ORPHA: 89838; DO: 4644;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.2 | Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive | 601001 | Autosomal recessive | 3 | KRT14 | 148066 |
A number sign (#) is used with this entry because of evidence that autosomal recessive generalized intermediate or severe epidermolysis bullosa simplex-1D (EBS1D) is caused by homozygous mutation in the KRT14 (148066) gene on chromosome 17q21.
Autosomal recessive generalized intermediate or severe epidermolysis bullosa simplex-1D (EBS1D) is a skin disorder characterized by blistering elicited by minor trauma that usually heals without scarring. Severity is variable; in some patients hands and feet are primarily affected, and in others blistering anywhere on the body may occur. In some patients the condition improves with age. Histology shows cleavage at the level of basal keratinocytes (Hovnanian et al., 1993; Jonkman et al., 1996).
For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).
Reviews
Fine et al. (2008) reviewed the classification of inherited epidermolysis bullosa.
Hovnanian et al. (1993) reported a consanguineous French family in which 2 sibs had a recessive form of localized EBS and mutation in the KRT14 gene. Both had recurrent, painful blistering affecting the lateral, dorsal, and plantar aspects of the feet after walking or minor trauma. Blistering occurred occasionally on the legs and thighs after horseback riding, but the palms and rest of the body were spared. Onset was in early childhood. Focal erythematous and slightly atrophic scars were present on the feet. Hair, nails, teeth, and oral mucosa were normal, and there were no milia. There was no hyperkeratosis of the palms or soles. The disorder did not appear to get better with age, and there was disease exacerbation in the summer. Electron microscopic examination of the skin showed cleavage within basal keratinocytes and no clumping of tonofilaments. The parents were unaffected.
Chan et al. (1994) studied a patient with severe autosomal recessive EBS who was homozygous for mutation in the KRT14 gene. He was born with skin blisters on the hands and feet; generalized bullous lesions, particularly pronounced on the hands and face, continued postnatally. Incidental trauma resulted in blisters, which healed without scarring. His consanguineous parents were unaffected. The patient had multiple bone abnormalities diagnosed as a type of osteogenesis imperfecta that were considered to be unrelated to the EBS.
Rugg et al. (1994) reported a child with severe generalized epidermal blistering beginning 3 days after birth who had homozygous mutation in the KRT14 gene. Blistering occurred virtually anywhere on the body, including arms, legs, trunk, face, scalp, and oral mucosa. There was no thickening of the palms or soles on examination at age 5 years. The front teeth were discolored and notched, but not pitted, and the fingernails were ridged and of uneven thickness. The tendency to blister had diminished with age. There was no KRT14 expression in the skin, and no intermediate filaments were seen in the basal cells of the epidermis. Neither of the parents, who were related, were affected.
Jonkman et al. (1996) studied 2 closely related Dutch families with 4 members with congenital skin blistering and homozygous mutation in KRT14. The patients were all adults (age range 34 to 74) who had severe generalized blistering after trivial trauma since birth. There was slight improvement with age. Mucous membranes of mouth, nose, and genitals were occasionally mildly affected. Esophagus and eyes were not affected. Physical examination revealed generalized serous and sanguinolent bullae surrounded by crusts and erythema especially around the inguinal, axillary, and submammary skin folds, on the spine, and on the upper arms and legs. Most of the blisters were solitary; some were arranged in groups, without circinate pattern. The lesions healed without scarring. Postinflammatory hyperpigmentation was present in skin folds.
The transmission pattern of EBSB1 in the family reported by Hovnanian et al. (1993) was consistent with autosomal recessive inheritance.
In 2 French sibs, born of consanguineous parents, with autosomal recessive EBS, Hovnanian et al. (1993) identified a homozygous mutation in the KRT14 gene (E144A; 148066.0004). The authors predicted that this change in amino acid size, shape, and hydrophobicity would interfere with K14-K5 heterodimer production essential to keratin formation.
In a patient with severe autosomal recessive EBS, Chan et al. (1994) identified a homozygous mutation in the KRT14 gene (Y204X; 148066.0006). Each of the unaffected parents, who were related, was heterozygous for the mutation. Skin biopsy of the patient showed lack of a discernible keratin filament network in basal epidermal cells.
In a patient with severe autosomal recessive EBS, Rugg et al. (1994) identified a homozygous 2-bp deletion in the KRT14 gene (148066.0017). Each unaffected parent was heterozygous for the mutation.
In 4 affected members of a kindred with autosomal recessive EBS, Jonkman et al. (1996) detected homozygosity for an acceptor splice site mutation in intron 1 of the KRT14 gene (148066.0008). Patient basal cells did not express keratin-14 and contained no keratin intermediate filaments. Heterozygous family members were unaffected.
Homozygosity for KRT14 M119I
For discussion of an EBS patient with homozygosity for a M119I mutation in the KRT14 gene, who was a member of a family in which other affected members were heterozygous for the same mutation, see localized epidermolysis bullosa simplex 1C (EBS1C; 131800) and 148066.0010.
Chan, Y., Anton-Lamprecht, I., Yu, Q.-C., Jackel, A., Zabel, B., Ernst, J.-P., Fuchs, E. A human keratin 14 'knockout': the absence of K14 leads to severe epidermolysis bullosa simplex and a function for an intermediate filament protein. Genes Dev. 8: 2574-2587, 1994. [PubMed: 7525408] [Full Text: https://doi.org/10.1101/gad.8.21.2574]
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]
Hovnanian, A., Pollack, E., Hilal, L., Rochat, A., Prost, C., Barrandon, Y., Goossens, M. A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex. Nature Genet. 3: 327-331, 1993. [PubMed: 7526933] [Full Text: https://doi.org/10.1038/ng0493-327]
Jonkman, M. F., Heeres, K., Pas, H. H., van Luyn, M. J. A., Elema, J. D., Corden, L. D., Smith, F. J. D., McLean, W. H. I., Ramaekers, F. C. S., Burton, M., Scheffer, H. Effects of keratin 14 ablation on the clinical and cellular phenotype in a kindred with recessive epidermolysis bullosa simplex. J. Invest. Derm. 107: 764-769, 1996. [PubMed: 8875963] [Full Text: https://doi.org/10.1111/1523-1747.ep12365805]
Rugg, E. L., McLean, W. H. I., Lane, E. B., Pitera, R., McMillan, J. R., Dopping-Hepenstal, P. J. C., Navsaria, H. A., Leigh, I. M., Eady, R. A. J. A functional 'knockout' of human keratin 14. Genes Dev. 8: 2563-2573, 1994. [PubMed: 7525407] [Full Text: https://doi.org/10.1101/gad.8.21.2563]