|Classification and external resources|
Crystal structure of the Bloom's syndrome helicase BLM in complex with DNA (PDB ID: 4CGZ).
Bloom syndrome (often abbreviated as BS in literature), also known as Bloom–Torre–Machacek syndrome, is a rare autosomal recessive 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.
Bloom syndrome is inherited through an autosomal recessive pattern, meaning that both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition both carry one copy of the mutated gene. However, the parents typically do not show signs of symptoms of the condition. Because the gene does not function properly, this creates an unusually high number of breaks or instability along their chromosomes. Mutations in the BLM gene are what causes Bloom syndrome. The BLM gene is responsible for making a member of the protein family known as RecQ helicases. Helicases are enzymes that attach to DNA and temporarily unravel the double helix of the DNA molecule. This unraveling is essential for DNA replication in preparation for cell division and for the repair of the damaged DNA molecule. RecQ helicases maintain the structure of the DNA so therefore they are commonly known as ‘caretakers of the genome.’
Bloom syndrome is an extremely rare disorder in most populations and the frequency of the disease still remains unknown. However, the disorder is most common amongst people of Central and Eastern European (Ashkenazi) Jewish background. Approximately 1 in 48,000 Ashkenazi Jews are infected with Bloom syndrome, who account for about one-third of affected individuals worldwide.
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 on in life when areas of the skin are exposed to the sun. 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. 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, 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. Most individuals with Bloom syndrome are born with a low birth weight and this can cause further health complications. 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. Therefore, both men and women can inherit Bloom syndrome and are both are equally like to inherit this rare disease. Complications of the disorder may include chronic lung problems, diabetes, and learning disabilities. In a small number of persons, there is mental retardation. People with Bloom Syndrome also have a shortened life expectancy meaning that the average person live to approximately 24 years old. 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.
Relationship to cancer
A greatly elevated rate of mutation in Bloom syndrome results in a high risk of cancer in affected individuals. 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. Persons with Bloom's syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 15 years old.
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 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.
- Online 'Mendelian Inheritance in Man' (OMIM) Bloom Syndrome; BLM -210900
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- Bloom's Syndrome on GONUTS
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- Blooms Connect — a forum by and for people with Bloom's Syndrome and their loved ones
- Bloom's Syndrome Registry — research and information about Bloom's Syndrome
- Bloom's Syndrome Foundation — devoted to medical & scientific research to discover a treatment or cure for Bloom's Syndrome
- DNA Repair
- Segmental Progeria
- Bloom syndrome at NLM Genetics Home Reference