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Other entities represented in this entry:
SNOMEDCT: 111389006, 75875004; ORPHA: 231568; DO: 0080224;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.31 | Epidermolysis bullosa dystrophica, autosomal dominant | 131750 | Autosomal dominant | 3 | COL7A1 | 120120 |
A number sign (#) is used with this entry because autosomal dominant epidermolysis bullosa dystrophica (DDEB) is caused by heterozygous mutation in the type VII collagen gene (COL7A1; 120120) on chromosome 3p21.
Autosomal recessive epidermolysis bullosa dystrophica (RDEB; 226600) is an allelic disorder.
Epidermolysis bullosa dystrophica is a clinically heterogeneous disorder characterized by blistering and scarring of the skin and mucous membranes in response to mechanical force. Microscopic examination of the skin shows cleavage below the basement membrane within the papillary dermis. All forms are caused by mutation in the COL7A1 gene. Fine et al. (2000) proposed that the Cockayne-Touraine and Pasini subtypes of dystrophic epidermolysis bullosa be combined into 1 category known as 'dominant dystrophic epidermolysis bullosa' (DDEB), since both are caused by mutations in the COL7A1 gene and show overlapping clinical features.
Epidermolysis bullosa simplex (see, e.g., 131800) and epidermolysis bullosa junctional (see, e.g., 226700) are clinically and genetically distinct disorders characterized by tissue separation at the levels of the basal keratinocyte layer and lamina lucida, respectively.
Hoffman (1926) first described an autosomal dominant form of epidermolysis bullosa (see also von Verschuer, 1959). Larger series of patients with DDEB were reported by Cockayne (1933) and Touraine (1942). Albopapuloid lesions were reported independently in a subset of DDEB patients by Pasini (1928) and Maschkilleisson (1928).
Davison (1965) reported 6 families with dystrophic epidermolysis bullosa, including 4 showing autosomal dominant inheritance and 2 showing autosomal recessive inheritance.
Bouwes Bavinck et al. (1987) described an extensively affected family with DDEB; at least 4 members of the family also had congenital localized absence of skin as seen in Bart syndrome. Bouwes Bavinck et al. (1987) concluded that there was no clear evidence to suggest that the Cockayne-Touraine, Pasini, and Bart forms of DEB are separate entities, and that the clinical features can be regarded as variations on a spectrum within and between families.
Ryynanen et al. (1991) reported a large Finnish family in which at least 20 individuals spanning 5 generations had epidermolysis bullosa dystrophica inherited in an autosomal dominant pattern. Patients developed blistering at birth or shortly thereafter. Blisters and erosions healed with extensive scarring and all also had nail dystrophy. Histopathologic examination of affected skin showed blister formation below the basal lamina, and electron microscopy of nonblistered skin showed a paucity of anchoring fibrils at the subbasal lamina region. Remaining fibrils were hypoplastic and reduced in diameter.
Christiano et al. (1996) reported 2 unrelated families with autosomal dominant DEB. In 1 family, the proband was a 28-year-old woman who was noted to have blisters at birth. The blistering primarily affected the extremities and resulted in the formation of scars and milia. She also had dystrophic toenails. Her father had similar clinical findings with onset at age 7 months.
Kon et al. (1997) reported a 42-year-old Japanese woman who developed blister and erosions on the extremities at day 7 of life. The blistering tendency persisted throughout childhood but the frequency of blister formation diminished gradually with age in her adult life. At age 17 years, she developed multiple white albopapuloid lesions on her back, consistent with the Pasini variant. Light microscopy of the white papules showed immature-appearing collagen bundles and deposition of amorphous material in the upper half of the dermis that stained with Alcian blue. Electron microscopy showed tissue separation below the basal lamina, as well as rudimentary and decreased numbers of anchoring fibrils. Her 2-year-old son developed blisters 3 days after birth. Affected individuals in a second family showed blistering tendency from birth that continued through childhood and diminished slightly with age. No albopapuloid lesions were observed, consistent with the Cockayne-Touraine variant.
Martinez-Mir et al. (2002) identified a heterozygous mutation in the COL7A1 gene (G2034R; 120120.0028) in affected members of a large 5-generation kindred originally reported by Fine et al. (1989) as having a variant form of epidermolysis bullosa simplex. Fine et al. (1989) reported that affected family members had a bullous skin disorder with variable sized clefts just beneath the level of the stratum corneum. However, clinical features included blisters, milia, atrophic scarring, nail dystrophy, and oral and conjunctival involvement, as seen in dystrophic EB. Two patients showed smaller, more focal clefts within the lower third of the epidermis. Sublamina densa cleavage was not noted, nor was any diminution of type VII collagen staining noted using the anti-type VII antibody LH 7:2. Transmission electron microscopy revealed no abnormalities within the lower epidermis or at the level of the basement membrane. Fine et al. (1989) proposed the term 'epidermolysis bullosa simplex superficialis' (EBSS; 607600) to describe this disorder, which they also identified in an unrelated patient. However, Martinez-Mir et al. (2002) concluded that the clinical phenotype in this kindred actually represented DDEB, rather than a unique subset of EBS. The molecular data suggested that the subcorneal cleavage observed in different members of this kindred would likely not be pathogenic or contribute to the disease process.
The transmission pattern of DDEB in the family reported by Ryynanen et al. (1991) and Christiano et al. (1994) was consistent with autosomal dominant inheritance.
In a large Finnish family with autosomal dominant dystrophic epidermolysis bullosa of the Cockayne-Touraine type, Ryynanen et al. (1991) found strong linkage to a PvuII RFLP in the COL7A1 gene on chromosome 3 (lod score of 5.37). Ryynanen et al. (1992) presented further evidence of the DDEB locus and COL7A1 linkage; maximum lod = 8.77 at theta = 0.0.
Uitto et al. (1992) demonstrated absolute linkage between a RFLP in the COL7A1 gene and dominant dystrophic epidermolysis bullosa; in 4 informative families a combined lod score of 14.6 at theta = 0 was found, with no recombinants. Since Hovnanian et al. (1992) reported similar linkage results in 19 families with autosomal recessive DEB, these 2 forms of epidermolysis bullosa were thought to be due to mutations in the same gene. In 3 British families with DDEB, Al-Imara et al. (1992) found close linkage to D3S2, a marker known to be close to the COL7A1 locus (combined lod score = 6.75 at theta = 0).
In 2 Dutch kindreds with intrafamilial characteristics of both the Cockayne-Touraine type and the Bart type of autosomal dominant dystrophic epidermolysis bullosa, Gruis et al. (1992) found linkage to COL7A1 with no recombination; maximum lod = 6.08 at theta = 0.00. These findings contributed to the accumulating evidence that the 3 types of autosomal dominant epidermolysis bullosa dystrophica, namely, the Cockayne-Touraine type, the Pasini type, and Bart syndrome, are due to mutations in the same gene for type VII collagen.
Anton-Lamprecht (1978) pointed out that electron microscopy is particularly revealing in dominant disorders in which structural abnormality of a protein is likely to be found, whereas biochemistry is more likely to be revealing in recessive disorders. The examples he used from dermatology to illustrate electron microscopic abnormalities in dominant disorders were structural defects of tonofibrils in hystrix-like ichthyoses (146600, 146590), of the anchoring fibrils in dominant dystrophic epidermolysis bullosa of Pasini, and of keratohyalin in autosomal dominant ichthyosis vulgaris (146700).
Bauer et al. (1979) found that cultured fibroblasts from patients with this disorder displayed deranged glycosaminoglycan metabolism. The cells accumulated increased amounts of sulfated glycosaminoglycans, likely due to increased synthesis. Secretion of glycosaminoglycans by the cells was also increased.
Gene Therapy
In 31 patients with a clinical diagnosis of dystrophic epidermolysis bullosa (DEB), 30 of whom had recessive disease (RDEB), Guide et al. (2022) analyzed healing of primary wound pairs, one treated with topical B-VEC (beremagene geperpavec), an investigational herpes simplex virus type 1-based gene therapy delivering COL7A1, and the other treated with placebo. At 6 months, the authors observed complete wound healing in 67% of B-VEC-treated wounds compared to 22% of those treated with placebo (p = 0.002). Complete wound healing at 3 months occurred in 71% of the B-VEC-treated wounds compared to 20% of those exposed to placebo (p less than 0.001). In the 1 patient with dominant disease (DDEB), the wound treated with B-VEC showed complete healing at 6 months, whereas the placebo-treated wound did not.
In affected members of a large 5-generation Finnish family reported by Ryynanen et al. (1991) as having the Cockayne-Touraine type of dominant dystrophic epidermolysis bullosa, Christiano et al. (1994) identified a heterozygous mutation in the triple helical domain of the COL7A1 gene (G2040S; 120120.0002). Christiano et al. (1994) noted that some family members had the Pasini type of DDEB with albopapuloid lesions. The authors postulated that the phenotype resulted from a dominant-negative effect in type VII collagen, resulting in the formation of structurally abnormal anchoring fibrils.
In affected members of 2 unrelated Japanese families with the Cockayne-Touraine and Pasini forms of DDEB, respectively, Kon et al. (1997) identified heterozygous mutations in the COL7A1 gene (120120.0028 and 120120.0035, respectively). The findings confirmed that the 2 clinical forms of the disorder are allelic.
In a Hispanic Mexican woman with the Pasini type of dominant epidermolysis bullosa dystrophica, Mellerio et al. (1998) identified a heterozygous mutation in the triple helical domain of the COL7A1 gene (G2043R; 120120.0016). The same mutation was found in 3 affected individuals from an unrelated Scottish family with dominant epidermolysis bullosa dystrophica. Although both families had some clinical features of the Pasini type, there was considerable interfamilial and intrafamilial variability. The mutation had previously been identified in 3 other families with dominant DEB, 1 Italian, 1 Hungarian, and 1 Norwegian.
Varki et al. (2007) analyzed the COL7A1 gene in 310 patients with dystrophic epidermolysis bullosa. Mutations were found in 1 or both alleles in 243 (78.4%) patients, comprising 355 mutant alleles of the anticipated 438 (81.1%) mutant alleles. The authors reviewed the spectrum of COL7A1 mutation and genotype-phenotype correlations, noting that patients with severe recessive DEB tended to have truncating mutations, whereas those with milder dominant DEB tended to have glycine substitutions. Seven patients had features of both dominant and recessive forms of disease and were found to carry both dominant and recessive mutations.
A mutation in the structural gene for anchoring fibril protein was postulated by Anton-Lamprecht and Hashimoto (1976).
In Faroe Islanders, Joensen et al. (1979) found that dystrophic epidermolysis bullosa was unlinked to GPT (138200) on chromosome 8q24 and thus distinct from the Ogna type of simplex epidermolysis bullosa (131950).
Mulley et al. (1985) could find no genetic linkage with 27 informative markers in a large Australian kindred with Cockayne-Touraine dystrophic EB, thereby extending the exclusion map.
Al-Imara, L., Richards, A. J., Eady, R. A. J., Leigh, I. M., Farrall, M., Pope, F. M. Linkage of autosomal dominant dystrophic epidermolysis bullosa in three British families to the marker D3S2 close to the COL7A1 locus. J. Med. Genet. 29: 381-382, 1992. [PubMed: 1377750] [Full Text: https://doi.org/10.1136/jmg.29.6.381]
Anton-Lamprecht, I., Hashimoto, I. Epidermolysis bullosa dystrophica dominans (Pasini)--a primary structural defect of the anchoring fibrils. Hum. Genet. 32: 69-76, 1976. [PubMed: 1262024] [Full Text: https://doi.org/10.1007/BF00569978]
Anton-Lamprecht, I., Schnyder, U. W. Epidermolysis bullosa dystrophica dominans--ein Defekt der anchoring fibrils? Dermatologica 147: 289-298, 1973. [PubMed: 4788473]
Anton-Lamprecht, I. Electron microscopy in the early diagnosis of genetic disorders of the skin. Dermatologica 157: 65-85, 1978. [PubMed: 78862] [Full Text: https://doi.org/10.1159/000250810]
Bauer, E. A., Fiehler, W. K., Esterly, N. B. Increased glycosaminoglycan accumulation as a genetic characteristic in cell cultures of one variety of dominant dystrophic epidermolysis bullosa. J. Clin. Invest. 64: 32-39, 1979. [PubMed: 447858] [Full Text: https://doi.org/10.1172/JCI109454]
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Christiano, A. M., McGrath, J. A., Tan, K. C., Uitto, J. Glycine substitutions in the triple-helical region of type VII collagen result in a spectrum of dystrophic epidermolysis bullosa phenotypes and patterns of inheritance. Am. J. Hum. Genet. 58: 671-681, 1996. [PubMed: 8644729]
Christiano, A. M., Ryynanen, M., Uitto, J. Dominant dystrophic epidermolysis bullosa: identification of a gly-to-ser substitution in the triple-helical domain of type VII collagen. Proc. Nat. Acad. Sci. 91: 3549-3553, 1994. [PubMed: 8170945] [Full Text: https://doi.org/10.1073/pnas.91.9.3549]
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Gruis, N. A., Bouwes Bavinck, J. N., Steijlen, P. M., van der Schroeff, J. G., van Haeringen, A., Happle, R., Mariman, E., van Beersum, S. E. C., Uitto, J., Vermeer, B. J., Frants, R. R. Genetic linkage between the collagen VII (COL7A1) gene and the autosomal dominant form of dystrophic epidermolysis bullosa in two Dutch kindreds. J. Invest. Derm. 99: 528-530, 1992. [PubMed: 1358979] [Full Text: https://doi.org/10.1111/1523-1747.ep12658066]
Guide, S. V., Gonzalez, M. E., Bagci, I. S., Agostini, B., Chen, H., Feeney, G., Steimer, M., Kapadia, B., Sridhar, K., Quesada Sanchez, L., Gonzalez, F., Van Ligten, M., Parry, T. J., Chitra, S., Kammerman, L. A., Krishnan, S., Marinkovich, M. P. Trial of beremagene geperpavec (B-VEC) for dystrophic epidermolysis bullosa. New Eng. J. Med. 387: 2211-2219, 2022. [PubMed: 36516090] [Full Text: https://doi.org/10.1056/NEJMoa2206663]
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Hovnanian, A., Duquesnoy, P., Blanchet-Bardon, C., Knowlton, R. G., Amselem, S., Lathrop, M., II, Dubertret, L., Uitto, J., Goossens, M. Genetic linkage of recessive dystrophic epidermolysis bullosa to the type VII collagen gene. (Abstract) Clin. Res. 40: 188A, 1992.
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Kon, A., Nomura, K., Pulkkinen, L., Sawamura, D., Hashimoto, I., Uitto, J. Novel glycine substitution mutations in COL7A1 reveal that the Pasini and Cockayne-Touraine variants of dominant dystrophic epidermolysis bullosa are allelic. J. Invest. Derm. 109: 684-687, 1997. [PubMed: 9347800] [Full Text: https://doi.org/10.1111/1523-1747.ep12338093]
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