Nijmegen breakage syndrome

Overview

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder characterized by chromosomal instability, microcephaly, growth retardation, distinctive facial features, immunodeficiency, and a markedly increased risk of developing cancer, particularly lymphoid malignancies. It is classified as a chromosomal instability syndrome, similar to ataxia-telangiectasia and Bloom syndrome.

The condition was first described in patients of Slavic origin and is more common in populations from Eastern Europe. Individuals with NBS typically show signs from birth or early infancy and require lifelong monitoring due to their vulnerability to infections and malignancies. The hallmark of the syndrome is the body's inability to repair DNA double-strand breaks efficiently, leading to genomic instability.

Causes

Nijmegen Breakage Syndrome is caused by mutations in the NBN gene (previously known as NBS1), located on chromosome 8q21. The NBN gene encodes a protein called nibrin, which is crucial for DNA repair, specifically in the homologous recombination pathway for repairing double-strand DNA breaks.

The most common mutation among affected individuals of Slavic descent is a 657del5 deletion in the NBN gene. The disorder is inherited in an autosomal recessive pattern, meaning that both copies of the NBN gene must be mutated for the syndrome to manifest.

Symptoms

Symptoms of Nijmegen Breakage Syndrome typically appear in early childhood and may vary in severity. The condition affects multiple body systems, including the nervous, immune, and lymphatic systems.

Neurological and Growth Features

• Microcephaly: A small head size evident at birth, often with normal intelligence

• Growth retardation: Short stature and failure to thrive

• Mild developmental delay: Some children may have mild motor or cognitive impairments

Facial and Craniofacial Features

• Prominent midface

• Receding forehead and jaw

• Upturned nose and long philtrum

• Large ears

Immunologic Features

• Combined immunodeficiency (especially affecting IgA and IgG subclasses)

• Recurrent respiratory and gastrointestinal infections

• Poor response to vaccines

Cancer Susceptibility

• High risk of lymphoid malignancies such as B-cell and T-cell non-Hodgkin lymphoma

• Increased risk of other cancers, including medulloblastoma and glioma

• Early onset of malignancies (often in childhood or adolescence)

Other Possible Features

• Skin abnormalities (e.g., café-au-lait spots)

• Delayed or abnormal puberty

• Radiosensitivity (increased sensitivity to radiation exposure)

Diagnosis

Diagnosis of Nijmegen Breakage Syndrome involves clinical evaluation, laboratory studies, and genetic testing. It is essential to differentiate NBS from other chromosomal instability syndromes due to the risk of cancer and the need for special treatment precautions.

Diagnostic Criteria and Tools

• Clinical features: Presence of microcephaly, growth failure, characteristic facial appearance, and recurrent infections

• Cytogenetic studies: Increased chromosomal breakage and rearrangements, especially involving chromosomes 7 and 14 in lymphocytes

• Immunological testing: Low immunoglobulin levels and poor vaccine response

• Genetic testing: Identification of pathogenic variants in the NBN gene confirms the diagnosis

• Family history: Helps identify autosomal recessive inheritance patterns and carrier status

Treatment

There is no cure for Nijmegen Breakage Syndrome. Treatment is supportive and preventive, focusing on managing infections, reducing cancer risk, and monitoring for complications.

Infection Management

• Immunoglobulin replacement therapy: IVIG or SCIG to reduce the frequency and severity of infections

• Prophylactic antibiotics: May be used in patients with frequent infections

• Avoidance of live vaccines: Due to compromised immunity

Cancer Surveillance and Management

• Regular screening: Frequent evaluations for lymphomas and other malignancies

• Modified chemotherapy regimens: Must avoid radiation and genotoxic agents due to radiosensitivity

• Bone marrow transplantation: Experimental in some cases with severe immunodeficiency or malignancy, though outcomes vary

Supportive and Multidisciplinary Care

• Endocrinologic evaluation for delayed puberty

• Psychological and educational support for developmental needs

• Genetic counseling for families

Prognosis

The prognosis for individuals with Nijmegen Breakage Syndrome depends largely on the severity of the immunodeficiency and the timing and type of cancers that may develop. Recurrent infections and malignancies, particularly lymphomas, are the primary causes of morbidity and mortality.

With early diagnosis, careful monitoring, infection control, and tailored cancer treatment, some patients can survive into adulthood. However, life expectancy is significantly reduced compared to the general population, with many affected individuals developing cancer during childhood or adolescence.

Ongoing research into gene therapy, targeted treatments, and immunologic support offers hope for improved outcomes in the future. Regular follow-up with a specialized multidisciplinary team is essential to managing this complex and high-risk condition.