Bloom syndrome is a genetic disorder that has a very rare occurrence and is marked by growth deficiency which means the patient has a short height. Patients who are affected by this syndrome carry an increased risk of having cancer.
They also have sunlight sensitivity and develop a rash on the skin when exposed to sunlight. Bloom syndrome patients also have genomic instability, immune deficiencies, problems with carbohydrate metabolism, and insulin resistance.
Dr David Bloom first described this condition in 1954. Bloom syndrome patients have BLM gene mutations.
Other names for this disorder are Bloom’s syndrome and Congenital telangiectatic erythema. Another name that has been given to this genetic condition in old literature is Bloom-Torre-Machacek syndrome.
1. What is the Bloom Syndrome Registry?
Established in 1960, the Bloom syndrome registry is a research and surveillance program that aims to collect genetic as well as clinical information regarding Bloom syndrome. It involves medical professionals who know how to care for and fulfil the needs of people with Bloom syndrome.
The Bloom syndrome registry collects information in a systematic way regarding the patient’s pedigree and genetics. They also maintain biological samples like DNA samples of these patients. The information is kept safely and privately in a database.
The medical records that they maintain can be used for further research and act as an informational resource for the patients, their families as well as medical professionals. Any latest research and novel clinical findings can be updated in these records.
2. How is Bloom Syndrome Caused?
Bloom syndrome is autosomal recessive. Autosomes are the chromosomes present in our cells, other than the sex cells. There are 22 pairs of autosomes in humans. While the somatic cell is diploid, the gamete cells are haploid, as they are formed from meiotic cell division. Hence a gamete contains 22 autosomes instead of 22 pairs of autosomes and 1 sex chromosome instead of 1 pair of sex chromosomes.
An autosomal disorder will be due to any genetic mutation that occurs in one of the autosomes, and not the sex chromosome. A recessive disorder implies that the patient with that disorder has inherited both chromosomes with mutation.
In an autosomal recessive disorder, like Bloom syndrome, both the gametes that were involved in fertilization, the egg cell and the sperm cell, carried the autosome with a mutation. Hence the patient will get one abnormal gene from each parent.
The parents are mostly unaffected as they are just the carriers of the chromosome with mutation. This means that though the parent has the mutated chromosome, as it is present in only one copy, they will not have the symptoms like the affected individuals.
3. What Are the Mutations Involved in Bloom Syndrome?
Mutation in the BLM gene causes Bloom syndrome. The BLM gene is found on chromosome 15. BLM protein or Bloom syndrome protein is encoded by the BLM gene and its expression is absent in Bloom syndrome patients.
The protein that is expressed by the BLM gene, Bloom syndrome protein or RECQL3, belongs to the protein family RecQ helicases.
Helicases are enzymes that function in unwinding the DNA duplex, which is required for several processes like copying of DNA before cell division.
The enzyme also plays a role in DNA repair. Also referred to as genome guardians, the RecQ helicase protein family helps in maintaining DNA stability under replicative and transcriptional stress.
In Bloom syndrome, the mutations that occur in the BLM gene are null mutations and missense mutations. Due to BLM gene mutations, DNA replication errors occur, which then lead to increased chromosomal instability, like an increase in chromosomal rearrangements and abnormal breakages.
Before cell division, DNA is replicated so that both the daughter cells formed after cell division contain an equal amount of DNA content. Hence the new daughter cells that are formed will contain two copies of every chromosome, where one chromosome is from the maternal side and one chromosome from the paternal side.
The two copies of the same chromosome, which are identical and are formed after copying of the DNA, form sister chromatids. These sister chromatids are joined together with a structure called the centromere.
During the initial stages of cell division, the sister chromatids remain attached. During this duration, the sister chromatids exchange some genetic material between them, and this process is called the sister chromatid exchange. According to some studies, this exchange could be due to DNA damage that may have occurred during the DNA replication process.
The BLM protein plays a role here and makes sure that an excess sister chromatid exchange does not take place, along with maintaining DNA stability during replication.
In this condition, the BLM protein which is functional is absent due to mutations caused. This leads to a very high frequency of sister chromatid exchange, which is ten times more than the normal level of exchange. There is genomic instability in the cells of Bloom syndrome patients. DNA exchange between maternal and paternal chromosomes is also increased.
There is also an increase in the frequency of chromosome breakages, where chromatid breaks, chromatid gaps, and fragmented chromosomes occur.
These breakages and gaps that occur disrupt the normal functioning of the cells and this causes various health problems that are observed in Bloom syndrome patients. As the BLM protein was also involved with DNA repair, its absence causes a decrease in DNA repair processes.
UV light can cause DNA damage which is difficult to repair due to the absence of BLM protein, and this causes sun sensitivity in Bloom syndrome patients.
4. Who is Affected by Bloom’s Syndrome?
Bloom syndrome is a rare disorder. Presently, there are less than 300 people around the globe who are known to have Bloom syndrome. Though it has been reported in many ethnic groups, the disorder is more frequent among individuals from the Ashkenazi Jewish population.
A pathogenic variation or mutation is a type of mutation that increases the chances of a person developing a particular disorder. In Ashkenazi Jewish people who have Bloom syndrome, the most common pathogenic variant of the gene that causes the BLM mutation is referred to as blmAsh.
In Ashkenazi Jewish people, the carrier frequency of this pathogenic variant is – 1 in 100 for those who live in New York City, 1 in 100 for those who live in Israel, and 1 in 37 for those who live in Israel but all their grandparents from both maternal and paternal side are from Poland.
5. What Are the Symptoms of Bloom’s Syndrome?
There are many symptoms of this condition, however, not every symptom is present in people affected.
- Growth deficiency causing short stature
- Microcephaly- the head circumference is decreased
- Decreased appetite
- High pitched voice
- Reduced fertility
- Intellectual disabilities though not common
- Immune system deficiency
- Sensitivity from sun exposure causes skin rash
- Long and narrow face
- Small jaw
- Large ears
- Increased risk of infections like infections in the ear or lung infections
- Developmental delays
6. What Are the Complications Involved With Bloom Syndrome?
Bloom syndrome patients have a higher chance of having infections, developing cancer, delays in growth as well and developing rashes due to sun sensitivity.
6.1. Increased Risk of Cancer
Patients with Bloom syndrome are at a high risk of developing cancer. Around 50% of the affected individuals are detected to have cancer. The mean age at which cancer is detected in patients is 23 years and these patients die before reaching the age of 30 years.
The types of tumours and the regions where these tumours develop also vary. Complications that occur due to these cancers form the major reason that the patients die.
It is also known as blood cancer. It occurs in the tissues that are responsible for forming blood cells. In people with Bloom syndrome, it is one of the most commonly occurring cancers in the earlier ages, where the mean age is 20 years. It can be of myeloid as well as lymphoid type.
6.1.2. Non-Hodgkin Lymphoma (NHL)
NHL causes the production of an abnormal amount of lymphocytes. Like leukaemia, non-Hodgkin lymphoma is also one of the most commonly occurring cancers in the earlier ages, where the mean age is 20 years. They have a frequency of occurring around 150 to 300 times more common in people with Bloom syndrome than in the general population.
6.1.3. Breast Cancer and Colorectal Cancer
In breast cancer, the cells of the breast grow uncontrollably. Cancer can also develop in the gastrointestinal tract, and in Bloom syndrome patients, colorectal carcinoma commonly occurs. In colorectal carcinoma, cancer can develop in the colon or the rectum, occurring in the lower part of the gastrointestinal tract.
Other cancers that may develop are liver cancer, skin cancer, and brain tumours.
6.2. Chronic Obstructive Pulmonary Disease (COPD)
It is a term for multiple lung diseases. They block the airflow and make it difficult for the patient to breathe. Some examples of these lung diseases are emphysema and chronic bronchitis. After cancer, the second leading reason for the death of people with Bloom syndrome is pulmonary disease.
6.3. Recurrent Infections
Immune system deficiency can also occur in Bloom syndrome patients. This immune system deficiency is due to some immunoglobulin classes being expressed in deficient levels. The most commonly affected immunoglobulins are IgM and IgA levels, and sometimes IgG levels are also affected. There are also some reported adaptive immune system abnormalities.
This immunodeficiency can be responsible for repeated infections in patients with Bloom syndrome. Some of the commonly occurring infections are infections in the upper respiratory tract, ear, and lung infections.
6.4. Fertility Problems
Men with Bloom syndrome are usually not able to produce sperm due to azoospermia or extreme oligospermia and are therefore infertile. Women may be fertile but may have reduced fertility and may have menopause prematurely.
6.5. Skin Rash or Lesions
During birth and infancy, the skin may have a normal appearance. During the first few years of life, after sun exposure, red rashes can be observed commonly on the nose and cheeks, and sometimes on the hands and forearms, on the dorsal side.
The rash can be described as telangiectasia or poikiloderma. Telangiectasia refers to small and dilated or enlarged blood vessels on the skin. In poikiloderma, the skin appears to have reddish-brown spots.
Some other skin conditions can include cheilitis (it is a condition where there is inflammation of the lips), fissuring of lips, alopecia areata (it is a condition where there is loss of hair in the form of bald patches), loss of hair in the eyelashes as well as the eyebrows of the patient, and presence of regions of hypopigmented skin which occur more often as well as cover larger areas in Bloom syndrome patients as compared to normal people.
Similarly, café au lait macules on the skin, which are hyperpigmented lesions, are also found in more numbers and larger areas in people with Bloom syndrome than in the normal population.
6.6. Feeding Complications
There are reports of feeding issues in infants and young children. They have a decreased appetite and eat limited types of food. This can lead to delayed growth and delayed weight gain. Feeding tubes may also be required and used.
A common problem that may be a cause of feeding issues in patients is gastroesophageal reflux. Gastroesophageal reflux is when the acid that is present in the stomach, or the bile goes backwards towards the oesophagus from the stomach. Hence in the oesophagus, it can lead to some irritation.
6.7. Diabetes Mellitus
This is caused due to insulin resistance in patients with Bloom syndrome. It resembles type-2 diabetes due to its insulin resistance, but unlike the age at which it occurs in the general population, in Bloom syndrome patients, it occurs at an earlier age.
7. How is Bloom Syndrome diagnosed?
Cytogenetic analysis can be done to test for increased levels of sister chromatid exchange in the cells. It can be done with blood lymphocytes which are cultured and then tested for the presence of quadriradial chromosome. The analysis can also be done to check for gaps, breaks, or rearrangements present in the chromatids.
Testing for BLM gene mutation can be done through genetic testing. Clinical features that are known to be associated with Bloom syndrome can also be observed for its detection, like growth deficiencies, and sun sensitivity causing skin rashes. Short stature is often misdiagnosed as dwarfism, and this should be taken care of through further testing.
For people having a high risk of being a carrier for BLM mutation, genetic testing can be performed. If the fetus is not growing normally, prenatal tests like amniocentesis can be done. A complete blood count can also be done, where the decreased levels of immunoglobulins like IgM and IgA, and sometimes IgG can be detected.
8. What is the Prognosis of Bloom’s Syndrome?
Prognosis means predicting what could be the likely course of development of a disease and what will be the chances of recovery from that disease or recurrence of that disease. A lot of Bloom syndrome patients live to adulthood.
The mean age of death in people with Bloom syndrome is 26 years, and death mostly occurs due to cancer. The next leading cause of death is pulmonary disorders.
9. What are the Current Treatments Available for Bloom Syndrome Patients?
Due to the rarity of the disorder, there is no known specific method or route for treatment. There are different ways to manage and treat the various complications and health problems that occur due to this disorder. During the neonatal period, to prevent dehydration, fluid management is required.
To prevent malnutrition, feeding tubes are used. High-calorie diets can also be used. To manage sun sensitivity, avoiding exposure to the sun and using sunscreens are recommended, along with routine skin screenings. To treat recurrent infections, antibiotics can be used.
As cancer develops at an earlier age in Bloom syndrome patients, early detection can be done. But a study also suggests that early detection using hematological malignancy screening in children reaps no prognostic advantage, and hence should be avoided.
As the patients are at a higher risk of breakages in chromosomes, they should avoid any radiation exposure. Hence when detecting cancer, instead of radiography and CT scans (which use X-rays), MRI or ultrasounds can be done. For example, to detect breast cancer, a mammogram is usually used.
But it employs low amounts of X-rays. An MRI can be used in such a case, as it does not use any ionizing radiation.
Proton beam therapy can replace radiography for Bloom syndrome patients. For chemotherapy, the doses of the agents used have to be adjusted to prevent any form of toxicity.
Genetic counselling can be done and psychosocial support can be provided to the people with Bloom syndrome, as well as their families, to help them navigate the disorder and its complications in a well-informed and appropriate manner.
10. Final Words
Bloom Syndrome is an inherited disorder, yet a rare one. Until now only a few hundred people have been affected by this condition, and about 30% of them belong to Central and Eastern Europe.
I hope this article gave you a proper insight into the condition.