SG14 Homozygous pathogenic variant in transgradient palmoplantar keratoderma: causative, contributory or irrelevant?

Abstract A 34-year-old man with transgradient palmoplantar keratoderma (PPK) first presented at 2 years of age. Only skin on the palmar and dorsal surfaces of the hands, and plantar surfaces of the feet are affected. He had severe atopic dermatitis during infancy, which became progressively better with age, now controlled with regular skin moisturization. He has asthma. There is a family history of atopic dermatitis. He is currently managed on acitretin 25 mg once daily and psoralen plus ultraviolet A. Acitretin at 50 mg alone was effective but was discontinued due to side-effects. Previous treatment with secukinumab and adalimumab was not beneficial. Next-generation sequencing analysis (panel R166) revealed a homozygous pathogenic frameshift variant in the FLG gene – Chr1: g.152285081_152285084del, c.2282_2285del p.(Ser761Cysfs*36). No other variants were identified. This variant results in premature termination of the biosynthesis of the filaggrin protein. FLG encodes profilaggrin and filaggrin. Profilaggrin is the major component of keratohyalin granules within epidermal granular cells. Profilaggrin is cleaved to form filaggrin, which condenses the keratin cytoskeleton and contributes to the cell compaction process, enabling the normal functioning of the stratum corneum. A recent study identified 22 unrelated patients with PPK who had monoallelic or biallelic pathogenic FLG variants. Previously, pathogenic variants in the FLG gene had not been described in the literature as a cause of PPK (Clabbers JM, Bolling MC, Burms C et al. Palmoplantar keratoderma as a clinical feature of pathogenic variants in the filaggrin gene. J Eur Acad Dermatol Venereol 2023; 37: e486–90). In 17 of these patients, variants in all other known PPK genes were excluded. The remaining five patients were only tested for variants in FLG due to the similarity of their phenotype with other patients. This patient did not have any features to suggest ichthyosis vulgaris, which would be expected in patients with homozygous FLG variants. This may be explained by reduced penetrance. Lack of other variants in this patient and increasing evidence in the literature supporting the relevance of FLG variants in PPK suggest a contributory effect. However, 10% of individuals with European ancestry are heterozygous carriers of loss-of-function variants in the FLG gene. This high carrier frequency in the general population suggests that FLG may be only a contributing factor, and other variants or environmental factors are important in the manifestation of PPK, if FLG variants are found in so many unaffected individuals.