NORD gratefully acknowledges Chris Cunniff, MD, Director of the Bloom Syndrome Registry, and Maeve Flanagan, BA, Research Assistant at the Bloom Syndrome Registry, for assistance in the preparation of this report.
Bloom syndrome (BSyn) is a rare genetic disorder characterized by short stature; a sun-sensitive, red rash that occurs primarily over the nose and cheeks; mild immune deficiency with increased susceptibility to infections; insulin resistance that resembles type 2 diabetes; and most importantly, a markedly increased susceptibility to many types of cancer, especially leukemia, lymphoma and gastrointestinal tract tumors. Diagnosis typically involves identification of the characteristic clinical features and/or molecular testing to identify changes to the BLM gene. BSyn is inherited in an autosomal recessive pattern, meaning that it occurs when a person inherits two changed (mutated) copies of the BLM gene. Because the most common BLM mutation is present at a high frequency in the Eastern European Jewish (Ashkenazi) population, it is often included among the Jewish genetic diseases. The genetic abnormality in Bloom syndrome causes problems with DNA repair, resulting in a high number of chromosome breaks and rearrangements. The abnormal DNA repair is responsible for the increased risk for cancer.
The most consistent clinical feature of BSyn, seen throughout all stages of life, is poor growth that affects height, weight and head circumference. This growth deficiency begins before birth, and the affected fetus is typically smaller than normal for gestational age. The average birth weight of affected males is 1760 g (range 900-3189 g) and of affected females, 1754 g (range 700-2892 g). Body proportions are nonetheless normal. The average adult height of affected males and females is 149 cm (range 128-164 cm) and 138 cm (range 115-160 cm), respectively.
While the facial appearance of people with BSyn is variable and may be undistinguishable from unaffected persons of similar age and size, infants and adults with Bloom syndrome usually present with a distinctively narrow head and face, but they have normal body proportions. Sparse subcutaneous fat may cause the nose and/or ears to appear prominent. Despite their very small head circumference, most affected individuals have normal intellectual ability.
Feeding difficulties are commonly reported in newborns, infants, and young children with BSyn. The child with BSyn characteristically feeds slowly, has a decreased appetite and eats a limited variety of foods. Some infants have had feeding tubes placed. Despite these interventions, weight gain continues to be modest, and children are rarely in the normal range for growth, even though their growth hormone levels are normal. Gastroesophageal reflux is common and may contribute to feeding issues.
Skin lesions are another hallmark of BSyn. Although the skin at birth and in infancy appears normal, a red rash later appears on the nose and cheeks in a “butterfly” shape, and sometimes on the hands and forearms due to the dilation of small blood vessels, called telangiectasia. The skin is highly sensitive to sunlight (photosensitive), and this rash often occurs for the first time following sun exposure in the first or second year of life. Areas of abnormal brown or gray skin coloration (cafe-au-lait spots) may occur on other parts of the body.
Male sterility is common because, for reasons that are not well understood, men with Bloom syndrome are unable to produce normal amounts of sperm. There has been one confirmed case of paternity in men with BSyn. Female infertility is also common because menstruation ceases at an abnormally early age among women with Bloom syndrome. Eleven women in the Bloom Syndrome Registry have become pregnant at least once, seven of whom have delivered a total of eleven healthy babies of normal size.
Many people with BSyn may show signs of immune deficiency. As a result, those affected can experience recurrent infections, primarily ear infections and respiratory infections. Additionally, about 10% of people with BSyn will develop diabetes.
At least 50% of people with this disorder eventually develop any one of a variety of cancers, especially leukemia and cancers of the gastrointestinal tract such as the colon. The types and locations in the body of cancer mimic those seen in the general population, but cancer occurs more frequently and at earlier ages among those with BSyn. Of the 283 persons in the Bloom Syndrome Registry, 148 individuals (52%) have developed a total of 240 cancers. Solid tumors account for 66.3% of all cancers, compared to 33.6% being leukemia/lymphoma. Among solid tumors, colorectal cancer is most common at 29 cases to date, followed by skin cancer (25 cases), then breast and oropharyngeal cancers (24 cases each). One-third of the people who have developed cancer develop multiple cancers.
People with Bloom syndrome appear to have 150-300 times the risk of developing cancerous growths as do people without this disorder. Most people with Bloom syndrome are likely to develop cancer over their lifetimes.
Bloom syndrome is inherited in an autosomal recessive pattern. This means that there is a mutation of both copies of the BLM gene in people with Bloom syndrome; and each parent carries one mutant copy and one normal copy. The causative gene has been mapped to chromosomal location 15q26.1 and is responsible for making a protein known as BLM. A single mutation, known as BLMAsh, is responsible for over 90% cases of Bloom syndrome among Ashkenazi Jews.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. This means that to be affected with Bloom syndrome, a person receives one mutated gene copy from his or her mother and one mutated gene copy from his or her father. The risk for two carrier parents to both pass down the disease-causing gene and therefore to have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Bloom syndrome is of special interest to geneticists because patients with this condition bear chromosomes that are highly unstable, so gene mutations are frequently encountered. In addition, the recombination of chromosomes in Bloom syndrome patients occurs with much greater frequency and seemingly with much greater ease than normal. Most clinicians engaged in studies of Bloom syndrome consider the volatility of the chromosomes to be a major contributor to both short stature and a predisposition to cancer.
One of the types of chromosomal recombination that occurs in Bloom syndrome because of mutations in the BLM gene is known as sister-chromatid exchange (SCE). This means that portions of the chromosomal-DNA are exchanged among paired (sister) chromosomes. Whereas persons without BSyn have an average SCE rate of <10 per cell division (metaphase), individuals with BSyn average 40-100 SCEs per metaphase. Previously, Bloom syndrome was the only known human genetic condition in which cells undergo high levels of SCE and therefore the presence of multiple SCE’s was a diagnostic indicator. However, SCE analysis alone is no longer sufficient to confirm a diagnosis of BSyn, because increased SCEs have since been observed in persons with two mutations on the RMI1, RMI2 and TOP3A genes (Hudson et al 2016, Martin et al 2018). Nonetheless, SCE analysis may be useful for diagnosis of BSyn in circumstances where only one BLM mutation is identified and molecular genetic testing finds no mutations in RMI1, RMI2 or TOP3A.
The BLM protein that is abnormal in people with Bloom syndrome is a RECQ helicase. Helicases help in DNA replication and repair by temporarily “unzipping” or “unwinding” the double helix of DNA so that it can be replicated. When this helicase is defective, as is the case in BSyn, a cell cannot detect and repair errors as effectively. This means that DNA damage during the course of a cell’s life is not found and repaired, so the cell cannot continue to function. The cell may die, or in some cases the damaged cells may continue to grow in an abnormal fashion and result in cancer.
Bloom syndrome is rare, with about 283 cases reported to the Bloom Syndrome Registry. Although it occurs in many ethnic groups, it is more prevalent in people of Ashkenazi Jewish heritage whose ancestors were from Poland or the Ukraine. Among Ashkenazi Jews in either New York City or Israel, the carrier frequency for Bloom syndrome is about 1 in 100. Among Ashkenazi Jews living in Israel, all four of whose grandparents were from Poland, the relative carrier rate is 1 in 37 (Shahrabani-Gargir, et al 1998). Bloom syndrome has been seen in many other persons from throughout the world however, and about 75% of cases occur in people who are not of Jewish ancestry.
The treatment of Bloom syndrome is symptomatic and supportive. Health supervision recommendations that address diagnosis, treatment and surveillance for complications in persons with Bloom syndrome have been published [Cunniff et al. 2018].
Both to prevent skin cancer and the typical red rash that is common in BSyn, persons with Bloom syndrome should limit contact with direct sunlight by seeking shade, especially between 10 a.m. and 4 p.m. Health recommendations also suggest covering exposed skin with clothing, including a broad-brimmed hat and UV-blocking sunglasses, and applying a broad-spectrum sunscreen with SPF of 30 twice daily, or every 2-3 hours if outdoors. Annual evaluation by a dermatologist is also advised.
Family members, friends and teachers are encouraged to relate to persons with BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. Nonetheless, infants, toddlers, and preschool-age children with BSyn should have close developmental monitoring and referral for early intervention services. If developmental delays are present, physical, occupational, and speech therapy can help. School performance should be assessed regularly, and parents should be aware of educational support available.
Growth hormone administration to children with BSyn has not consistently increased growth rate in most persons, but some have experienced improved linear growth. Use of growth hormone has been approached cautiously in this population, because of concerns regarding an increased risk to develop tumors as a result of their treatment. If growth hormone is prescribed, the growth response and serum IGF-1 and IGFBP-3 levels should be closely monitored, and unless there is an increase in growth velocity while under treatment, it should be discontinued.
Because of an increased incidence of hypothyroidism among the BSyn population, serum TSH with reflex to T4 should be measured annually beginning at 10 years. Additionally, recent health supervision guidelines suggest screening and family education on the signs and symptoms of hypothyroidism, including fatigue, constipation, cold sensitivity, and weight gain.
Until additional information is available regarding treatment of problematic feeding behaviors and gastrointestinal symptoms, standard treatment for these concerns is recommended. This may include consultation with a gastroenterologist or feeding specialist, use of high calorie diets, institution of reflux precautions and use of anti-reflux medications. While supplemental feeding may result in increased fat deposition, it does not necessarily result in improved linear growth. Because abnormalities have been identified in the lipid profile of persons with BSyn, caution should be exercised in the use of high fat and/or high cholesterol diets. A lipid profile to detect dyslipidemia is recommended annually beginning at 10 years; for those with dyslipidemia, dietary treatment according to standard protocols is recommended.
Diabetes mellitus is also prevalent among the BSyn population, so fasting blood glucose and hemoglobin A1C should be measured annually beginning at 10 years, and patients, their families, and their doctors should be alert for signs and symptoms such as increased thirst, increased urination, and weight loss. Treatment of diabetes mellitus in BSyn is the same as in other persons.
For those with defects in humoral immunity, weekly subcutaneous or monthly intravenous infusions of gamma globulin may be beneficial. Cough assist devices, vibration vests, and daily nasal lavage can be used to for mucociliary clearance for bronchiectasis. If an individual with BSyn experiences recurrent, severe, or opportunistic infection, then immunodeficiency screening, including immunoglobulin level, antibody responses to vaccines, and quantitative B and T lymphocyte measurements, are recommended.
Physicians must be conscientious in watching for indications of cancer, especially with patients who reach adulthood. A timeline for when to begin the suggested screenings and how often they should recur has been published [Cunniff et al. 2018]. It should be recognized however, that these recommendations are based on limited data from the Bloom Syndrome Registry and on expert opinion. There are currently no clinical trials or case control studies that address outcomes in people with BSyn. Because of the unusually high risk for early development of cancer, much of the health supervision effort is directed to early detection and treatment.
For pediatric patients, recent health supervision guidelines suggest screening for Wilms tumor by performing an abdominal ultrasound every 3 months from the age of diagnosis until 8 years, in addition to screening for signs and symptoms such as hematuria and a painless abdominal mass. Surveillance for hematological cancers largely depends on awareness of sign/symptoms, including unintentional weight loss and fatigue; additionally, pallor, abnormal bleeding, and petechiae when surveilling for leukemia and enlarged lymph nodes, unexplained fevers, and drenching night sweats for lymphoma. Screening for colorectal cancer begins at 10-12 years, with an annual colonoscopy and fecal immunochemical testing (FIT) every 6 months. In affected females over the age of 18, a breast MRI to detect breast cancer is recommended annually. The most recent guidelines also recommend a whole-body MRI every 1-2 years beginning at age 12 or 13 to detect other solid tumors or lymphomas.
When treating cancer, the hypersensitivity of persons with BSyn to both DNA-damaging chemicals and ionizing radiation ordinarily necessitates modification of standard cancer treatment regimens, which usually includes a reduction of both dosage and duration. Individuals with BSyn have usually tolerated doses at or below 50% of the standard chemotherapy dosage, with no clear evidence that this has resulted in poorer outcomes. However, full weight-based dosing may be appropriate for some chemotherapeutic drugs such as steroids and tyrosine kinase inhibitors. Absence of information as to the ideal dosages makes such treatment particularly challenging to the physician; nevertheless, the fact that the cancers themselves often appear unusually responsive to the treatment justifies the special effort. If HSCT is being contemplated, nonmyeloablative transplantation is likely to be tolerated more readily than other regimens. Additionally, the required ablative therapy prior to BMT often may require modification of standard protocols because of the hypersensitivity of persons with BSyn to DNA-damaging agents.
Because infertility is a common issue, men with BSyn can undergo semen analysis to assess for abnormalities in the quantity and motility of sperm (azoospermia, oligospermia, or asthenospermia). Women with BSyn should be aware of signs of early menopause and may also consider oocyte (egg) freezing (cryopreservation). Additionally, assisted reproductive technology (ART) may be beneficial if natural conception is not possible, but there are currently no reports of ART in this population. Those who wish to conceive should consider consulting with a fertility specialist.
Genetic counseling is recommended for people with Bloom syndrome and their families. Preimplantation and prenatal diagnosis are possible if the BLM mutations have been identified in the at-risk couple.
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