Shwachman–Diamond syndrome

The Shwachman - Bodian - Diamond syndrome ( SBDS ) is a rare congenital disorder that is characterized by a lack of education of digestive enzymes in the pancreas ( exocrine pancreatic insufficiency ), functional disorders of the bone marrow with a propensity to develop leukemia, skeletal deformities and short stature. After cystic fibrosis, it is the second most common cause of exocrine pancreatic insufficiency in childhood.

History

The disease was first recognized by Bodian and colleagues in 1964 and described in the same year by Shwachman and Diamond. 2001 was shown by a linkage analysis in several SBDS families that are looking for the gene locus must lie on chromosome 7. A year later, the exact region was defined in the vicinity of the centromere and later demonstrated the association of the SBDS gene with the disease.

Genetics

The SBDS is characterized by an autosomal recessive mode of inheritance. The causative gene ( SBDS ) gene is located on chromosome 7 at position 7q11. It consists of five exons coding for a 1.6 kb mRNA. The SBDS gene is located in a duplicated region. To 97% identical copy is not functional because it contains a number of inactivating mutations and is thus considered to be a pseudogene. In a study of 158 families was found that about 3/4 of disease-related mutations are a result of a gene conversion and about 90 percent of these patients had such mutations. A gene conversion occurs when intact gene and pseudogene recombine in meiosis, while mutant sequences of the pseudo gene in the functional gene will be copied and then inactivate. The most commonly observed in the SBDS gene conversions involve a mutation of a splice site and a nonsense mutation in exon 2

Pathophysiology

SBDS the gene is expressed in all tissues, and encodes a protein having 250 amino acids. The function is not known. So far, one knows no sequence homology to any other gene, from which the function would open up. The three-dimensional structure of the SBDS gene orthologous protein of Archaea has been solved and it was found that most of the mutations in humans involve a region relating to an unusual structure at the N -terminal end of the protein. There are a number of indications that the SBDS protein plays a role in the assembly of ribosomes. The wide distribution of the protein in all tissues and in eukaryotes and archaea suggests that it is involved in a very fundamental and evolutionarily highly conserved biological process. For a contribution from the SBDS protein in the metabolism or assembly of ribosomes is supported by the localization of the protein in the nucleolus. So far it is not clear why the fault of a very fundamental cellular process causes very specific disorders. However, one finds a similar situation also in Diamond Blackfan syndrome, the X -linked dyskeratosis congenita, and cartilage - hair hypoplasia. Three diseases in which a defective connection with ribosome functions is assumed.

Clinical picture

The patients affected by this disorder show a variety of disorders and symptoms. It usually takes the Triassic exocrine pancreatic insufficiency, leukopenia and skeletal changes. Neutropenia ( special form of leukopenia ) may intermittently (intermittent ) or permanent occur. The low Neutrophilenanteil may be associated with an increased risk of infection and may be life -threatening for the patient. Also, anemia (anemia ) and a lack of platelets (thrombocytopenia ) may occur. The cause of these changes in blood count is a decrease of cells in the bone marrow, showing a termination of cell maturation in the myeloid cells. Patients may suffer as a result an increasing loss of bone marrow function or develop acute myeloid leukemia.

Exocrine pancreatic insufficiency is a consequence of loss of pancreatic acinar cells that produce digestive enzymes. This decrease in number and are replaced by fatty tissue. The lack of digestive enzymes resulting in a disturbance of the digestion of fat, with the consequence of a malabsorption syndrome. Unlike other disorders with congenital exocrine pancreatic insufficiency - for example, the Johanson - Blizzard syndrome, in which the malfunction of the pancreas has a progressive character - can the SDS, the pancreas function improve with time.

More than half of the patients exhibit short stature, which is not linked to the nutritional status. The skeletal changes occur in every second patient, a metaphyseal dysostosis as frequent changes of the chest, for example, with short ribs. The skeletal changes are highly variable symptom. But you seem to occur with a certain diagnosis, albeit in very different forms in all patients. The symptoms in individuals with the same genotype are different. A genotype -phenotype relationship could not be observed.

Diagnosis

Upon detection of the first symptoms of the SBDS may have similarities with cystic fibrosis. A cystic fibrosis can also be excluded by a normal sweat test. The difference in severity of the symptoms, their temporary nature and the fact that improve some symptoms over time, make it sometimes difficult to diagnose a SBDS. This can present itself either with a malabsorption syndrome or with blood dyscrasias. In some patients, skeletal changes are in the foreground, including deformations of the ribs, which can lead to breathing difficulties. Usually the diagnosis is made with blood disorders in the presence of exocrine Pankreasinsuffizinez in childhood. The skeletal change and short stature may support the diagnosis. Since the gene responsible for the disease is identified, a genetic test can be performed, although this careful clinical diagnosis is not superfluous.

Treatment

Exocrine pancreatic insufficiency can be treated by a substitution of pancreatic enzymes and skeletal abnormalities may make surgery necessary. Neutropenia may be treated with G -CSF. Fears that the treatment with G -CSF increases the risk of leukemia could not be confirmed. If the patients show a progressive bone marrow depression, a stem cell transplant may be necessary. However, patients should have a SBDS an increased risk for the development of graft - versus-host reaction. From the analysis of the SBDS underlying genetic disorder is hoped that an improved understanding of the molecular causes of the disease and potentially new therapeutic possibilities.

Used literature

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