scholarly journals Somatic development in children with Shwachman-Diamond Syndrome

2020 ◽  
Author(s):  
Agnieszka Bogusz-Wójcik ◽  
Honorata Kołodziejczyk ◽  
Maja Klaudel-Dreszler ◽  
Grzegorz Oracz ◽  
Joanna Pawłowska ◽  
...  
Keyword(s):  
Short Stature ◽  
Bone Marrow Failure ◽  
Systemic Disease ◽  
Pancreatic Insufficiency ◽  
Anthropometric Measurements ◽  
Leg Length ◽  
Somatic Development ◽  
Lower Weight ◽  
Shwachman Diamond Syndrome ◽  
Lower Height

Abstract Background: Shwachman-Diamond syndrome (SDS) is a rare genetic, multi-systemic disease characterized by exocrine pancreatic insufficiency, immune deficiency, bone marrow failure and skeletal abnormalities. Most patients present with failure in somatic development and short stature, but systematic data concerning those features are limited. The aim of the study was to assess the prevalence of failure in somatic development in the children with SDS.Methods: An analysis of anthropometric measurements of 21 patients (14 girls and 7 boys),aged 2 to 17 years (mean age 6.3 years) with SDS diagnosed in The Children’s Memorial Health Institute in Warsaw, Poland was performed. The patients were measured using a Holtain Limited stadiometer, an electronic scale, a Harpenden anthropometer, a metric tape and a spreading caliper. The assessed anthropometric parameters were expressed as standard deviation scores in relation to the reference values in Poland, suitable for sex as well as calendar and growth age.Results: A total of 66 measurements was collected and analyzed with a median number of 3 observations per patient. The group of boys presented with a significantly lower height (-3.0 SD, p<0.0001) and BMI (-1.4 SD, p<0.00001), and in the relation to the growth age a lower weight ( -1.0 SD, p<0.001) as well as a smaller chest width (-0.9 SD, p<0.05), hip width (-0,5 SD, p<0,05) and lower limb length (-0,5 SD, p<0,05). The group of girls also showed significantly lower height (-2.6 SD, p<0.00001) and BMI (-0.8 SD, p<0.00001), and in relation to the growth age, lower weight (-0.5 SD, p<0.001) as well as decreased width of the chest (-1.7 SD, p<0.0001) and shoulder (‑1.0 SD, p<0.001) were observed. Boys and girls were also characterized by significantly decreased circumference and width of head, additionally, girls had also smaller head length.Conclusions: Patients with SDS have abnormal somatic development. Both boys and girls are characterized by short stature, decreased weight, BMI, leg length, chest width as well as circumference and width of head. Anthropometric measurements provide important data on the process of growth and body proportions in children with SDS.

scholarly journals Somatic development in children with Shwachman-Diamond syndrome

2020 ◽  
Vol 46 (1) ◽  
Author(s):  
Agnieszka Bogusz-Wójcik ◽  
Honorata Kołodziejczyk ◽  
Maja Klaudel-Dreszler ◽  
Grzegorz Oracz ◽  
Joanna Pawłowska ◽  
...  
Keyword(s):  
Short Stature ◽  
Bone Marrow Failure ◽  
Systemic Disease ◽  
Pancreatic Insufficiency ◽  
Anthropometric Measurements ◽  
Leg Length ◽  
Somatic Development ◽  
Lower Weight ◽  
Shwachman Diamond Syndrome ◽  
Lower Height

Abstract Background Shwachman-Diamond syndrome (SDS) is a rare genetic, multi-systemic disease characterized by exocrine pancreatic insufficiency, immune deficiency, bone marrow failure and skeletal abnormalities. Most patients present with failure in somatic development and short stature, but systematic data concerning those features are limited. The aim of the study was to assess the prevalence of failure in somatic development in the children with SDS. Methods An analysis of anthropometric measurements of 21 patients (14 girls and 7 boys),aged 2 to 17 years (mean age 6.3 years) with SDS diagnosed in The Children’s Memorial Health Institute in Warsaw, Poland was performed. The patients were measured using a Holtain Limited stadiometer, an electronic scale, a Harpenden anthropometer, a metric tape and a spreading caliper. The assessed anthropometric parameters were expressed as standard deviation scores in relation to the reference values in Poland, suitable for sex as well as calendar and growth age. Results A total of 66 measurements was collected and analyzed with a median number of 3 observations per patient. The group of boys presented with a significantly lower height (− 3.0 SD, p < 0.0001) and BMI (− 1.4 SD, p < 0.00001), and in the relation to the growth age a lower weight (− 1.0 SD, p < 0.001) as well as a smaller chest width (− 0.9 SD, p < 0.05), hip width (− 0,5 SD, p < 0,05) and lower limb length (− 0,5 SD, p < 0,05). The group of girls also showed significantly lower height (− 2.6 SD, p < 0.00001) and BMI (− 0.8 SD, p < 0.00001), and in relation to the growth age, lower weight (− 0.5 SD, p < 0.001) as well as decreased width of the chest (− 1.7 SD, p < 0.0001) and shoulder (− 1.0 SD, p < 0.001) were observed. Boys and girls were also characterized by significantly decreased circumference and width of head, additionally, girls had also smaller head length. Conclusions Patients with SDS have abnormal somatic development. Both boys and girls are characterized by short stature, decreased weight, BMI, leg length, chest width as well as circumference and width of head. Anthropometric measurements provide important data on the process of growth and body proportions in children with SDS.

scholarly journals Somatic Development in Children With Shwachman-diamond Syndrome

2020 ◽  
Author(s):  
Agnieszka Bogusz-Wójcik ◽  
Honorata Kołodziejczyk ◽  
Maja Klaudel-Dreszler ◽  
Grzegorz Oracz ◽  
Joanna Pawłowska ◽  
...  
Keyword(s):  
Short Stature ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Anthropometric Measurements ◽  
Leg Length ◽  
Anthropometric Parameters ◽  
Somatic Development ◽  
Lower Weight ◽  
Shwachman Diamond Syndrome ◽  
Lower Height

Abstract Background: Shwachman-Diamond syndrome (SDS) is a rare genetic, multi-systemic diseasecharacterised by exocrine pancreatic insufficiency, immune deficiency, bone marrow failure and skeletal abnormalities.Most patients present with failure in somatic development and short stature, but systematic data concerning those features are limited. The aim of the study was to assess the prevalence of failure in somatic development in the children with SDS.Methods: An analysis of anthropometric measurements of 21 patients (14 girls and 7 boys),eaged 2 to 17 years (mean age 6.3 years) with SDS diagnosed in The Children’s Memorial Health Institute in Warsaw, Polandwas performed.The patients were measured using a Holtain Limited stadiometer, an electronic scale, a Harpenden anthropometer, a metric tape and a spreading caliper. The assessed anthropometric parameters were expressed as standard deviation scores in relation to the reference values in Poland, suitable for sex as well as calendar and growth age.Results: A total of66measurements was collected and analysed with a median number of 3 observations per patient.The group of boyspresented with a significantly lower height (-3.0 SD, p<0.0001) and BMI (-1.4 SD, p<0.00001), and in the relation to the growth age a lower weight ( -1.0 SD, p<0.001) as well as a smaller chest width (-0.9 SD, p<0.05), hip width (-0,5 SD, p<0,05) and lower limb length (-0,5 SD, p<0,05). The group of girls also showed significantly lower height (-2.6 SD, p<0.00001) and BMI (-0.8 SD, p<0.00001), and in relation to the growth age, lower weight (-0.5 SD, p<0.001) as well as decreased width of the chest (-1.7 SD, p<0.0001) and shoulder (‑1.0 SD, p<0.001) were observed. Boys and girls were alsocharacterised by significantly decreased circumference and width of head, additionally, girls had also smaller head length.Conclusions: Patients with SDS have abnormal somatic development. Both boys and girls are characterised by short stature, decreased weight, BMI, leg length, chest width as well as circumference and width of head. Anthropometric measurements provide important data on the process of growth and body proportions in children with SDS.

SBDS Protein Plays a Role in Ribosome Biogenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 185-185
Author(s):  
Karthik A. Ganapathi ◽  
Karyn M. Austin ◽  
Maggie Malsch ◽  
Akiko Shimamura
Keyword(s):  
Ribosome Biogenesis ◽  
Actinomycin D ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Protein Translation ◽  
Exocrine Pancreatic Insufficiency ◽  
Nucleolar Localization ◽  
28S Rrna ◽  
Wild Type ◽  
Shwachman Diamond Syndrome

Abstract Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow failure, and leukemia predisposition. The majority of patients with Shwachman-Diamond syndrome harbor mutations in the SBDS gene. SBDS is a novel gene of unknown function and is highly conserved throughout evolution. Studies of the yeast orthologue, YLR022c/SDO1, suggest that SBDS may play a role in ribosome biogenesis. In support of this hypothesis, we have found that the SBDS protein shuttles in and out of the nucleolus. Previously we have shown that SBDS nucleolar localization is regulated in a cell cycle-dependant manner. We now find that SBDS nucleolar localization is also lost following exposure to actinomycin D, suggesting that SBDS nucleolar localization is dependent on active ribosomal RNA (rRNA) transcription. In cell survival assays, SBDS−/− patient-derived cells are sensitive to actinomycin D treatment relative to normal control cells. Introduction of the wild-type SBDS cDNA into SBDS−/− cells corrects their actinomycin D sensitivity, confirming that the observed sensitivity is SBDS-dependent. In contrast, SBDS−/− cells do not exhibit increased sensitivity to cyclohexamide, a protein translation inhibitor. Consistent with this result, SBDS protein co-localizes with ribosomal precursor subunits but not with mature polysomes upon sucrose gradient sedimentation. No differences in polysome profiles are observed between SBDS−/− cells and wild type control cells. Gel filtration studies suggest that SBDS associates into a complex with other proteins. SBDS co-immunoprecipitates with other nucleolar proteins involved in rRNA biogenesis. RNA immunoprecipitation studies reveal that SBDS also associates with the 28S rRNA but not the 18S rRNA. These findings support the hypothesis that SBDS plays a role in ribosome biogenesis

scholarly journals The Shwachman-Diamond SBDS protein localizes to the nucleolus

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1253-1258 ◽  
Author(s):  
Karyn M. Austin ◽  
Rebecca J. Leary ◽  
Akiko Shimamura
Keyword(s):  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Intracellular Localization ◽  
Gene Mutations ◽  
Exocrine Pancreatic Insufficiency ◽  
Nucleolar Localization ◽  
Shwachman Diamond Syndrome ◽  
Low Levels ◽  
Cycle Dependent ◽  
Novel Protein

AbstractShwachman-Diamond syndrome (SDS) is an autosomal recessively inherited disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. The gene for this syndrome, SBDS, encodes a highly conserved novel protein. We characterized Shwachman-Bodian-Diamond syndrome (SBDS) protein expression and intracellular localization in 7 patients with SDS and healthy controls. As predicted by gene mutation, 4 patients with SDS exhibited no detectable full-length SBDS protein. Patient DF277, who was homozygous for the IVS2 + 2 T&gt;C splice donor mutation, expressed scant levels of SBDS protein. Patient SD101 expressed low levels of SBDS protein harboring an R169C missense mutation. Patient DF269, who carried no detectable gene mutations, expressed wild-type levels of SBDS protein to add further support to the growing body of evidence for additional gene(s) that might contribute to the pathogenesis of the disease phenotype. The SBDS protein was detected in both the nucleus and the cytoplasm of normal control fibroblasts, but was particularly concentrated within the nucleolus. SBDS localization was cell-cycle dependent, with nucleolar localization during G1 and G2 and diffuse nuclear localization during S phase. SBDS nucleolar localization was intact in SD101 and DF269. The intranucleolar localization of SBDS provides further supportive evidence for its postulated role in rRNA processing.

Dilated cardiomyopathy in a case of Shwachman–Diamond syndrome

2011 ◽  
Vol 21 (5) ◽  
pp. 588-590 ◽  
Author(s):  
Liliane Kopel ◽  
Paulo S. Gutierrez ◽  
Silvia G. Lage
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Failure ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Exocrine Pancreatic Insufficiency ◽  
Bone Marrow Failure Syndrome ◽  
Organ Systems ◽  
History Of ◽  
Shwachman Diamond Syndrome

AbstractThe Shwachman–Diamond syndrome is an autosomal recessive bone marrow failure syndrome with exocrine pancreatic insufficiency. Additional organ systems, such as the liver, heart and bone, may also be affected. We report a patient with a long history of cardiac failure and diagnosis of dilated cardiomyopathy with intermittent neutropenia. Periodic follow-up revealed progressive cardiac failure and pulmonary hypertension. A diagnosis of Shwachman–Diamond syndrome was made at the autopsy.

scholarly journals Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects

2021 ◽  
Vol 22 (24) ◽  
pp. 13331
Author(s):  
Annalisa Frattini ◽  
Simona Bolamperti ◽  
Roberto Valli ◽  
Marco Cipolli ◽  
Rita Maria Pinto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Ribosome Biogenesis ◽  
Collagen Type ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Collagen Type I ◽  
Type I ◽  
Protein Levels ◽  
Shwachman Diamond Syndrome

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.

Mouse Model for Shwachman-Diamond Syndrome with the R126T Disease Mutation Leads to Severe Growth and Developmental Deficiencies with Impairment of Hematopoiesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1283-1283
Author(s):  
Siyi Zhang ◽  
Jian Zhong ◽  
Olga I. Gan ◽  
John E. Dick ◽  
Johanna M. Rommens
Keyword(s):  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Mutant Mice ◽  
Null Alleles ◽  
Wild Type ◽  
Disease Mutation ◽  
Disease Phenotypes ◽  
Growth Difference ◽  
Shwachman Diamond Syndrome

Abstract Shwachman-Diamond syndrome (SDS) is a bone marrow failure syndrome characterized by exocrine pancreatic insufficiency and skeletal abnormalities, as well as hematological dysfunction. SDS is caused by mutations in SBDS, a highly conserved gene that has been suggested to be involved in RNA metabolism and/or ribosome biogenesis. It is essential, based on our mouse knock-out model studies and the absence of observed patients with the combination of two null alleles. We have generated an allele with the disease mutation, R126T, in the murine ortholog in order to develop new models of SDS. This mutation has been interpreted to be hypomorphic in nature, as it occurs in combination with the common null disease allele in two patients. Interestingly, these patients also have severe hematological disease phenotypes. SbdsR126T/+mice develop normally and show no disease phenotypes, in accordance with the recessive inheritance of SDS. However, the SbdsR126T/R126T and SbdsR126T/- mice did not survive birth, and exhibited marked size reduction. The growth difference became apparent in embryos during the mid-fetal period, at E12.5–14.5; there were also noted disturbances of major organs including the skeleton, brain and lung. Comparable deficiencies were noted overall, but the SbdsR126T/- embryos were consistently more severely affected than were SbdsR126T/R126T embryos. Examination of hematopoietic progenitors from the fetal livers of SbdsR126T/R126T and SbdsR126T/- mutant mice also showed marked reductions in BFU-E, CFU-G, CFU-M, CFU-GM and CFU-GEMM numbers, as revealed by standard colony formation assays, when compared to wild type and heterozygote littermates. In additional studies, primary fibroblast cultures from E16.5 day mutant embryos were found to exhibit slower growth and an extended G1 phase of the cell cycle compared to fibroblasts from wild type embryos. Further, total protein synthesis was measured by incorporation of radio-labeled amino acids and found to be notably reduced in the mutant fibroblasts. The small size, organ deficiencies and early death of the mutant mice together with the cellular deficiencies, which indicate severe autologous growth problems, emphasize the severe consequences of loss of Sbds. These animal disease models provide new avenues for investigation to elucidate basic functions of SBDS and the pathobiology of SDS.

scholarly journals Defective ribosome assembly in Shwachman-Diamond syndrome

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4305-4312 ◽  
Author(s):  
Chi C. Wong ◽  
David Traynor ◽  
Nicolas Basse ◽  
Robert R. Kay ◽  
Alan J. Warren
Keyword(s):  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Ribosomal Subunit ◽  
Initiation Factor ◽  
Ribosome Assembly ◽  
Restrictive Temperature ◽  
Poor Growth ◽  
Shwachman Diamond Syndrome ◽  
Subunit Joining

AbstractShwachman-Diamond syndrome (SDS), a recessive leukemia predisposition disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, skeletal abnormalities and poor growth, is caused by mutations in the highly conserved SBDS gene. Here, we test the hypothesis that defective ribosome biogenesis underlies the pathogenesis of SDS. We create conditional mutants in the essential SBDS ortholog of the ancient eukaryote Dictyostelium discoideum using temperature-sensitive, self-splicing inteins, showing that mutant cells fail to grow at the restrictive temperature because ribosomal subunit joining is markedly impaired. Remarkably, wild type human SBDS complements the growth and ribosome assembly defects in mutant Dictyostelium cells, but disease-associated human SBDS variants are defective. SBDS directly interacts with the GTPase elongation factor-like 1 (EFL1) on nascent 60S subunits in vivo and together they catalyze eviction of the ribosome antiassociation factor eukaryotic initiation factor 6 (eIF6), a prerequisite for the translational activation of ribosomes. Importantly, lymphoblasts from SDS patients harbor a striking defect in ribosomal subunit joining whose magnitude is inversely proportional to the level of SBDS protein. These findings in Dictyostelium and SDS patient cells provide compelling support for the hypothesis that SDS is a ribosomopathy caused by corruption of an essential cytoplasmic step in 60S subunit maturation.

scholarly journals Mutation Screening of Elongation Factor 2 in Shwachman-Diamond Syndrome Patients Lacking Mutations in the SBDS Gene

ISRN Genetics ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-4
Author(s):  
Elena Nicolis ◽  
Marco Cipolli
Keyword(s):  
Autosomal Recessive ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Mutation Screening ◽  
Elongation Factor ◽  
Autosomal Recessive Disorder ◽  
Deleterious Mutations ◽  
Italian Experience ◽  
Elongation Factor 2 ◽  
Shwachman Diamond Syndrome

Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by bone marrow failure, pancreatic insufficiency, and skeletal abnormalities. Mutations in SBDS gene explain, by literature, 90% of SDS cases. The Italian experience shows that only the 5% of individuals diagnosed as affected by SDS on clinical and hematological grounds lack mutations in the SBDS gene. It is well established that SBDS protein is essential for the assembly of mature ribosomes. The yeast SBDS ortholog functions within a pathway containing elongation factor-like 1, homologous to human GTPase elongation factor-2, to promote the release and recycling of the nucleolar shuttling factor Tif6 from cytoplasmic pre-60S subunits in a cascade targeted to form the active ribosome. We considered that mutations of genes that disrupt pathways shared by SBDS may result in disease with comparable clinical features. EEF2 was evaluated as a candidate gene by mutation screening in clinically defined SDS which lack mutations in the SBDS gene. To date, no deleterious mutations were found in EEF2 in four Italian patients without SBDS mutations, but with a clinical diagnosis of SDS.

Sign in / Sign up

Export Citation Format

Share Document