile with no gastrointestinal/pancreatic side effects and low-grade hematological toxicities allowing adherence to the treatment and serving as a bridge toallogeneic-SCT performed to consolidate the CR based on the consideration that a secondary ALL is per se an high risk disease.
2016-09-22 | Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia
Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia.
2008-11-18 | Depletion of the Shwachman-Diamond syndrome gene product, SBDS, leads to growth inhibition and increased expression of OPG and VEGF-A
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure and leukemia predisposition, pancreatic exocrine dysfunction, and skeletal abnormalities, manifesting as skeletal dysplasia and osteoporosis. Mutations in SBDS have been shown to cause SDS, but the function of the SBDS gene product is unclear. Accelerated angiogenesis has recently been described in bone marrow cells from SDS patients. To clarify the unknown function of SBDS, we performed experiments analyzing the cellular effects of depleting SBDS by RNA interference. The growth of HeLa cells constitutively depleted of SBDS was markedly hindered when compared to cells stably transfected with siRNA against an irrelevant control gene. Similarly, growth of HeLa cells induced to express siRNA against SBDS was specifically inhibited. Inducible SBDS knockdown was associated with modestly increased levels of apoptosis, suggesting a partial contribution of this process to growth inhibition. By microarray analysis of knockdown cells, we found marked differences in expression of genes in multiple pathways, and we chose to examine a selected subset more closely using quantitative PCR arrays. In constitutive and inducible SBDS-depleted HeLa cell clones, we found 3- to 6-fold elevated mRNA levels of osteoprotegerin (OPG or TNFRSF11B) and vascular endothelial growth factor-A (VEGF-A). We confirmed significant overexpression of both secreted proteins by ELISA from supernatants of SBDS-depleted HeLa cells. Osteoprotegerin and VEGF-A are known to have diverse effects on osteoclast differentiation, angiogenesis, and monocyte/macrophage migration, all processes that may be aberrant in SDS, and we propose that overexpression of these factors may contribute to its pathology.
proteins
2025-08-17 | Growth Patterns in Shwachman-Diamond Syndrome: Findings from the North American Shwachman-Diamond Syndrome Registry.
To characterize growth patterns in individuals with Shwachman-Diamond syndrome (SDS) in North America by generating SDS-specific growth curves and assessing the impact of hematopoietic stem cell transplant (HSCT) and growth hormone (GH) on growth. We conducted a retrospective cohort study of 127 subjects with confirmed biallelic Shwachman-Bodian-Diamond syndrome mutations enrolled on the North American SDS Registry. Height-for-age, weight-for-age, and body mass index (BMI)-for-age Z-scores were analyzed and compared with Centers for Disease Control and Prevention and World Health Organization reference populations. The effects of HSCT and GH therapy on growth velocity and final height outcomes were assessed. Individuals with SDS demonstrated significantly lower height-for-age Z-scores, with median adult height being approximately 7 cm shorter in females and 11 cm shorter in males compared with Centers for Disease Control and Prevention standards. Although weight-for-age was diminished, BMI-for-age trajectories were preserved. HSCT significantly reduced height-for-age Z-scores slope, and in a small subsample, GH therapy showed limited efficacy in improving final height. This study of SDS across a diverse North American sample extends available growth data for this rare condition, confirming persistent short stature but normal BMI for age in SDS. HSCT was associated with a reduction in growth. No significant change in height velocity was observed with GH therapy. These data will inform clinical growth evaluation in SDS patients.
2025-05-29 | Correction of nutrient deficiencies in children with Shwachman–Diamond syndrome
Shwachman–Diamond syndrome (SDS) is a rare genetic ribosomopathy caused by impaired hematopoiesis, exocrine pancreatic insufficiency, delayed puberty, and skeletal abnormalities. Objective. To evaluate the efficacy of correcting nutrient deficiencies in children with SDS using specialized therapeutic formulas and enzyme replacement therapy (ERT). Patients and methods. The study included 69 patients with a diagnosis of SDS confirmed by genetic testing. During the first hospitalization and one year after the start of treatment with specialized therapeutic formulas and ERT, anthropometric data of patients were evaluated using the WHO Anthro and WHO Anthro Plus programs. Laboratory markers of nutritional status included total protein, albumin, urea, creatinine, cholesterol, high-density lipoproteins, low-density lipoproteins, triglycerides, glucose, iron, calcium, phosphorus, and vitamin D in blood serum. Food specific IgE antibodies, IgA and IgG to gliadin and tissue transglutaminase were examined. Fecal elastase-1 levels were determined to assess the exocrine pancreatic function. According to the results of examination, correction of diet therapy with selection of specialized therapeutic formulas was performed considering the age, basal metabolic rate and concomitant pathology. ERT with pancreatin minimicrospheres was prescribed. Results. In patients with SDS during their first hospitalization, the height Z-score (median, 1st and 3rd quartiles (Me [Q1; Q3])) was -1.60 [-2.4; -0.8], the weight Z-score was -1.5 [-2.2; -0.7], and the body mass index (BMI) Z-score was -0.8 [-1.5; 0.2]. IgE-mediated food allergy was laboratory confirmed in 43 (62.3%) children, and non-celiac gluten sensitivity was detected in 35 (50.7%) children. Celiac disease was diagnosed in 1 child, as was diabetes. Exocrine pancreatic insufficiency was revealed in 98.7% of patients as decreased fecal elastase-1 levels (24 [15; 53.5] μg/g). All children were prescribed individually selected diet therapy and therapeutic formulas (Alfare, Peptamen), ERT with pancreatin minimicrospheres. Comprehensive treatment for 1 year showed a statistically significant improvement in weight/height and laboratory parameters in children with SDS. Conclusion. Children with SDS require nutritional support that includes individually selected diet therapy considering food allergies/intolerances, supplemental therapeutic formulas, and pancreatin minimicrospheres in an adequate dose. Key words: Shwachman–Diamond syndrome, children, physical development, protein-energy undernutrition, diet therapy, therapeutic formulas, pancreatin
2025-04-01 | Shwachman–Diamond Syndrome: A Rare Possibility in a Child with Failure to Thrive and Recurrent Infections - A Case Report
Abstract Background: Shwachman–Diamond Syndrome (SDS) is a rare inherited autosomal recessive multisystem disorder, with features of pancreatic exocrine insufficiency, skeletal malformations, immunodeficiency, and bone marrow failure having a high risk of myeloid malignancies at a young age. Clinical Description: A 6.5-year-old girl presented with recurrent episodes of loose stools, cough with fever, and ear discharge since the age of 1 year, requiring multiple hospitalizations and blood transfusions. On examination, she was malnourished and stunted and had pallor, clubbing, oral mucositis, pectus carinatum, and hepatomegaly with crepitations in bilateral lung fields. Management and Outcome: Investigations showed anemia and leukopenia with normal iron, vitamin B12, and folic acid stores but elevated Hemoglobin F. Chest X-ray showed bilateral bronchiectasis, and bronchoscopy showed left lower lobe bronchomalacia. Diagnostic tests revealed low fecal elastase levels, absence of CFTR gene mutation, normal immunoglobulin profile, and a hypocellular bone marrow without dysplasia. Whole-exome sequencing from blood and buccal swab revealed a homozygous pathogenic mutation in SBDS gene, thus confirming SDS. Granulocyte colony-stimulating factor and pancreatic enzyme replacement therapy were started, though the latter could not be continued, the former being continued in follow-up. Thrombocytopenia developed later, though malignancy was ruled out. The child was referred for stem-cell transplantation. Conclusion: A possibility of SDS is to be kept in a child presenting with failure to thrive with recurrent respiratory and gastrointestinal infections requiring repeated blood transfusions. After ruling out cystic fibrosis and immunodeficiency disorders, an evaluation of the hematological system and exocrine pancreatic function, followed by genetic analysis, can confirm the diagnosis.
2025-03-27 | Genetic and clinical characteristics of patients with Shwachman Diamond syndrome with special consideration of treatment with granulocyte-colony stimulating factor
Not available.
2025-02-26 | Shwachman–Diamond syndrome: characteristics of exocrine and endocrine functions of the pancreas in children
Shwachman–Diamond syndrome (SDS) is a rare genetic disorder that belongs to the group of ribosomopathies. It is characterized by impaired hematopoiesis, exocrine pancreatic insufficiency (EPI), delay in physical development, and bone anomalies. Objective. To study the characteristics of exocrine and endocrine functions of the pancreas in children with a genetically confirmed diagnosis of SDS. Patients and methods. The study included 74 patients with a genetically confirmed diagnosis of SDS. The levels of total and pancreatic amylase and lipase in blood, the results of coprological examination, and the levels of fecal elastase-1 were evaluated to study the exocrine function of the pancreas. The endocrine function of the pancreas was assessed by determining the levels of fasting glucose, C-peptide and insulin. All children underwent abdominal ultrasound examination. Results. A total of 68.9% of children with SDS had delay in physical development, and 66.2% had protein-energy undernutrition of varying severity. In 98.7% of patients, a pronounced EPI was revealed, manifested by low fecal elastase-1 levels, median: 24 [15; 53.5] μg/g. Patients with SDS commonly had low levels of pancreatic amylase (95.9%) and lipase (83.8%). Ultrasound signs of pancreatic steatosis were detected in 78.4% of SDS patients. The median of glucose levels in SDS patients was 4.5 mmol/L [4.1; 5.1]. In 42 (56.8%) children, insulin levels were within the reference range, and in 32 (43.2%) children, they were below age norms – 3.4 [2; 6.8 mIU/mL]. In 47 (63.5%) children, C-peptide levels were below age norms – 0.7 [0.48; 1.5] ng/mL. There was a positive tendency toward higher C-peptide and insulin levels with age. One child in the study group was diagnosed with diabetes, which required insulin therapy. Conclusion. Patients with SDS need careful monitoring of both exocrine and endocrine functions of the pancreas. Severe EPI in children with SDS requires administration of high-dose pancreatic enzyme replacement therapy using pancreatic enzymes encapsulated in mini-microspheres (Creon®). Key words: Shwachman–Diamond syndrome, SBDS gene, children, pancreas, exocrine pancreatic insufficiency, carbohydrate metabolism, diabetes
small molecules
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.
2026-03-18 | Hydroxyl radical footprinting modification reveals an intradomain communication pathway in EFL1 disrupted by a Shwachman-Diamond syndrome-associated mutation.
Shwachman-Diamond syndrome (SDS) is a rare genetic disorder characterized by pancreatic insufficiency and neutropenia. While most cases are linked to mutations in the SBDS gene, some involve mutations in the GTPase EFL1. This protein works with SBDS to release the anti-association factor eIF6 from the 60S ribosomal subunit during ribosome biogenesis. The pathogenic EFL1 R1095Q mutant (R1086Q in yeast) exhibits altered guanine nucleotide recognition and impaired eIF6 release, prompting an investigation into its structural consequences. Using the yeast Efl1 orthologue in X-ray hydroxyl radical footprinting experiments, we tracked changes in solvent accessibility caused by the mutation. Although the mutation is situated in domain IV, widespread conformational changes were observed across the protein, particularly in domain I, suggesting a long-range intramolecular communication. Strikingly, the growth defect caused by the pathogenic mutation was rescued by a second mutation located in a allosteric pathway that spans from the nucleotide-binding pocket to domain IV. This compensatory mutation restored proper nuclear localization of eIF6 (Tif6 in yeast). These findings reveal that the R1086Q mutation disrupts a structural communication network within Efl1, impairing the conformational dynamics required for its activity. The loss of this coordination likely underlies the ribosome maturation defects observed in SDS cases linked to EFL1, offering new insights into the molecular basis of the disease.
2026-02-13 | Hog1/p38 and ZAKα drive Shwachman-Diamond syndrome and provide targets to improve cell growth.
Shwachman-Diamond syndrome (SDS) is a ribosomopathy characterized by neutropenia, pancreatic insufficiency, skeletal defects, and predisposition to leukemia. Most cases result from biallelic SBDS mutations that impairing 80S ribosome and polysome assembly. In yeast lacking SDO1 (the SBDS ortholog), growth slows dramatically and the p38 ortholog Hog1 signaling is elevated by multiple types of stress. SBDS-deficient HeLa cells exhibited reduced proliferation and slowed cell cycling. The p38 kinase was constitutively activated in SBDS mutants and SDS patient-derived blood cells. Because ZAKα detects ribosome dysfunction, its activation links ribosomal defects to stress kinase pathways in SDS. Suppressing p38α or its upstream activator ZAKα restored cell growth and reduced stress signaling. These findings reveal an evolutionarily conserved-independent mechanism via p38 drives SDS pathophysiology and identifies stress kinases as potential therapeutic targets for ribosomal dysfunction.
2025-12-28 | Ribosomes: Engines of Protein Synthesis
Ribosomes are essential macromolecular complexes that translate genetic information from mRNA into proteins. Composed of rRNA and ribosomal proteins, they consist of two subunits, large and small, in both prokaryotic (70S) and eukaryotic (80S) cells, with structural differences reflecting their evolutionary adaptations. Ribosome biogenesis (Ribi) is a tightly regulated process initiated by rDNA transcription and subunit assembly in eukaryotes and involving factors like NusA and NusG in prokaryotes. Ribosomes drive protein synthesis through complex processes of initiation, elongation, termination, and recycling, facilitated by GTPases and elongation factors, ribosomopathies cause diseases such as Diamond-Blackfan Anemia and Shwachman-Diamond Syndrome, linked to mutations in ribosomal proteins. Ribosomal dysfuntion can lead to both hypo- and hyper-proliferation, increasing cancer risk. Recent advances in targeting ribosome-related pathways, such as mTORC1 inhibition, and techniques like ribosome profiling have provided insights into diseases like leukemia and medulloblastoma, revealing non-canonical ORF translation and novel therapeutic targets. These findings highlight the therapeutic potential of modulating ribosome function in disease treatment.
2025-10-01 | Management Of Dental Caries In Shwachman-Diamond Syndrome Children
Shwachman-Diamond syndrome (SDS), a rare autosomal recessive disorder caused by SBDS gene mutations (c.258+2T>C in homozygous state), presents significant challenges in dental care due to rapid caries progression and systemic complications. Three children with SDS under surveillance at a regional orphan disease center presented with rapidly progressing caries immediately after tooth eruption. Despite adherence to oral hygiene practices (500 ppm fluoride toothpaste) and therapeutic dietary modifications with enzyme replacement therapy (Creon), early restorative treatment of primary teeth using glass ionomer cement under general anesthesia failed. Further evaluations revealed Proteus spp. in the oral microbiota and neutral salivary pH. Radical treatment was implemented, involving restoration of posterior teeth with stainless steel crowns, anterior teeth with zirconia crowns, and extraction of teeth with poor prognosis. Home maintenance included 1450 ppm fluoride toothpaste twice a day and a probiotic with D3 (Streptococcus salivarius K12 + cholecalciferol 5mg—30-day courses biannually). Patients were monitored biannually for up to 2 years. Radical treatment stabilized the caries process, with restorations remaining in satisfactory condition. This approach highlights the limitations of conservative treatment in SDS patients and the need for personalized management addressing systemic and microbial factors. The findings align with the limited literature on SDS-related dental challenges, underscoring the importance of tailored care. This case series demonstrates the efficacy of radical treatment in managing aggressive caries in SDS patients, emphasizing its relevance in stabilizing complex dental conditions associated with rare disorders.
cell therapies
2026-09-23 | Cumulative Hematologic Morbidity and Outcomes in Shwachman–Diamond Syndrome
In an international cohort of 865 patients, Shwachman–Diamond syndrome was associated with a high risk of myeloid cancer and poor survival. Early hematopoietic stem-cell transplantation for high-risk features had a potential benefit.
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.
2025-11-05 | SUPERIOR SURVIVAL FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR HIGH-RISK MARROW FEATURES IN PATIENTS WITH SHWACHMAN-DIAMOND SYNDROME
Background: Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome with a high risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).Outcomes following allogeneic hematopoietic stem cell transplantation (HSCT) for SDS-associated MDS/AML are poor.The role of HSCT for bone marrow (BM) high-risk features (HRF) in the absence of overt malignancy remains undefined.Objective: To evaluate outcomes of HSCT for HRF compared to HSCT for MDS/AML in SDS patients.Methods: We retrospectively analyzed 254 patients enrolled in the North American SDS Registry.HRF was defined as the presence of a somatic mutation in TP53 or other high-risk genes with variant allele frequency 3.0% in at least two consecutive BM samples, with or without morphologic abnormalities.Survival was estimated using the Kaplan-Meier method and compared by log-rank testing, accounting for HSCT and death as competing risks.Results: MDS and AML were diagnosed in 21 (median age 18 years) and 14 (median age 28 years) patients, respectively.HRF was identified in 26 patients (median age 13 years), of whom 24 (92%) harbored somatic TP53 mutations.Morphologic abnormalities were present in nine patients (35%).Nineteen patients underwent HSCT for HRF (median age 20 years).The 2-year overall survival (OS, 95% CI) after HSCT was 35.0%(11.8-59.8)for MDS (n=15), 37.5% (8.7-67.4) for AML (n=9), and 87.7% (58.8-96.8)for HRF (n=19; p=0.035).Notably, all 14 patients transplanted for HRF at 25 years were alive at last follow-up, while OS for those >25 years was 60.0% (12.6-88.2).Conclusions: HSCT for HRF in SDS was associated with favorable outcomes, particularly in patients 25 years.These findings support early identification and consideration of HSCT prior to malignant transformation.The benefit of HSCT for HRF in older patients warrants further investigation.
2025-11-03 | Allogeneic hematopoietic stem cell transplantation in treatment of Shwachman- diamond syndrome: A Report of 25 Pediatric cases from a Single center
Abstract Objective: To explore the effectiveness of allogeneic hematopoietic stem cell transplantation(allo-HSCT) for Shwachman-Diamond Syndrome(SDS) complicated with severe hemocytopenia, myelodysplastic syndrome(MDS) and acute myeloid leukemia(AML). Methods: A total of 25 patients with SDS who underwent allo-HSCT in Beijing JingDu Children's Hospital from July 2015 to July 2025 were enrolled. The clinical manifestations and details about allo-HSCT were summarized. Results: There were 17 males and 8 females enrolled. The male/female ratio was 2.125. All the patients were clinically and genetically diagnosed as SDS. The median age at diagnosis was 8 months(ranging from 1 day to 158 months) old. The patients' median age at HSCT was 28 months (ranging from 7 to 162) old. The patients' median weight and height was 9.7kg (ranging from 5.2 to 38.2) and 80cm(ranging from 60 to 160). All cases had neutropenia, 9 cases complicated with anemia or thrombopenia, 9 cases had pancytopenia. 1 case was diagnosed with AML, 5 cases were diagnosed with myelodysplastic syndrome(MDS) with low balsts. 2 cases complicated with complex karyotypes. 5 cases had mutated Tp53. 6 girls had their ovaries frozen before HSCT. The donors consisted of 14 cases of unrelated cord blood(UCB), 6 cases of mismatched related donors(MMRD) and 5 cases of mismatched unrelated donors(MMUD). All patients used myeloablating conditioning.The regimen of the case with AML consisted of busulfan, fludarabine, cytarabine, cyclophosphamide and anti-thymocyte globulin(ATG). Other patients' regimens consisted of busulfan, fludarabine, ATG with or without cyclophosphamide. All were given cyclosporine and mycophenolate mofetil to prevent graft-versus- host disease(GVHD). Balliximab was given at +1 day to the patients whose donor was MMRD and methotrexate was given at +1,+4,+7,+11 days to the patients whose donor was MMUD or UCB. 24 cases achieved engraftment, the other case underwent haploid HSCT following failure of cord blood transplantation, currently at day +6 post-infusion, and the engraftment rate was 96%. The median time to neutrophil engraftment and platelet engraftment was 12 (ranging from 9 to 22)days and 16.5 (ranging from 11 to 66)days, respectively. There were 0/13, 3/6, 2/5 cases with acute GVHD (grades II to IV) and 1/13, 2/6, 1/5 mild chronic GVHD in UCB, MMRD and MMUD groups. There was no middle and severe chronic GVHD. Within the follow-up of 10.5(ranging from 0 to 119) months, 2 patients died and 1 patient with MDS relapsed. The patient with complex karyotype and Tp53 mutation experienced MDS recurrence with increased blasts after cord blood transplantation. Then he got chemotherapy and second transplantation(haploid), but failed to achieve negative MRD. Melphalan was administered before donor peripheral blood stem cell infusion, resulting in negative MRD. But he subsequently developed grade IV acute GVHD and thrombotic microangiopath. Finally, another relapse occurred at +29 months post-second transplant, and he is currently receiving palliative care. The OS and EFS rate was 92% and 88%. Conclusions: Allo-HSCT is an effective treatment for SDS complicated with severe hematological abnormalities.Compared with MMRD and MMUD HSCT, the incidence of GVHD in CBT is lower. MDS complicated with both complex karyotype and Tp53 mutation was associated with an extremely poor prognosis.
2025-01-02 | Outcomes of allogeneic hematopoietic stem cell transplantation in Shwachman-Diamond syndrome: a systematic review and meta-analysis.
We conducted a systematic review and meta-analysis to evaluate the outcomes of Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in the treatment of Shwachman-Diamond syndrome (SDS). A literature search was performed on PubMed, Embase, and Web of Science. After screening 397 articles, 10 studies were included. Data was extracted in accordance with the PRISMA guidelines and analyzed using the R 'meta' package. The pooled median 3 (1-5)-year overall survival (OS) after Allo-HSCT were 63.7% (95% CI 56.9-70.2%), 80.3% (95% CI 68.% 5-92.1%), 41.1% (95% CI 21.7-60.4%), 48.9% (95% CI 29.0-68.9%), and 8.7% (95% CI 0.0-60.8%) in SDS patients, SDS patients with bone marrow failure (BMF), SDS patients with myeloid neoplasms (MN), SDS patients with myelodysplastic syndrome (MDS), and SDS patients with acute myeloid leukemia (AML), respectively. Allo-HSCT is an efficacious approach for treating SDS patients with severe hematologic complications. However, poor outcomes were revealed in SDS patients with MN with a pooled 3 (1-5)-year relapse rate (RR) after Allo-HSCT of 25.8% (95% CI 12.5-39.0%), and a pooled 3-year non-relapse mortality (NRM) was 52.6% (95% CI 34.2-70.9%). These findings were consistent with the clinical findings that transplant-related complications are the main cause of the poor transplantation prognosis of SDS patients with MN. Efficacious bone marrow conditioning regimens, graft-versus-host disease (GVHD) prevention, and bridging treatment regimens are potential means to improve the transplantation prognosis of SDS patients.
gene therapies
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.
2026-02-02 | Liver stiffness in patients with Shwachman‐Diamond syndrome
Abstract Objective This case series aims to describe whether transient elastography (TE) as a marker of liver stiffness is associated with clinically important liver disease in children and young adults with Shwachman‐Diamond Syndrome (SDS). Methods All patients ≤25 years of age with genetically confirmed SDS seen in the Pediatric Gastroenterology Clinic at Boston Children's Hospital from 07/2017 to 11/2019 were included. Data collected included TE, hepatic transaminases, fecal elastase, and anthropometry. The correlation of liver stiffness measurements with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was assessed by Spearman rank correlation accompanied by 95% confidence intervals based on Fisher's Z transformation. Results Eight patients (six female) were identified with genetically confirmed SDS for whom the median age on the day of TE was 6years. Median (range) AST and ALT were 31 U/L (17–61) and 30 U/L (12–87), respectively, obtained within a median of 18 days (range 0–168) from liver stiffness measurement (LSM). All patients had exocrine pancreatic insufficiency as defined by fecal elastase <200 μg/g. Five patients had abdominal ultrasound within a median of 1.7 years (range 0.0–5.1), of whom four had normal results (one unknown). All eight patients underwent TE with median (range) LSM and controlled attenuation parameter (CAP) measurement ( n = 6) of 5.2 kPa (3.3–6.4) and 171 dB/m (113–250), respectively. LSM greater than METAVIR F0 was not associated with AST and ALT elevations. Conclusion In our case series of eight patients with SDS, LSM greater than METAVIR F0 was reported in three patients, two of whom had normal transaminases. This suggests that subclinical liver disease may exist in SDS patients with normal hepatic transaminases.
2025-12-12 | Beyond Cystic Fibrosis: Recognising Shwachman-Diamond Syndrome in the Respiratory Clinic.
Cystic fibrosis (CF) and Shwachman-Diamond Syndrome (SDS) share overlapping features, including recurrent respiratory infections and pancreatic insufficiency, which can complicate diagnosis. We report a case of a six-year-old girl who presented with productive cough, steatorrhea and recurrent infections. Initial evaluation showed abnormal liver enzymes, elevated immunoreactive trypsin, neutrophil dysfunction and skeletal anomalies. Sweat test was equivocal and CFTR genetic panel was negative. Further genomic analysis identified compound heterozygous mutations in the SBDS gene: c.258+2T>C (known pathogenic variant) and c.284T>A (novel variant), confirming SDS. Over a 42-year follow-up, she experienced intermittent neutropenia, recurrent respiratory infections and pregnancy-related complications. This case emphasises the importance of considering SDS in CF-like presentations with atypical features and equivocal CF testing. Milder SDS phenotypes can survive into adulthood. Further work is needed to refine genotype-phenotype correlations and guide long-term management.
other
2024-11-05 | Acute Lymphoblastic Leukemia in Shwachman-Diamond Syndrome: Challenges and Treatment Outcomes
Introduction Shwachman-Diamond Syndrome (SDS) is a rare multisystem disorder characterized by skeletal abnormalities, pancreatic exocrine insufficiency, and bone marrow dysfunction. Individuals affected by SDS are predisposed to severe cytopenia and have an increased susceptibility to myeloid malignancies. Methods We report our experience of a young girl diagnosed with SDS who developed Acute Lymphoblastic Leukemia (ALL) at the age of 15-years. Results At the age of 14 months, the patient was diagnosed with SDS. Hematological follow-up was initiated to monitor for myelodysplastic syndrome(MDS)/Acute Myeloid Leukemia (AML) progression, a long side treatment for gastroenterological and nutritional complications. In September 2020, the patient was diagnosed with B-Cell-ALL. A dose-reduced AIEOP-BFM ALL 2017 protocol, containing vincristine and daunorubicin and omitting asparaginase to prevent pancreatic toxicity was started. Due to prolonged cytopenia following the first course, following the administration of day +8 vincristine and daunorubicin, chemotherapy was discontinued and patient received two courses of Blinatumomab treatment achieving complete remission (CR) with undetectable minimal residual disease (MRD). Patient then received consolidation therapy with allogeneic-stem cell transplantation (SCT). The conditioning regimen consisted of 12 Gy- total body irradiation (TBI)plus etoposide and graft versus host disease (GVHD) prophylaxis was obtained with Cyclosporin A; no short-course methotrexate (MTX) was given in order to minimizing toxicities. In September 2021, the patient experienced a molecular relapse detected by two consecutive bone marrow evaluations. Treatment involved Blinatumomab (1 cycle) and 4 DLI, resulting in a second CR. The patient is currently in molecular CR with full donor chimerism, 41 months after HSCT. Conclusions SDS is associated with predisposition to develop MDS or AML. Children with SDS develop AML in 12-25% of cases. Lymphoid malignancies are rare in SDS patients, with four cases reported cases in the literature: two patients with a diagnosis of ALL and 2 patients affected by CNS and primary mediastinal B cell lymphoma respectively treated with standard chemo-or chemo-immunotherapy. To our knowledge, our patient represents the fifth reported lymphoid malignancy in SDS who achieved a CR in a relatively short time and is the only one alive and in CR after transplantation with a follow-up exceeding three years from diagnosis. Second ALL can be very aggressive disease with poor prognosis, particularly challenging to treat in patients with SDS where treatment experience is limited. The BFM-inspired protocols emphasize the importance of dose density and intensity for achieving CR, which is difficult to obtain due to the SDS features, such as long time to bone marrow recover and the pancreatic insufficiency which did not allow the use of a crucial drug of the chemotherapy protocol Blinatumomab emerged as the optimal treatment option for low toxicity and well tolerable profile with no gastrointestinal/pancreatic side effects and low-grade hematological toxicities allowing adherence to the treatment and serving as a bridge toallogeneic-SCT performed to consolidate the CR based on the consideration that a secondary ALL is per se an high risk disease.
2016-09-22 | Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia
Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia.
2008-11-18 | Depletion of the Shwachman-Diamond syndrome gene product, SBDS, leads to growth inhibition and increased expression of OPG and VEGF-A
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure and leukemia predisposition, pancreatic exocrine dysfunction, and skeletal abnormalities, manifesting as skeletal dysplasia and osteoporosis. Mutations in SBDS have been shown to cause SDS, but the function of the SBDS gene product is unclear. Accelerated angiogenesis has recently been described in bone marrow cells from SDS patients. To clarify the unknown function of SBDS, we performed experiments analyzing the cellular effects of depleting SBDS by RNA interference. The growth of HeLa cells constitutively depleted of SBDS was markedly hindered when compared to cells stably transfected with siRNA against an irrelevant control gene. Similarly, growth of HeLa cells induced to express siRNA against SBDS was specifically inhibited. Inducible SBDS knockdown was associated with modestly increased levels of apoptosis, suggesting a partial contribution of this process to growth inhibition. By microarray analysis of knockdown cells, we found marked differences in expression of genes in multiple pathways, and we chose to examine a selected subset more closely using quantitative PCR arrays. In constitutive and inducible SBDS-depleted HeLa cell clones, we found 3- to 6-fold elevated mRNA levels of osteoprotegerin (OPG or TNFRSF11B) and vascular endothelial growth factor-A (VEGF-A). We confirmed significant overexpression of both secreted proteins by ELISA from supernatants of SBDS-depleted HeLa cells. Osteoprotegerin and VEGF-A are known to have diverse effects on osteoclast differentiation, angiogenesis, and monocyte/macrophage migration, all processes that may be aberrant in SDS, and we propose that overexpression of these factors may contribute to its pathology.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Synthetic porcine secretin [Secreflo] | peptides | FDA | Approved | ChiRhoClin, Inc. |
Synthetic human secretin | peptides | FDA | ChiRhoClin, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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