What is Chromosome Instability Syndromes?
Chromosomal instability syndromes are a group of hereditary diseases linked to unstable chromosomes that can spontaneously break or break when affected by substances that damage DNA. It’s noteworthy to mention that these syndromes often result in various degrees of weakened immune system, susceptibility to infections, and a higher risk of developing certain types of cancers. Some well-studied but rare chromosomal instability syndromes include Ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and Nijmegen breakage syndrome.
Additionally, there are other less common syndromes such as ataxia telangiectasia-like disorder, immunodeficiency, centromeric instability, facial anomalies syndromes, Cockayne syndrome, trichothiodystrophy, xeroderma pigmentosum, DNA ligase I deficiency, PMS2 deficiency, and flaws in DNA recombinase repair mechanisms.
What Causes Chromosome Instability Syndromes?
Chromosomal instability syndromes happen when the proteins or enzymes responsible for chromosomes don’t work properly. This can cause the chromosomes to break randomly or when they come into contact with agents that can damage DNA.
Risk Factors and Frequency for Chromosome Instability Syndromes
- Ataxia-telangiectasia, a chromosomal instability syndrome, occurs in approximately 1 in 40,000 to 100,000 live births.
- Bloom syndrome has been reported in various ethnic groups, but it is more commonly found among Eastern European (Ashkenazi) Jews. It is estimated that 1 in 120 people in this population are carriers of the syndrome.
- Fanconi anemia, although a rare condition, is the most common inherited bone marrow failure syndrome. Cases have been reported in all racial and ethnic groups.
- Nijmegen breakage syndrome is more commonly found in individuals of Eastern European descent.
Signs and Symptoms of Chromosome Instability Syndromes
Ataxia-Telangiectasia is a medical condition that often shows itself at a young age with symptoms like imbalance while walking, trouble coordinating hand movements, and eye movement disorders. Small, dilated blood vessels, or telangiectasias, can appear on the surface of the eyes (conjunctiva) when individuals are at school-going age. People with this condition often have frequent sinus and lung infections resulting from low levels of antibodies (immunoglobulins) and reduction of newly developed B and T cells. Without immediate treatment, these infections can progress to more severe conditions like bronchiectasis and pulmonary fibrosis. Young adults with this condition may also develop blood disorders like lymphoma and leukemia and are at a higher risk of acquiring other types of cancer and developing diabetes.
Bloom Syndrome symptoms can vary significantly between individuals. Symptoms might include abnormal short stature, a smaller head size (microcephaly), weakened immune system, sinus, and lung infections, decreased mental capability, facial anomalies, skin rash worsened by sun exposure, abnormal skin spots, infertility, a tendency to develop blood disorders and carcinomas, and insulin resistance.
Fanconi Anemia is an inherited disorder typically characterized by reduced blood cell count (pancytopenia), a higher probability of developing cancer, short stature, microcephaly, developmental delay, and various anomalies. These anomalies include :
- Skin pigmentation abnormalities
- Thumb or radial ray abnormalities
- Hand abnormalities such as clinodactyly or inwardly bent fingers
- Skeletal abnormalities such as a short or webbed neck and abnormally developed vertebrae
- Eye malformations
- Kidney and urinary tract alterations
- Genital malformations
- Ear abnormalities like middle ear anomalies or an underdeveloped ear canal
- Congenital heart conditions including patent ductus arteriosus and a hole in the wall separating the heart’s lower chambers
- Gastrointestinal and central nervous system abnormalities
Nijmegen Breakage Syndrome, like other disorders mentioned, exhibits progressively worsening symptoms. These include smaller head size, facial malformations leading to “bird-like” faces, slower growth while in the womb, intellectual disability, compromised immune system with frequent sinus and lung infections, a predisposition to lymphoid cancers, early ovarian failure, and heightened sensitivity to radiation.
Testing for Chromosome Instability Syndromes
Ataxia-Telangiectasia
Ataxia-Telangiectasia is diagnosed by checking for symptoms like difficulty in maintaining balance and small, red, spider-like veins, along with lung or sinus diseases. A brain MRI might also show signs of this disease. Comprehensive blood tests are conducted to check for a decrease in lymphocytes – a type of white blood cell. Certain proteins and another substance, immunoglobulin, might also be higher or lower than normal. The most decisive test involves looking for a mutation in a specific gene, the ATM gene. An important thing to note is that it is possible to identify this gene mutation even before birth.
Bloom Syndrome
In cases of Bloom Syndrome, doctors primarily evaluate the immune system. This involves specific blood tests including ‘serology’ (which studies the blood serum) and a basic blood count. These tests often show that there are decreased levels of immunoglobulins (proteins that play a key role in the body’s immune response) and a decreased count of lymphocytes.
Fanconi Anemia
Fanconi Anemia is most commonly diagnosed using ‘chromosomal stress testing’ and a wider check of a person’s DNA using a method called ‘next-generation sequencing’. The stress test involves checking the rate at which chromosomes in white blood cells break upon exposure to certain chemicals. Another useful test is ‘flow cytometry’ which assesses how cells move through different stages of their life-cycle when exposed to agents that could damage the DNA. In these cases, the cells are unable to repair such damages and get stuck at a certain stage, leading to an increase in the number of cells at this stage. Confirming the presence of Fanconi Anemia usually involves sequencing the genes associated with this condition.
Nijmegen Breakage Syndrome
Testing for Nijmegen Breakage Syndrome involves a detailed evaluation of the immune system. This includes checking the levels of immunoglobulin and certain types of white blood cells. Doctors might also use a technique called ‘karyotyping’ to check for any oddities in the chromosomes of the white blood cells. There are also tests to check the body’s sensitivity to radiation and the presence of mutations in certain genes or the lack of certain proteins.
Treatment Options for Chromosome Instability Syndromes
Ataxia-Telangiectasia is a condition that does not have a cure. However, its symptoms can be managed and supported. This includes physical therapy to help with movement difficulties, quick response to infections, and regulating diabetes if present.
Bloom Syndrome is similar, as there’s no definitive cure but its symptoms can be managed. Treatment includes immediate response to infections and regular screening for cancer. Also, to prevent any potential harm, it’s recommended for patients to avoid sun and radiation exposure.
For Fanconi Anemia, the primary focus of treatment is managing bone marrow failure and organ dysfunction, and regularly monitoring for cancer. The only cure for this condition is a type of stem cell transplant called allogeneic hematopoietic cell transplantation (HCT). There are also supportive treatments such as androgen therapy to boost blood cell levels, the use of a medication called granulocyte colony-stimulating factor, and blood transfusions.
Lastly, Nijmegen Breakage Syndrome treatment is aimed at managing symptoms. Quick treatment of any immunodeficiency is crucial, which may involve the use of antibiotics and intravenous immunoglobulins (a type of protein) to reduce risks or complications associated with this syndrome.
What else can Chromosome Instability Syndromes be?
When doctors assess patients with ataxia-telangiectasia, they have to make sure the symptoms aren’t caused by these other conditions:
- Cerebral palsy
- Friedreich’s ataxia (a genetic disorder that affects the nervous system)
- Gaucher disease (a genetic disorder affecting metabolism)
- Niemann-Pick disease (a group of severe inherited metabolic disorders)
In the case of Bloom syndrome, doctors may look for these conditions which can also result in shorter height:
- Skeletal dysplasia (abnormal growth and development of bones and joints)
- Growth hormone deficiency (when body doesn’t produce enough growth hormones)
- Constitutional delay of growth (slow but normal pattern of growth)
When trying to detect Fanconi anemia, a serious blood disorder, physicians need to rule out these conditions:
- Acquired aplastic anemia (fall in the count of all types of blood cells)
- Paroxysmal nocturnal hemoglobinuria (a rare, life-threatening blood disease)
- Drug-induced or infection-related loss of blood cells
- Certain genetically passed down bone marrow failure syndromes
- Other conditions including Nijmegen breakage syndrome, Bloom syndrome, Ataxia-telangiectasia, LIG4 syndrome, and more
For Nijmegen breakage syndrome, a rare genetic disorder, doctors may consider ruling out these conditions:
- Ataxia-telangiectasia and Ataxia-telangiectasia–like disease
- Fanconi anemia
- Bloom syndrome
- RAD50 deficiency (a condition that can lead to cancer)
- Seckel syndrome (a very rare inherited disorder)
And finally, when doctors detect cancers in patients with chromosomal instability disorders, they may also look into the possibility of patients having cancer syndromes, which could be due to mutations in genes that help control cell growth.
What to expect with Chromosome Instability Syndromes
The outlook for these genetic disorders associated with chromosomal instability vary as follows:
In the case of Ataxia-Telangiectasia, the rate of disease progression varies. With the classic form of the disease, patients often experience poor quality of life and high mortality rates by early adulthood.
For Bloom Syndrome, most patients live into adulthood. Regular cancer check-ups have shown to be associated with better health outcomes.
People with Fanconi anemia are managed differently depending on how severe their bone marrow failure is.
Lastly, the prognosis for Nijmegen breakage syndrome depends on how severe the patient’s symptoms are and how well infections are managed.
Possible Complications When Diagnosed with Chromosome Instability Syndromes
The main problems related to chromosomal instability are a higher likelihood of developing cancer, experiencing infections, and suffering from organ dysfunction.
Preventing Chromosome Instability Syndromes
Several conditions involving chromosomal instability often have a family link; early treatment can massively influence a patient’s chances of improvement. These conditions could potentially have a better outcome with proper management initiated at an early stage.