What to Know About Bloom Syndrome (BSyn)

What is Bloom Syndrome?

Bloom syndrome is an extremely rare inherited disorder. Since it was first diagnosed in medical literature in 1954, there are fewer than 300 cases documented by the Bloom Syndrome Registry.

Of these, about one-third are from Central and Eastern European (Ashkenazi) Jewish backgrounds.

People with this condition are usually smaller than 97 percent of the population in height and weight when they are born. As adults, they will remain short in stature and are rarely more than five feet tall ¹.

Individuals also will develop skin rashes after exposure to the sun because the mutated DNA associated with Bloom syndrome does not offer ultraviolet protection.

People with Bloom syndrome are also at a higher risk of developing cancer in their lifetimes.

Bloom syndrome is sometimes abbreviated as BSyn. It is also referred to as Bloom-Torre-Machacek syndrome or congenital telangiectatic erythema.

Causes of Bloom Syndrome

A mutation of the BLM gene causes bloom syndrome. It is inherited from one generation to the next through an autosomal recessive pattern ².

For this to happen, both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

With Bloom syndrome, the BLM gene, which provides instructions for making a member of the protein family called RecQ helicases, does not function correctly.

Regularly, when a cell gets ready to divide into two cells, the DNA in the original cell is copied so that each new cell will have a copy of each chromosome, one from each parent.

The copied DNA is arranged in two identical structures. These are called sister chormatids. They attach to each other and sometimes exchange small snippets of DNA when this happens. This is known as sister chromatid exchange.

Researchers believe these exchanges are a response to DNA damage during the copying process.

The BLM protein acts as a gatekeeper to prevent any excess chromatid exchanges from taking place. It provides stability for DNA during the copying process for this function, and for other processes as well.

RecQ helicases in the BLM gene are what helps to maintain the structure and integrity of a person's DNA. They are often referred to as "caretakers of the genome."

When the BLM gene mutates and does not function properly, the integrity of the RecQ helicases is undermined. Without proper regulation, chromatid exchanges do not take place as they are supposed to happen.

The BLM mutation deletes six DNA nucleotides and replaces them with seven others. Nucleotides are the building blocks of DNA.

Overall, more than 70 BLM gene mutations have been identified in people with Bloom syndrome.

One, in particular, the blmAsh mutation, results in the production of an abnormally short, nonfunctional version of the BLM protein.

Other BLM gene mutations change single protein building blocks (amino acids) in the protein sequence. They may also create a premature stop signal in the instructions for making the protein, reducing the amount of functional BLM protein.

With the absence of the functional BLM protein, the frequency of chromatid exchanges takes place ten times more frequently than it should, resulting in Bloom syndrome.

Chromosome breakage also occurs more frequently in affected individuals. All of these gaps and breaks in the genetic material impair normal cell activities and cause the health problems associated with Bloom syndrome.

For example, without the BLM protein, a cell is less effective in repairing DNA damage caused by ultraviolet light.

This leads to increased sun sensitivity. Also, genetic changes that allow cells to divide in an uncontrolled way lead to a higher frequency of cancers in people with Bloom syndrome.

Who Gets Bloom Syndrome?

Bloom syndrome is inherited from parents when both copies of the BLM gene in each cell have mutations.

This is known as an autosomal recessive inheritance pattern. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but in general, they do not show signs and symptoms of the condition.

Approximately 1 in 48,000 Ashkenazi Jews is affected by Bloom syndrome. They account for about one-third of affected individuals worldwide.

Signs & Symptoms of Bloom Syndrome

Bloom syndrome is characterized by several signs and symptoms:

Height and Weight. The most common sign of Bloom syndrome that takes place throughout a person's life is growth deficiencies in height, weight, and head circumference. Body proportions are normal, just smaller.

Before birth, an affected fetus is also smaller than usual throughout the gestational period.

Although fat tissue is sparse during childhood and in young adults with the condition, it is not uncommon for adults to develop central obesity over time.

Changes in diet and a healthy nutritional lifestyle do not impact growth patterns.

In some cases, people with Bloom syndrome have faces that are normal and indistinguishable from unaffected persons of similar age and size

However, for most of the affected population, the face will appear to be narrow. There may be underdeveloped malar and mandibular prominences and retrognathia or micrognathia.

Excess subcutaneous fat in the face may cause the nose or ears to appear prominent.

Individuals with Bloom syndrome also tend to have a high-pitched voice.

Feeding issues. Newborns, infants, and young children with Bloom syndrome will typically eat slowly, have less of an appetite, and eat a limited variety of foods.

Because of their slow growth and limited weight gain, children are often given formula with increased caloric density. Later in life, they may also be prescribed nutritional supplements that deliver additional calories.

Immunodeficiency issues. Children and adults with Bloom syndrome may suffer from one or more of the abnormally low plasma immunoglobulins

IgM and IgA levels are most commonly affected. T and B cells are usually healthy. However, these abnormalities of the adaptive immune system can lead to more frequent infections.

Infections. Affected children have more childhood infections than their siblings and peers. However, few persons with Bloom syndrome have had bacterial sepsis, meningitis, or pneumonia.

Skin lesions. Following exposure to the sun during the first one or two years of life can produce a red, sun-sensitive rash on the nose, cheeks, hands, and forearms.

The most common of these is that they usually develop a butterfly-shaped patch of reddened skin across the nose and cheeks.

The intensity of the rashes will vary; sometimes it is mild, and at other times it is bright red and can extend into other areas of the body.

Small clusters of enlarged blood vessels called telangiectases often appear in the rash.

In some cases, skin lesions such as cheilitis, blistering, and fissuring of the lips, eyebrow and eyelash hair loss, alopecia areata, and vesicular and bullous lesions can take place when there is excessive exposure to the sun.

Fertility. Most men with Bloom syndrome suffer from azoospermia or severe oligospermia. Women are generally fertile but may enter menopause prematurely.

Intelligence. Most people with Bloom syndrome appear to perform within the normal range of intellectual development.

Some require academic support for attention-related issues, but many others have excelled in school, with some earning graduate degrees.

Diagnosis of Bloom Syndrome

Bloom syndrome is diagnosed through prenatal genetic testing of the BLM gene. The condition should be suspected in persons with clinical or cytogenetic findings that include:

Clinical findings ³:

• Prenatal-onset growth deficiency that usually includes linear growth, weight gain, and head circumference and that persists into infancy, childhood, and adulthood
• Moderate-to-severe growth deficiency and a sun-sensitive, erythematous rash that commonly involves the face and appears in a butterfly distribution
• Moderate-to-severe growth deficiency and a diagnosis of cancer, usually occurring at an earlier age than in the general population

Cytogenetic findings ⁴:

• Increased numbers of sister-chromatid exchanges
• Increased quadriradial configurations (Qrs) in cultured blood lymphocytes (a mean of 1%-2% Qrs are observed in cultured blood lymphocytes from a person with BSyn vs. none in controls)
• Chromatid gaps, breaks, and rearrangements

Genetic testing can include either single-gene or multigene testing as well as comprehensive genomic testing.

Targeted testing means that the clinician must determine which genes are likely involved.

But because genomic testing is comprehensive and comprises a look at the DNA in all chromosomes, the specific gene will not need to be targeted.

Genomic testing can also help to identify other inherited disorders that are growth deficiency related.

According to the NCBI, recommended evaluations following an initial diagnosis of people with Bloom syndrome should include:

Carrier Screening and the Genetic Components for Bloom Syndrome

Genetic counseling and screening provide individuals and families with information on the nature, inheritance, and implications of Bloom syndrome.

It is possible to use the tools of genetic risk assessment, family history, and genetic testing to provide a more accurate genetic profile for family members who may be at risk for Bloom syndrome.

Bloom syndrome passes through generations in an autosomal recessive manner.

Genes come in pairs. One gene comes from the mother, and the other gene comes from the father.

For a condition such as Bloom syndrome to be inherited, both pairs of genes must be abnormal to cause the condition to present itself.

If only one parent has a defective gene, they are known as carriers, but they will not be affected by the condition. However, they can pass the abnormal gene to their children.

If both people carry the mutated gene but do not have signs of the disease, the odds of the expected outcome for each pregnancy is ⁵:

1. A 25% chance that the child is born with two normal genes (normal)
2. A 50% chance that the child is born with one normal and one abnormal gene (carrier, without disease)
3. A 25% chance that the child is born with two abnormal genes (at risk for the disease)

It is critical to note that these outcomes do not mean a child will definitely be carriers or be severely affected.

The optimal time to determine if someone is at genetic risk for a mutated BLM gene, or if they are simply a carrier, is before starting a family.

Prenatal genetic testing can give a clear picture of risks before entering pregnancy.

From this, people who are tested and found to be carriers can have an informed discussion with a genetic counselor about potential risks to offspring and their reproductive options.

If BLM variants are identified in a family member, then it is possible to perform a prenatal diagnosis on a pregnant mother through chorionic villus sampling (CVS) or by amniocentesis.

Preimplantation genetic diagnosis (PGD) is also possible and involves genetic testing of one or more cells removed from early embryos conceived by in vitro fertilization.

Only those embryos that do not have the mutated BLM gene are identified and transferred to the mother’s uterus.

Complications Associated with Bloom Syndrome

Several possible health complications can take place in people who have Bloom syndrome. They include but are not limited to:

• Many forms of cancer, especially at early ages
• Issues with treating those cancers due to chemotherapy sensitivities
• Recurrent infections of the upper respiratory tract, ears, and lungs, especially during infancy.
• Genetic instability
• Chronic obstructive pulmonary disease (COPD) and pulmonary failure
• Chronic bronchitis and bronchiectasis
• Diabetes mellitus as a result of insulin resistance
• Fertility issues
• Early menopause in women
• Hypothyroidism
• Cognitive delays

Treatments and Care Options for Bloom Syndrome

Several effective treatments and care steps can be taken for those who suffer from Bloom syndrome.

Because skin rashes are due to sun sensitivity, affected persons should avoid excessive exposure to sunlight.

They can do this by staying in the shade as much as possible, covering exposed skin with clothing and a hat, and using copious amounts of sunscreen with SPF 30 or higher at least twice daily, or every two to three hours if outdoors ⁶.

Growth deficiencies are countered to some degree by administering growth hormones.

This does not always consistently produce results, but some people have experienced improved growth over time.

There are concerns about using growth hormones because it can lead to an increased risk of developing tumors in people with Bloom syndrome.

People with Bloom syndrome are hypersensitive DNA-damaging chemicals and ionizing radiation ordinarily, and this means that standard cancer treatment regimens must be modified.

Both duration and dosage must be reduced to below 50 percent of conventional chemotherapy treatments.

Full weight-based dosing may be appropriate for some chemotherapeutic drugs such as steroids and tyrosine kinase inhibitors.

Hematopoietic bone marrow stem cell transplantation (HSCT) was performed in three persons in the Bloom Syndrome Registry.

One person had more than five years of disease-free survival before succumbing to another cancer, and the other two persons died in the immediate post-transplant period.

If HSCT is contemplated, nonmyeloablative transplantation is likely to be tolerated more readily than other regimens.

If infants or toddlers exhibit cognitive developmental delays, they can be referred for early intervention services.

In these cases, physical, occupational, and speech therapy can help. As the child grows and goes to school, performance should be assessed regularly, and support should be continued for as long as needed.

Because adequate nutrition is often a concern, consultations with a gastroenterologist or feeding specialist are commonly employed.

This can result in the introduction of high-calorie diets, the implementation of reflux precautions, and the use of anti-reflux medications.

Supplemental feeding may result in increased fat deposition, but studies have not indicated improved linear growth.

Treatment of diabetes mellitus in Bloom syndrome is the same as in other persons. Hyperglycemia from insulin resistance is treated as in type 2 diabetes.

Hypothyroidism may be present in Bloom syndrome patients, and if that is the case, standard protocols are used to administer thyroid hormone replacement therapy.

Defects in the immune system are managed with weekly or monthly infusions of gamma globulin.

Cough assist devices, vibration vests, and daily nasal lavage can be used to clear mucus or for bronchiectasis.

If a person with Bloom syndrome experiences recurrent or severe infections, immunodeficiency screenings are recommended.

If fertility issues are suspected, men can undergo semen analysis and also consult with a fertility specialist.

Women should be aware of the signs of early menopause. In both men and women, assisted reproductive technology (ART) may or may not be helpful in some instances.

People with Bloom syndrome should consider several additional medical surveillance procedures. At the direction of a medical professional, these may include ⁷:

1. Abdominal ultrasound examination every three months until age eight years for Wilms tumor.
2. Screening and family education regarding signs/symptoms of leukemia and lymphoma at every health visit.
3. Whole-body MRI every one to two years beginning at age 12-13 for risk of lymphoma.
4. Annual colonoscopy beginning at age 10-12.
5. Fecal immunochemical testing every six months beginning at age 10-12.
6. Annual breast MRI in women beginning at age 18.
7. Annual fasting blood glucose and hemoglobin A1C beginning at age ten.
8. Annual serum TSH with reflex to T4 beginning at age ten.
9. Annual lipid profile beginning at age ten.

There is also a psychosocial component to consider in people with Bloom syndrome. This is particularly important with school-age children.

Parents and teachers should both monitor their child's development from a developmental and a social point of view.

Children should be treated accordingly based on their chronologic age instead of a younger age than might be suggested by their abnormally small size.

People with Bloom syndrome may also benefit from genetic counseling.

Testing for a BLM gene variant in at-risk families, including expanded carrier screenings, can help to identify issues early and help carriers make essential decisions about family planning.

The Prognosis of People with Bloom Syndrome

People with Bloom syndrome have an average life expectancy of about 27 years. The most common cause of death is from cancers, most notably leukemias, lymphomas, and carcinomas.

According to Wikipedia, of 281 people followed by the Bloom Syndrome Registry, 145 persons (51.6%) have been diagnosed with a malignant neoplasm, and there have been 227 malignancies.

The types of cancer and the anatomic sites at which they develop resemble the cancers that affect persons in the general population.

What differs is that the age of diagnosis for these cancers is earlier than for the same cancer in healthy persons.

And many persons with Bloom syndrome have been diagnosed with multiple cancers.

What to do Next: Living with Bloom Syndrome

Because Bloom syndrome is so rare, research and monitoring of existing patients have not always been consistent.

For example, the Bloom's Syndrome Registry (BSR), established in 1960, has only operated intermittently, with limited funding and periods of closed enrollment.

In 2014, a new director was appointed, and since then, there has been an ongoing effort to revitalize the organization.

The BSR is integral to the research infrastructure needed for the Bloom syndrome community.

Many people with Bloom syndrome have been discouraged by the lack of progress and information available for this condition.

That also has limited participation in finding ways to manage the condition better.

Work continues in a more general effort to try and find better treatments for cancers and genetic solutions.

Currently, there are no cohesive efforts for developing a therapy for Bloom syndrome or the precision treatment of Bloom syndrome-related cancers.

Through a series of experiments in the 1970s, 1980s, and 1990s, the BLM gene was identified and was mapped to Chromosome 15.

But a complete understanding of the role of the associated BLM protein and its interaction with other proteins is lacking ⁸.

At present, the best way to live with Bloom syndrome is to take regular and preventative precautions through proactive self-care and to be aggressive in dealing with symptoms and complications as they flare up.

Resources

Support organizations and registries for individuals with Bloom syndrome include:

Bloom's Syndrome Association (BSA)
P.O. Box 727
Hanover NH 03755-0727
Phone: 603-643-2850
Email: [email protected]
www.bloomssyndromeassociation.org

Bloom's Syndrome Foundation (BSF)
7095 Hollywood Boulevard
#583
Los Angeles CA 90028
Email: [email protected]
www.bloomssyndrome.org

National Library of Medicine Genetics Home Reference
Bloom syndrome

Center for Jewish Genetics
Ben Gurion Way
30 South Wells Street
Chicago IL 60606
Phone: 312-357-4718
Email: [email protected]
www.jewishgenetics.org

Xeroderma Pigmentosum Society, Inc (XP Society)
XP Society has material on its site related to UV protection/avoidance.
437 Syndertown Road
Craryville NY 12521
Phone: 877-XPS-CURE (877-977-2873); 518-851-2612
Email: [email protected]
www.xps.org

Bloom Syndrome Registry
Weill Cornell Medicine
505 East 70th Street
3rd floor, Box 128
New York NY 10021
Phone: 646-962-2205
Bloom Syndrome Registry

Powered by Froala Editor