Hyperkeratosis lenticularis perstans: a case report of a rare entity

Background Hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease, is a rare skin disease presenting with asymptomatic small hyperkeratotic papules. The lesions often appear on the dorsal feet and lower legs, and typically develop after the fourth decade of life. A genetic basis for HLP is suspected; however, so far no gene defect linked to the development of HLP has been identified. Objectives We aimed to identify the genetic cause of HLP. Methods For mutational analysis we studied a cohort of five patients with HLP using next-generation sequencing (NGS). We used DNA extracted from fresh skin biopsies alongside ethylenediamine tetraacetic acid (EDTA) blood samples from two patients, and formalin-fixed paraffin-embedded skin biopsy material from three patients. In addition, immunofluorescence staining of HLP lesions from four patients was investigated. Results In all samples from the five patients with HLP we identified by NGS rare variants in the SPTLC1 gene. In four patients we detected small deletions/frameshift variants and in one patient a splicing variant, predicted to disturb the splicing process. In blood samples the detected variants were heterozygous with an allele frequency of 49% and 50%, respectively. In skin biopsies the allele frequency was within the range of 46–62%. Immunofluorescence staining revealed reduced SPTLC1 protein levels in skin of patients. Conclusions Our findings suggest that pathogenic variants in the SPTLC1 gene are the underlying genetic cause of HLP. Of note, the identified variants were either frameshift- or splicing variants probably leading to nonsense-mediated mRNA decay and thus reduced SPTLC1 protein levels. We conclude that diminished SPTLC1, the key enzyme in sphingolipid biosynthesis, leads to the development of HLP, which highlights the sphingolipid pathway as a new therapeutic target.

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Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans

Jägle

Hsu

Juratli

et al. 2022

British Journal of Dermatology

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Asymptomatic keratotic papules on the lower limbs

Guedes,

Ávila,

Nico

2024

Clinical and Experimental Dermatology

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A 71-years-old fair-skinned woman with symmetrical asymptomatic keratotic papules on the dorsal feet, legs, thighs and upper limbs. Histopathological examination showed orthokeratotic hyperkeratosis, hypogranulosis and a band-like inflammatory lymphocytic infiltrate on the dermis, consistent with hyperkeratosis lenticular perstans (HLP) or Flegel's disease. HLP is a rare dermatosis of unknown cause, characterized by multiple erythematous hyperkeratotic papules with a symmetrical distribution. The treatment of HLP is challenging since there is no standardized therapy.

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Hyperkeratosis lenticularis perstans: a case report of a rare entity

Cited by 2 publications

References 4 publications

Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans

Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans

Asymptomatic keratotic papules on the lower limbs

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