Nijmegen breakage syndrome

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Nijmegen breakage syndrome


Nijmegen breakage syndrome (NBS) is a condition in which chromosomes are susceptible to breakage and symptoms include short stature, small head size, and increased risk for learning disabilities/mental retardation, infections, and cancer .


Nijmegen breakage syndrome gets its name from the fact that the first patient was described in Nijmegen in the Netherlands. A registry of patients is maintained there, and patients with the syndrome are susceptible to having their chromosomes break. These breaks result in rearrangements of chromosomes called translocations, in which two chromosomes exchange pieces, and inversions, in which a section of a chromosome breaks off and rejoins the chromosome upside down. Chromosome rearrangements in NBS most commonly involve chrmosomes 7 and 14. Genes involved in the immune system, which fights infection, are located on these chromosomes; as a result of disruptions of these genes, most patients with NBS have an increased rate of infections, particularly those involving the respiratory system and the urinary tract. The chromosome breaks also increase susceptibility to cancer. People with NBS are more prone to chromosome breaks when exposed to radiation as well. Other defining features of NBS are short stature and small head size.

Genetic profile

NBS is an autosomal recessive disease, which means that one abnormal gene from each parent must be inherited to develop symptoms. A person with only one defective gene copy is called a carrier and will not show signs of NBS but has a 50% chance of passing along the gene to offspring with each pregnancy. Couples in which both parents are carriers of NBS have a 25% chance in each pregnancy of conceiving an affected child. The gene for NBS is on chromosome 8 and is called the NBS1 gene, coding for a protein called nibrin, which is found in all cells throughout the body. Normal nibrin is believed to be important in the repair of DNA which has been damaged by breaks in both strands.

Most patients have a specific change in both copies of the nibrin gene in which a string of five DNA bases, ACAAA, is missing from a specific area of the gene, leading to a shortened, or truncated, version of nibrin. A few other mutations have been reported in single patients. All of these mutations also result in a shortened, nonfunctional version of nibrin.


NBS is extremely rare. Approximately 70 patients have been reported. A total of 55 patients from 44 families had been reportedly enrolled in the Nijmegen registry as of 2001. Most patients have been of Slavic or other European descent, with a few patients reported from New Zealand, Mexico, and the United States.

Signs and symptoms

Virtually all patients with NBS have microcephaly, or a small head size (in the lower 3%), with about 75% having this feature present at birth. Young children with NBS show impaired growth. Babies with NBS are either born small or begin to experience growth delay during their first two years. The growth rate is normal after that, but the children always remain small for their ages. According to data available in 2001, approximately 40% have normal intelligence, 50% have borderline to mild mental retardation (IQ of 55 to 70), and 10% have moderate mental retardation (IQ of 40 to 54). As of 2001, the 55 patients studied in detail showed no correlation between head circumference at birth and IQ. There is a characteristic facial appearance, which includes a receding forehead, long nose, receding chin, extra folds of skin underneath the eyes, freckles on the nose and cheeks, large ears, and thin hair. Patients frequently have café au lait spots (areas of skin that are the color of coffee with milk), and other pigment changes in the skin and eyes.

The incidence of certain birth defects is increased in NBS, with about half of patients having malformed fingers or extra skin between the fingers (called syndactyly). A few patients have been reported to have anal malformations, lack of development of the ovaries and consequent infertility, hip abnormalities, and bone, kidney, and brain abnormalities. Notably lacking is the ataxia, which is progressive loss of coordination, seen in a disorder called ataxia-telangiectasia (A-T), which is otherwise very similar to NBS but is caused by a mutation in a different gene.

People with NBS are at increased risk for infections, most commonly affecting the respiratory tract and urinary tract. Infections of the gastrointestinal tract have also been reported. They are also at increased risk for cancer, mostly B cell lymphoma. Leukemia and other cancers have also been reported.


A diagnosis of NBS is suspected in children with small head size, slow growth at birth, characteristic facial features including a receding chin and prominent nose, recurrent infections, cancer (particularly B cell lymphoma), and borderline to moderate mental retardation. Prior to the discovery of the nibrin gene, diagnosis could only be confirmed by studying the levels of immune system proteins called immunoglobulins, looking for particular chromosomal changes involving chromosomes 7 and 14, and assessing radiation sensitivity in cells from patients.

Since the gene for NBS was discovered in 1998, it is now possible to look for a mutation in a patient's nibrin gene. As of 2001, all patients of Slavic origin and approximately 70% of the small number of patients in North America have had two copies of the common five DNA base mutation in the nibrin gene. Other North American patients have had at least one copy of another mutation unique to their family. If a mutation other than the common one is found, it is important to do further investigation to determine whether or not it causes disease, as non-disease causing changes have been reported in the nibrin gene.

Adults who are at risk for having children with NBS, such as siblings of patients, can have carrier testing to determine if they have one altered nibrin gene and are carriers for NBS. During pregnancy, the DNA of a fetus can be tested using cells obtained using the procedures called chorionic villi sampling (CVS), in which cells from the placenta are studied, or amniocentesis , in which skin cells from the amniotic fluid surrounding the baby are tested.

Treatment and management

As of 2001, there is no specific treatment for NBS, although folic acid (a vitamin B derivative) is recommended for prevention of chromosome breaks, since repair of these breaks is compromised in NBS. Similarly, vitamin E is recommended for prevention of further cell damage. For treatment of cancer, high doses of radiation must be avoided, since the damage inflicted on the cells could be fatal.


Patients with NBS have a decreased life span because of the tendency toward infection and cancer. Of the 55 patients in the NBS registry described in 2000, five had died from infections between infancy and eight years of age. Fourteen had died of cancer between the ages of two and 21 years of age. The remaining 36 living patients were between the ages of four and 30.



Wegner, Rolf-Dieter, et al. "Ataxia-Telangiectasia Variants (Nijmegen Breakage Syndrome)." In Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, edited by Hans D. Ochs, et al. New York: Oxford University Press, 1999, pp. 324-334.


The International Nijmegen Breakage Syndrome Study Group. "Nijmegen Breakage Syndrome." Archives of Disease in Childhood 82 (2000): 400-406.


Concannon, Patrick J., and Richard A. Gatti. "Nijmegen Breakage Syndrome." GeneClinics. University of Washington, Seattle. <>. (March 31, 2001).

"Nijmegen Breakage Syndrome." OMIM—Online Mendelian Inheritance in Man.<>. (March 31, 2001).

"Nijmegen Breakage Syndrome." Virginia Mason Research Center.<>. (March 31, 2001).

Toni I. Pollin, MS, CGC