ShwachmanDiamond syndrome - Wikipedia, the free encyclopedia

28/03/15 10:47

ShwachmanDiamond syndrome
From Wikipedia, the free encyclopedia

ShwachmanDiamond syndrome
(SDS) or ShwachmanBodian
Diamond syndrome 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.

ShwachmanDiamond syndrome
Classification and external resources
ICD-10

Q45.3
(http://apps.who.int/classifications/icd10/browse/2015/en#/Q45.3)

OMIM

260400 (http://omim.org/entry/260400)

DiseasesDB 11894 (http://www.diseasesdatabase.com/ddb11894.htm)

eMedicine ped/2060 (http://www.emedicine.com/ped/topic2060.htm)

Contents
1 Signs and symptoms
2 Genetics
3 Mechanisms
4 Diagnosis
5 Management
6 Epidemiology
7 History
7.1 Eponym
8 References
9 External links

Signs and symptoms

This syndrome shows a wide range of abnormalities and symptoms. The main characteristics of the syndrome
are exocrine pancreatic dysfunction, hematologic abnormalities and growth retardation. Only the first two of
these are included in the clinical diagnostic criteria.[1]
Hematologic abnormalities: Neutropenia may be intermittent or persistent and is the most common
hematological finding. Low neutrophil counts leave patients at risk of developing severe recurrent
infections that may be life-threatening. Anemia (low red blood cell counts) and thrombocytopenia (low
platelet counts) may also occur. Bone marrow is typically hypocellular, with maturation arrest in the
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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 radiographs from 15 patients
indicated that all of them had at least one skeletal anomaly, though many were subclinical.
Other features include metaphysial dysostosis, mild hepatic dysfunction, increased frequency of
infections.

Genetics
ShwachmanDiamond syndrome is characterized by an autosomal
recessive mode of inheritance. The gene that is mutated in this syndrome
(SBDS)[2][3][4] lies on the long arm of chromosome 7 at cytogenetic
position 7q11.[5][6] 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.

ShwachmanDiamond syndrome is
inherited in an autosomal recessive
pattern.

Mechanisms
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The SBDS gene is expressed in all tissues and encodes a protein 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 archaeal ortholog of the human protein has been
determined by x-ray crystallography and indicates a novel three-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 subdomain where
these processes occur. At present, it is not obvious how disruption of a basic cellular process causes the tissueand organ-specific manifestations seen in SDS. However, unusual and combinations of tissues and organs are
also affected in DiamondBlackfan anemia, X-linked dyskeratosis congenita, and cartilage-hair hypoplasia
three diseases that may also be linked to defective ribosome function.

Diagnosis
Initially, the clinical presentation of SDS may appear similar to cystic fibrosis. However, CF can be excluded
with a normal chloride in sweat test but faecal elastase as a marker of pancreatic function will be reduced. 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.

Management
Pancreatic exocrine insufficiency may be treated through pancreatic enzyme supplementation,[7] 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 therapy and other gene- or
protein-based approaches.

Epidemiology
It is thought to have an estimated incidence of 1 in 75,000 people.[8]
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History
The disease was first described as a coherent clinical entity in May 1964 by Bodian, Sheldon, and Lightwood.[9]
It was subsequently described by Shwachman, Diamond, Oski, and Khaw in November of the same year.[10] In
2001, linkage analysis in SDS families indicated that affected gene mapped to a large region of human
chromosome seven.[11] In 2002, this interval was refined to a region on the long arm of the chromosome next to
the centromere.[12]
In 2003 mutations in the SBDS gene (ShwachmanBodianDiamond syndrome) were found to be associated
with disease.[13]

Eponym
ShwachmanDiamond syndrome, less commonly known as ShwachmanBodianDiamond syndrome, is named
for Harry Shwachman (1910 -September 12, 1986), an American physician, Martin Bodian (1912 - May 12,
1994), a British ophthalmologist who worked in New York City, and Louis Klein Diamond (May 11, 1902 June 14, 1999), an American pediatrician.

References
1. Orkin, Stuart H.; Nathan, David G.; Ginsburg, David; A. Thomas Look (2009). Nathan and Oski's hematology of infancy
and childhood (http://books.google.com/books?id=_9CmOIvgJm4C&pg=PA344). Elsevier Health Sciences. pp. 344.
ISBN 978-1-4160-3430-8. Retrieved 8 August 2011.
2. Shammas C, Menne TF, Hilcenko C, Michell SR, Goyenechea B, Boocock GR, Durie PR, Rommens JM, Warren AJ
(2005). "Structural and mutational analysis of the SBDS protein family. Insight into the leukemia-associated
ShwachmanDiamond Syndrome.". J Biol Chem. 280 (19): 192219. doi:10.1074/jbc.M414656200
(https://dx.doi.org/10.1074%2Fjbc.M414656200). PMID 15701631 (https://www.ncbi.nlm.nih.gov/pubmed/15701631).
3. Austin KM, Leary RJ, Shimamura A (2005). "The ShwachmanDiamond SBDS protein localizes to the nucleolus."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895203). Blood 106 (4): 12538. doi:10.1182/blood-2005-02-0807
(https://dx.doi.org/10.1182%2Fblood-2005-02-0807). PMC 1895203
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895203). PMID 15860664
(https://www.ncbi.nlm.nih.gov/pubmed/15860664).
4. Makitie O, Ellis L, Durie PR, Morrison JA, Sochett EB, Rommens JM, Cole WG (2004). "Skeletal phenotype in patients
with ShwachmanDiamond syndrome and mutations in SBDS.". Clin Genet 65 (2): 10112. doi:10.1111/j.00099163.2004.00198.x (https://dx.doi.org/10.1111%2Fj.0009-9163.2004.00198.x). PMID 14984468
(https://www.ncbi.nlm.nih.gov/pubmed/14984468).
5. Goobie, S; Popovic, M; Morrison, J; Ellis, L; Ginzberg, H; Boocock, GR; Ehtesham, N; Btard, C; Brewer, CG; Roslin,
NM; Hudson, TJ; Morgan, K; Fujiwara, TM; Durie, PR; Rommens, JM (April 2001). "Shwachman-Diamond syndrome
with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1275624). American Journal of Human Genetics 68 (4): 104854.
doi:10.1086/319505 (https://dx.doi.org/10.1086%2F319505). PMC 1275624
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(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1275624). PMID 11254457

(https://www.ncbi.nlm.nih.gov/pubmed/11254457).
6. Popovic, M; Goobie, S; Morrison, J; Ellis, L; Ehtesham, N; Richards, N; Boocock, G; Durie, PR; Rommens, JM (April
2002). "Fine mapping of the locus for Shwachman-Diamond syndrome at 7q11, identification of shared disease
haplotypes, and exclusion of TPST1 as a candidate gene.". European journal of human genetics : EJHG 10 (4): 2508.
doi:10.1038/sj.ejhg.5200798 (https://dx.doi.org/10.1038%2Fsj.ejhg.5200798). PMID 12032733
(https://www.ncbi.nlm.nih.gov/pubmed/12032733).
7. Disorders, National Organization for Rare (2003). NORD guide to rare disorders (http://books.google.com/books?
id=99YPDvFWBB0C&pg=PA417). Lippincott Williams & Wilkins. pp. 417. ISBN 978-0-7817-3063-1. Retrieved
8 August 2011.
8. Hassan, Fauziya; Byersdorfer, Craig; Nasr, Samya (1 January 2010). "Severe Shwachman-Diamond syndrome and
associated CF carrier mutations". Respiratory Medicine CME 3 (1): 1819. doi:10.1016/j.rmedc.2009.02.001
(https://dx.doi.org/10.1016%2Fj.rmedc.2009.02.001).
9. Bodian M, Sheldon W, Lightwood R (1964). "Congenital hypoplasia of the exocrine pancreas.". Acta Paediatr 53: 282
93. doi:10.1111/j.1651-2227.1964.tb07237.x (https://dx.doi.org/10.1111%2Fj.1651-2227.1964.tb07237.x).
PMID 14158482 (https://www.ncbi.nlm.nih.gov/pubmed/14158482).
10. Shwachman H, Diamond LK, Oski FA, Khaw KT (1964). "The syndrome of pancreatic insufficiency and bone marrow
dysfunction.". J Pediatr 65: 64563. doi:10.1016/S0022-3476(64)80150-5 (https://dx.doi.org/10.1016%2FS00223476%2864%2980150-5). PMID 14221166 (https://www.ncbi.nlm.nih.gov/pubmed/14221166).
11. Goobie S, Popovic M, Morrison J, Ellis L, Ginzberg H, Boocock GR, Ehtesham N, Betard C, Brewer CG, Roslin NM,
Hudson TJ, Morgon K, Fujiwara TM, Durie PR, Rommens JM (2001). "ShwachmanDiamond syndrome with exocrine
pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7."
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1275624). Am J Hum Genet 68 (4): 104854. doi:10.1086/319505
(https://dx.doi.org/10.1086%2F319505). PMC 1275624 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1275624).
PMID 11254457 (https://www.ncbi.nlm.nih.gov/pubmed/11254457).
12. Popovic M, Goobie S, Morrison J, Ellis L, Ehtesham N, Richards N, Boocock G, Durie PR, Rommens JM (2002). "Fine
mapping of the locus for ShwachmanDiamond syndrome at 7q11, identification of shared disease haplotypes, and
exclusion of TPST1 as a candidate gene.". Eur J Hum Genet 10 (4): 2508. doi:10.1038/sj.ejhg.5200798
(https://dx.doi.org/10.1038%2Fsj.ejhg.5200798). PMID 12032733 (https://www.ncbi.nlm.nih.gov/pubmed/12032733).
13. Boocock GRB, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM (2003). "Mutations in SBDS are
associated with ShwachmanDiamond syndrome". Nat Genet 33 (1): 97101. doi:10.1038/ng1062
(https://dx.doi.org/10.1038%2Fng1062). PMID 12496757 (https://www.ncbi.nlm.nih.gov/pubmed/12496757).

External links
Foerster. "Ch 37. Inherited Aplastic Anemia Syndromes". In John P. Greer, Daniel A. Arber, Bertil
Glader, Alan F. List, Robert T. Means Jr., Frixos Paraskevas, George M. Rodgers, John Foerster.
Wintrobe's clinical hematology (https://www.inkling.com/read/wintrobes-clinical-hematology-greer13th/chapter-37/shwachman-diamond-syndrome) (13th ed.). p. Shwachman-Diamond Syndrome.
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ISBN 1451172680.
GeneReviews/NCBI/NIH/UW entry on ShwachmanDiamond Syndrome
(http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=sds)
ShwachmanDiamond Syndrome research study of Inherited Bone Marrow Failure Syndromes (IBMFS)
(http://www.marrowfailure.cancer.gov/index.html)
ShwachmanDiamond Syndrome Foundation (http://www.shwachman-diamond.org/)
Retrieved from "http://en.wikipedia.org/w/index.php?title=Shwachman
Diamond_syndrome&oldid=650415679"
Categories: Pediatrics Autosomal recessive disorders Pancreas disorders Blood disorders
Noninfectious immunodeficiency-related cutaneous conditions
Congenital defects of phagocyte number, function, or both
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