| #131760 | ||||||||||||||||||||||||||||||||||||||||||
| EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE | ||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||
| EPIDERMOLYSIS BULLOSA HERPETIFORMIS, DOWLING-MEARA TYPE EBS-DM | ||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because the Dowling-Meara type of epidermolysis bullosa simplex (EBS-DM) can be caused by mutation in either the keratin-5 (KRT5; 148040) or the keratin-14 (KRT14; 148066) gene. | ||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||
| Epidermolysis bullosa simplex (EBS) is a clinically and genetically heterogeneous skin disorder characterized by recurrent blistering of the skin following minor physical trauma as a result of cytolysis within basal epidermal cells. Most forms show autosomal dominant inheritance. The Dowling-Meara type of EBS is the most severe form, with generalized blistering that often occurs in clusters (herpetiform), is often associated with hyperkeratosis of the palms and soles, and shows clumping of keratin filaments in basal epidermal cells. The other 2 main types of EBS include the milder generalized Koebner type (131900) and the milder and localized Weber-Cockayne type (131800) (Fine et al., 2008). All 3 forms can be caused by mutation in the KRT5 or the KRT14 gene. See 601001 for a rare autosomal recessive form caused by mutation in the KRT14 gene. | ||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||
| Dowling and Meara (1954) first described a form of epidermolysis bullosa simplex that resembled dermatitis herpetiformis (601230). Onset of generalized bullae in a herpetiform (arciform) arrangement occurred during the first 3 months of life. Serous and hemorrhagic blisters could occur on any part of the body, but most frequently on the palms and soles, around the mouth, and on the trunk and neck. In general, the lesions healed without scarring, but pronounced inflammatory reactions, especially seen in hemorrhagic blisters, was accompanied by milia and occasional scar formation. Anton-Lamprecht and Schnyder (1982) reported a 2-year-old girl of Turkish origin with congenital generalized blister formation in a herpetiform arrangement. Direct immunofluorescence ruled out juvenile dermatitis herpetiformis. Ultrastructural investigation of a fresh blister and clinically intact preblistering skin revealed intraepidermal blister formation via cytolysis of basal cells, preceded by clumping of tonofilaments and partial attachment to the hemidesmosomes at the dermo-epidermal junction. This type of blister formation was significantly different from all other epidermolysis bullosa types and was a characteristic feature of the Dowling-Meara type of EBS. McGrath et al. (1992) reviewed the clinicopathologic features of 22 cases varying in age from 5 days to 46 years. All cases presented clinically within the first 5 days of life. Early blisters were often large (up to 5 cm in diameter), and were mostly acral and particularly periungual. Some patients presented with more widespread erosive skin changes, and 2 neonates with extensive skin involvement died as a result of overwhelming sepsis. After the neonatal period, the pattern of blistering became more proximal, with hemorrhagic, herpetiform clusters of blisters. Central healing with recurrent blistering at the margins of these areas was frequent. Other physical signs included varying degrees of intraoral blistering, nail shedding, nail dystrophy, minor scarring, palmoplantar keratoderma, a lack of seasonal variation, and improvement during later childhood. Basal cell cytolysis in association with clumping of tonofilaments was the underlying pathologic mechanism. The clumping was found even in some nonlesional skin, suggesting that it is of primary pathogenetic significance. The disease was occasionally so severe, especially during the neonatal period, as to be confused with junctional (see, e.g., 226700) or severe recessive dystrophic EB (see, e.g., 226600). Kitajima et al. (1993) described 2 cases of the Dowling-Meara type of EBS with severe blistering at birth that improved gradually with age. Both had vesicles and small bullae clustering in a herpetiform fashion. In 1, there was a mild pincer deformity of the nails, whereas in the other, the nail plates shed after subungual blistering but regrew without deformity. Both had histopathologic and ultrastructural evidence of cytolysis of the basal cells, but with ultrastructural differences in the form of the tonofilament clumps present in epidermal keratinocytes. One case had typical round clumping of tonofilaments, while the other had whisk-type clumping of tonofilaments. The same difference in form was observed in cultured keratinocytes. The authors suggested possible subgrouping of this disorder. Although laryngeal involvement is generally associated with junctional forms of EB, Shemanko et al. (2000) reported 2 unrelated infants with no family history of skin disease who presented within hours of birth with extensive blistering of the skin and oral mucosa and subsequently developed hoarse cries, consistent with a diagnosis of Dowling-Meara EBS. DNA analysis revealed a heterozygous KRT5 mutation (S181P; 148040.0012) in 1 infant and a heterozygous KRT14 mutation (R125H; 148066.0003) in the other. | ||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | ||||||||||||||||||||||||||||||||||||||||||
| Prenatal Diagnosis Holbrook et al. (1992) made a diagnosis of this disorder by in utero fetal skin biopsy. Two earlier-born sibs had been affected. The mother, who had been thought to be normal, was found to have had blistering of the skin as a child and hyperkeratotic palms and soles. | ||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||
| In a large family with Dowling-Meara EBS, Lane et al. (1992) identified a heterozygous mutation in the KRT5 gene (E475G; 148040.0001) that segregated with the disorder in an autosomal dominant pattern. In affected members of a large French family with Dowling-Meara EBS, Rugg et al. (1999) identified a heterozygous splice site mutation in the KRT5 gene (148040.0011), resulting in a deletion of the last 5 amino acids of the H1 head domain and the first 17 amino acids of the conserved N-terminal end of the 1A rod domain, including the first 2 heptad repeats and the helix initiation peptide. In 2 unrelated patients with Dowling-Meara EBS, Coulombe et al. (1991) identified 2 different heterozygous mutations in the KRT14 gene (148066.0002; 148066.0003). Hut et al. (2000) identified 3 different mutations in the KRT14 gene (148066.0011-148066.0013) in patients with EBS-DM. In 4 unrelated probands with Dowling-Meara EBS, Pfendner et al. (2005) identified a heterozygous mutation in the KRT14 gene (N123S; 148066.0018). All of the patients had a de novo mutation and severe generalized blistering with oral mucous membrane involvement. The mutation was predicted to severely perturb the intermediate filament network. 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. | ||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||
| Letai et al. (1993) reported that clinical severity of EBS and epidermolytic hyperkeratosis (EHK; 113800) is related to the location of point mutations within the keratin polypeptides and the degree to which these mutations perturb keratin intermediate filament (IF) structure. Point mutations in the most severe forms have been clustered in the highly conserved ends of the K5 or K14 rod domains in EBS-DM (e.g., 148066.0002) and in the corresponding regions of the K10 (e.g., 148080.0003) and K1 rod in EHK. Mutations in milder cases have been found in less-conserved regions, either within or outside the rod domain. Of 11 known Dowling-Meara EBS or EHK mutations, 6 affected a single, highly evolutionarily conserved arginine residue which, when mutated, markedly disturbs keratin filament structure and network formation. The site also appeared to be a hotspot for mutation by CpG methylation and deamination. Letai et al. (1993) suggested that arg125 of K14 and arg156 of K10 must play a special role in maintaining keratin network integrity. | ||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||||||||||||||||||||
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