Nijmegen Breakage Syndrome Health Article

Definition

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.

Description

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 chromosomes 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.

Demographics

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). 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.