Nijmegen breakage syndrome (NBS), also known as Berlin breakage syndrome, is a rare genetic disorder that is characterized by a small head, stunted growth, immunodeficiency (weakened immune system), increased sensitivity to radiation therapy, and an increased risk of developing cancer, especially lymphoma.
NBS patients are born with a mutated gene that normally codes for a protein called nibrin. Nibrin helps repair DNA that has been damaged by chromosome breaks. DNA is present inside chromosomes. Therefore, NBS patients are susceptible to chromosomal breakage, which leads to rearrangements of translocations. In other words, one piece of a chromosome is broken off and joined to another chromosome.
Chromosomal rearrangements typically occur in chromosomes 7 and 14, both of which are involved in the development of the immune system.
Since NBS patients are immunocompromised, they have an increased risk of developing infections (especially respiratory tract and urinary tract infections) and cancer. They also have an increased risk of developing learning disabilities and mental retardation. In addition, NBS patients are more susceptible to chromosome breaks when they are exposed to radiation (often used to treat cancer) because they lack the nibrin necessary to repair damaged chromosomes.
The syndrome is named after the city Nijmegen in the Netherlands, where the first case of NBS was described in 1998. Currently, a registry of NBS patients is located in Nijmegen. The registry was developed to study the clinical, laboratory, and genetic features of NBS.
The disorder is extremely rare. About 70 cases have been reported worldwide. A total of 55 patients from 44 families have been enrolled in the Nijmegen registry since 2001. Most NBS patients are of Slavic or other European decent. However, a few cases have also been reported in New Zealand, Mexico, and the United States. Men and women are affected equally.
Patients with NBS have a decreased life span because they have an increased risk of developing infections and cancer. Cancer, especially lymphoma or leukemia, is the most common cause of death in NBS patients, accounting for about one-third of all NBS fatalities. Most NBS patients do not live beyond young adulthood.
Nijmegen breakage syndrome (NBS) is an autosomal recessive genetic disease. One mutated gene from each parent must be inherited in order for the child to develop the disease. Individuals who have the gene but do not express symptoms are called carriers. However, some reports suggest that carriers may also have a slight increased risk of developing cancer.
Carriers have a 50% chance of passing the abnormal gene to each of their children. If both parents are carriers of NBS, there is a 25% chance that each of their children will inherit the disease.
The gene for NBS, located on chromosome 8, is called the NBS1 gene. This gene codes for a protein called nibrin, which is present in all cells throughout the body. Nibrin helps repair DNA that has been damaged by chromosome breaks. Factors such as tobacco smoke, radiation therapy, and a hallucinogenic drug called LSD have been shown to cause chromosomal breakage in healthy individuals. Mutations in the NBS1 gene result in a shortened, nonfunctional version of nibrin throughout the body.
Therefore, NBS patients are susceptible to chromosomal breakage, which leads to rearrangements of translocations. In other words, one piece of a chromosome is broken off and joined to another chromosome. Chromosomal rearrangements typically occur in chromosomes 7 and 14, both of which are involved in the development of the immune system.
Birth defects: Individuals with Nijmegen breakage syndrome (NBS) have an increased risk of expressing birth defects. Most patients are born with a small head, and about half of NBS patients are born with malformed fingers or syndactyly (extra skin between fingers). There have also been reports of undeveloped ovaries (leading to infertility), as well as small brain size. Bone abnormalities, such as osteoporosis (hollow, brittle bones), hip dysplasia (malformed hip joint), and sacral agenesis (undeveloped parts of the spinal column and pelvis), are less common.
Mental: According to a 2001 study, about 40% of NBS patients have normal intelligence, 50% have borderline to mild mental retardation with an intelligence quotient (IQ) ranging from 55 to 70, and about 10% have moderate mental retardation with an IQ ranging from 40 to 54. Normal IQ ranges from 85-115, according to the Stanford-Binet scale. Out of the 55 NBS patients who were studied in 2001, the researchers found no correlation between head circumference at birth and IQ. Symptoms of mental retardation may include failure to reach intellectual development markers, decreased ability to learn, persistence of child-like behavior, and lack of curiosity.
Physical: Virtually all NBS patients are born with microcephaly (small head). Babies are usually either born small (the average weight of healthy babies at birth is seven pounds, six ounces) or experience growth delays during their first two years of life. The growth rate is normal once the patient is about two years old. However, adult NBS patients typically have a short stature. Facial characteristics often include a receding hairline and chin, long nose, extra folds of skin below the eyes, freckles, large ears, and thin hair. Also, many patients have pigment irregularities in the skin and eyes.
Cancer: Individuals with Nijmegen breakage syndrome (NBS) have an increased risk of developing cancer, especially B-cell lymphoma. Leukemia and other cancers have also been reported.
Infection: Individuals with NBS have an increased risk of developing infections, primarily respiratory tract and urinary tract infections. Gastrointestinal infections have also been reported.
General: If a patient exhibits NBS symptoms or a parent is aware that the genetic defect is present in their family, the following tests may be performed to confirm a diagnosis. A DNA test is the standard diagnostic tool for NBS.
Amniocentesis: Prenatal testing, such as amniocentesis, may be conducted if one of the parents is a carrier for the syndrome. Amniocentesis is used at about 15-18 weeks gestation to determine whether the fetus has NBS. During the procedure, a long, thin needle is inserted into the abdominal wall to the uterus and a small amount of amniotic fluid is removed from the sac surrounding the fetus. The fluid is then analyzed for a mutation in the NBS1 gene. There is a risk of miscarriage, ranging from one out of 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
Chorionic villus sampling: Prenatal testing, such as chorionic villus sampling (CVS), may be conducted if one of the parents is a carrier for the syndrome. Chorionic villus sampling may be performed in utero to determine whether the fetus has NBS. During the procedure, a small piece of tissue (chorionic villi) is removed from the placenta during early pregnancy. Depending on where the placenta is located, CVS can be performed through the cervix (transcervical) or through the abdomen (transabdominal). The tissue sample is then analyzed for a mutation in the NBS1 gene. The risks of infection or fetal damage are slightly higher than the risks of amniocentesis. Fetal loss (miscarriage) occurs in about two percent of women who undergo this procedure.
Cytogenetic analysis: Cytogenetic analysis is a test that is used to detect chromosomal instability, which is a characteristic of NBS. During the procedure, a sample of the patient's blood is taken, and the patient's chromosomes are stained during specific stages of replication. The sample is then observed to determine whether chromosomal abnormalities are present.
DNA analysis: A DNA analysis is the standard diagnostic tool for NBS. During the procedure, a sample of blood is analyzed for a mutation in the NBS1 gene. The patient's parents can also be tested to determine whether they are carriers of the mutated gene.
Nijmegen breakage syndrome (NBS) carriers, individuals diagnosed with NBS or individuals who suspect they may have NBS may benefit from genetic counseling. Genetic counselors work with a patient's healthcare team to provide information to patients about their disorders. They also help patients and their families understand the risks of inheriting a condition, their treatment options, and the risks of passing a disorder on to their children.
Healthcare providers can help patients locate genetic counselors that fit their individual needs.
There is currently no treatment for NBS. Individuals often require treatment for infections and cancer that develop as a result of the disease.
Cancer treatment: Since NBS patients are unable to repair damaged DNA after radiotherapy or chemotherapy, these therapies should be used cautiously in NBS patients.
Hormone therapy: Patients who experience delayed or absent sexual development may require hormone therapy. Hormone replacement therapy may help promote the development of secondary sexual characteristics and reduce the risk of osteoporosis.
Intravenous immune globulin (IVIG): Intravenous immune globulin (IVIG) can help reduce the number and severity of infections associated with the disease. IVIG preparations consist of antibodies that have been extracted from healthy donors. Antibodies detect and bind to foreign substances (like bacteria, fungi, and viruses) that enter the body. Therefore, treatment helps boost the body's immune system.
Antibiotics: Antibiotics may help reduce the number and severity of infections associated with the disease. Qualified healthcare providers may prescribe prophylactic (preventative) antibiotics for individuals who have recurrent respiratory tract infections or urinary tract infections due to congenital malformations of the kidneys. However, it is possible that individuals may become resistant to antibiotics, if they are taken regularly.
Supplements: Folic acid supplementation has been used to help prevent chromosome breaks, and vitamin B supplements have been used to help prevent further cell damage.
Currently, there is insufficient available evidence on the safety and efficacy of integrative therapies for the treatment or prevention of Nijmegen breakage syndrome (NBS).
Currently there is no known method to prevent NBS. However, people with familial histories of NBS may be tested to determine whether they are carriers of the disease.
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
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- [No authors listed]. Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child. 2000 May;82(5):400-6. .View abstract
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