A transient epidermolysis bullosa simplex‐like phenotype associated with bexarotene treatment in a G138E KRT5 heterozygote

Abstract

Basal keratinocyte lysis is the hallmark histopathological finding of epidermolysis bullosa simplex (EBS), a group of rare heritable mechanobullous disorders characterized by intraepidermal blister formation and skin fragility. Over 100 mutations, found predominantly in the genes encoding keratins 5 and 14 (KRT5, KRT14), have been described to account for a variety of clinical subtypes. EBS with mottled pigmentation (EBS‐MP) is a rare variant featuring childhood‐onset reticulate hyperpigmentation and focal palmoplantar keratoderma, typically associated with a P25L KRT5 mutation. In this report, we present the case of a 77‐year‐old woman with a history of palmoplantar keratoderma who developed a transient EBS‐MP‐like phenotype associated with bexarotene treatment for cutaneous T‐cell lymphoma. Genetic sequencing revealed a heterozygous G138E KRT5 variant, present in approximately 10% of the European population and only rarely associated with pathology. Bexarotene, which has been reported to alter keratin synthesis, caused vesiculobullous reactions with similar frequency in clinical trials. We propose that the cumulative effect of drug treatment and underlying G138E polymorphism resulted in transient basal keratinocyte lysis in our patient and provides a plausible explanation for this unusual bexarotene side effect. Trufant JW, Kreizenbeck GM, Carlson KR, Muthusamy V, Girardi M, Bosenberg MW. A transient epidermolysis bullosa simplex‐like phenotype associated with bexarotene treatment in a G138E KRT5 heterozygote.

Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype‐phenotype correlation and in silico modeling analysis

“…The reticulated pattern of erythema, pigmentation, or both observed in these patients appears distinct and perhaps pathognomonic and is also noted by Komori et al in a recent report. It is different from the pigmentation observed in EBS with mottled pigmentation (EBS‐MP), a condition due to different mutations in K5 (p.Pro25Leu, p.Gly138Glu, p.[Ile140AsnfsX0]+[Asp328His], p.Gly550AlafsX77), K14 (p.Met119Thr, p.Ile373GlufsX53), and EXPH5 encoding exophilin‐5 . The condition is described as mottled pigmentation that may or may not be related to healing of blisters plus punctate palmoplantar keratoderma and onychodystrophy .…”

“…The condition is described as mottled pigmentation that may or may not be related to healing of blisters plus punctate palmoplantar keratoderma and onychodystrophy . Mutations in the V1 domain of the nonhelical head domain of K5 have been found in most cases of EBS‐MP . It is unclear why this mutation results in this unique clinical phenotype, though research done by Irvine et al indicates that the nonhelical head domain of K5 may be implicated in melanosome transport.…”

Severe epidermolysis bullosa simplex phenotype caused by codominant mutations p.Ile377Thr in keratin 14 and p.Gly138Glu in keratin 5

“…The authors postulated that this variant enhanced the effect of bexarotene known to inhibit K5 synthesis, leading to transient lysis of basal epidermal cells. [ 27 ]…”

Keratins and epidermolysis bullosa simplex

“…The important point is that as the patient's age increases, upon increasing or compensating the expression of keratin genes with less expression in the basal cell layer (such as KRT15) and reducing the expression of mutated keratin genes, the patient phenotype is relatively improves (Jonkman et al, 1996). The genetic background of people and their ethnicity is also important in determining the genotype-phenotype communicative aspects in different families and populations (Sa'd et al, 2006 gene (Trufant et al, 2010).…”