Alternative titles; symbols
ORPHA: 79402, 79406;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q25.1 | Epidermolysis bullosa, junctional 4, intermediate | 619787 | Autosomal recessive | 3 | COL17A1 | 113811 |
A number sign (#) is used with this entry because of evidence that intermediate junctional epidermolysis bullosa-4 (JEB4) is caused by homozygous or compound heterozygous mutation in the COL17A1 gene (113811) on chromosome 10q25.
Intermediate junctional epidermolysis bullosa-4 (JEB4) is an autosomal recessive, nonlethal skin disorder characterized by blistering and erosions at birth or shortly afterward. The plane of cleavage of blistering is through the lamina lucida of the cutaneous basement zone. Blisters may heal with atrophic scarring and variable hypo- or hyperpigmentation. Oral mucosa may be involved. Nails may be lost or dystrophic, and dental enamel defects are present (summary by Has et al., 2020). A previous designation, GABEB (generalized atrophic benign epidermolysis bullosa), was used to classify patients whose phenotype included alopecia; see NOMENCLATURE.
For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (226650).
Generalized atrophic benign epidermolysis bullosa (GABEB) was the designation given to a form of JEB with good prognosis by Hintner and Wolff (1982). Clinical features include continuous blistering since birth, healing with cigarette paper-like atrophic skin with pigment shifts at sites of recurrent blistering with no scarring or milia. Follicular atrophy begins in childhood and may result in scalp baldness, partial absence of eyelashes and eyebrows, and universal alopecia; this alopecia distinguishes GABEB from other forms of non-Herlitz JEB. Nails, dentition, and mucous membranes are affected. Growth is normal and moderate improvement is seen with age (summary by Jonkman et al., 1996). COL17A1 gene mutations were found to underlie the majority of cases classified as GABEB (Floeth and Bruckner-Tuderman, 1999). However, mutations in the LAMB3 gene (150310) have also been identified in patients with this phenotype (Varki et al., 2006).
In a report of a consensus meeting, Fine et al. (2000) stated that the term 'GABEB' is an inaccurate term to describe this disorder and suggested the term 'non-Herlitz type of junctional epidermolysis bullosa.'
McGrath et al. (1995) described a 14-year-old boy with typical clinical features of non-Herlitz JEB and mutation in the COL17A1 gene. The phenotype was described as 'generalized atrophic benign epidermolysis bullosa' (GABEB). Extensive dystrophy was present in all nails, and all teeth showed abnormal enamel, with pitting and widespread caries. Focal scarring alopecia was present on the posterior vertex of the scalp, and there was partial alopecia of eyelashes. Additionally there was patchy macular hyperpigmentation on the trunk.
Jonkman et al. (1996) stated that GABEB is a form of nonlethal junctional epidermolysis bullosa, clinically characterized by generalized blistering after birth, atrophic healing, and incomplete universal atrophic alopecia with onset in childhood. The authors studied 18 patients with generalized intermediate JEB, 9 of whom presented with clinical characteristics of GABEB. One of these patients was studied further by Jonkman et al. (1997) who found that the presence of patches of clinically unaffected skin were explained by mosaicism caused by reversion of 1 of the 2 mutations in the COL17A1 gene carried by the patient. The patient otherwise displayed generalized blistering after minor trauma resulting in cutaneous atrophy, mild mucous membrane involvement, universal alopecia, pigmentary changes, dental anomalies, and nail dystrophy. There was no evidence of scarring or milia formation.
Gatalica et al. (1997) studied 2 Finnish families with non-Herlitz JEB and mutation in the COL17A1 gene. Both probands had blisters at birth as well as nail dystrophy, dental anomalies, and alopecia, which are characteristic features of GABEB. The parents of affected individuals in both families were unaffected.
Schumann et al. (1997) reported 3 patients with non-Herlitz JEB and mutation in the COL17A1 gene. Patient 1 was an 18-year-old female who had multiple blisters of the arms and legs at birth. Mechanically induced and spontaneous blisters continued to appear, mostly on the extremities, head, and face. Blisters healed without scarring but with some atrophy and hyperpigmentation. Periungual blistering and paronychia led to dystrophy of all nails. Beginning at age 6 years, patchy alopecia of the scalp developed, leading to loss of all parietal hair. Erosions regularly occurred on oral mucosa and tongue. Electron microscopy showed junctional blistering and hypoplastic hemidesmosomes. Patient 2 was a 9-year-old girl who had had blistering of the skin and mucous membranes since birth. Mechanically induced blisters occurred usually on the extremities and face and healed without scarring but with skin atrophy. Blistering of the scalp led to diffuse alopecia. Electron microscopy showed junctional blistering and severely hypoplastic hemidesmosomes in the basal keratinocytes at the blister roof. Patients 1 and 2 were described as having the GABEB phenotype. Patient 3, described as having the localisata phenotype, was a 53-year-old male who had had trauma-induced blistering since school age but developed an overall milder phenotype, with blistering predominantly at distal extremities and occasionally of the oral mucosa. All nails were lost and mild skin atrophy developed on the extremities. Electron microscopy showed slight structural alterations of the hemidesmosomes.
Chavanas et al. (1997) described a 28-year-old Italian woman with JEB, classified as GABEB type, and mutation in the COL17A1 gene. She presented continuous mild blistering of the skin that healed with atrophy, universal alopecia, and dystrophic nails and teeth. Immunohistochemistry showed the blister cleavage plane within the lamina lucida of the basement membrane zone.
Darling et al. (1998) studied a 19-year-old Austrian man, originally described by Hintner and Wolff (1982) as case 8, with non-Herlitz JEB and mutation in the COL17A1 gene. He had diffuse scalp alopecia and sparse body, pubic, and axillary hair, as well as pitted, discolored teeth. Blisters occurred predominantly on hands, feet, and face. Large melanocytic nevi developed at sites of blistering.
Floeth et al. (1998) reported 4 unrelated probands with JEB4. Patients 1, 2, and 3, ages 75, 6, and 12 years, respectively, had a similar phenotype, with fragility of skin and oral mucosa since birth and generalized blistering most often affecting the face and extremities. Blisters healed without scarring but with atrophy and hyperpigmentation. Dystrophy or loss of nails as well as sparse hair or alopecia on head or body occurred in all 3. Dental caries were present in 2. The phenotype in these patients was classified as GABEB. Patient 4 was a 34-year-old man with nonscarring blistering since birth, initially generalized but later localized to the distal extremities, with hyperpigmentation and dystrophy of toe nails. He had no dental anomalies but did have a tendency to caries. Scalp and body hair were normal. Based on the clinical presentation, he was initially thought to have epidermolysis bullosa simplex, until antigen mapping revealed junctional splitting and abnormal expression of collagen XVII in the skin. This patient was classified as having the localisata variant of JEB.
Tasanen et al. (2000) described a 13-year-old German boy with JEB4. He had developed blisters on both hands 3 days after birth, and mechanically induced bullae continued to appear, extremities being most often affected. The blistering activity diminished over the following years but increased again at the age of 12. At that time the blisters became disseminated and healed with hyperpigmentation and hypopigmentation. The overall clinical picture was relatively mild, however. The patient showed no skin atrophy or scarring, but milia were present on the forehead and occasionally in other areas. The teeth were abnormal, with pits and grooves on the front surfaces. The fingernails were normal, but toenails were dystrophic as a consequence of repeated sports trauma. The scalp hair was normal; however, no genital or axillary hair had developed at the age of 13.
The transmission pattern of JEB4 in the family reported by McGrath et al. (1995) was consistent with autosomal recessive inheritance.
In a 14-year-old male with intermediate JEB, 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.
In a 53-year-old man (patient 3) with mild manifestations of non-Herlitz JEB, Schumann et al. (1997) detected homozygosity for an arg1303-to-gln mutation of the COL17A1 gene (R1303Q; 113811.0006). He was the only child of third-cousin parents. His heterozygous daughter was unaffected. Patients 1 and 2, with more typical clinical features, were each homozygous for a different nonsense mutation (e.g., R1226X, 113811.0001).
Gatalica et al. (1997) identified a 5-bp deletion in the COL17A1 gene (113811.0003) in 2 Finnish families with JEB4. The proband of family A was homozygous for the deletion, and the proband of family B carried the deletion in compound heterozygosity with a nonsense mutation (Q1023X; 113811.0004).
In a 28-year-old Italian woman with JEB4, Chavanas et al. (1997) demonstrated homozygosity for a splice site mutation in intron 31 of the COL17A1 gene (113811.0007).
In a 19-year-old Austrian man with JEB4, Darling et al. (1999) identified a splicing mutation in intron 31 of the COL17A1 gene (113811.0008), inherited from the unaffected mother. A mutation on the paternal allele could not be identified.
In 3 patients with JEB, Floeth et al. (1998) identified homozygous or compound heterozygous mutations in the COL17A1 gene. Patients 1 and 2 were homozygous for frameshift mutations resulting in premature termination of the protein (520delAG, 113811.0010 and 2965delG, 113811.0011, respectively). Patient 3 was compound heterozygous for a missense and a frameshift mutation. Patient 4, classified as having the localisata variant, was heterozygous for the R1226X mutation (113811.0001). No mutation was identified on the other COL17A1 allele. The patient had inherited the mutation from his father, who was unaffected; the mutation was present in heterozygosity in his unaffected sister as well.
In a 13-year-old German boy with JEB4, Tasanen et al. (2000) identified compound heterozygosity for mutations in the COL17A1 gene, a missense mutation (G633D; 113811.0013) and a nonsense mutation (R145X; 113811.0014). The G633D mutation was shown to reduce the thermal stability of the Col15 domain of the COL17A1 protein, resulting in abnormal folding and susceptibility to degradation.
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.
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.
Jonkman et al. (1995, 1996) observed a mosaic pattern of immunoreactive type XVII collagen in clusters of basal cells in patches of clinically unaffected skin in a Dutch GABEB patient, in whom the remainder of the skin demonstrated characteristic blistering from mechanical trauma. Jonkman et al. (1997) demonstrated that the mosaic phenotype in this compound heterozygote patient was caused by reversion of one of the mutations in the COL17A1 gene. They also demonstrated that the reverse mutation was the result of the nonreciprocal transfer of a part of 1 parental allele for the other by a mitotic gene conversion mechanism. The maternal allele, carrying a 1706delA mutation (113811.0005), showed reversion of the mutation and loss of heterozygosity (LOH) along a tract of at least 381 bp in revertant keratinocytes derived from clinically unaffected skin patches. The paternal mutation, R1226X (113811.0001), remained present in all cell samples. Jonkman et al. (1997) stated that the natural gene therapy reported here has 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 with this autosomal recessive disorder.
Darling et al. (1999) described a 56-year-old Austrian woman with non-Herlitz JEB with a GABEB phenotype and mutation in the COL17A1 gene. She was a member of a large kindred with 5 affected and 5 unaffected sibs that had originally been identified by Hintner and Wolff (1982). While most skin biopsies from her contained no immunoreactive type XVII collagen, the serendipitous observation that her epidermal basement membrane showed focal, interrupted expression of type XVII collagen (not present in other affected family members) suggested that she was mosaic for either a normal COL17A1 allele or a second genetic alteration that allowed production of immunoreactive protein. She did not have the islands of normal-appearing skin present in other patients with revertant mosaicism (e.g., Jonkman et al., 1997). She was found to have a frame-restoring mutation on 1 allele of COL17A1 in addition to homozygosity for a premature termination codon mutation (113811.0009).
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.
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