A Comprehensive Analysis of FLG Mutations in Children with Atopic Dermatitis: Clinical Patterns and Genetic Diversity

Year 2026, Volume: 7 Issue: 1, 1 - 8, 24.02.2026

Oğuzhan Yaralı , Tuğba Güler

https://doi.org/10.56766/ntms.1744180

https://izlik.org/JA89WP26BL

Abstract

Objective: Atopic dermatitis (AD) is a prevalent chronic skin disorder that manifests in early childhood. It is characterised by a heterogeneous clinical presentation and a multifactorial etiology. Early-onset and severe AD have been closely linked to loss-of-function mutations in the FLG gene, which codes for the epidermal barrier protein filaggrin. The therapeutic ramifications of these results are not yet fully understood, yet a significant proportion of individuals continue to be wild-type or to carry rare variations of undetermined significance (VUS). In addition to examining the distribution and phenotypic impact of FLG mutations, including both likely pathogenic and unclear alterations, the present study sought to assess the clinical characteristics of paediatric AD.
Methods: The evaluation of 67 children (aged 0–5) with clinically confirmed AD was conducted using laboratory data, environmental history, and SCORAD severity levels. Utilising a targeted next-generation sequencing (NGS) technique, the FLG gene was comprehensively sequenced.
Results: Amongst the sample of 28 patients (41.8%) who exhibited FLG variations, 10 cases were found to contain mutations with the potential to be deleterious, while 18 cases revealed Variants of Uncertain Significance (VUS). Elevated levels of immunoglobulin E (IgE) and moderate-to-severe atopic dermatitis (AD) were more frequently associated with likely pathogenic allergen carriers. While wild-type patients also exhibited severe cases, individuals with VUS carriers demonstrated a range of phenotypes, thereby emphasising the significance of non-genetic variables.
Conclusion: This study suggests that certain VUS may possess developing clinical significance and reinforces the role of FLG mutations in paediatric AD. A combined clinical and molecular evaluation may enhance illness stratification and facilitate the development of individualised treatment plans.

Keywords

Atopic dermatitis , FLG gene , Next-generation sequencing , Genetic variants

References

• 1. Marasca C, Annunziata MC, Camela E, et al. Teledermatology and inflammatory skin conditions during COVID-19 era: new perspectives and applications. J Clin Med. 2022;11(6):1511.
• 2. Hoyer A, Rehbinder EM, Färdig M, et al. Filaggrin mutations in relation to skin barrier and atopic dermatitis in early infancy. British Journal of Dermatology. 2022;186(3):544-52.
• 3. Saunders SP, Moran T, Floudas A, et al. Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity. JACI. 2016;137(2):482-491.
• 4. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. JACI. 2013;131(2):280-91.
• 5. Hönzke S, Wallmeyer L, Ostrowski A, et al. Influence of Th2 cytokines on the cornified envelope, tight junction proteins, and β-defensins in filaggrin-deficient skin equivalents. J Invest Dermatol 2016;136(3):631-39.
• 6. Haftek M, McAleer MA, Jakasa I, McLean WI, Kezic S, Irvine AD. Changes in nano-mechanical properties of human epidermal cornified cells in children with atopic dermatitis. Wellcome Open Res. 2020;5:97.
• 7. Martin MJ, Estravís M, García-Sánchez A, Dávila I, Isidoro-García M, Sanz C. Genetics and epigenetics of atopic dermatitis: an updated systematic review. Genes. 2020;11(4):442.
• 8. Dytiatkovskyi VO, Abaturov OE. Filaggrin genotype associations with atopic march at children. Alergol Pol. 2019;6(1):24-29.
• 9. Moosbrugger-Martinz V, Leprince C, Méchin M-C, et al. Revisiting the roles of filaggrin in atopic dermatitis. Int J Mol Sci. 2022;23(10):5318.
• 10. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. ActaDV. 1980;60(92).
• 11. Sajić D, Asiniwasis R, Skotnicki-Grant S. A look at epidermal barrier function in atopic dermatitis: physiologic lipid replacement and the role of ceramides. Skin therapy letter. 2012;17(7):6-9.
• 12. Kopanos C, Tsiolkas V, Kouris A, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35(11):1978-980.
• 13. Abou Tayoun AN, Pesaran T, DiStefano MT, et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat. 2018;39(11):1517-524.
• 14. Park K, Park M, Seok J, Li K, Seo S. Clinical characteristics of Korean patients with filaggrin‐related atopic dermatitis. Clin Exp Dermatol. 2016;41(6):595-600.
• 15. Nutten S. Atopic dermatitis: global epidemiology and risk factors. ANM. 2015;66(Suppl. 1):8-16.
• 16. Roduit C, Frei R, Depner M, et al. Phenotypes of atopic dermatitis depending on the timing of onset and progression in childhood. JAMA Pediatr. 2017;171(7):655-662.
• 17. Barbarot S, Auziere S, Gadkari A, et al. Epidemiology of atopic dermatitis in adults: results from an international survey. Allergy. 2018;73(6):1284-293.
• 18. Amat F, Saint-Pierre P, Bourrat E, et al. Early-onset atopic dermatitis in children: which are the phenotypes at risk of asthma? Results from the ORCA cohort. PLoS One. 2015;10(6):e0131369.
• 19. Aoki V, Lorenzini D, Orfali RL, et al. Consensus on the therapeutic management of atopic dermatitis-Brazilian Society of Dermatology. An Bras Dermatol. 2019;94(2 Suppl 1):67-75.
• 20. Mathyer ME, Quiggle AM, Wong XCC, et al. Tiled array‐based sequencing identifies enrichment of loss‐of‐function variants in the highly homologous filaggrin gene in African‐American children with severe atopic dermatitis. Exp Dermatol. 2018;27(9):989-92.
• 21. Brown SJ, Kroboth K, Sandilands A, et al. Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Invest Dermatol. 2012;132(1):98-104.
• 22. Marenholz I, Esparza-Gordillo J, Rüschendorf F, et al. Meta-analysis identifies seven susceptibility loci involved in the atopic march. Nature communications. 2015;6(1):8804.
• 23. Ziaali A, Sharifi L, Teimourian S, Hasani B, Isaian A, Shariat M. Clinical features of children with atopic dermatitis according to filaggrin gene variants. Allergol Immunopathol. 2021;49(4):162-66.
• 24. Hirano A, Goto M, Mitsui T, Hashimoto-Hachiya A, Tsuji G, Furue M. Antioxidant Artemisia princeps extract enhances the expression of filaggrin and loricrin via the AHR/OVOL1 pathway. Int J Mol Sci. 2017;18(9):1948.
• 25. Szegedi K, Lutter R, Bos J, Luiten R, Kezic S, Middelkamp‐Hup M. Cytokine profiles in interstitial fluid from chronic atopic dermatitis skin. J Eur Acad Dermatol Venereol. 2015;29(11):2136-44.
• 26. Navarro-López V, Ramírez-Boscá A, Ramón-Vidal D, et al. Effect of oral administration of a mixture of probiotic strains on SCORAD index and use of topical steroids in young patients with moderate atopic dermatitis: a randomized clinical trial. JAMA dermatology. 2018;154(1):37-43.
• 27. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-51.
• 28. Sarıcaoğlu H, Yazici S, Zorlu Ö, Başkan EB, Aydoğan K. Cyclosporine-A for severe childhood atopic dermatitis: clinical experience on efficacyand safety profile. Turk J Med Sci. 2018;48(5):933-38.
• 29. Johnson H, Aquino MR, Snyder A, et al. Prevalence of allergic contact dermatitis in children with and without atopic dermatitis: a multicenter retrospective case-control study. J Am Acad Dermatol. 2023;89(5):1007-1014.
• 30. Fan X, Zang T, Dai J, et al. The associations of maternal and children’s gut microbiota with the development of atopic dermatitis for children aged 2 years. Front Immunol. 2022;13:1038876.