What is the pathophysiology of Bloom syndrome (congenital telangiectatic erythema)?

Updated: Apr 15, 2019
  • Author: Amira M Elbendary, MBBCh, MSc; Chief Editor: Dirk M Elston, MD  more...
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Bloom syndrome (congenital telangiectatic erythema) is caused by a mutation in both alleles of the gene designated BLM, traced to band 15q26.1. [2, 3, 4, 5]  (see the image below). BLM encodes 1417 amino acids that code for a protein in the nuclear matrix of growing cells, which is a member of the RecQ family of helicases. This protein plays a pivotal role in DNA recombination and repair. BML mutations thus result in defects in DNA repair and genomic instability in the somatic cells, predisposing the patients to cancer development. [6]

Crystal structure of the Bloom syndrome helicase B Crystal structure of the Bloom syndrome helicase BLM in complex with DNA (PDB ID: 4CGZ). Courtesy of Arthur Zalevsky (own work), via Wikimedia Commons.

The BLM mutations can be found in compound heterozygous forms, homozygous forms, or as single gene mutation forms.

There is a 10-fold increase in the sister chromatid exchanges, [7] in addition to the presence of chromatid gaps, breaks, and gross structural rearrangements. [7, 8]  Sister chromatid exchanges are considered a sensitive indicator for cell genome instability, as they are thought to be the outcome of DNA double-strand breaks resulting from homologous recombination repair. [9]

Over 60 mutations of the BLM gene have been found in Bloom syndrome. The most common mutation is the deletion of 6 nucleotides at position 2281 and their replacement with 7 others, which occurs most commonly in Ashkenazi Jews. [10]

In 1989, Nicotera et al suggested that the major biochemical defect in persons with Bloom syndrome is chronic overproduction of the superoxide radical anion. They thought that inefficient removal of peroxide might be responsible for the high rates of sister chromatid exchange and chromosomal damage in Bloom syndrome cells. [11]

MM1 and MM2 are proteins identified in Bloom syndrome and Fanconi anemia, creating a link between them. The gene encoding these proteins is FANCM. Both diseases show phenotypical similarity and both demonstrate bone marrow failure, skeletal growth deficiency, short stature, and predisposition to hematological malignancies, although they are genetically unrelated. Both diseases involve the BRAFT and FANCM complexes, which are important in DNA repair. [12, 13]

Bugreev et al suggest that a function of BLM is stimulation of RAD51 DNA pairing; results from their study show the importance of the RAD51 nucleoprotein filament conformation for stimulating DNA pairing by BLM. [14]

Photosensitivity in Bloom syndrome patients is a result of increased susceptibility to 313-nm light, approaching the ultraviolet (UV)–A range. The minimal erythema dose threshold for both UV-A and UV-B are reduced. [15] Cellular sensitivity in Bloom syndrome patients is in the form of phototoxicity and not photocarcinogenicity, as is seen in xeroderma pigmentosa. [16] Bloom syndrome patients exhibit a greater vulnerability of their DNA to UV radiation than DNA of healthy populations.

Bloom syndrome patients also demonstrate impairment in lymphocytic proliferation, deficient immunoglobulin synthesis, and lowered response to mitogen stimulation, resulting in impairment of both cellular and humoral immune responses. [17]

The overall result of the genomic instability in the proliferating cells is a high risk of malignancy, reduced fertility or infertility, B- and T-cell immunodeficiencies, and cutaneous manifestations, including photosensitivity, poikiloderma, and telangiectatic erythema.

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