Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.13 | Epidermolysis bullosa simplex 2B, generalized intermediate | 619588 | Autosomal dominant | 3 | KRT5 | 148040 |
A number sign (#) is used with this entry because of evidence that generalized intermediate epidermolysis bullosa simplex-2B (EBS2B) is caused by heterozygous mutation in the KRT5 gene (148040) on chromosome 12q13.
Another form of generalized intermediate EBS, EBS1B (131900), is caused by mutation in the KRT14 gene (148066).
Generalized intermediate epidermolysis bullosa simplex-2B (EBS2B) is an autosomal dominant disorder of skin in which intraepidermal blistering occurs after minor mechanical trauma. Skin blistering is generalized, begins at birth, and is worsened by heat, humidity, and sweating. The tendency to blistering diminishes in adolescence, when it may become localized to hands and feet. Intermediate EBS has previously been known as the Koebner type (summary by Has et al., 2020).
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.
Hacham-Zadeh et al. (1988) described a large Arab family originating from Jerusalem in which 38 affected individuals spanning 4 generations had EBS. Onset occurred between birth and 2 weeks of age. The main clinical features were bullae, generalized, solitary, and in groups, with predilection to the skin of the palms and soles. Mild to moderate patchy hyperkeratosis of the palms and soles was found in 5 affected members of the family. Blisters in oral mucous membranes were noted and found in summer and in periods of fever. Hair, teeth, and nails were normal. Improvement was noted by progression of age from 5 to 23 years, and by some in summer and by others in winter. Ultrastructural studies from a fresh blister disclosed intraepidermal blister via cytolysis of basal cell cytoplasm. The pedigree indicated transmission of an autosomal dominant gene. However, in 1 instance, affected first cousins were married and all 6 of their offspring were affected. There was marked intrafamilial variability. Although the family was originally thought to have the Dowling-Meara form of EBS, Stephens et al. (1995) reclassified the phenotype as the Koebner type based on the lack of keratin filament clumping on electron microscopy; they also identified a mutation in the KRT5 gene in affected individuals (see MOLECULAR GENETICS).
Ryynanen et al. (1991) studied a 4-generation Finnish family with 14 members affected with EBS. A tendency towards generalized blistering was noted at birth or shortly thereafter and continued during early years of life. With advancing age, the blistering became localized predominantly on the hands and feet, and was worse during the summer months. Histopathology and electron microscopy demonstrated intraepidermal blistering with evidence of cytolysis of basal keratinocytes. The disorder in this family was mapped to the pericentromeric region of chromosome 12q and a mutation in the KRT5 gene later identified.
Galligan et al. (1998) reported a 3-generation family with 4 affected members with EBS Koebner type and mutation in the KRT5 gene. Generalized blistering with minimal oral involvement developed at birth or in early infancy, and basal layer degeneration was seen on histopathologic investigation. Affected individuals exhibited significant variation in severity of symptoms. All reported that blistering was more severe and generalized during childhood, but the proband and his mother continued to suffer from generalized blistering, while other affected members of the family reported that with time, blistering rarely occurred outside of palmoplantar surfaces.
Livingston et al. (2001) reported a 57-year-old man with a mutation in the KRT5 gene who presented at 3 to 4 days of age with widespread generalized blistering. He required multiple hospitalizations for blistering during childhood. Painful hyperkeratosis of the palms and soles developed in his teen years, whereas blistering improved somewhat with age. During his employment as a horse trainer, he would also blister on the buttocks and thighs. As an adult, he continued to get occasional blisters in the mouth and cutaneous blisters with increased heat and/or activity. His skin examination was striking for severe palmoplantar keratosis, underlying erythema in a 'glove and moccasin' distribution, and limited range of motion in the fingers. There was no scarring and no significant nail changes. Clinical, histologic, and ultrastructural features were consistent with a diagnosis of generalized EBS (Koebner subtype).
Liovic et al. (2001) studied a 3-generation family with 5 affected members with EBS Koebner type and mutation in the KRT5 gene. All affected individuals had widespread blistering on large areas of the trunk, neck, cheeks, and extremities from early childhood. A 2-year-old girl and her paternal aunt, whose age was not given, continued to have widespread blistering, but the girl's father and paternal grandfather had improved spontaneously at puberty with only minor blistering activity remaining on the sides of the palms and soles, and occasionally on the trunk when traumatized. The girl had occasional feeding problems due to erosions inside the mouth. Blistering was usually worse in heat and humidity.
Epstein (1991) cited evidence that linkage to the keratin gene cluster on chromosome 12 had been demonstrated in at least 1 family with generalized epidermolysis bullosa simplex.
In a large Finnish family with 14 affected members in 3 generations with generalized EBS, Ryynanen et al. (1991) found linkage to DNA marker D12S17, which is located on 12q (maximum lod score of 4.65 at theta = 0.0). In the full report (Ryynanen et al., 1991), the maximum lod score for linkage to D12S17 was given as 5.55 at theta = 0.0.
The transmission pattern of EBS2B in the families reported by Dong et al. (1993) and Stephens et al. (1995) was consistent with autosomal dominant inheritance.
In affected members of a large Finnish family with the generalized Koebner type of EBS in which Ryynanen et al. (1991) found linkage to 12q, Dong et al. (1993) identified a heterozygous mutation in the KRT5 gene (L463P; 148040.0002).
In affected members of family EB13, previously described by Hacham-Zadeh et al. (1988), with autosomal dominant epidermolysis bullosa simplex of the Koebner type, Stephens et al. (1995) identified a heterozygous mutation in the KRT5 gene (K173N; 148040.0006). One family member was homozygous for the K173N allele, having inherited it from each of her affected first-cousin parents. However, this patient showed no significant differences from heterozygotes in either the clinical severity or the ultrastructural organization of the homozygous keratin intermediate filament cytoskeleton. These data demonstrated that the K173N mutation behaves as a fully dominant allele.
Galligan et al. (1998) identified heterozygosity for a val7-to-ala mutation (V7A; 148040.0010) in the KRT5 gene in all affected members of a 3-generation family with EBS Koebner type.
In a 3-generation family with EBS Koebner type, Liovic et al. (2001) identified a heterozygous val186-to-leu substitution (V186L; 148040.0014) in the KRT5 gene in all affected members.
In a 57-year-old man with EBS Koebner type, Livingston et al. (2001) identified a heterozygous nonsense mutation in the KRT5 gene (K472X; 148040.0016), predicting the synthesis of a truncated keratin-5, missing the entire tail domain and a highly conserved motif in the central rod. Ultrastructural analysis of the patient's nonhyperkeratotic skin was remarkable for basal keratinocytes with dense and irregular keratin filaments proximal to the basement membrane. The occurrence of severe palmoplantar hyperkeratosis suggested that the keratin-5 tail domain may have important functions in palmoplantar tissues.
Dong, W., Ryynanen, M., Uitto, J. Identification of a leucine-to-proline mutation in the keratin 5 gene in a family with the generalized Koebner type of epidermolysis bullosa simplex. Hum. Mutat. 2: 94-102, 1993. [PubMed: 7686424] [Full Text: https://doi.org/10.1002/humu.1380020206]
Epstein, E. H., Jr. Personal Communication. San Francisco, Calif. 5/5/1991.
Galligan, P., Listwan, P., Siller, G. M., Rothnagel, J. A. A novel mutation in the L12 domain of keratin 5 in the Koebner variant of epidermolysis bullosa simplex. J. Invest. Derm. 111: 524-527, 1998. [PubMed: 9740251] [Full Text: https://doi.org/10.1046/j.1523-1747.1998.00308.x]
Hacham-Zadeh, S., Rappersberger, K., Livshin, R., Konrad, K. Epidermolysis bullosa herpetiformis Dowling-Meara in a large family. J. Am. Acad. Derm. 18: 702-706, 1988. [PubMed: 3372762] [Full Text: https://doi.org/10.1016/s0190-9622(88)70093-6]
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]
Liovic, M., Stojan, J., Bowden, P. E., Gibbs, D., Vahlquist, A., Lane, E. B., Komel, R. A novel keratin 5 mutation (K5V186L) in a family with EBS-K: a conservative substitution can lead to development of different disease phenotypes. J. Invest. Derm. 116: 964-969, 2001. [PubMed: 11407988] [Full Text: https://doi.org/10.1046/j.1523-1747.2001.01334.x]
Livingston, R. J., Sybert, V. P., Smith, L. T., Dale, B. A., Presland, R. B., Stephens, K. Expression of a truncated keratin 5 may contribute to severe palmar-plantar hyperkeratosis in epidermolysis bullosa simplex patients. J. Invest. Derm. 116: 970-974, 2001. [PubMed: 11407989] [Full Text: https://doi.org/10.1046/j.1523-1747.2001.01324.x]
Ryynanen, M., Knowlton, R. G., Uitto, J. An epidermolysis bullosa simplex mutation maps to chromosome 12. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 358 only, 1991.
Ryynanen, M., Knowlton, R. G., Uitto, J. Mapping of epidermolysis bullosa simplex mutation to chromosome 12. Am. J. Hum. Genet. 49: 978-984, 1991. [PubMed: 1718160]
Stephens, K., Zlotogorski, A., Smith, L., Ehrlich, P., Wijsman, E., Livingston, R. J., Sybert, V. P. Epidermolysis bullosa simplex: a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function. Am. J. Hum. Genet. 56: 577-585, 1995. [PubMed: 7534039]