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Molecular diagnosis of shwachman-diamond syndrome presenting with pancytopenia at an early age: the first report from Turkey.

ABSTRACT: A three-month-old boy presented with growth failure, skeletal abnormalities, otitis media and pancytopenia. Exocrine pancreatic insufficiency was confirmed by low levels of fecal elastase. He was diagnosed as Shwachman-Diamond syndrome by clinical and laboratory findings. The diagnosis was confirmed by sequence analysis for SBDS gene on chromosome seven revealing compound heterozygous mutation, which are c.258+2T-C and c.183-184TA-CT. Matched unrelated donor screening for hematopoietic stem cell transplantation was initiated. Unfortunately, he died of respiratory difficulty at 5 months of age. Our case is the youngest patient whose presumptive Shwachman-Diamond syndrome diagnosis was confirmed by molecular analysis.

SUBMITTER: Gokce M

PROVIDER: S-EPMC3710552 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Molecular diagnosis of shwachman-diamond syndrome presenting with pancytopenia at an early age: the first report from Turkey.

Gokce Muge M Tuncer Murat M Cetin Mualla M Gumruk Fatma F

Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion 20120604 3

A three-month-old boy presented with growth failure, skeletal abnormalities, otitis media and pancytopenia. Exocrine pancreatic insufficiency was confirmed by low levels of fecal elastase. He was diagnosed as Shwachman-Diamond syndrome by clinical and laboratory findings. The diagnosis was confirmed by sequence analysis for SBDS gene on chromosome seven revealing compound heterozygous mutation, which are c.258+2T-C and c.183-184TA-CT. Matched unrelated donor screening for hematopoietic stem cell ...[more]

PMID: 24426364

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Project description:Background and purposeShwachman-Diamond Syndrome (SDS) is an autosomal recessive disease belonging to the inherited bone marrow failure syndromes and characterized by hypocellular bone marrow, exocrine pancreatic insufficiency, and skeletal abnormalities. SDS is associated with increased risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). Although SDS is not primarily considered an inflammatory disorder, some of the associated conditions (e.g., neutropenia, pancreatitis and bone marrow dysfunction) may involve inflammation or immune system dysfunctions. We have already demonstrated that signal transducer and activator of transcription (STAT)-3 and mammalian target of rapamycin (mTOR) were hyperactivated and associated with elevated IL-6 levels in SDS leukocytes. In this study, we analyzed the level of phosphoproteins involved in STAT3 and mTOR pathways in SDS lymphoblastoid cells (LCLs) and the secretomic profile of soluble pro-inflammatory mediators in SDS plasma and LCLs in order to investigate the systemic inflammation in these patients and relative pathways.MethodsTwenty-six SDS patients and seven healthy donors of comparable age were recruited during the programmed follow-up visits for clinical evaluation at the Verona Cystic Fibrosis Center Human. The obtained samples (plasma and/or LCLs) were analyzed for: phosphoproteins, cytokines, chemokines and growth factors levels by Bio-plex technology; microRNAs profiling by next generation sequencing (NGS) and microRNAs expression validation by Real Time-PCR (RT-PCR) and droplet digital PCR (ddPCR) .ResultsWe demonstrated dysregulation of ERK1/2 and AKT phosphoproteins in SDS, as their involvement in the hyperactivation of the STAT3 and mTOR pathways confirmed the interplay of these pathways in SDS pathophysiology. However, both these signaling pathways are strongly influenced by the inflammatory environment. Here, we reported that SDS is characterized by elevated plasma levels of several soluble proinflammatory mediators. In vitro experiments show that these pro-inflammatory genes are closely correlated with STAT3/mTOR pathway activation. In addition, we found that miR-181a-3p is down-regulated in SDS. Since this miRNA acts as a regulator of several pro-inflammatory pathways such as STAT3 and ERK1/2, its down-regulation may be a driver of the constitutive inflammation observed in SDS patients.ConclusionsThe results obtained in this study shed light on the complex pathogenetic mechanism underlying bone marrow failure and leukemogenesis in SDS, suggesting the need for anti-inflammatory therapies for SDS patients.

Dataset Information

Molecular diagnosis of shwachman-diamond syndrome presenting with pancytopenia at an early age: the first report from Turkey.

Publications

Molecular diagnosis of shwachman-diamond syndrome presenting with pancytopenia at an early age: the first report from Turkey.

Similar Datasets

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