Patients with JEB-gi due to COL17A1 and LAMB3 mutations frequently have revertant mosaicism: previously described in as many as 35 % of cases [30], a recent series of patients with COL17A1-mutant JEB-gi have all been shown to have areas of revertant mosaicism recognized by skin hyperpigmentation [31].

Revertant mosaicism may be unnoticed in localized JEB localized [31], possibly because revertant patches do not stand out against the surrounding mildly affected mutant skin or because basal keratinocytes with revertant C17 do not have a growth advantage against those with reduced C17 in localized JEB.

All JEB-gi patients have abnormalities of primary and secondary dentition. LM-332 and C17 are crucial in ameloblast differentiation and enamel formation, resulting in enamel defects of the entire dentition, consisting of hypoplasia, pitting, roughness, and thinning or furrowing of enamel in all patients with JEB-gi [32]. COL17A1 glycine substitutions may have a dominant-negative effect on dentition with enamel hypoplasia and pitting in carriers with [33] or without [34] skin blistering. In one study, carriers of mutations in the C17 gene displayed enamel hypoplasia [35], whereas in another it was absent [13].

Yuen et al. reported two related heterozygous carriers of the novel LAMA3 deletion c.488delG who did not suffer from skin blistering, but showed dental enamel defects, consisting of roughness and pits, which led to a higher susceptibility of caries in both [36]. As the mutation c.488delG creates a frameshift resulting in a PTC and mRNA decay, and as alternatively spliced cDNA products could not be found in cDNA analysis, they hypothesized that haploinsufficiency of laminin α3 is the cause of the enamel defects in these carriers and that in the complex process of enamel formation in which LM-332 plays such a vital role, there is no compensation for the loss of one LAMA3 allele, whereas this mechanism exists in the skin. However, it remains notable that enamel defects have not been reported in carriers of LAMB3 or LAMC2 null mutations.

Patients with LM-332-deficient JEB-gi may be clinically different from those with C17 or α6β4 deficiency due to the occurrence of persistent deep small ulcers [21, 37]. These patients suffer from impaired wound healing due to LM-332 deficiency, mostly caused by mutations in LAMA3. The predilection sites are palmoplantar and pretibial skin and on hips and buttocks. LM-332 plays an important role in the process of epidermal wound healing, where cell motility is necessary for wound closure [38]. Basal keratinocytes secrete unprocessed LM-332 around the wound edge. In its unprocessed form, the LG3 domain of the laminin α3 chain favors interaction with integrin α3β1 (α3β1). This interaction stimulates the mitogen-activated protein (MAP) kinase signaling cascade to promote epithelial cell migration and proliferation. Upon wound closure, the LG4–5 domain of the laminin α3 chain is cleaved by plasmin. This changes the favored interaction of LM-332 with α3β1 to an interaction with α6β4, after which hemidesmosomes are formed [38–46]. LM-332-α3β1 interaction enhances plasmin production, making the process self-regulatory with an inhibitory feedback loop [46, 47].

JEB-gi wounds have been successfully treated by simple punch grafting of autologous (mutant) skin [37].

The frequency of developing a cutaneous squamous cell carcinoma (SCC) among adult JEB patients in the Dutch center was 25 % (n = 7) [48]. In the literature, seven case reports of JEB complicated by SCC are published, bringing the total number of documented cases to 14 [49–56]. All patients were adults and classified as JEB-gi. The first SCC developed at an average age of 50 years (median 52 years, range 28–70 years). In nine patients, multiple primary SCCs occurred, with a total of 45 SCCs. The SCCs were most often located on the lower extremities, in areas of chronic blistering, long-standing erosions, or atrophic scarring. The treatment of first choice is surgical excision, although no guidelines for the excision margins are given. Three (21 %) patients developed metastases and died on average 8.9 years after diagnosis of the initial SCC. Because SCCs can develop in early adulthood, we recommend checking the entire skin of JEB patients from age 25. Although SCCs can look like normal wounds, suspicious lesions are chronic nonhealing ulcers or erosions, hypergranulation, induration, and hyperkeratotic, exophytic, verrucous nodules or plaques. Additional clues can be pain, a stinging or burning sensation, and noticeable changes in a lesion. Multiple biopsies of suspicious lesions should be taken to avoid missing malignancies.

The role of LM-332 seems to be more complicated in carcinogenesis. Cell migration and invasion are important stages in tumor progression and establishing metastasis. The basement membrane zone (BMZ) has traditionally been viewed as a protective barrier, and its proteolytic degradation by metalloproteinases merely as a way to facilitate tumor spread [57]. However, in a great diversity of cancers, expression of LM-332 is elevated and is considered as a predictive factor related to tumor invasiveness [58–61]. Considering the importance of (increased) expression of LM-332 in cell migration and carcinogenesis, it seems paradoxical that LM-332-deficient JEB-gi patients have an increased risk of developing invasive metastatic SCC, whereas they also suffer from an impaired wound healing. Further research in the tumor microenvironment of LM-332-deficient JEB-gi keratinocytes should be performed to gain more clarity on this subject.

JEB of late onset (JEB-lo) (Fig. 37.4) is a very rare form of JEB, recently shown to arise from mutations in COL17A1 [63]. In this report, two siblings with JEB-lo suffered from blistering on the feet and around the toe- and fingernails starting at the age of 6 years. With age, blistering also occurred on the hands, nose, and oral mucosa, along with nail deformities, pretibial atrophic patches, palmoplantar hyperhidrosis, loss of dermatoglyphs, and amelogenesis imperfecta. However, the primary and secondary hair pattern was normal.

IF antigen staining showed loss of the apical-lateral C17 staining and a broadened distribution of staining against the ectodomain of C17, LM-332, and type VII collagen. Mutation analysis of COL17A1 showed compound heterozygosity for a novel mutation c.1992_1995delGGGT and the known mutation c.3908G>A in both patients. The deletion c.1992_1995delGGGT results in a PTC and mRNA decay, leaving the patients functionally hemizygous for the missense mutation c.3908G>A (p.R1303Q). It is hypothesized the mutation p.R1303Q, located in the C17 ectodomain, results in a disturbed ligand binding that interferes with the normal deposition of extracellular matrix, explaining the broadened IF staining against LM-332 and type VII collagen, as the C17 ectodomain has an interaction with LM-332 and thus with type VII collagen.

In a previous study, a patient carrying the mutation p.R1303Q homozygously showed clinical symptoms matching JEB-lo [9]. This supports a hypothesis that p.R1303Q and other missense mutations in the NC4 domain of C17 are specific for JEB-lo. To date, no other missense mutations in the NC4 domain have been described.