Shwachman–Bodian–Diamond syndrome
Encyclopedia
Shwachman–Diamond syndrome (SDS) is a rare congenital disorder characterized by exocrine pancreatic insufficiency
, bone marrow
dysfunction, skeletal abnormalities, and short stature
. After cystic fibrosis
(CF), it is the second most common cause of exocrine pancreatic insufficiency in children.
. 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 gene
responsible for the disease has been identified and genetic testing
is now available. Though useful in diagnostics, a genetic test does not surmount the need for careful clinical assessment and monitoring of all patients.
next to the centromere
.
In 2003 mutations in the SBDS
gene (Shwachman–Bodian–Diamond syndrome) were found to be associated with disease.
Shwachman–Diamond syndrome is characterized by an autosomal recessive mode of inheritance. The gene that is mutated in this syndrome (SBDS) lies on the long arm of chromosome 7 at cytogenetic position 7q11. It is composed of five exons and has an associated mRNA transcript that is 1.6 kilobase pairs 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 recombine
at 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 site mutation affecting the 5' splice site of intron
two, while the second is an exon
two nonsense mutation
.
of 250 amino acid
residues. The function of this protein is not known and it has no primary sequence similarity to any other protein or structural domain that would indicate a possible function. The atomic structure of an archeal ortholog of the human protein has been determined by x-ray crystallography and indicates a novel 3 dimensional fold in the most N-terminal of the three structural domains and many of the known human disease associated mutations and truncations occur within this structural domain. There is however, a great deal of indirect evidence to suggest that the SBDS protein may be involved in an aspect of cellular RNA
metabolism or ribosome
assembly or function. The wide occurrence of the gene in all Archaea
and Eukaryotes supports 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-linked dyskeratosis congenita
, and cartilage-hair hypoplasia
—three diseases that may also be linked to defective ribosome function.
. 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 therapy
and other gene- or protein-based approaches.
Exocrine pancreatic insufficiency
Exocrine pancreatic insufficiency is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. This disease is found frequently in dogs. EPI is also found in humans afflicted with cystic fibrosis and Shwachman-Diamond Syndrome. EPI is caused by a progressive...
, bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
dysfunction, skeletal abnormalities, and short stature
Short stature
Short stature refers to a height of a human being which is below expected. Shortness is a vague term without a precise definition and with significant relativity to context...
. After cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
(CF), it is the second most common cause of exocrine pancreatic insufficiency in children.
Clinical features
This syndrome shows a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, haematologic abnormalities and growth retardation. Only the first two of these are included in the clinical diagnostic criteria.- haematologic abnormalities: NeutropeniaNeutropeniaNeutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
may be intermittent or persistent and is the most common haematological finding. Low neutrophil counts leave patients at risk of developing severe recurrent infections that may be life-threatening. AnemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
(low red blood cellRed blood cellRed blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
counts) and thrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(low plateletPlateletPlatelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
counts) 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.
- exocrine pancreatic dysfunction: 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 enzymes leaves patients unable to digest and absorb fat. However, pancreatic status may improve with age in some patients.
- growth retardation: 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 radiographsRadiographyRadiography is the use of X-rays to view a non-uniformly composed material such as the human body. By using the physical properties of the ray an image can be developed which displays areas of different density and composition....
from 15 patients indicated that all of them had at least one skeletal anomaly, though many were sub-clinical.
Diagnosis
Initially, the clinical presentation of SDS may appear similar to cystic fibrosisCystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
. 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
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
, 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 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
responsible for the disease has been identified and genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
is now available. Though useful in diagnostics, a genetic test does not surmount the need for careful clinical assessment and monitoring of all patients.
History
The disease was first described as a coherent clinical entity in May 1964 by 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 region on the long arm of the chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
next to the centromere
Centromere
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment...
.
In 2003 mutations in the SBDS
SBDS
Ribosome maturation protein SBDS is a protein that in humans is encoded by the SBDS gene.-External Links:* -Further reading:...
gene (Shwachman–Bodian–Diamond syndrome) were found to be associated with disease.
Genetics
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
. In a study of 158 SDS families, 75% of disease-associated mutations appeared to be the result of gene conversion
Gene conversion
Gene conversion is an event in DNA genetic recombination, which occurs at high frequencies during meiotic division but which also occurs in somatic cells. It is a process by which DNA sequence information is transferred from one DNA helix to another DNA helix, whose sequence is altered.It is one...
, while 89% of patients harbored at least one such mutation. Gene conversion occurs when the intact SBDS gene and its pseudogene copy aberrantly recombine
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
at meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
, 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 site mutation affecting the 5' splice site of intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
two, while the second is an exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
two nonsense mutation
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
.
Molecular basis of disease
The SBDS gene is expressed in all tissues and encodes a proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
of 250 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues. The function of this protein is not known and it has no primary sequence similarity to any other protein or structural domain that would indicate a possible function. The atomic structure of an archeal ortholog of the human protein has been determined by x-ray crystallography and indicates a novel 3 dimensional fold in the most N-terminal of the three structural domains and many of the known human disease associated mutations and truncations occur within this structural domain. There is however, a great deal of indirect evidence to suggest that the SBDS protein may be involved in an aspect of cellular RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
metabolism or ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
assembly or function. The wide occurrence of the gene in all Archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
and Eukaryotes supports 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
Nucleolus
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus. Ribosomal RNA is transcribed and assembled within 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-linked dyskeratosis congenita
Dyskeratosis congenita
Dyskeratosis congenita , also called Zinsser-Cole-Engman syndrome, is a rare progressive congenital disorder which results in what in some ways resembles premature aging...
, and cartilage-hair hypoplasia
Cartilage-hair hypoplasia
Cartilage–hair hypoplasia , also known as McKusick type metaphyseal chondrodysplasia, is a rare form of short-limbed dwarfism due to skeletal dysplasia. It was first reported in 1965 by McKusick et al...
—three diseases that may also be linked to defective ribosome function.
Clinical management and treatments
Pancreatic 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 leukemiaLeukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
. 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
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
(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 therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
and other gene- or protein-based approaches.