Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children

Abstract

Background: Null mutations within the filaggrin gene (FLG) cause ichthyosis vulgaris and are associated with atopic eczema. However, the dermatological features of filaggrin haploinsufficiency have not been clearly defined.

Objectives: This study investigated the genotype-phenotype association between detailed skin phenotype and FLG genotype data in a population-based cohort of children.

Methods: Children (n = 792) aged 7-9 years were examined by a dermatologist. Features of ichthyosis vulgaris, atopic eczema and xerosis were recorded and eczema severity graded using the Three Item Severity score. Each child was genotyped for the six most prevalent FLG null mutations (R501X, 2282del4, R2447X, S3247X, 3702delG, 3673delC). Fisher's exact test was used to compare genotype frequencies in phenotype groups; logistic regression analysis was used to estimate odds ratios and penetrance of the FLG null genotype and a permutation test performed to investigate eczema severity in different genotype groups.

Results: Ten children in this cohort had ichthyosis vulgaris, of whom five had mild-moderate eczema. The penetrance of FLG null mutations with respect to flexural eczema was 55.6% in individuals with two mutations, 16.3% in individuals with one mutation and 14.2% in wild-type individuals. Summating skin features known to be associated with FLG null mutations (ichthyosis, keratosis pilaris, palmar hyperlinearity and flexural eczema) showed a penetrance of 100% in children with two FLG mutations, 87.8% in children with one FLG mutation and 46.5% in wild-type individuals (P < 0.0001, Fisher exact test). FLG null mutations were associated with more severe eczema (P = 0.0042) but the mean difference was only 1-2 points in severity score. Three distinct patterns of palmar hyperlinearity were observed and these are reported for the first time.

Conclusions: Filaggrin haploinsufficiency appears to be highly penetrant when all relevant skin features are included in the analysis. FLG null mutations are associated with more severe eczema, but the effect size is small in a population setting.

Fig 1

Column chart to illustrate the eczema severity scores of 778 children with different filaggrin genotypes. TIS score, Three Item Severity score, where a score of 1–2 represents mild eczema, 3–5 moderate and 6–9 severe disease.*Individuals with two FLG null mutations include one homozygote (with two copies of the R501X null mutation) and seven compound heterozygotes (with two different null mutations). A permutation test demonstrates that there is a significant difference in eczema severity when the three genotype groups are compared (P= 0·0042).

Fig 2

Diagrammatic representation of the patterns of palmar skin markings observed in a series of 308 English school children aged 7–9 years. The palmar skin features of a total of 792 children were examined by a single experienced dermatologist (S.J.B.). Examination of 484 children led to the observation of three distinct patterns of palmar hyperlinearity and the patterns of palmar markings were then recorded for the subsequent 308 children. The majority of children in this cohort had very smooth palmar skin; within the series of 308 children, 65 had palmar hyperlinearity of whom 18% showed pattern 1, 20% showed pattern 2 and 62% showed pattern 3. Diagrams have been used to illustrate the hyperlinearity patterns as clinical photos were not permitted because of ethical constraints, but examples of the distinct patterns may be seen in published literature.,,–