Nezelof syndrome

Overview

Nezelof syndrome, also known as thymic dysplasia or Nezelof-type severe combined immunodeficiency (SCID), is a rare congenital immunodeficiency disorder characterized by the underdevelopment (hypoplasia) or absence (aplasia) of the thymus gland. This results in a severe deficiency of T lymphocytes (T cells), which play a critical role in the adaptive immune response. As a result, affected individuals are highly susceptible to recurrent and often severe infections early in life.

Nezelof syndrome is considered a variant of severe combined immunodeficiency, although it primarily affects cell-mediated immunity. It typically presents in infancy or early childhood with recurrent bacterial, viral, and fungal infections, failure to thrive, and complications related to immune system dysfunction.

Causes

Nezelof syndrome is caused by a genetic defect that impairs the development or function of the thymus gland. Although the exact genetic basis is not completely understood, some cases have been linked to autosomal recessive inheritance patterns.

The condition is distinct from other types of SCID in that B cells are often present in near-normal numbers, but T cells are significantly deficient or functionally impaired due to thymic hypoplasia. Immunoglobulin levels may be normal or slightly reduced, but the absence of T-cell help renders the immune response ineffective.

Symptoms

Symptoms of Nezelof syndrome usually appear in the first few months of life and are primarily related to immunodeficiency. Without functional T cells, the body cannot effectively respond to pathogens, resulting in recurrent and potentially life-threatening infections.

Common Clinical Features

• Recurrent bacterial, viral, and fungal infections (e.g., pneumonia, otitis media, thrush, skin infections)

• Failure to thrive (poor weight gain and growth)

• Chronic diarrhea

• Persistent oral candidiasis (thrush)

• Lymphopenia (low lymphocyte count)

• Hepatosplenomegaly (enlargement of liver and spleen)

• Skin rashes or eczema-like dermatitis

• Severe reactions to live vaccines (e.g., MMR, BCG)

Other Potential Features

• Delayed or absent lymphoid tissue development (e.g., small or absent tonsils and lymph nodes)

• Increased susceptibility to opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP)

Diagnosis

Early diagnosis of Nezelof syndrome is critical due to the high risk of severe infections and mortality. Diagnosis typically involves a combination of clinical evaluation, laboratory studies, and immunologic testing.

Diagnostic Tests

• Complete blood count (CBC): Often reveals lymphopenia

• Lymphocyte subset analysis: Shows marked reduction in CD3+ T cells; B cells (CD19+) may be present

• Immunoglobulin levels: May be normal or reduced; functional antibody responses are typically poor

• Thymic imaging: Chest X-ray may show absence of thymic shadow

• Delayed-type hypersensitivity skin testing: Often absent due to lack of T-cell response

• Genetic testing: May be used to rule out other types of SCID or related immunodeficiencies

Treatment

There is no definitive cure for Nezelof syndrome, but several treatment strategies aim to restore immune function, prevent infections, and manage symptoms. Early intervention significantly improves outcomes.

Infection Management

• Prophylactic antibiotics: To prevent bacterial infections

• Antifungal and antiviral prophylaxis: To prevent opportunistic infections such as thrush or CMV

• Aggressive treatment of infections: Prompt use of appropriate antimicrobial agents

Immunological Support

• Immunoglobulin replacement therapy (IVIG): To provide passive immunity

• Avoidance of live vaccines: Due to the risk of vaccine-derived infections

Curative or Restorative Treatments

• Hematopoietic stem cell transplantation (HSCT): The most effective and potentially curative treatment; best outcomes if performed early

• Thymus transplantation: Experimental in some centers for patients with thymic aplasia

• Gene therapy: Currently under investigation; may become a future option

Supportive Care

• Nutrition support for children with failure to thrive

• Regular follow-up with an immunologist

• Psychosocial support for families

Prognosis

The prognosis of Nezelof syndrome depends on the severity of the immune deficiency and the timing of diagnosis and treatment. Without intervention, the condition is often fatal in early childhood due to overwhelming infections. However, with early hematopoietic stem cell transplantation or effective supportive care, survival rates can improve significantly.

Lifelong monitoring is essential to manage complications, ensure appropriate immune function, and support physical and developmental milestones. Advances in genetic testing, early newborn screening for immunodeficiencies, and improved transplant protocols continue to enhance outcomes for children born with Nezelof syndrome.