Clinical characteristics.

Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. Despite their very small head circumference, most affected individuals have normal intellectual ability. Women may be fertile but often have early menopause, and men tend to be infertile, with only one confirmed case of paternity. Serious medical complications that are more common than in the general population and that also appear at unusually early ages include chronic obstructive pulmonary disease, diabetes mellitus as a result of insulin resistance, and cancer of a wide variety of types and anatomic sites.

Diagnosis/testing.

The diagnosis of BSyn is established in a proband with characteristic clinical features and/or biallelic pathogenic variants in BLM identified on molecular genetic testing. Identification of increased frequency of sister-chromatid exchanges on specialized cytogenetic studies and exclusion of RMI1, RMI2, and TOP3A-related disorders may be helpful in establishing the diagnosis in those with characteristic clinical features who do not have biallelic pathogenic variants in BLM.

Management.

Treatment of manifestations: Skin protection, including coverage of exposed skin and use of broad-spectrum sunscreen with SPF of at least 30 to reduce the sun-sensitive rash. Increased-calorie-density formulas and foods may promote weight gain. Although growth hormone treatment may improve linear growth, many clinicians caution against its use because of reports of early onset of cancer in some treated children. Developmental services and therapies as needed. Hyperglycemia from insulin resistance is treated as in type 2 diabetes. In persons with BSyn who have cancer, reduced chemotherapy dosage and duration to reduce risks of severe complications; caution should be exercised with use of ionizing radiation or alkylating agents, particularly busulfan, cyclophosphamide, or melphalan. Individuals with recurrent infections and defects in humoral immunity may be treated with gamma globulin infusions to decrease frequency and severity of infections.

Surveillance: Abdominal ultrasound examination every three months until age eight years for Wilms tumor. Screening and family education regarding signs/symptoms of leukemia and lymphoma at every health visit. Whole-body MRI every one to two years beginning at age 12-13 years for risk of lymphoma. Annual colonoscopy beginning at age 10-12 years. Fecal immunochemical testing every six months beginning at age 10-12 years. Annual breast MRI in women beginning at age 18 years. Annual fasting blood glucose and hemoglobin A1C beginning at age ten years. Annual serum TSH with reflex to T4 beginning at age ten years. Annual lipid profile beginning at age ten years.

Agents/circumstances to avoid: Sun exposure may provoke an erythematous rash, especially on the face. Exposure to ionizing radiation should be minimized.

Genetic counseling.

BSyn is inherited in an autosomal recessive manner. Identification of both pathogenic BLM variants in the proband is required for carrier (heterozygote) testing in at-risk families. BLM is included in expanded carrier screening panels, and most pathogenic variants can be identified through sequencing. Preimplantation and prenatal diagnosis are possible if the BLM pathogenic variants have been identified in the at-risk couple.

Suggestive Findings

Bloom syndrome (BSyn) should be suspected in an individual with any of the following clinical or cytogenetic findings.

Clinical findings

• Prenatal-onset growth deficiency that usually includes linear growth, weight gain, and head circumference and that persists into infancy, childhood, and adulthood
• Moderate-to-severe growth deficiency and a sun-sensitive, erythematous rash that commonly involves the face and appears in a butterfly distribution
• Moderate-to-severe growth deficiency and a diagnosis of cancer, usually occurring at an earlier age than in the general population

Cytogenetic findings

• Increased numbers of sister-chromatid exchanges
• Increased quadriradial configurations (Qrs) in cultured blood lymphocytes (a mean of 1%-2% Qrs are observed in cultured blood lymphocytes from a person with BSyn vs none in controls)
• Chromatid gaps, breaks, and rearrangements

Establishing the Diagnosis

The diagnosis of BSyn is established in a proband by identification of biallelic pathogenic variants in BLM on molecular genetic testing (see Table 1).

Note: An increased frequency of sister-chromatid exchanges (SCEs) on specialized cytogenetic studies may be helpful in circumstances where BLM variant analysis is inconclusive. SCE analysis alone is not sufficient to confirm a diagnosis of BSyn because increased SCEs are also observed in persons with biallelic pathogenic variants in RMI1, RMI2, and TOP3A [Hudson et al 2016, Martin et al 2018].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of BSyn is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with growth deficiency are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The range of clinical features in persons with Bloom syndrome (BSyn) has been tracked through the Bloom Syndrome Registry. The clinical and genetic histories have been obtained from registered persons diagnosed between 1954 and 2018 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 consistent clinical feature of BSyn seen throughout all stages of life is growth deficiency affecting height, weight, and head circumference. Body proportions are normal. Subcutaneous adipose tissue is sparse throughout childhood and adolescence, but adults may develop central obesity. Providing increased calories in childhood and adolescence does not usually result in substantial changes in growth parameters, particularly linear growth. Plasma growth hormone concentration is normal.
  The affected fetus is smaller than normal for gestational age. The mean birth weight of affected males is 1,760 g (range 900-3,189 g) and of affected females, 1,754 g (range 700-2,892 g). The average adult height of men is 149 cm (range 128-164 cm) and of women, 138 cm (range 115-160 cm).
  The facial appearance of people with BSyn is variable and may be indistinguishable from unaffected persons of similar age and size. More commonly, the face appears narrow, with underdeveloped malar and mandibular prominences and retrognathia or micrognathia. A paucity of subcutaneous fat may cause the nose and/or ears to appear prominent.
• Feeding problems. Most parents report that feeding is an issue for their newborns, infants, and young children. The child with BSyn characteristically feeds slowly, has a decreased appetite, and eats a limited variety of foods. In a minority of infants with BSyn, nursing and eating are normal. Because of their slow growth and weight gain, many children are prescribed formula with increased caloric density and later are prescribed nutritional supplements that provide extra calories. Many infants have had gastrostomy tubes placed. Despite these maneuvers, weight gain continues to be modest, and children are rarely in the normal range for growth. Gastroesophageal reflux is common and may contribute to the feeding issues.
• Skin lesions. The skin at birth and during early infancy appears normal; however, typically following sun exposure during the first or second year of life, a red, sun-sensitive rash appears on the nose and cheeks and sometimes also on the dorsa of the hands and forearms. This rash varies in severity and extent among affected individuals; in some, it is minimal. It is usually characterized by telangiectasia but in others is described as poikiloderma. In severely affected individuals, the lesion can be bright red and can extend onto adjacent areas. Additional dermatologic manifestations include cheilitis, blistering and fissuring of the lips, eyebrow and eyelash hair loss, alopecia areata, and vesicular and bullous lesions with excessive or intense sun exposure. Café au lait macules and areas of hypopigmented skin are more numerous and larger than in those without BSyn.
• Immunodeficiency. In children and adults who have had laboratory evaluation of their immune system, the concentration of one or more of the plasma immunoglobulins is usually abnormally low. IgM and IgA levels are most commonly affected. Although the numbers of T and B cells are usually normal, variable abnormalities of the adaptive immune system suggest a possible role in the frequent infections reported in affected individuals.
• Infections. Parents of children with BSyn report that their affected children have more childhood infections than their sibs and peers; none, however, has had an opportunistic infection, and few persons with BSyn have had bacterial sepsis, meningitis, or pneumonia.
• Fertility. Most men with BSyn appropriately examined have had azoospermia or severe oligospermia. There is, however, one confirmed case of paternity [Ben Salah et al 2014]. Women with BSyn, although often fertile, may enter menopause prematurely. Eleven women with BSyn followed in the Registry have become pregnant at least once; seven of them have delivered a total of 11 healthy babies of normal size.
• Intelligence. There are no systematic studies of academic achievement or cognitive performance in persons with BSyn. The great majority appear to perform within the normal range of intellectual development. Some have required academic support for attention-related issues and task orientation, but it is not clear that the prevalence of these problems is different from that seen in the general population. Many others have excelled in school, with some earning graduate degrees.
• Other clinical features. Major anatomic defects are not increased in frequency. In the 281 persons in the Registry as of 2018, only single examples of the following have occurred: tracheoesophageal fistula, cardiac malformation, absent thumbs, and absence of a toe and malformation of a thumb.

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

• Chronic obstructive pulmonary disease. Chronic bronchitis and bronchiectasis are common, and pulmonary failure has been the cause of death in six persons.
• Myelodysplasia has been diagnosed in 23 persons in the Registry at a median age of 22.1 years (range 3-47), and it has progressed to acute myelogenous leukemia in at least seven. In all but three, the myelodysplasia was preceded by some form of cancer for which chemotherapy and/or radiotherapy had been administered.
• Diabetes mellitus. Abnormalities in insulin release and glucose tolerance have been detected in the eight healthy children (ages 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]. Because of insulin resistance, the diabetes mellitus of BSyn resembles type 2 diabetes but has a much earlier age of onset than in the general population. Paradoxically, diabetes in persons with BSyn commonly occurs in the setting of low body mass index (BMI), rather than high BMI. Diabetes has been diagnosed in 47 of 281 persons in the Registry (16.7%) at a mean age of 26.6 years (range 4-45 years). Although most individuals do not have severe complications, 16 have required insulin, and retinopathy has developed in two. Lipid profile abnormalities were also identified by Diaz et al [2006] in five of the ten subjects tested.
• Cancer is the most frequent medical complication in BSyn and the most common cause of death. Although the wide distribution of cell 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 2 summarizes the cancers diagnosed in individuals followed in the Registry.

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 pathogenic variants in BLM identified to date.

Prevalence

Few individuals with 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 Syndrome Registry.

Although rare in all populations, BSyn is relatively less rare among Ashkenazi Jews. Sixty-seven of the 281 persons in the Registry are of Ashkenazi Jewish ancestry. The predominant BLM pathogenic variant identified in Ashkenazi Jews is c.2207_2212delinsTAGATTC, a 6-bp deletion/7-bp insertion in exon 10 of BLM, often (for brevity) designated blm^Ash; the second most common pathogenic variant is c.2407dupT.

The approximate carrier frequency of the blm^Ash allele:

• One in 100 Ashkenazi Jews dwelling both in New York City [Li et al 1998] and in Israel [Peleg et al 2002]
• One in 37 Ashkenazi Jews dwelling in Israel, all four of whose grandparents were from Poland [Shahrabani-Gargir et al 1998]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Bloom syndrome (BSyn), in addition to the routine medical history, family history, and physical examination, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Health supervision recommendations that address diagnosis, treatment, and surveillance for complications in persons with BSyn have been published [Cunniff et al 2018].

Skin. Reduce excessive exposure to sunlight by seeking shade, particularly between 10 am and 4 pm. Cover exposed skin with clothing, including a broad-brimmed hat and UV-blocking sunglasses. Apply a broad-spectrum sunscreen with SPF of 30 twice daily, or every two to three hours if outdoors.

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 not consistently increased growth rate in most persons, but some have experienced improved linear growth. Use of growth hormone has been approached cautiously in this population because of concerns regarding an increased risk of developing tumors as a result of their treatment. If growth hormone is prescribed, the growth response and serum IGF-1 and IGFBP-3 levels should be closely monitored, and unless there is an increase in growth velocity while under treatment, it should be discontinued.

Nutrition. Until additional information is available regarding treatment of problematic feeding behaviors and gastrointestinal symptoms, standard treatment for these concerns is recommended. This may include consultation with a gastroenterologist or feeding specialist, use of high-calorie diets, institution of reflux precautions, and use of anti-reflux medications. Studies of small cohorts of individuals with BSyn have shown that supplemental feeding may result in increased fat deposition but not in improved linear growth. Because abnormalities have been identified in the lipid profile of persons with BSyn, caution should be exercised in the use of high-fat and/or high-cholesterol diets.

Cognitive. Infants, toddlers, and preschool-age children with BSyn should have close developmental monitoring and referral for early intervention services. If developmental delays are present, physical, occupational, and speech therapy can help. School performance should be assessed regularly and parents made aware of available educational support.

Diabetes mellitus. Treatment of diabetes mellitus in BSyn is the same as in other persons.

Hypothyroidism. Thyroid hormone replacement therapy is recommended according to standard protocols.

Dyslipidemia. Dietary treatment according to standard protocols is recommended.

Cancer. The hypersensitivity of persons with BSyn to both DNA-damaging chemicals and ionizing radiation ordinarily necessitates modification of standard cancer treatment regimens, which usually includes a reduction of both dosage and duration. Individuals with BSyn have usually tolerated doses at or below 50% of the standard chemotherapy dosage, with no clear evidence that this has resulted in poorer outcomes. However, full weight-based dosing may be appropriate for some chemotherapeutic drugs such as steroids and tyrosine kinase inhibitors. Absence of information as to the ideal dosages makes such treatment particularly challenging to the physician; nevertheless, the fact that the cancers themselves often appear unusually responsive to the treatment justifies the special effort.

Bone marrow transplantation (BMT). Hematopoietic stem cell transplantation (HSCT) has been performed in three persons in the Bloom Syndrome Registry. One person had more than five years of disease-free survival before succumbing to another cancer, and the other two persons died in the immediate post-transplant period. If HSCT is being contemplated, nonmyeloablative transplantation is likely to be tolerated more readily than other regimens. Additionally, 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.

Immune. Defects in humoral immunity can be managed with weekly subcutaneous or monthly intravenous infusions of gamma globulin. Cough assist devices, vibration vests, and daily nasal lavage can be used for mucociliary clearance for bronchiectasis. If an individual with BSyn experiences recurrent, severe, or opportunistic infection, immunodeficiency screening (including immunoglobulin level, antibody responses to vaccines, and quantitative B- and T-lymphocyte measurements) is recommended.

Fertility

• Men with BSyn can undergo semen analysis to reveal azoospermia, oligospermia, or asthenospermia. Those who wish to conceive should consider consulting a fertility specialist. It is unclear if assisted reproductive technology (ART) may be helpful in persons with oligospermia or other abnormalities.
• Women with BSyn should be aware of signs of early menopause. Oocyte cryopreservation can be considered. Additionally, ART may be beneficial if natural conception is not possible; the authors are not aware of any prior use of ART in this population.

Surveillance

Health supervision recommendations for surveillance in persons with BSyn have been published [Cunniff et al 2018]. It should be recognized, however, that these recommendations are based on limited data from the Bloom Syndrome Registry and on expert opinion. There are currently no clinical trials or case-control studies that address outcomes in people with BSyn. Because of the unusually high risk for early development of cancer, much of the health supervision effort is directed to early detection and treatment.

Agents/Circumstances to Avoid

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

Exposure to ionizing radiation should be minimized.

Evaluation of Relatives at Risk

It is appropriate to evaluate sibs of a proband in order to identify as early as possible those who would benefit from avoidance of sun exposure to the face and early surveillance for cancer (see Surveillance).

• Molecular genetic testing can be used to evaluate sibs if the BLM pathogenic variants in the family are known.
• An unusually low birth weight followed by short stature throughout childhood is typically present in affected sibs; sibs of normal stature are likely unaffected and may not need further testing.

See Genetic Counseling for issues related to the testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Eleven women with BSyn followed in the Registry have become pregnant at least once; seven of them have delivered a total of 11 healthy babies of normal size.

See MotherToBaby for more information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Both parents of an individual with BSyn may be assumed to be heterozygous for a pathogenic variant in BLM. However, a single example of uniparental disomy has been reported [Woodage et al 1994], suggesting that molecular testing of parents may be warranted to confirm their genetic status.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing BSyn.
• The cancer risk of heterozygotes as a group has been examined in association studies but is yet to be determined [Antczak et al 2013, Prokofyeva et al 2013].

Sibs of a proband

• At conception, each sib of an individual with BSyn has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier of a BLM pathogenic variant, and a 25% chance of being unaffected and not a carrier.
• The cancer risk of heterozygotes as a group has been examined in association studies but is yet to be determined [Antczak et al 2013, Prokofyeva et al 2013].

Offspring of a female proband

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

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

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the BLM pathogenic variants in the family.

Population Screening

Individuals of Ashkenazi Jewish heritage. Because of the relatively increased carrier rate of the blm^Ash allele in Ashkenazi Jews, individuals of Ashkenazi heritage should be aware of their carrier risk, and practitioners should consider screening in this population [ACOG Committee on Genetics 2017].

Expanded carrier screening. Bloom syndrome is included on most expanded carrier screening panels.

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 and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the BLM pathogenic variants have been identified in an affected family member, prenatal diagnosis (by amniocentesis or chorionic villus sampling [CVS]) and preimplantation genetic diagnosis are possible. Preimplantation genetic diagnosis has been successfully utilized in a single family [Bloom Syndrome Registry, unpublished data].

Note: Ultrasound measurements are not reliable for estimating gestation age if prenatal diagnosis confirms the diagnosis of BSyn in the fetus.

Molecular Pathogenesis

Bloom 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, ataxia-telangiectasia-like disorder (OMIM 604391), Nijmegen breakage syndrome, and Werner syndrome. These clinically disparate disorders are caused by pathogenic variants 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 reversion (mutation) to the normal state 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.

Pathogenic variants. Most individuals of Ashkenazi Jewish heritage with BSyn have the pathogenic variant c.2207_2212delinsTAGATTC [Ellis et al 1998]. A second, rarer pathogenic variant segregating in the Ashkenazi Jewish population, c.2407dupT, has been identified [Ellis et al 1998, German et al 2007].

Pathogenic variants identified in several studies of individuals with BSyn fall into the following four broad classes [German et al 2007, Amor-Guéret et al 2008, Shastri & Schmidt 2015]:

• 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 is therefore absent from the nucleus (~1/3 of all pathogenic variants)
• Nonsense variants that convert sense codons to nonsense or chain-terminating codons that predict translation of a truncated BLM protein (~1/3 of all pathogenic variants)
• Intron variants that cause splicing defects (~1/6 of all pathogenic variants)
• Missense variants that result in the production of nonfunctional BLM protein (~1/6 of all pathogenic variants)

See Table 7 (pdf) for pathogenic variants identified in registered persons of various nationalities and ethnic groups.

Normal gene product. The 1,417-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. 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, Cunniff et al 2017].

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 on in the cell remain to be identified.

Abnormal gene product. The major consequence of loss of BLM function for a somatic cell is an abnormally high rate of recombination and mutation. The pathogenic variants that arise in the cells of a person with BSyn are of several types and affect many regions of the genome. Thus, although the cancer predisposition in 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.

Literature Cited

• ACOG Committee on Genetics. ACOG Committee Opinion No. 691: Carrier screening for genetic conditions. Obstet Gynecol. 2017;129:e41–55. [PubMed: 28225426]
• Amor-Guéret M, Dubois-d'Enghien C, Laugé A, Onclercq-Delic R, Barakat A, Chadli E, Bousfiha AA, Benjelloun M, Flori E, Doray B, Laugel V, Lourenço MT, Gonçalves R, Sousa S, Couturier J, Stoppa-Lyonnet D. Three new BLM gene mutations associated with Bloom syndrome. Genet Test. 2008;12:257–61. [PubMed: 18471088]
• Antczak A, Kluźniak W, Wokołorczyk D, Kashyap A, Jakubowska A, Gronwald J, Huzarski T, Byrski T, Dębniak T, Masojć B, Górski B, Gromowski T, Nagorna A, Gołąb A, Sikorski A, Słojewski M, Gliniewicz B, Borkowski T, Borkowski A, Przybyła J, Sosnowski M, Małkiewicz B, Zdrojowy R, Sikorska-Radek P, Matych J, Wilkosz J, Różański W, Kiś J, Bar K, Domagała P, Stawicka M, Milecki P, Akbari MR, Narod SA, Lubiński J, Cybulski C, Bryniarski P, Paradysz A, Jersak K, Niemirowicz J, Słupski P, Jarzemski P, Skrzypczyk M, Dobruch J, Domagała W, Chosia M, van de Wetering T, Serrano-Fernández P, Puszyński M, Soczawa M, Switała J, Archimowicz S, Kordowski M, Zyczkowski M, Borówka A, Bagińska J, Krajka K, Szwiec M, Haus O, Janiszewska H, Stembalska A, Sąsiadek MM, et al. A common nonsense mutation of the BLM gene and prostate cancer risk and survival. Gene. 2013;532:173–6. [PubMed: 24096176]
• Ben Salah G, Salem IH, Masmoudi A, Kallabi F, Turki H, Fakhfakh F, Ayadi H, Kamoun H. A novel frameshift mutation in BLM gene associated with high sister chromatid exchanges (SCE) in heterozygous family members. Mol Biol Rep. 2014;41:7373–80. [PubMed: 25129257]
• 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]
• Cunniff C, Bassetti JA, Ellis NA. Bloom's syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol Syndromol. 2017;8:4–23. [PMC free article: PMC5260600] [PubMed: 28232778]
• Cunniff C, Djavid AR, Carrubba S, Cohen B, Ellis NA, Fein Levy C, Jeong S, Lederman HM, Vogiatzi M, Walsh MF, Zauber AG. Health supervision for people with Bloom syndrome. Am J Med Genet. 2018;176:1872–81. [PubMed: 30055079]
• 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]
• 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]
• 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]
• German J. Bloom syndrome: a Mendelian prototype of somatic mutational disease. Medicine (Baltimore). 1993;72:393–406. [PubMed: 8231788]
• 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.
• German J, Passarge E. Bloom's syndrome. XII. Report from the Registry for 1987. Clin Genet. 1989;35:57–69. [PubMed: 2647324]
• 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]
• 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]
• Hudson DF, Amor DJ, Boys A, Butler K, Williams L, Zhang T, Kalitsis P. Loss of RMI2 increases genome instability and causes a Bloom-like syndrome. PLOS Genetics. 2016;12:e1006483. [PMC free article: PMC5157948] [PubMed: 27977684]
• 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]
• 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]
• Martin CA, Sarlós K, Logan CV, Thakur RS, Parry DA, Bizard AH, Leitch A, Cleal L, Ali NS, Al-Owain MA, Allen W, Altmüller J, Aza-Carmona M, Barakat BAY, Barraza-García J, Begtrup A, Bogliolo M, Cho MT, Cruz-Rojo J, Dhahrabi HAM, Elcioglu NH, Gorman GS, Jobling R, Kesterton I, Kishita Y, Kohda M, Le Quesne Stabej P, Malallah AJ, Nürnberg P, Ohtake A, Okazaki Y, Pujol R, Ramirez MJ, Revah-Politi A, Shimura M, Stevens P, Taylor RW, Turner L, Williams H, Wilson C, Yigit G, Zahavich L, Alkuraya FS, Surralles J, Iglesais A, Murayama K, Wollnik B, Dattani M, Heath KE, Hickson ID, Jackson AP. Mutations in TOP3A cause a Bloom syndrome-like disorder. Am J Hum Genet. 2018;103:221–31. [PMC free article: PMC6080766] [PubMed: 30057030]
• 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]
• 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]
• Prokofyeva D, Bogdanova N, Dubrowinskaja N, Bermisheva M, Takhirova Z, Antonenkova N, Turmanov N, Datsyuk I, Gantsev S, Christiansen H, Park-Simon TW, Hillemanns P, Khusnutdinova E, Dörk T. Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom's syndrome, is associated with breast cancer in Slavic populations. Breast Cancer Res Treat. 2013;137:533–9. [PubMed: 23225144]
• 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]
• 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]
• Shastri VM, Schmidt KH. Cellular defects caused by hypomorphic variants of the Bloom syndrome helicase gene BLM. Mol Genet Genomic Med. 2015;4:106–19. [PMC free article: PMC4707026] [PubMed: 26788541]
• 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.
• 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]

Acknowledgments

The authors would like to acknowledge Dr James L German III (b. January 2 1926, d. April 21 2018), who founded the Bloom Syndrome Registry and who dedicated much of his career to the understanding of Bloom syndrome and the support of affected persons and their families. They would also like to thank the New York Community Trust and Weill Cornell Medicine's Clinical and Translational Science Center for providing funding.

Author Notes

The Bloom 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 much of the data included in this entry.

Bloom Syndrome Registry Contact Information

Chris Cunniff, MD, FACMG
Weill Cornell Medicine
505 E 70th Street
3rd floor, Box 128
New York, NY 10021
Tel: (646) 962-2205
Email: ude.llenroc.dem@9309cmc

Author History

Christopher Cunniff, MD, FACMG (2016-present)
Maeve Flanagan, BA (2019-present)
James German, MD, FACMG (hon); Weill Cornell Medical College (2006-2019)
Maureen M Sanz, PhD, FACMG; Molloy College (2006-2019)

Revision History

• 14 February 2019 (sw) Comprehensive update posted live
• 7 April 2016 (sw) Comprehensive update posted live
• 28 March 2013 (me) Comprehensive update posted live
• 24 August 2010 (me) Comprehensive update posted live
• 22 March 2006 (me) Review posted live
• 10 December 2004 (ms) Original submission