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British Journal of Haematology May 2017The inherited bone marrow failure syndromes (IBMFS) typically present with significant cytopenias in at least one haematopoietic cell lineage that may progress to... (Review)
Review
The inherited bone marrow failure syndromes (IBMFS) typically present with significant cytopenias in at least one haematopoietic cell lineage that may progress to pancytopenia, and are associated with increased risk of cancer. Although the clinical features of the IBMFS are often diagnostic, variable disease penetrance and expressivity may result in diagnostic dilemmas. The discovery of the genetic aetiology of the IBMFS has been greatly facilitated by next-generation sequencing methods. This has advanced understanding of the underlying biology of the IBMFS and been essential in improving clinical management and genetic counselling for affected patients. Herein we review the clinical features, underlying biology, and new genomic discoveries in the IBMFS, including Fanconi anaemia, dyskeratosis congenita, Diamond Blackfan anaemia, Shwachman Diamond syndrome and some disorders of the myeloid and megakaryocytic lineages.
Topics: Anemia, Aplastic; Anemia, Diamond-Blackfan; Blood Platelet Disorders; Bone Marrow Diseases; Bone Marrow Failure Disorders; DNA Repair-Deficiency Disorders; Dyskeratosis Congenita; Exocrine Pancreatic Insufficiency; Fanconi Anemia; Genetic Counseling; Genomics; Hemoglobinuria, Paroxysmal; Humans; Lipomatosis; Neutropenia; Ribosomes; Shwachman-Diamond Syndrome; Telomere
PubMed: 28211564
DOI: 10.1111/bjh.14535 -
Blood Advances Jan 2022Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with...
Shwachman-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.
Topics: Adolescent; Adult; Bone Marrow Diseases; Child; Child, Preschool; Cohort Studies; Exocrine Pancreatic Insufficiency; Hematologic Diseases; Humans; Infant; Middle Aged; Shwachman-Diamond Syndrome; Young Adult
PubMed: 34758064
DOI: 10.1182/bloodadvances.2021005539 -
Frontiers in Genetics 2018Ribosomes have been long considered as executors of the translational program. The fact that ribosomes can control the translation of specific mRNAs or entire cellular... (Review)
Review
Ribosomes have been long considered as executors of the translational program. The fact that ribosomes can control the translation of specific mRNAs or entire cellular programs is often neglected. Ribosomopathies, inherited diseases with mutations in ribosomal factors, show tissue specific defects and cancer predisposition. Studies of ribosomopathies have paved the way to the concept that ribosomes may control translation of specific mRNAs. Studies in and mice support the existence of heterogeneous ribosomes that differentially translate mRNAs to coordinate cellular programs. Recent studies have now shown that ribosomal activity is not only a critical regulator of growth but also of metabolism. For instance, glycolysis and mitochondrial function have been found to be affected by ribosomal availability. Also, ATP levels drop in models of ribosomopathies. We discuss findings highlighting the relevance of ribosome heterogeneity in physiological and pathological conditions, as well as the possibility that in rate-limiting situations, ribosomes may favor some translational programs. We discuss the effects of ribosome heterogeneity on cellular metabolism, tumorigenesis and aging. We speculate a scenario in which ribosomes are not only executors of a metabolic program but act as modulators.
PubMed: 30498507
DOI: 10.3389/fgene.2018.00533 -
Pediatric Blood & Cancer May 2022Because they can experience neutropenia due to bone marrow failure, patients with Shwachman-Diamond syndrome (SDS) carry increased risk for serious infections compared...
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.
Topics: Bone Marrow Diseases; COVID-19; COVID-19 Vaccines; Exocrine Pancreatic Insufficiency; Humans; Neutropenia; Shwachman-Diamond Syndrome; Vaccination
PubMed: 35253346
DOI: 10.1002/pbc.29647 -
Blood Nov 2017Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure,... (Review)
Review
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Humans; Inheritance Patterns
PubMed: 29167174
DOI: 10.1182/blood-2017-05-781799 -
Hematology. American Society of... Dec 2017Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure,... (Review)
Review
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.
Topics: Allografts; Bone Marrow Diseases; Genetic Diseases, Inborn; Hematopoietic Stem Cell Transplantation; Humans; Syndrome
PubMed: 29222241
DOI: 10.1182/asheducation-2017.1.88 -
JPGN Reports May 2024Shwachman-Diamond syndrome (SDS) is a genetic disorder caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The syndrome is characterized by...
Shwachman-Diamond syndrome (SDS) is a genetic disorder caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The syndrome is characterized by multiorgan dysfunction primarily involving the bone marrow and exocrine pancreas. Frequently overlooked is the hepatic dysfunction seen in early childhood which tends to improve by adulthood. Here, we report a child who initially presented with failure to thrive and elevated transaminases, and was ultimately diagnosed with SDS. A liver biopsy electron micrograph revealed hepatocytes crowded with numerous small mitochondria, resembling the hepatic architecture from patients with inborn errors of metabolism, including mitochondrial diseases. To our knowledge, this is the first report of the mitochondrial phenotype in an SDS patient. These findings are compelling given the recent cellular and molecular research studies which have identified SBDS as an essential regulator of mitochondrial function and have also implicated SBDS in the maintenance of mitochondrial DNA.
PubMed: 38756125
DOI: 10.1002/jpr3.12064 -
Advances in Biological Regulation Jan 2018Mutations that target the ubiquitous process of ribosome assembly paradoxically cause diverse tissue-specific disorders (ribosomopathies) that are often associated with... (Review)
Review
Mutations that target the ubiquitous process of ribosome assembly paradoxically cause diverse tissue-specific disorders (ribosomopathies) that are often associated with an increased risk of cancer. Ribosomes are the essential macromolecular machines that read the genetic code in all cells in all kingdoms of life. Following pre-assembly in the nucleus, precursors of the large 60S and small 40S ribosomal subunits are exported to the cytoplasm where the final steps in maturation are completed. Here, I review the recent insights into the conserved mechanisms of ribosome assembly that have come from functional characterisation of the genes mutated in human ribosomopathies. In particular, recent advances in cryo-electron microscopy, coupled with genetic, biochemical and prior structural data, have revealed that the SBDS protein that is deficient in the inherited leukaemia predisposition disorder Shwachman-Diamond syndrome couples the final step in cytoplasmic 60S ribosomal subunit maturation to a quality control assessment of the structural and functional integrity of the nascent particle. Thus, study of this fascinating disorder is providing remarkable insights into how the large ribosomal subunit is functionally activated in the cytoplasm to enter the actively translating pool of ribosomes.
Topics: Bone Marrow Diseases; Cryoelectron Microscopy; Exocrine Pancreatic Insufficiency; Humans; Lipomatosis; Mutation; Proteins; Ribosome Subunits, Large, Eukaryotic; Ribosome Subunits, Small, Eukaryotic; Shwachman-Diamond Syndrome
PubMed: 28942353
DOI: 10.1016/j.jbior.2017.09.002 -
Endokrynologia Polska 2021Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by pancreatic exocrine insufficiency, immune deficiency, bone marrow failure, and...
INTRODUCTION
Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by pancreatic exocrine insufficiency, immune deficiency, bone marrow failure, and bone malformations. Systematic data concerning endocrine function in SDS are limited. We studied patients diagnosed in The Children's Memorial Health Institute in Warsaw, Poland, to assess the prevalence of various endocrinopathies.
MATERIAL AND METHODS
In the pilot study, retrospective data were collected for 5 patients with SDS. Subsequently, patients with SDS aged 3-16 years were recruited prospectively. In total, 19 patients with mutations in the SBDS gene were studied. Data were collected on anthropometric measurements, systemic screening tests of pituitary, thyroid, adrenal, pancreatic, and gonadal function, as well as bone mineral density. Descriptive statistics were tabulated and group differences assessed.
RESULTS
Twelve patients (63%) had ≥ 1 endocrine disorder, including growth hormone dysfunction (10 patients, 53%), hypothyroidism (2 patients, 10%), congenital hypopituitarism (1 patient, 5%), and/or type 1 diabetes mellitus (T1DM) (1 patient, 5%). The group of boys presented with a significantly lower height (-2.1 SD, p < 0.0001) and BMI (-1.0 SD, p < 0.00001). The group of girls also showed significantly lower height (-2.6 SD, p < 0.00001) and BMI (-0.7 SD, p < 0.0001). All patients had significantly lower height than their mid-parental height. Delayed bone age was found in 15 patients (84%) and osteopaenia in 12 of 15 patients (80%).
CONCLUSIONS
Endocrine dysfunctions are common in SDS, especially growth hormone (GH) deficiency. Children with poor growth can benefit from an endocrinological evaluation and tests for GH deficiency. Bone mineral density measurements should be a part of a routine screening. Longitudinal studies are needed to better understand the aetiology and true prevalence of these disorders.
Topics: Child; Endocrine System Diseases; Exocrine Pancreatic Insufficiency; Female; Growth Hormone; Humans; Male; Pilot Projects; Retrospective Studies; Shwachman-Diamond Syndrome
PubMed: 33619711
DOI: 10.5603/EP.a2021.0014 -
Korean Journal of Pediatrics Aug 2014Inherited bone marrow failure syndrome (IBMFS) encompasses a heterogeneous and complex group of genetic disorders characterized by physical malformations, insufficient... (Review)
Review
Inherited bone marrow failure syndrome (IBMFS) encompasses a heterogeneous and complex group of genetic disorders characterized by physical malformations, insufficient blood cell production, and increased risk of malignancies. They often have substantial phenotype overlap, and therefore, genotyping is often a critical means of establishing a diagnosis. Current advances in the field of IBMFSs have identified multiple genes associated with IBMFSs and their pathways: genes involved in ribosome biogenesis, such as those associated with Diamond-Blackfan anemia and Shwachman-Diamond syndrome; genes involved in telomere maintenance, such as dyskeratosis congenita genes; genes encoding neutrophil elastase or neutrophil adhesion and mobility associated with severe congenital neutropenia; and genes involved in DNA recombination repair, such as those associated with Fanconi anemia. Early and adequate genetic diagnosis is required for proper management and follow-up in clinical practice. Recent advances using new molecular technologies, including next generation sequencing (NGS), have helped identify new candidate genes associated with the development of bone marrow failure. Targeted NGS using panels of large numbers of genes is rapidly gaining potential for use as a cost-effective diagnostic tool for the identification of mutations in newly diagnosed patients. In this review, we have described recent insights into IBMFS and how they are advancing our understanding of the disease's pathophysiology; we have also discussed the possible implications they will have in clinical practice for Korean patients.
PubMed: 25210520
DOI: 10.3345/kjp.2014.57.8.337