Bloom syndrome is an autosomal recessive disorder characterized by proportionate pre- and postnatal growth deficiency; sun-sensitive, telangiectatic, hypo- and hyperpigmented skin; predisposition to malignancy; and chromosomal instability.
Landau et al. (1966) described a patient whose parents were second cousins and who showed low gamma-A and gamma-M serum proteins.
German et al. (1984) collected information on 103 patients. German and Takebe (1989) suggested that differences ...Landau et al. (1966) described a patient whose parents were second cousins and who showed low gamma-A and gamma-M serum proteins. German et al. (1984) collected information on 103 patients. German and Takebe (1989) suggested that differences in skin pigmentation in various ethnic groups may confer a degree of protection against actinic radiation and thus obscure one of the characteristic facial signs of Bloom syndrome, i.e., telangiectasia. As a result, Bloom syndrome may be underdiagnosed in some populations. Legum et al. (1991) described an affected Iranian Jewish male, possibly the first definite non-Ashkenazi Jewish patient. The patient had another unique complication, cardiomyopathy. Ferrara et al. (1967) described the disease in a 'Chinese-American'; however, the diagnosis was later (Ferrara, 1972) revised to focal dermal hypoplasia (305600). The 14 Japanese cases reported by German and Takebe (1989) differed somewhat from most cases recognized elsewhere in that dolichocephaly was a less constant feature, the facial skin lesions were less prominent, and life-threatening infections were less frequent. The characteristic predisposition to neoplasia, as well as the probable tendency to diabetes mellitus, was found, however. German (1990) stated that diabetes mellitus of maturity-onset type, developing, however, in the second or third decade, is proving to be a frequent feature. Mori et al. (1990) reported diabetes mellitus in Bloom syndrome. Kelly (1977) observed a case of Bloom syndrome in a black female. German (Szalay, 1978) confirmed the diagnosis of Bloom syndrome in the black female reported by Szalay (1972). German (1988) stated that the longest survival known to him is that of a man who died of esophageal cancer at the age of 48 years, having survived sigmoid cancer which had occurred 10 years earlier. Almost 150 cases worldwide have been cataloged by German (1990); he has personally examined 96 of these patients. Jewish patients represent 32% of the group, all but 1 of them being Ashkenazi. Complementation studies using sister chromatid exchange (SCE) as the measure of cross-correction indicate that this is one disease. Parental consanguinity was identified in 2 of 36 Jewish cases and in 25 of 75 non-Jewish cases. Heterozygotes do not show increased sister chromatid exchanges. German (1990) has not found an increased frequency of cancer in obligatory heterozygotes. Passarge (1991) observed 10 patients in Germany during a 20-year period. One patient died at the age of 5 years of acute leukemia, a second at the age of 18 years of pulmonary fibrosis and bronchiectasis, and a third at the age of 21 years of Hodgkin lymphoma and subsequently leukemia. German (1992) reported that there were 132 cases in the Bloom's Syndrome Registry as of January 1, 1990. One hundred and twenty seven had survived infancy. In all, 93 were still alive. Of the 39 deceased patients, 31 had died of cancer at a mean age of 27.8; cancer had been diagnosed at ages ranging from 4 years to 46 years. Of the 46 cancer patients, 14 had more than 1 primary, 2 had more than 2 primaries, and 1 had more than 3 primaries. Chisholm et al. (2001) reported a 19-year-old woman with typical clinical features of Bloom syndrome with a successful pregnancy. Because of her small pelvis on clinical examination, the patient underwent computed tomography pelvimetry, which showed adequate pelvic capacity. Preterm labor occurred at 32 weeks' gestation, and the infant was ultimately delivered at 35 weeks' gestation. The infant was less than the tenth percentile for length and weight for gestational age, but was otherwise healthy. Since preterm labor had occurred in this and a previously reported pregnancy in Bloom syndrome (Mulcahy and French, 1981), Chisholm et al. (2001) suggested increased surveillance for preterm labor in pregnancies of women with Bloom syndrome
Willis and Lindahl (1987) and Chan et al. (1987) independently demonstrated an abnormality of DNA ligase I (126391) in Bloom syndrome. DNA ligase I and DNA polymerase alpha (312040) are enzymes that function during DNA ...- Phenotype/Genotype Willis and Lindahl (1987) and Chan et al. (1987) independently demonstrated an abnormality of DNA ligase I (126391) in Bloom syndrome. DNA ligase I and DNA polymerase alpha (312040) are enzymes that function during DNA replication; DNA ligase II and DNA polymerase beta (174760) function during DNA repair. That the primary defect resides in the structural gene for DNA ligase I was suggested by the changes in the physical properties of the enzyme, specifically, heat sensitivity (Willis and Lindahl, 1987) and altered aggregation properties (Chan et al., 1987). Experiments with a fibroblast line derived from a Japanese case of Bloom syndrome showed that DNA ligase I from that source was not obviously heat sensitive or present in reduced amounts. Chan and Becker (1988) also came to the conclusion that mutation of the DNA ligase I gene may account for the primary metabolic defect in Bloom syndrome. Their data suggested that the defect in DNA ligase I is not due to a reduction in the number of protein molecules or to inhibitory substances but rather, at least in part, to the ATP binding and/or hydrolytic activity of the enzyme. Willis et al. (1987) found that all cell lines derived from 7 patients with Bloom syndrome contained a DNA ligase I with unusual properties. In 6 lines the enzyme activity was reduced and the residual enzyme was anomalously heat-labile. In the seventh line, they found a dimeric rather than a monomeric form of ligase I. Several cell lines representative of other inherited disorders had apparently normal DNA ligases. The data were interpreted as indicating that BLM is due to a defect in the structure of DNA ligase I caused by a 'leaky' point mutation occurring at one of at least 2 alternative sites. If the primary defect lies in the structural gene for DNA ligase I, then Barnes et al. (1990) reasoned that the mutation for Bloom syndrome is on chromosome 19, which encodes DNA ligase I. Since alteration of the DNA ligase I activity is a consistent biochemical feature of Bloom syndrome cells, Petrini et al. (1991) cloned DNA ligase I cDNA from normal human cells. Human DNA ligase I cDNAs from normal and BS cells complemented an S. cerevisiae DNA ligase mutation, and protein extracts prepared from S. cerevisiae transformants expressing normal and BS cDNA contained comparable levels of DNA ligase I activity. DNA sequencing and Northern blot analysis of DNA ligase I expression in 2 BS fibroblast lines representing each of 2 aberrant DNA ligase I molecular phenotypes demonstrated that the gene was unchanged in BS cells. Thus, a factor other than mutation in the ligase I gene must be involved as the basic defect. Nicotera et al. (1989) suggested that the major biochemical defect in Bloom syndrome is chronic overproduction of the superoxide radical anion. They thought that inefficient removal of peroxide might be responsible for high rates of sister chromatid exchange and chromosomal damage in Bloom syndrome cells. Seal et al. (1988) described a monoclonal antibody, defined by enzyme-linked immunosorbent assay (ELISA), that reacted with normal uracil DNA glycosylase (191525) of human placenta as well as with the glycosylases from normal human cell types and 13 abnormal human cell strains. On the other hand, the antibody neither recognized nor inhibited native uracil DNA glycosylase from any of 5 separate Bloom syndrome cell strains. Lack of immunoreactivity with this antibody, which the authors designated 40.10.09, was suggested as a test for the early diagnosis of Bloom syndrome. Cairney et al. (1987) described Wilms tumor in 3 patients with Bloom syndrome. Wilms tumor was bilateral in 1 of the 3 patients. Cairney et al. (1987) postulated that the elevated somatic recombination may mediate a high rate of conversion to homozygosity. Somatic recombination leading to homozygosity in Bloom syndrome has been suggested by several findings, including 'twin spots' or areas of hyper- and hypopigmentation on the skin of affected black children (Festa et al., 1979), increased frequency of exchange between the satellite stalks of acrocentric chromosomes (Therman et al., 1981), and increased variant blood group phenotypes in red cells from a patient with Bloom syndrome who was heterozygous for the AB blood group (Ben-Sasson et al., 1985). Petrella et al. (1991) observed autosomal triple trisomy involving chromosomes 2, 8, and 11 in a pregnancy conceived by a couple at risk for an offspring with Bloom syndrome. The SCE rate suggested that the conceptus was either heterozygous for the Bloom syndrome mutation or homozygous normal. They also found the Bloom syndrome gene in a non-Ashkenazi Jew and reported medulloblastoma in a patient with Bloom syndrome. The hypermutability of Bloom syndrome cells includes hyperrecombinability. Ellis et al. (1995) noted that although cells from all persons with Bloom syndrome exhibit the diagnostic high SCE rate, in some persons a minor population of low SCE lymphocytes exist in the blood. Lymphoblastoid cell lines (LCLs) with low SCE rates can be developed from these low SCE lymphocytes. In multiple low SCE LCLs examined from 11 patients with BS, polymorphic loci distal to BLM on 15q had become homozygous in LCLs from 5 persons, whereas polymorphic loci proximal to BLM remained heterozygous in all low SCE LCLs. These observations supported the hypothesis that low SCE lymphocytes arose through recombination within BLM in persons with BS who had inherited paternally and maternally derived BLM alleles mutated at different sites. Such a recombination event in a precursor stem cell in these compound heterozygotes thus gave rise to a cell whose progeny had a functionally wildtype gene and phenotypically a low SCE rate (Ellis et al., 1995). Ellis et al. (1995) used the low SCE LCLs in which reduction to homozygosity had occurred for localizing BLM by an approach referred to as somatic crossover point (SCP) mapping. The precise map position of BLM was determined by comparing the genotypes of the recombinant low SCE LCLs from the 5 persons mentioned above with their constitutional genotypes at loci in the region around BLM. The strategy was to identify the most proximal polymorphic locus possible that was constitutionally heterozygous and that had been reduced to homozygosity in the low SCE LCLs, and to identify the most distal polymorphic locus possible that had remained constitutionally heterozygous in them. BLM would have to be in the short interval defined by the reduced (distal) and the unreduced (proximal) heterozygous markers. The power of this approach was limited only by the density of polymorphic loci available in the immediate vicinity of BLM. A candidate for BLM was identified by direct selection of a cDNA derived from a 250-kb segment of the genome to which BLM had been assigned by SCP mapping. cDNA analysis of the candidate gene identified a 4437-bp cDNA that encoded a 1417-amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases (RECQL3; 604610). The presence of chain-terminating mutations in the candidate gene in persons with Bloom syndrome proved that it was BLM. Mutational analysis in the first 13 unrelated persons with BS examined permitted the identification of 7 unique mutations in 10 of them. The fact that 4 of the 7 mutations resulted in premature termination of translation indicated that the cause of most Bloom syndrome is the loss of enzymatic activity of the BLM gene product. Identification of loss-of-function mutations in BLM is consistent with the autosomal recessive transmission, and the homology of BLM and RecQ suggested that BLM has enzymatic activity. In 4 persons with Jewish ancestry, a 6-bp deletion and a 7-bp insertion at nucleotide 2281 were identified, and each of the 4 persons were homozygous for the mutation (604610.0001). Homozygosity was predictable because linkage disequilibrium had been detected in Ashkenazi Jews with Bloom syndrome between BLM, D15S127, and FES (Ellis et al., 1994). Thus a person who carried this deletion/insertion mutation was a founder of Ashkenazi Jewish population and nearly all Ashkenazi Jews with Bloom syndrome inherited the mutation identical by descent from this common ancestor. The RecQ gene family, of which BLM is a member, is named after the E. coli gene. RecQ is an E. coli gene that is a member of the RecF recombination pathway, a pathway of genes in which mutations abolish the conjugational recombination proficiency and ultraviolet resistance of a mutant strain. RecQL (600537) is a human gene isolated from HeLa cells, the product of which possesses DNA-dependent ATPase, DNA helicase, and 3-prime-to-5-prime single-stranded DNA translocation activities. Ellis et al. (1995) suggested that the absence of the BLM gene product probably destabilizes other enzymes that participate in DNA replication and repair, perhaps through direct interaction and through more general responses to DNA damage. Ellis and German (1996) reported that the BLM protein has similarity to 2 other proteins that are members of the RecQ family of helicases, namely the gene product encoded by the Werner syndrome gene (WRN; 277700) and the product of the yeast gene SGS1. SGS1 was identified by a mutation that suppressed the slow-growth phenotype of mutations in the topoisomerase gene. These proteins have 42 to 44% amino acid identity across the conserved helicase motifs. In addition, the proteins are of similar length and contain highly negatively charged N-terminal regions and highly positively charged C-terminal regions. Ellis and German (1996) noted that these similarities in overall structure have raised the possibility that the proteins play similar roles in metabolism. Since the SGS1 gene product is known to interact with the products of the yeast topoisomerase genes, they predicted that the BLM and WRN genes interact with human topoisomerases. Sinclair et al. (1997) showed that mutation of the yeast SGS1 gene causes premature aging in yeast mother cells as demonstrated by shortened life span and the aging-induced phenotypes of sterility and redistribution of the Sir3 silencing protein from telomeres to the nucleolus. Further, in old SGS1 cells the nucleolus was enlarged and fragmented, changes that also occur in old wildtype cells. Their findings suggested a conserved mechanism of cellular aging that may be related to nucleolar structure. The similar effect of the related SGS1 and WRN genes on yeast and human aging, along with age-associated changes in rDNA content reported for several mammalian species, suggested that a common mechanism may underlie aging in eukaryotes. Men with Bloom syndrome are sterile; women have reduced fertility and a shortened reproductive span. In an immunocytologic study of mouse spermatocytes, Walpita et al. (1999) showed that the BLM protein is first evident as discrete foci along the synaptonemal complexes of homologously synapsed autosomal bivalents in late zygonema of meiotic prophase. BLM foci progressively dissociated from the synapsed autosomal axes during early pachynema and were no longer seen in mid-pachynema. BLM colocalized with the single-stranded DNA-binding replication protein A (see 179835), which had been shown to be involved in meiotic synapsis. However, there was a temporary delay in the appearance of BLM protein along the synaptonemal complexes relative to replication protein A, suggesting that BLM is required for a late step in processing of a subset of genomic DNA involved in establishment of interhomolog interactions in early meiotic prophase. In late pachynema and into diplonema, BLM is more dispersed in the nucleoplasm, especially over the chromatin most intimately associated with the synaptonemal complexes, suggesting a possible involvement of BLM in resolution of interlocks in preparation for homologous chromosome disjunction during anaphase I. Ellis et al. (1999) described the effects on the abnormal cellular phenotype of BS, namely an excessive rate of SCE, when normal BLM cDNA was stably transfected into 2 types of BS cells, SV40-transformed fibroblasts and Epstein-Barr virus-transformed lymphoblastoid cells. The experiments proved that BLM cDNA encodes a functional protein capable of restoring to or toward normal the uniquely characteristic high-SCE phenotype of BS cells. In a patient with Bloom syndrome and both high- and low-SCE cell lines, Foucault et al. (1997) identified compound heterozygosity for a cys1036-to-phe (C1036F; 604610.0004) substitution in the C-terminal region of the peptide and an unidentified mutation affecting expression of the RECQL3 gene. Foucault et al. (1997) concluded that somatic intragenic recombination resulted in cells that had an untranscribed allele carrying the 2 parental RECQL3 mutations and a wildtype allele which allowed reversion to the low-SCE phenotype. Topoisomerase II-alpha (126430) mRNA and protein levels were decreased in the high-SCE cells, whereas they were normal in the corresponding low-SCE cells. Foucault et al. (1997) proposed that in addition to its putative helicase activity, RECQL3 might be involved in transcription regulation
Bloom’s syndrome (referred to as BSyn in this GeneReview) [German & Ellis 2002] should be considered in the following:...
DiagnosisClinical DiagnosisBloom’s syndrome (referred to as BSyn in this GeneReview) [German & Ellis 2002] should be considered in the following:An individual with unexplained, severe intrauterine growth deficiency that persists into infancy, childhood, and adulthoodAn unusually small, but roughly normally proportioned individual with the appearance after sun exposure of an erythematous skin lesion in the “butterfly area” of the face An unusually small individual who develops cancer TestingThe clinical diagnosis of, or suspicion of, BSyn can and must be confirmed by cytogenetic and/or molecular analysis of BLM, the gene in which mutations are known to cause BSyn. A sister chromatid exchange (SCE) analysis has become the standard test by which the clinical diagnosis of BSyn is confirmed.Cytogenetic analysis. The diagnosis of BSyn can be confirmed or ruled out by analysis of any cell type that can be cultured in vitro. The most commonly examined cells are blood lymphocytes in short-term culture; cultured skin fibroblasts and exfoliated fetal cells can also be studied. The cytogenetic features of BSyn cells in mitosis are increased numbers of the following:Chromatid gaps, breaks, and rearrangementsQuadriradial configurations (Qrs); a mean of 1%-2% in cultured BSyn blood lymphocytes (vs. none in the controls) Sister-chromatid exchanges (SCEs); a mean of 40-100 per metaphase (vs. <10 in controls). A greatly increased frequency of SCEs is demonstrable in BSyn cells allowed to proliferate in a medium containing 5’bromo-2’-deoxyuridine (BrdU). BSyn is the only disorder in which such evidence of hyper-recombinability is known to occur. In an individual with BSyn the mean and range of SCEs per metaphase are higher in lymphocytes than in fibroblasts, but the differences from controls in both types of cells are so great that interpretation of findings is not a problem (i.e., the normal and abnormal ranges do not overlap significantly). Note: In a minority of persons with BSyn, varying numbers of lymphocytes with normal SCE rates circulate in the blood alongside cells with the characteristically greatly increased SCE frequency and presumably are the result of mutation back to normal in a stem cell. In theory, low (normal) SCE cells could predominate, even to the exclusion of the high-SCE cells. Therefore, when the clinical phenotype of an individual strongly suggests the diagnosis of BSyn and when no lymphocytes freshly removed from the circulation display the high number of SCEs per metaphase characteristic of BSyn, cytogenetic examination of cultured dermal fibroblasts may be necessary; low (i.e., normal) rates of SCE in fibroblasts have never been found in an individual with BSyn.Molecular Genetic TestingGene. BLM is the only gene in which mutations are known to cause BSyn. Mutations in BLM have been identified in the vast majority of persons with BSyn who have been appropriately tested. There are very few instances of affected individuals in whom BLM mutation(s) were not identified; these instances probably were attributable to technical limitations.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Bloom’s SyndromeView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityBLMTargeted mutation analysisc.2207_2212delinsTAGATTC 2100% 3Clinical Sequence analysisMultiple BSyn-causing mutations 490%Deletion / duplication analysis 5Exonic and whole gene deletionsUnknown 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. The predominant BSyn-causing mutation identified in Ashkenazi Jews with BSyn (and in ~1% of unaffected Ashkenazi Jews) is c.2207_2212delinsTAGATTC, a 6-bp deletion along with a 7-bp insertion in exon 10 of BLM. Often for brevity, this mutation is designated blmAsh [Ellis et al 1998].3. In Ashkenazi Jewish individuals. Its frequency varies in individuals of other ancestry, as shown in Table 2. 4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. German et al [2007]Table 2 summarizes by Jewish vs non-Jewish parental ancestry the results of BLM mutational analysis in 137 persons with BSyn, each from a different family [German & Ellis 2002; Bloom's Syndrome Registry, unpublished data]. Table 2. Results of Molecular Genetic Testing in 137 Persons with Bloom's SyndromeView in own windowPersons with Bloom’s SyndromeNumber of Persons Having the Indicated Genotype 1Parental Ancestry 2Number 3blmAsh/blmAshdupT/blmAshblmAsh/mutxmutx/mutxmutx/––/–A/A282620000A/J2101000A/N5005000J/J1000001N/N1013 4 02 4 7989German et al [2007] blmAsh = c.2207_2212delinsTAGATTC A = Ashkenazi Jewish J = Jewish, but not Ashkenazi N = Non-Jewish A/A = Both parents are Ashkenazi Jewish. A/J = One parent is Ashkenazi Jewish and one parent is Jewish but not Ashkenazi. A/N = One parent is Ashkenazi Jewish and one parent is non-Jewish. J/J = Both parents are Jewish, but not Ashkenazi. N/N = Neither parent is Jewish.dupT = c.2407dupTmutx = any of the 62 BSyn-causing mutations so far identified other than blmAsh and c.2407dupT– = no BSyn-causing mutation identified 1. The number of persons with BSyn comprising the parental ancestry group indicated2. Technical limitation is probably the explanation for failure to detect one or either of the BSyn-causing mutations in BLM in 18 persons. 3. The parental ancestry of persons with BSyn with identified BSyn-causing mutations in BLM [Bloom’s Syndrome Registry] 4. Those in the N/N parental ancestry group who are homozygous or compound heterozygotes for blmAsh are from one particular geographic area that once was part of Spain's Nueva España (Central America, Mexico, and the US Southwest) [Ellis et al 1998]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis Bloom’s syndrome Cytogenetic demonstration of a characteristically greatly increased SCE frequency OR Molecular demonstration either of homozygosity for a BSyn-causing mutation in BLM or of compound heterozygosity for two different BSyn-causing mutations. Sequence analysis should be performed first. If neither or only one mutation in BLM is identified, deletion/duplication analysis should be considered.Carrier testing for at-risk relatives requires prior identification of the BLM disease-causing mutations in the family. Note: Heterozygotes (i.e., carriers of a BLM disease-causing mutation) exhibit no features of BSyn. Population screening. Because of a carrier rate of approximately 1% for the blmAsh allele in Ashkenazi Jews, individuals who are Ashkenazi Jewish and of reproductive age may choose to be tested [ACOG Committee on Genetics 2009]. Prenatal diagnosis of at-risk pregnancies is possible by cytogenetic analysis, specifically by an SCE analysis.Prenatal diagnosis by molecular genetic testing and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the BLM disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with mutations in BLM.
Homozygotes and compound heterozygotes. A similar phenotype is produced by either homozygosity or compound heterozygosity for any of the more than 60 mutations in BLM identified so far. ...
Genotype-Phenotype CorrelationsHomozygotes and compound heterozygotes. A similar phenotype is produced by either homozygosity or compound heterozygosity for any of the more than 60 mutations in BLM identified so far. Heterozygotes. Carriers of a single BSyn-causing BLM mutation (heterozygotes) are normally developed and healthy. The cancer risk to heterozygotes as a group and specifically to those carrying various classes of BSyn-causing BLM mutations has yet to be determined.
A greatly elevated SCE rate distinguishes Bloom’s syndrome (BSyn) from all other clinical disorders, notably Russell-Silver syndrome, and specifically those that feature small stature and evidence of excessive genomic instability, including the following: ...
Differential DiagnosisA greatly elevated SCE rate distinguishes Bloom’s syndrome (BSyn) from all other clinical disorders, notably Russell-Silver syndrome, and specifically those that feature small stature and evidence of excessive genomic instability, including the following: Fanconi anemiaAtaxia-telangiectasia (AT) AT-like syndrome Werner syndrome Nijmegen breakage syndrome Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To evaluate an individual newly diagnosed with Bloom’s syndrome (BSyn) the following are recommended in addition to the routine case history (including family history) and physical examination:...
ManagementEvaluations Following Initial DiagnosisTo evaluate an individual newly diagnosed with Bloom’s syndrome (BSyn) the following are recommended in addition to the routine case history (including family history) and physical examination:Evaluation for gastroesophageal reflux and micro-aspirations into the lung of gastric contentsFasting blood glucose determination, both at the time of diagnosis and annually thereafterDetermination of plasma immunoglobulin concentrationsObservation of urination for evidence of urethral obstructionIf diagnosis occurs in adulthood, colonoscopy and stool guaiac at the time of diagnosisMedical genetics consultationTreatment of ManifestationsPsychosocial. Family and teachers are encouraged to relate to persons with BSyn appropriately for their chronologic age rather than the (younger) age suggested by their unusually small size. Growth. Growth hormone administration to children with BSyn has increased neither growth rate nor adult height. Supplemental feeding by intubation results in increased fat deposition but not in improved linear growth. Diabetes mellitus. Treatment of diabetes mellitus in BSyn is the same as in other persons. Cancer. The hypersensitivity of persons with BSyn to both DNA-damaging chemicals and ionizing radiation ordinarily necessitates modification of standard cancer treatment regimens, often a reduction of both dosages and durations. Information as to the ideal dosages being unavailable makes such treatment particularly challenging to the physician; nevertheless, that the cancers themselves often appear unusually responsive to the treatment justifies the special effort. SurveillanceFamilies benefit from counseling regarding the risk of cancer, a serious risk for all but clearly a much greater one for persons with BSyn. The wide variety of types and sites of cancer in BSyn, plus the unusually early onset of the so-called solid tumors (carcinomas and sarcomas), makes surveillance for cancer a life-long undertaking, requiring planning and cooperation among the affected person, the family, and the physician in charge (see Note). In persons younger than age 20 years, leukemia is the main type of cancer. Until evidence becomes available that treatment at the earliest stages of leukemia is more effective than treatment after full-blown symptoms appear, hematologic surveillance other than that used in general pediatrics appears unnecessary, if not contraindicated. Close contact between individuals age 20 years and older and their physicians is advisable, and symptoms that cannot be accounted for otherwise should be evaluated promptly as potential early indicators of cancer. Screening for colon cancer, the most common single “solid tumor” in individuals with BSyn (see Table 3), should begin decades earlier than in others, and should be carried out more frequently. In adults, colon cancer screening may include colonoscopy every one to two years, and stool guaiac testing for blood every three to six months. Note: Medical personnel caring for persons with BSyn (including those cooperating in devising and carrying out programs of surveillance for several of the serious medical complications seen in BSyn) need to resort to medical literature other than standard textbooks of internal medicine and pediatrics because coverage of BSyn in standard textbooks is as yet minimal. Agents/Circumstances to AvoidSun exposure to the face, particularly in infancy and early childhood, should be avoided.Evaluation of Relatives at RiskAn unusually low birth weight followed by short stature throughout childhood readily identifies affected sibs; sibs of normal stature are unaffected and need not be subjected to cytogenetic analysis.See Genetic Counseling for issues related to the testing of at-risk relatives for genetic counseling purposes. Therapies Under Investigation Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. OtherBone marrow transplantation (BMT). Too few persons with BSyn have had BMT to permit conclusions as to its value (which in theory could be great). The required ablative therapy prior to BMT often may require modification of standard protocols because of the hypersensitivity of persons with BSyn to DNA-damaging agents.Growth. Feeding through indwelling tubes into the upper gastrointestinal tract during infancy and early childhood has been shown to increase fat deposition but not linear growth.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Bloom's Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDBLM15q26.1Bloom syndrome proteinResource of Asian Primary Immunodeficiency Diseases (RAPID) BLM homepage - Mendelian genesBLMData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Bloom's Syndrome (View All in OMIM) View in own window 210900BLOOM SYNDROME; BLM 604610RECQ PROTEIN-LIKE 3; RECQL3Molecular Genetic PathogenesisBloom’s syndrome (BSyn) is the prototype of the class of human diseases sometimes referred to as the chromosome breakage syndromes [German 1969]. These include BSyn, Fanconi anemia, ataxia-telangiectasia, the AT-like syndrome, the Nijmegen breakage syndrome, and Werner syndrome. These clinically disparate disorders are caused by mutations in genes encoding enzymes comprising pathways of DNA replication and repair that are responsible for the maintenance of genomic stability. In all of these disorders, the diagnostic cytogenetic abnormalities are accompanied by an increased rate of spontaneous mutations in somatic cells. This hypermutability explains the cancer predisposition shared by these disorders. Normal allelic variants. A 4,528-bp cDNA sequence defines BLM, which contains a long open reading frame encoding a 1,417-amino acid protein, BLM. BLM comprises 22 exons and is located at chromosome band 15q26.1. Seventeen normal allelic variants without apparent clinical effect have been reported [German et al 2007; Bloom's Syndrome Registry, unpublished data].Pathologic allelic variantsMost individuals of Ashkenazi Jewish heritage with BSyn have the mutation c.2207_2212delinsTAGATTC (Table 4) [Ellis et al 1998]. A second rarer mutation segregating in the Ashkenazi Jewish population, c.2407dupT, has been identified [Ellis et al 1998, German et al 2007]. The 64 mutations identified in a study comprising 137 individuals with BSyn fall into the following four broad classes [German et al 2007]: Nucleotide insertions and deletions that result in frameshifts and elimination of the C-terminus of the protein where the nuclear localization signals of BLM are located; BLM therefore is absent from the nucleus (~1/3 of all mutations). Nonsense mutations that convert sense codons to nonsense or chain-terminating codons that predict translation of a truncated BLM protein (~1/3 of all mutations) Intron mutations that cause splicing defects (~1/6 of all mutations)Missense mutations that result in the production of non-functional BLM protein (~1/6 of all mutations)Table 4. BLM Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.2207_2212delinsTAGATTC 2(2281del6/ins7) (blmAsh)p.Tyr736Leufs*5 2NM_000057.2 NP_000048.1c.2407dupT (insT2407)p.Trp803Leufs*4See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Also known as the blmAsh alleleSee Table 5 (pdf) for BSyn-causing mutations identified in registered persons of various nationalities and ethnic groups. Normal gene product. The 1417-amino-acid protein named BLM contains an amino acid domain consisting of seven motifs characteristic of DNA and RNA helicases. The helicase domain of BLM is 40%-45% identical to the helicase domain in the RecQ subfamily of DNA helicases and is known to be important in other species for the maintenance of genomic integrity. BLM is a cell cycle-regulated protein that is distributed diffusely throughout the nucleus but also is concentrated in nuclear foci, many of which have been identified as PML (promyelocytic leukemia protein) bodies [Sanz et al 2000]. DNA-dependent ATPase and DNA duplex-unwinding activities have been demonstrated for BLM; the nucleic acid substrates that it acts upon in the cell remain to be identified. Molecular and genetic evidence implicates BLM in the cellular mechanisms that maintain genomic stability [Hickson et al 2001, Monnat 2010, Larsen & Hickson 2013, Suhasini & Brosh 2013]. Abnormal gene product. The major consequence for a somatic cell, in which BLM is either absent or present but non-functional, is an abnormally high rate of recombination and mutation. The mutations that arise in the cells of a person with BSyn are of several types and affect many (presumably any) regions of the genome. Thus, although the cancer of BSyn is attributable to the cellular hyper-recombinability and hypermutability, the proportional small size – the constant feature of BSyn – remains unexplained, as do the important medical complications of BSyn other than cancer.