Hashimoto et al. (1976) observed this disorder in 3 offspring of a first-cousin marriage and named for Disentis, the place of birth of the patients. The proband was a 38-year-old man with extensive blistering. He also had 2 ... Hashimoto et al. (1976) observed this disorder in 3 offspring of a first-cousin marriage and named for Disentis, the place of birth of the patients. The proband was a 38-year-old man with extensive blistering. He also had 2 sibs who had died from blistering in the first days of life. Electron microscopy showed reduced or absent hemidesmosomes. Ridley and Levy (1968) observed survival of a possible case of the same condition to age 35 years. Marras et al. (1984) emphasized the frequent occurrence of amniotic band constriction with epidermolysis bullosa. During a 10-year period at their institute, 8 newborns were hospitalized and 3 of these had associated anomalies due to amniotic band constriction. One of them had epidermolysis bullosa-pyloric atresia association. The 8 patients represented several different types of EB (Gedde-Dahl, 1981). Bircher et al. (1993) reported a Swiss family in which 2 brothers and a sister demonstrated dystrophy of the nails, nonscarring blistering of skin, mild skin atrophy, hypodontia, and dental caries from school age. Light microscopy showed subepidermal blistering. Indirect immunofluorescence staining of a fresh spontaneous blister showed that the bullous pemphigoid antigens (DST, 113810 and COL17A1, 113811) and several forms of laminin were localized to the blister roof, and collagen IV (see, e.g., COL4A3, 120070) and collagen VII (see, e.g., COL7A1, 120120) to the blister base, indicating junctional splitting. Electron microscopy showed a normal dermoepidermal junction zone, including normal hemidesmosomes. There were no deposits of electron-dense amorphous material. Bircher et al. (1993) tabulated reported cases, including their 3 cases, and identified 18 patients from 10 families. McGrath et al. (1995) reported 3 brothers with non-Herlitz JEB. who were examined in their thirties. All had a history of generalized trauma-induced blistering from birth, which particularly affected the lower legs. Excellent clinical photographs were provided which showed, among other features, dystrophic changes of the fingernails and toenails with only a small amount of residual nail plate, abnormal dentition with extensive enamel hypoplasia, focal pitting, and discoloration, and marked loss of eyelashes with mild scarring of the lower lid margin. Patchy atrophic alopecia and sparse secondary sexual hair were also found. - Recessive Junctional Epidermolysis Bullosa Inversa Junctional EB 'inversa' refers to a different pattern of skin involvement, involving intertriginous zones (Fine et al., 2008). Ridley (1977) reported a 55-year-old English woman with scattered blisters since birth with significant involvement of the genitocrural area. Histologic examination showed subepidermal lesions consistent with junctional cleavage. She also had corneal abrasions, mouth ulcerations, and enamel hypoplasia. Gedde-Dahl et al. (1994) reported 4 Scandinavian families with autosomal recessive inheritance of junctional epidermolysis bullosa inversa; some had been reported by Gedde-Dahl (1971). Linkage analysis of 3 informative families identified linkage to a polymorphism in intron 20 of the laminin gamma-1 gene (LAMC1; 150290) on chromosome 1q31 (lod score of 1.65). All 4 patients of these families were homozygous for a 146-bp LAMC1 allele present on only 5% of random Norwegian chromosomes. A daughter of a deceased patient in a fourth family was found to carry the same 146-bp allele. The very strong association confirmed that the disease locus, which the authors termed 'EBR2A,' was at or closely linked to 1q31. Families with other clinical variants of JEB did not appear to be linked to or associated with this locus. However, the authors noted that LAMC2, which is involved in the Herlitz type of junctional epidermolysis bullosa, is located near the LAMC1 gene and may be the gene responsible. Gedde-Dahl et al. (1994) stated the English patient reported by Ridley (1977) was clinically indistinguishable from the Norwegian JEB-I patients and suggested that the Norwegian EBR2A allele may have been brought to England by the Vikings.
Nakano et al. (2002) studied the mutational differences between the Herlitz and non-Herlitz forms of junctional EB. They examined a cohort of 27 families, 15 with Herlitz and 12 with non-Herlitz junctional EB, for mutations in the candidate ... Nakano et al. (2002) studied the mutational differences between the Herlitz and non-Herlitz forms of junctional EB. They examined a cohort of 27 families, 15 with Herlitz and 12 with non-Herlitz junctional EB, for mutations in the candidate genes LAMA3, LAMB3, and LAMC2. The largest number of mutations for both forms occurred in the LAMB3 gene. Most cases with Herlitz junctional EB harbored premature termination codon (PTC) mutations in both alleles. In non-Herlitz cases, the PTC mutation was frequently associated with a missense mutation or a putative splicing mutation in trans, i.e., the patient was a compound heterozygote. Varki et al. (2006) performed genetic analysis in 234 patients diagnosed with junctional or hemidesmosomal EB and identified a mutation in at least 1 allele in 209 cases (89.3%); in that cohort of 209 patients, 393 (94.0%) mutant alleles were discovered among the total 418 alleles studied. The majority (70.4%) of the mutations occurred in LAMA3, LAMB3, and LAMC2, the 3 genes that comprise laminin-5, and most of those (80.1%) were in LAMB3. Varki et al. (2006) reviewed the clinical and molecular heterogeneity of the junctional and hemidesmosomal subtypes of EB, discussed exceptions to the general rules on genotype-phenotype correlations, and noted unusual phenotypes and genetics observed in patients and families with EB. Kiritsi et al. (2011) identified 34 distinct COL17A1 mutations, including 12 novel mutations, among 43 patients with non-Herlitz JEB of varying clinical severity. Most (69%) were nonsense or predicted to result in premature termination, whereas 19% were missense and 12% were splice site mutations. Although most mutations were private, the R1226X mutation (113811.0001) was found in 10% of alleles. A genotype/phenotype correlation was apparent, with the more severe generalized phenotypes associated with truncating mutations. Detailed investigation of 3 patients with splice site mutations indicated that 12 to 14% residual collagen XVII levels in skin biopsies was sufficient to compensate, resulting in later onset of symptoms, milder cutaneous involvement, and longer life span. The data suggested that low levels of collagen XVII restoration can improve skin stability and alleviate symptoms in patients with COL17A1 mutations.
In a 14-year-old male with typical clinical features of this disorder, McGrath et al. (1995) identified compound heterozygosity for nonsense mutations in the COL17A1 gene (113811.0001 and 113811.0002). The unrelated ... - Mutations in the COL17A1 Gene In a 14-year-old male with typical clinical features of this disorder, McGrath et al. (1995) identified compound heterozygosity for nonsense mutations in the COL17A1 gene (113811.0001 and 113811.0002). The unrelated parents were clinically normal and each was heterozygous for 1 of the mutations, respectively. - Mutations in the LAMB3 Gene In 3 brothers with non-Herlitz JEB, McGrath et al. (1995) identified compound heterozygosity for 2 mutations in the LAMB3 gene: a nonsense (150310.0002) and a missense (150310.0006) mutation. - Mutations in the LAMC2 Gene In a Turkish girl with non-Herlitz JEB, Nakano et al. (2002) identified a homozygous mutation in the LAMC2 gene (150292.0006). - Mutations in the LAMA3 Gene Nakano et al. (2002) identified a homozygous mutation in the LAMA3 gene (600805.0003) in a Saudi Arabian girl with non-Herlitz JEB. - Mutations in the ITGB4 Gene Inoue et al. (2000) reported a homozygous mutation in the ITGB4 gene (G931D; 147557.0012) in a 68-year-old male, born of consanguineous parents, with a history of congenital blisters, recurrent urethral stenosis since age 12 years, progressive alopecia since childhood, loss of permanent dentition by age 30 years, nail dystrophy, and absence of pubic and axillary hair. There was no history of gastrointestinal symptoms or previous abdominal surgery. - Revertant Mosaicism In a 28-year-old Dutch woman with a mosaic non-Herlitz JEB phenotype (Jonkman et al., 1995; Jonkman et al., 1996), Jonkman et al. (1997) identified compound heterozygosity for mutations in COL17A1 and demonstrated that the mosaic phenotype was caused by reversion of the maternally inherited 1-bp deletion (113811.0005) due to the nonreciprocal transfer of a part of 1 parental allele for the other by a mitotic gene conversion mechanism. The paternal mutation, R1226X (113811.0001), remained present in all cell samples. Jonkman et al. (1997) stated that this natural gene therapy had implications for the design of gene therapy, since reversion of the affected genotype to carrier genotype of approximately 50% of the basal keratinocytes appeared to be sufficient to normalize the function of the skin, as noted in clinically unaffected skin patches of the patient. In a 56-year-old Austrian woman with GABEB and revertant mosaicism, Darling et al. (1999) demonstrated partial correction of a maternally inherited germline 2-bp deletion in COL17A1 (113811.0009) by a frame-restoring mutation. Pasmooij et al. (2007) described 2 unrelated non-Herlitz junctional EB patients with revertant mosaicism. The first was a 46-year-old man who was compound heterozygous for germline R635X (150310.0001) and E210K (150310.0006) mutations in the LAMB3 gene and who had reversion to clinically unaffected skin on his left lower leg. The authors identified 2 different somatic second-site mutations (150310.0012 and 150310.0013) on the E210K allele in 2 different lower leg biopsies; the compensatory mutations were not found in fibroblasts taken from the same biopsies or in more than 80 control subjects. Reversion of the inherited R635X mutation did not occur. The second patient was a 64-year-old man who was homozygous for an E210K germline mutation in LAMB3 and who had reversion to clinically normal skin at his upper arms, shoulders, and chest. Pasmooij et al. (2007) identified 3 different somatic second-site mutations on 1 of the E210K alleles in 3 different biopsies of reverted skin (150310.0014-150310.0016, respectively). The second-site mutations were not found in more than 160 control chromosomes. Analysis of mRNA from the newly normal skin in both patients revealed that all of the second-site mutations had effects at the RNA level. Jonkman and Pasmooij (2009) analyzed data from 20 patients with non-Herlitz junctional EB, 14 of whom had type XVII collagen deficiency due to mutant COL17A1 and 6 of whom had laminin-beta-3 deficiency due to mutant LAMB3. The authors found an unexpectedly high number of patients with revertant patches including 5 (36%) of 14 patients with collagen deficiency and 2 (33%) of 6 with laminin deficiency, as reflected by the reexpression of the deficient protein on immunofluorescence-antigen mapping of skin-biopsy specimens. In addition, at least 6 of the 7 patients with revertant mosaicism had multiple patches, each caused by a different molecular event. Jonkman and Pasmooij (2009) suggested that revertant somatic mosaicism should be considered when a patient has an atypical phenotype.