Bloom syndrome is a disorder characterized by poor growth, frequent infections, sun sensitivity and increased cancer risk at a young age. This disorder occurs due to the inhibited function of a protein necessary for maintaining the integrity of the genome, leading to DNA instability and chromosomal changes.
What are the Symptoms of Bloom Syndrome?
Affected people have normal body proportions and muscle development but are smaller than normal at birth and remain shorter than normal as they grow. Infants and young children usually have very limited body fat and often do not show much interest in feeding. Immune problems result in frequent infections, particularly ear infections and lung infections (pneumonia). Gastroesophageal reflux is common in affected infants and may contribute to the risk of pneumonia and further complications, including bronchiectasis (abnormal widening of the bronchi) and chronic lung disease.
People with Bloom syndrome are extremely sensitive to sun exposure and develop patchy red skin lesions, particularly on the face and sometimes on the hands and forearms. Both benign and malignant tumors occur more frequently and at a younger age in affected children and adults. There is a significantly increased risk of leukemia and colorectal and breast cancers. Often affected people develop the typical adult-onset form of diabetes at a much younger age. Men are infertile, whereas some women may be fertile but menopause occurs unusually early. Other features can include a high-pitched voice, a long, narrow face, prominent nose and ears and an undersized jaw. Some individuals may also have learning disabilities. People with Bloom syndrome have a shortened life expectancy, often due to cancer occurring by their early to mid 20s.
What Causes Bloom Syndrome?
Bloom syndrome is caused by genetic changes in the BLM gene, which encodes RECQL3. RECQL3 is an enzyme that is involved in repairing damage to the DNA, therefore maintaining the integrity of the genome. Most affected Ashkenazi Jewish individuals have an inactivated RECQL3 protein, due to a genetic change in BLM commonly called 2281del6/ins7. This mutation is also known as c.2207_2212delinsTAGATTC (nucleotide change) and p.Tyr736LeufsTer5 (protein amino acid change).
Without the RECQL3 protein, damaged DNA cannot be repaired effectively, leading to mutations that affect growth, the immune system, an increased cancer risk and sensitivity to sun exposure. Between 1 in 100 and 1 in 134 people of Ashkenazi Jewish heritage have one copy the defective BLM gene (and one normal copy) and are known as carriers. Bloom Syndrome occurs when a person has two defective copies of the BLM gene and affects 1 out of every 40,000 – 50,000 people of Ashkenazi Jewish heritage. Bloom syndrome is very rare in the general population.
How is Bloom Syndrome Diagnosed?
Bloom syndrome is diagnosed by molecular genetic testing and cytogenetic testing. The cytogenetic tests are performed on cultured cells, such as lymphocytes, skin fibroblasts or exfoliated fetal cells. This analysis looks for abnormal chromosomal changes, including chromatid gaps, breaks and rearrangements, quadriradial configuration and sister-chromatid exchanges.
RECQL3 is known as a caretaker of the genome, so in the absence of functional RECQL3 (in Bloom syndrome patients), there is an increased number of gaps, breaks and rearrangements in the chromosomes. Quadriradial configurations occur between paired chromosomes in 1 – 2% of cultured blood lymphocytes from Bloom patients compared to none in controls. Before a cell divides to form two cells, the DNA is duplicated so that each new cell will have two copies of each chromosome. These duplicated chromosomes are organized into identical structures called sister chromatids. Genetic material can be swapped between these sister chromatids and is known as a sister chromatid exchange. In a healthy cell less than 10 sister chromatid exchanges will occur. In a single cell of a Bloom syndrome patient, 40 – 100 exchanges can occur.
Molecular genetic testing is a very useful technique to directly identify the underlying cause of Bloom syndrome – a defective BLM gene. The DNA analysis offered in the Jewish Disease Panel identifies the 2281del6/ins7 mutation in the BLM gene. This analysis is useful for confirming a Bloom syndrome diagnosis and identifying unaffected carriers of the Bloom syndrome mutation.
How is Bloom Syndrome Treated?
There are no cures for Bloom syndrome and often the life span of an individual with Bloom syndrome is shortened, most commonly due to cancer. Preventative management is very important, such as avoiding exposure to sun and regular screening for cancer. Children will require nutritional monitoring to assure maximum growth. Symptoms such as middle ear infections and pneumonia can be effectively treated using antibiotics to prevent permanent lung damage. Cases of diabetes in Bloom patients are treated in standard ways to avoid further complications.
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Ferreira JC, Schreiber-Agus N, Carter SM, Klugman S, Gregg AR, Gross SJ. (2014) Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. Am J Obstet Gynecol. 211(3): 197-204.
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