Bloom syndrome (BSyn), also known as Bloom-Torre-Machacek syndrome or Congenital Telangiectatic Erythema, is a rare, inherited genetic disorder. It is characterized by photosensitive skin, short stature, a red rash that appears primarily on the nose and cheeks, mild immune deficiency with increased sensitivity to insulin resistance similar to type 2 diabetes, and a significantly increased vulnerability to various types of cancer, (particularly lymphoma, leukemia, and gastrointestinal tract tumors) and infections.
A mutation in the BLM gene (RecQ helicase) provokes abnormal chromosomal breaks in the cells, which causes Bloom's syndrome. The lack of a BLM protein results in excessive homologous recombination, chromosome instability, and a significantly higher amount of sister chromatid exchanges, which are all the pathological characteristics of the syndrome.
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Causes and Symptoms
Bloom syndrome has an autosomal recessive inheritance pattern. It means that people with Bloom syndrome have a mutation in both copies of their BLM gene, and each parent carries one mutant copy and one normal copy. There is a 25% (1 in 4) chance of developing the condition when two autosomal recessive carriers have children.
The causative gene is located on chromosome 15q26.1 and is responsible for the production of a protein known as BLM. A single mutation known as BLMAsh is responsible for more than 90% of Bloom syndrome cases in the Ashkenazi Jews.
Poor growth - affecting height, weight, and head circumference, is the most consistent clinical symptoms of BSyn, seen at all stages of life. This growth disorder usually begins before birth, and the affected fetus is typically smaller than usual for gestational age.
The facial features of persons with Bloom syndrome are variable and are mostly indistinguishable from those of unaffected persons of the same age and size. Infants and adults with BSyn generally have normal body proportions but have notably narrow heads and faces.
Skin lesions are another BSyn symptom. Although the skin appears normal at birth and in infancy, due to the dilation of small blood vessels, known as telangiectasia, a "butterfly" shaped red rash appears later in life on the nose and cheeks, and sometimes on the hands and forearms. The skin is extremely photosensitive, and the rash usually appears for the first time after sun exposure in the first or second year of life. Other parts of the body may also have abnormal brown or grey skin coloration (cafe-au-lait spots).
Male sterility is one of the most common causes of Bloom's syndrome, as it causes the inability to produce normal amounts of sperm; the reasons for this are not well understood. Infertility in women is also common as BSyn ceases menstruation at an abnormally early age.
Most people with BSyn show signs of immune deficiency, which leads to frequent infections of various types, such as; ear infections, respiratory infections, etc.
In people with BSyn, the occurrence of any one variety of cancer is high. Leukemia, Lymphoma, and gastrointestinal tract tumors are the most common. At least 50% of people with BSyn develop cancer at some point in their lifetime. The types of cancer and locations mimic the general population. However, they occur more frequently in people with BSyn and at early ages.
Epidemiology
Although BSyn occurs in several ethnic groups, its occurrence is most visible in people with ancestral backgrounds from Poland or Ukraine, especially the Ashkenazi Jewish. A study conducted by Shahrabani-Gargir, et al. showed that carrier frequency among Ashkenazi Jews in New York City was 1 in 100. But for those in Israel with ancestors from Poland, the carrier frequency was observed 1 in 37.
Bloom's syndrome is rare and is seen across the globe, with about 283 cases reported to the Bloom syndrome registry. However, 75% of cases reported were in people with no Jewish ancestry.
Among the 283 reported individuals in the Bloom Syndrome Registry, around 148 (52%) people reported a total of 240 cancers. With 29 cases of colorectal cancer, 25 cases of skin cancer, 24 cases of oropharyngeal, and 24 cases of breast cancers, solid tumors were the most reported type of cancer (66%), compared to leukemia & lymphoma (33.6%). Around one-third of people who reported cancer, developed cancer more than once.
Diagnosis
Bloom's syndrome can be confirmed by conducting a few laboratory tests like chromosome study; blood and skin cells follow a pattern of chromosomal breaking and rearranging. Also, performing the tests to find chromosome instability, such as the presence of increased sister chromatid exchanges and quadriradicals.
Genetic screening is helpful for persons with higher chances of being a carrier of the syndrome, such as Ashkenazi Jews. Performing Polymerase Chain Reaction (PCR) and Targeted Mutation Analysis is also essential to examine the deletion of BLM 6 or insertion of BLM 7 mutation.
Periodic screening for leukemia and early screening for cervical, colorectal, and breast cancers are suggested. Opting for MRI and ultrasonography is advised to reduce radiation exposure in vulnerable patients.
Treatment
Because of the condition's rarity and complexities, there is no consensus on management or treatment. To avoid life-threatening dehydration, strict fluid management is necessary during the neonatal period. Supplemental feeding through gastrostomy tubes may help in preventing dehydration and malnutrition. However, it does not appear to improve linear growth. Growth hormone therapy is found ineffective in increasing the growth rate or adult height, and it may increase the risk of tumor development. Infections can be treated with appropriate antibiotics.
In patients with severe immunodeficiency, IV immune globulin replacement can be used. Frequently following up with endocrinology is important in order to treat diabetes mellitus. Dermatologic suggestions include avoiding exposure to the sun and frequent skin screenings.
Due to the lack of any signs of benefit, hematologic malignancy screening should be avoided in minors. However, it may be beneficial to adults, and hence annual cervical, breasts, and colorectal cancer screenings are important. As mentioned before, opting for MRI and ultrasonography is advised to reduce radiation exposure in vulnerable patients. Radiotherapy is not safe, hence suggested to be avoided. However, Proton beam therapy is very likely safer compared to radiotherapy.
References:
- Genetic and Rare Disease Information Center (2021). Bloom Syndrome. Retrieved Nov 10, 2021, from https://rarediseases.info.nih.gov/diseases/915/bloom-syndrome
- Hafsi, W., Badri, T., & Rice, A. S. (2021). Bloom Syndrome. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK448138/#_NBK448138_pubdet_
- (2020). Bloom syndrome. [Online] National Organization for Rare Disorders. Available at: https://rarediseases.org/rare-diseases/bloom-syndrome/
- Amira M. E., Bajoghli A., et al. Bloom Syndrome (Congenital Telangiectatic Erythema). Medscape. (2019). Accessed Nov 10, 2021. https://emedicine.medscape.com/article/1110271-overview
- Cunniff, C., Bassetti, J. A., & Ellis, N. A. (2017). Bloom’s syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Molecular syndromology, 8(1), 4-23. https://doi.org/10.1159/000452082
- Mizumoto, M., Hashii, H., Senarita, M., Sakai, S., Wada, T., Okumura, T., Tsuboi, K., & Sakurai, H. (2013). Proton beam therapy for malignancy in Bloom syndrome. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al], 189(4), 335–338. https://doi.org/10.1007/s00066-012-0274-1
- Thomas, E. R. A., Shanley, S., Walker, L., & Eeles, R. (2008). Surveillance and treatment of malignancy in Bloom syndrome. Clinical Oncology, 20(5), 375-379. https://doi.org/10.1016/j.clon.2008.01.007
- Shahrabani-Gargir, L., Shomrat, R., Yaron, Y., Orr-Urtreger, A., Groden, J., & Legum, C. (1998). High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin. Genetic testing, 2(4), 293–296. https://doi.org/10.1089/gte.1998.2.293
Further Reading
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