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Shwachman-Diamond syndromeShwachman-Diamond syndrome (SDS) is a rare congenital disorder characterized by exocrinepancreaticinsufficiency, bone marrowdysfunction, skeletalabnormalities, and short stature. After cystic fibrosis(CF), it is the second most common cause of exocrine pancreatic insufficiency in children.
Clinical FeaturesThis syndrome shows a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, haematologic abnormalities and growth retardation. Neutropeniamay be intermittent or persistent and is the most common haematological finding. Low neutrophilcounts leave patients at risk of developing severe recurrent infections that may be life-threatening. Anemia(low red blood cellcounts) and thrombocytopenia(low plateletcounts) may also occur. Bone marrow is typically hypocellular, with maturation arrest in the myeloid lineages that give rise to neutrophils, macrophages, platelets and red blood cells. Patients may also develop progressive marrow failure or transform to acute myelogenous leukemia. Pancreatic exocrine insufficiency arises due to a lack of acinar cells that produce digestive enzymes. These are extensively depleted and replaced by fat. A lack of pancreatic digestive enzymesleaves patients unable to digest and absorb fat. However, pancreatic status may improve with age in some patients. More than 50% of patients are below the third percentile for height, and short stature appears to be unrelated to nutritional status. Other skeletal abnormalities include metaphyseal dysostosis (45% of patients), thoracic dystrophy (rib cage abnormalities in 46% of patients), and costochondral thickening (shortened ribs with flared ends in 32% of patients). Skeletal problems are one of the most variable components of SDS, with 50% affected siblings from the same family discordant for clinical presentation or type of abnormality. Despite this, a careful review of radiographsfrom 15 patients indicated that all of them had at least one skeletal anomaly, though many were sub-clinical. DiagnosisInitially, the clinical presentation of SDS may appear similar to cystic fibrosis. However, CF can be excluded with a normal sweat chloride test result. The variation, intermittent nature, and potential for long-term improvement of some clinical features make this syndrome difficult to diagnose. SDS may present with either malabsorption, or hematological problems. Rarely, SDS may present with skeletal defects, including severe rib cage abnormalities that lead to difficulty in breathing. Diagnosis is generally based on evidence of exocrine pancreatic dysfunction and neutropenia. Skeletal abnormalities and short stature are characteristics that can be used to support the diagnosis. The generesponsible for the disease has been identified and genetic testingis now available. Though useful in diagnostics, a genetic test does not surmount the need for careful clinical assessment and monitoring of all patients. HistoryThe disease was first described as a coherent clinical entity in May 1964by Bodian, Sheldon, and Lightwood. It was subsequently described by Shwachman, Diamond, Oski, and Khaw in November of the same year. In 2001, linkage analysis in SDS families indicated that affected gene mapped to a large region of human chromosome seven. In 2002, this interval was refined to a 1.9 centimorganregion on the long arm of the chromosomenext to the centromere. In 2003mutations in the SBDS gene (Shwachman-Bodian-Diamond syndrome) were found to be associated with disease. GeneticsShwachman-Diamond syndrome is characterized by an autosomal recessivemode of inheritance. The gene that is mutated in this syndrome (SBDS) lies on the long arm of chromosome seven at cytogeneticposition 7q11. It is composed of five exons and has an associated mRNAtranscript that is 1.6 kilobasepairs in length. The SBDS gene resides in a block of genomic sequence that is locally duplicated on the chromosome. The second copy contains a non-functional version of the SBDS gene that is 97% identical to the original gene, but has accumulated inactivating mutations over time. It is considered to be a pseudogene. In a study of 158 SDS families, 75% of disease-associated mutations appeared to be the result of gene conversion, while 89% of patients harbored at least one such mutation. Gene conversion occurs when the intact SBDS gene and its pseudogene copy aberrantly recombineat meiosis, leading to an incorporation of pseudogene-like sequences into the 'good copy' of the SBDS gene, thereby inactivating it. Two gene conversion mutations predominate; one is a splice sitemutation affecting the 5' spice site of introntwo, while the second is an exontwo nonsense mutation. Molecular Basis of DiseaseThe SBDS gene is expressed in all tissues and encodes a proteinof 250 amino acidresidues. The function of this protein is not known and it has no primary sequence similarity to any other protein or structural domainthat has been previously described. Nevertheless, a great deal of indirect evidence suggests that the SBDS protein may be involved in an aspect of cellular RNAmetabolism or ribosomeassembly or function. The wide occurrence of the gene in all Archaeaand Eukaryotessupports a role for this protein in a very fundamental and evolutionarily conserved aspect of cellular biology. A specific function for SBDS in RNA metabolism or ribosome assembly or function is supported by its localization to the nucleolus, the nuclear sub-domain where these processes occur. At present, it is not obvious how disruption of a basic cellular process causes the tissue- and organ-specific manifestations seen in SDS. However, unusual and combinations of tissues and organs are also affected in Diamond-Blackfan anemia, X-linkeddyskeratosis congenita, and cartilage-hair hypoplasia- three diseases that may also be linked to defective ribosome function. Clinical Management and TreatmentsPancreatic exocrine insufficiency may be treated through pancreatic enzyme supplementation, while severe skeletal abnormalities may require surgical intervention. Neutropenia may be treated with granulocyte-colony stimulating factor(GCSF) to boost peripheral neutrophil counts. However, there is ongoing and unresolved concern that this drug could contribute to the development of leukemia. Signs of progressive marrow failure may warrant bone marrow transplantation(BMT). This has been used successfully to treat hematological aspects of disease. However, SDS patients have an elevated occurrence of BMT-related adverse events, including graft-versus-host disease(GVHD) and toxicity relating to the pre-transplant conditioning regimen. In the long run, study of the gene that is mutated in SDS should improve understanding of the molecular basis of disease. This, in turn, may lead to novel therapeutic strategies, including gene therapyand other gene- or protein-based approaches. See also
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