IL17RA – Chronic Mucocutaneous Candidiasis

Autosomal recessive IL17RA deficiency underlies chronic mucocutaneous candidiasis (CMC) by abolishing IL-17 signaling and compromising mucocutaneous immunity.

IL17RA encodes the interleukin-17 receptor A, essential for IL-17A/F-mediated defense of the skin, nails, and mucosae. Homozygous loss-of-function variants in IL17RA cause autosomal recessive CMC, characterized by recurrent or persistent infections with Candida albicans and staphylococci in early life.

In a landmark study, 21 individuals from 12 unrelated kindreds harbored complete AR IL17RA deficiency across 12 distinct alleles, including eight upstream stop-gains and one missense allele (p.Asp387Asn), all abolishing receptor expression or function. All patients experienced first CMC episodes by 6 months, and 14 had staphylococcal skin disease (PMID:27930337).

A recent family report described four affected members of a consanguineous kindred presenting with CMC and staphylococcal skin lesions; homozygosity for IL17RA variants segregated with disease, and elevated IgG levels were documented (PMID:36866994).

A novel homozygous nonsense variant, c.787C>T (p.Arg263Ter), was identified in a 6-year-old male with refractory candidiasis and eczema; Sanger sequencing confirmed segregation, and flow cytometry revealed markedly reduced IL-17RA surface expression and impaired Th17 cell responses (PMID:37317577).

The variant spectrum spans splice-site (e.g., c.598+1G>T), frameshift (e.g., c.166_169dup (p.Cys57fs)), nonsense (e.g., c.787C>T (p.Arg263Ter)), and missense alleles, underscoring allelic heterogeneity and recurrent LoF mechanisms.

Functional assays in patient fibroblasts and leukocytes uniformly demonstrate abolished responses to IL-17A, IL-17F, and IL-25, confirming a loss-of-function disease mechanism (PMID:27930337, PMID:37317577).

Definitive evidence supports IL17RA as a causal gene for CMC, with robust genetic and experimental concordance. IL17RA sequencing should be included in diagnostic panels to guide targeted therapeutic interventions.

References

• Proceedings of the National Academy of Sciences of the United States of America | 2016 | Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. PMID:27930337
• The Turkish journal of pediatrics | 2023 | A family with interleukin-17 receptor A deficiency: a case report and review of the literature. PMID:36866994
• Turkish archives of pediatrics | 2023 | A Novel Interleukin 17 Receptor A Mutation in a Child with Chronic Mucocutaneous Candidiasis and Staphylococcal Skin Infections. PMID:37317577
• The Journal of allergy and clinical immunology | 2016 | IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation. PMID:26607704

Evidence Based Scoring (AI generated)