IRF8 deficiency

Interferon regulatory factor 8 (IRF8) deficiency is a primary immunodeficiency condition caused by defects in the IRF8 transcription factor, a key member of the IRF family of transcription factors that helps shape the inflammatory response. Affected patients have early-onset recurrent infections, particularly serious viral infections, due to low levels of dendritic cells and monocytes.

IRF8 deficiency can present in two ways: autosomal recessive disease with complete deficiency tends to present with broader immune dysregulation, while autosomal dominant IRF8 deficiency typically presents with milder disease at a later age.

Autosomal recessive IRF8 deficiency features:

• recurrent bacterial, viral and fungal infections from an early age, which may be invasive and difficult to treat;
• severe Epstein Barr virus (EBV) mononucleosis;
• lymphoproliferation;
• absent or very low levels of dendritic cells;
• absent or very low levels of monocytes; and
• reduced NK cells.

Autosomal dominant IRF8 deficiency features:

• susceptibility to atypical mycobacterial infections; and
• absent or very low levels of dendritic cells.

IRF8 deficiency is caused by biallelic (mostly missense) pathogenic genetic variants in the IRF8 gene. The gene encodes IRF8, a key transcription factor in regulating dendritic cell and monocyte development and function of NK cells.

Autosomal dominant loss-of-function variants in the IRF8 gene have been described, and are associated with a milder phenotype of predominant susceptibility to mycobacterial disease. Reported variants are all missense variants spread throughout the gene.

IRF8 deficiency may be diagnosed following clinical evaluation of recurrent or severe mycobacterial infections. Patients may have a family history of early-onset immunodeficiency.

Laboratory tests will show:

• absent or reduced monocytes (CD14+ CD16+) and dendritic cells (CD11c+ CD1c+);
• reduced NK cell number; and/or
• absent or reduced IFN-γ and IL-12 production in complete deficiency, though both may be present in partial forms of the condition.

Genomic testing confirms the diagnosis and differentiates IRF8 deficiency from other forms of primary immunodeficiency known to cause Mendelian susceptibility to mycobacterial disease.

The European Society for Immunodeficiencies diagnostic criteria for inborn errors of mycobacterial susceptibility are:

• infections caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, tuberculosis, salmonellosis, candidiasis, or other intramacrophagic bacteria, fungi or parasites; and
• altered IFN-γ mediated immunity tests or altered IL-12 mediated immunity tests; and
• no IFN-γ auto-antibodies.

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

IRF8 deficiency may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

IRF8 deficiency is a rare genetic condition caused by biallelic pathogenic genetic variants in the IRF8 gene. Complete deficiency shows autosomal recessive inheritance.

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 heterozygous carriers may have symptoms of immunodeficiency or immune dysregulation.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1-in-4 (25%) chance of the child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of the 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 the 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.

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

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

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. Patients require long-term monitoring following HSCT to assess immune reconstitution and monitor for potential complications.

IRF8 deficiency may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• European Society for Immunodeficiencies: Diagnosis criteria
• OMIM: 614893 Immunodeficiency 32A
• OMIM: 226990 Immunodeficiency 32B

References:

• Hambleton S, Salem S, Bustamante J and others. ‘IRF8 mutations and human dendritic-cell immunodeficiency‘. The New England Journal of Medicine 2011: volume 365, issue 2, pages 127–138. DOI: 10.1056/NEJMoa1100066
• Salem S, Salem D and Gros P. ‘Role of IRF8 in immune cells functions, protection against infections, and susceptibility to inflammatory diseases‘. Human Genetics 2020: volume 139, issue 6–7, pages 707–721. DOI: 10.1007/s00439-020-02154-2

For patients

• Immunodeficiency UK