Nijmegen breakage syndrome

Other Names: Berlin Breakage syndrome; Ataxia-Telangiectasia variant V1; Microcephaly with normal intelligence immunodeficiency and lymphoreticular malignancies; Nonsyndromal microcephaly autosomal recessive with normal intelligence; Seemanova syndrome 2; Microcephaly immunodeficiency lymphoreticuloma

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.

Epidemiology

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.

Cause

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

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).

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal hair quantity
• Abnormality of chromosome stability
• Anal atresia(Absent anus)
• Anal stenosis(Narrowing of anal opening)
• Attention deficit hyperactivity disorder(Attention deficit)
• Autoimmune hemolytic anemia
• Cachexia(Wasting syndrome)
• Chronic diarrhea
• Convex nasal ridge(Beaked nose)
• Deep philtrum
• Depressed nasal bridge(Depressed bridge of nose)
• Hearing abnormality(Abnormal hearing)
• Low anterior hairline(Low frontal hairline)
• Macrotia(Large ears)
• Mental deterioration(Cognitive decline)
• Microcephaly(Abnormally small skull)
• Prominent nasal bridge(Elevated nasal bridge)
• Prominent nose(Big nose)
• Recurrent pneumonia
• Recurrent sinopulmonary infections(Recurrent sinus and lung infections)
• Retrognathia(Receding chin)
• Short neck(Decreased length of neck)
• Short stature(Decreased body height)
• Sloping forehead(Inclined forehead)
• Thrombocytopenia(Low platelet count)
• Upslanted palpebral fissure(Upward slanting of the opening between the eyelids)

30%-79% of people have these symptoms

• Pollakisuria(Frequent urination)

5%-29% of people have these symptoms

• Abnormality of neuronal migration
• Acute leukemia
• B-cell lymphoma
• Cleft palate(Cleft roof of mouth)
• Cutaneous photosensitivity(Photosensitive skin)
• Freckling
• Glioma
• Muscle weakness(Muscular weakness)
• Non-midline cleft lip
• Respiratory failure
• Rhabdomyosarcoma
• Skeletal muscle atrophy(Muscle degeneration)
• T-cell lymphoma

Diagnosis

Diagnosis is based on the clinical manifestations, chromosomal instability (spontaneous and induced), increased cellular sensitivity to ionizing radiation in vitro, combined immunodeficiency, mutations in both alleles of the NBN gene, and complete absence of full-length nibrin. Early diagnosis is very important to avoid severe recurrent infections, unnecessary exposure to radiation for diagnostic purposes, and adverse effects of radiotherapy for treatment of tumors. Analysis of the family pedigree can also support diagnosis (malignancies, microcephaly or hydrocephaly, early death of a sibling). Molecular testing confirms diagnosis.

Differential diagnosis Differential diagnosis includes Fanconi anemia, Bloom syndrome, NBS-like disorder, ataxia-telangectasia-like disorder, LIG4 syndrome, NHEJ1 syndrome and Seckel syndrome .

Antenatal diagnosis Affected families may be offered prenatal diagnosis by molecular analysis if both disease-causing gene mutations are known.

Treatment

There is no specific therapy for NBS. Due to the specific defect underlying immune deficiency and sensitivity to IR radiation, patients require multidisciplinary management and long term follow-up (malignancy, immunodeficiency, growth, hypergonadotropic hypogonadism in females).

Prognosis

Prognosis is poor, with malignancy as the major cause of death.

NIH genetic and rare disease info

• NIH info on Nijmegen breakage syndrome

Nijmegen breakage syndrome is a rare disease.

Nijmegen breakage syndrome Resources
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