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Conditions

IKBKB-associated immunodeficiency

IKBKB-associated immunodeficiency is a rare genetic condition causing severe defects in innate and adaptive immune signalling, leading to early-onset severe infections.

Overview

IKBKB-associated immunodeficiency is a rare, autosomal recessive life-threatening primary immunodeficiency condition, involving activation defects in adaptive and innate immunity. IKBKB encodes a subunit of the IKK complex, a key element of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) immune pathway. Both under- and over-activity of IκB kinase-β leads to failure of activation of T cells when exposed to pathogens. Affected patients can develop early-onset severe infections or, in autosomal dominant disease, autoimmune and autoinflammatory features.

Clinical features

Patients with autosomal recessive IKBKB-associated immunodeficiency present in infancy with features of combined immunodeficiency due to failure of activation of T and B cells. These features include:

  • severe, life-threatening infections:
    • bacterial, viral, fungal and mycobacterial pathogens;
    • opportunistic infections, such as Pneumocystis jiroveci; and
    • vaccine-strain infection following administration of live vaccinations such as BCG;
  • failure to thrive;
  • chronic diarrhoea;
  • hepatosplenomegaly; and
  • dermatitis.

Autosomal dominant IKBKB-associated immunodeficiency has also been described with predominantly autoimmune and autoinflammatory features, such as:

  • autoimmune haemolytic anaemia;
  • episodes of fever;
  • rash, including dermatitis and vitiligo;
  • arthritis;
  • lymphoproliferation; and
  • later-onset combined immunodeficiency features (initial T-cell proliferation is maintained but declines in adolescence) with recurrent infections.

Genomics

IKBKB-associated immunodeficiency is caused by biallelic pathogenic variants in the IKBKB gene. The gene encodes IκB kinase-β, a component of the NF-κB signalling pathway, which activates the transcription factor NF-κB. Complete loss of function leads to early combined immunodeficiency. Causative variants are biallelic and the majority are protein-truncating, resulting in a non-functional protein and absence of IκB kinase-β. Nonsense, frameshift, splice site and untranslated region variants have been reported.

Autosomal dominant gain-of-function variants in the IKBKB gene have been described, and are associated with a phenotype of autoimmunity and autoinflammation. Hyperactivation of the NF-κB signalling pathway leads to excessive inflammatory responses with paradoxical immune dysfunction. Biallelic missense variants leading to a gain-of-function effect have also been reported.

Diagnosis

IKBKB-associated immunodeficiency can be diagnosed following clinical and laboratory evaluation. Patients may have a family history of immunodeficiency. Clinical evaluation may allow identification of either loss- or gain-of-function disease, but laboratory tests can facilitate this.

Loss-of-function biallelic disease may show:

  • normal T- and B-cell counts;
  • impaired T-cell proliferation;
  • hypogammaglobulinaemia; and
  • reduced NK cell count.

Autosomal dominant gain-of-function disease may show:

  • reduced T- and B-cell numbers, particularly naive T cells; and
  • increased T regulatory cells.

The European Society for Immunodeficiencies diagnostic criteria is outlined below.

  • Recurrent and/or severe infections and at least two of the following:
    • normal T- and B-cell responses;
    • mild inflammatory reaction;
    • polysaccharide-specific serum antibodies deficiency; and/or
    • anhidrotic ectodermal dysplasia features.

For information about testing, see ‘Infant or child with severe, recurrent, persistent and/or unusual infections‘.

IKBKB-associated immunodeficiency may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to a clinical immunology service. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

IKBKB-associated immunodeficiency may be caused by biallelic (autosomal recessive) or monoallelic (autosomal dominant) pathogenic genetic variants in the IKBKB gene.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise, and that carriers do not appear to be affected by disease.

  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.
  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
    • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
    • Incomplete penetrance can occur (that is, not everyone who has the variant develops the disease).

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

Immediate management principles involve treating infection and preventing opportunistic infections. This includes:

  • no live vaccinations;
  • aggressive treatment of infections, including with anti-fungal and anti-viral agents;
  • antibiotic prophylaxis;
  • immunoglobulin replacement therapy; and
  • immunosuppressive agents if required.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications. Five-year survival rates are >90% if HSCT is undertaken when the patient is less than three months old. However, this survival rate declines with increasing age of transplantation and presence of active infections at the time of transplant. Patients require long-term monitoring following HSCT to assess immune reconstitution and monitor for potential complications.

IKBKB-associated immunodeficiency may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 01/08/2025
  • Next review due: 01/08/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay