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 (in the literature, often abbreviated BS),[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]

Presentation[edit]

Bloom syndrome is a type of progeroid syndrome, and shows much of the common characteristics, such as short stature and a rash that develops early in life in sun-exposed areas of the skin. The skin rash is erythematous, telangiectatic, infiltrated, and scaly, and it appears in the butterfly-shaped patch of skin across the nose and on the cheeks. The 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, such as a long, narrow face, micrognathism, and prominent nose and ears; pigmentation changes of the skin including hypo- and hyper-pigmented areas and cafe-au-lait spots; 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, that apparently leads to recurrent pneumonia and ear infections; hypogonadism 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.

Complications of the disorder may include chronic lung problems, diabetes, and learning disabilities. In a small number of persons, there is mental retardation. The most striking complication of the disorder is susceptibility to cancer, as described in more detail in the next section.

Bloom syndrome shares many phenotypes with Fanconi anemia and this may be because of overlap in the function of the proteins mutated in this related disorder.[6]

Relationship to cancer[edit]

A greatly elevated rate of mutation in Bloom syndrome results in a high risk of cancer in affected individuals.[7] 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.[8] Persons with Bloom's syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 25 years old.

Pathophysiology[edit]

Mutations in the BLM gene (located at 15q26.1), which is a member of the RecQ DNA helicase family, are associated with Bloom syndrome. DNA helicases are enzymes that unwind the two strands of a duplex DNA molecule. DNA unwinding is required for most processes that involve the DNA, including synthesis of DNA copies, RNA transcription, DNA repair, etc.

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. The mutations in the BLM gene associated with Bloom's syndrome inactivate the BLM protein's DNA helicase activity or nullify protein expression (the protein is not made). 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.

Bloom syndrome is inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. The carrier frequency in individuals of Eastern European Jewish (Ashkenazi Jewish) ancestry is about 1/100. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. As a consequence of this inheritance, the syndrome affects males and females equally; however, females are perhaps slightly under-diagnosed as the skin lesion can be perhaps less severe in females. Genetic counseling and genetic testing is recommended for families who may be carriers of Bloom syndrome. For families in which carrier status is known, prenatal testing is available using cytogenetic or molecular methods. Molecular DNA testing for the mutation that is common in the Ashkenazi Jewish population is also available. There is currently no evidence to suggest that the symptoms of Bloom syndrome vary depending on the types of mutations a person inherits.

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.[9]

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. ^ 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. 
  7. ^ Amor-Guéret M (2006). "Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis". Cancer Lett. 236 (1): 1–12. doi:10.1016/j.canlet.2005.04.023. PMID 15950375. 
  8. ^ German J (1997). "Bloom's syndrome. XX. The first 100 cancers". Cancer Genet Cytogenet 93 (1): 100–106. doi:10.1016/S0165-4608(96)00336-6. PMID 9062585. 
  9. ^ 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]