Shwachman-Diamond Syndrome Research Articles

Rare Association of Tuberous sclerosis with Acute Lymphoblastic Leukemia: Case Report with Review of Literature

AbstractAcute lymphoblastic leukemia (ALL) is the most common leukemia in children in which 85% of all cases are of B-cell ALL and approximately 15% cases are of T-cell ALL (T-ALL). Recent revolution in next-generation sequencing has uncovered many novel somatic mutations and rearrangements in ALL cells, which have prognostic and therapeutic implications, and it has also led to recognition of germline variants in the same genes with somatic mutations commonly associated with ALL. Apart from increasing the risk of developing ALL, germline variants may influence diagnostic testing, genetic counseling, and response to antileukemic treatment. This emphasizes importance of identification of new germline variants, or association of inherited syndromes with ALL or other malignancies. Down's syndrome, Shwachman's syndrome, Fanconi anemia, Bloom's syndrome, neurofibromatosis, and ataxia telangiectasia are well-recognized conditions associated with ALL. In this communication, we report a rare association of T-ALL with tuberous sclerosis (TS). This is the first reported case, showing association of T cell leukemia and TS with confirmatory genetic work-up.

Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene.

Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G > A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann–Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases.

A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman-Bodian-Diamond Syndrome Protein SBDS.

The Shwachman–Diamond Syndrome (SDS) is an autosomal recessive disease whose majority of patients display mutations in a ribosome assembly protein named Shwachman–Bodian–Diamond Syndrome protein (SBDS). A specific therapy for treating this rare disease is missing, due to the lack of knowledge of the molecular mechanisms responsible for its pathogenesis. Starting from the observation that SBDS single-point mutations, localized in different domains of the proteins, are responsible for an SDS phenotype, we carried out the first comparative Molecular Dynamics simulations on three SBDS mutants, namely R19Q, R126T and I212T. The obtained 450-ns long trajectories were compared with those returned by both the open and closed forms of wild type SBDS and strongly indicated that two distinct conformations (open and closed) are both necessary for the proper SBDS function, in full agreement with recent experimental observations. Our study supports the hypothesis that the SBDS function is governed by an allosteric mechanism involving domains I and III and provides new insights into SDS pathogenesis, thus offering a possible starting point for a specific therapeutic option.

Abstract 5777: Germline variants of cancer predisposition genes in a large cohort of Chinese sarcoma patients

Abstract Background: Sarcomas represent a rare and heterogeneous group of soft tissue and bone cancers, including more than 100 histological subtypes. Although genomic profiling has identified oncogenic fusion genes as the major molecular drivers of many sarcoma subtypes, direct targeting of these fusion genes is clinically challenging and novel treatment approaches are needed. Methods: To explore new therapeutic targets in sarcoma, we performed germline testing of 148-cancer predisposition genes (OncoPanscan࣪, Genetronhealth) on genomic DNA from a cohort of 822 unselected Chinese sarcoma patients. Results: The median age of this cohort was 45 (1-88) years, and 84% were soft tissue sarcoma (STS), 16% were osteosarcoma. 9.3% (n =82) of patients harbored at least one predicted pathogenic germline variant in 37 cancer disposition genes including APC, BRCA1, BRCA2, CDKN2A, CHEK2, DICER1, MSH6, PMS2, SBDS, SMARCA4, and TP53. Twenty-four (2.9%) patients had a variant that mapped to a known sarcoma-associated cancer predisposition syndrome gene (CHEK2, DICER1, NF1, RECQL4, SMARCA4, TP53, WRN). The most frequently mutated genes are involved in the DNA damage repair pathway, with a prevalence of 6.3% (n =52). Twelve patients carried pathogenic mutations in TP53, which was associated with cancer-predisposing Li-Fraumeni syndrome (LFS). Interestingly, we also observed 12 patients harboring the same SBDS c.258+2T>C variant. Biallelic SBDS mutations were linked to Shwachman-Diamond Syndrome (SDS) associated with leukemia predisposition. Additionally, four patients carried pathogenic mutations in SMARCA4 (n =2) and SMARCE1 (n =2), two genes encoding key components of the BAF chromatin-remodeling complex. Patients with pathogenic SMARCA4 germline variants could participate in clinical trials of EZH2 inhibitor tazemetostat. Four patients harbored pathogenic germline variants in core homologous recombination genes (BRCA1/2 and PALB2), which may be targeted with platinum-based chemotherapy or PARP inhibitor olaparib. Conclusions: In summary, our genomic profiling approach revealed novel predisposition variants associated with sarcoma, and some of them can serve as therapeutic targets for future clinical investigation. Our work provided proof of principle that sarcoma patients may benefit from genetic counseling and participate in genomically-matched clinical trials. Citation Format: Jingnan Shen, Xiaomo Li, Xianbiao Xie, Si Liu, Tonghui Ma. Germline variants of cancer predisposition genes in a large cohort of Chinese sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5777.

OTHR-25 Germline Mutations in Pediatric Brain Tumor

Abstract BACKGROUND: The exploration of germline mutations in pediatric brain tumor is helpful to improve the understanding of tumor genesis, guide the treatment, and provide genetic counseling for patients and their families. METHODS: In this study, children with primary brain tumor aged ≤18 years old in Guangdong Sanjiu Brain Hospital were enrolled．Tumor tissue or cerebrospinal fluid (CSF) next-generation sequencing (NGS) tests were required for all included patients. The genetic mutations in these children were analyzed and patients with germline mutations were screened. RESULTS: 135 pediatric patients with NGS detection were included in this patients. 63 patients were medulloblastoma, 54 were glioma. The rest were 5 ependymoma, 2other embryonal tumors, 2 pineoblastoma, 2 germ cell tumors, 1 pituitary adenoma, 1 neuroepithelial tumor, 1 Schwannoma, 1 neuronal tumor, 1 craniopharyngioma and 1 Rosai-Dorfman disease. NGS was performed on tissues of 122 patients and CSF of 13 patients. 7 patients underwent whole exome sequencing and the remaining 115 patients underwent panel detection. 6.67% (9/135) patients took germline mutations, which included 4 gliomas, 3 medulloblastomas, 1 schwannoma and 1 ependymoma. The rate of germline mutations were 7.41% (4/54) and 4.76% (3/63) in gliomas and medulloblastoma, respectively. The germinal mutations included TP53 missense mutation, BLM nonsense mutation, MSH2 nonsense mutation, MSH2 frameshift mutation, SUFU frameshift mutation, FANCI frameshift mutation, SBDS splicing site mutation, NF2 nonsense mutation and DIS3L2 nonsense mutation. These mutations are closely related to with Ligemeni syndrome, Bloom syndrome, Lynch syndrome, nevus basal cell carcinoma syndrome, Fanconi anemia, Shwachman-Diamond syndrome, neurofibromatosis type II and Perlman syndrome, respectively. 2 glioma patients had a family history of cancer. CONCLUSION: Pediatric patients with glioma, medulloblastoma, schwannoma and ependymoma are easily harboring germline mutations. For these patients, a detailed genetic history of family members is required and genetic counseling is recommended.

Unusual combination of Shwachman-Diamond syndrome and porphyria.

Unusual combination of Shwachman-Diamond syndrome and porphyria.

Genetics and genomics of bone marrow failure syndrome.

Inherited bone marrow failure syndrome (IBMFS) is a group of clinically heterogeneous disorders characterized by significant hematological cytopenias of one or more hematopoietic cell lineages and is associated with an increased risk of cancer. The genetic etiology of IBMFS includes germline mutations impacting several key biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, which may cause four major syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Although the clinical features of some patients may be typical of a particular IBMFS, overlapping and atypical clinical manifestations and variable penetrance pose diagnostic challenges. Here, we review the clinical and genetic features of the major forms of IBMFS and discuss their molecular genetic diagnosis. Next-generation sequencing-based gene panel testing or whole exome sequencing will help elucidate the genetic causes and underlying mechanisms of this genetically heterogeneous group of diseases.

Novel Translational Read-through-Inducing Drugs as a Therapeutic Option for Shwachman-Diamond Syndrome.

Shwachman-Diamond syndrome (SDS) is one of the most commonly inherited bone marrow failure syndromes (IBMFS). In SDS, bone marrow is hypocellular, with marked neutropenia. Moreover, SDS patients have a high risk of developing myelodysplastic syndrome (MDS), which in turn increases the risk of acute myeloid leukemia (AML) from an early age. Most SDS patients are heterozygous for the c.183-184TA>CT (K62X) SBDS nonsense mutation. Fortunately, a plethora of translational read-through inducing drugs (TRIDs) have been developed and tested for several rare inherited diseases due to nonsense mutations so far. The authors previously demonstrated that ataluren (PTC124) can restore full-length SBDS protein expression in bone marrow stem cells isolated from SDS patients carrying the nonsense mutation K62X. In this study, the authors evaluated the effect of a panel of ataluren analogues in restoring SBDS protein resynthesis and function both in hematological and non-hematological SDS cells. Besides confirming that ataluren can efficiently induce SBDS protein re-expression in SDS cells, the authors found that another analogue, namely NV848, can restore full-length SBDS protein synthesis as well, showing very low toxicity in zebrafish. Furthermore, NV848 can improve myeloid differentiation in bone marrow hematopoietic progenitors, enhancing neutrophil maturation and reducing the number of dysplastic granulocytes in vitro. Therefore, these findings broaden the possibilities of developing novel therapeutic options in terms of nonsense mutation suppression for SDS. Eventually, this study may act as a proof of concept for the development of similar approaches for other IBMFS caused by nonsense mutations.

Expression of Concern: Shwachman-Diamond Syndrome in a Child Presenting With Chronic Diarrhea: A Rare Case in Family Medicine Practice.

Expression of Concern: Shwachman-Diamond Syndrome in a Child Presenting With Chronic Diarrhea: A Rare Case in Family Medicine Practice.

EIF6 rebinding dynamically couples ribosome maturation and translation

Protein synthesis is a cyclical process consisting of translation initiation, elongation, termination and ribosome recycling. The release factors SBDS and EFL1—both mutated in the leukemia predisposition disorder Shwachman-Diamond syndrome — license entry of nascent 60S ribosomal subunits into active translation by evicting the anti-association factor eIF6 from the 60S intersubunit face. We find that in mammalian cells, eIF6 holds all free cytoplasmic 60S subunits in a translationally inactive state and that SBDS and EFL1 are the minimal components required to recycle these 60S subunits back into additional rounds of translation by evicting eIF6. Increasing the dose of eIF6 in mice in vivo impairs terminal erythropoiesis by sequestering post-termination 60S subunits in the cytoplasm, disrupting subunit joining and attenuating global protein synthesis. These data reveal that ribosome maturation and recycling are dynamically coupled by a mechanism that is disrupted in an inherited leukemia predisposition disorder.

The Difficult Differential Diagnosis for A Pediatric Patient with Shwachman-Diamond Syndrome; A Case Report and Literature Review

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disease characterized by bone marrow dysfunction, exocrine pancreatic insufficiency and skeletal abnormalities. Persistent or intermittent neutropenia caused by bone marrow hypoplasia is the most common hematological abnormality in SDS. It can be difficult to diagnose the disease that usually occurs in early childhood. SDS should be kept in mind in the differential diagnosis of neutropenic patients. If the signs of pancreatic insufficiency are not observed, the diagnosis may be missed. The article wanted to present a patient with pancreatic insufficiency and SDS with the biallelic mutation who presented with neutropenia in a newborn.

Coronavirus disease 2019 and vaccination in patients with Shwachman-Diamond syndrome.

Because they can experience neutropenia due to bone marrow failure, patients with Shwachman‐Diamond syndrome (SDS) carry increased risk for serious infections compared with the general population; however, there has been a paucity of data on the incidence and severity of coronavirus disease 2019 (COVID‐19) in patients with SDS. We compiled results from a survey distributed to participants in the SDS Registry in May‐June 2021. In this report, we describe the characteristics and outcomes of patients with SDS who had COVID‐19. Patients reported a short clinical course without significant complications or cytopenias. Additionally, COVID‐19 vaccines were well tolerated with minor side effects.

SBDS interacts with RNF2 and is degraded through RNF2-dependent ubiquitination

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder caused by mutation in the Shwachman-Bodian-Diamond syndrome (SBDS) gene that has a variety of clinical features, including exocrine pancreatic insufficiency and hematological dysfunction. The SBDS protein is considered to be involved in ribosome biogenesis, ribosomal RNA metabolism, stabilization of mitotic spindles and cellular stress responses, yet the function of SBDS in detail is still incompletely understood. The multiple functions imply that certain proteins might associate with SBDS and affect its function. In this study, we identified Ring finger protein 2 (RNF2) as a candidate for the SBDS interactor by yeast two-hybrid screening. Moreover, we confirmed the interaction by GST-pull down assay using recombinant proteins and co-immunoprecipitation in HEK293T cells overexpressing RNF2. In addition, it is shown that RNF2 ubiquitinates SBDS and promotes its proteasomal degradation in HEK293T cells. These findings provide new insights into the regulation of SBDS.

1010 – CONVERGENT SOMATIC EVOLUTION FROM EARLY LIFE IN A GERMLINE RIBOSOMOPATHY

Clonal tracking of stem cells and their progeny by whole genome sequencing permits exploration of evolutionary genetics in human disease. We performed phylogenetic reconstruction of haematopoiesis using somatically acquired mutations in 323 single haematopoietic stem and progenitor cell-derived colonies from 10 individuals with an inherited disorder of ribosome assembly, Shwachman-Diamond syndrome. We observed numerous clonal expansions, with recurrent acquisition of mutually exclusive mutations (EIF6, TP53, RPL5, RPL22, PRPF8, chromosomes 7 and 15) in multiple different clones in utero or early childhood converging on the p53-dependent nucleolar surveillance pathway that monitors ribosome integrity. In contrast to clones carrying biallelic TP53 mutations, genomes derived from colonies carrying mono-allelic TP53 mutations displayed no increase in mutation burden or specific mutational signatures. Our study highlights striking loss of clonal diversity with convergent somatic evolution on the p53-dependent nucleolar surveillance pathway from early life to offset the deleterious effects of a germline mutation in a Mendelian haematopoietic disorder. Clonal tracking of stem cells and their progeny by whole genome sequencing permits exploration of evolutionary genetics in human disease. We performed phylogenetic reconstruction of haematopoiesis using somatically acquired mutations in 323 single haematopoietic stem and progenitor cell-derived colonies from 10 individuals with an inherited disorder of ribosome assembly, Shwachman-Diamond syndrome. We observed numerous clonal expansions, with recurrent acquisition of mutually exclusive mutations (EIF6, TP53, RPL5, RPL22, PRPF8, chromosomes 7 and 15) in multiple different clones in utero or early childhood converging on the p53-dependent nucleolar surveillance pathway that monitors ribosome integrity. In contrast to clones carrying biallelic TP53 mutations, genomes derived from colonies carrying mono-allelic TP53 mutations displayed no increase in mutation burden or specific mutational signatures. Our study highlights striking loss of clonal diversity with convergent somatic evolution on the p53-dependent nucleolar surveillance pathway from early life to offset the deleterious effects of a germline mutation in a Mendelian haematopoietic disorder.

Fludarabine-based Reduced Intensity Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in a Pediatric Patient With Bone Marrow Failure Syndrome Type 3.

Bone marrow failure syndrome (BMFS) type 3 is a rare genetic heterogeneous disorder, considered to be one of Inherited BMFSs related to ribosomopathies. It caused by a novel Homozygous variant in DNAJC21 gene, which affects cytoplasmic maturation of 60S ribosomal, leading to increase cell death, and inhibits cellular proliferation causing shwachman-diamond Syndrome-like syndrome. Only 15 cases of BMFS type 3 have been published in the literature. Therefore, the full phenotypic spectrum and the experience of hematopoietic stem cell transplantation (HSCT) are limited. Herein, we report an uncomplicated HSCT from human leukocyte antigen-identical sibling for a BMFS-3 patient at 22 months of age, who suffered from chronic diarrhea, severe failure to thrive and cytopenia required transfusions. We used a reduced intensity conditioning regimen including fludarabine, low-dose cyclophosphamide, and antithymocyte globulin with cyclosporine for prevent graft versus host disease. This regimen was safe and sufficient to achieve rapid engraftment without significant toxicity. Although, Mixed chimerism between 80% and 90% was observed since day +30, she gained 2 kg during 12 months post-transplant and no need for transfusions has been reported any more. Thus, we recommend HSCT with fludarabine-based reduced intensity conditioning regimen in this syndrome as progressive cytopenia occurs and an human leukocyte antigen-matched family donor is available.

Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman-Diamond Syndrome Subjects.

Shwachman–Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS-OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions.

Shwachman–Diamond Syndrome

This article describes a clinical case of a rare Schwachman–Diamond syndrome. It covers the features of the clinical picture of the disease and the laboratory examinations. A multidisciplinary approach for the purpose of early diagnosis, timely initiation of complex treatment, including nutritional therapy, prescription of enzyme preparations and granulocyte colony-stimulating factor, makes it possible to improve the quality of life and prognosis in such patients.

The frequent and clinically benign anomalies of chromosomes 7 and 20 in Shwachman-diamond syndrome may be subject to further clonal variations

BackgroundAn isochromosome of the long arm of chromosome 7, i(7)(q10), and an interstitial deletion of the long arm of chromosome 20, del(20)(q), are the most frequent anomalies in the bone marrow of patients with Shwachman-Diamond syndrome, which is caused in most cases by mutations of the SBDS gene. These clonal changes imply milder haematological symptoms and lower risk of myelodysplastic syndromes and acute myeloid leukaemia, thanks to already postulated rescue mechanisms.ResultsBone marrow from fourteen patients exhibiting either the i(7)(q10) or the del(20)(q) and coming from two large cohorts of patients, were subjected to chromosome analyses, Fluorescent In Situ Hybridization with informative probes and array-Comparative Genomic Hybridization. One patient with the i(7)(q10) showed a subsequent clonal rearrangement of the normal chromosome 7 across years. Four patients carrying the del(20)(q) evolved further different del(20)(q) independent clones, within a single bone marrow sample, or across sequential samples. One patient with the del(20)(q), developed a parallel different clone with a duplication of chromosome 3 long arm. Eight patients bore the del(20)(q) as the sole chromosomal abnormality. An overall overview of patients with the del(20)(q), also including cases already reported, confirmed that all the deletions were interstitial. The loss of material varied from 1.7 to 26.9 Mb and resulted in the loss of the EIF6 gene in all patients.ConclusionsAlthough the i(7)(q) and the del(20)(q) clones are frequent and clinically benign in Shwachman Diamond-syndrome, in the present work we show that they may rearrange, may be lost and then reconstructed de novo, or may evolve with independent clones across years. These findings unravel a striking selective pressure exerted by SBDS deficiency driving to karyotype instability and to specific clonal abnormalities.

Congenital neutropenia: disease models guiding new treatment strategies.

Purpose of reviewMyeloid diseases are often characterized by a disturbed regulation of myeloid cell proliferation, survival, and maturation. This may either result in a severe paucity of functional neutrophils (neutropenia), an excess production of mature cells (myeloproliferative disorders) or in clonal expansions of dysplastic or immature myeloid cells (myelodysplasia and acute myeloid leukemia). Although these conditions can be regarded as separate entities, caused by the accumulation of distinct sets of somatic gene mutations, it becomes increasingly clear that they may also evolve as the prime consequence of a congenital defect resulting in severe neutropenia. Prominent examples of such conditions include the genetically heterogeneous forms of severe congenital neutropenia (SCN) and Shwachman-Diamond Syndrome. CSF3 treatment is a successful therapy to alleviate neutropenia in the majority of these patients but does not cure the disease nor does it prevent malignant transformation. Allogeneic stem cell transplantation is currently the only therapeutic option to cure SCN, but is relatively cumbersome, e.g., hampered by treatment-related mortality and donor availability. Hence, there is a need for new therapeutic approaches.Recent findingsDevelopments in disease modeling, amongst others based on induced pluripotent stem cell and CRISPR/Cas9 based gene-editing technologies, have created new insights in disease biology and possibilities for treatment. In addition, they are fueling expectations for advanced disease monitoring to prevent malignant transformation.SummaryThis review highlights the recent progress made in SCN disease modeling and discusses the challenges that are still ahead of us to gain a better understanding of the biological heterogeneity of the disease and its consequences for patient care.

Hematologic complications with age in Shwachman-Diamond syndrome

AbstractShwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.