Nijmegen breakage syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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 and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal hair quantity · Very frequent (99-80%)

An abnormal amount of hair.

Abnormality of chromosome stability · Very frequent (99-80%)

A type of chromosomal aberration characterized by reduced resistance of chromosomes to change or deterioration.

Abnormality of the face · Very frequent (99-80%)

An abnormality of the face.

Abnormality of the hair · Very frequent (99-80%)

An abnormality of the hair.

Anal atresia · Very frequent (99-80%)

Congenital absence of the anus, i.e., the opening at the bottom end of the intestinal tract.

Anal stenosis · Very frequent (99-80%)

Abnormal narrowing of the anal opening.

Anorectal anomaly · Very frequent (99-80%)

An abnormality of the anus or rectum.

Attention deficit hyperactivity disorder · Very frequent (99-80%)

Attention deficit hyperactivity disorder (ADHD) manifests at age 2-3 years or by first grade at the latest. The main symptoms are distractibility, impulsivity, hyperactivity, and often trouble organizing tasks and projects, difficulty going to sleep, and social problems from being aggressive, loud, or impatient.

Other findings in the same source

From: Orphanet

Additional reported features include Autoimmune hemolytic anemia (Very frequent (99-80%)); Cachexia (Very frequent (99-80%)); Chronic diarrhea (Very frequent (99-80%)); Convex nasal ridge (Very frequent (99-80%)); Deep philtrum (Very frequent (99-80%)); Depressed nasal bridge (Very frequent (99-80%)); Hearing abnormality (Very frequent (99-80%)); Hemolytic anemia (Very frequent (99-80%)); Low anterior hairline (Very frequent (99-80%)); Macrotia (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Nijmegen breakage syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Nijmegen breakage syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.