Omenn syndrome

Overview

Omenn syndrome is a rare and severe inherited immunodeficiency disorder that falls under the spectrum of Severe Combined Immunodeficiency (SCID). It is characterized by profound defects in both T-cell and B-cell immunity, but with the presence of a few abnormal, autoreactive T cells. The syndrome presents in early infancy with symptoms resembling autoimmune and allergic disorders, including widespread skin rashes, persistent diarrhea, enlarged lymphoid tissues, and failure to thrive.

Named after Dr. Gilbert Omenn, who first described the condition in the 1960s, Omenn syndrome is life-threatening if not treated promptly. Early identification and intervention, especially hematopoietic stem cell transplantation (HSCT), are critical for survival. The syndrome is considered a medical emergency in infants presenting with signs of severe immunodeficiency and autoimmunity.

Causes

Omenn syndrome is caused by mutations in genes that are essential for the development and function of the adaptive immune system, particularly for V(D)J recombination, a process crucial for the formation of functional T-cell and B-cell receptors.

Common Genetic Mutations

• RAG1 and RAG2: The most common genes associated with Omenn syndrome. These genes encode recombination-activating proteins 1 and 2, which are essential for assembling T-cell and B-cell receptors.

• Other implicated genes:

  • IL7R (interleukin-7 receptor alpha)

  • DCLRE1C (Artemis)

  • IL2RG (common gamma chain, also linked to X-linked SCID)

  • ADA (adenosine deaminase)

The syndrome is usually inherited in an autosomal recessive manner. Mutations in these genes do not completely abolish the function of immune cells but lead to the development of a small number of autoreactive T cells, contributing to the inflammatory and autoimmune-like symptoms seen in Omenn syndrome.

Symptoms

Symptoms of Omenn syndrome usually manifest within the first few weeks to months of life. Unlike classical SCID, where patients are prone to recurrent infections without signs of inflammation, Omenn syndrome presents with a paradoxical combination of immunodeficiency and immune hyperactivation.

Common Clinical Features

• Generalized erythroderma: A severe, red, scaly rash covering most of the body, present in nearly all cases.

• Lymphadenopathy: Enlarged lymph nodes.

• Hepatosplenomegaly: Enlarged liver and spleen.

• Chronic diarrhea: Often severe and associated with failure to thrive.

• Recurrent infections: Especially of the respiratory and gastrointestinal tracts, due to impaired immunity.

• Failure to thrive: Poor weight gain and growth despite adequate feeding.

Other Possible Features

• Elevated eosinophils and IgE: Despite overall immune deficiency, affected infants often show increased eosinophils and immunoglobulin E, mimicking an allergic response.

• Alopecia: Hair loss in some infants.

• Skin infections and superinfections: Due to skin barrier breakdown and impaired immunity.

Diagnosis

Early diagnosis is critical for initiating life-saving treatment. Diagnosis is based on clinical presentation, immunological studies, and genetic testing.

Clinical Evaluation

• Infants with early-onset rash, lymphadenopathy, diarrhea, and growth failure should raise suspicion.

Laboratory Tests

• Complete blood count: May show eosinophilia and lymphopenia.

• Serum immunoglobulins: Often low IgG and IgA, but paradoxically high IgE levels.

• Lymphocyte subsets (flow cytometry):

  • Low or absent B cells

  • Oligoclonal, activated T cells (often CD4+ dominant)

• T-cell receptor excision circles (TRECs): Absent or significantly reduced, indicating poor T-cell generation.

Genetic Testing

• RAG1/RAG2 sequencing: Confirms diagnosis in most cases.

• Whole exome sequencing: May be needed if RAG mutations are not found.

Skin Biopsy

• May show features of dermatitis with T-cell infiltration but is not diagnostic alone.

Treatment

Treatment of Omenn syndrome is urgent and focuses on restoring immune function and managing infections and inflammation. The cornerstone of curative therapy is hematopoietic stem cell transplantation (HSCT).

Curative Therapy

• Hematopoietic Stem Cell Transplantation (HSCT): The only curative option. Ideally performed as early as possible, before the onset of severe infections or organ damage.

Supportive Management

• Antimicrobial prophylaxis: To prevent infections (e.g., cotrimoxazole, antifungals).

• Immunoglobulin replacement therapy: Intravenous or subcutaneous IgG to support humoral immunity.

• Nutritional support: For infants with failure to thrive and gastrointestinal symptoms.

• Topical or systemic steroids: May help control inflammation and skin symptoms prior to HSCT.

Infection Management

• Prompt treatment of bacterial, viral, and fungal infections with appropriate agents.

• Avoidance of live vaccines due to the risk of severe vaccine-associated infections.

Prognosis

The prognosis of Omenn syndrome depends largely on the timing of diagnosis and the success of hematopoietic stem cell transplantation. Without treatment, the condition is typically fatal within the first year of life due to overwhelming infections, malnutrition, or multiorgan failure.

With early HSCT and aggressive supportive care, many infants can survive and experience improved immune function. However, complications such as graft-versus-host disease (GVHD), infection, and poor engraftment may still occur. Long-term follow-up is necessary to monitor immune reconstitution, developmental milestones, and possible endocrine or neurologic sequelae.

Genetic counseling is essential for affected families to understand inheritance risks and explore options for prenatal or preimplantation genetic diagnosis in future pregnancies.