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Bloom's Syndrome

, PhD, FACMG and , MD, FACMG (hon).

Author Information
, PhD, FACMG
Adjunct Assistant Professor, Department of Pediatrics
Weill Medical College of Cornell University
New York, New York
Associate Professor, Department of Biology
Molloy College
Rockville Centre, New York
, MD, FACMG (hon)
Professor, Department of Pediatrics
Weill Medical College of Cornell University
New York, New York

Initial Posting: ; Last Update: March 28, 2013.

Summary

Disease characteristics. Bloom’s syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, highly characteristic sparseness of subcutaneous fat tissue throughout infancy and early childhood, and short stature throughout postnatal life that in most affected individuals is accompanied by an erythematous and sun-sensitive skin lesion of the face. Gastroesophageal reflux (GER) is common and very possibly responsible for infections of the upper respiratory tract, the middle ear, and the lung that occur repeatedly in most persons with BSyn. Although most affected individuals have normal intellectual ability, many exhibit a poorly defined (and little studied) learning disability. Women may be fertile, but menopause occurs unusually early; men are infertile. Serious medical complications that are much more common than in the general population and that also appear at unusually early ages are chronic obstructive pulmonary disease, diabetes mellitus resembling the adult-onset type, and cancer of a wide variety of types and anatomic sites. BSyn is very rare in all national and ethnic groups but is relatively less rare in Ashkenazi Jews.

Diagnosis/testing. The clinical diagnosis is confirmed cytogenetically in either of two ways, preferably both: either by demonstrating a certain symmetric, four-armed chromatid interchange configuration known as a quadriradial (Qr) in cultured blood lymphocytes, or by a greatly increased frequency of sister-chromatid exchanges (SCEs) in cultured cells of any type. The diagnosis can also be confirmed by molecular genetic analysis of BLM, the gene in which mutations are known to cause BSyn.

Management. Treatment of manifestations: Otitis media and pneumonia respond promptly to routine antibiotic treatment regimens, and in theory, control of GER, if present, decreases their frequency. Diabetes mellitus is treated in the standard manner, as is cancer – except that in persons with BSyn, hypersensitivity of cells to both ionizing radiation and DNA-damaging chemicals may require reduction of the dosage and/or the duration of the treatment if serious and even life-threatening complications of the treatment itself are to be avoided.

Surveillance: Unexplained signs and symptoms that are potential indications of a malignancy should be investigated promptly and thoroughly. Screening for breast and colon cancer decades earlier and more frequently than in other screening programs is advisable.

Agents/circumstances to avoid: Sun exposure to the face.

Other: Measures that increase linear growth in persons with BSyn have not been identified.

Genetic counseling. BSyn is inherited in an autosomal recessive manner. Characterization of the two disease-causing BLM alleles in a family is required for carrier (heterozygote) identification, as cytogenetic testing cannot distinguish between carriers and non-carriers. Prenatal diagnosis of pregnancies at increased risk is possible using either cytogenetic testing (specifically SCE analysis) or BLM molecular genetic testing if the causative mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

Bloom’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 adulthood
  • An 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

Testing

The 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 rearrangements
  • Quadriradial 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 Testing

Gene. 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 testing

Table 1. Summary of Molecular Genetic Testing Used in Bloom’s Syndrome

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
BLMTargeted mutation analysisc.2207_2212delinsTAGATTC 4100% 5
Sequence analysis 6Multiple BSyn-causing mutations90%
Deletion/duplication analysis 7Exonic and whole gene deletionsUnknown 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. 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].

5. In Ashkenazi Jewish individuals. Its frequency varies in individuals of other ancestry, as shown in Table 2.

6. 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. For issues to consider in interpretation of sequence analysis results, click here.

7. Testing that identifies exonic or whole-gene 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.

8. 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 Syndrome

Persons with Bloom’s SyndromeNumber of Persons Having the Indicated Genotype 1
Parental Ancestry 2Number 3blmAsh/blmAshdupT/blmAshblmAsh/mutxmutx/mutxmutx/––/–
A/A282620000
A/J2101000
A/N5005000
J/J1000001
N/N1014 04 7989

German et al [2007]

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.2407dupT

blmAsh = c.2207_2212delinsTAGATTC 

mutx = 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 indicated

2. 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].

Testing Strategy

To 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.

Clinical Description

The range of clinical features of Bloom’s syndrome (BSyn) has been elucidated in a program of clinical investigation now in effect for five decades that is referred to as the Bloom's Syndrome Registry [weill.cornell.edu/bsr]. The clinical and genetic histories have been obtained from most of the persons diagnosed between 1954 and 2012, and their clinical courses have been followed [German & Passarge 1989, German 1993, German & Ellis 2002].

The main clinical features of BSyn are the following:

  • Size and appearance. The most impressive and the only constant clinical feature of BSyn, one seen in all stages of life, is exceptionally small size, with roughly normal body proportions with the exception of a slightly disproportionately small cranium. Subcutaneous adipose tissue is exceptionally sparse, typically resulting in a wasted appearance. Plasma growth hormone concentration is normal.

    The affected fetus is smaller than normal for gestational age. The mean birth weight of affected males is 1760 g (range 900-3189 g), of affected females 1754 g (range 700-2892 g). The average adult height of men is 149 cm (range 128-164 cm), of women 138 cm (range 115-160 cm).

    The face in BSyn often is striking because of the small and somewhat narrow cranium, seemingly underdeveloped malar and lower mandibular areas, and a resulting relative prominence of the nose and ears [weill.cornell.edu/bsr].

    The voice is high-pitched and somewhat coarse in timbre.
  • Feeding problems. These are prominent in the majority of newborns, infants, and young children, the child with BSyn very characteristically showing a seeming lack of interest in nursing, and then eating. Surprisingly, in an occasional infant with BSyn, nursing and then eating is completely normal. Because gastroesophageal reflux (G-ER) of severe degree has been demonstrable in the few young infants appropriately examined, it is the hypothesis of the authors that this is a major feature of BSyn, and the most probable basis for both the repeated bouts of middle ear and lung infections, via repeated micro-aspirations of gastric contents, and the wasted appearance of infants and young children.
  • Skin lesions. The skin at birth and during early infancy appears normal, but, typically following sun exposure during the first or second year of life, a red sun-sensitive skin lesion appears on the nose and cheeks, sometimes faintly also on the dorsa of the hands and forearms. This lesion varies in severity and extent among affected individuals; in some the lesion is minimal. In severe cases, the lesion can be bright red and can extend onto adjacent areas. Loss of the lower eyelashes and blister and fissure formation of the lower lip are common, the latter often becoming particularly bothersome and difficult to treat.

    Café-au-lait spots, typically with neighboring hypopigmented areas of skin, are more numerous and larger than in other people.
  • Immunodeficiency. The concentration of one or more of the plasma immunoglobulins is usually abnormally low. Delayed hypersensitivity is undetected by the standard testing method.
  • Infections. Repeated bouts of otitis media and pneumonia that respond promptly and well to antibiotics occur throughout infancy and early childhood in at least 20% of persons with BSyn. Because the frequency of these infections does not correlate well with the severity of the immunodeficiency, and because G-ER is so common (whenever it has been tested for appropriately in BSyn), they are more readily attributable to the G-ER.
  • Fertility. Men with BSyn appropriately examined have had azoospermia or severe oligospermia. Women with BSyn, although often fertile, enter menopause prematurely. Eleven women with BSyn followed in the Registry have become pregnant at least once; seven of them have been delivered of a total of eleven healthy babies of normal size.
  • Intelligence. Intellectual abilities of affected persons vary, being clearly limited in some and normal in others. The majority display a peculiar lack of interest in learning and do poorly in school in courses requiring abstract thought. Some have excelled in school, a few earning graduate degrees.
  • Other clinical features. Major anatomic defects are not increased in frequency. In the 272 persons in the Registry in 2012, only single examples of the following having occurred: a tracheoesophageal fistula, a cardiac malformation, absence of the thumbs, and absence of a toe and malformation of a thumb.

    Very minor anatomic defects such as clinodactyly of the fifth finger and dimple are increased in frequency.

Medical complications of BSyn, all serious, in order of increasing frequency are the following:

  • Lower urinary tract obstruction in men. Several men have had a so-far poorly characterized urethral or bladder neck obstruction, resulting in death in two.
  • Chronic obstructive pulmonary disease. Chronic bronchitis and bronchiectasis are common, and pulmonary failure has been the cause of death in five persons.
  • Diabetes mellitus. Although the diabetes mellitus of BSyn has as yet not been well characterized, it resembles the typical adult-onset type except for an exceptionally early age of onset. Diabetes has been diagnosed in 47 of 272 persons in the Registry (17.7%) at a mean age of 26.6 years (range 4-45 years). Although most of the cases have been mild, 16 have required insulin, and retinopathy has developed in two.
  • Abnormalities in insulin release and glucose tolerance have been detected in the eight healthy children (age 9 months to 13 years) and the three healthy young adults with BSyn (ages 22, 28, and 28 years) appropriately studied [Diaz et al 2006].
  • Myelodysplasia. This heterogeneous group of disorders has been diagnosed in 22 persons in the Registry at a median age of 23.1 years (range 3-47), and it has progressed to leukemia in at least six. In all but two, the myelodysplasia had been preceded by some form of cancer for which chemotherapy and/or radiotherapy had been administered.
  • Cancer. Cancer is the most frequent medical complication in BSyn and the most common cause of death. Although the wide distribution of the cellular types and anatomic sites of cancer resemble that in the general population, it occurs more frequently and at much earlier ages in BSyn. Development of multiple cancers in a single individual is also much more common. Table 3 summarizes the cancers diagnosed in individuals followed in the Registry.

Table 3. The 205 Malignant Neoplasms Diagnosed in 129 Persons in the Bloom's Syndrome Registry, 1954-2012

Anatomic Sites/TypesMean Age at Diagnosis (Range)Number
Epithelial (Carcinoma)
Lower enteric tract 35.1 (16-49) 30
Integument 31.7 (18-46) 27
Upper entero/respiratory tract 37.8 (25-48) 22
Genitalia & urinary tract16.6 (<1-43) 17
Breast 35.8 (21-48) 16
Lower respiratory tract 33.0 (26-40) 9
Liver15.0 1
Lymphoid
Lymphoma 21.7 (4-49) 35
Acute lymphoblastic leukemia19.6 (5-40)12
Hematopoietic
Acute myelogenous leukemia17.9 (2-47)25
Other
Connective tissue (sarcoma)16.3 (4-30)4
Germ-cell24.0 (22-26)2
Central nervous system (brain)3.0 1
Retinoblastoma1.0 1
Primary site unidentified, metastatic33.7 (28-33)3
All26.6 (<1-49)205

Genotype-Phenotype Correlations

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.

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.

Prevalence

Few cases of BSyn have been reported in the medical literature since its description half a century ago [Bloom 1954], and fewer than 300 are known to the Bloom’s Syndrome Registry.

Although very rare in all populations, BSyn is relatively less rare among Ashkenazi Jews. Seventy-two of the 265 persons in the Registry are of Ashkenazi Jewish ancestry. The predominant BSyn-causing BLM mutation identified in Ashkenazi Jews is c.2207_2212delinsTAGATTC, a 6-bp deletion/7-bp insertion in exon 10 of BLM, often (for brevity) designated blmAsh; the second most common mutation is c.2407dupT.

The carrier frequency of the blmAsh allele is approximately:

Differential Diagnosis

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:

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

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:

  • Evaluation for gastroesophageal reflux and micro-aspirations into the lung of gastric contents
  • Fasting blood glucose determination, both at the time of diagnosis and annually thereafter
  • Determination of plasma immunoglobulin concentrations
  • Observation of urination for evidence of urethral obstruction
  • If diagnosis occurs in adulthood, colonoscopy and stool guaiac at the time of diagnosis
  • Medical genetics consultation

Treatment of Manifestations

Psychosocial. 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.

Surveillance

Families 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 Avoid

Sun exposure to the face, particularly in infancy and early childhood, should be avoided.

Evaluation of Relatives at Risk

An 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.

Other

Bone 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Bloom’s syndrome (BSyn) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of an individual with BSyn

  • Both parents of an affected person may be assumed to carry a mutation in BLM. However, a single example of uniparental disomy has been reported [Woodage et al 1994] suggesting that carrier testing of parents may be warranted.
  • Carriers of a BSyn-causing mutation (i.e., heterozygotes) manifest none of the features of BSyn.
  • The cancer risk of heterozygotes as a group and specifically those carrying various classes of BSyn-causing BLM mutations has yet to be determined.

Sibs of an individual with BSyn

  • At conception, each sib of an individual with Bloom’s syndrome has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier of a Bloom’s syndrome-causing mutation, and a 25% chance of being unaffected and not a carrier
  • Once a sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a woman with BSyn

  • Children born to a woman with Bloom's syndrome are usually heterozygous for a BLM mutation. However, because approximately 1% of individuals of Ashkenazi Jewish descent carry a BLM mutation, the risk for BSyn in the children of a union between a woman with BSyn and an Ashkenazi Jewish man whose Bloom’s syndrome carrier status has not been determined is 1/200.
  • Children born to a woman with Bloom’s syndrome and a reproductive partner who is a carrier of a Bloom’s syndrome-causing mutation have a 50% chance of having Bloom syndrome and a 50% chance of being carriers.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a BLM mutation.

Carrier Detection

  • Carrier testing for at-risk family members is possible only if the BLM mutations in the family have been identified.
  • Individuals of Ashkenazi Jewish heritage. Because of the relatively increased carrier rate of the blmAsh allele in Ashkenazi Jews, population screening may be available for Ashkenazi Jewish individuals of reproductive age [ACOG Committee on Genetics 2009].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Cytogenetic analysis. Prenatal diagnosis for pregnancies at increased risk is possible by SCE analysis of fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation.

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis or CVS. Both BLM mutations of an affected family member or of the carrier parents must be identified before prenatal testing employing DNA-based methods is possible.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Ultrasound measurements are not reliable if prenatal diagnosis confirms the diagnosis of BSyn in the fetus.

Preimplantation genetic diagnosis (PGD) has been successfully utilized for one couple [Bloom's Syndrome Registry, unpublished data], and may be an option for some families in which the BLM mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Bloom's Syndrome Foundation (BSF)
    7095 Hollywood Boulevard
    #583
    Los Angeles CA 90028
    Email: info@bloomssyndrome.org
  • National Library of Medicine Genetics Home Reference
  • Chicago Center for Jewish Genetic Disorders
    Ben Gurion Way
    30 South Wells Street
    Chicago IL 60606
    Phone: 312-357-4718
    Email: jewishgeneticsctr@juf.org
  • Xeroderma Pigmentosum Society, Inc (XP Society)
    XP Society has material on their site related to UV protection/avoidance.
    437 Syndertown Road
    Craryville NY 12521
    Phone: 877-XPS-CURE (877-977-2873); 518-851-2612
    Email: xps@xps.org
  • Bloom's Syndrome Registry
    Weill Medical College of Cornell University
    1300 York Avenue
    New York NY 10065
    Phone: 212-746-3956; 516-678-5000 ext 6217
    Email: jlg2003@med.cornell.edu; msanz@molloy.edu
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org

Molecular Genetics

Information 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 Databases

Data 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)

210900BLOOM SYNDROME; BLM
604610RECQ PROTEIN-LIKE 3; RECQL3

Molecular Genetic Pathogenesis

Bloom’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.

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Seventeen benign variants without apparent clinical effect have been reported [German et al 2007; Bloom's Syndrome Registry, unpublished data].

Pathogenic allelic variants

  • Most 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 Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.2207_2212delinsTAGATTC 2
(2281del6/ins7)
(blmAsh)
p.Tyr736LeufsTer5 2NM_000057​.2
NP_000048​.1
c.2407dupT
(insT2407)
p.Trp803LeufsTer4

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Also known as the blmAsh allele

See 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.

References

Literature Cited

  1. ACOG Committee on Genetics; ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2009t;114:950–3. [PubMed: 19888064]
  2. Bloom D. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity. AMA Am J Dis Child. 1954;88:754–8. [PubMed: 13206391]
  3. Diaz A, Vogiatzi MG, Sanz MM, German J. Evaluation of short stature, carbohydrate metabolism and other endocrinopathies in Bloom's syndrome. Horm Res. 2006;66:111–7. [PubMed: 16763388]
  4. Ellis NA, Ciocci S, Proytcheva M, Lennon D, Groden J, German J. The Ashkenazic Jewish Bloom syndrome mutation blmAsh is present in non-Jewish Americans of Spanish ancestry. Am J Hum Genet. 1998;63:1685–93. [PMC free article: PMC1377640] [PubMed: 9837821]
  5. German J. Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients. Am J Hum Genet. 1969;21:196–227. [PMC free article: PMC1706430] [PubMed: 5770175]
  6. German J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore). 1993;72:393–406. [PubMed: 8231788]
  7. German J, Passarge E. Bloom's syndrome. XII. Report from the Registry for 1987. Clin Genet. 1989;35:57–69. [PubMed: 2647324]
  8. German J, Ellis N. Bloom syndrome. In: Vogelstein B, Kingler RW, eds. The Genetic Basis of Human Cancer. 2 ed. New York, NY: McGraw-Hill; 2002:267-88.
  9. German J, Sanz MM, Ciocci S, Ye TZ, Ellis NA. Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry. Hum Mutat. 2007;28:743–53. [PubMed: 17407155]
  10. Hickson ID, Davies SL, Li JL, Levitt NC, Mohaghegh P, North PS, Wu L. Role of the Bloom's syndrome helicase in maintenance of genome stability. Biochem Soc Trans. 2001;29:201–4. [PubMed: 11356154]
  11. Larsen NB, Hickson ID. RecQ helicases: conserved guardians of genomic integrity. In: Spies M, ed. DNA Helicases and DNA Motor Proteins, Advances in Experimental Medicine and Biology. New York, NY: Springer Science; 2013:161-84. [PubMed: 23161011]
  12. Li L, Eng C, Desnick RJ, German J, Ellis NA. Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population. Mol Genet Metab. 1998;64:286–90. [PubMed: 9758720]
  13. Monnat RJ. Human RECQ helicases: Roles in DNA metabolism, mutagenesis and cancer biology. Semin Cancer Biol. 2010;20:329–39. [PMC free article: PMC3040982] [PubMed: 20934517]
  14. Peleg L, Pesso R, Goldman B, Dotan K, Omer M, Friedman E, Berkenstadt M, Reznik-Wolf H, Barkai G. Bloom syndrome and Fanconi's anemia: rate and ethnic origin of mutation carriers in Israel. Isr Med Assoc J. 2002;4:95–7. [PubMed: 11876000]
  15. Sanz MM, Proytcheva M, Ellis NA, Holloman WK, German J. BLM, the Bloom's syndrome protein, varies during the cell cycle in its amount, distribution, and co-localization with other nuclear proteins. Cytogenet Cell Genet. 2000;91:217–23. [PubMed: 11173860]
  16. Shahrabani-Gargir L, Shomrat R, Yaron Y, Orr-Urtreger A, Groden J, Legum C. High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin. Genet Test. 1998;2:293–6. [PubMed: 10464606]
  17. Suhasini AN, Brosh Jr RM. DNA helicases associated with genetic instability, cancer, and aging. In: Spies M, ed. DNA Helicases and DNA Motor Proteins, Advances in Experimental Medicine and Biology. New York, NY: Springer Science; 2013:123-44.
  18. Woodage T, Prasad M, Dixon JW, Selby RE, Romain DR, Columbano-Green LM, Graham D, Rogan PK, Seip JR, Smith A, Trent RJ. Bloom syndrome and maternal uniparental disomy for chromosome 15. Am J Hum Genet. 1994;55:74–80. [PMC free article: PMC1918231] [PubMed: 7912890]

Suggested Reading

  1. German J, Ellis NA. Bloom syndrome. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 46. Available online. 2014. Accessed 6-18-14.

Chapter Notes

Author Notes

The Bloom's Syndrome Registry is a long-term surveillance program in which the clinical courses of persons diagnosed with BSyn and close members of their families are followed. The Registry comprises bona fide cases of individuals with this very rare disorder living in various parts of the world. The Registry is the source of the data included in this entry.

Bloom's Syndrome Registry Contact Information:

Registrars: Dr Maureen M Sanz and Dr James German
Eberhard Passarge, MD
University of Essen, Germany
Tel: 49/2324-41603
Email: ed.nesse-inu@egrassap.drahrebe

Revision History

  • 28 March 2013 (me) Comprehensive update posted live
  • 24 August 2010 (me) Comprehensive update posted live
  • 22 March 2006 (me) Review posted to live Web site
  • 10 December 2004 (ms) Original submission
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