出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/28 15:56:03」(JST)
| Bloom syndrome | |
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Crystal structure of the Bloom's syndrome helicase BLM in complex with DNA (PDB ID: 4CGZ).
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| 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 |
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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]
Bloom syndrome is an autosomal recessive disorder, caused by mutations in the maternally- and paternally-derived copies of the gene BLM.[7] 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.[8] 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,[9] 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.[10] The hyper-recombination can also be detected by molecular assays [11] 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 [12] 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.
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.[13]
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.[14] 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.[15] Bloom syndrome shares some features with Fanconi anemia possibly because there is overlap in the function of the proteins mutated in this related disorder.[16]
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.[17] 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.[15]
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 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.[18] The test is designed to identify healthy individuals who carry a gene that could cause Bloom Syndrome in their offspring.[19]
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 affects 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]
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| リンク元 | 「癌」「ファンコニー貧血」「ブルーム症候群」 |
| 関連記事 | 「bloom」「syndrome」 |
| Neoplasm | Causes | Effect |
| Small cell lung carcinoma | ACTH or ACTH-like peptide | Cushing’s syndrome |
| Small cell lung carcinoma and intracranial neoplasms | ADH | SIADH |
| Squamous cell lung carcinoma, renal cell carcinoma, breast carcinoma, multiple myeloma, and bone metastasis (lysed bone) | PTH-related peptide, TGF-β, TNF-α, IL-1 | Hypercalcemia |
| Renal cell carcinoma, hemangioblastoma | Erythropoietin | Polycythemia |
| Thymoma, small cell lung carcinoma | Antibodies against presynaptic Ca2+ channels at neuromuscular junction | Lambert-Eaton syndrome (muscle weakness) |
| Leukemias and lymphomas | Hyperuricemia due to excess nucleic acid turnover (i.e., cytotoxic therapy) | Gout, urate nephropathy |
| ●2005年の死亡数が多い部位は順に | ||||||
| 1位 | 2位 | 3位 | 4位 | 5位 | ||
| 男性 | 肺 | 胃 | 肝臓 | 結腸 | 膵臓 | 結腸と直腸を合わせた大腸は4位 |
| 女性 | 胃 | 肺 | 結腸 | 肝臓 | 乳房 | 結腸と直腸を合わせた大腸は1位 |
| 男女計 | 肺 | 胃 | 肝臓 | 結腸 | 膵臓 | 結腸と直腸を合わせた大腸は3位 |
| ●2001年の罹患数が多い部位は順に | ||||||
| 1位 | 2位 | 3位 | 4位 | 5位 | ||
| 男性 | 胃 | 肺 | 結腸 | 肝臓 | 前立腺 | 結腸と直腸を合わせた大腸は2位 |
| 女性 | 乳房*1 | 胃 | 結腸 | 子宮*1 | 肺 | 結腸と直腸を合わせた大腸は1位 |
| 男女計 | 胃 | 肺 | 結腸 | 乳房*1 | 肝臓 | 結腸と直腸を合わせた大腸は2位 |
| *1上皮内がんを含む。 | ||||||
| Table 79-1 Cancer Predisposition Syndromes and Associated Genes | ||||
| Syndrome | Gene | Chromosome | Inheritance | Tumors |
| ataxia telangiectasia | ATM | 11q22-q23 | AR | breast cancer |
| autoimmune lymphoproliferative syndrome | FAS | 10q24 | AD | lymphomas |
| FASL | 1q23 | |||
| Bloom syndrome | BLM | 15q26.1 | AR | cancer of all types |
| Cowden syndrome | PTEN | 10q23 | AD | breast, thyroid |
| familial adenomatous polyposis | APC | 5q21 | AD | intestinal adenoma, colorectal cancer |
| familial melanoma | p16INK4 | 9p21 | AD | melanoma, pancreatic cancer |
| familial Wilms tumor | WT1 | 11p13 | AD | pediatric kidney cancer |
| hereditary breast/ovarian cancer | BRCA1 | 17q21 | AD | breast, ovarian, colon, prostate |
| BRCA2 | 13q12.3 | |||
| hereditary diffuse gastric cancer | CDH1 | 16q22 | AD | stomach cancers |
| hereditary multiple exostoses | EXT1 | 8q24 | AD | exostoses, chondrosarcoma |
| EXT2 | 11p11-12 | |||
| hereditary prostate cancer | HPC1 | 1q24-25 | AD | prostate carcinoma |
| hereditary retinoblastoma | RB1 | 13q14.2 | AD | retinoblastoma, osteosarcoma |
| hereditary nonpolyposis colon cancer (HNPCC) | MSH2 | 2p16 | AD | colon, endometrial, ovarian, stomach, small bowel, ureter carcinoma |
| MLH1 | 3p21.3 | |||
| MSH6 | 2p16 | |||
| PMS2 | 7p22 | |||
| hereditary papillary renal carcinoma | MET | 7q31 | AD | papillary renal tumor |
| juvenile polyposis | SMAD4 | 18q21 | AD | gastrointestinal, pancreatic cancers |
| Li-Fraumeni | TP53 | 17p13.1 | AD | sarcoma, breast cancer |
| multiple endocrine neoplasia type 1 | MEN1 | 11q13 | AD | parathyroid, endocrine, pancreas, and pituitary |
| multiple endocrine neoplasia type 2a | RET | 10q11.2 | AD | medullary thyroid carcinoma, pheochromocytoma |
| neurofibromatosis type 1 | NF1 | 17q11.2 | AD | neurofibroma, neurofibrosarcoma, brain tumor |
| neurofibromatosis type 2 | NF2 | 22q12.2 | AD | vestibular schwannoma, meningioma, spine |
| nevoid basal cell carcinoma syndrome (Gorlin's syndrome) | PTCH | 9q22.3 | AD | basal cell carcinoma, medulloblastoma, jaw cysts |
| tuberous sclerosis | TSC1 | 9q34 | AD | angiofibroma, renal angiomyolipoma |
| TSC2 | 16p13.3 | |||
| von Hippel–Lindau | VHL | 3p25-26 | AD | kidney, cerebellum, pheochromocytoma |
| 疾患 | 危険因子 | 防御因子 | |
| 悪性腫瘍 | 胃癌 | 塩辛い食品、喫煙、くん製製品、ニトロソアミン土壌、腸上皮化生、Helicobacter pyroli | ビタミンC、野菜、果実 |
| 食道癌 | 喫煙、飲酒、熱い飲食物 | 野菜、果実 | |
| 結腸癌 | 高脂肪食、肉食、低い身体活動、腸内細菌叢の変化、遺伝(家族性大腸腺腫症) | ||
| 肝癌 | HBVキャリア・HCVキャリア、アフラトキシン、住血吸虫、飲酒 | ||
| 肺癌 | 喫煙(特に扁平上皮癌)、大気汚染、職業的暴露(石綿(扁平上皮癌、悪性中皮腫)、クロム) | 野菜、果実 | |
| 膵癌 | 高脂肪食、喫煙 | ||
| 口腔癌 | 喫煙(口唇・舌-パイプ)、ビンロウ樹の実(口腔、舌)、飲酒 | ||
| 咽頭癌 | EBウイルス(上咽頭癌)、飲酒 | ||
| 喉頭癌 | 喫煙、男性、アルコール | ||
| 乳癌 | 高年初産、乳癌の家族歴、肥満、未婚で妊娠回数少ない、無授乳、脂肪の過剰摂取、低年齢初経、高年齢閉経 | 母乳授乳 | |
| 子宮頚癌 | 初交年齢若い、早婚、多産、性交回数が多い(売春)、貧困、不潔]、HSV-2、HPV、流産、人工妊娠中絶回数が多い | ||
| 子宮体癌 | 肥満、糖尿病、ピル、エストロゲン常用、未婚、妊娠回数少ない、乳癌後のタモキシフエン内服 | ||
| 膀胱癌 | 喫煙、鎮痛剤乱用、ビルハルツ住血吸虫、サッカリン、防腐剤 | ||
| 皮膚癌 | 日光(紫外線)、ヒ素(Bowen病) | ||
| 白血病 | 放射線、ベンゼン、地域集積性(ATL)、ダウン症(小児白血病) | ||
| 骨腫瘍 | 電離放射線 | ||
| 甲状腺癌 | ヨード欠乏または過剰 | ||
ファンコニ貧血 : 約 3,560 件 ファンコニ貧血症 : 55 件 ファンコーニ貧血 : 約 1,830 件 ファンコーニ貧血症 : 13 件 ファンコニー貧血 : 約 30,000 件 ファンコニー貧血症 : 35 件
| FAMILIAL CANCER SYNDROME AR: DNA repair abnormalities |
| xeroderma pigmentosum |
| Fanconi's anemia |
| ataxia telangiectasia |