Bloom syndrome

2023-12-13   Alessandro Beghini 

University of Milan


Bloom syndrome is an autosomal recessive disorder with a higher prevalence among Ashkenazi Jews and the Japanese due to a founder effect. Caused by mutations in the {BLM} gene, a multifunctional ATP-dependent DNA helicase, it leads to genomic instabi

BLM; DNA helicase; SCE; DNA repair


Phenotype and clinics

Bloom syndrome 1,2is characterized by phenotypic heterogeneity 3 and is generally associated with death by age 30 with a diagnosis of cancer by age 24.
growth : dwarfism: intrauterine growth retardation; birth weight: below 2.3 kg; mean length: 44 cm; adult length <145cm.
skin: hyperpigmented (café au lait) spots; hypopigmented areas; sun sensitive telangiectatic erythema; in butterfly
configuration across the face: resembles lupus erythematous
head: microcephaly; dolichocephaly; narrow face; prominent nose and\/or ears; characteristic high-pitched voice
normal intelligence
immune deficiency: frequent infections (may be life-threatening) 4.
other: myocardopathy; hypogonadism in male patients; hypertriglyceridemia; abnormality of the cortical neuron 5; refractory gastroduodenal ulcers 6.
It is an extremely rare syndrome, only 281 patients listed in the Bloom syndrome registry as of 2018, particularly
among Ashkenazi Jews (frameshift mutation defined BLMAsh is present in all affected among Ashkenazi Jews with a 1% frequency as a carrier in this ethnicity)7.
This is manifested by the accumulation of abnormal replication intermediates and an increase in the frequency of sister chromatid exchange (SCE) 8. SCEs are created by homologous recombination and appear to originate as a result of DNA-strand breakage that occurs during DNA replication or as a result of attempts to repair damage to the replication fork 9.

Neoplastic risk

•    nearly half of patients have had at least one cancer (10% of whom having had more than one primary cancer, which is quite characteristic of Blooms); mean age at first cancer onset: 25 yrs (range: 2-49 yrs)10,11.
•    acute leukaemias (ALL and ANLL) in 15 % of cases; lymphomas (particularly non-Hodgkin’s Lymphoma) in 15 % as well; these occur mainly before the thirties.
•    carcinomas (carcinomas of the breast, gut and skin) occur in 30 % of cases, mainly after the age of 20 yrs.
•    benign tumours (10%)
•    germline BLM+/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma 12.


Treatment typically focuses on managing the symptoms and complications associated with the condition. Medical care often involves a multidisciplinary approach addressing various aspects such as:
Cancer Surveillance: Regular cancer screenings and surveillance are crucial due to the increased risk of various cancers associated with Bloom syndrome. Early detection can significantly impact treatment outcomes.
Infection Management: Given the immune deficiencies observed in some individuals with Bloom syndrome, managing infections promptly is essential. This might involve a proactive approach to prevent infections and immediate treatment when infections occur.
Symptomatic Care: Addressing specific symptoms associated with Bloom syndrome, such as skin issues or growth abnormalities, might require tailored medical interventions or therapies to manage these concerns.
Genetic Counseling: For families with a history of Bloom syndrome, genetic counseling can help in understanding the risks and making informed decisions regarding family planning and prenatal testing.
Research in genetic disorders like Bloom syndrome is ongoing. While there isn't a specific treatment targeting the
underlying genetic cause at present, advances in medical research, including gene therapy or targeted treatments, may offer potential avenues for managing or mitigating the condition in the future. It's essential to consult healthcare professionals who specialize in genetic disorders for the most current information and guidance regarding Bloom syndrome management and available treatments 13.


Bloom syndrome is characterized by significant genomic instability due to mutations in the BLM gene. This instability results in an increased frequency of sister chromatid exchanges (SCEs) and chromosomal aberrations, leading to various manifestations in affected individuals.
Physical Features: Individuals with Bloom syndrome often exhibit distinct physical characteristics that become apparent as they grow. These may include dwarfism, a narrow face, microcephaly (small head size), distinctive facial features (such as a prominent nose and ears), and skin abnormalities like hyperpigmentation (café-au-lait spots) and sun-sensitive telangiectatic erythema.
Growth Abnormalities: Bloom syndrome is associated with intrauterine growth retardation and low birth weight. Adult height is generally well below average, with individuals rarely exceeding a height of 145 cm.
Immune Deficiencies: Some individuals may experience immune deficiencies, leading to frequent infections that can be potentially life-threatening.
Cancer Predisposition: One of the most significant characteristics of Bloom syndrome is a significantly heightened risk of developing various types of cancers at an earlier age than the general population. This increased cancer predisposition includes acute leukemias (such as ALL and ANLL), lymphomas, carcinomas (e.g., breast, gastrointestinal, skin), and benign tumors.
Other Health Complications: Apart from cancer, individuals with Bloom syndrome might experience additional medical complications, such as chronic lung disease, diabetes mellitus (in 10%), and myocardopathy.
Understanding the evolution of Bloom syndrome involves recognizing the progressive nature of its characteristic features, the heightened risk of developing cancers, and the various health challenges that individuals affected by this condition face throughout their lives. Regular medical monitoring, early intervention, and comprehensive care are crucial in managing the evolving symptoms and complications associated with this rare genetic disorder.


The prognosis of individuals with Bloom syndrome varies, with a substantial number succumbing to complications related to cancer at a relatively young age, 1\/3 of patients are dead at mean age 24 yrs (oldest died at 49 yrs, youngest died before 1 yr). However, some individuals might survive into their 40s or 50s, the mean age of the 2\/3 remaining alive patients is 22 yrs (range: 4-46 yrs) albeit with significant health challenges.



Inborn condition
• chromatid\/chromosome breaks; triradial and quadriradial figures, in particular symetrical quadriradial configuration involving homologous chromosomes (Class I qr), which are pathognomonic and which may be due to a mitotic crossingover; micronuclei.
• Cells derived from patients with Bloom syndrome show a high level of homologous recombination events.
• diagnosis is on the (pathognomonic) highly elevated spontaneous sister chromatid exchange rate (90 SCE per cell; more than 10 times what is normally found); in some persons a minor population of low SCE cells exists, suggesting a recombination event between maternal and paternal alleles (with different mutations), giving rise to a wild type functional gene; this allowed to localize the gene in a very elegant strategy.
• heterozygotes are not detectable by cytogenetic studies.

Figure 1: much rarer otherwise micronuclei (left); sister chromatid exchange (right) in a normal subject (herein: 19 SCE, instead of the hundred found in Bloom, see below).

Figure 2: sister chromatid exchange in a normal subject (left) and in a Bloom syndrome patient (right) (from: Mounira Amor-Guéret).

Fish analysis

The underlying cause of Bloom syndrome is a mutation in the BLM gene, leading to genomic instability and increased sister chromatid exchange (SCE). FISH analysis might not directly pinpoint these mutations but could be employed to study related chromosomal aberrations or anomalies observed due to the genomic instability associated with the condition.
Specifically, FISH analysis could be used to:
Detect Chromosomal Aberrations: FISH can identify certain chromosomal abnormalities that might result from the genomic instability associated with Bloom syndrome, such as increased SCEs or structural rearrangements in chromosomes.
Study Genomic Instability: While FISH might not detect BLM gene mutations directly, it can be used to observe and quantify SCEs or other chromosomal irregularities that are characteristic of Bloom syndrome.
Additional anomalies/Variants
• slowing of the cell cycle (lenthening of the G1 and S phases)
• spontaneous mutation rate 10 times higher than normal cells
Moreover recent data shows that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Homozygous Blm mice exhibit accelerated methylation age in multiple tissues 14.


Data provide evidence of a novel link between BLM dysfunction and transcriptional changes in condensin complex I and II genes 15.


Bloom syndrome, an autosomal recessive disorder primarily caused by mutations in the BLM gene 16, is associated with a multifunctional ATP-dependent DNA helicase 17. The BLM gene product functions as a critical enzyme in DNA replication and repair processes, unwinding both single- and double-stranded DNA in a 3'-5' direction 18-25. Types of mutations observed in the BLM gene 4,22,24.


Reference NumberPubmed IDLast YearTitleAuthors
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6361103322022Refractory gastroduodenal ulcers: A rare complication with Bloom syndrome.Usami M et al
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12333182032020Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma.Bononi A et al
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1793884801997BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal.Kaneko H et al
18375038372023BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures.Danino YM et al
19372674082023Biochemical properties of naturally occurring human bloom helicase variants.Cueny RR et al
20351199172022The CDK1-TOPBP1-PLK1 axis regulates the Bloom's syndrome helicase BLM to suppress crossover recombination in somatic cells.Balbo Pogliano C et al
21351153992022Mechanism of Bloom syndrome complex assembly required for double Holliday junction dissolution and genome stability.Hodson C et al
2275859681995The Bloom's syndrome gene product is homologous to RecQ helicases.Ellis NA et al
23333574702021A Structural Guide to the Bloom Syndrome Complex.Bythell-Douglas R et al
2492857781997Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome.Foucault F et al
2593881931997The Bloom's syndrome gene product is a 3'-5' DNA helicase.Karow JK et al