Bloom syndrome

Bloom syndrome
Bloom-Torre-Machacek syndrome

Crystal structure of the Bloom's syndrome helicase BLM in complex with DNA (PDB ID: 4CGZ).
Classification and external resources
Specialty medical genetics
ICD-10 Q82.8
ICD-9-CM 757.39
OMIM 210900
DiseasesDB 1505
eMedicine derm/54
MeSH D001816
GeneReviews
Orphanet 125

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, predisposition to the development of cancer and genomic instability.[5] BS is caused by mutations in the BLM gene leading to mutated DNA helicase protein formation. Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive crossovers between homologous chromosomes and sister chromatid exchanges (SCEs). The condition was discovered and first described by New York dermatologist Dr. David Bloom in 1954.[6]

Symptoms

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, it can appear across the nose, on the cheeks and around the lips. As well as these areas the rash will develop on any other sun-exposed areas including, the backs of the hands and neck. 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-pigmented and hyper-pigmented areas, cafe-au-lait spots, and telangiectasias (dilated blood vessels), which can appear on the skin and eyes. Moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes has also been related to BS, leading to recurrent pneumonia and ear infections.[7] 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.[8] Bloom syndrome shares some features with Fanconi anemia possibly because there is overlap in the function of the proteins mutated in this related disorder.[9]

Genetics

Bloom syndrome is an autosomal recessive disorder, caused by mutations in the maternally- and paternally-derived copies of the gene BLM.[10] As in other autosomal recessive conditions, the parents of an individual with Bloom syndrome do not necessarily exhibit any features of the syndrome. The mutations in BLM associated with Bloom syndrome are nulls and missense mutations that are catalytically inactive.[11] The cells from persons with Bloom syndrome exhibit a striking genomic instability that is characterized by hyper-recombination and hyper-mutation. Human BLM cells are sensitive to DNA damaging agents such as UV and methyl methanesulfonate,[12] indicating deficient repair capability. 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 fragmented chromosomes.[13] The hyper-recombination can also be detected by molecular assays [14] 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 in nucleoplasm and 0.13 at nucleoli [15] 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.

Relationship to cancer and aging

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.[16] 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.[8]

Pathophysiology

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 in 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

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. The US Food and Drug Administration (FDA) announced on February 19, 2015 that they have authorized marketing of a direct-to-consumer genetic test from 23andMe.[17] The test is designed to identify healthy individuals who carry a gene that could cause Bloom Syndrome in their offspring.[18]

Epidemiology

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.[19]

Bloom's Syndrome Registry

The Bloom's Syndrome Registry lists 265 individuals reported as suffering from this rare disorder (as of 2009), collected from the time it was first recognised in 1954. The registry was developed as a surveillance mechanism to observe the effects of cancer in the patients, which has shown 122[20] individuals have been diagnosed with cancer. As well as this it acts as a report to show current findings and data on all aspects of the disorder.[21]

See also

References

  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 18638Freely accessible. 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. ↑ Bischof, Oliver; Kim, Sahn-Ho; Irving, John; Beresten, Sergey; Ellis, Nathan A.; Campisi, Judith (16 April 2001). "Regulation and Localization of the Bloom Syndrome Protein in Response to DNA Damage". Journal of Cell Biology. 153: 367–380. doi:10.1083/jcb.153.2.367. Retrieved 17 April 2015.
  6. ↑ Bloom D (1954). "Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity". AMA American journal of diseases of children. 88 (6): 754–8. doi:10.1001/archpedi.1954.02050100756008. PMID 13206391.
  7. ↑ German, James M.D. (November 1993). "Bloom Syndrome: A Mendelian Prototype of Somatic Mutational Disease.". Medicine. 72: 393–406. doi:10.1097/00005792-199311000-00003. Retrieved 17 April 2015.
  8. 1 2 http://weill.cornell.edu/bsr/
  9. ↑ 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.
  10. ↑ Ellis NA, Groden J, Ye TZ, Straughen J, Ciocci S, Lennon DJ, Proytcheva M, Alhadeff B, German J (1995). "The Bloom's syndrome gene product is homologous to RecQ helicases". Cell. 83: 655–666. doi:10.1016/0092-8674(95)90105-1. PMID 7585968.
  11. ↑ German J, Ciocci S, Ye TZ, Sanz MM, Ellis NA (2007). "Syndrome-causing mutations at BLM in persons in the Bloom's Syndrome Registry". Hum Mutation. 28: 743–753. doi:10.1002/humu.20501. PMID 17407155.
  12. ↑ So S, Adachi N, Lieber MR, Koyama H (2004). "Genetic interactions between BLM and DNA ligase IV in human cells". J. Biol. Chem. 279 (53): 55433–42. doi:10.1074/jbc.M409827200. PMID 15509577.
  13. ↑ German J (Jan 1995). "Bloom's syndrome". Dermatol Clin. 13 (1): 7–18.
  14. ↑ Langlois RG, Bigbee WL, Jensen RH, German J (Jan 1989). "Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome". Proc Natl Acad Sci U S A. 86 (2): 670–4. doi:10.1073/pnas.86.2.670. PMC 286535Freely accessible. PMID 2911598.
  15. ↑ 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. 43: 509–16. doi:10.1007/s00249-014-0981-x. PMID 25119658.
  16. ↑ German J (Jan 1997). "Bloom's syndrome. XX. The first 100 cancers". Cancer Genet Cytogenet. 93 (1): 100–6. doi:10.1016/s0165-4608(96)00336-6.
  17. ↑ "FDA permits marketing of first direct-to-consumer genetic carrier test for Bloom syndrome". U.S. Food and Drug Administration. Retrieved 19 May 2015.
  18. ↑ Sanz, MM; German, J; Pagon, RA; Adam, MP; Bird, TD; Dolan, CR; Fong, CT; Stephens, K (1993). GeneReviews; Pagon RA; Adam MP; Bird TD; et al., eds. "Bloom's Syndrome". Seattle. PMID 20301572.
  19. ↑ Li L, Eng C, Desnick B, German J, Ellis NA (1998). "Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population". Mol Genet Metab. 64: 286–290.
  20. ↑ "Data from the Bloom's Syndrome Registry, 2009". Weill Cornell Medical College. Weill Cornell Medical Center. 2009. Retrieved 17 April 2015.
  21. ↑ German, James; Bloom, David; Passarge, Eberhard (23 April 2008). "Bloom's syndrome. V. Surveillance for cancer in affected families". Clinical Genetics. 12: 162–168. doi:10.1111/j.1399-0004.1977.tb00919.x. Retrieved 17 April 2015.

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