Palmoplantar keratodermas

Gene: FLG

Green List (high evidence)

Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Both monoallelic and biallelic variants in FLG may cause palmoplantar keratoderma - PPK is frequently seen in combination with ichthyosis (PMID:36308042 Clabbers et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

Created: 18 Sep 2025, 2:22 p.m. | Last Modified: 18 Sep 2025, 2:22 p.m.

Panel Version: 4.1

Comment on list classification: There are at least 17 unrelated patients with variants in FLG with palmoplantar keratoderma (PPK). PPK is frequently seen in combination with ichthyosis.

PMID:36308042 (Clabbers et al., 2022): 22 Dutch patients with palmoplantar keratoderma were found to carry mono- or bi-allelic variants in FLG. In 17/22 of the patients, variants in other known PPK genes were excluded through an exome sequencing panel. Ten patients were heterozygous, six homozygous, and six compound heterozygous, including nonsense and frameshift mutations. Phenotypes: diffuse PPK (100% of patients), palmoplantar erythema (82%), palmar hyperlinearity (91%), transgrediens (62%), and generalized xerosis cutis (100%).

Functional studies: Newborn Flg(-/-) mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Palmoplantar keratodermas.

Created: 18 Sep 2025, 2:20 p.m. | Last Modified: 18 Sep 2025, 2:24 p.m.

Panel Version: 4.1

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM: 605803; hereditary palmoplantar keratoderma, MONDO:0019272

Publications

• 16444271
• 16550169
• 22409988
• 36308042

Green List (high evidence)

This gene was part of an initial gene list collated by Thomas Cullup, GOSH and Veronica Kinsler, UCL, 25.Jan.2019 on behalf of the GMS Skin Specialist Test Group. Gene Symbol submitted: FLG; Suggested initial gene rating: Green; Evidence for inclusion: none provided; Evidence for exclusion: none provided; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): Hard to sequence with short-read sequencing (highly repetitive).

Created: 28 Jan 2019, 10:47 a.m.

Variants in this GENE are reported as part of current diagnostic practice