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A novel keratin 5 mutation in a familial cluster

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A novel keratin 5 mutation in a familial cluster
Hadar Lev-Tov MD, Raja K Sivamani MD, Barbara Burrall MD
Dermatology Online Journal 18 (6): 1

Department of Dermatology, University of California at Davis, Davis, California


We report a case of epidermolysis bullosa simplex (EBS) associated with a family cluster of EBS and a novel KRT5 mutation. The case is presented in the context of recent advances in the study of the disease.

Case report

A 36-year-old female was referred to our center by her family physician for management of painful blisters on the soles of her feet. The patient reported a biopsy-based childhood diagnosis of epidermolysis bullosa simplex (EBS). She described recurrent eruptions of painful blisters on both soles of her feet since infancy. Blisters typically appeared around pressure areas on her feet. Blistering was frequent and severe, preventing her from keeping steady employment and at times forcing her to ambulate on her knees. The patient described blisters on her fingertips but did not have any active bullae at the time of her visit. The patient reported an extensive family history of similar problems. Her father, two paternal uncles, and a paternal aunt were diagnosed with EBS at an outside facility. In addition, two paternal sisters were diagnosed with epidermolysis bullosa. Subsequently, her son has been diagnosed as well. The patient reported additional affected paternal cousins but could not provide details. By her description, all family members appear to have the same presentation, with disease limited to the feet and distal fingers (Figure 1). The rest of her history was unremarkable.

Figure 1
Figure 1. Epidermolysis bullosa simplex family pedigree. Red staining represents affected indivuduals.

Physical exam revealed an obese female with bilateral, tender, hyperkeratotic palms and soles. There were no frank bullae, but small erosions and scale collarettes attested to the underlying bullous nature of the primary lesions. The findings were more marked around pressure points (Figure 2).

A clinical diagnosis of EBS of the Weber-Cockayne subtype was made. A decision was made to avoid additional biopsy and order genetic testing for EBS-associated mutations. A palliative home regimen was constructed for the patient including topical urea based creams to the hyperkeratotic areas and skin protection for pressure points.

Figure 2Figure 3
Figure 2. Hyperkeratotic palms with small erosions and scale collarettes.

Figure 3. Left: KRT5 gene sequence with known mutation highlighted and reported mutation marked with arrows (source: Right: The patient’s sequence chromatogram and amino acid code aligned to a reference sequence and in the context of the other KRT5 domains. (source: GeneDx)

Genetic testing (GeneDx, Gaithersburg, MD) revealed the patient is heterozygous for a novel A424P mutation in exon 7 of the KRT5 gene (Figure 3). The mutation is a result of a G>C nucleotide substitution resulting in a replacement of an alanine codon (GCC) with a proline codon (CCC). This missense mutation is located in the highly conserved 2B domain of keratin 5. Subsequently, genetic testing was performed on the patient’s son and the same missense mutation resulting in an A424P substitution was identified.


Epidermolysis bullosa simplex is an autosomal dominant keratin fragility disorder resulting in vesiculobullous disease. The estimated prevalence of EBS is 1:25,000 to 1:50,000 [1, 2, 3]. Epidermolysis bullosa simplex is classified clinically as generalized or localized. Koebner and Dowling-Meara (herpetiform) are the more common generalized variants and Weber-Cockayne is the more common localized variant [4]. Epidermolysis bullosa simplex is linked to mutations in the KRT5 and KRT14 genes encoding epidermal basal keratins [5, 6]. Recent evidence suggests that as many as 75 percent of clinically evident EBS cases have KRT5 and KRT14 mutations, whereas other cases may be a result of mutations in a variety of genes, such as the PLEC gene coding for plectin [1, 7]. In addition, a recent genetic expression study found significant differences in the expression of genes related to fatty acid metabolism in EBS patients compared to matched controls [8]. However, the implications of these findings on pathophysiology, management, and prognosis are yet to be determined.

At the genetic level the severity of EBS could be affected by the location of the mutation (via effect on keratin assembly), the polarity of the affected amino acid (via effect on the protein’s secondary structure), and/or the size of the substituted amino acid [9]. In the case of our patient the mutation is localized to the 2B domain on keratin 5. Twenty-eight of the 121 known mutation variants in keratin 5 are known to occur in the 2B domain [10]. Of those 28, the vast majority are substitution mutations, localized to the distal part of the 2B domain known as the helix termination motif and result in one of the EBS phenotypes. Mutations in the helix termination motif are associated with a more severe clinical course [11]. Our patient’s mutation is proximal to this hot spot. Nonetheless, the two known substitution mutations occurring in the neighboring 428 codon result in the EBS phenotype. Additionally, substitution of the non-polar alanine with a non-polar proline is also consistent with a milder clinical course. The relatively mild severity of our patient’s disease is therefore consistent with the current literature.

Despite recent advances in the understanding of the genetic and molecular underpinning of EBS, treatment options are restricted to palliation [12]. Evidence is lacking to support any particular regimen [13]. There is anecdotal evidence for use of isotretinoin, which permitted resolution of blisters in an adult female [14]. Clearly, any definitive approach to treatment of EBS must target genetic pathways. Recently, emerging evidence highlights two genetic modification strategies. First, there is promising evidence for the use of RNA interference to silence the mutant allele and promote the disease free wild-type phenotype [15]. An alternative innovative strategy utilizes genetic redundancy in the keratin gene family and aims to increase induction of other keratin genes, namely K16 and K17, to act as surrogates and copolymerize with KRT5; this would alleviate the lack of the KRT14 gene product [16]. It has been shown that the naturally occurring molecule, sulforaphane, can promote such genetic induction and eliminate skin blistering in an EBS mouse model [17].

To conclude, we present a familial cluster of EBS with a novel A424P mutation. It is our hope that continued characterization of genotype and phenotype variations will lead to increased understanding of the genetic basis of EBS. Such understanding is cardinal to the discovery of effective therapy for this debilitating condition.

ACKNOWLEDGEMENT: The authors wish to thank Gabriele Richard, MD, FACMG, Chief Medical Officer, GeneDx for providing images.


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