Bloom syndrome

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Bloom syndrome
Classification and external resources
4cgz.png
Crystal structure of the Bloom's syndrome helicase BLM in complex with DNA (PDB ID: 4CGZ).
ICD-10 Q82.8
ICD-9 757.39
OMIM 210900
DiseasesDB 1505
eMedicine derm/54
MeSH D001816
GeneReviews

Bloom syndrome (often abbreviated as BS in literature),[1] also known as Bloom–Torre–Machacek syndrome,[2] is a rare autosomal recessive[3][4] disorder characterized by short stature and predisposition to the development of cancer. Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive homologous recombination. The condition was discovered and first described by New York dermatologist Dr. David Bloom in 1954.[5]

Genetics[edit]

Bloom syndrome is an autosomal recessive disorder, caused by disease-causing mutations in the maternally- and paternally-dervied copies of the gene BLM.[6] As in other autosomal recessive conditions, the parents of an individual with Bloom syndrome do not exhibit any features of the syndrome. The mutations in BLM associated with Bloom syndrome are nulls and missense mutations that are catalytically inactive.[7] The cells from persons with Bloom syndrome exhibit a striking genomic instability that is characterized by hyper-recombination and hyper-mutation. At the level of the chromosomes, the rate of sister chromatid exchange in Bloom's syndrome is approximately 10 fold higher than normal and quadriradial figures, which are the cytologic manifestations of crossing-over between homologous chromosome, are highly elevated. Other chromosome manifestations include chromatid breaks and gaps, telomere associations, and fragments chromosomes.[8] The hyper-recombination can also be detected by molecular assays [9] The BLM gene is a member of the protein family referred to as RecQ helicases. The diffusion of BLM has been measured to 1.34  \tfrac{\mathrm{\mu m}^2}{\mathrm{s}} in nucleoplasm and 0.13  \textstyle \tfrac{\mathrm{\mu m}^2}{\mathrm{s}} at nucleoli [10]DNA helicases are enzymes that attach to DNA and temporarily unravel the double helix of the DNA molecule. DNA helicases function in DNA replication and DNA repair. BLM very likely functions in DNA replication, as cells from persons with Bloom syndrome exhibit multiple defects in DNA replication, and they are sensitive to agents that obstruct DNA replication.

Frequency[edit]

Bloom syndrome is an extremely rare disorder in most populations and the frequency of the disease has not been measured in most populations. However, the disorder is relatively more common amongst people of Central and Eastern European (Ashkenazi) Jewish background. Approximately 1 in 48,000 Ashkenazi Jews are affected by Bloom syndrome, who account for about one-third of affected individuals worldwide.[11]

Symptoms[edit]

Bloom syndrome is characterized by genome instability. The most prominent features include short stature and a rash on the face that develops early in life when exposed to the sun. The skin rash is erythematous, telangiectatic, infiltrated, and scaly, and it appears across the nose, on the cheeks and around the lips. This rash can develop on other sun-exposed areas such as the backs of the hands. Other clinical features include a high-pitched voice; distinct facial features, including a long, narrow face, micrognathism, and prominent nose and ears; pigmentation changes of the skin including hypo- and hyper-pigmented areas, cafe-au-lait spots, and telangiectasias (dilated blood vessels) which can appear on the skin but also in the eyes; moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes and apparently leading to recurrent pneumonia and ear infections. Most individuals with Bloom syndrome are born with a low birth weight. Hypogonadism is characterized by a failure to produce sperm, hence infertility in males, and premature cessation of menses (premature menopause), hence sub-fertility in females. However, several women with Bloom syndrome have had children. The most serious and common complication of Bloom syndrome is cancer. Other complications of the disorder include chronic obstructive lung disease, diabetes, and learning disabilities. There is no evidence that mental retardation is more common in Bloom syndrome than in other people. People with Bloom Syndrome also have a shortened life expectancy; the current average live span is approximately 27 years old.[12] Bloom syndrome shares some features with Fanconi anemia possible because there is overlap in the function of the proteins mutated in this related disorder.[13]

Relationship to cancer and aging[edit]

As noted above, there is greatly elevated rate of mutation in Bloom syndrome and the genomic instability is associated with a high risk of cancer in affected individuals.[14] The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity, that is, synchronous or metachronous cancers. There is at least one person with Bloom syndrome who had five independent primary cancers. Persons with Bloom syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 26 years old.[12]

Pathophysiology[edit]

When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called DNA replication. Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. Lack of BLM protein or protein activity leads to an increase mutations; however, the molecular mechanism(s) by which BLM maintains stability of the chromosomes is still a very active area of research.

Persons with Bloom syndrome have an enormous increase in exchange events between homologous chromosomes or sister chromatids (the two DNA molecules that are produced by the DNA replication process); and there are increases in chromosome breakage and rearrangements compared to persons who do not have Bloom's syndrome. Direct connections between the molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom syndrome are also areas of intense research.

Bloom syndrome has an autosomal recessive pattern of inheritance.

Diagnosis[edit]

Bloom syndrome is diagnosed using any of three tests - the presence of quadriradial (Qr, a four-armed chromatid interchange) in cultured blood lymphocytes, and/or the elevated levels of Sister chromatid exchange in cells of any type, and/or the mutation in the BLM gene.[15]

See also[edit]

References[edit]

  1. ^ Online 'Mendelian Inheritance in Man' (OMIM) Bloom Syndrome; BLM -210900
  2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 575. ISBN 0-7216-2921-0. 
  3. ^ Karow, JK; Constantinou, A; Li, JL; West, SC; Hickson, ID (2000). "The Bloom's syndrome gene product promotes branch migration of holliday junctions". Proceedings of the National Academy of Sciences of the United States of America 97 (12): 6504–8. doi:10.1073/pnas.100448097. PMC 18638. PMID 10823897. 
  4. ^ Straughen, Je; Johnson, J; Mclaren, D; Proytcheva, M; Ellis, N; German, J; Groden, J (1998). "A rapid method for detecting the predominant Ashkenazi Jewish mutation in the Bloom's syndrome gene". Human Mutation 11 (2): 175–8. doi:10.1002/(SICI)1098-1004(1998)11:2<175::AID-HUMU11>3.0.CO;2-W. PMID 9482582. 
  5. ^ Bloom D (1954). "Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity". A.M.A. American journal of diseases of children 88 (6): 754–8. PMID 13206391. 
  6. ^ Ellis NA, Groden J, Ye T-Z, Straughen J, Ciocci S, Lennon DJ, Proytcheva M, Alhadeff B, German J. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 1995; 83: 655-666
  7. ^ German J, Ciocci S, Ye TZ, Sanz MM, Ellis NA. Syndrome-causing mutations at BLM in persons in the Bloom’s Syndrome Registry. Hum Mutation 2007; 28:743-753
  8. ^ German J. Bloom's syndrome. Dermatol Clin. 1995 Jan;13(1):7-18
  9. ^ Langlois RG, Bigbee WL, Jensen RH, German J. Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome. Proc Natl Acad Sci U S A. 1989 Jan;86(2):670-4
  10. ^ Kristian Moss Bendtsen, Martin Borch Jensen, Alfred May, Lene Juel Rasmussen, Ala Trusina, Vilhelm A. Bohr & Mogens H. Jensen (2014). "Dynamics of the DNA repair proteins WRN and BLM in the nucleoplasm and nucleoli". European Biophysics Journal. doi:10.1007/s00249-014-0981-x. PMID 25119658. 
  11. ^ 23. Li L, Eng C, Desnick B, German J, Ellis NA. Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population. Mol Genet Metab 1998; 64:286-290
  12. ^ a b http://weill.cornell.edu/bsr/
  13. ^ Deans AJ, West SC (December 2009). "FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia". Mol. Cell 36 (6): 943–53. doi:10.1016/j.molcel.2009.12.006. PMID 20064461. 
  14. ^ German J. Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet. 1997 Jan;93(1):100-6
  15. ^ Sanz, MM; German, J; Pagon, RA; Adam, MP; Bird, TD; Dolan, CR; Fong, CT; Stephens, K (1993). GeneReviews™ [Internet].Pagon RA, Adam MP, Bird TD, et al, ed. "Bloom's Syndrome". Seattle. PMID 20301572. 

External links[edit]