Nijmegen breakage syndrome is a condition characterized by short stature, an unusually small head size (microcephaly), distinctive facial features, recurrent respiratory tract infections, an increased risk of cancer, intellectual disability, and other health problems.

People with this condition typically grow slowly during infancy and early childhood. After this period of slow growth, affected individuals grow at a normal rate but remain shorter than their peers. Microcephaly is apparent from birth in the majority of affected individuals. The head does not grow at the same rate as the rest of the body, so it appears that the head is getting smaller as the body grows (progressive microcephaly). Individuals with Nijmegen breakage syndrome have distinctive facial features that include a sloping forehead, a prominent nose, large ears, a small jaw, and outside corners of the eyes that point upward (upslanting palpebral fissures). These facial features typically become apparent by age 3.

People with Nijmegen breakage syndrome have a malfunctioning immune system (immunodeficiency) with abnormally low levels of immune system proteins called immunoglobulin G (IgG) and immunoglobulin A (IgA). Affected individuals also have a shortage of immune system cells called T cells. The immune system abnormalities increase susceptibility to recurrent infections, such as bronchitis, pneumonia, sinusitis, and other infections affecting the upper respiratory tract and lungs.

Individuals with Nijmegen breakage syndrome have an increased risk of developing cancer, most commonly a cancer of immune system cells called non-Hodgkin lymphoma. About half of individuals with Nijmegen breakage syndrome develop non-Hodgkin lymphoma, usually before age 15. Other cancers seen in people with Nijmegen breakage syndrome include brain tumors such as medulloblastoma and glioma, and a cancer of muscle tissue called rhabdomyosarcoma. People with Nijmegen breakage syndrome are 50 times more likely to develop cancer than people without this condition.

Intellectual development is normal in most people with this condition for the first year or two of life, but then development becomes delayed. Skills decline over time, and most affected children and adults have mild to moderate intellectual disability.

Most affected woman have premature ovarian failure and do not begin menstruation by age 16 (primary amenorrhea) or have infrequent menstrual periods. Most women with Nijmegen breakage syndrome are unable to have biological children (infertile).

Mutations in the NBN gene cause Nijmegen breakage syndrome. The NBN gene provides instructions for making a protein called nibrin. This protein is involved in several critical cellular functions, including the repair of damaged DNA. DNA can be damaged by agents such as toxic chemicals or radiation. Breaks in DNA strands also occur naturally when chromosomes exchange genetic material in preparation for cell division. Repairing DNA prevents cells from accumulating genetic damage that can cause them to die or to divide uncontrollably. The nibrin protein helps maintain the stability of a cell's genetic information through its roles in repairing damaged DNA and regulating cell division.

The NBN gene mutations that cause Nijmegen breakage syndrome typically lead to the production of an abnormally short version of the nibrin protein, which prevents it from responding to DNA damage effectively. As a result, affected individuals are highly sensitive to the effects of radiation exposure and other agents that can cause breaks in DNA. Nijmegen breakage syndrome gets its name from numerous breaks in DNA that occur in affected people's cells. A buildup of these breaks lead to errors in DNA that can trigger cells to grow and divide abnormally, increasing the risk of cancer in people with Nijmegen breakage syndrome. Additionally, medical radiation or chemotherapy, which is often used to treat cancers, can cause further DNA damage in people with Nijmegen breakage syndrome.

Nibrin's role in regulating cell division and cell growth (proliferation) is thought to lead to the immunodeficiency seen in individuals with Nijmegen breakage syndrome. A lack of functional nibrin results in less immune cell proliferation. A decrease in the amount of immune cells that are produced leads to reduced amounts of immunoglobulins and other features of immunodeficiency. It is unclear how mutations in the NBN gene cause the distinctive facial features, slow growth, and other features of Nijmegen breakage syndrome.

Normal Function

The NBN gene provides instructions for making a protein called nibrin. This protein is involved in several critical cellular functions, including the repair of damaged DNA.

Nibrin interacts with two other proteins, produced from the MRE11A and RAD50 genes, as part of a larger protein complex. Nibrin regulates the activity of this complex by carrying the MRE11A and RAD50 proteins into the cell's nucleus and guiding them to sites of DNA damage. The proteins work together to mend broken strands of DNA. DNA can be damaged by agents such as toxic chemicals or radiation, and breaks in DNA strands also occur naturally when chromosomes exchange genetic material in preparation for cell division. Repairing DNA prevents cells from accumulating genetic damage that may cause them to die or to divide uncontrollably.

The MRE11A/RAD50/NBN complex interacts with the protein produced from the ATM gene, which plays an essential role in recognizing broken strands of DNA and coordinating their repair. The MRE11A/RAD50/NBN complex helps maintain the stability of a cell's genetic information through its roles in repairing damaged DNA and regulating cell division. Because these functions are critical for preventing the formation of cancerous tumors, nibrin is described as a tumor suppressor.

Health Conditions Related to Genetic Changes

Nijmegen breakage syndrome

At least 10 mutations in the NBN gene have been found to cause Nijmegen breakage syndrome, a condition characterized by slow growth, recurrent infections, and an increased risk of developing cancer. The NBN gene mutations that cause Nijmegen breakage syndrome typically lead to the production of an abnormally short version of the nibrin protein. The mutation found in most affected individuals, particularly in Slavic populations of Eastern Europe, deletes five DNA building blocks (nucleotides) from the NBN gene (written as 657_661del5). This mutation leads to the production of a shortened version of the nibrin protein called p70-nibrin. This shortened protein is not as effective as normal nibrin in responding to DNA damage, but p70-nibrin does appear to have some residual function.

When breaks in DNA are not repaired properly, genetic damage can accumulate. A buildup of errors in DNA can trigger cells to grow and divide abnormally, increasing the risk of cancer in people with Nijmegen breakage syndrome. Nibrin's role in regulating cell division and cell growth (proliferation) is thought to lead to the problems with the immune system that are seen in affected individuals. A lack of functional nibrin results in less immune cell proliferation. A decrease in the amount of immune cells that are produced leads to a malfunctioning immune system. It is unclear how mutations in the NBN gene cause the other features of Nijmegen breakage syndrome.

Breast cancer

Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in each cell may be more likely to develop breast cancer than people who do not carry NBN mutations. Cells with a mutation in one copy of the NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time, which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.

Ovarian cancer

Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in each cell may be more likely to develop ovarian cancer than people who do not carry NBN mutations. Cells with a mutation in one copy of the NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time, which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.

Prostate cancer

Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in each cell may be more likely to develop prostate cancer than people who do not carry NBN mutations. Cells with a mutation in one copy of the NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time, which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.

Other cancers

Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in each cell may be more likely to develop an aggressive form of skin cancer (melanoma) or cancer of blood-forming cells (leukemia) than people who do not carry NBN mutations. Cells with a mutation in one copy of the NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time, which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.

Other Names for This Gene

• AT-V1
• AT-V2
• ATV
• Cell cycle regulatory protein p95
• NBN_HUMAN
• NBS
• NBS1
• Nijmegen breakage syndrome 1
• p95 protein of the MRE11/RAD50 complex

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The exact prevalence of Nijmegen breakage syndrome is unknown. This condition is estimated to affect one in 100,000 newborns worldwide, but is thought to be most common in the Slavic populations of Eastern Europe.