Bloom Syndrome (Bloom Torre Machacek Syndrome)

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Bloom syndrome is a rare genetic disease chiefly characterized by short stature, increased sensitivity to light and incidence of various malignancies. It is most commonly found among Central and Eastern European Jews (Ashkenazi Jews).

This disease develops due to the following process: congenital.

Presentation

Patients with Bloom syndrome present very early after birth, and the most prominent manifestation is a significant delay in growth that can begin prenatally and persist throughout life. Affected individuals tend to have a short stature in combination with facial lesions and erythema upon exposure to sunlight. They also have a very characteristic and sparse distribution of subcutaneous fat until early childhood. Gastroesophageal reflux is a commonly associated complication that increases the risk for infections in the lung, the middle ear and the upper respiratory tract. Most patients will have normal intelligence although some may exhibit difficulty in learning. Bloom syndrome also targets the reproductive system. Men are universally infertile while women experience menopause earlier than usual although they may still retain their ability to conceive. Other associated complications include chronic obstructive pulmonary disease (COPD), adult-type diabetes mellitus and malignancies that occur in a range of tissues throughout the body.

Workup

Bloom syndrome is diagnosed through genetic and chromosomal studies. In particular, specific tests can detect chromosomal breaks as well as chromosomal rearrangements in tissue samples obtained from patients. The US National Institutes of Health and the US Armed Forces Institute of Pathology run laboratories that can assess chromosomal stability through the identification of quadriradicals and exchanges in sister chromatids. Prenatal diagnosis is possible and amniocentesis can be performed to assess the frequency of gene exchanges between sister chromatids. 

Individuals in populations at high risk such as Ashkenazi Jews may also be advised to undergo genetic screening and counseling to determine any carrier state for the mutated gene. Polymerase chain reaction (PCR) and mutation analysis are performed to detect the BLM mutation that is most common among Ashkenazi Jews. The mutation is identified by a deletion of 6 nucleotides and the insertion of 7 others at the specified locus. The risk of disease in individuals whose parents are both carriers of the mutation is 25% [19].

In addition to laboratory workup directed at diagnosis, individuals should be screened for the more frequent complications associated with the disease. Levels of immunoglobulins should be assessed with the usual pattern showing decreased levels of IgA and IgM, with variable levels of IgG. Patients should also be periodically screened for various malignancies, particularly leukemias, cervical, breast and colorectal cancers. Because Bloom patients are vulnerable to the damaging effects of radiation, the imaging modalities of choice are MRI and ultrasonography.

Treatment

Treatment is targeted at the various manifestations of the disease. Supplementation with growth hormone has proven ineffective in resolving growth abnormalities. Feeding through intubation can help in increasing fat deposition but has no effects on growth. Because many chemotherapeutic agents are directed at mechanisms involved in cell replication and differentiation, it is often necessary to reduce both the dose and duration of cancer treatment. The absence of specific information about dosage and duration of the treatment in those patients is particularly challenging for the physician. Diabetes mellitus in patients with Bloom is not treated in a different manner than that occurring in the normal population. Finally, psychosocial intervention is very important. Family and teachers are advised to behave with the patients according to their true age rather than what is suggested by their stature.

Prognosis

Patients with Bloom syndrome have 150 to 300 times the risk of developing malignancies in comparison to normal individuals. Malignancies will occur in around 20% of patients, particularly leukemias that usually manifest around a mean age of 22 years. Patients who survive beyond 22 years will develop solid tumors at an average of 35 years. Around 10% of patients are affected by diabetes mellitus across their life time, although the risk of infection and the sensitivity to sunlight decreases with age.

Etiology

Bloom syndrome is transmitted in an autosomal recessive fashion, so that each parent of the individual affected carries one copy of the gene with the mutation without showing any symptoms. The gene involved is the BLM gene, resulting in a defective BLM protein. This protein plays a critical role in several domains. A mutation increases chromosomal exchange, in particular between sister chromatids and paternal and maternal chromosomes. In addition, BLM abnormalities impair the repair of DNA damage caused as a result of exposure to ultraviolet light, manifesting in increased sensitivity to sunlight. Mutations accumulate in the genome and ultimately increase the risk of cancer in patients suffering from this disorder. 

The major end protein affected in Bloom syndrome is DNA ligase I, an enzyme involved in DNA replication. Scientists were able to show that patients with Bloom syndrome have a DNA ligase I with different physical properties, particularly in regards to heat sensitivity and the ability to aggregate [2] [3]. Other studies further corroborated the connection between Bloom syndrome, DNA Ligase I and metabolic abnormalities associated with the disease, in addition to uncovering the specific pathophysiological mechanisms involved. They report changes in the hydrolytic capacity of DNA Ligase I and its ability to bind ATP, without any reduction of the level of expression of the protein or other inhibitory molecules [4]. DNA Ligase I is part of a broader complex of enzymes involved in DNA repair and replication, that also includes DNA polymerase alpha, DNA polymerase beta and DNA ligase II.

Epidemiology

Bloom syndrome is a rare disease and affects men slightly more than women. Reports in the literature are scarce because only few hundred cases have been recorded, but the available reports indicate a higher incidence of disease in families with consanguinity among parents, as compared to the general population. As revealed through records of Bloom patients' registry, the syndrome has a high carrier frequency in the ratio of 1:120 and accounts for 25 % patients  among Ashkenazi Jews [5]. The syndrome has also been reported from Japan and other countries in families where there is consanguinity among parents. In comparison to the general population, patients also have 150 to 300 times higher risk of developing malignancy in their life time [6]. It is associated with premature delivery in affected pregnant women and diabetes in approximately 10% of patients. It manifests in the first months of life but does not seem to decrease overall intelligence levels, except in select cases.

Sex distribution
Age distribution

Pathophysiology

Bloom syndrome, also known as telangiectacic erythema, results from a mutation to the BLM gene present on chromosome 15. The exact location can be traced to 15q26.1 [7] [8] [9]. The BLM protein is a member of the RecQ family of helicases and is composed of 1417 amino acids. It is usually present in the nuclear matrix and is essential for DNA repair and replication. Mutations in the BML gene lead to defective protein that result in loss of genomic stability in somatic cells, and thus significantly increasing the risk of malignancy [10].

Around 60 mutations of the BLM gene have been associated with Bloom syndrome. Among the most common of mutations, which is present mostly among Ashkenazi Jews, involves a substitution of 6 nucleotides with 7 new ones at position 2281 in the gene sequence. Reports indicate an increased rate of chromatic exchange, chromosomal gaps, breaks and structural rearrangement and is 10 times more elevated in comparison to the normal population [11] [12] [13].

Bloom syndrome has been associated with Fanconi anemia, given the involvement of proteins MM1 and MM2 in both diseases. They tend to show similar phenotypes and share distinctive features such as abnormalities in skeletal growth and short stature, failure of the bone marrow and hematologic cancers. Although the two diseases are not related genetically, pathophysiological mechanisms include disturbances along common pathways in DNA repair, involving the complexes , BRAFT and FANCM [14] [15].

Patients with Bloom syndrome are known to be sensitive to sunlight with a reduction of the threshold for minimal erythema for both, UV-A and UV-B light [16]. This is caused by an increased vulnerability of the DNA to ultraviolet radiation, particularly for wavelengths corresponding to 313 nm. They are especially susceptible to radiation in UV-A range although it is important to note that, unlike in xeroerma pigmentosa, there is increased phototoxicity and not photocarcinogenicity [17].

Other prominent features of the disease are related to the immune system and affect both the humoral and cellular immune responses [18]. They include deficits in lymphocytic proliferation, abnormal immunoglobulin synthesis and impaired reaction to mitogen stimulation.

Prevention

There is no cure for Bloom syndrome but important preventive measures can be performed to reduce the risk of complications. Sunscreens and the avoidance of sunlight may prevent the skin damage associated with sun exposure. In addition, patients are recommended to avoid known mutagens [20]. Immunoglobulin replacement can help in preventing infections due to deficiencies in immunoglobulin production. In addition, patients should be periodically screened for any malignancy [21].

Summary

David Bloom was the first to describe Bloom syndrome in 1954 in a group of patients suffering from facial erythema and short stature [1]. The disease is most commonly encountered among Ashkenazi Jews (Jews of Central and Eastern European origin) and is chiefly characterized by growth abnormalities and sun sensitivity usually manifested by erythema of the face upon sun exposure. The facial rash has a butterfly shape over the cheeks and the nose and can also involve other areas of the body subjected to sunlight, including the forearms and the back of hands. 

Individuals with Bloom syndrome also suffer from a range of other abnormalities. They commonly develop frequent infections of the lung and the middle ear, most likely due to a higher incidence of gastroesophageal reflux associated with aspiration. As the age advances, the patient is more likely to have chronic obstructive pulmonary disease with severe bronchiectasis, as well as diabetes mellitus resembling the disease in the normal population. They are at a significantly increased risk of acquiring various malignancies that can affect different tissues at different sites of the body, necessitating frequent screening and monitoring. In addition, the disease affects the reproductive system with women undergoing early menopause although retaining their ability to conceive and men unable to produce sperm, leading to infertility.

Bloom syndrome is a genetic disease inherited in an autosomal recessive fashion. Individuals usually have a defective BLM gene, resulting in abnormalities in DNA replication and repair. 

Patient Information

Bloom syndrome was first described in 1954 by dermatologist David Bloom. It is a rare genetic disease, chiefly characterized by growth abnormalities and short stature. Patients usually retain normal body proportions although the head is disproportionately smaller. Increased sensitivity to sunlight, resulting especially in cracking and blistering of the lower lip, is another prominent feature and can be prevented with adequate avoidance of sun exposure. Growth abnormalities are commonly noticed at birth and infants typically show problems with feeding and decreased interest in nursing and eating. Patients develop frequent infections, especially of the lung (pneumonia) and the middle ear (otitis media), possibly resulting from the increased risk of aspiration and gastroesophageal reflux.

Bloom syndrome additionally affects the development of reproductive system. While women undergo premature menopause, they retain their ability to conceive. But, men are faced with an inability to develop normal sperm (azoospermia), leading to infertility. Patients with Bloom syndrome have a higher risk of developing several specific disorders as they age. These include chronic obstructive disease, mild diabetes mellitus that closely resembles the disease observed in the normal population as well as a variety of cancers that can affect different tissue types in various locations. The risk of developing malignancy makes it particularly important for patients to undergo regular screening and monitoring for the early detection of any cancer and the prevention of resulting complications. Patients with Bloom syndrome appear to have a normal mental capacity but demonstrate a decreased interest in learning, with a select few being affected by mental retardation.

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References

  1. Bloom D. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs; probably a syndrome entity. AMA Am J Dis Child. 1954; 88(6):754-758.
  2. Willis AE, Lindahl T. DNA ligase I deficiency in Bloom's syndrome. Nature. 1987; 325: 355-357. 
  3. Chan JYH, Becker FF, German J, Ray JH. Altered DNA ligase I activity in Bloom's syndrome cells. Nature. 1987; 325: 357-359.
  4. Chan JYH, Becker F F. Defective DNA ligase I in Bloom's syndrome cells: simultaneous analysis using immunoblotting and the ligase-(32-P) AMP adduct assay. J Biol Chem. 1988; 263: 18231-18235.
  5. 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(4):286-290. 
  6. Kaneko H, Inoue R, Fukao T, et al. Two Japanese siblings with Bloom syndrome gene mutation and B-cell lymphoma. Leuk Lymphoma. 1997; 27(5-6):539-542.
  7. Straughen J, Ciocci S, Ye TZ, et al. Physical mapping of the bloom syndrome region by the identification of YAC and P1 clones from human chromosome 15 band q26.1. Genomics. 1996; 35(1):118-128.
  8. Kim SY, Hakoshima T, Kitano K. Structure of the RecQ C-terminal domain of human Bloom syndrome protein. Sci Rep. 2013; 3:3294. 
  9. Salah GB, Salem IH, Masmoudi A, et al. Chromosomal instability associated with a novel BLM frameshift mutation (c.1980-1982delAA) in two unrelated Tunisian families with Bloom syndrome. J Eur Acad Dermatol Venereol. 2014; 28(10):1318-1323.
  10. Payne M, Hickson ID. Genomic instability and cancer: lessons from analysis of Bloom's syndrome. Biochem Soc Trans. 2009; 37:553-559. 
  11. Seki M, Nakagawa T, Seki T, et al. Bloom helicase and DNA topoisomerase IIIalpha are involved in the dissolution of sister chromatids. Mol Cell Biol. 2006; 26(16):6299-6307.
  12. LaRocque JR, Stark JM, Oh J, et al. Interhomolog recombination and loss of heterozygosity in wild-type and Bloom syndrome helicase (BLM)-deficient mammalian cells. Proc Natl Acad Sci U S A. 2011; 19. 108 (29):11971-11976. 
  13. Risch N, Tang H, Katzenstein H, Ekstein J. Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection. Am J Hum Genet. 2003; 72(4):812-822.
  14. Deans AJ, West SC. FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. Mol Cell. 2009; 36(6):943-953. 
  15. Guo R, Xu D, Wang W. Identification and analysis of new proteins involved in the DNA damage response network of Fanconi anemia and Bloom syndrome. Methods. 2009; 48(1):72-79. 
  16. Zbinden I, Cerutti P. Near-ultraviolet sensitivity of skin fibroblasts of patients with Bloom's syndrome.Biochem Biophys Res Commun. 1981; 98(3):579-587.
  17. Lehmann AR, Kirk-Bell S, Arlett CF, Paterson MC, Lohman PH, de Weerd-Kastelein EA, et al. Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation.Proc Natl Acad Sci U S A. 1975; 72(1):219-223. 
  18. Hütteroth TH, Litwin SD, German J. Abnormal immune responses of Bloom's syndrome lymphocytes in vitro. J Clin Invest. 1975; 56(1):1-7. 
  19. Arora H, Chacon AH, Choudhary S, et al. Bloom syndrome. Int J Dermatol. 2014; 53(7):798-802.
  20. Thomas ER, Shanley S, Walker L, Eeles R. Surveillance and treatment of malignancy in Bloom syndrome. Clin Oncol (R Coll Radiol). 2008; 20(5):375-379.
  21. Sanz MM, German Jw. et al. Bloom’s Syndrome. Gene Reviews. Available at http://www.ncbi.nlm.nih.gov/books/NBK1398/. Accessed: September 14, 2015.

  • A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome - AR Meetei, S Sechi, M Wallisch, D Yang - and cellular biology, 2003 - Am Soc Microbiol
  • Acquired immunodeficiency syndrome in infants - , BE Buck, JG Leterman, FL Bloom - New England Journal , 1984 - Mass Medical Soc
  • A novel coronavirus associated with severe acute respiratory syndrome - TG Ksiazek, D Erdman, CS Goldsmith - England Journal of , 2003 - Mass Medical Soc
  • Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients. - J German - American journal of human genetics, 1969 - ncbi.nlm.nih.gov
  • A clinical study of a family with Cockayne's syndrome - R Proops, AMR Taylor, J Insley - Journal of medical genetics, 1981 - jmg.bmj.com
  • A contribution to Bloom's syndrome: congenital telangiectatic erythema resembling lupus erythematosus in dwarfs - I KATZENELLENBOGEN, ZVI LARON - Archives of dermatology, 1960 - Am Med Assoc
  • A comprehensive scoring system for evaluating Noonan syndrome - , RB Ross, AW Wright, KR Bloom - American journal of , 2005 - Wiley Online Library
  • Analysis of single and twin sister chromatid exchanges in endoreduplicated normal and Bloom syndrome B-lymphoid cells - Y Shiraishi, TH Yosida, AA Sandberg - Chromosoma, 1982 - Springer
  • Abnormal skeletal phenotypes: from simple signs to complex diagnoses - A Castriota-Scanderbeg, B Dallapiccola - 2005 - books.google.com
  • A comprehensive scoring system for evaluating Noonan syndrome - , RB Ross, AW Wright, KR Bloom - American journal of , 2005 - Wiley Online Library
  • A manyfold increase in sister chromatid exchanges in Bloom's syndrome lymphocytes - RSK Chaganti, S Schonberg - Proceedings of the , 1974 - National Acad Sciences
  • An increased risk for malignant neoplasms in heterozygotes for a syndrome of microcephaly, normal intelligence, growth retardation, remarkable facies, - E Seemanova - Mutation Research/Reviews in Genetic Toxicology, 1990 - Elsevier
  • A new familial intrauterine growth retardation syndrome the “3-M syndrome” - J Spranger, JM Opitz, A Nourmand - European journal of pediatrics, 1976 - Springer
  • Bloom's syndrome. V. Surveillance for cancer in affected families - J German, D Bloom, E Passarge - Clinical genetics, 1977 - Wiley Online Library

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