• ophthalmic genetics
• rod-cone dystrophy
• shwachman-diamond syndrome

• Humans
• Female
• Adolescent
• Retrospective Studies
• Shwachman-Diamond Syndrome
• Cone-Rod Dystrophies/diagnosis
• Cone-Rod Dystrophies/genetics
• Cone-Rod Dystrophies/physiopathology
• Tomography, Optical Coherence/methods
• Electroretinography
• Visual Acuity
• Retinitis Pigmentosa/diagnosis
• Retinitis Pigmentosa/complications
• Fluorescein Angiography/methods
• Bone Marrow Transplantation

• Wellcome Trust
• 099173 Wellcome Trust
• 099173/Z/12/Z National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
• 099173/Z/12/Z Wellcome Trust
• CD-CL-0623-0843-UCL Foundation Fighting Blindness

• Genodermatoses
• genetics
• ichthyosis

• Humans
• Shwachman-Diamond Syndrome
• Male
• Lipomatosis/diagnosis
• Lipomatosis/complications
• Infant
• Exocrine Pancreatic Insufficiency/diagnosis
• Ichthyosis/diagnosis
• Bone Marrow Diseases/diagnosis
• Diagnosis, Differential
• Failure to Thrive/diagnosis
• Failure to Thrive/etiology
• Infant, Newborn

• Humans
• Registries
• Italy/epidemiology
• Shwachman-Diamond Syndrome
• Lipomatosis/epidemiology
• Lipomatosis/diagnosis
• Bone Marrow Diseases/epidemiology
• Diabetes Mellitus, Type 1/epidemiology
• Exocrine Pancreatic Insufficiency/epidemiology
• Male
• Female
• Diabetes Mellitus/epidemiology

• IUGR
• Shwachman-Diamond syndrome (SBDS)
• placental histology
• placental vascular malperfusion
• prenatal exome sequencing
• ribosomes
• whole-exome sequencing

• Humans
• Shwachman-Diamond Syndrome
• Female
• Pregnancy
• Fetal Growth Retardation/genetics
• Fetal Growth Retardation/diagnosis
• Diagnosis, Differential
• Phenotype
• Fetus
• Proteins

• SBDS
• complex underlying genotype
• neonatal deaths

• cephalogram
• craniofacial morphology
• dental features
• japanese sibling pair
• shwachman–diamond syndrome

• AML
• DDX41
• GATA2
• Germline predisposition to myeloid malignancy
• MDS
• RUNX1

• Adult
• Humans
• Child
• Myelodysplastic Syndromes/diagnosis
• Myelodysplastic Syndromes/genetics
• Hematologic Neoplasms/diagnosis
• Hematologic Neoplasms/genetics

• Achondroplasia
• Nutrition
• Obesity
• Osteogenesis imperfecta
• Skeletal dysplasia

• Humans
• Comorbidity
• Dwarfism
• Obesity
• Osteochondrodysplasias

• Case report
• Diabetes mellitus
• Pancreatic exocrine insufficiency
• Shwachman-Diamond syndrome

• Humans
• Shwachman-Diamond Syndrome
• Exocrine Pancreatic Insufficiency/complications
• Exocrine Pancreatic Insufficiency/diagnosis
• Exocrine Pancreatic Insufficiency/genetics
• Lipomatosis/complications
• Lipomatosis/diagnosis
• Lipomatosis/genetics
• Bone Marrow Diseases/complications
• Bone Marrow Diseases/diagnosis
• Bone Marrow Diseases/therapy
• Diabetes Mellitus, Type 1/complications
• Diabetes Mellitus, Type 1/diagnosis
• Diabetes Mellitus, Type 1/genetics
• Disease Progression

• Universitätsklinikum Ulm (8941)

• myelopoiesis
• haematopoietic stem cells
• neutrophils
• interferons

• bone cells
• mineralization
• p53
• ribosomopathies
• transcriptome

• Calcification, Physiologic
• Cells, Cultured
• Female
• Humans
• Male
• Osteoblasts/metabolism
• Osteoblasts/pathology
• Proteins/genetics
• Proteins/metabolism
• Shwachman-Diamond Syndrome/genetics
• Shwachman-Diamond Syndrome/metabolism
• Shwachman-Diamond Syndrome/pathology
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• Dentists
• Oral presentation
• Periodontitis
• Phagocyte defects
• Primary immunodeficiency diseases

Nucleolar stress occurs when ribosome production or function declines. Nucleolar stress in stem cells or progenitor cells often leads to disease states called ribosomopathies. Drosophila offers a robust system to explore how nucleolar stress causes cell cycle arrest, apoptosis, or autophagy depending on the cell type. We provide an overview of nucleolar stress in Drosophila by depleting nucleolar phosphoprotein of 140 kDa (Nopp140), a ribosome biogenesis factor (RBF) in nucleoli and Cajal bodies (CBs). The depletion of Nopp140 in eye imaginal disc cells generates eye deformities reminiscent of craniofacial deformities associated with the Treacher Collins syndrome (TCS), a human ribosomopathy. We show the activation of c-Jun N-terminal Kinase (JNK) in Drosophila larvae homozygous for a Nopp140 gene deletion. JNK is known to induce the expression of the pro-apoptotic Hid protein and autophagy factors Atg1, Atg18.1, and Atg8a; thus, JNK is a central regulator in Drosophila nucleolar stress. Ribosome abundance declines upon Nopp140 loss, but unusual cytoplasmic granules accumulate that resemble Processing (P) bodies based on marker proteins, Decapping Protein 1 (DCP1) and Maternal expression at 31B (Me31B). Wild type brain neuroblasts (NBs) express copious amounts of endogenous coilin, but coilin levels decline upon nucleolar stress in most NB types relative to the Mushroom body (MB) NBs. MB NBs exhibit resilience against nucleolar stress as they maintain normal coilin, Deadpan, and EdU labeling levels.

• Drosophila
• Nopp140
• P bodies
• neuroblasts
• nucleolar stress
• ribosomopathy

• Anthropometric parameters
• Short stature
• Shwachman-Diamond syndrome
• Somatic development

• Adolescent
• Anthropometry/methods
• Child
• Child Development
• Child, Preschool
• Female
• Humans
• Infant
• Male
• Poland
• Shwachman-Diamond Syndrome/physiopathology

• 257/18 Children's Memorial Health Institute
• Children’s Memorial Health Institute

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disease of the SBDS gene. It has multi-organ involvement but primarily affects the bone marrow and the pancreas. This disease is more commonly found in males than females, and its earliest manifestation in infancy is pancytopenia, most especially neutropenia. Our article attempts an in-depth analysis of the hepatic and cardiac association in this disease and the severity of this association.

For the purpose of this study, we engaged in an in-depth research of critically appraised literature and published articles. We searched for such articles on PubMed and Google Scholar using regular and Medical Subject Headings (MeSH) keywords. We eventually selected 32 articles from the search results and carefully read through and analyzed them. These articles showed the usual age of diagnosis of SDS to be at infancy (before age one), with a predominantly median survival age of 35 years.

All the published articles we reviewed showed some hepatic and cardiac associations with SDS, but the extent of the associations varied. Even though most hepatic involvements were found to be benign, some severe cases led to fibrosis and hepatic failure. Although there is no particular consensus as to the exact outcome of cardiac involvement, the few cases we reviewed showed that cardiac association could be a severe complication and could even be fatal. Most of the cases reported in the literature had been diagnosed at autopsy.

• cardiomyopathy
• hepatomegaly
• myelodysplasia
• shwachman diamond

The features of Shwachman-Diamond syndrome (SDS) include exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow dysfunction; an often overlooked feature is hepatic involvement.

We report a child who initially presented with failure to thrive and mildly elevated transaminase levels and was determined to have pancreatic insufficiency due to SDS. During follow-up he had persistently elevated transaminase levels and developed hepatosplenomegaly. An investigation was performed to determine the etiology of ongoing liver injury, including a liver biopsy which revealed hepatic cirrhosis.

Cirrhosis has rarely been reported with SDS. While many of the hepatic disorders associated with SDS improve with age, there are rare exceptions with serious implications for long-term outcome.

• Shwachman-Diamond syndrome
• Cirrhosis
• Liver dysfunction
• Case report

• Shwachman–diamond syndrome
• genetics
• growth charts

• Body Height
• Body Mass Index
• Body Weight
• Child
• Child, Preschool
• Female
• Growth Charts
• Humans
• Infant
• Infant, Newborn
• Italy
• Male
• Mutation
• Reference Values
• Registries
• Retrospective Studies
• Shwachman-Diamond Syndrome/genetics
• Shwachman-Diamond Syndrome/physiopathology

• Italian Association for Shwachman Syndrome

• aplastic anemia
• bone marrow failure syndromes
• children
• histopathology
• refractory cytopenia of childhood

• Adolescent
• Anemia, Aplastic/diagnosis
• Anemia, Aplastic/pathology
• Bone Marrow Diseases/diagnosis
• Bone Marrow Diseases/pathology
• Bone Marrow Failure Disorders
• Child
• Child, Preschool
• Diagnosis, Differential
• Female
• Hemoglobinuria, Paroxysmal/diagnosis
• Hemoglobinuria, Paroxysmal/pathology
• Histological Techniques
• Humans
• Infant
• Male

• SBDS gene
• Shwachman–Diamond syndrome
• compound heterozygous
• hypotonia

• Greek
• Shwachman-Diamond syndrome
• psoriasis
• registry
• transplantation

• ribosome biogenesis
• ribosomopathies
• specialized ribosomes

Ribosomopathies are a family of inherited disorders caused by mutations in genes necessary for ribosomal function. Shwachman-Diamond Bodian Syndrome (SDS) is an autosomal recessive disease caused, in most patients, by mutations of the SBDS gene. SBDS is a protein required for the maturation of 60S ribosomes. SDS patients present exocrine pancreatic insufficiency, neutropenia, chronic infections, and skeletal abnormalities. Later in life, patients are prone to myelodisplastic syndrome and acute myeloid leukemia (AML). It is unknown why patients develop AML and which cellular alterations are directly due to the loss of the SBDS protein. Here we derived mouse embryonic fibroblast lines from an Sbds^R126T/R126T mouse model. After their immortalization, we reconstituted them by adding wild type Sbds. We then performed a comprehensive analysis of cellular functions including colony formation, translational and transcriptional RNA-seq, stress and drug sensitivity. We show that: 1. Mutant Sbds causes a reduction in cellular clonogenic capability and oncogene-induced transformation. 2. Mutant Sbds causes a marked increase in immature 60S subunits, limited impact on mRNA specific initiation of translation, but reduced global protein synthesis capability. 3. Chronic loss of SBDS activity leads to a rewiring of gene expression with reduced ribosomal capability, but increased lysosomal and catabolic activity. 4. Consistently with the gene signature, we found that SBDS loss causes a reduction in ATP and lactate levels, and increased susceptibility to DNA damage. Combining our data, we conclude that a cell-specific fragile phenotype occurs when SBDS protein drops below a threshold level, and propose a new interpretation of the disease.

Shwachman Diamond syndrome (SDS) is an inherited disease. SDS presents, as hallmarks, exocrine pancreatic insufficiency, increased rate of infections, and higher incidence of leukemia. Most cases are due to mutations in the SBDS gene. SBDS encodes for a ribosome maturation factor. In this study, we immortalized mouse fibroblasts carrying one of the most common mutation of SDS patients and performed a thorough analysis of their properties. We show that the loss of SBDS activity causes a rewiring of gene expression and cellular metabolism. Overall we find a reduction of protein synthesis capability, a lower energy status, and increased lysosomal capability. SBDS mutant cells have an increased susceptibility to various forms of stress, but are strikingly resistant to oncogene-induced transformation. We propose a model that explains the complex phenotype of SDS patients and suggests roads for a rationale treatment.

• Adenosine Triphosphate/metabolism
• Animals
• Cell Line
• Cell Transformation, Neoplastic
• DNA Damage
• Fibroblasts/metabolism
• Homeostasis
• Lactic Acid/metabolism
• Mice
• Phenotype
• Proteins/genetics
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Ribosome Subunits, Large, Eukaryotic/genetics
• Ribosome Subunits, Large, Eukaryotic/metabolism

• 338999 European Research Council
• GGP10012 Telethon
• Fondazione Telethon

• Shwachman-Diamond syndrome
• gastroenterology
• genetics
• haematology
• neonatology

Genetic models of ribosome dysfunction show selective organ failure, highlighting a gap in our understanding of cell-type specific responses to translation insufficiency. Translation defects underlie a growing list of inherited and acquired cancer-predisposition syndromes referred to as ribosomopathies. We sought to identify molecular mechanisms underlying organ failure in a recessive ribosomopathy, with particular emphasis on the pancreas, an organ with a high and reiterative requirement for protein synthesis. Biallelic loss of function mutations in SBDS are associated with the ribosomopathy Shwachman-Diamond syndrome, which is typified by pancreatic dysfunction, bone marrow failure, skeletal abnormalities and neurological phenotypes. Targeted disruption of Sbds in the murine pancreas resulted in p53 stabilization early in the postnatal period, specifically in acinar cells. Decreased Myc expression was observed and atrophy of the adult SDS pancreas could be explained by the senescence of acinar cells, characterized by induction of Tgfβ, p15^Ink4b and components of the senescence-associated secretory program. This is the first report of senescence, a tumour suppression mechanism, in association with SDS or in response to a ribosomopathy. Genetic ablation of p53 largely resolved digestive enzyme synthesis and acinar compartment hypoplasia, but resulted in decreased cell size, a hallmark of decreased translation capacity. Moreover, p53 ablation resulted in expression of acinar dedifferentiation markers and extensive apoptosis. Our findings indicate a protective role for p53 and senescence in response to Sbds ablation in the pancreas. In contrast to the pancreas, the Tgfβ molecular signature was not detected in fetal bone marrow, liver or brain of mouse models with constitutive Sbds ablation. Nevertheless, as observed with the adult pancreas phenotype, disease phenotypes of embryonic tissues, including marked neuronal cell death due to apoptosis, were determined to be p53-dependent. Our findings therefore point to cell/tissue-specific responses to p53-activation that include distinction between apoptosis and senescence pathways, in the context of translation disruption.

Growth of all living things relies on protein synthesis. Failure of components of the complex protein synthesis machinery underlies a growing list of inherited and acquired multi—organ syndromes referred to as ribosomopathies. While ribosomes, the critical working components of the protein synthesis machinery, are required in all cell types to translate the genetic code, only certain organs manifest clinical symptoms in ribosomopathies, indicating specific cell-type features of protein synthesis control. Further, many of these diseases result in cancer despite an inherent deficit in growth. Here we report a range of consequences of protein synthesis insufficiency with loss of a broadly expressed ribosome factor, leading to growth impairment and cell cycle arrest at different stages. Apparent induction of p53-dependent cell death and arrest pathways included apoptosis in the fetal brain and senescence in the mature exocrine pancreas. The senescence, considered a tumour suppression mechanism, was accompanied by the expression of biomarkers associated with early stages of malignant transformation. These findings inform how cancer may initiate when growth is compromised and provide new insights into cell-type specific consequences of protein synthesis insufficiency.

• Acinar Cells/metabolism
• Acinar Cells/pathology
• Acinar Cells/physiology
• Animals
• Apoptosis
• Bone Marrow Diseases/genetics
• Bone Marrow Diseases/metabolism
• Bone Marrow Diseases/pathology
• Cells, Cultured
• Cellular Senescence
• Exocrine Pancreatic Insufficiency/genetics
• Exocrine Pancreatic Insufficiency/metabolism
• Exocrine Pancreatic Insufficiency/pathology
• Lipomatosis/genetics
• Lipomatosis/metabolism
• Lipomatosis/pathology
• Mice
• Mice, Inbred C57BL
• Pancreas/growth & development
• Pancreas/metabolism
• Pancreas/pathology
• Protein Biosynthesis
• Proteins/genetics
• Proteins/metabolism
• Ribosomes/genetics
• Ribosomes/metabolism
• Shwachman-Diamond Syndrome
• Transforming Growth Factor beta/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• FRN11530 Canadian Institutes of Health Research
• MOP102506 Canadian Institutes of Health Research

• Amylase
• Diamine oxidase
• Lipase
• PEI
• Trypsin

• Immune deficiency
• Pancytopenia
• Schwachman-Diamond Syndrome

• Animals
• Diabetes Mellitus, Experimental/metabolism
• Glucagon/metabolism
• Insulin/metabolism
• Insulin-Secreting Cells/drug effects
• Ki-67 Antigen/metabolism
• Ligation
• Male
• Pancreatic Ducts/surgery
• Pancreatic Polypeptide/metabolism
• Rats
• Rats, Inbred Lew
• Regeneration/physiology

• R01 DK093909 NIDDK NIH HHS
• R01DK66056 NIDDK NIH HHS
• DK93909 NIDDK NIH HHS
• R01 DK066056 NIDDK NIH HHS
• P30 DK36836 NIDDK NIH HHS
• P30 DK036836 NIDDK NIH HHS

• Cartilage hair hypoplasia
• Ribosome biogenesis
• Roberts syndrome
• Shwachman–Diamond syndrome
• Skeletal development
• Treacher Collins syndrome

• Bone Marrow Diseases/diagnosis
• Bone Marrow Diseases/epidemiology
• Bone Marrow Diseases/genetics
• Exocrine Pancreatic Insufficiency/diagnosis
• Exocrine Pancreatic Insufficiency/epidemiology
• Exocrine Pancreatic Insufficiency/genetics
• Humans
• Incidence
• Infant
• Italy/epidemiology
• Lipomatosis/diagnosis
• Lipomatosis/epidemiology
• Lipomatosis/genetics
• Shwachman-Diamond Syndrome

The differential diagnosis of a neonate or fetus presenting with a bell-shaped or long narrow thorax includes a wide range of bony dysplasia syndromes. Where this is accompanied by respiratory distress, asphyxiating thoracic dystrophy (ATD, Jeune syndrome) is an important potential diagnosis. Shwachman-Diamond syndrome (SDS) is widely recognised as a cause of exocrine pancreatic dysfunction, short stature and bone marrow failure. It is not so well appreciated that rib and/or thoracic cage abnormalities occur in 30–50% of patients and that, in severe cases, these abnormalities may lead to thoracic dystrophy and respiratory failure in the newborn. There are, however, at least three previous case reports of children who were initially diagnosed with ATD who were subsequently shown to have SDS.

This report details the case history of a patient misdiagnosed as having ATD as a neonate following the neonatal asphyxial death of her brother. She subsequently developed progressive pancytopenia but was only diagnosed with SDS at 11 years of age after referral for haematopoietic stem cell transplantation for bone marrow failure accompanied by trilineage dysplasia and clonal cytogenetic abnormalities on bone marrow examination. Subsequent testing revealed the presence of fat globules in stools, reduced faecal chymotrypsin, fat-soluble vitamin deficiency, metaphyseal dysplasia on skeletal survey and heterozygous mutations of the SBDS gene.

This report highlights the potential for diagnostic confusion between ATD and SDS. It is important to include SDS in the differential diagnosis of newborns with thoracic dystrophy and to seek expert clinical and radiological assessment of such children.