Alternative titles; symbols
SNOMEDCT: 294705005; ORPHA: 79400; DO: 0080510;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.2 | Epidermolysis bullosa simplex 1C, localized | 131800 | Autosomal dominant | 3 | KRT14 | 148066 |
A number sign (#) is used with this entry because localized epidermolysis bullosa simplex-1C (EBS1C) is caused by heterozygous mutation in the keratin-14 gene (KRT14; 148066) on chromosome 17q21.
Another form of localized EBS, EBS2C (619594), is caused by heterozygous mutation in the KRT5 gene (148040).
Localized epidermolysis bullosa simplex-1C (EBS1C) is an autosomal dominant skin disorder with intraepidermal blistering after minor trauma mainly restricted to hands and feet beginning in infancy. Nails may be thick and dystrophic (summary by Has et al., 2020). Localized epidermolysis bullosa simplex has previously been known as the Weber-Cockayne type.
For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).
Reviews
Has et al. (2020) reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility.
Fine et al. (2008) reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system.
Chen et al. (1993) studied a 5-generation family (EBS-WC-Ma) with at least 16 affected individuals with EBS of the Weber-Cockayne type and mutation in the KRT14 gene. Nonscarring blisters were limited to hands and feet. Blistering was much more prominent in the summer and was minimal to absent in the winter.
Hu et al. (1997) reported a French-Portuguese family (EBS-WC-Ta) with localized EBS and heterozygous mutation in the KRT14 gene. Blistering began around 1 year of age and was limited to the hands and feet. There was disease exacerbation in the summer, and the disorder tended to decrease with age. One family member, born of a consanguineous union, was homozygous for the mutation (see MOLECULAR GENETICS). This patient had a more severe phenotype, with earlier onset, more generalized blistering, and involvement of the oral, vaginal, and anal mucosa. Since age 14, blistering had been limited to the hands and feet. The distal skin was scarred, all 10 toenails were missing, and small areas of palmar hyperkeratosis were present.
Vahidnezhad et al. (2016) reported a large Iranian family (family 9) in which 14 members over 4 generations with mutation in the KRT14 gene experienced a relatively mild blistering tendency, limited to the palms and soles, when subjected to considerable trauma or heat. In addition, 3 family members who were born of consanguineous unions exhibited generalized spontaneous blistering.
The transmission pattern of EBS1C in the family reported by Chen et al. (1993) was consistent with autosomal dominant inheritance.
The genetic heterogeneity of the Weber-Cockayne form of EBS was indicated by the findings of McKenna et al. (1992) in 2 families. One family showed linkage to the region containing the keratin 5 gene and was excluded from linkage to the keratin-14 gene. The other showed linkage to markers on chromosome 17 flanking the keratin-14 gene and was excluded from linkage to markers on chromosome 12 flanking the keratin-5 gene.
In a family (EBS-WC-Ma) with at least 16 affected individuals in 5 generations with Weber-Cockayne type EBS, Chen et al. (1993) identified a heterozygous mutation in the KRT14 gene (148066.0005).
Among 18 families with various forms of EBS, Pfendner et al. (2005) identified KRT5 mutations in 7 probands and KRT14 mutations in 11 probands, indicating that mutations in either gene can result in EBS at approximately equal frequencies. A large number (15 of 18) were de novo mutations. The clinical spectrum was highly variable.
From a cohort of 22 Scottish families with autosomal dominant EBS, Rugg et al. (2007) identified a proband (family 15) who was heterozygous for a missense mutation in the KRT14 gene (I377T; 148066.0021). The proband had blistering that was limited to the hands and feet. Skin biopsy revealed keratin aggregates, and the cleavage plane was through the cytoplasm of the basal keratinocytes. The proband was the only family member examined, and familial segregation was not reported.
Semidominant Inheritance
Hu et al. (1997) reported a French-Portuguese family (EBS-WC-Ta) with localized EBS due to a heterozygous KRT14 met119-to-ile mutation (M119I; 148066.0010). One family member, born of a consanguineous union, was homozygous for the M119I mutation. This individual had a more severe phenotype, and Hu et al. (1997) concluded that this mutation acts as a 'partial dominant' in that heterozygotes have milder localized disease and homozygotes have a more severe disease.
From a cohort of Iranian patients with clinical presentations and immunoepitope mapping suggestive of EBS, Vahidnezhad et al. (2016) identified 2 families (families 9 and 11) with heterozygous mutations in KRT14 and localized disease. In 1 of them (family 9), some affected individuals who were born of consanguineous unions exhibited more generalized lesions and were found to be homozygous for the segregating I377T variant (148066.0021). The authors designated family 9 as having a 'semidominant' mode of inheritance.
Kim et al. (2017) screened 52 Australian patients with EBS for mutations in the KRT5 and KRT14 genes and identified 32 different mutations in 39 pedigrees. The authors found that mutations causing localized EBS occurred sporadically across the KRT5 and KRT14 peptides. Mutations resulting in generalized severe EBS were most commonly clustered at the helix boundary motifs, the helix initiation (HIP) and termination (HTP) regions, which are critical for normal keratin formation. In most other cases phenotypes correlated with the location of the mutations and were in agreement with previous reports.
Readett (1961) described a family in which 14 members in 5 generations had localized epidermolysis bullosa of the hands and feet inherited in an autosomal dominant pattern. Treatment with adrenosteroid depressed bulla formation, but recurrence occurred with the end of therapy. An enormous pedigree with many affected persons was reported from West Virginia by Cartledge and Myers (1943). The affected persons were descendants of one Zachariah Piles, born in 1762. The blistering occurred only on the hands and feet, and mainly in warm weather after unusual walking or labor with hand tools. Friction-induced blisters in the Weber-Cockayne type of EBS are temperature-dependent. Lesions can be prevented by cooling the skin with ice before friction (Pearson, 1967). This is thus an example in man of a temperature-sensitive mutant.
Roth et al. (2009) found that skin from Krt5-null mice showed increased levels of the inflammatory cytokines MCP1 (CCL2; 158105), CCL19 (602227), and CCL20 (601960), all of which are regulated by NFKB (see 164011) and involved in the recruitment, maturation, and migration of Langerhans cells in the epidermis. These changes were not observed in Krt14-null mice. The number of Langerhans cells were increased 2-fold in epidermis of neonatal Krt5-null mice. In contrast, TNFA (191160) was not changed, demonstrating the specificity of that process. The basal epidermis from Krt5-null mice also showed decreased p120-catenin (CTNND1; 601045). Enhanced Langerhans cell recruitment within the epidermis was found in 5 patients with various forms of EBS due to KRT5 mutations, but not in EBS patients with KRT14 gene mutations. These data provided an explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS, and suggested that the pathophysiology of EBS involves more than mutant keratins.
Bonifas, J. M., Rothman, A. L., Epstein, E., Jr. Linkage of epidermolysis bullosa simplex to probes in the region of keratin gene clusters on chromosomes 12q and 17q. (Abstract) Clin. Res. 39: 503A only, 1991.
Cartledge, J. L., Myers, V. W. Inherited foot blistering in an American family. J. Hered. 34: 24 only, 1943.
Chen, M. A., Bonifas, J. M., Matsumura, K., Blumenfeld, A., Epstein, E. H., Jr. A novel three-nucleotide deletion in the helix 2B region of keratin 14 in epidermolysis bullosa simplex: delE375. Hum. Molec. Genet. 2: 1971-1972, 1993. [PubMed: 7506606] [Full Text: https://doi.org/10.1093/hmg/2.11.1971]
Cockayne, E. A. Recurrent bullous eruption of the feet. Brit. J. Derm. Syph. 50: 358-362, 1938.
Fine, J. D., Johnson, L., Wright, T., Horiguchi, Y. Epidermolysis bullosa simplex: identification of a kindred with autosomal recessive transmission of the Weber-Cockayne variety. Pediat. Derm. 6: 1-5, 1989. [PubMed: 2539587] [Full Text: https://doi.org/10.1111/j.1525-1470.1989.tb00256.x]
Fine, J.-D., Eady, R. A. J., Bauer, E. A., Bauer, J. W., Bruckner-Tuderman, L., Heagerty, A., Hintner, H., Hovnanian, A., Jonkman, M. F., Leigh, I., McGrath, J. A., Mellerio, J. E., Murrell, D. F., Shimizu, H., Uitto, J., Vahlquist, A., Woodley, D., Zambruno, G. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on diagnosis and classification of EB. J. Am. Acad. Derm. 58: 931-950, 2008. [PubMed: 18374450] [Full Text: https://doi.org/10.1016/j.jaad.2008.02.004]
Haldane, J. B. S., Poole, R. A new pedigree of recurrent bullous eruption of the feet: four generations of foot blisters. J. Hered. 33: 17-18, 1942.
Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Brit. J. Derm. 183: 614-627, 2020. [PubMed: 32017015] [Full Text: https://doi.org/10.1111/bjd.18921]
Hu, Z. L., Smith, L., Martins, S., Bonifas, J. M., Chen, H., Epstein, E. H., Jr. Partial dominance of a keratin 14 mutation in epidermolysis bullosa simplex: increased severity of disease in a homozygote. J. Invest. Derm. 109: 360-364, 1997. [PubMed: 9284105] [Full Text: https://doi.org/10.1111/1523-1747.ep12336051]
Kim, E. N., Harris, A. G., Bingham, L. J., Yan, W., Su, J. C., Murrell, D. F. A review of 52 pedigrees with epidermolysis bullosa simplex identifying ten novel mutations in KRT5 and KRT14 in australia. Acta Derm. Venereol. 97: 1114-1119, 2017. [PubMed: 28561874] [Full Text: https://doi.org/10.2340/00015555-2715]
McKenna, K. E., Hughes, A. E., Bingham, E. A., Nevin, N. C. Linkage of epidermolysis bullosa simplex to keratin gene loci. J. Med. Genet. 29: 568-570, 1992. [PubMed: 1381443] [Full Text: https://doi.org/10.1136/jmg.29.8.568]
Pearson, R. W. Epidermolysis bullosa, porphyria cutanea tarda and erythema multiforme.In: Zelickson, A. S. : Ultrastructure of Normal and Abnormal Skin. Philadelphia: Lea and Febiger (pub.) 1967. Pp. 320-334.
Pfendner, E. G., Sadowski, S. G., Uitto, J. Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis. J. Invest. Derm. 125: 239-243, 2005. [PubMed: 16098032] [Full Text: https://doi.org/10.1111/j.0022-202X.2005.23818.x]
Readett, M. D. Localized epidermolysis bullosa. Brit. Med. J. 1: 1510-1511, 1961. [PubMed: 13740079] [Full Text: https://doi.org/10.1136/bmj.1.5238.1510]
Roth, W., Reuter, U., Wohlenberg, C., Bruckner-Tuderman, L., Magin, T. M. Cytokines as genetic modifiers in K5-/- mice and in human epidermolysis bullosa simplex. Hum. Mutat. 30: 832-841, 2009. [PubMed: 19267394] [Full Text: https://doi.org/10.1002/humu.20981]
Rugg, E. L., Horn, H. M., Smith, F. J., Wilson, N. J., Hill, A. J. M., Magee, G. J., Shemanko, C. S., Baty, D. U., Tidman, M. J., Lane, E. B. Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations. J. Invest. Derm. 127: 574-580, 2007. [PubMed: 17039244] [Full Text: https://doi.org/10.1038/sj.jid.5700571]
Vahidnezhad, H., Youssefian, L., Saeidian, A. H., Mozafari, N., Barzegar, M., Sotoudeh, S., Daneshpazhooh, M., Isaian, A., Zeinali, S., Uitto, J. KRT5 and KRT14 mutations in epidermolysis bullosa simplex with phenotypic heterogeneity, and evidence of semidominant inheritance in a multiplex family. J. Invest. Derm. 136: 1897-1901, 2016. [PubMed: 27283507] [Full Text: https://doi.org/10.1016/j.jid.2016.05.106]