Chromosomal Breakage Syndrome - An Overview

Introduction:

The chromosomal breakage syndrome or chromosomal instability disorder is a group of disorders occurring due to the instability of the chromosomes resulting in breakage or damage to the genetic material. They are very rare conditions where the clinician has not encountered such cases in clinical practice. There are several conditions associated with chromosomal instability, but the major ones are ataxia-telangiectasia, Bloom syndrome, Fanconi syndrome, and Nijmegen breakage syndrome. These syndromes are often associated with other health conditions such as high chances for malignancies, etc. In addition, a defect in the DNA (deoxyribonucleic acid) repair mechanism causes genomic instability in these disorders. Therefore, there are high chances for cancer predisposition. However, diagnosing these syndromes is often tricky due to their complex characteristics.

What Is the Incidence of Chromosomal Breakage Syndromes?

The incidence depends on the type of the syndrome. However, most cases are extremely rare and have not been encountered in clinical practice until now.

• Ataxia-telangiectasia is seen in 1 in 40,000 to 100,000 live births.

• Bloom syndrome is commonly seen in the Ashkenazi Jews, with a carrier frequency of 1 in 120 cases.

• Fanconi anemia is commonly seen in bone marrow failures. It is seen in almost all races and ethnic populations.

• Nijmegen breakage syndrome is common in eastern Europe.

What Is the Etiology for Chromosomal Breakage Disorders?

The defective proteins or the enzymes may be responsible for chromosomal breakage or instability.

What Are the Other Syndromes With Chromosomal Instability?

• Cockayne syndrome.

• Trichothiodystrophy.

• Xeroderma pigmentosum.

• DNA ligase 1 deficiency.

• PMS2 deficiency (PMS1 Homolog 2, Mismatch Repair system component).

• DNA recombinant repair defect.

What Are the Clinical Presentations?

The signs and symptoms vary in each of the disorders. The clinical presentation of each of the types is listed below:

Ataxia-Telengiectasia:

• Ataxia is seen at a very early age. Ataxia refers to incoordination of the hands and feet with improper eye movements.

• Conjunctival telangiectasia is the presence of tiny dilated blood vessels seen in the mucus membrane of the eye.

• Recurrent sinopulmonary infections due to reduced immunoglobulins, B, and T cells. Sinopulmonary infections are the inflammation of the paranasal sinuses and the airways of the lungs.

• Bronchiectasis and pulmonary fibrosis.

• High risk for malignancies such as lymphoma, leukemia, esophageal, breast, and lung cancers.

• Diabetes.

• Neurological problems include dystonia (a movement disorder that results in involuntary contractions of the muscles.

Bloom Syndrome:

• The typical presentation of Bloom syndrome is the presence of short stature.

Other findings include:

• Facial malformations with microcephaly.

• Sinopulmonary infections.

• Intellectual disabilities.

• Skin lesions such as cafe-au-lait spots or hypopigmented skin surfaces.

• Erythematous rashes.

Fanconi Syndrome:

• The typical sign of Fanconi syndrome is inherited bone marrow failure with pancytopenia (deficiency of the white blood cells, red blood cells, and platelets). There are high chances for malignancies. It includes other features like:

• The affected individuals are short with microcephaly (small head).

• The neck appears short and webbed.

• Clinodactyly (the finger appears to be curved, resembling a hook).

• Vertebral abnormalities.

• Presence of developmental delays.

• Skin pigmentations are seen. In Fanconi syndrome, the skin lesions are either hypopigmented or hyperpigmented.

• Malformations of the urinary tract, genitals, central nervous system, gastrointestinal, and renal systems.

• Eye deformities and dysfunction like microopthalmia, microcornea, ptosis, and delay in visual processing skills.

• Middle ear deformations like bilateral hearing loss.

• Cardiac problems such as patent ductus arteriosus and septal defects.

Nijmegen Syndrome:

• Microcephaly with facial deformities.

• The typical bird-like face appearance is present.

• Reduced intellectual ability.

• Sinopulmonary infections.

What Are the Possible Complications?

The major and serious complications associated with chromosomal breakage syndromes are increased predisposition to cancers and organ dysfunctions.

What Is the Prognosis?

• The patient will have a compromised or poor quality of life. Most of them are fatal and survive maximum till adulthood.

• Most of the affected individuals with Bloom syndrome may survive till adulthood. However, regular monitoring for cancers is required.

• The prognosis of Fanconi syndrome and Nijmegam syndrome depends on the severity.

How Are Chromosomal Breakage Syndromes Diagnosed?

Ataxia-Telengiectasia:

• Magnetic Resonance Imaging of the Brain: The brain MRI shows cerebellar atrophy (deterioration of the nerve cells of the brain).

• Complete Blood Count: It assesses lymphopenia (lack of white blood cells, particularly the lymphocytes).

• Serological Test: It is also called the antibody test that measures the levels of immunoglobulins or any antibodies specific to any infection. It also shows increased alpha-fetoprotein levels and decreased Immunoglobulin A (Ig A), Ig G, and Ig E are measured from this test.

Bloom Syndrome:

• Complete Blood Count and Serology Test: It shows decreased levels of immunoglobulins in the body, such as IgA, IgG, IgE, and lymphopenia.

Fanconi Syndrome:

• Chromosomal Stress Testing: This test assesses the chromosomal breakage seen in the T-lymphocytes obtained from the peripheral smear of the blood.

• Flow Cytometry: Flow cytometry analyzes the cell cycle and the types of cells in the blood and bone marrow. It also detects cell damage for the presence of any cancer cells.

Nijmegen Syndrome:

• Complete Blood Count: The complete blood count measures the immunoglobulin levels in the body and the CD4, CD8, CD-19, and CD-57 counts.

• Karyotyping: A test to identify the chromosomes and the presence of any genetic or chromosomal abnormalities in the cells.

What Is the Treatment Modality?

Most often, genetic disorders are treated only symptomatically for life support, and there is no definitive management and permanent cure for the disease.

• Ataxia-Telangiectasia: The primary treatment is treating the infections, and regular monitoring for cancer is essential. Treatment for diabetes is also necessary to keep the glycemic levels regular.

• Bloom Syndrome: These patients are requested to limit their exposure to sunlight and radiation.

• Fanconi Anemia: The primary treatment is to cure bone marrow failure. In addition, regular monitoring for cancer and organ dysfunction is essential.

• Androgen Therapy and Blood Product Transfusions: It increases the blood cell count.

• Allogeneic Hematopoietic Cell Transplantation: The best option to cure Fanconi anemia is allogeneic cell transplantation.

• Nijmegen Breakage Syndrome: Immunodeficiency is treated with antibiotics and intravenous immunoglobulins, reducing mortality and morbidity rates.

Conclusion:

The chromosomal breakage syndromes are extremely rare conditions that run in families. Hence, genetic testing is necessary during the preconception stage or the prenatal stage. If the child is diagnosed with such conditions, parents need not lose hope. Early diagnosis and management can improve their survival rate. However, regular follow-ups are required for the betterment of the child.