Dystrophic Epidermolysis Bullosa and Kindler Epidermolysis Bullosa

Inherited mechanical fragility of the skin and mucous membranes with cleavage below the lamina densa due to COL7A1 variants (dominant and recessive forms), and fragility with cleavage at multiple levels, photosensitivity and poikiloderma due to loss of kindlin-1 (FERMT1).

Literature and regulatory information update: 17 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Inherited epidermolysis bullosa (EB) is the prototype of the genetic skin fragility disorders, defined by blister formation after minimal mechanical trauma as a consequence of a disruption at the dermo-epidermal junction. The international consensus meeting held in London in April 2019 and published in 2020 recognises four classical types, distinguished by the level of cleavage: EB simplex (EBS, intraepidermal), junctional EB (JEB, in the lamina lucida), dystrophic EB (DEB, below the lamina densa, in the most superficial papillary dermis) and Kindler EB (KEB, with mixed cleavage) [1]. DEB, in all its dominant and recessive forms, and KEB are covered together; EBS and JEB, including EB with pyloric atresia, form part of the differential diagnosis.

DEB is caused exclusively by pathogenic variants in COL7A1, the gene for the α1 chain of collagen VII, the main component of the anchoring fibrils that attach the basement membrane to the dermis [1, 2]. The clinical hallmark of DEB is scarring after blistering, on the skin and on several mucous membranes, accompanied by milia in healed areas and dystrophy or loss of the nails [1]. Inheritance may be dominant (DDEB) or recessive (RDEB); RDEB is generally more severe, but there is phenotypic overlap between the two types, and the same allele may behave as dominant in one family and as recessive in another [1, 2]. The spectrum ranges from isolated nail dystrophy to generalised disease with oesophageal strictures, malnutrition, anaemia, mutilating contractures and metastatic squamous cell carcinoma (SCC) in the third decade of life [2, 19].

KEB results from biallelic loss of function of FERMT1, which encodes kindlin-1, an intracellular focal adhesion protein that links the actin cytoskeleton to integrins [1, 37]. It combines traumatic acral blistering in childhood, which decreases at around 10–12 years, with progressive photosensitivity, atrophy and poikiloderma, mucosal fragility and a risk of SCC in adulthood [6]. It shares with RDEB the scarring mucosal involvement, oesophageal strictures, the risk of SCC and the cross-cutting guidelines of DEBRA International and the European Reference Network for Rare and Undiagnosed Skin Diseases (ERN-Skin) [35, 38, 39].

1.2. Historical overview

Hoffman described an autosomal dominant form of EB in 1926; Pasini and Maschkilleisson independently described, in 1928, the albopapuloid lesions in a subgroup of dominant patients, and Cockayne (1933) and Touraine (1942) published larger series, which gave rise to the eponyms Cockayne-Touraine and Pasini [3]. The generalised mutilating recessive form became associated with the names of Hallopeau and Siemens, and the inversa form was characterised by Gedde-Dahl in 1971 in 13 patients from 6 Norwegian families, with lesions predominantly in the skin folds [4]. Bouwes Bavinck and colleagues concluded in 1987, from an extended family with DDEB in which at least four members had localised congenital absence of skin (Bart syndrome), that the Cockayne-Touraine, Pasini and Bart forms are expressions of a single intrafamilial and interfamilial spectrum [3]. Kindler syndrome was described by Theresa Kindler in 1954 as congenital poikiloderma with traumatic blistering and progressive skin atrophy [40].

Ultrastructure guided the molecular search: the paucity or hypoplasia of anchoring fibrils observed on electron microscopy and the identification of collagen VII as their main component justified the study of COL7A1 as a candidate gene [41]. In 1991, Ryynänen and colleagues demonstrated linkage of a COL7A1 PvuII polymorphism to DDEB in a five-generation Finnish family (LOD score, logarithm of the odds, of 5.37; θ=0) and located the gene on chromosome 3 [41]. In 1992, Hovnanian and colleagues established linkage of generalised mutilating RDEB to COL7A1 in 19 informative families (maximum LOD 3.97; θ=0) [42], and Dunnill and colleagues confirmed locus homogeneity in 1994 in 26 British, Italian, Irish and South African families, with the D3S1100 microsatellite at 3p21 (Zmax 6.8) proposed for prenatal diagnosis [43]. The first COL7A1 mutation in RDEB, a homozygous methionine-to-lysine substitution in a conserved region of the carboxyl terminus, was published by Christiano and colleagues in 1993 in two siblings, with the unaffected mother and a half-brother heterozygous [44]. The Kindler syndrome gene was identified in 2003 by two groups, by homozygosity mapping at 20p12.3 in consanguineous families from North Africa and Senegal and in an isolated Panamanian cohort; Siegel and colleagues showed that it was the human homologue of Caenorhabditis elegans UNC-112 and characterised the disease as the first skin fragility disorder due to a defect of the actin–extracellular matrix linkage, rather than of the keratin–matrix linkage [37, 45].

1.3. Nomenclature and reclassifications

The nomenclature of DEB changed five times in about 20 years [2]. The 2008 classification abandoned some of the eponyms; the 2014 classification introduced the «onion skin» approach, which combines the level of cleavage, the mode of inheritance, the phenotype (distribution and severity) and the gene and variant type [2, 46]. The 2020 consensus retained this approach, removed the qualifier «generalised», recognised compound heterozygous DEB and proposed the designation «Kindler EB» instead of «Kindler syndrome» to avoid confusion about the syndromic nature of the disease [1]. The correspondence between the classifications is as follows.

Source: GeneReviews, Table 3, and 2020 consensus [1, 2, 6].

The DEB subtypes recognised in 2020 are, in DDEB, intermediate, localised, pruriginosa and self-improving; in RDEB, severe, intermediate, inversa, localised, pruriginosa and self-improving; and, with mixed inheritance, severe DEB due to compound heterozygosity for one dominant and one recessive allele [1]. Localised DDEB encompasses the former nail-only, pretibial and acral forms; intermediate DDEB corresponds to the former generalised DDEB; intermediate RDEB to the former generalised intermediate RDEB; and severe RDEB to the former generalised severe Hallopeau-Siemens RDEB [1]. Transient bullous dermolysis of the newborn is now designated self-improving DEB, dominant or recessive [1, 2]. RDEB centripetalis is marked as obsolete in Orphanet [11]. Bart syndrome (OMIM 132000), localised aplasia cutis congenita of the extremities with nail dystrophy and blistering, does not appear as an autonomous subtype in 2020 and is understood as a presentation of DEB, mostly dominant, linked to COL7A1 in Dutch families [2, 3]. Epidermolysis bullosa acquisita (EBA, ORPHA:46487) is an autoimmune disease with autoantibodies against collagen VII, without genetic transmission, and should not be confused with DEB [19, 47].

2. Molecular Genetics and Pathophysiology

2.1. COL7A1 and collagen VII

COL7A1 is located at 3p21.31 (OMIM 120120; HGNC:2214; RefSeq NM_000094; UniProt Q02388) and encodes the α1 chain of collagen VII [2, 7]. The protein is expressed by keratinocytes, including basal keratinocytes, and is restricted to the basement membrane zone beneath stratified squamous epithelia [2, 7]. Three identical α1(VII) chains form homotrimers with a central collagenous triple-helical domain of Gly-X-Y repeats, flanked by the amino-terminal non-collagenous domain NC1 and the carboxyl domain NC2; the homotrimers associate through disulphide bonds into dimers in the extracellular matrix below the lamina densa and are organised into anchoring fibrils [2, 28]. The fibrils bind to the basement membrane through laminin-332 and collagen IV and attach it to the papillary dermis; above, hemidesmosomes link the basement membrane to the keratin intermediate filament network of basal keratinocytes [2, 7]. Without functional fibrils, the skin separates below the lamina densa, the level that distinguishes DEB from EBS (intraepidermal) and JEB (lamina lucida) [1, 7].

Severity follows the amount and function of residual protein. Biallelic null variants lead to absence of collagen VII and to severe RDEB; dominant-negative changes incorporated into the trimer produce reduced and altered fibrils and a DDEB that is as a rule milder [2, 7]. The variant type, the properties of the substituted amino acid and its position determine both the severity and the mode of inheritance [2].

2.2. Mechanisms by mode of inheritance

RDEB. RDEB is due to a wide spectrum of variants that lead to absence or marked reduction of collagen VII [1]. In severe RDEB, biallelic nonsense variants, frameshift insertions or deletions and splicing variants without production of functional protein predominate; in an analysis of 236 patients with RDEB, the functional type of the variants correlated with severity [2, 48]. In intermediate RDEB, the combination of a glycine substitution in the triple-helical domain on one allele with a premature termination codon on the other is common, allowing a small amount of partially functional protein; other (non-glycine) substitutions and splicing variants are associated with milder forms [2]. Some glycine substitutions are associated with RDEB and others may give DDEB or RDEB depending on the family [1, 49]. RDEB inversa is associated with genotypes with missense variants in the homozygous, compound heterozygous or hemizygous state within the triple-helical domain; in a review of 29 complete genotypes, all 19 known missense variants were arginine or glycine substitutions, 3 of the 5 arginine and 9 of the 14 glycine substitutions being specific to the inversa form, and it has been proposed that these substitutions reduce the thermostability of collagen VII [1, 4, 50].

DDEB. In DDEB, glycine substitutions with a dominant-negative effect in the collagenous domain predominate (more than 75%), especially in exons 73, 74 and 75, in the hinge region; the most frequent substitution is p.(Gly2043Arg) [1, 2]. These substitutions disturb folding of the triple helix and incorporate abnormal chains into the trimers [2]. Monoallelic splicing variants or indels with in-frame skipping of whole exons (for example, exon 87) and large in-frame deletions of the triple-helical domain are associated with mild localised DDEB [1]. The same glycine substitution may have very variable clinical expression between individuals and within the same family [1, 51].

Compound heterozygous and self-improving DEB. Compound heterozygosity for one dominant and one recessive variant is repeatedly associated with severe DEB; most of these patients have a picture similar to that of RDEB [1, 2]. Self-improving DEB has been associated with in-frame exon skipping (for example, exon 36) and with specific glycine substitutions; on electron microscopy, membrane-bound inclusions with amorphous material and stellate bodies in basal keratinocytes are considered pathognomonic [1, 10]. In the self-improving form, testing mostly reveals heterozygous COL7A1 variants and rarely biallelic variants [2].

2.3. Variant spectrum and nomenclature

GeneReviews and many articles use transcript NM_000094.3, whose c. numbering coincides with that of the current MANE Select transcript, NM_000094.4 (protein NP_000085.1) [8]. More than 700 COL7A1 alterations have been described [52]. The following table brings together the COL7A1 variants mentioned in the main clinical sources and in the clinical case, normalised according to Human Genome Variation Society (HGVS) nomenclature in VariantValidator (GRCh38) and with the ClinVar classification consulted on 17 October 2026, where available.

Sources: VariantValidator and ClinVar, consulted on 17 October 2026 [8]. The protein notation given by GeneReviews for c.325_326insCG omits the terminator and should read p.(Glu109AlafsTer39). The description c.8074delG corresponds, under the right-alignment rule of HGVS nomenclature, to c.8075del. Variants c.7157G>A and c.6341G>A are presented in the case articles as causal, but the current ClinVar classification is uncertain significance and conflicting, respectively; the clinical interpretation of each depends on the phase, segregation and protein data of the patient. The first published mutation, a homozygous methionine-to-lysine substitution in the carboxyl terminus, has no HGVS coordinate in the original abstract [44].

2.4. Founder and recurrent variants

The c.6527dup variant (formerly c.6527insC) is the most frequent pathogenic variant in patients with RDEB in Spain and Chile and acts as a founder allele; laboratories in those countries test for it directly, together with frequent variants in exons 5, 23–25, 57–60, 76, 80–82, 105 and 106 [10]. In South America, c.325_326insCG is prevalent in patients of South American ancestry and c.7957G>A in Argentina [2, 53]. The DEBRA International laboratory diagnosis recommendation includes testing for recurrent variants in defined populations or phenotypes as a valid strategy [10].

2.5. Penetrance, expressivity, mosaicism and modifiers

The penetrance of DDEB is reduced: unaffected heterozygotes have been identified, and heterozygosity for a glycine substitution may or may not cause disease, even within the same family [2, 49]. Heterozygosity for a null variant does not cause DEB, and the parents of patients with RDEB are as a rule clinically normal [2, 4]. In some families with RDEB, heterozygotes have only congenital nail dystrophy (NDNC8, OMIM 607523), which segregates as a dominant trait [4].

Postzygotic mosaicism for a dominant COL7A1 variant explains a parent with a mild phenotype and a child with more severe disease, and areas of affected skin along Blaschko's lines may result from mosaicism for a second recessive variant [1]. Maternal germline mosaicism has been described in DDEB [2, 10, 55]. Revertant mosaicism, through spontaneous repair of the causal variant in a keratinocyte clone, has been described for COL7A1 and for FERMT1 and explains areas of skin with greater mechanical stability [1].

Among modifiers, variants in cis may alter expression of the allele, for example by leading to in-frame skipping of the exon carrying the causal variant, which attenuates the disease because the truncated molecules retain partial function [1]. A functional promoter polymorphism of MMP1 (rs1799750), which encodes matrix metalloproteinase 1, a collagenase that degrades collagen VII, was associated with greater severity of RDEB in three discordant siblings and in a French cohort of 31 unrelated patients (p=6.27×10⁻⁵) [1, 4]. Phenytoin, proposed to inhibit collagenase, had no effect in a controlled study [4]. Changes in the expression of decorin and transforming growth factor β (TGF-β) in RDEB are seen as a consequence of chronic wound healing and as therapeutic targets [1]. The cycle of injury, inflammation and fibrosis underlies pseudosyndactyly, strictures and the risk of SCC; RDEB SCCs show an APOBEC mutational signature, and the inflammatory, infectious and fibrotic microenvironment and the altered immune response contribute to their aggressiveness [7, 56]. Non-genetic factors, such as the family context, access to care and climate, also modulate the clinical course [1].

2.6. Allelic disorders and related entities

Beyond the DEB spectrum, no other phenotypes associated with germline COL7A1 variants are known [2]. The OMIM entries associated with the gene all correspond to forms of DEB: DDEB (131750), RDEB (226600, with the inversa form included), pretibial DEB (131850), EB pruriginosa (604129), transient bullous dermolysis of the newborn (131705), Bart syndrome (132000) and non-syndromic congenital nail disorder 8 (607523) [2, 4]. Table B of GeneReviews also lists entry 226650 (JEB 1A intermediate), which belongs to another gene, in the JEB group. Collagen VII is the autoantigen of EBA, without a COL7A1 variant [7]. Biallelic variants of PLOD3, which encodes lysyl hydroxylase 3, produce a phenotype similar to that of RDEB, with fragmentation of the lamina densa, altered fibrils and reduced collagen VII, and constitute a molecular differential diagnosis [10].

2.7. Kindler EB: FERMT1 and kindlin-1

FERMT1 (aliases KIND1, URP1, UNC112A, C20orf42, FLJ20116) is located at 20p12.3 (OMIM 607900; HGNC:15889; MANE Select transcript NM_017671.5) and has 15 exons encoding kindlin-1, a protein of 677 amino acids (about 77.4 kDa) [6, 9, 57]. Kindlin-1 is expressed in basal keratinocytes and in the epithelium of the colon, lung, placenta, adrenal gland and prostate; it has a bipartite FERM domain interrupted by a pleckstrin homology (PH) domain and acts as an adaptor between filamentous actin and integrins, in the integrin β1 adhesion complex [6, 45, 58]. It belongs to a family of three kindlins: kindlin-2 (FERMT2, 14q22.1) and kindlin-3 (FERMT3, 11q13.1), whose loss causes leucocyte adhesion deficiency type III [59]. Kindlin-1 contributes, with talin, to «inside-out» activation of integrins and is required for polarisation, proliferation, adhesion to fibronectin and laminin and migration of keratinocytes [9, 59]. Its absence disorganises basal keratinocytes, which explains cleavage at multiple levels (intraepidermal, junctional and dermal, sometimes in the same biopsy) and reduplication of the lamina densa [6, 10]. Keratinocytes lacking kindlin-1 secrete interleukins 20 and 24, which induce collagen I in fibroblasts, and the fibroblasts express more tenascin-C, periostin and TGF-β1, a proposed mechanism for the progressive fibrosis [60].

The mechanism is loss of function. Ninety-one pathogenic variants had been described: missense, nonsense, splicing, small insertions and deletions and Alu-mediated rearrangements, including 8 large deletions, as well as regulatory, in-frame and deep intronic variants [6, 10, 60]. A deep intronic variant, c.1139+740G>A, which creates a pseudoexon, explained genetically unresolved cases, which means that exon-only panels do not exclude KEB [26, 61]. Sequence analysis detects about 95% of known pathogenic variants and targeted deletion and duplication analysis about 3%; these proportions refer to described variants and not to the clinical sensitivity of the test [6].

Source of normalisation: VariantValidator, GRCh38, consulted on 17 October 2026 [8].

Founder effects are documented by shared haplotypes: c.676dup in Pakistani families, c.910G>T in British patients, the c.958-1G>A variant in Italy, an Omani variant (W616X), c.811C>T in Panama and c.450del in four unrelated Paraguayan families [57, 64, 65]. Most variants lead to premature termination codons, and no robust genotype–phenotype correlations have been established [6, 67]. Missense variants and small in-frame deletions are associated with milder phenotypes and later complications: the c.299_301del deletion reduces messenger RNA by 50% and protein by 90%, the misfolded protein is degraded in lysosomes, and sodium phenylbutyrate increased RNA and protein in vitro, with improvement of the cellular phenotype even at low kindlin-1 levels [66, 67]. Among other substitutions, p.Tyr293Asp prevents localisation of kindlin-1 to focal adhesions and does not respond to chaperones, whereas p.Trp559Arg and p.Ile623del retain localisation and respond, so each variant has to be tested individually [68]. Variability is not fully explained by genotype, and environmental factors, especially sun exposure, and modifiers contribute [67]. Revertant mosaicism has been described in KEB [69]. There are no established allelic disorders of FERMT1; an isolated case of autoimmune retinopathy in a 25-year-old man with KEB, Hashimoto's thyroiditis and ulcerative colitis, with the homozygous variant c.1718+2T>C and variants of uncertain significance in immune genes, led the authors to propose a component of immune dysregulation, without this defining an allelic entity [70].

3. Clinical Spectrum and Manifestations by System

3.1. Overview of the subtypes

In DEB, skin fragility and nail dystrophy or absence are generally present at birth [2]. Blisters heal with atrophic scarring and milia, and the scarring sequelae of the skin and oral mucosa and the loss of nails are irreversible and progressive, becoming more evident with age [1]. In the newborn, clinical distinction between the main EB types is unreliable: blisters predominate on the extremities and in the nappy area, and the pattern becomes characteristic only with growth; in the intermediate and severe forms of DEB, fragility is concentrated over bony prominences such as the knees and elbows [1]. The following table summarises the most frequent features of the common subtypes.

Source: GeneReviews, Table 2 [2, 71].

Absence of lingual papillae is a clinical criterion of the generalised recessive forms, useful when cutaneous scarring has not yet become established [2, 71]. The extracutaneous complications of RDEB are not primary, as in the syndromic forms of skin fragility, but secondary to chronic and extensive loss of skin and mucosa [1].

3.2. Severe RDEB: natural history by system

Skin. Blisters and erosions appear at birth or in the neonatal period and may affect the whole body; aplasia cutis congenita, especially of the extremities, is frequent in the newborn [2]. Blisters heal with milia and scarring, and many wounds become chronic and do not heal, with secondary infection by Staphylococcus, Pseudomonas and Streptococcus [2]. Large, irregular brown patches, EB naevi (collections of naevus cells), frequently appear, in which melanoma has not been described to date [2]. In the US national registry (NEBR), the cumulative risk of melanoma in severe RDEB was 2.5% at 12 years [25]. Pain is chronic in most patients and has nociceptive, neuropathic and psychogenic components from the first days; intraepidermal nerve fibre density is decreased in RDEB, which supports the neuropathic component [34, 56]. Pruritus is frequent, feeds the itch–scratch cycle and worsens wounds [34].

EB naevi often arise at the site of an old blister and may measure several centimetres, with heterogeneous colour and network, asymmetry and evolution over time; despite these clinical and dermoscopic criteria of malignancy, histology is benign in most cases [36]. The French national protocol (PNDS) reports that melanoma has been described in inherited EB, without data showing an incidence higher than in the general population [36]. Verruciform xanthomas, benign erosive and papillomatous plaques, mimic SCC clinically and histologically and complicate RDEB and other chronic inflammatory genodermatoses; the diagnosis requires confirmation by an experienced pathologist [36].

Mouth. Oral fragility produces blisters, erosions, fusion of the tongue to the floor of the mouth (ankyloglossia), obliteration of the vestibule and progressive reduction of mouth opening (microstomia), with difficult oral hygiene, multiple caries and dental crowding [2, 34, 72]. Enamel hypoplasia is typical of JEB but may occur in RDEB; in RDEB, the teeth are as a rule affected secondarily to fragility and scarring [10, 34].

The systematic review of the DEBRA International oral guideline (2020; 202 publications from 1947 to March 2020, mostly case reports and case series with laboratory diagnosis often undocumented, and therefore with a high risk of bias) gives the scale of these changes [73]. In an old series of 101 patients with EB, oral blisters were present in 97% of patients with RDEB and in 45% of patients with DDEB, and microstomia in 54% of patients with RDEB and in none with DDEB; in a cohort of 197 patients with a clinical diagnosis, microstomia and lingual adhesions were observed only in DEB [73]. In generalised RDEB, microstomia is progressive and severe in more than 80% of patients with the severe form, and results from scarring of the buccal and labial mucosa and the commissures, where fibrous bands are sometimes palpable; the mucosa sloughs on touch, serous or haemorrhagic blisters appear on any surface, especially the tongue, and some are caused by the edges of broken teeth or restorations [73]. The tongue loses its papillae, the palate loses its rugae, ankyloglossia may affect all patients (in a functional study, only 7 of 10 patients could protrude the tongue, on average 6 mm beyond the teeth, and only 2 of 9 and 1 of 8 could touch the left and right cheek, respectively, with the tip), and obliteration of the labial and buccal vestibules hinders hygiene, treatment and the use of removable prostheses [73]. In the newborn, erosions and ankyloglossia require special feeding bottles; later, ulcers and dysphagia may lead to a liquid diet [73].

Dental plaque and gingivitis are intense: in 23 patients with DEB (18 with RDEB and 5 with DDEB), the plaque index was 33.7 ± 31.3 in the primary dentition and 28.6 ± 31.6 in the permanent dentition, versus 1.8 ± 3.3 and 4.6 ± 5.6 in controls, and the gingival index 21.5 ± 29 and 27.5 ± 34.9, versus 0 and 2 ± 4.6; in generalised severe RDEB, erythema was the most prevalent gingival lesion (66.2%) [73]. There is, however, no increase in periodontal bone loss; the deep pockets found on probing correspond to pseudopockets, and only one report described mobility and bone loss in the lower incisors [73]. Salivary flow, pH and buffering capacity are normal, with increased salivary IgA, albumin and total protein, probably due to blistering, and without relation to caries [73]. The decayed, missing and filled teeth index is significantly higher in RDEB than in controls, with pain, abscesses, cellulitis of periapical origin and loss of the entire dentition in some patients; the associated factors are a soft diet, microstomia and finger contractures, caries may be concentrated on the lingual surfaces, and the enamel has a normal chemical composition [73]. Severe crowding, increased overjet and overbite, crossbite and skeletal class II are frequent; in a cephalometric study of 42 patients with severe RDEB, maxillary and mandibular length and middle and lower facial heights were significantly reduced, which is attributed to poor nutrition and early perioral scarring [73]. Dental maturation is not delayed, agenesis of a single tooth has been described in three cases, and alveolar bone atrophy was observed in all 6 patients of a surgical series, together with osteoporosis [73]. In RDEB inversa, blisters are mainly sublingual, with ankyloglossia, loss of the papillae and palatal rugae, partial obliteration of the vestibule, microstomia and mucosal milia; in a series of 10 patients, 90% had oesophageal involvement and the decayed, missing and filled surfaces index was 50.9, versus 12.8 in controls [73]. In DDEB, the frequency of oral blisters ranges from 20% in one review to 71.1–89.6% in series with history or observation; significant scarring, vestibular obliteration and ankyloglossia do not appear to be late complications, but reduction or absence of keratinised gingiva has been described, and the risk of caries is not increased [73]. Oral SCC is rare but severe in RDEB: the cases described affected the tongue (most frequent site), the lip and the hard palate, between 25 and 54 years of age, and at least three were fatal [73].

Oesophagus and digestive tract. Blisters, erosions, webs and oesophageal strictures cause severe dysphagia, drooling, regurgitation, food impaction and odynophagia, with malnutrition and anaemia [2, 56]. Strictures are most often located in the upper oesophagus [56]. In the NEBR, the cumulative risk of oesophageal stricture in severe RDEB was 6.7% by 1 year and 35.2% by 5 years, reaching 94.7% at 45 years [38, 74]. Rarely there is oesophageal disease with little cutaneous manifestation [2]. Acute obstructive blisters of the hypopharynx or oesophagus cause acute aphagia, and the sloughed oesophageal mucosa may be expelled as casts with vomiting and haematemesis [38]. Gastro-oesophageal reflux disease (GORD) is common. Severe constipation is frequent, owing to painful anal erosions, low fluid and fibre intake and opioid use [2]. A subgroup of children with RDEB has colitis [74]. Oesophageal SCC has rarely been described in RDEB with chronic strictures [38].

The French PNDS summarises the frequency of oesophageal stricture as ranging from 1.37% in localised EBS to 100% in RDEB inversa; about half of strictures are located in the upper third, at Killian's mouth, with a risk of aspiration and pulmonary infection, the middle third is more affected than the lower, and there are multiple strictures [36]. Acute dysphagia, due to a blister or erosion caused by food or a tablet, resolves within a few days, whereas chronic dysphagia as a rule reflects a stricture [36]. Constipation is defined as fewer than two bowel movements per week or pain on defecation; scanty daily bowel movements may conceal a large faecal impaction, with a risk of ureteral compression or respiratory difficulty, and anal stenoses, which are rare, occur mainly in generalised RDEB and in the inversa form [36].

Nutrition and growth. Malnutrition results from low intake and from requirements increased by wound healing, protein and fluid losses through wounds, infections and a hypercatabolic state; it leads to growth restriction in young children and to delayed or absent puberty in older ones [2, 56]. Deficiencies of iron, zinc, carnitine, selenium, vitamin A and vitamin D are frequent [2]. Energy requirements are usually between 100% and 150% of the estimated average for healthy children of the same age, height and sex, with high protein requirements [56].

According to the PNDS, the growth curve may slow from 18 months, and half of the children with RDEB have weight or height below −3 standard deviations at 10 years [36]. In the severe forms (large surface affected or mucosal involvement), the PNDS estimates energy requirements 20–30% higher and protein requirements about 50% higher than those of individuals of the same chronological age, to be modulated according to the surface affected, infection and growth delay, and stresses that there are no studies of nutritional requirements in EB and that extrapolation from major burns has limits [36]. The deficiencies described cover the protein-energy compartment, lipids, iron, zinc, selenium, carnitine and vitamins D, K, A, B, PP and C, with consequences such as oedema and anasarca, osteoporosis, dilated cardiomyopathy, anaemia and neuropathy [36].

Anaemia. Anaemia is multifactorial, owing to haemorrhagic losses from wounds, low iron intake and absorption and anaemia of chronic inflammation with marrow suppression, and may appear in the first year [2, 56]. In series from Australia, Peru and the United Kingdom, the frequency of anaemia was 96–100% in RDEB, 62.5–100% in JEB and 11–30% in EBS [75]. In the cohort of the Freiburg reference centre (Germany), with 200 children (157 with RDEB and 43 with intermediate JEB), anaemia appeared from the second year of life in 91% of children with RDEB; haemoglobin decreased with age in RDEB, and serum iron, ferritin and transferrin saturation were below normal in half of the children aged 2–10 years and in more than 80% of those over 10 years; low weight correlated with low haemoglobin, iron, vitamin D, zinc and albumin, raised C-reactive protein (CRP) and absence of collagen VII [75].

Source: Reimer and colleagues, reproduced in the DEBRA International anaemia guideline [75]. The original table gives haemoglobin in «g/L», but the values correspond to g/dL.

Eye. Ocular involvement affects more than half of patients with RDEB, from the first months: chronic blepharitis, eyelid blisters, recurrent corneal erosions with scarring, opacities and reduced vision, rarely blindness [2, 56]. Corneal erosion presents with pain, a red and watering eye, photophobia and blepharospasm [35].

The PNDS adds that ocular lesions may begin in the first month of life and increase with age; reduced visual acuity affects 40% of patients with RDEB and blindness 6% [36]. The most specific complication is symblepharon (adhesions between the bulbar and palpebral conjunctiva), especially in severe RDEB and in the inversa form; lacrimal duct obstruction is described mainly in RDEB inversa, and meibomian gland dysfunction and refractive errors are frequent; corneal involvement also includes exposure keratitis, limbal thickening, pannus, cornea plana and sclerocornea, and eyelid involvement includes ectropion, entropion and sparse eyelashes [36]. Acute corneal ulcers cause intense photophobia that may require rest in the dark for several days [36].

Heart. Dilated cardiomyopathy has been described in RDEB, sometimes associated with selenium and carnitine deficiency and sometimes fatal [2, 76]. Iron overload from repeated transfusions has been raised as a possible aggravating factor, without clarification [75].

In the PNDS, non-obstructive dilated cardiomyopathy affects 4.5% of patients with generalised severe RDEB from 20 years of age and may begin in childhood; it has a multifactorial origin: selenium and carnitine deficiencies, chronic anaemia and post-transfusion iron overload, AA amyloidosis, thromboembolic and infectious complications of central venous catheters, drugs (amitriptyline, cisapride) and viral infections [36].

Kidney and urinary tract. Urethral erosions and strictures, bladder dysfunction and urinary retention occur rarely [2, 35]. Renal involvement includes IgA nephropathy, post-infectious glomerulonephritis, C3 glomerulonephritis, proteinuria or nephrotic syndrome due to amyloidosis and focal segmental glomerulosclerosis, with possible progression to renal failure [56, 77]. Creatinine overestimates renal function in malnutrition, so cystatin C is preferred in this context [56].

The PNDS describes, in generalised RDEB, frequent tubular-type proteinuria and hyponatraemia, of unknown significance and functional consequences, and considers IgA nephropathy very frequent in generalised RDEB and JEB, with mainly microscopic haematuria and glomerular proteinuria [36]. AA amyloidosis may appear very early, including in children, in the highly inflammatory generalised forms, usually with nephrotic syndrome without hypertension or renal failure with enlarged or normal kidneys, and may affect the liver, spleen, digestive tract and heart; the predictive value of serum amyloid A measurement is unknown [36]. Obstructive nephropathy due to endourethral or meatal stenosis occurs mainly in males, in JEB and in RDEB inversa [36]. Two kidney transplants in generalised EB with end-stage renal failure (one JEB and one RDEB) have been published, without immediate surgical or post-transplant complications, with an apparent cutaneous benefit from immunosuppression [36].

Liver. RDEB may rarely be accompanied by fulminant hepatic failure, sometimes fatal, and some drugs used for pain, pruritus and infection in severe RDEB are hepatotoxic [2].

Bone, puberty and hands. Delayed puberty affects one third to one half of patients with RDEB [56, 78]. Low bone mineral density affects about 30% of children with RDEB, often before 10 years of age, worsening in adolescence, and osteoporosis has been described in 75% of adults with severe RDEB; vertebral fractures may be silent [56, 74]. Poor nutrition, little sun exposure, inactivity and inflammation contribute [2]. Adduction contracture of the thumb, pseudosyndactyly («glove» or «mitten» deformity) and flexion contractures of all the joints of the hand, including the wrist, are almost constant in severe RDEB; fusion of the toes compromises function less, but painful blisters and contractures of the foot, ankle, knees, hips and neck hinder walking [2, 56].

US registry data cited by the PNDS give a cumulative risk of pseudosyndactyly of 100% at 20 years in generalised severe RDEB and of 54.3% at 35 years in RDEB inversa, with deformities that may begin in the first year of life [36]. Non-acral contractures (knees, elbows, axillae) have a cumulative risk of 98.8% at 20 years in generalised severe RDEB, 48.7% at 25 years in generalised non-severe RDEB (designated «RDEB-m» in the PNDS), 24.5% at 15 years in RDEB inversa and 8.1% at 55 years in DDEB [36]. Aplasia cutis congenita of the feet is often deep, slow to heal and very painful, and may leave limb atrophy with asymmetric growth of the feet; palmoplantar keratoderma also occurs in RDEB and causes pain independent of blistering [36].

Sexuality, fertility and psychosocial aspects. Sexuality is affected; vulvovaginal involvement causes dyspareunia and rarely vaginal stenosis, and fertility may be reduced by malnutrition, low body mass index and delayed puberty [56, 79]. Stress for the patient and family is intense; anxiety, depression and substance dependence or misuse have been described in older patients [2]. In adolescence, adherence to treatment decreases as complications (SCC, renal failure) increase [56].

Ear, nose and larynx. In DEB, a hoarse voice was recorded in 1.6–5.8% of patients, depending on the subtype, and there are sporadic cases of stridor due to glottic or supraglottic stenosis that required tracheostomy; the warning signs of an obstructive airway blister are inspiratory dyspnoea (stridor), a weak or hoarse cry and dysphonia [36]. Blisters of the auricle are frequent in all forms of EB; chronic otitis externa (pain, otorrhoea, crusts) affects 9.5% of patients with JEB, severe RDEB and RDEB inversa, and stenosis of the external auditory canal, rare in EB in general, affects 10% of patients with RDEB inversa, in whom deafness also appears more frequent [36]. Nasal complications are limited to rhinitis and crusting in rare patients [36].

3.3. Squamous cell carcinoma in RDEB

Cutaneous SCC is the leading cause of premature death in RDEB [39, 56]. It arises at sites of chronic blistering, wounds and scars, not in sun-exposed areas; it is often multiple and more aggressive than SCC in the general population; it has been described in a 6-year-old child and frequently occurs before 20 years of age [39, 80]. In the NEBR (3280 patients enrolled between 1986 and 2002 in the continental USA, with a random longitudinal subcohort of 450), the cumulative risk of at least one SCC in Hallopeau-Siemens RDEB (now severe RDEB) was 7.5% at 20 years, 67.8% at 35, 80.2% at 45 and 90.1% at 55 years; the cumulative risk of death from SCC was 38.7% at 35 years, 70.0% at 45 and 78.7% at 55 years, despite aggressive surgical resection [25, 39]. The genotype was known in a minority of registry patients [25]. GeneReviews summarises this as a lifetime risk greater than 90% [2].

European cohorts confirm the severity. In London, over 28 years, 44 patients with EB developed 221 primary SCCs; 31 (70%) had severe RDEB, 4 (9%) other RDEB and 5 (11.4%) DDEB; the median age at first SCC was 29.5 years (13–52) in severe RDEB and 47.1 years (30–89) in the other groups; there was an average of 5.8 tumours per patient; SCC-associated mortality in severe RDEB was 64.5% and median survival after the first SCC was 2.4 years (0.5–12.6) [81]. In the Dutch registry (Groningen, 1988–2020), 22 of 578 patients (3.8%) developed 78 SCCs; the frequency was highest in severe RDEB, 9 of 34 (26%), with a median age at first SCC of 27.7 years (14.3–42.2), metastases in 7 of 9 (78%), death in 8 of 9 (89%), death from metastatic SCC in 7 of 8 and a median age at death of 37.5 years; median survival after the first SCC was 41 months (9–199) [82]. In this cohort, 89% of primaries were on the extremities, 74% in areas of chronic wounds without a distinctive appearance, 63% were at least 2 cm, 55% were well differentiated and only one had perineural or lymphovascular invasion, so the aggressiveness is not explained by the classical histological risk factors [82]. The frequency of SCC was 1 in 23 (4%) in intermediate RDEB and 1 in 11 (9%) in RDEB inversa [82]. In a systematic review of 157 cases of SCC in RDEB, 64.1% were well differentiated, 59.6% ulcerated and 77.6% were at least 2 cm, and the median age at diagnosis was 30 years (6–68.4) [80]. The other DEB subtypes have a lower, later and less aggressive risk [39].

The PNDS characterises the SCCs of inherited EB as early, multifocal and recurrent, frequently well differentiated but sometimes very aggressive from the outset (rapid progression in surface and depth, lymphophilia), with a worse prognosis in the undifferentiated forms [36]. They do not arise de novo: they always develop on pre-epitheliomatous lesions, the dystrophic areas (scars or chronic wounds) of RDEB, which explains their multifocal and recurrent nature; ultraviolet radiation and viral infection do not appear to be involved (non-sun-exposed areas, negative virological data), and patients with RDEB, despite their poor general condition, do not appear clinically immunosuppressed [36]. Local extracutaneous (especially bone) or nodal invasion severely compromises the possibility of cure, and visceral metastases as a rule lead to palliative treatment, because these tumours are poorly chemo- and radiosensitive [36].

3.4. Other recessive subtypes

Intermediate RDEB. It may be mild, with blisters on the hands, feet, knees and elbows and dystrophic nails, or more extensive, involving the skin folds and trunk; it leaves scars, milia and naevi without mutilating scarring [2]. It begins between birth and childhood. Scarring with partial interdigital webbing, without complete pseudosyndactyly, nail loss and oral lesions are possible; growth failure is less marked; oesophageal strictures, corneal lesions, anaemia and developmental delay may appear, less frequently than in the severe form; SCC develops in some patients [2, 19, 83].

RDEB inversa. It is rare (about 100 cases according to Orphanet) [18]. It begins with generalised blistering of intermediate severity in childhood; later the lesions concentrate in the skin folds (neck, axillae, groins, breasts, thighs), with atrophy, and the hands, feet, elbows and knees are little affected; the fingernails are normal or little involved, the toenails dystrophic; oral, oesophageal, anal and genital involvement is marked, and oesophageal strictures are common [1, 2, 4, 19]. The hands become scarred but do not progress to mitten deformity [83].

Localised RDEB. It is rare: blisters with scarring, which may be severe, limited to the hands and feet, nails often absent, without growth restriction or systemic disease, and with no SCC described [2]. Clinically it cannot be distinguished from localised DDEB; the difference is genetic [19].

DEB pruriginosa (dominant or recessive). It mainly affects the shins: pretibial blisters progress to prurigo-like nodules and hyperkeratotic linear lesions, sparing the knees, with extension proximally and to the arms over time; it is associated with nail dystrophy, small white scars (albopapuloid lesions) and hypertrophic scars, with intense pruritus; the onset of the pruriginous features may be very late, in advanced adulthood [1, 2]. Orphanet estimates about 100 families [14].

Self-improving DEB (transient bullous dermolysis of the newborn). It presents at birth or shortly afterwards with blisters, sometimes generalised, which disappear between 6 and 24 months of life [2, 19]. It is mostly dominant; the recessive form is rare [2]. Orphanet records 52 cases [15]. The history of three generations with the self-improving form illustrates dominant transmission [2].

3.5. Dominant subtypes

Intermediate DDEB. Blisters are generalised at sites of friction in infancy and the course becomes less severe in adults; there are scarring, milia, albopapuloid lesions (Pasini form) and nails that are often absent; other organs are generally spared, and growth failure, severe anaemia and SCC are rare or absent [2, 3, 19]. Blistering improves somewhat with age, possibly owing to reduced activity [2]. Microstomia, caries and tooth loss may also occur in DDEB [34].

Localised DDEB. It includes the acral, pretibial and nail-only forms [1]. In the nail-only form, the nails, especially the toenails, are dystrophic and fragile, sometimes as the only manifestation, and other relatives may have more severe forms [2]. Pretibial DEB (about 40 families in Orphanet) progresses with age and is classically pruriginous [1, 13, 19]. The acral and nail-only forms have about 10 families each in Orphanet [13].

DDEB pruriginosa. Rare, on the anterior aspect of the legs, with intense pruritus, sometimes with prurigo nodularis [2].

Bart syndrome. Localised aplasia cutis congenita of the extremities, blisters and nail deformity; described in families with DDEB in which members with and without aplasia cutis coexist, and also in patients with RDEB [3, 4]. Aplasia cutis of the extremities is observed in all types of EB [2].

3.6. Compound heterozygous DEB

One DDEB allele and one RDEB allele produce manifestations ranging from mild to severe, depending on the type of recessive variant; most resemble RDEB, and the parent carrying the dominant variant may have only a mild form [1, 2].

3.7. Kindler EB

Overview. The spectrum ranges from mild forms, with minimal skin involvement and diagnosis in the seventh or eighth decade, to severe forms with intense mucosal involvement, severe oesophageal stricture, pseudo-ainhum, anaemia and neoplasms [6, 62]. The relative frequency of the manifestations is as follows.

Source: GeneReviews, Table 2, and the cohorts indicated [6].

Skin. Blisters are present at birth or appear in early childhood, mainly on the extremities, triggered by trauma or sunlight, and their number decreases at around 10–12 years [6, 37, 64]. Atrophy (thin, wrinkled, cigarette-paper skin) appears first on the dorsa of the hands and feet and becomes generalised by adolescence [6]. Photosensitivity, with erythema and burning minutes after sun exposure, is more marked in childhood and decreases with age, with facial erythema persisting after minimal exposure [6]. Poikiloderma, absent at birth, frequently appears between 2 and 3 years of age, first in sun-exposed areas and then in unexposed areas, with reticulate telangiectasia and mottled pigmentation, and persists into adult life [6]. Palmoplantar keratoderma is fissured or punctate, with a waxy appearance and loss of dermatoglyphics (fingerprints) [6]. Pseudosyndactyly, especially between the 3rd and 4th and the 4th and 5th toes, forms interdigital webs without the exuberant scarring or milia of the other forms of EB; pseudo-ainhum constricting bands have been described [6, 64]. Joint hypermobility, xerosis, eczema and nail dystrophy are other findings [6].

Mouth and teeth. Periodontal disease (haemorrhagic mucositis, gingivitis, periodontitis and early tooth loss) usually begins in early adolescence, but has been described from the primary dentition [6, 73]. In a series of 18 patients, the prevalence of periodontitis was 72% versus 46% in controls, with earlier onset and faster progression; on follow-up of the same cohort with 26 individuals, 81% had severe periodontitis and early tooth loss [73]. In isolated reports, a 14-year-old girl lost all her teeth to severe periodontitis, and another, aged 16, with spontaneous gingival bleeding, had exfoliation of all her primary teeth between 4 and 7 years and of a permanent lower central incisor at 10 years [73]. In a family with five patients aged 6 to 14 years, all had microstomia; there were periodontal pockets greater than 4 mm from 6 to 10 years and aggressive periodontitis with pockets of 7 mm or more at 12 and 14 years, with slight alveolar resorption up to 12 years and severe resorption at 14, and thin gingiva whose epithelium sloughed at the slightest abrasion [73]. Unlike RDEB, poor hygiene is rarely reported, the prevalence of caries does not appear to differ from the general population, and the only implant rehabilitation described failed after 6 years [73]. The perioral areas show erosions, crusts and chronic cheilitis (cheilitis glandularis of the lower lip described at 7 years), microstomia due to fibrosis of the commissures is frequent but rarely a cause of complaint, and partial obliteration of the vestibule («adhesions between the lips and gums») has been described in several patients; the mucosa ranges from absence of lesions, especially in younger patients, to scattered painful ulcers, and reticulate buccal pigmentation, white hyperkeratotic papules and xerostomia are rare findings [73]. In the longitudinal cohort of Freiburg and DEBRA Chile (2003–2023; 36 patients, mean age at first examination 23 years), gingivitis or periodontal disease was present in 90%, intraoral lesions in 73%, angular cheilitis in 73%, cheilitis in 65%, gingival hypertrophy in 65%, microstomia in 56% and vestibular obliteration in 50%; in the 11 patients in whom enamel was assessed, all had hypoplastic pitted amelogenesis imperfecta, a finding proposed as characteristic of KEB; two patients died of oral SCC [84]. Labial leucokeratosis was observed in 3 of the 26 patients from Panama [73]. At least 7 oral SCCs have been described, 2 fatal, between 34 and 55 years of age, on the hard palate, buccal mucosa and lips [73].

Eye. Conjunctivitis, conjunctival scarring, corneal erosion and ectropion of the lower eyelids [6]. At an ophthalmology centre in New Delhi, three patients had chronic sequelae: recurrent epithelial breakdown with severe dry eye and post-keratitis opacity (10 years), symblepharon with keratinisation of the ocular surface (28 years) and partial limbal stem cell deficiency (16 years) [85].

Digestive tract. Oesophageal stricture, severe colitis with bloody diarrhoea, constipation, fissures and rectal strictures; children born with imperforate anus have been described [6]. Chronic dysphagia is common in KEB, as in RDEB [38]. A patient with severe haemorrhagic colitis of the descending colon, sigmoid and rectum led the authors to propose active investigation for intestinal involvement [86]. A 2-month-old Palestinian infant presented with watery diarrhoea from the first week, loss of 500 g in 2 weeks, hyponatraemia (127 mEq/L), metabolic acidosis, faecal occult blood and anaemia (haemoglobin 6.8 g/dL), with vesicles on the feet since birth and homozygosity for FERMT1 c.137_140del; he improved with an amino acid formula via nasogastric tube [87]. Cytomegalovirus colitis has been described in two patients [88].

Genitourinary tract. Meatal stenosis and urethral strictures, phimosis, vaginal stenosis and labial adhesions [6]. In Panama, 80% of men had severe phimosis [64]. In a review of 186 cases, urethral stricture and anal stenosis were more frequent in men [63].

Evolution with age. In the same review of 186 cases (110 men; mean age 28 ± 16 years), oral inflammation, keratoderma, webbing and pseudo-ainhum, dysphagia and urethral stricture correlated with age and were more frequent above 32 years; 41 tumours were recorded in 27 patients, 92.7% SCC, mainly on the hand and in the mouth [63]. Morbidity and mortality result from mucosal strictures, infections and cancer [6].

SCC in KEB. In a retrospective multicentre European and American series of 91 patients over 16 years of age with a clinical and molecular diagnosis, 13 developed non-melanoma skin cancer (25 cutaneous tumours and 2 of the oral mucosa; all SCC except one basal cell carcinoma), the first SCC appeared at 29 years and the cumulative risk rose with age to 66.7% above 60 years [26]. There were metastases in 7 of the 13 patients (53.8%) and 5 (38.5%) died of the tumour 2 to 7 years later [26]. In 37 SCCs from 22 patients, 78% were located on the perioral face and the hands, areas of chronic inflammation and sun exposure, in contrast with the predominance on the lower limbs and over chronic wounds in RDEB; SCCs in KEB appeared 10 to 20 years later than in RDEB [26]. Age at first SCC ranged from 16 to 69 years, with 14 of the 22 patients between 40 and 59 years, and isolated cases at 16, 23 and 27 years in the literature [26]. The 66.7% estimate comes from a reference series with few patients above 60 years and is not a lifetime risk validated in a population cohort. In the Dutch registry, 1 of 5 patients with KEB (20%) had SCC [82]. Transitional cell carcinoma of the bladder has been described [6].

3.8. Natural history and treated disease

The cumulative risks of SCC, oesophageal stricture and death come mainly from registries and series predating the targeted therapies approved from 2022 onwards and reflect the natural history with supportive care; there are as yet no data showing that topical collagen VII therapies, with 1 to 8 years of follow-up, alter these risks [25, 89, 90]. The fall in births of children with severe RDEB in England and Wales over 19 years (r=−0.44) was attributed by the authors to genetic counselling and not to changes in the natural history [23].

4. Clinical Recognition and Warning Signs

4.1. Newborn and infant

DEB should be suspected in a newborn with blisters or erosions after minimal trauma, with areas of absent skin (aplasia cutis congenita), especially on the extremities, with oral erosions or with dystrophic or absent nails [2]. Scarring, the defining feature of DEB, may not yet be established in the newborn, and clinical distinction between the EB types in the neonatal period is unreliable [1, 2]. Aplasia cutis of the scalp requires examination of the skin elsewhere for blisters and scars and enquiry about pyloric atresia, because EB may be the cause of the scalp lesions [91]. Bilious or repeated vomiting or abdominal distension in a newborn with EB points to EB with pyloric atresia and requires ultrasound and surgical referral [92]. Any newborn with skin lesions or absent skin should receive protective care as if they had EB until diagnosis, and a newborn with signs of severe EB should be referred, after stabilisation, to a specialist centre [19, 92]. The Brazilian Guidelines and the DEBRA International guidelines recommend that laboratory diagnosis be requested at first suspicion [10, 19].

There is no population newborn screening for EB. The DEBRA International neonatal guideline recommends that, in a newborn with EB, the sample for routine newborn screening be collected by venepuncture on day 2–3, marking the sample as venous, instead of a heel prick, to avoid skin detachment (recommendation ↑, high evidence) [92].

4.2. Child, adolescent and adult

Suggestive findings include blisters after minimal trauma that heal with milia and scarring, mainly on the hands, feet, knees and elbows in the mild forms and over the whole body, with mucosal involvement, in the severe forms; pseudosyndactyly of the hands and feet; oral or oesophageal stricture; corneal erosions with scarring; absence of lingual papillae; and dystrophic or absent nails, especially toenails [2]. In the mildest forms of DDEB, toenail dystrophy may be the only manifestation, and the pruriginosa form may appear only in adulthood, with pretibial nodules [1, 2]. A family history consistent with recessive inheritance (affected siblings, consanguinity) or dominant inheritance (several generations, both sexes) supports the diagnosis, but the absence of a family history does not exclude it [2].

4.3. Warning and emergency signs

ERN-Skin has identified emergency situations specific to EB, with guidance for general emergency departments and a dedicated emergency card [35].

Source: ERN-Skin, emergency recommendations [35].

Acute worsening of dysphagia in an adult with chronic strictures requires immediate endoscopy and/or imaging, because oesophageal SCC has been described in RDEB [38].

4.4. Warning signs of squamous cell carcinoma

A wound should be biopsied to exclude SCC when it does not heal despite adequate treatment (for example, for 4 weeks or longer than the patient's usual wounds), enlarges rapidly, is deep with raised or rolled edges (punched-out ulcer), has an exuberant or vegetating appearance similar to granulation tissue, shows areas of thick hyperkeratosis with a «shoulder» of raised skin, or causes new pain, increased pain or a tingling sensation [34, 39, 56]. The non-healing interval that defines a suspicious wound is individual and should be compared with the patient's own usual pattern [56]. In KEB, the priority sites for surveillance are the hands and the perioral region and the oral mucosa, including in edentulous patients [26, 73].

The PNDS considers suspicious for SCC, on the skin or on a mucous membrane, any lesion (ulceration, exuberant granulation tissue, hyperkeratosis, nodule) that has been chronic for more than 1 month and is spreading, any abnormally tender or painful lesion, a friable or spongy wound or hyperkeratosis, and a lesion that is simply «unusual» compared with the others, often pointed out by the patient; a foul-smelling wound is a sign of advanced SCC [36]. Serial medical photographs help to document extent, and any change in the usual healing pattern of a wound in a given patient justifies expert assessment [36].

4.5. Kindler EB: when to suspect

KEB should be considered in the presence of acral traumatic blisters from birth, also triggered by sunlight; early cigarette-paper atrophy on the dorsa of the hands and feet; photosensitivity with erythema and burning within minutes; poikiloderma from 2–3 years of age; palmoplantar keratoderma with fissures and loss of fingerprints; interdigital webbing of the toes; and fragility of the mucous membranes (conjunctiva, periodontium, digestive tract, genitals and urinary tract) [6]. In the first years, before photosensitivity and poikiloderma appear, KEB is frequently mistaken for DEB, JEB or EBS; acral atrophy and the improvement of blistering with age, unlike the other forms of EB, point to KEB [1, 6]. The major clinical criteria cited in the literature are acral blisters in childhood, progressive poikiloderma, skin atrophy, photosensitivity and gingival fragility [65]. In adulthood, patients with mild forms may have been followed under other diagnoses, such as scleroderma, and reach the diagnosis only after precancerous lesions [62].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The diagnosis of DEB is established in a proband with suggestive findings and (1) biallelic pathogenic or likely pathogenic variants in COL7A1 (RDEB), (2) a heterozygous pathogenic variant in COL7A1 (DDEB), or (3) a skin biopsy with transmission electron microscopy (TEM) showing absent or abnormal anchoring fibrils, and/or IFM of collagen VII consistent with DEB [2]. Molecular testing is the preferred method; diagnostic biopsy is considered only if the molecular result is inconclusive or testing is not available [2, 93]. Variants of uncertain significance (VUS), heterozygous or biallelic, neither establish nor exclude the diagnosis [2]. The diagnosis of KEB is established by identification of biallelic pathogenic or likely pathogenic variants in FERMT1; no published consensus clinical criteria exist [6].

Molecular determination has three practical consequences specific to this disease. First, only characterisation of the COL7A1 variants accurately determines inheritance and recurrence risk, because the severity of the phenotype and the biopsy are not sufficient to distinguish DDEB from RDEB [2]. Second, beremagene geperpavec is indicated in the USA and the EU in patients with a mutation or mutations in COL7A1, and a histological diagnosis alone may block this access; in Japan, the authorisation does not require genetic testing [7, 28, 29, 94]. Third, eligibility for trials and autologous therapies (for example, the requirement for expression of the NC1 fragment of collagen VII and absence of anti-collagen VII immunity in the VIITAL trial) depends on the genotype and residual protein [95].

5.2. Algorithm

The 2020 DEBRA International guidelines, the 2021 ERN-Skin position and the 2021 Brazilian Guidelines converge on an algorithm in which genetic testing is always recommended, in the index case and, whenever possible, in the parents, and IFM is used for rapid diagnosis and prognosis, especially in the newborn, and to guide and interpret genetic testing [10, 19, 34].

The Brazilian Guidelines add that, given the limited number of specialist services performing biopsy in the Unified Health System (SUS), the flowchart allows patients with suspected EB to be referred either for biopsy or for genetic testing, and that children and adults who already have typical manifestations may be referred directly to a rare disease reference centre [19, 96].

The French PNDS (2021) retains biopsy with immunohistochemistry (antigen mapping) as the indispensable laboratory step and regards electron microscopy as practically abandoned [36]. The biopsy is taken from a fresh blister with incipient cleavage, without complete dermo-epidermal separation, and two samples are taken: one fixed in formalin for conventional histology and the other frozen or in Michel's medium for immunohistochemistry, in a specialised laboratory [36]. For the PNDS, immediate molecular study is rarely needed for diagnosis, except when histology is inconclusive or when the EB type is clinically evident (in which case mapping adds little), but it is essential for genetic counselling and prenatal diagnosis; blood or, more rarely, a buccal mucosa swab is collected, parental samples are needed and DNA is stored for preservation; the technique is the next-generation sequencing panel in a specialised laboratory [36]. In France, molecular diagnosis is carried out in the genetics laboratories of the CHU de Nice (which also performs immunohistochemistry) and the Hôpital Necker-Enfants Malades (postnatal, prenatal and preimplantation diagnosis, gene panel), and histological diagnosis (histology, immunohistochemistry and electron microscopy) in the pathology department of Necker [36]. Disclosure of the diagnosis, especially in the neonatal period, requires the presence of the dermatologist, the neonatologist, a psychologist and both parents, and a professional interpreter, not a family member, whenever language may prevent understanding [36].

5.3. Molecular testing

A multigene EB panel including COL7A1 and the genes of the differential diagnosis is the approach most likely to identify the cause, because DEB is difficult to distinguish from other types of EB, especially in infants; the genes included and the sensitivity vary between laboratories [2]. The exome is the most widely used alternative when the phenotype is indistinguishable from other skin fragility disorders, and the genome is an option [2]. In single-gene testing, COL7A1 is sequenced and, if the result is negative, targeted deletion and duplication analysis is performed [2].

Sources: GeneReviews on DEB (Table 1) and on Kindler syndrome (Table 1) [2, 6].

These values are proportions of variants detectable by each method in patients already diagnosed, not the clinical sensitivity of a test in a patient with suspected disease; a negative result does not exclude DEB or KEB. Sanger sequencing does not detect large insertions or deletions, deep intronic or regulatory variants or low-level mosaicism [10]. In KEB, a pseudoexon-creating deep intronic variant explained unresolved cases, and in the Dutch registry 2 of 4 patients with a KEB phenotype had no pathogenic variant identified [22, 61]. Apparent homozygosity for a COL7A1 variant may correspond to a deletion of one or more exons on the other allele (false homozygosity) or to uniparental isodisomy; complete maternal isodisomy of chromosome 3 has been described in a child with RDEB [2, 97]. When two variants are found in COL7A1, parental testing is needed to confirm that they are in trans [2]. Mosaicism in clinically normal parents is detected by NGS more often than expected, with an impact on counselling [10].

The report should state the gene, the reference transcript with version (NM_000094.4 for COL7A1; NM_017671.5 for FERMT1), the verified HGVS nomenclature, the zygosity, the phase when known and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [8, 10]. For a VUS, segregation studies, bioinformatic analysis, RNA and protein studies and correlation with IFM are recommended [10]. Some COL7A1 variants have been described with both dominant and recessive inheritance, which makes interpretation dependent on the family context [2, 49].

5.4. Skin biopsy: IFM and TEM

The 4–6 mm punch or shave biopsy should include perilesional skin and part of a fresh blister (less than 12 hours old) or of a blister induced by gentle friction of the adjacent skin (for example, by rotating a pencil eraser) until erythema or a blister appears; non-sun-exposed skin, such as the inner aspect of the arm, is preferably sampled [2, 10, 34]. Topical anaesthetic creams may induce artefactual cleavage and should be avoided [10, 34]. For IFM, the sample is sent in Michel's medium at room temperature (with cytolysis after 48 hours; the medium is not frozen), frozen in liquid nitrogen or dry ice, or in normal saline or culture media arriving within 1–3 days; for TEM a specific fixative (glutaraldehyde) is required, and formaldehyde is unsuitable [2, 10]. Conventional light microscopy is inadequate for the diagnosis of DEB [2].

In IFM, collagen IV staining marks the cleavage plane: in the blister roof it indicates a dermal blister (DEB), in the floor a junctional or intraepidermal blister [10]. Absence of collagen VII is associated with severe phenotypes and residual expression with a milder course; normal staining for laminin-332, collagen XVII, plectin, integrin α6β4 and keratins 5 and 14 helps to confirm DEB [2, 10]. In the mild forms of RDEB and in DDEB, collagen VII may appear normal and IFM is often not sufficient; in the localised forms NGS or Sanger is preferable [2, 10]. IFM requires anti-collagen VII antibodies, which routine immunofluorescence for autoantibodies does not include [2]. In a prospective study with a genetic gold standard, IFM was more sensitive and specific than TEM, without a significant difference [10].

On TEM, all DEB shows cleavage below the lamina densa; in severe RDEB the anchoring fibrils are absent or rudimentary, and in the other forms of RDEB and in DDEB they are hypoplastic to a variable degree; in self-improving DEB the stellate inclusions described in section 2.2 are observed [2, 10]. TEM is inconclusive in very mild DEB [10].

In KEB, histopathology shows changes of poikiloderma (hyperkeratosis, epidermal atrophy, dermal oedema, pigment incontinence, focal vacuolisation of the basal layer) and, as suggestive findings, extensive reduplication of the basement membrane with collagen deposition in the clefts [6]. TEM shows intraepidermal, junctional and dermal planes, sometimes in the same biopsy, and reduplication of the basal lamina with interruptions of the lamina densa, with normal hemidesmosomes and anchoring fibrils [6]. IFM shows an intense, broad, reticulate and branching pattern with anti-laminin-332 and anti-collagen IV and VII antibodies, and kindlin-1 is absent or reduced [6, 10]. This pattern is not specific: it has been observed in a 5-year-old boy with a de novo PLCG2 variant (APLAID, autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation), and reduced kindlin-1 with reduplication of the lamina densa has been observed in a patient with poikiloderma with neutropenia due to a homozygous USB1 variant [27, 98]. Final confirmation of KEB is molecular [6].

5.5. Prenatal diagnosis and preimplantation genetic testing

DNA-based prenatal diagnosis is possible in all subtypes, at the family's request and in accordance with national legislation, provided that the familial variants are known and the parents' carrier status has been determined (DEBRA 2020: B, 2++) [10, 34]. Preimplantation genetic testing (PGT) is also possible [2, 34]. Before the molecular era, prenatal diagnosis of Hallopeau-Siemens RDEB was performed by fetoscopy and electron microscopy of fetal skin, and first-trimester molecular diagnosis by COL7A1 analysis was performed successfully in six families in 1995 [4]. To allow prenatal diagnosis in future pregnancies, an EDTA blood sample from the index case should be stored early, especially in the potentially lethal forms [34], and DNA banking is recommended in probands without a confirmed molecular diagnosis [2].

Exceptionally, EB is suspected in utero through indirect ultrasound signs (pyloric atresia, aplasia cutis, hydramnios) or even through skin denudation [36]. The PNDS lists ultrasound, amniocentesis and preimplantation genetic diagnosis among the prenatal diagnostic examinations [36].

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differential diagnoses

In the presence of neonatal blisters, the first step is to exclude acquired causes, especially bacterial infections (bullous impetigo, staphylococcal scalded skin syndrome) and viral infections (herpes simplex), and, when the mother has a compatible history, transplacentally transmitted autoimmune blistering diseases [2]. Among the genetic causes, the separation of DEB from EBS and JEB rests on the level of cleavage and the affected protein, not on the clinical picture in the newborn: scarring, which defines DEB, may not yet be present, and the granulation tissue characteristic of JEB becomes evident only in the first months [1, 2]. The list of differential diagnoses in the Brazilian Síndromes Genéticas textbook also includes dyshidrosis, insect bites, friction blisters, thermal burns, bullous congenital ichthyosiform erythroderma, chronic bullous disease of childhood due to linear IgA, bullous systemic lupus erythematosus, cicatricial pemphigoid and pemphigus vulgaris [103].

The most relevant differential diagnosis in adults is EBA, which shares the autoantigen, scarring and milia with DEB; it is distinguished by the absence of a family history and of a COL7A1 variant and by the demonstration of tissue-bound autoantibodies against collagen VII in the basement membrane zone, and it has no genetic transmission [7, 19]. In nail-only DEB, the differential diagnosis is with acquired nail dystrophies and other inherited nail dystrophies, and the diagnosis is molecular [2].

In KEB, initial confusion with other forms of EB is the rule, and the differential diagnosis later shifts to the genetic poikilodermas; the presence of congenital acral blisters, early acral atrophy and mucosal fragility separates KEB from dyskeratosis congenita, Rothmund-Thomson syndrome, Bloom syndrome and xeroderma pigmentosum [6]. The molecular phenocopies (CD151, USB1, PLCG2) show that neither the reticulate IFM pattern nor reduced kindlin-1 is pathognomonic, so the panel should include these genes [27, 98, 102]. EBS with mottled pigmentation is distinguished from the true poikiloderma of KEB by the absence of epidermal atrophy and telangiectasia and by intraepidermal cleavage [104].

7. Treatments and Risk Management Strategies

7.1. Organisation of care and initial assessment

There is no curative treatment. The three authorised targeted therapies treat wounds and do not correct the systemic disease, and the remaining treatment is supportive, preventive and multidisciplinary [7, 19]. The 2025 Italian consensus on RDEB, drawn up by experts from six reference centres (five of them in ERN-Skin) and voted on by 30 professionals from 17 specialties, with consensus on all 86 statements in the first round, recommends lifelong care at a reference centre with a multidisciplinary team and states that there are no clinical practice guidelines specifically addressing RDEB as a whole [56]. DEBRA International has published thematic guidelines (laboratory diagnosis, wounds, pain, SCC, anaemia, oral health, oesophageal strictures, hand, pregnancy, newborn, palliative care, emergencies) and ERN-Skin a practical position on wounds, oral health, pain and pruritus [2, 34]. In Brazil, the Brazilian Guidelines for the Care of Patients with Epidermolysis Bullosa (Joint Ordinance SAES/SCTIE No. 24 of 23 December 2021) are national in scope and regulate access within the SUS [19].

The evaluations recommended after diagnosis are as follows.

Source: GeneReviews, Table 5 [2, 105]. The starting ages for DXA and pubertal assessment in GeneReviews Table 5 (8 and 6–8 years) differ from those given in the surveillance table of the same chapter (6 and 10–12 years); section 11 presents each interval with its source.

The Italian consensus recommends, after neonatal discharge, the first appointment with the specialist team at 2–4 weeks, then at one month, then every 3 months in the first year (every 6 months in the mild forms) and, from the first year, at least every 6 months (every 2–3 months in the more severe forms or with difficult adherence), with planned paediatric-to-adult transition [56]. ERN-Skin recommends a complete assessment of the skin and wounds at least every 6 months [34].

The French PNDS (Haute Autorité de Santé, HAS, and the FIMARAD network; first version in 2015, revised in 2021) entrusts coordination to the dermatologist of the reference or competence centre, who organises the multidisciplinary network and the community-hospital link, with the paediatrician and the general practitioner at the centre of local follow-up; it considers the severe forms (RDEB and severe JEB) systemic diseases, because of chronic inflammation and multivisceral complications [36]. It recommends at least one consultation, day hospital visit or admission per year at a reference centre for all forms of EB, more frequently in the severe forms; in the neonatal period and the first year, monthly (or more frequent) reassessments and then every 3–6 months [36]. In DDEB, an assessment at the centre 3 months after diagnosis (in person or by teleconsultation) checks the initial care, and subsequent follow-up depends on the request of the patient or the attending doctor [36]. In RDEB and KEB, children are seen in a day hospital or as inpatients 2–4 times a year, depending on severity and distance, by dermatology, pain medicine, dietetics, psychology, gastroenterology, ophthalmology, otolaryngology, podiatry, dentistry and physical and rehabilitation medicine, with blood tests 1–2 times a year; adults 1–4 times a year, with gynaecology included, and dermatology every 3 months from the first carcinoma [36]. The complete dermatological assessment of the severe forms is carried out during a «full dressing change», after or during a bath with removal of crusts and hyperkeratosis; because it requires 2–5 hours, an adapted bath and a dedicated nurse, it justifies a day hospital admission in itself [36]. The PNDS stresses that the home dressing change, lasting 30 minutes to 2–3 hours, has no specific tariff in the French health system, which hinders the organisation of community nursing and increases the number and length of hospital admissions [36].

7.2. Newborn

The DEBRA International neonatal guideline (2024; GRADE method, Grading of Recommendations Assessment, Development and Evaluation; funded by DEBRA UK) and the Italian consensus give the recommendations for the newborn with EB, with preventive care instituted within the first 48 hours in any newborn with suspected or confirmed EB [56, 92]. In the table, ↑↑ indicates a strong recommendation for, ↑ a conditional recommendation, ↓↓ a strong recommendation against and GPP a good practice point defined by the panel.

The Italian consensus adds the identification band over a protective dressing, silicone tapes for electrodes and catheters, avoiding naso- and oropharyngeal suction, breastfeeding recommended with mild to moderate oral involvement (petroleum jelly on the nipple and lips), a bottle with a softened teat and enlarged hole when the breast is not possible, early prevention of constipation, individual finger dressings from the first days, and discharge only when the child is stable and the parents trained [56]. In a severely affected newborn, it recommends full blood count, electrolytes, CRP, urea, creatinine, total protein, albumin, iron and zinc, blood cultures if indicated, swabs of suspicious wounds, venous access and regular analgesia and before each procedure, maintaining vaccination according to the schedule [56]. The first bath is given only when birth trauma has healed; salt in the water (9 g/L) reduces pain [83, 92].

The French PNDS broadly agrees and adds practical details [36]. In the first month of life, investigations include full blood count, electrolytes, urea, ESR, CRP, total protein, albumin, iron and ferritin, repeated only when clinically needed, with swabs of blisters or erosions that look infected; in severely affected newborns, venous access is via an umbilical catheter and, if necessary, a long-term central venous catheter (Broviac® type) [36]. Electrodes should be small, with the adhesive part removed so that only the lubricated centre contacts the skin, and are held, like saturation sensors, by a non-adhesive hydrocellular dressing; silicone tapes (Mepitac®) secure devices, and adhesive remover sprays (or, failing these, a mixture of equal parts of liquid paraffin and white soft paraffin) release adherent dressings and clothing [36]. Underwear is worn inside out, to keep seams away, pyjamas open at the front, and disposable nappies are lined with a silicone interface or hydrocellular dressing at the elastic edges [36]. Bathing is initially daily, in non-sterile water at 37 °C, with superfatted soap on crusted lesions or antiseptic soap (chlorhexidine 0.1%) followed by rinsing if wounds appear infected, and the skin is dried by dabbing [36]. On the hands and feet, finger-separating dressings are instituted before confirmation of the EB type, with the thumb held in extension and abduction, checking every day that they do not limit fine motor skills [36].

Breastfeeding is not contraindicated; if the newborn cannot breastfeed, expressed milk is used, which may be fortified, and, except in the moderate forms, breast milk is often insufficient for protein-energy requirements, and fortified formulas are used (in France, Infatrini® is authorised and reimbursed for this indication) [36]. Formula is given lukewarm, with very soft silicone or rubber teats with an X- or Y-shaped cut, which let the baby control the flow, or with special feeders with an adjustable teat (Haberman® type) when the mucosa is very fragile; application of paraffin or petroleum jelly to the teat has no safety studies [36]. When oral involvement prevents feeding, a temporary nasogastric tube or gastrostomy may be discussed in the first months, always with early stimulation of oral skills by a psychomotor therapist or speech and language therapist [36]. Discharge requires clinical stability, trained and confident parents, a community-hospital network with direct contact with the attending doctor, adapted housing, involvement of a social worker and psychologist and, in France, the application for 100% coverage before leaving; ideally, a nursing practice contacted before discharge provides dressing changes, skin assessment, training and support for the parents, and the first review appointment takes place 1–2 weeks later, or later, depending on severity [36]. Skin-to-skin contact with the parents should be encouraged as soon as possible, and assessment of pain behaviour begins on the first day of life [36].

Placement of a nasogastric tube is a point of divergence. GeneReviews and the Italian consensus advise against it because of oral and oesophageal fragility, and one study associated early use of nasogastric tubes with severe oesophageal complications; the palliative care guideline gives a strong recommendation against it [2, 56, 106, 107]. The neonatal guideline allows it in the severe forms when the oral route does not meet requirements, with careful technique, and prefers the nasogastric to the orogastric route when the pharyngo-oesophageal mucosa is not at risk, noting that oesophageal trauma may accelerate stricture formation in RDEB [92]. In practice, the tube is a short-term measure, fine-bore, polyurethane and lubricated, placed by an experienced professional when oral alternatives have failed [56, 92]. The PNDS allows a nasal tube in the first weeks of life in the forms without severe mucosal involvement, always as a transitional route, and points out that in the other forms it is poorly tolerated and induces mucosal blisters with a risk of later stricture [36].

7.3. Skin and wounds

Prevention. Teach carers to handle infants and children avoiding shear forces; wrap and pad the extremities; soft, loose, front-opening clothing, with seams on the outside and without labels; cut or line the elastic of nappies; appropriate footwear, silver socks, insoles and orthoses; age-appropriate play with minimal trauma [2, 34, 56]. Regular debridement of plantar hyperkeratosis and calluses by a podiatrist reduces pain on walking [34].

Blisters. New blisters are punctured with a sterile lancet or needle and drained to prevent extension through fluid pressure, leaving the roof in place to promote healing and reduce pain and infection [2, 34].

Dressings. GeneReviews describes three-layer dressings: (1) a non-adherent primary contact layer that does not strip the epidermis, such as emollient-impregnated gauze, non-stick dressings (Telfa®, N-Terface®), non-adhesive silicone (Mepitel®, Mepilex®) and, when indicated, topical antibiotic or antiseptic (bacitracin, mupirocin, silver, honey); (2) a secondary layer for stability and padding, with gauze rolls (Kerlix®, Conform®); (3) an elastic knitted tertiary layer, with tubular netting (Tubifast®, BandNet®) or Coban® [2, 108]. ERN-Skin and the Italian consensus choose the dressing according to the wound: silicone foams and polymeric membranes for exuding wounds; silicone interfaces or lipidocolloids and hydrogels for dry or slightly exuding wounds; hydrofibres for abundant exudate; alginates (which absorb up to 20 times their weight and have a haemostatic effect) for exuding and infected wounds; without infection, changes every 2–4 days with advanced dressings; without access to advanced dressings, paraffin gauze changed daily [34, 56]. Adhesives and adhesive dressings are prohibited, and removal is by soaking, bathing or silicone adhesive removers [2, 34]. Individual finger dressings, with contact layers or mouldable foams, are essential in RDEB to delay digital fusion [34, 83]. Cleansing is with low-toxicity solutions: normal saline, polyhexanide, sodium hypochlorite (5–10 mL in 5 L of water), acetic acid up to 0.25% or chlorhexidine 0.1%; petroleum jelly helps to remove crusts [34, 56]. Analgesia should precede dressing changes [34, 56].

Assessment. The chronic wound is assessed with the modified MEASURE algorithm (measure, exudate, appearance, suffering, reassessment, edge) and critical colonisation and infection with the NERDS and STONEES criteria; a 20–40% reduction in area over 2–4 weeks predicts healing at 12 weeks [34]. Nutrition should be optimised and anaemia treated to keep haemoglobin above 8–10 g/dL [34].

Colonisation and infection. Infection is suspected when there is an increase in size, exudate, odour and pain, with perilesional erythema and oedema [56]. In critically colonised wounds, after cleansing, lipid-stabilised hydrogen peroxide cream, medical honey or silver are used; silver is limited in time and surface area, especially in children, because of systemic absorption [34, 56]. Topical antimicrobials are applied for short periods (the recommendations suggest up to 2 weeks), preferring agents without a systemic formulation (fusidic acid, mupirocin) and rotating them to avoid resistance and sensitisation; retapamulin 1% is an option for resistant Gram-positive bacteria [34]. Systemic antibiotics are reserved for deep or systemic infection (lymphadenopathy, malaise, fever) or multiple infected wounds, guided by a swab with antibiogram; blood cultures are taken if there are systemic symptoms [34, 56]. Repeated swabs are justified only when infection does not respond, because bacterial eradication is difficult [56]. The 2017 DEBRA wound guideline mentions antimicrobial baths or vinegar compresses for Gram-negative bacteria such as Pseudomonas, dilute bleach with subsequent rinsing, and salt baths (about 90 g in 10 L of water, a 0.9% solution), which reduce pain [83]; the neonatal guideline advises against dilute bleach and vinegar in the newborn [92]. Before application of beremagene geperpavec, dilute bleach requires rinsing and virucides are not used for wound cleansing [29, 54].

Non-healing wounds. Targeted therapies (section 7.4), biological skin substitutes or temporary porcine or cadaveric skin grafts are used; short-course topical corticosteroids are applied to hypergranulation, especially in JEB [2, 34]. The 2017 guideline summarises low-level evidence for systemic trimethoprim (crossover trial in 7 patients with RDEB and 42 wounds: reduction of more than 50% in area in 6 of 7 versus 2 of 7 with placebo), systemic granulocyte colony-stimulating factor (pilot in 7 patients with DEB) and oral epigallocatechin-3-gallate (crossover trial in 16 patients with RDEB, not statistically significant) [83]. Management of DEB should control critical colonisation and infection, protect from trauma, prevent contractures and reduce pruritus; abundant exudate and odour require containment and may be impossible to eradicate [83].

French practice. In the PNDS, bathing is daily in the newborn and infant and is later spaced out, with an average of two baths per week (or a shower) in the older child and adult; dressings are assessed every day and any soiled dressing is changed [36]. Care proceeds in five stages: preparation of the environment and equipment, with the child calm and fed; cutting and removal of dressings (with silicone sprays, ampoules of liquid paraffin or prolonged soaking in the bath); a cleansing bath with antiseptic or mild soap, as prescribed; a rinsing bath; and redressing and dressing the child; it may take several hours and require more than one carer and strong analgesics, with premedication timed to its onset of action [36]. Interfaces (Mepitel®, Adaptic®, Urgotul®) and thin hydrocellular dressings (Mepilex® Lite) serve dry wounds and are changed every 3–4 days; bordered dressings (Mepilex® Border, Allevyn® Gentle Border) conform well, but may adhere too much to the most fragile skin; thick hydrocellular dressings protect pressure areas (elbows, knees); hydrofibres (Aquacel®) and absorbent hydrocellular dressings serve highly exuding or haemorrhagic wounds, and alginates have high absorbent capacity [36]. The choice is made patient by patient, without dogmatism, preferring the dressing that the family handles best and that is best tolerated; dressings are held with tubular bandages (Tubifast®), preferred to conventional bandages, which compress and fix joints in abnormal positions [36]. Infection is diagnosed by the history (evolution over weeks, recent increase in size or exudate), by the appearance (friable tissue, pus, yellowish crusts, necrosis, foul odour, oedema, perilesional erythema and warmth) and by systemic signs; on infected wounds, dressings are changed daily [36]. Systemic antibiotic therapy is indicated for multiple or extensive lesions and in the presence of general signs, and in malnourished patients, poorly adherent patients and infants it is started at the first signs of infection; in chronically colonised wounds, only clinically significant infection is treated [36]. Topical antibiotics (silver sulfadiazine, mupirocin, fusidic acid) carry a risk of resistance and sensitisation with prolonged use, and silver products are limited in time and surface area because of the risk of argyria [36]. Crusts and hyperkeratosis are curetted atraumatically with daily emollients or petroleum jelly, short courses of potent topical corticosteroids reduce hypergranulation, and in both cases persistence requires exclusion of an underlying SCC [36]. In the severe forms at risk of cancer, the complete assessment of the integument at a reference centre is carried out at least 1–2 times a year, and more often after a skin cancer [36].

7.4. Authorised targeted therapies

7.4.1. Beremagene geperpavec (Vyjuvek®)

Mechanism and presentation. It is a gene therapy vector based on herpes simplex virus type 1 (HSV-1), live, replication-defective and non-integrating, which expresses human collagen VII in wound cells; it is applied as a topical gel [28]. Each pack contains a 1 mL vial of suspension with 5×10⁹ plaque-forming units (PFU) per mL and a 1.5 mL vial of excipient gel (hydroxypropyl methylcellulose 44 mg/mL); after mixing in the pharmacy, 5×10⁹ PFU in 2.5 mL are obtained [28]. The suspension is stored between −15 and −25 °C (or at 2–8 °C for up to 1 month), and prepared syringes for up to 8 hours at room temperature or up to 48 hours at 2–8 °C [28]. In the initial study (n=6), biopsy showed linear deposition of the NC1 and NC2 domains of collagen VII at the dermo-epidermal junction [28].

Indication. According to the label of the US medicines agency (FDA, Food and Drug Administration), it is indicated for the treatment of wounds in adult and paediatric patients with DEB with a mutation or mutations in COL7A1, with no lower age limit since September 2025 [28, 109]. In the EU, according to the summary of product characteristics (SmPC) approved with the opinion of the European Medicines Agency (EMA), it is indicated for the treatment of wounds in patients with DEB with a mutation or mutations in COL7A1 «from birth»; treatment should be initiated by professionals experienced in DEB [29]. The indication covers DDEB and RDEB.

Dosage. It is applied once a week. The maximum weekly dose is 1 mL (2×10⁹ PFU) up to 3 years of age and 2 mL (4×10⁹ PFU) from 3 years of age, in adolescents and adults [28, 29]. The dose for each wound depends on its area.

Sources: FDA label, section 2, and EU SmPC, section 4.2 [28, 29].

The gel is applied as droplets spaced about 1 cm × 1 cm apart, in a grid, and covered with a hydrophobic dressing and then with the usual dressing; according to the FDA label, the dressing is left until the next change, and according to the European SmPC for about 24 hours [28, 29]. It may not be possible to treat all wounds at each session: wounds are treated until closure before choosing new ones, and priority is given to previously treated wounds that reopen; a missed dose is applied as soon as possible [28]. If there are no wounds, it is not applied [29]. The wound is first cleansed with a virucide-free product and other topical medicines are removed from the area; the European SmPC prohibits other topical medicines at the same time [29]. In the USA, application may be performed by a healthcare professional, the patient or a carer, in a clinic or at home, since September 2025; in the EU, the patient or a trained carer may apply it if the healthcare professional considers it appropriate [29, 109]. In the Italian series, 1.6 mL (3.2×10⁹ PFU) per week was used, applied by a dermatologist in a day hospital [54]. An isolated report of a temporary off-label doubled dose, in a patient with extensive wounds after acute urticaria, does not constitute a recommendation [110].

Safety. In the controlled trial (31 patients; median exposure 25 weeks), adverse reactions above 5% were pruritus (10%), chills (10%), erythema (6%), rash (6%), cough (6%) and rhinorrhoea (6%), with no discontinuations; 18 of 31 (58%) had at least one adverse reaction [28, 29]. The profile was similar in two infants aged 6 and 7 months in an open-label study [28]. In the open-label extension (47 patients, median exposure 565 days), adverse events occurred in 74.5%, almost all mild or moderate (COVID-19 31.9%, cough 19.1%, fever 14.9%, skin infection 12.8%); two were considered related (mild wound bleeding in the same patient) and none of the 17 serious events was attributed to the drug [89]. Vector DNA was detected in skin swabs from 19 of 31 patients, becoming negative in 16 of 19 within 6 weeks, and in 94% of dressings; it was not detected in blood and only in one urine sample, and no infectious particles were detected on the skin surface [28]. Of the 22 patients tested, 64% were HSV-1 seropositive at baseline and 6 of 8 seronegative patients seroconverted; anti-collagen VII antibodies appeared in 13 of 18 (72%), with insufficient data to correlate them with efficacy, and no neutralising immunity was observed [28, 29]. Contacts and carers avoid touching treated wounds and dressings until the next change and wear gloves; an ocular or mucosal splash is washed with water for at least 15 minutes; dressings from the first change are disinfected with a virucide (70% isopropyl alcohol, 6% hydrogen peroxide or <0.4% ammonium chloride) and disposed of in a sealed bag in household waste [28]. Pregnant women do not prepare or apply the gel and avoid contact with treated wounds and dressings [28, 29].

Contraindications and precautions. The FDA label has no contraindications; the European SmPC contraindicates hypersensitivity to the active substance or excipients [28, 29]. The European SmPC states that the gel is not applied to wounds with a confirmed or suspected diagnosis of SCC, but may be applied to other wounds of patients with SCC, and provides for inclusion of patients in a multinational non-interventional long-term safety study; the safety of live vaccines has not been studied [29]. There are no carcinogenicity, mutagenicity or fertility studies [28].

7.4.2. Prademagene zamikeracel (Zevaskyn®)

Mechanism and presentation. These are cell sheets of autologous keratinocytes, obtained by punch biopsies, transduced ex vivo with a replication-incompetent retroviral vector carrying full-length COL7A1 (LZRSE-Col7A1) [32]. Each sheet measures 5.5 × 7.5 cm and covers 41.25 cm²; up to 12 sheets can be manufactured per patient, supplied in up to 3 containers of up to 4 sheets [32]. The sheets are sent directly to a qualified treatment centre, stored at 15–25 °C, are stable for 84 hours at room temperature and undergo a release quality control by the manufacturer immediately before surgery; in case of manufacturing failure, a second manufacture can be attempted with a new biopsy [32]. The single-arm phase 1/2 study (n=7) detected the NC2 domain and anchoring fibrils by immunoelectron microscopy in 6 patients at 3 months, 5 at 6 months and 3 at 1 year [32].

Indication and application. In the USA, treatment of wounds in adult and paediatric patients with RDEB, with no age limit on the label; the evidence comes from patients aged 6 years or older and the indication for all ages was obtained by extrapolation (monogenic disease, dose by area, same efficacy criteria, absence of serious safety signals) [32, 111]. The dose depends on the wound area. Wounds are debrided under general or other anaesthesia; the sheets are handled only by the titanium clips, are not trimmed, are secured to the wound bed with absorbable sutures, without overlapping or suturing onto intact skin, and are all applied in a single surgical session; they are covered with non-adherent dressings and antibiotic ointment, with immobilisation for 5–10 days, keeping the area dry until the gauze falls off (2–3 weeks) [32]. It is not authorised in the EU: the EMA medicines database, consulted on 17 October 2026, had no record of the product, which does not exclude an unpublished application under evaluation.

Safety. In the VIITAL trial (11 patients; median of 6 sheets), adverse reactions of at least 5% were procedural pain (27%) and pruritus (9%); in the safety database of 18 patients aged 6–45 years, reactions of at least 10% were procedural pain (38.9%), local reaction (16.7%), wound infection (16.7%) and pruritus (11.1%), with 16 serious adverse events in 6 patients, none related, and two deaths in phase 1/2a considered unrelated [32, 111]. There are no contraindications; the warnings include severe hypersensitivity to vancomycin, amikacin or the excipients, risk of transmission of infectious agents through human and bovine reagents and potential risk of insertional oncogenesis mediated by the retroviral vector, which requires lifelong monitoring for neoplasms and contacting the marketing authorisation holder in case of a neoplasm [32]. Integration site analysis showed low-level dispersed integration, without predilection for genes of malignant transformation, and no case of insertional oncogenesis was observed in the trials [32, 111]. The FDA post-marketing requirement is a prospective observational study of 100 patients followed for 15 years, with completion expected in 2045 [112]. Post-launch experience shows the risk of manufacturing failure: in 12 treatments up to August 2026, two patients had batches with low yield or out of specification [113, 114].

7.4.3. Dry birch bark extract, birch triterpenes (Filsuvez®)

Mechanism and presentation. Topical gel with 10% (100 mg/g) dry extract of the bark of Betula pendula and B. pubescens in refined sunflower oil, without other excipients; the extract contains betulin (72–88%), lupeol, betulinic acid, erythrodiol and oleanolic acid (84–95 mg of triterpenes per gram of gel) [30, 31]. The mechanism is unknown; in culture and in ex vivo porcine skin it modulates inflammatory mediators and keratinocyte differentiation and migration pathways [30, 31]. It is presented in sterile single-use tubes, to be stored at 20–25 °C without freezing [30].

Indication and dosage. In the USA, wounds associated with DEB and JEB in patients aged 6 months or older; in the EU, partial-thickness wounds associated with DEB and JEB in patients from 6 months of age [30, 31]. A layer of about 1 mm is applied only to the wound, without rubbing, covered by a sterile non-adherent dressing, or it is applied to the dressing so that it contacts the wound, repeating at each dressing change until healing [30, 31]. GeneReviews indicates two applications daily, but the labels and the pivotal trial define the frequency by the dressing change (in the EASE trial every 1–4 days, with 70–78% of patients applying it daily or on alternate days), and this is the dosage to follow [2, 30, 31]. Median exposure in the open-label phase was 10 g/day (15 g/day below 4 years of age), with a median of 19 tubes per month; the maximum total area treated was 5300 cm² and there was no overdose with up to 69 g/day for more than 90 days [31]. It is not used on mucous membranes or in the eye [30]. If the wound becomes infected, it is suspended on that wound until resolution [30, 31]. Other topical products are applied sequentially or alternately [31].

Safety. In EASE, application site reactions occurred in 7.3% versus 6.1% with placebo; the European SmPC lists wound complication (11.6%), application site reaction (5.8%), wound infection (4.0%), pruritus (3.1%) and hypersensitivity (1.3%) [30, 31]. Cutaneous SCCs were reported in 4 patients with RDEB (aged 20, 22, 46 and 49 years), two of them in the treated area; the European SmPC instructs suspension of treatment on the affected area in case of SCC or another skin neoplasm, because of a theoretical risk that cannot be excluded [30, 31]. Systemic absorption is low (betulin below the limit of quantification in 68% at day 90) [30]. It can be used in people allergic to birch pollen [31]. In the 24-month open-label phase (n=205), serious adverse events occurred in 18.0%, discontinuation due to adverse events in 7.8% and there were 9 deaths, none attributed to treatment [115]. The non-interventional FOSteR study is evaluating the incidence of skin neoplasms with follow-up of at least 3 years [116].

7.4.4. Comparative regulatory status

Vyjuvek® was launched initially in Germany and France in the EU, with price under negotiation, and in Italy access was through the 5% fund of the Italian Medicines Agency (AIFA) before marketing [54, 119]. The sources consulted do not identify access data for any of the three therapies in Portugal or Brazil. The 2021 Brazilian Guidelines, which predate the authorisations, state that there is no disease-modifying drug treatment and recommend analgesics, antihistamines, antibiotics and supplements [19].

7.4.5. Pivotal trials and supporting studies

The three pivotal trials use selected wounds as the unit of analysis and do not measure systemic outcomes (anaemia, nutrition, strictures, SCC, survival). The two analyses of GEM-3 (FDA and publication/SmPC) differ in the method of handling missing data and should each be cited with its source. VIITAL was open-label, compared with usual dressings and not with placebo, and included only patients with expression of the NC1 fragment and without anti-collagen VII immunity, which limits generalisation to patients without residual protein [95]. In EASE, the primary endpoint was met overall, but the effect at day 90 was not significant and there was no demonstrated benefit in DDEB or JEB, which had small samples; the European SmPC recommends regular reassessment of benefit in these forms [31, 126]. The methodology of the EASE open-label phase has been the subject of published debate [115]. The three products cannot be compared indirectly, because the populations, comparators, wounds and endpoints differ. Italian experience outside trials, in three patients with chronic wounds of more than a decade, showed more variable and smaller responses than in the trials, with no change in anaemia, transfusions or inflammatory markers [54]. Negative or interrupted trials of other approaches are described in section 7.12.

7.5. Pain and pruritus

Pain is assessed with visual analogue or numerical rating scales (NRS) from 7 years of age, with the FLACC scale (Faces, Legs, Activity, Cry, Consolability) in younger children and with the revised faces scale (FPS-R); the DN4 questionnaire (score ≥4 out of 10) screens for neuropathic pain in adults, with a sensitivity of 78–83% and specificity of 81–90%, without equivalent validation in children [34, 56]. Non-pharmacological measures (cognitive behavioural therapy, hypnosis, distraction, biofeedback, relaxation) have a grade B recommendation for chronic and acute pain, and habit reversal training a grade C recommendation for pruritus [34, 74]. The following doses, by oral or intravenous (IV) route, are those proposed by ERN-Skin for clinical practice; they are not indications specifically approved for EB and should be adjusted to age, weight, renal function and national prescribing standards [34].

Source: ERN-Skin, Table 5 [34].

Opioids worsen pruritus (except methadone, which does not release histamine) and constipation, and require monitoring for hypogonadism, osteopenia and delayed puberty [34]. Transmucosal opioids (intranasal or buccal fentanyl) are used for short procedures when no other route is available [34, 74]. Before baths and dressings, premedication should have time to act (about 45 minutes orally, 5–10 minutes for intranasal fentanyl, 5 minutes IV); midazolam (oral, IV or intranasal) is the preferred benzodiazepine because of its rapid onset, and oral or intranasal ketamine is an option when strong opioids are insufficient [34]. Topical ropivacaine 0.2% on wounds has been studied in a small pilot, without long-term safety data for routine use [34]. The DEBRA International pain guideline recommends caution with tricyclic antidepressants in RDEB because of the risk of QT prolongation and cardiomyopathy, with one fatal outcome described [74]. Cannabinoids (tetrahydrocannabinol with cannabidiol) have been used for pain in EB [34, 56]. The Brazilian Guidelines include ibuprofen, dipyrone, paracetamol, morphine and gabapentin before dressings, baths and other procedures, referring to the SUS chronic pain protocol [19].

The dose table of the French PNDS coincides with that of ERN-Skin (the two share authors) and adds practical information [36]. Combinations of paracetamol with powdered opium, with or without caffeine (Lamaline®, Izalgi®; France), are used from 12 years of age, 1–2 capsules every 5 hours, which may be opened; the PNDS gives no maximum daily dose, which follows the French SmPC of each combination [36]. The PNDS presents tramadol (0.5–2 mg/kg every 6 hours) without a minimum age or maximum dose, and the ERN-Skin emergency recommendations also propose it in infants [35, 36]. The French SmPC for the 100 mg/mL oral solution (Contramal®) contraindicates it below 3 years and gives 1 mg/kg per dose as the usual dose and 2 mg/kg as the maximum per dose, 3–4 doses per day at 6–8-hour intervals, not exceeding 100 mg per dose and 400 mg/day (the paediatric trials cited in the SmPC used up to 8 mg/kg/day); it recommends prescribing in drops because of reported cases of overdose [128]. The FDA label contraindicates tramadol below 12 years and, up to 18 years, after tonsillectomy or adenoidectomy, because of the risk of respiratory depression in CYP2D6 ultrarapid metabolisers, so use in infants and below 3 years (or 12 years, in the USA) is outside the SmPC and requires respiratory monitoring [129]. Tramadol, these combinations, morphine and oxycodone are avoided in renal failure because of the risk of accumulation, whereas nefopam and fentanyl are used without adjustment; nefopam may be given on a sugar cube, via tube or gastrostomy, or IV [36]. The analgesic equivalences given are: 1 mg of IV morphine = 3 mg of oral morphine; oral oxycodone = 2 times oral morphine (10 mg of oxycodone = 20 mg of morphine); IV morphine = IV oxycodone; transdermal fentanyl 25 µg/h = 60 mg of oral morphine per 24 h = 20 mg of IV morphine per 24 h [36]. Prolonged-release morphine and oxycodone are given every 12 hours (morphine capsules may be opened without crushing the granules), immediate-release forms every 4 hours, and oral morphine solution (2 mg/mL; Oramorph®) given sublingually has a very rapid action in acute pain; transdermal fentanyl (every 72 h) is applied only to intact skin and removed immediately if fever exceeds 38.5 °C; methadone is introduced with the pain team [36]. The equimolar mixture of oxygen and nitrous oxide (EMONO) is very useful during care, in hospital or in hospital-at-home and for a limited time, and topical anaesthetics (lidocaine) before puncturing blisters or veins have a limited total dose because of the risk of seizures and methaemoglobinaemia [36]. NSAIDs are used with great caution in chronic infections and renal involvement, with monitoring for abdominal pain and bleeding, and bone pain due to demineralisation (severe RDEB) improves with nutrition and physiotherapy, and bisphosphonates may help, limited by infusion difficulties and adverse effects [36]. The FLACC is validated between 2 months and 7 years of age, and the PNDS points out that non-pharmacological treatment (music, yoga, relaxation, hypnosis; sugar water on the teat in infants) should always be offered, even if many adults decline it [36].

Pruritus is treated with lukewarm baths with synthetic soap or oil, emollients without sodium lauryl sulphate, emollients with antiseptic, menthol in an oily base and topical corticosteroids in short courses (with increased systemic absorption owing to the damaged barrier) [34, 56, 83]. Systemically, sedating antihistamines at night (hydroxyzine, diphenhydramine, chlorphenamine; in Brazil, dexchlorpheniramine maleate) and non-sedating antihistamines during the day (cetirizine, loratadine, fexofenadine), gabapentin, pregabalin, amitriptyline and doxepin are used, with results that are often unsatisfactory [19, 56, 74]. Series and case reports describe olanzapine, selective serotonin reuptake inhibitors, opioid antagonists (naloxone, naltrexone), kappa agonists, 5-HT3 antagonists, neurokinin 1 receptor (NK1) antagonists (aprepitant, serlopitant), cannabinoids, ciclosporin and thalidomide; dupilumab has been effective in several patients, especially in DEB pruriginosa, and is in a phase 1 trial [34, 56, 83, 131]. The phase 2 trial with serlopitant (28 patients) and the trial of cannabidiol in children (10 patients) have been completed [132, 133]. All these uses are off-label.

The PNDS adds environmental measures against pruritus: avoid overly warm clothing and hot or dry environments (sweating worsens pruritus), consider an air-conditioning unit at home in the severe forms with extensive dressings and adapt the school setting (not seating the child next to the radiator in winter or by the window in summer); regular bathing avoids antiseptics except during superinfection, because they dry the skin and cause irritation and contact allergy [36]. Antipruritic gabapentin is given as oral solution, 5–30 mg/kg/day in 3 doses, and ciclosporin and thalidomide, proposed in severe and disabling cases, require caution with immunosuppressants because of the carcinogenic risk inherent in EB; dupilumab and naltrexone were under evaluation in DDEB pruriginosa [36]. All are off-label uses.

7.6. Mouth, oesophagus, digestive tract and nutrition

Oral health. Prevention begins before tooth eruption, with a dentist ideally at 3–6 months; a small soft or electric toothbrush with a demonstrated technique, fluoride toothpaste or mouthwash, alcohol-free antiseptic mouthwash twice a day (chlorhexidine 0.12% or polyhexanide 0.12%) and regular professional cleaning [38, 56, 72]. The Brazilian Guidelines propose gentle rinses with alcohol-free chlorhexidine 0.12% twice a day for two weeks every three months [96]. In severe RDEB, early extraction of the molars may be considered before mouth opening becomes very reduced [34]. Extractions for caries and crowding are carried out when needed, and six-monthly dental reviews also serve to examine the mucosa and biopsy chronic ulcers or leucoplakia [2, 39].

The French PNDS, which follows the 2020 DEBRA International oral guideline, bases prevention on four pillars (dietary advice, oral hygiene, fluoridation and fissure sealants) and schedules reviews according to severity: annual in the mild forms, every 3–6 months in the moderate and monthly in the severe, with the first appointment at 1 year of age [36]. It recommends a soft or surgical small-headed manual toothbrush twice a day, with bristles that may be trimmed in microstomia, and advises against electric toothbrushes because of tissue trauma; adapted handles or orthoses serve pseudosyndactyly, and dental floss with a floss holder and low-pressure irrigators complete the cleaning [36]. Alcohol-free chlorhexidine 0.12% has no demonstrated efficacy against caries or periodontal disease and is prescribed only when brushing is impossible (it is effective against Candida); fluoride toothpaste is prescribed after fluoride assessment, 22,600 ppm fluoride varnish is applied every 3–6 months and resin or glass ionomer cement sealants protect the posterior surfaces (ICDAS 1–3 lesions) [36]. In severe RDEB, daily mouth-opening exercises (for example, during dressing changes, and half an hour before dental treatment) maintain access, speech and swallowing, and surgical division of intraoral bands may be considered after multidisciplinary discussion [36].

During the appointment, the lips and perioral surfaces are lubricated with petroleum jelly, tissues are handled only by compression and never by shear, (very gentle) suction is used only in the mild forms, resting on the occlusal surfaces or on a lubricated cotton roll, manual scaling is preferred to ultrasonic scaling, and blisters that appear are drained at the most dependent point, keeping the roof and repositioning loose mucosa; the panoramic radiograph is the technique of choice, and the periapical radiograph, difficult in severe and intermediate RDEB, is taken with the sensor edge covered in wax [36]. Conventional restorative materials are not contraindicated, with preference for glass ionomer cements, silver diamine fluoride and the atraumatic restorative technique; the rubber dam is used with the skin side lubricated or protected, local anaesthesia preferably by the intraseptal route, and, under general anaesthesia, prior clinical and radiographic examination, nasal intubation and neuromuscular blockade are recommended, with the anaesthetist choosing the lubricant (petroleum jelly is contraindicated in the presence of oxygen) [36]. Pulp and periodontal treatments are possible (laser or scalpel gingivectomy treats the hyperplastic papillae of KEB), multiple extractions are planned with the attending doctor because of anaemia, starting with the anterior teeth, and prophylactic extraction of the third (or even second and first) molars before 12 years is considered in moderate to severe microstomia; fixed orthodontic appliances are possible in the forms with lesser mucosal fragility and scarring (EBS, JEB, DDEB, KEB), removable appliances are in principle proscribed, and implants have given good functional results, limited by cost [36]. In DDEB, routine dental treatment is carried out with few modifications; in severe and intermediate RDEB it requires multiple adaptations and a multidisciplinary team; in KEB, sloughing of the mucosa after scaling and aggressive periodontitis (grades B to C) require follow-up by a periodontist [36].

DEBRA International oral guideline (2020). The update of the 2012 guideline, endorsed by DEBRA International and funded by DEBRA UK, has five chapters (general information, systematic review of oral manifestations, oral care and dental treatment, implants in RDEB, sedation and anaesthesia); the recommendations were graded by the SIGN system, discussed in panels with patient representatives (Dubai, 2018; Santiago de Chile, 2018), externally reviewed and tested for three months at centres in the United Kingdom, New Zealand, Hungary and Taiwan, with an update planned for 2025 [73]. The evidence is almost all level 3 (non-analytical studies) [73]. The patient should be referred to the dentist at diagnosis, ideally at 3–6 months and before problems arise; the first appointment serves to teach parents about diet (including sugar-free medicines), hygiene, fluoride and technical aids, even before eruption, and to detect crowding (especially in RDEB) and incipient caries early [73]. When the patient lives far from the centre, the dental appointment is scheduled on the same day as the other appointments, and a local dentist can provide regular prevention under shared care [73]. The EB oropharyngeal severity score (EBOS) measures activity (erythema, atrophy, blisters, erosions and ulcers) and damage (microstomia, ankyloglossia, scarring and enamel hypoplasia), has good intra-observer and lower inter-observer reproducibility, and studies using it found no strict correlation between genotype and oropharyngeal phenotype in DEB [73].

During the appointment, the environment should be cool, no adhesive is applied to the skin and the patient positions themselves in the chair, padded or with their own cushion, with breaks to change position; the infant is lifted with one hand under the buttocks and the other under the nape, never by the axillae, and the young child is examined on the parents' lap, in the knee-to-knee position [73]. For oral lesions, there are only two treatment studies: sucralfate suspension reduced the appearance, duration and pain of blisters and ulcers and improved the plaque and gingival indices, and cord blood platelet gel combined with low-level laser, applied once a day for 3 days to 19 symptomatic chronic lesions in 7 patients with DEB, reduced pain and size from the first day, with a single new lesion at the same site during follow-up and a persistent unpleasant taste in 2 patients (28%) at 24 weeks [73]. Commercial healing gels and mouthwashes and salt-water rinses are in common use, without efficacy studies in EB [73].

Toothbrushing is possible in all patients, even in severe RDEB, with the smallest brush available (baby size), with a small head and soft bristles, which can be softened in hot water or shortened to reach the occlusal surfaces of the molars in microstomia; a manual brush is preferable to an electric one because of the greater risk of trauma and blisters, and three-sided brushes, silicone finger brushes and adapted handles or orthoses serve pseudosyndactyly [73]. Parents help children, and some adolescents and adults need a carer; rinsing with water after meals, low-pressure irrigators and plaque-disclosing agents complete hygiene [73]. Gentle ultrasonic scaling and selective polishing can be used in all patients, including severe RDEB, although some clinicians prefer hand instruments; haemorrhagic blisters caused by vibration are drained immediately [73]. Chlorhexidine 0.12%, alcohol-free when there are lesions, is effective against Candida but not in caries control; a possible preventive regimen is a rinse twice a day for 2 weeks every 3 months, also as a swab, spray, gel or varnish [73]. Fluoride toothpaste is used from eruption, at the age-appropriate dose (without flavour or foam if there is sensitivity); high-concentration fluoride varnish is applied every 3 months in high-risk patients or at each appointment, fluoride supplements are prescribed in communities without fluoridated water according to local regulations, age and weight, and alcohol-free 0.05% and 0.2% fluoride solutions may be applied with a cotton bud once a day [73]. High-calorie sucrose-rich supplements, necessary for growth, are cariogenic, and the dietary caries prevention programme should be agreed between dentist and dietitian from an early stage, to avoid giving contradictory advice [73]. Fissure sealants protect the occlusal surfaces (with glass ionomer when isolation is difficult), silver diamine fluoride treats caries without instrumentation, and xylitol chewing gum has been used without mucosal effects [73].

Microstomia is the greatest technical difficulty [73]. With resin plugs of increasing calibre, one patient went from 19 to 23 mm of opening after 10 minutes and to 30 mm at the end of the session, but returned to the initial values on stopping; wooden spatulas, threaded acrylic cones and commercial opening devices are alternatives, and the guideline recommends daily exercises in generalised severe RDEB (for example, during dressing changes) and half an hour before treatment [73]. Surgical release of buccal bands and commissures has been described in a few cases, without long-term efficacy data [73]. Medicines are prescribed in soluble or liquid form, because of oesophageal stricture; when there is no sugar-free formulation, the family is warned and brushes the teeth or rinses with water immediately after the dose [73]. The review interval is defined individually according to plaque and caries risk, from 3–6 months to monthly; each review includes prevention and early diagnosis of caries, professional plaque removal, topical fluoride, dietary advice, assessment of progress and screening for intraoral SCC, with clinical photographs for follow-up [73].

Treatment precautions depend on the type. In DDEB, routine treatment is carried out with few or no modifications, with careful handling [73]. In severe and intermediate RDEB, the lips are always lubricated with petroleum jelly or another emollient before any procedure and the back of the mirror in particular is lubricated; suction rests on hard tissue (occlusal surface or moist cotton roll) and high-volume suction, which may detach large areas, is avoided; blisters formed during treatment are drained at the most dependent point with a sterile needle or scissors, keeping the roof, and detached mucosa is repositioned; tissues are handled by compression and never by lateral traction; the extraoral skin can be protected with non-adherent transfer dressings; the air syringe is used with care (it can form air blisters, which are drained); paediatric instruments, the laryngeal mirror and flat malleable retractors facilitate access; cotton rolls are lubricated with water-soluble gel, can be cut in half for obliterated vestibules and are removed soaked in water; the rubber dam is secured with carefully placed clamps, wooden wedges or a stabilising cord, with the mucosal side lubricated or with a dam napkin; at the end of the session, the floor of the mouth and the vestibules are checked for blisters and material debris, which the patient with ankyloglossia cannot clear [73]. Orthopantomography is the technique of choice in severe and intermediate RDEB; bitewing radiographs with small films and wax-covered edges, the extraoral bitewings of some digital panoramic units, cone-beam computed tomography, edgeless sensors (with a glove finger as a sleeve) and occlusal or lateral oblique views are alternatives; in DDEB, localised RDEB and KEB all techniques are possible with little or no modification [73].

There is no contraindication to conventional dental materials; the choice depends on isolation, caries risk and cultural and economic factors, with short-shank burs, small-head contra-angles, minimally invasive techniques (silver diamine fluoride, atraumatic restorative technique) and stainless steel crowns, and with well-fitting and polished restorations and prostheses; iatrogenic mucosal lesions heal in 1–2 weeks without specific treatment [73]. Endodontic treatment is possible in all patients with sufficient access (buccal access in the anterior teeth, electronic apex locator or cone-beam computed tomography for working length, short 21 mm files and occlusal reduction of the cusps), with caution in the use of hypochlorite when the dam cannot be maintained [73]. Impressions are taken with any material and with special care in RDEB, in custom acrylic trays or with putty silicone as a tray, without excess material; intraoral scanners and stereolithographic models avoid trauma [73]. Fixed rehabilitation is preferred whenever possible and has been described with fixed bridges in severe RDEB; mucosa-supported removable prostheses have been tolerated in DDEB and pretibial RDEB and, in selected cases of generalised RDEB, with adapted borders and flat clasps [73]. Periodontal treatment is possible in all patients, with bleeding sometimes abundant in RDEB; laser or scalpel gingivectomy removes the hyperplastic papillae of KEB [73]. Vestibuloplasty to deepen the vestibule has been published in two patients with DDEB and the panel has limited but positive experience in RDEB; it is recommended when obliteration affects function or quality of life, with a soft acrylic stent or periodontal surgical dressing to prevent refusion [73]. Sutures are possible but require careful placement [73].

Surgical extractions are the responsibility of an experienced dentist; for multiple extractions, the physician is consulted because of anaemia, the anterior teeth (from premolar to premolar) are extracted first and then the molars, with firm incisions, haemostasis by pressure with moist gauze and, if necessary, collagen or gelatin sponges or oxidised cellulose [73]. Mucosal sloughing and blisters occur after almost all surgical extractions in severe RDEB, sometimes of 4 × 3 cm and noticed only on the second day; detached tissue is repositioned or cut with scissors, never pulled off, healing takes place in 1–2 weeks, sockets heal normally, scarring of the commissures may become more marked, and mouth-opening, lip and tongue exercises are continued during healing; antibiotic prophylaxis is decided case by case, without an EB-specific indication [73]. Preventive extraction of healthy third or second molars to facilitate hygiene is controversial and, with current nutrition, orthodontics and exercises, is assessed individually [73]. In orthodontics, EBS, JEB, DDEB and KEB require only minor modifications; in severe RDEB, serial extractions at the appropriate stage of the dentition are strongly recommended to avoid crowding, preferring local anaesthesia with behavioural support to repeated general anaesthesia, and fixed appliances have been well tolerated (correction of a single-tooth crossbite, closure of a diastema and anterior alignment), with removal of hooks that injure the lip and protective wax; tooth-supported removable appliances and clear aligners are possible options [73]. A submandibular gland stone was removed under local anaesthesia with great difficulty because of microstomia and ankyloglossia [73].

Dental implants in RDEB. By April 2019, rehabilitations with implants had been published in 35 patients with RDEB (222 implants): osseointegration at 1 year was 98.6% (217 implants), 100% at 3 years (110 implants) and at 5 years (40 implants), and the mean success of rehabilitation was 98%, with two repaired prosthetic fractures [73]. In a retrospective study with a mean follow-up of 7.5 years, success was 97.5%; 50% of implants had mucositis and 67.5% bleeding on probing, but probing depth remained 1–3 mm in 96.2%, peri-implant bone loss was 1.65 ± 0.54 mm after 7.7 years, and 38% had no buccal keratinised mucosa [73]. Overall satisfaction after fixed rehabilitation was 9.0–9.6 out of 10 in the published series [73]. Osteoporosis and alveolar atrophy did not prevent osseointegration [73].

Source: DEBRA International oral guideline, chapter 4 [73].

As for drugs, the guideline instructs following the usual implant surgery protocols, without an EB-specific regimen [73]. In the adults with RDEB of the published series, the regimen most used was oral amoxicillin 500 mg every 8 hours for 7 days (one author added clavulanic acid and another a preoperative dose), with no infectious complications described, local anaesthesia with 4% articaine (or 2% mepivacaine) and postoperative analgesia with oral ibuprofen 600 mg every 8 hours for 3–7 days (1800 mg/day), or 400 mg every 8 hours for 3 days, or piroxicam 20 mg once a day for 5 days [73]. These are adult doses extrapolated from general oral surgery practice, not tested in EB; ERN-Skin sets a maximum of 30 mg/kg/day for ibuprofen for pain in EB and points out the risk of ulcer and gastrointestinal bleeding with mucosal fragility [34]. Anxiety is managed with behavioural techniques, sedation or general anaesthesia [73].

Oesophageal strictures. The 2025 DEBRA International guideline (GRADE; funded by DEBRA Ireland) issued ten recommendations.

Source: El Hachem and colleagues, 2025 [38].

Oral viscous budesonide is an off-label use: in an open-label trial in 6 children with EB, the 0.5 mg/2 mL nebuliser solution taken orally twice a day for 4 months improved symptoms and imaging in 5, with one case of oesophageal candidiasis; in adults 1–2 mg/day is suggested by extrapolation from eosinophilic oesophagitis [38]. Dilatation has a success rate above 95% in retrospective series, and in a multicentre study major complications (haemorrhage, laceration, chest pain) occurred in 12 of 451 dilatations (2.7%) [38, 134]. The median interval between dilatations ranged from 7 months to 18 months in the series, and recurrence is associated with long (≥1 cm) and multiple strictures [38]. Short-course systemic corticosteroids after dilatation are used without proof of prevention of restenosis, and losartan reduced short-term recurrences in a small case-control study, with insufficient evidence [38]. Radiation in repeated dilatations should be minimised because of susceptibility to SCC [38]. A soft, non-spicy diet and oral care are part of prevention [56].

The French PNDS follows the same radiological approach (pharyngo-oesophago-gastroduodenal contrast study with water-soluble contrast, which confirms the stricture, measures its height and diameter and excludes dissection or perforation) and advises against digestive fibreoptic endoscopy, except in exceptional circumstances; the otolaryngology fibrescope for the pharyngo-oesophageal junction is discussed case by case [36]. Prevention includes puréed or small-piece food, avoiding hard foods (crisps, bread crust, sweets), very dry or hot foods, chewing well, an absolute contraindication to tablets (even crushed) and capsules, and a proton pump inhibitor (PPI) in sachet form if there is reflux, which may be given systematically in children and in the severe forms even without symptoms [36]. In acute dysphagia, no fibreoptic endoscopy or other investigations are performed (unless food is impacted), the diet is changed to liquids, preferably cold, and oral corticosteroids are given for a few days, 1 mg/kg/day, with a PPI for 15 days and adapted analgesia; without improvement in 2–3 days, with complete dysphagia without sufficient hydration or with uncontrollable pain, the patient is admitted to the nearest reference or specialist centre for the same treatment IV, and swallowed budesonide may reduce the risk of stricture after systemic corticosteroids [36]. For stricture, dilatation is indicated when dysphagia affects weight, nutrition and social life, by balloon under fluoroscopy and general anaesthesia, with efficacy checked during the procedure and without a control contrast study; feeding is resumed after a few hours (cold milk diet on the first day, then soft solids), with a PPI for several months and oral corticosteroids for 3 days, 1–2 mg/kg/day, to try to prevent early recurrences; recurrences are frequent, usually after 1 year in the severe forms, and replacement of the oesophagus by colon is reserved for impassable strictures and perforations [36]. GORD is treated with appropriate formulations (syrup, sachets, never capsules) [36].

Gastrostomy. It is considered when growth is insufficient, there are severe oral problems, severe chronic constipation, intractable stricture or high feeding stress, maintaining some oral intake; it improves nutrition and the quality of life of carers, and stoma complications (leakage, pain, erosion, chronic wound, granulation tissue) are frequent but rarely require removal; the laparoscopy-assisted technique was safe in 32 children [38, 56]. In the newborn, gastrostomy is very rare in the first 4 weeks and is considered when long-term supplementary nutrition is necessary and securing the tube is problematic [92].

The PNDS distinguishes two situations: in the neonatal period, in children with major skin losses and severe oral involvement but limited to the mouth, gastrostomy makes it possible to get through the first years with good growth and may be removed if the mucosa and skin improve; in childhood or adulthood, in the severe forms (DEB and non-Herlitz JEB), it is indicated in case of nutritional deterioration despite specialist support or inoperable oesophageal stricture, ideally in childhood, for better tolerance and efficacy on growth [36]. The decision is discussed in advance, so that it is not experienced as a punishment; the drawbacks are the button, skin irritation, reduced oral intake, worsening of reflux and the night-time discomfort of infusions; placement is endoscopic or percutaneous under low-radiation fluoroscopy, by an interventional radiologist or surgeon, under general anaesthesia in children and local anaesthesia in adolescents and adults; oral feeding should be maintained, especially when gastrostomy is early, and parenteral nutrition is kept for temporary situations (extreme malnutrition, acute complication with anorexia or complete dysphagia) [36].

Nutrition. Screening for malnutrition uses the STRONGkids tool; caloric increase should be gradual because of the risk of refeeding syndrome, with high-calorie, high-protein supplements [56]. Zinc, selenium, vitamin C, 25-OH-vitamin D, vitamin K, niacin and vitamins B6 and B12 are measured regularly, and iron deficiency is almost constant [56]. Vitamin A and zinc are supplemented if low, for corneal stability and wound healing, and selenium and carnitine if low, with the aim of preventing cardiomyopathy [2]. The Brazilian Guidelines include folic acid, ferrous sulphate and a micronutrient sachet [19]. Meals should have the maximum caloric value with the minimum volume, and solids are introduced at the same age as in unaffected children, avoiding hard and sharp foods [107]. Constipation is prevented with fluids and fibre and treated with macrogol when necessary [56, 74]. GORD is screened for from the first year and treated with standard therapy [56].

The French PNDS monitors the weight and height curve monthly in infants and then every 2–3 months, with head circumference and body mass index (BMI); from 0 to 3 years, the mid-upper arm circumference/head circumference ratio should be above 0.3, and below 0.28 malnutrition is suspected [36]. In the less severe forms with normal BMI, blood tests (full blood count, ferritin, iron, 25-OH-vitamin D, zinc, plus ESR and CRP in children) are performed on average once a year in children and every 2 years in adults; in malnutrition or the severe forms, full blood count, iron, ferritin, protein, calcium, albumin, prealbumin, ESR, CRP, prothrombin time, activated partial thromboplastin time, total cholesterol, triglycerides, 25-OH-vitamin D, selenium and zinc every 6 months, and vitamins A, B6, B12, B9, C, K and PP and carnitine annually [36]. Curative nutritional treatment is indicated when the curve flattens, BMI falls below 16 or weight loss exceeds 5% of body weight [36]. Vitamin D supplementation is systematic because of low sun exposure, with one 100,000 IU ampoule every 3 months, combined with calcium if the child does not consume dairy products; food is enriched without increasing volume (full-fat milk, butter, cream, maltodextrin), avoiding acidic or spicy foods, serving them lukewarm, puréed or in small pieces, dry foods with sauce, and with soft plastic spoons; zinc, selenium, carnitine and multivitamins are given in liquid form if there is a deficiency, and non-reimbursement of these products is the main cause of non-adherence [36]. The PNDS warns that parental insistence on the child eating may lead to feeding behaviour disorders with the opposite effect, and of the need for speech and language therapy or physiotherapy specialised in oral skills when swallowing is difficult [36]. In constipation, the aim is a daily formed, soft and painless bowel movement: plentiful hydration (magnesium-rich waters), fibre, fibre-containing enteral formulas via gastrostomy, treatment of painful anal wounds (anaesthetic or healing creams, local vasodilators) and, if necessary, long-term osmotic laxatives (macrogol, lactulose; in adults 1–3 sachets per day); enemas and endoscopic investigations are avoided, but in faecal impaction daily enemas of water with liquid paraffin are indispensable and usually well tolerated, with manual evacuation under spinal anaesthesia if insufficient; anal stenoses may require dilatations, always with recurrence [36].

7.7. Anaemia

The DEBRA International anaemia guideline (2023; consensus of 57 professionals from 18 countries, adoption with ≥70% agreement) defines anaemia by World Health Organization (WHO) criteria, with haemoglobin (Hb) as the reference parameter, and establishes screening at the age of diagnosis in the severe and generalised forms, screening from 1 year of age in the moderate forms and assessment every 6 months in the severe forms [75]. The initial assessment includes full blood count with indices, serum iron, ferritin, total iron-binding capacity (TIBC), transferrin saturation, soluble transferrin receptor, reticulocytes and CRP [75]. Ferritin, an acute-phase reactant, may be normal or high despite iron deficiency in inflammation; in the general population, ferritin <45 ng/mL has a sensitivity of 85% and specificity of 92% for iron deficiency [75].

The IV iron doses in the guideline come from general references and not from EB-specific labels: iron sucrose in children ≥2 years 5–7 mg/kg per dose (maximum initial dose 100 mg; maximum 300 mg per dose) and in adults 100–300 mg per dose; ferric carboxymaltose in adults ≥50 kg 750 mg in two doses at least 7 days apart or 15 mg/kg as a single dose up to 1000 mg, with a cumulative maximum of 1500 mg per course; sodium ferric gluconate in children ≥6 years 1.5 mg/kg (maximum 125 mg) [75]. The total deficit is calculated by the Ganzoni formula: weight (kg) × (target Hb − current Hb, g/dL) × 2.4 + stores (500 mg if >35 kg; 15 mg/kg if <35 kg), and venous access for other procedures should be taken advantage of [75]. In 43 adults with severe EB, periodic ferric carboxymaltose, administered over 15 minutes and repeated every 3–4 months, was safe and effective; repeated doses may cause chronic hypophosphataemia and osteomalacia, so parathyroid hormone and the bone profile are monitored [75]. Erythropoietin or darbepoetin have insufficient evidence outside erythropoietin deficiency or renal failure [75]. The guideline contains unit typos in its own text («mg/dL» instead of g/dL); the correct thresholds are those given above [75]. Menstrual suppression avoids worsening anaemia [2]. The French PNDS prefers oral iron in liquid preparations (sachets or syrup), taken with vitamin C (fruit juice), mentions studies suggesting an absorption test before prescribing oral iron, which is often poorly tolerated, and reserves IV iron for failure of the oral route [36]. It indicates red cell transfusion in the event of an intercurrent event that worsens the anaemia (oesophageal stricture, surgery), clinical signs of anaemia (dyspnoea, angina, dizziness, hypotension), a significant fall from the patient's baseline value or a haemoglobin below 5 (unit printed as «g/L», which makes clinical sense only as 5 g/dL) [36]. In iron-resistant anaemia, folate and vitamin B12 deficiencies, hypothyroidism and renal failure are investigated; the role of erythropoietin, limited by inflammation, is yet to be defined; and, in women of childbearing age, a continuous progestogen-only or oestrogen-progestogen pill may be discussed to suppress menstruation, without published studies [36]. In the Italian series, tranexamic acid and vitamin K were used for wound bleeding [54].

7.8. Eye, hands and feet, bone, puberty, heart and kidney

Eye. The baseline ophthalmological examination is carried out at a reference centre, with follow-up according to severity; sterile lubricating ointments and preservative-free tears, a humidifier in the bedroom, a therapeutic contact lens with antibiotic prophylaxis for recurrent erosions affecting acuity, and fusidic acid ointment for eyelash collarettes are used, avoiding rubbing the eyelids [56]. The therapeutic contact lens improves pain and the frequency of abrasions and may be used for years [107]. Acute corneal erosion is treated as an emergency (section 7.10). Ophthalmic beremagene geperpavec (KB803) is in a trial (section 7.12) [135].

The French PNDS recommends an initial ophthalmological examination outside any acute episode, by a local ophthalmologist informed of the fragility, ideally annual and systematic in the severe forms (on average twice a year), with record sheets sent to the ophthalmologist of the reference centre, and an urgent consultation in the event of pain or a red eye [36]. The examination is gentle, all usual examinations are possible with caution, and glasses should be perfectly fitted so as not to rub the skin; prevention uses artificial tears, preferably single-dose and preservative-free, rinsing with normal saline and an ultrasonic humidifier by the bed [36]. In the first acute episode of ocular surface injury, the French protocol applies on day 0 monthly continuous-wear soft silicone hydrogel contact lenses for at least 15 days, with azithromycin eye drops for 3 days; on day 15, if the epithelium has healed, a preventive strategy is adopted with azithromycin eye drops 3 days a month and reviews at 6 weeks and 3 months; if it has not healed, the lenses and azithromycin are repeated on the same schedule; at 2 months, in the event of several episodes, an age-adapted scleral lens is discussed [36]. Vitamin A ointment is not used with the lenses in place, but may be applied at night as prevention, with lubricating eye drops [36]. Ocular pain is assessed by VAS at each appointment, and the family receives an anticipatory prescription: oral paracetamol 15 mg/kg every 6 hours, tramadol 1 mg/kg every 6 hours and, if insufficient, oral morphine 0.2–0.3 mg/kg every 4 hours, with 30% increments, without a maximum dose stated in the protocol (titration by response) [36]. Complications are treated mainly by surgery (eyelids with skin grafting for ectropion and symblepharon, amniotic membrane, limbal or corneal grafts), and significant refractive errors with glasses, sometimes with occlusion [36].

Hands and feet. The DEBRA International hand surgery and therapy guideline (2022; international survey with 37 complete responses from 14 countries and literature review) and the Italian consensus agree that the functional improvement from surgery is temporary, with recurrence expected within 1–2 years [56, 136]. Recurrence has been reported from a few months to 11 years, about half of patients need further surgery, and in the best result described (45 patients, 80 hands) release of thumb adduction was maintained for 2 years and improvement of contractures for up to 5 years, with reoperation on average 2.4 years later [136]. Of the surgeons surveyed, 67% prefer to operate for the first time before 11 years of age; some paediatric surgeons release only the first web space, because a stable thumb opposed to a stable «post» serves many functions, and adults tend to prefer release of the whole hand [2, 136]. Full-thickness skin grafting is the standard to reduce recurrence; in adults, a dermal matrix under a thin split-thickness graft is an alternative; swabs are taken 2 months before, and surgery is cancelled if Streptococcus is present, because of the risk of graft failure [136]. After surgery, continuous dressings are maintained for at least 2 weeks (up to 3 months), full-time splints from the 3rd–4th week, night-time splints from 2–4 months and, for most therapists, long term, and exercises several times a day for at least 12 weeks [136]. Bandaging the hand with a soft 2.5 cm strip that pulls the web spaces downwards, or finger by finger, helps to preserve the web spaces [83]. The Brazilian Guidelines recommend separating dressings or soft seamless gloves and hand surgery in cases of fusion, with recurrence if separation is not maintained [19]. On the feet, appropriate footwear, padding, insoles or orthoses and regular nail trimming are used, and physiotherapy is essential for walking [2, 56].

The French PNDS describes as measures to delay digital fusion daily dressings with interface strips between the fingers (damaged skin) or cotton strips (intact skin), adapted rings, made-to-measure non-compressive mittens, seamless and of breathable fabric, kinesitherapy and self-exercises, and made-to-measure thermoformed silicone splints, static at night (wrist neutral or in slight extension, fingers in extension, thumb in abduction) or dynamic, without comparative studies between methods [36]. The main aim of surgery is to recover pinch grip, releasing the first web space and flexion contractures; the indication is loss of function affecting independence, with optimised general and nutritional condition and broad-spectrum antibiotic prophylaxis before, during and after the operation; after surgery, a perforated thermoformed splint (to reduce sweating) is worn all day until complete healing and then at night, with kinesitherapy and gloves; even so, recurrence is the rule, with a mean interval of 2–5 years [36]. On the feet, interdigital strips delay fusion of the toes, cotton socks hold the dressings, shoes are soft and seamless (with a soft sole before walking and a shock-absorbing sole afterwards), of leather, with a round toe and good fastening, and thermoformed silicone or foam insoles and made-to-measure footwear are made by a podiatric orthotist; monthly chiropody trims the nails and hyperkeratosis, and artificial nails are not contraindicated [36]. At school, an individualised reception plan may authorise adapted footwear [36]. The wheelchair should be occasional, because it accelerates contractures, muscle loss and loss of walking; physiotherapy uses soft or protected equipment and wide grips, and occupational therapy makes splints, made-to-measure gloves and technical aids (bottle openers, pen adapters, cutlery holders) [36].

Bone and puberty. Nutrition, calcium, vitamin D and physiotherapy from early childhood prevent osteoporosis; IV bisphosphonates treat osteopenia and osteoporosis (GeneReviews gives no dose) [2, 56]. Treatment of delayed puberty with sex hormones may be useful, without EB-specific data [2, 56]. Treatment of osteoporosis also reduces pain [74].

The PNDS assesses bone by densitometry, 25-OH-vitamin D, serum calcium and parathyroid hormone, pointing out that densitometry involves radiation in patients at risk of skin cancer, so the number of examinations should be weighed; it treats osteopenia with vitamin D and calcium, considers the role of bisphosphonates yet to be defined and requires prior treatment of dental foci of infection before using them; regular kinesitherapy, standing frames and wheelchairs with a standing function improve mineralisation, and vibration platforms are under study [36]. Delayed puberty is referred to paediatric endocrinology [36].

Heart. In the presence of dilated cardiomyopathy on echocardiography, cardiology may control or reverse the disease with beta-blockers and/or angiotensin-converting enzyme inhibitors, and selenium and carnitine are corrected if low [2, 76]. The PNDS advises an annual echocardiogram in the severe forms without known heart disease and stresses that control of anaemia contributes to cardiac stability [36].

Kidney. Creatinine (with cystatin C in malnutrition), urinalysis and blood pressure are monitored every 6–12 months, with nephrology if there are abnormalities; haemodialysis and peritoneal dialysis have both been described, with a case-by-case decision [56, 77]. Erosions, urethral strictures and bladder dysfunction are treated by urology [2].

The French PNDS recommends, in the absence of a known uronephrological complication, blood pressure once a year (with protection of the skin under the cuff), a urine dipstick at each assessment, with urine microscopy and culture, protein/creatinine ratio, microalbuminuria and electrolytes if positive, and, in the severe forms, an annual spot urine test (proteinuria, microalbuminuria, urinary creatinine, protein/creatinine ratio, urinary electrolytes, microscopy and culture) [36]. In the presence of hypertension or a laboratory abnormality, renal ultrasound and nephrology assessment are performed; renal biopsy, which is not contraindicated in EB with the usual precautions, is proposed when proteinuria exceeds 1 g/L or to confirm amyloidosis, and NSAIDs are limited because they may cause or worsen tubulopathy [36]. Invasive procedures (catheterisation, endoscopies) should be exceptional, decided with the reference physician and as atraumatic as possible, because secondary stricture or hypergranulation may cause permanent obstruction [36].

Ear and airway. Blisters of the auricle decrease with petroleum jelly twice a day; chronic otitis externa is treated with topical antibiotic (ofloxacin) adjusted to the antibiogram, and prevention avoids cotton buds and uses normal saline rinses; stenosis of the external auditory canal may require excision of scars, bony widening and full-thickness skin grafting, and profound deafness may be treated with a cochlear implant; the nose is cleaned with normal saline, without contact with the skin [36]. Moderate stridor leads to admission for dexamethasone, nebulised adrenaline and oxygen, and any invasive examination of the airway without suggestive symptoms is proscribed [36].

7.9. Squamous cell carcinoma

The 2016 DEBRA International guideline on cutaneous SCC in EB (systematic review to April 2014; grades of recommendation A–D and good practice points, GPP) is addressed to adolescents and adults with RDEB, DDEB, intermediate JEB and KEB and remains the reference, supplemented by the 2025 Italian consensus and the later literature on immunotherapy [39, 56, 80].

Biopsy. Multiple 3–4 mm punch biopsies are taken at the edge of the lesion, recorded on a diagram or photograph, under local anaesthesia or general anaesthesia if they are multiple, especially in children, taking advantage of another anaesthetic when possible; histopathology should be read by a pathologist experienced in EB, because of the differential diagnosis with granulation tissue and pseudoepitheliomatous hyperplasia (D, III–IV) [39, 56].

Staging. The case is discussed at a multidisciplinary meeting (dermatology, plastic surgery, histopathology, oncology) (GPP). For SCCs of 5 cm or more or at difficult anatomical sites, magnetic resonance imaging (or computed tomography) assesses tendons, nerves and vessels (D, III). Palpable lymph nodes are studied by ultrasound-guided fine-needle aspiration cytology; if negative, they are reassessed every 3 months; if positive, lymph node dissection is performed, ideally in the same operation. Sentinel lymph node biopsy is possible, but all those described in EB were negative and without demonstrated prognostic value, and elective dissection is not recommended, because lymphoedema worsens blistering and exudate. Distant staging is carried out if the primary is 5 cm or more or there are symptoms, with fluorodeoxyglucose positron emission tomography (with non-specific uptake in wounds, reactive lymph nodes, oesophagus and bone marrow) or thoraco-abdomino-pelvic computed tomography or magnetic resonance imaging [39].

Surgery. Wide local excision is the treatment of choice (D, III), ideally with a 2 cm clinical margin, an oriented specimen and a report with margins, thickness, differentiation and vascular and perineural invasion; a positive margin leads to re-excision or amputation [39, 56]. All SCCs in EB may be aggressive regardless of grade [39]. Amputation of a digit or limb is performed when excision is not possible, without a demonstrated survival advantage over wide excision and with shared decision-making, because some patients prefer to preserve function; prostheses have been used successfully after amputation (D, III) [39]. Mohs surgery has a role when the tumour is difficult to delineate or to spare tissue, without demonstrated benefit on recurrence [39]. Closure is mainly with meshed split-thickness skin grafts (donor sites heal poorly), or by secondary intention, full-thickness graft, allograft, cadaveric skin, skin equivalents, flaps or keratinocyte suspensions (GPP) [39].

Non-surgical treatment. Palliative radiotherapy is useful in inoperable local recurrence, after lymph node dissection and in subcutaneous, nodal and bone metastases (D, III); high total doses cause severe desquamation, so smaller fractions, for example of 2 Gy, are preferred (GPP); as definitive treatment it has no evidence on the skin, but it has been used as primary treatment of mucosal SCCs in KEB and RDEB [39]. Conventional chemotherapy (cisplatin, carboplatin, paclitaxel, 5-fluorouracil, doxorubicin, methotrexate) has given partial responses in case reports, and the risk of catheter-related septicaemia and neutropenia may outweigh the benefit (GPP) [39]. Cetuximab has had favourable results in cases of metastatic SCC with strong expression of the epidermal growth factor receptor (EGFR), and erlotinib is potentially useful, with acne and gastrointestinal effects (GPP); electrochemotherapy is a potential option (D, III) [39]. The Italian consensus reports that antibodies against the programmed cell death 1 receptor (anti-PD-1), approved for metastatic or locally advanced cutaneous SCC, have been used in a limited number of patients with RDEB with some clinical benefit [56]. In the systematic review of 157 cases, median survival from the first SCC to death, in 50 cases with data, was 2 years with surgery alone (n=19), 1.85 years with surgery and chemotherapy (n=6), 4.0 years with anti-EGFR (n=10), 4 years with surgery and radiotherapy (n=9) and 4.6 years with immunotherapy (n=4); causal attribution is impossible because of the multimodal nature and small samples, and immunotherapy was associated with poorer wound healing [80]. A 51-year-old woman with RDEB and unresectable SCC of the flank had marked regression after 3 incomplete doses of cemiplimab, but a severe infusion reaction required sedation and immune-mediated colitis led to discontinuation [137]. Rigosertib, a polo-like kinase 1 (PLK1) inhibitor, gave 2 complete responses within 6 months in 5 patients with refractory locally advanced or metastatic SCC in two single-arm phase 2 trials, with non-infectious cystitis and haematuria and dose reductions; it is experimental [138–140]. A phase 2 trial is evaluating whether beremagene geperpavec applied to the skin after SCC excision reduces recurrence at 2 years [141].

French practice. The PNDS entrusts SCC in EB to a centre with competence in both dermatological oncology and EB [36]. Routine surveillance in RDEB takes place during the «full dressing change» (section 7.1), and suspicious lesions are biopsied immediately, at sufficient depth and after removal of hyperkeratosis, under careful local anaesthesia (lidocaine with adrenaline, very fine intradermal needles, with or without prior lidocaine/prilocaine cream), using nitrous oxide or hypnosis for anticipatory anxiety; for large or multiple lesions a map is made with photographs of the numbered and identified lesions (the location written on a hydrocellular dressing next to the lesion, visible in the photograph), and the report should state thickness, depth (Clark level), differentiation and perineural invasion [36]. Staging follows the criteria of the French Society of Dermatology, the National Cancer Institute and the HAS (2009): as SCCs in EB always arise in an area of chronic inflammation and as a rule measure at least 1 cm, almost all belong to group 2 (significant prognostic risk), and the combination of several clinical or histological criteria (especially lack of differentiation) and/or a diameter greater than 5 cm defines a potentially very aggressive tumour, discussed at a multidisciplinary team meeting, which may be held by videoconference between centres [36]. For pre-epitheliomatous keratosis, SCC in situ and group 1, a thorough clinical examination is sufficient; for group 2 invasive SCC without multiple criteria, preoperative investigation is limited to lymph node ultrasound and, if this is not possible (overlying wounds) or inconclusive (dermatopathic lymphadenopathy, constant in severe RDEB), positron emission tomography with computed tomography (PET-CT) distinguishes metastatic from reactive lymph nodes better than CT alone, with reporting by a nuclear medicine physician familiar with EB; with several poor-prognosis criteria (including size greater than 5 cm), magnetic resonance imaging or CT assesses locoregional extent, especially on the extremities, and PET-CT may be performed even without a suspicious lymph node; a radiologically suspicious lymph node is aspirated or biopsied, and nodal confirmation leads to staging by PET-CT, CT or magnetic resonance imaging [36]. Surgery, the only curative treatment, is performed as soon as possible after histological confirmation; for SCC on a chronic ulceration the whole ulceration is removed with a margin of at least 1 cm, and in generalised RDEB, in which clear margins are often impossible because the whole segment is dystrophic, the margins should be at least 1 cm from the invasive SCC [36]. Split-thickness skin grafting (from non-dystrophic skin or the scalp), in one or two stages, with or without an intermediate dermal equivalent, is preferred to healing by secondary intention because it heals faster, is less painful and speeds functional recovery, especially on the lower limbs, without demonstrated benefit in preventing recurrences [36]. Refusal of amputation must be informed: without complete excision there is no cure and the functional and vital prognosis is at risk in the short term [36]. There are no data on non-surgical treatments of pre-epitheliomatous keratoses and SCC in situ (topical antimitotics, physical destruction, laser, photodynamic therapy, imiquimod) [36]. Among palliative treatments, the PNDS highlights radiotherapy in smaller fractions (grade D), conventional chemotherapy (grade D), with difficult digestive tolerance in oesophageal stricture, cetuximab and erlotinib, with better tolerance despite increased skin fragility, cemiplimab (an anti-PD-1 antibody authorised in 2019 for locally advanced or metastatic SCC), with efficacy described in one patient with EB and proposed as first line in the locally advanced forms, possibly as neoadjuvant, a complete response of multiple SCCs with another anti-PD-1 and electrochemotherapy in a series of 5 patients with RDEB [36]. EB naevi are monitored clinically and dermoscopically at each complete dermatological examination, with measurements and photographs in the record, reserving biopsy or excision for suspicious lesions [36].

Prevention and end of life. There are no chemoprevention trials; isotretinoin up to 0.5 mg/kg/day for 8 months was well tolerated in a phase 1 trial in RDEB, with increased fragility in some patients, and photodynamic therapy, topical 5-fluorouracil and imiquimod have no evidence in early disease (D, III; GPP); these are off-label uses [39]. After an SCC, the patient is reassessed clinically every 3 months, and routine imaging has no evidence [39]. At the end of life, opioids by various routes are the mainstay (C), including topical morphine in hydrogel on the painful malignant wound, renewed at each dressing change, and subcutaneous infusion with a cannula secured by silicone tape [39, 74].

7.10. Emergencies, anaesthesia and circumstances to avoid

Emergencies. The doses below are those of ERN-Skin, all off-label for EB specifically and dependent on age and weight [35].

Source: Mellerio and colleagues, ERN-Skin, 2020 [35].

The French PNDS takes up these recommendations (annex 13, based on the same source) and adds some points [36]. In sepsis, which has a cutaneous source in most cases, the most frequent agents are Staphylococcus aureus, Streptococcus and Pseudomonas aeruginosa, with a risk of multidrug-resistant bacteria in patients repeatedly treated with topical and systemic antibiotics [36]. In acute dysphagia, treatment is outpatient if dysphagia is incomplete (liquids possible) and rapidly reversible or if the patient has a gastrostomy, and inpatient if it is complete or there is dehydration or chronic malnutrition, with parenteral therapy (peripheral or central venous) and transfer to the oral route as soon as possible; a PPI is added (esomeprazole sachets, 20–40 mg according to age and weight, or IV omeprazole or pantoprazole) for at least 15 days, feeding may be suspended for 2–3 days without consequence in a patient who is maintaining hydration, and dilatation is never performed in the acute phase, on inflamed mucosa [36]. In acute airway obstruction, rare in DEB and mainly characteristic of JEB, the ERN-Skin doses are nebulised budesonide 2 mg, repeatable every 20 minutes up to 3 times, oral dexamethasone 0.6 mg/kg and, in the severe forms, nebulised adrenaline 0.1 mg/kg, repeatable every 20 minutes up to 3 times, with oxygen, and for anxiety midazolam 50 µg/kg as an IV bolus or 250 µg/kg orally, or oral amitriptyline 0.5 mg/kg/day in 3 doses or IV 0.3 mg/kg/day [35, 36]. In corneal erosion, the PNDS asks that nothing be instilled before ophthalmological assessment and that eyelid occlusion be maintained without adhesives until then [36]. Without advance directives, no decision to limit care should be taken without prior contact with the reference centre team; in the very severe forms, such limitation is discussed before acute complications occur, with the community-hospital network and a form for the prehospital emergency medical service agreed with the family [36]. The route of administration takes into account the lack of venous access (central catheter, subcutaneous infusion or hypodermoclysis), oesophageal stricture and gastrostomy, and invasive procedures (catheterisation, cystoscopy, laryngoscopy, bronchoscopy) require the agreement of a specialist from the reference centre, exploratory invasive examinations being proscribed [36].

Anaesthesia and perioperative care. Anaesthesia or sedation is reserved for strictly necessary procedures, with multidisciplinary and anaesthetic reassessment 1–2 weeks beforehand (anaemia, infection), sedative premedication, padding, no adhesives, moving with a sheet, disinfection by pouring or gentle dabbing, lubrication of all airway equipment (laryngoscope blade, tube, mask), masks with an inflated rim, silicone tapes, otolaryngology in the team if there is microstomia or oropharyngeal scarring, and venous access maintained postoperatively for transfusion, iron, albumin and antibiotics [56, 92]. Perioperative analgesia follows that of patients without EB with adaptations (A), and regional anaesthesia is appropriate, with catheters secured by non-adhesive dressings (C) [74]. The PNDS considers awake fibreoptic intubation the rule in generalised or severe inversa RDEB, favours deep sedation and local anaesthesia when possible and allows all techniques (intubation, mask, epidural, spinal anaesthesia) with the precautions of the operating theatre protocol; adapted equipment includes reusable silicone electrosurgical plates instead of self-adhesive ones [36]. Planned surgery (and deliveries) preferably take place in university hospitals with a reference or competence centre, because surgical departments rarely have the staff and equipment for dressings lasting several hours a day, and in emergency surgery an inexperienced team should contact the team at the centre following the patient and listen to the family [36].

Anaesthesia for dental treatment (DEBRA 2020). The choice between local anaesthesia, sedation and general anaesthesia results from risk assessment and discussion with the patient and family, weighing age, extent of treatment and anxiety [73]. In the mild forms, simple procedures are performed under local anaesthesia, which, with microstomia under control, allows all treatments (multiple extractions, implants, endodontics, restorations), spares the airway, prolongs analgesia and as a rule causes less mucosal injury than general anaesthesia; topical anaesthetic gel is used normally, the injection is given deeply and slowly so as not to separate tissue planes, computer-controlled delivery systems may help, iatrogenic blisters are drained immediately keeping the roof, and the patient is warned not to bite or rub the lips while the effect lasts [73]. Moderate sedation is performed only with expertise and the means for emergency access to a difficult airway; nitrous oxide has been used successfully for dressing changes at home, with no reports in dental treatment [73]. General anaesthesia serves extensive treatment when microstomia, vestibular obliteration, fragility or the patient's tolerance require it, but it does not resolve microstomia or prevent generalised mucosal sloughing; the attending physician is consulted, a team with experience in EB is preferred (or, failing that, local anaesthesia or referral to a specialist centre) and other procedures may be combined under the same anaesthetic (oesophageal dilatation, dressings after hand surgery), discussing the risk of transient bacteraemia from dental treatment [73].

Under general anaesthesia, nasal intubation is the first choice, because it gives more space to the operative field and can be secured without adhesive; a smaller laryngoscope and a small-calibre cuffed tube, videolaryngoscopy or fibreoptic intubation (also with spontaneous ventilation), minimal chin lift and minimal head tilt, non-adhesive tape on the tube and a mandatory oropharyngeal pack in any dental procedure, lubricated with water-soluble gel or soaked in water, are used [73]. The eyes are always protected, because of the high incidence of perioperative corneal injury: with normal eyelid closure, sodium hyaluronate 2 mg/mL eye gel and a non-adherent dressing; with lagophthalmos (frequent owing to scarring and ectropion), petrolatum-based eye ointment renewed every hour under non-adherent pads; therapeutic contact lenses are kept in, with preservative-free lubricant (sodium hyaluronate 1 mg/mL) every 20–30 minutes, and refractive lenses are removed beforehand [73]. For monitoring, the adhesive part of oximetry probes is cut off (or a clip on the earlobe or on a finger wrapped in a silicone interface, petrolatum dressing or cling film is used), the adhesive is removed from electrocardiogram electrodes and the electrosurgical plate, leaving only the central area in contact, and the blood pressure cuff is placed over the wrapped limb; the tourniquet is applied over gauze or with manual pressure with lubricated gloves and released slowly, the venous cannula is secured with non-adhesive tape and a self-adherent bandage, and the operative field is disinfected by pouring or dabbing, without rubbing [73]. Discharge varies from the same day to 3 days, depending on the extent of surgery and the risk of hospital-acquired infection [73]. In a review of 121 procedures there were no deaths or major anaesthetic complications, and in a series of 344 general anaesthetics at a reference centre, postoperative nausea or vomiting was recorded in 2.3%, new blisters in 2.0%, regurgitation in 0.6% and corneal ulcer in 0.3%; serious injuries result mainly from handling by inexperienced staff (for example, eyelids closed with tape), and a fracture of the maxillary alveolar process during laryngoscopy has been described in a patient with severe RDEB, osteopenia, microstomia and prominent incisors [73]. Postoperatively, badly damaged lips may stick together, so the lips and commissures are continuously lubricated and mouth-opening, lip and tongue exercises are resumed early [73].

Agents and circumstances to avoid. Ordinary medical adhesives and sticking plasters; ill-fitting or rough clothing and footwear; traumatic activities (long walks, mountain biking, contact sports), encouraging skin protection in those who take part; nasogastric tubes, except in the situations of section 7.2; naso- and oropharyngeal suction; incubators and heat; antithrombotic compression stockings; fetal scalp electrodes; and oesophageal dilatation with bougies [2, 38, 56, 79, 92]. Prolonged topical antimicrobials, silver over large surfaces in children and barium in suspected oesophageal obstruction are also avoided [34, 35]. In KEB, sun exposure is added [6].

7.11. Pregnancy, lactation, transition and palliative care

Pregnancy and delivery. The DEBRA International guideline on pregnancy, childbirth and the postpartum period (2022; GRADE) is based mainly on case reports and series; the largest series included 44 women with EB and 112 pregnancies (12 with DDEB and 3 with RDEB), with 91 vaginal deliveries and 21 caesarean sections, and a survey did not detect an increase in pregnancy complications [2, 79, 142]. The main recommendations are: assess vulvovaginal involvement and consider medically assisted reproduction if there is severe stenosis or dyspareunia (↑↑); preconception genetic counselling, prenatal testing for couples at risk of severe forms and carrier screening of a non-consanguineous partner (↑↑); folic acid and correction of micronutrients, anaemia, infection, malnutrition and oral health before and during pregnancy; monitor nausea and vomiting with GORD or strictures; early multidisciplinary team; antenatal anaesthetic assessment, ideally always in RDEB; surveillance for skin cancer during pregnancy [56, 79]. Vaginal delivery is the preferred route in all subtypes (↑↑, very low evidence), does not appear to increase scarring or vaginal stenosis even in severe RDEB, and RDEB is not an absolute contraindication [56, 79]. Caesarean section is reserved for the usual obstetric indications, extensive genital involvement, vaginal stenosis or strong maternal preference; in breech presentation external cephalic version is not performed (shear) (↓↓) [79]. Instrumental delivery (vacuum, forceps) (↓↓), fetal scalp electrodes and fetal blood sampling if the fetus may be affected (↓↓), and antithrombotic compression stockings are avoided, using low-molecular-weight heparin if there is a thromboembolic risk (↓↓); induction of labour is not contraindicated; caesarean section is preferably performed under regional anaesthesia (↑↑), without adhesive tapes on the skin, with minimal handling [79]. For a possibly affected fetus, GeneReviews allows caesarean section in certain circumstances to reduce trauma [2]. Women with dominant forms have a 50% probability of an affected child, and vaginal delivery remains the preferred route even when an affected baby is expected, with the neonatal team involved before delivery [79].

Medicines in pregnancy and lactation. The European SmPC does not recommend beremagene geperpavec in pregnancy and asks for a decision between discontinuing breastfeeding or treatment; the FDA label reports an absence of data and advises effective contraception during treatment [28, 29]. The European SmPC for birch bark extract allows use in pregnancy and breastfeeding, except if the breast is being treated; the FDA label reports only an absence of human data and low systemic absorption [30, 31]. For prademagene zamikeracel there are no data, and effective contraception is recommended at the time of treatment [32]. After delivery, breastfeeding (positioning, latch, nipple shields) and mothers with pseudosyndactyly are supported, with screening for mood disorders [79].

Gynaecology, contraception and pregnancy in the PNDS. The French PNDS points out that sexual life, life as a couple and pregnancy are possible in the great majority of patients, even in the severe forms, and that parenthood, prenatal diagnosis and medically assisted reproduction should be addressed from puberty and revisited during transition [36]. Gynaecological examination and breast palpation follow the recommendations for the general population with a lubricated speculum; symptomatic vulvar atrophy may be treated locally, with or without hormones (topical oestriol), and mammography, traumatic for the skin of some patients, may be replaced by magnetic resonance imaging [36]. During pregnancy, nutritional, haematological and infection surveillance is reinforced; the mode of delivery is decided by the obstetric situation, the general and mucocutaneous condition and the woman's choice, cervicovaginal and perineal tolerance of vaginal delivery is generally good, even in the generalised forms, with fewer postpartum mucocutaneous complications than with caesarean section, and the level of the maternity unit is chosen according to the severity in the mother and in the expected newborn; breastfeeding is possible, but difficult in the severe forms because of blisters on the nipples and areolae [36]. No contraceptive method is contraindicated; petroleum jelly reduces the effectiveness of condoms and should be avoided with them, the pill is adapted to swallowing capacity if there is oesophageal stricture, and continuous oestrogen-progestogen, by suppressing withdrawal bleeding, improves local comfort and prevents iron deficiency [36].

Transition, psychosocial care and palliative care. Transition from paediatric to adult care should be planned, and therapeutic education begins at birth and is addressed to the child from about 5 years of age; psychosocial support is lifelong, for the patient, the family, siblings and professionals [56, 92]. Early physiotherapy (motor milestones, walking, weight-bearing) and occupational therapy (activities of daily living, hand function, feeding) are part of care [56]. The DEBRA International palliative care guideline (2023) recommends an interdisciplinary team centred on the patient and carers, nursing care for carer respite and attention to the mental health of professionals, and points out that correct diagnosis of the EB type improves management [107]. At the end of life, preferences regarding place of death, feeding and hydration are respected [39].

For the PNDS, transition is planned ahead and never carried out in an unprepared young person on the occasion of an acute, surgical or oncological complication; the maturity and wishes of the patient and parents count more than age, and members of the adult team are progressively integrated into joint consultations [36]. Psychological support is systematic in the severe forms and in vulnerable periods (pre-adolescence and adolescence) and offered in all forms according to the situation; in children, it follows psychomotor and psychoaffective development, entry to school and educational and vocational guidance, and clear explanations reduce anxiety; in adults, depression and anxiety are frequent, and the PNDS acknowledges that the provision of psychologists and social coverage is insufficient [36]. In parents, shock, denial and anxiety at disclosure, overprotection, burnout and professional, social and marital repercussions require psychological and social support [36]. Early rehabilitation (physiotherapy, psychomotor therapy, occupational therapy, speech and language therapy) stimulates sensory integration of the hands without dressings (textured balls), supports the acquisition of walking, which is achievable for all, prevents abnormal postures and treats oral skill disorders, frequent in EB and accentuated in adolescence in the severe forms of RDEB, avoiding forcing the teat or food in the acute phase [36]. Therapeutic education programmes, authorised and evaluated annually by the French regional health agencies, are addressed to children, adolescents, adults and carers; the PNDS warns against the temptation to make parents specialised care providers to make up for the lack of community nursing [36]. In the very severe forms, the reference centre draws up a palliative care protocol with the patient and parents, which is given to the emergency team [36].

7.12. Investigational therapies, developments and negative trials

Developments from October 2025 to October 2026, by level of evidence.

Gene and cell therapies in development. In addition to the authorised products, autologous skin equivalents corrected with a self-inactivating retroviral vector (EBGraft, France, 3 adults with residual collagen VII) and mesenchymal stromal cell extracellular vesicles are under study [155, 156]. GeneReviews also mentions stem cell therapies (bone marrow, mesenchymal stromal cells, induced pluripotent stem cells), corrected fibroblasts, termination codon read-through, exon skipping, collagen VII protein therapy and harnessing of revertant mosaicism, and trials with antifibrotic, anti-inflammatory and antipruritic agents [2, 157]. A review of five years of advances concluded that gene and protein therapies have limited efficacy, regenerative cell therapies a limited effect, and that the cost of approved therapies limits global access [157].

Losartan. In the REFLECT trial (Freiburg, open-label single-arm phase 1/2), 29 children aged 2–16 years with RDEB received losartan with titration over 16 weeks up to 1.4 mg/kg, 24 weeks at the target dose, 4 weeks of tapering and 12 weeks off drug; 27 completed, without serious complications (severe hypotension, hypersensitivity, potassium abnormalities); at week 40, the damage index of the EB Disease Activity and Scarring Index (EBDASI) decreased by 10.50 (95% CI −20.81 to −0.19) and the opening between thumb and index finger increased by 6.92 mm (95% CI 3.48–10.37), with no significant difference in pain, pruritus, quality of life, dysphagia or hand function [158]. The authors hold a patent and have a company related to losartan [158]. A systematic review of 5 studies (59 patients) showed no relevant hypotension, hyperkalaemia or hypersensitivity and concluded that use should not be standardised without further trials [159]. It is an off-label use.

Haematopoietic cell transplantation. In 2010, seven children with RDEB were treated with immunomyeloablative chemotherapy and allogeneic transplantation: one died of cardiomyopathy before transplantation and one on day 183 from rejection and infection; in the others there was improved wound healing, increased collagen VII at the junction in 5 of 6 without normalisation of anchoring fibrils, and donor cells in the skin [160]. In the MT2009-09 protocol (Minnesota; 32 patients ≤25 years), transplant-related mortality at 180 days was 43% with myeloablative conditioning and 19% with reduced intensity in RDEB, and 2-year event-free survival was 44% and 80%, respectively [161]. With post-transplant cyclophosphamide and donor stromal cells in 10 patients, the surface area with blisters and erosions decreased from 49.5% to 27.5% at day 100, with graft failure in 3, veno-occlusive disease in 2 and one death from chronic graft-versus-host disease [162]. Transplantation remains experimental, with relevant procedure-related mortality [163].

Negative, interrupted or discontinued trials. Phenytoin, proposed to inhibit collagenase, had no effect in a controlled study [4]. The phase 3 DEFI-RDEB trial of dabocemagene autoficel enrolled only 6 patients, far below the planned number, and did not allow a conclusion on efficacy (complete healing of the first pair at week 24 in 1 treated wound versus 0 control) [164]. The antisense oligonucleotide QR-313 for exon 73 skipping was interrupted owing to low recruitment, and thymosin β4 gel (RGN-137) for commercial reasons [165, 166]. Holostem's corrected autologous epidermal grafts and a protocol of palifermin with transplantation were terminated [167–169]. Two studies with SD-101 were terminated because the sponsor voluntarily withdrew the product after good manufacturing practice deficiencies detected in an FDA inspection; the published result of the phase 3 ESSENCE trial (169 patients) was not read in the sources [170–172]. IV recombinant collagen VII (PTR-01) had phase 1/2 and 2 trials completed in 2021–2022 without a registered phase 3, and the trials of topical, intradermal and IV gentamicin for termination codon read-through were completed in samples of 5 and 6 patients, without registered continuation [173–178]. The absence of results published in registries does not demonstrate that the trials were negative.

7.13. Guideline recommendations and divergences

7.14. Kindler EB: treatment

There are no clinical practice guidelines or specific treatments for KEB, and the aims are to treat the manifestations and prevent complications, preferably at a centre with experience in skin fragility and with a multidisciplinary team (dermatology, paediatrics, ophthalmology, dentistry, gastroenterology, urology, gynaecology, specialist nursing, nutrition) [6]. The initial assessment includes a complete dermatological examination (fragility, blisters, photosensitivity, SCC risk), ophthalmology, dentistry with attention to the periodontium, gastroenterology with nutritional assessment, urology in men (urethral or preputial stenosis) and gynaecology in women (vaginal or labial stenosis), genetic counselling and family support [6].

None of the three medicines authorised for EB includes KEB in its indication, in the USA or the EU [9]. The EASE trial admitted patients with KEB and stratified JEB and KEB wounds together, but no patient with KEB was enrolled, so there are no efficacy data for birch bark extract in KEB [33]. In October 2026, ClinicalTrials.gov had no trials dedicated to KEB and no gene or cell therapies targeting FERMT1; a phase 2 trial of cannabinol cream (INM-755) admitted patients with KEB, with no results posted in the registry [181]. Kindlin-1-directed approaches are preclinical (chemical chaperones for hypomorphic variants), and a 2024 review of gene therapies for EB describes no programme for FERMT1 [66, 68, 182]. A negative registry search does not prove the absence of unregistered programmes.

8. Reproductive Options and Family Counselling

8.1. Principle: the genotype defines the inheritance

DEB may be dominant or recessive, and some COL7A1 variants are associated with both modes of inheritance [2]. Molecular characterisation of the COL7A1 variants is the only accurate method for determining inheritance and recurrence risk; the severity of the phenotype, TEM and IFM are not sufficient, because the variability of RDEB is extreme, a mild phenotype without a family history may be dominant or recessive, and some very mild RDEB mimics DDEB [2]. The description of several patients compound heterozygous for a dominant and a recessive allele calls for caution when predicting risk from the parents' phenotype [2]. The Brazilian Guidelines and DEBRA International recommend testing the parents whenever possible to provide reliable counselling, and recurrence is possible even when the calculated risk is very low [10, 19].

8.2. Dominant DEB

About 70% of patients with DDEB have an affected parent, and about 30% may have a de novo variant, a figure subject to ascertainment bias [2, 51]. A proband may appear isolated because the disease is not recognised in relatives (for example, isolated nail dystrophy) or because of reduced penetrance; a variant is considered de novo only if neither parent carries it [2]. If the variant is not found in the parents, with paternity and maternity confirmed, the explanation is a de novo variant or gonadal (or somatic and gonadal) mosaicism in a parent; maternal germline mosaicism has been described, leucocyte DNA may not detect somatic mosaicism and does not detect gonadal mosaicism, and a mosaic parent may have a mild form [2, 55]. The risk to siblings is 50% if a parent is affected or heterozygous, with intrafamilial variability and reduced penetrance; if the variant is not present in the parents' leucocyte DNA, the risk is slightly higher than that of the population because of gonadal mosaicism [2]. The Brazilian Síndromes Genéticas textbook describes this risk as negligible when the parents are not affected, but GeneReviews qualifies it as slightly higher than that of the population [2, 103]. Each child of a patient has a 50% risk of inheriting the variant [2]. In DDEB, prenatal testing is often not requested because it is not a life-limiting form, and vaginal delivery remains preferred even when an affected baby is expected [79].

8.3. Recessive DEB

The parents of a patient are presumed to be heterozygous and should both be tested [2]. If the variant is present in only one parent, the other may be de novo in the proband or result from a postzygotic event in a mosaic parent [2]. Apparent homozygosity should raise the possibility of a deletion of one or more exons not detected by sequencing (false homozygosity) or uniparental isodisomy, described for maternal chromosome 3 [2, 97]. The siblings of a patient have a 25% risk of being affected, 50% of being heterozygous and 25% of not being carriers [2, 103]. Heterozygosity for a null variant does not cause DEB, and these carriers are not at risk; heterozygosity for a glycine substitution in the Gly-X-Y domain may or may not cause DEB, with variation even within the family, and in some families carriers have isolated nail dystrophy [2, 4, 49]. The children of a patient are obligate heterozygotes, and the parents' siblings have a 50% risk of being carriers [2]. The estimated carrier frequency for RDEB in the USA is 1 in 370 [2, 21]. The pregnancy guideline recommends considering carrier screening of the unaffected, non-consanguineous partner [79]. Consanguineous marriages are frequent in families with RDEB [103].

8.4. Kindler EB

Inheritance is autosomal recessive, and the parents of a patient are obligate heterozygotes; parental testing confirms the status and allows recurrence to be assessed [6]. If the variant is present in only one parent, a de novo variant, a postzygotic event in a mosaic parent or uniparental isodisomy is considered [6]. Heterozygotes are asymptomatic and not at risk of disease. Siblings have a 25% risk of being affected, 50% of being carriers and 25% of not being carriers; the children of a patient are obligate carriers, unless the partner is affected or a carrier, in which case 50% are affected [6]. As KEB is more frequent in populations with high consanguinity, the probability that the partner is a carrier is greater, and FERMT1 testing of the partner is appropriate especially when there is consanguinity [6, 64, 183]. The parents' siblings have a 50% risk of being carriers [6]. In practice, homozygosity in a patient whose parents have not been tested does not exclude a large deletion in compound heterozygosity, as in the case in section 10.2 [60].

8.5. Cascade testing and at-risk relatives

Molecular testing of at-risk relatives should be offered for early diagnosis and intervention, especially for the prevention of skin trauma [2]. The at-risk newborn should be assessed for blisters from birth, and, given the clinical variability of DDEB, the status of apparently asymptomatic relatives, older and younger, should be clarified by testing for the familial variants [2]. Detection of heterozygotes requires that the familial variants have been identified [2, 6].

8.6. Prenatal and preimplantation diagnosis and minors

DNA-based prenatal diagnosis and PGT are possible once the familial variants have been identified, at the family's request and in accordance with national law [2, 10, 34]. The ideal time to discuss risk and options is before pregnancy, and counselling should be offered to young adults who are affected, carriers or at risk [2, 6]. Professionals and families may have different perspectives on the use of prenatal diagnosis, and the decision is personal [2]. Communication of the diagnosis in the newborn is made to both parents, by a dermatologist, neonatologist or paediatrician and a geneticist, with psychological support, and explanations may need to be repeated [34, 56]. Testing of a newborn or child at risk of having the disease is justified by the benefit of preventing skin trauma [2]; the sources consulted do not specifically address carrier testing in asymptomatic minors. In England and Wales, births of children with severe RDEB decreased over 19 years, which the authors attribute to uptake of genetic counselling [23].

The French PNDS points out that the molecular result is not a prerequisite for the genetic counselling appointment, which may be offered to the patient, the parental couple and relatives, and in which the modes of transmission, the usefulness of molecular analysis, the legal rules and the modalities of prenatal and preimplantation diagnosis are discussed [36]. In France, prenatal and preimplantation diagnosis is performed at the molecular genetics laboratory of the Hôpital Necker-Enfants Malades, and the CHU de Nice announced prenatal diagnosis from 2022 [36].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each figure measures

Estimates of the frequency of DEB vary with registry recruitment and case definition, and values per live births (incidence or birth prevalence) are not comparable with point prevalence in the population [1, 7].

Sources: GeneReviews, NEBR, 2020 consensus, Eichstadt 2019, Orphanet, Petrof 2022, Has 2023 and Baardman 2021 [1, 2, 11, 16, 20, 22–24, 52].

GeneReviews calls the NEBR values expressed per million live births «prevalence» [2]. The values in the Brazilian Síndromes Genéticas textbook for the USA («11:1,000» for all EB, «3:1,000» for DEB) contain a unit error and correspond to values per million; the same source cites for the United Kingdom an overall EB frequency of 1 in 17,000 live births, with 25% DEB [2, 103]. The allele frequency model estimating 95 cases of RDEB per million live births was funded by a company with a product for RDEB and is a modelled estimate, not an observed prevalence [52]. DEB accounts for about a quarter of all EB, and DDEB and RDEB have similar frequencies despite very different severities, so the frequency of a subtype cannot be used to infer the inheritance in a patient [7]. The French PNDS estimates the prevalence of all inherited EB at 5–20 cases per million inhabitants, values it considers imprecise and variable between countries, and presents no French data of its own [36]. For KEB there is no validated population prevalence: the figures of 250 cases (2020) and of about 400 patients with biallelic variants (2022) are cumulative counts of published cases [1, 6]. In the Dutch registry, 2 of the 4 patients with KEB included in the calculation had no variant identified [22].

9.2. Ancestry and founder populations

In RDEB, c.6527dup is the most frequent variant in Spain and Chile, c.325_326insCG prevails in patients of South American ancestry and c.7957G>A in Argentina (section 2.4) [2, 10, 53]. In KEB, there are clusters of 26 Ngöbe-Buglé patients from isolated rural villages in Panama and of 24 Iranian patients, and founder effects in Pakistan, the United Kingdom, Italy, Oman and Paraguay; the disease is more common in isolated or consanguineous populations [1, 57, 64, 65, 183]. In a Chinese series of 13 patients with KEB, consanguinity was present in 41.67% and a family history in 23.08% [184]. In the pivotal trials, most patients were white (65% in GEM-3; 91% in VIITAL; 83% in EASE), with 19% Asian patients and 16% American Indian or Alaska Native patients in GEM-3, which limits the representation of other populations [28, 30, 32].

9.3. Portugal and Brazil

The sources consulted include no epidemiological data on DEB or KEB in Portugal; DEBRA International did not list, when consulted in October 2026, a Portuguese national group, and Portugal was one of the countries participating in the international phase 3 trial with ABCB5+ stromal cells [146]. In Brazil, the 2021 Brazilian Guidelines state that there are no epidemiological data on the frequency of EB in the country and use international values (prevalence of about 11 per million inhabitants and incidence of about 20 per million live births for all inherited EB) [19, 103]. The National Policy for Comprehensive Care of People with Rare Diseases (Ordinance GM/MS No. 199/2014) structures care between primary care and specialised and reference services for rare diseases, with about 50 university hospitals as the main place of care [19]. DEBRA Brasil maintains a national registry and a free sequencing programme. The sources do not identify the status of the three targeted therapies with ANVISA or within the SUS. A Brazilian review of EB provides no data on patients with KEB [58].

9.4. Special populations

Infants under 6 months are not covered by the indication for birch bark extract, and beremagene geperpavec had been studied in only 2 infants aged 6 and 7 months before the extension to all ages [28, 30]. There are no patients aged 65 years or over in the trials of the targeted therapies [28, 32]. Patients with current or previous SCC at the site were excluded from VIITAL [32]. Adolescence is associated with lower adherence and more complications, and pregnancy requires multidisciplinary planning (section 7.11) [56, 79]. In low-resource settings, advanced dressings may be replaced by paraffin gauze changed daily, and hospitals without access to EB specialists should contact a reference centre [34, 92]. In Japan, DEB is classified as an intractable disease by the Ministry of Health [124].

9.5. Reference networks and patient organisations

ERN-Skin (https://ern-skin.eu) brings together the European reference centres for rare skin diseases, is the author of the emergency recommendations and the practical position on EB, and lists EB diagnostic laboratories in Austria, Czechia, France, Germany, Hungary, Italy, Poland, Romania, the Netherlands and the United Kingdom [34, 35]. DEBRA International (https://www.debra-international.org) publishes the clinical practice guidelines and patient versions, the emergency card and the directory of national groups, which includes DEBRA Brasil (https://debrabrasil.com.br) [34, 35]. Other resources are DEBRA UK, DEBRA of America (with its own page on KEB), DebRA Chile, the EB Research Partnership, the EB Medical Research Foundation, the DEB Register (international registry of patients with DEB and COL7A1 variants) and the EBCare Registry [2, 6, 185].

Organisation in France. The reference and competence centres for inherited EB belong to the group of centres for rare dermatological diseases of genetic origin and to the FIMARAD network (https://fimarad.org), which coordinated the 2021 PNDS with validation by the DEBRA France association (https://www.debra.fr), a member of DEBRA International [36]. The reference centres are MAGEC (multisite centre of the Assistance Publique–Hôpitaux de Paris, Necker-Enfants Malades and Saint-Louis hospitals; accredited in 2004), the reference centre for inherited EB of the CHU de Nice (2007) and the rare skin diseases centre of Bordeaux-Toulouse (2005), supplemented by competence centres; the PNDS notes the lack of dedicated funding for these centres, where the skin assessment, with bathing and redressing, takes 2–4 hours, and the use of local hospitals for blood tests (with EMONO in children), IV iron or transfusions [36]. The PNDS is accompanied by a list of procedures and services that serves as a reference for the chronic disease care protocol (long-term condition, ALD, with exemption from co-payments) and for exceptional coverage, by agreement between the centre and the rare diseases service of the National Health Insurance Fund, of procedures not otherwise covered (for example, haemodialysis); it includes devices such as TheraBite® (maintenance of mouth opening), equipment for amblyopia, hair prostheses for scarring alopecia, orthoses, wheelchairs, a shower chair or adapted bath, a medical bed and mattress, and adaptations of the home and daily life (electric shutters, sliding doors, ramps, a spacious bathroom, humidifier, air conditioning of the home and vehicle, lift, adapted vehicle) [36].

Social support begins at diagnosis, with the opening of entitlements (ALD, a file at the Departmental Office for People with Disabilities, MDPH) and benefits: the education allowance for a child with a disability (AEEH, up to 20 years of age, with supplements according to severity), the disability compensation benefit (PCH; human and technical assistance, home adaptation up to 10,000 euros over 10 years, transport and specific aids, without means testing), the mobility inclusion card (parking, priority, disability) and, for parents, parental presence leave and daily allowance (AJPP, up to 310 working days over 3 years per child) [36]. Schooling, compulsory at the local reference school under the law of 11 February 2005, is prepared about six months before entry, with an individualised reception plan (PAI; for example, two sets of books, adapted footwear) and, when this is not enough, a personalised schooling plan through the MDPH, with a support worker for pupils with disabilities (AESH, who does not provide care), a special education and home care service (SESSAD), adapted school transport and educational support at home or in hospital (APADHE) for absences of 2–3 weeks; vocational guidance is addressed from collège (lower secondary school, from 11 years of age) [36]. The PNDS identifies as gaps the low remuneration for EB dressings, which deters independent nurses, the scarcity of long-term care facilities and unreimbursed expenses (dressings and products, clothing, transport, reduced working hours), and recommends home parenting support (social and family intervention workers) and respite solutions for carers [36].

10. Illustrative Clinical Case

10.1. Severe RDEB treated with beremagene geperpavec outside trials

Brena, Guez and Lospalluti described in 2026, following the CARE guidelines, three patients with severe RDEB treated with beremagene geperpavec at two Italian centres (Policlinics of Milan and Bari) between 2024 and 2026, through the early access programme of the AIFA 5% fund; selection also depended on the ability to travel to hospital weekly [54]. The dose was 1.6 mL (3.2×10⁹ PFU) per week on previously cleansed target wounds, with a protective dressing for about 24 hours [54].

The first case is that of an 11-year-old girl, compound heterozygous for COL7A1 (NM_000094.4) c.7157G>A p.(Gly2386Asp) and c.1041G>A p.(Trp347Ter), with about 60% of the body surface involved, dorsal wounds since the first month of life and about 40% of wounds older than 6 weeks, bleeding and colonisation by multidrug-resistant bacteria [54]. She had multifactorial anaemia treated with oral and IV iron and periodic transfusions, and used tranexamic acid and vitamin K for bleeding. She started treatment in May 2024, applied by a dermatologist in a day hospital; at 16 months, the upper dorsal target wound had reduced in area by 70% and was more superficial, with less exudate and inflammation, without complete closure; the treated area was extended while keeping the weekly dose, the use of tranexamic acid decreased, transfusion requirements did not change and there were no adverse effects [54]. In the current ClinVar classification, c.7157G>A is a variant of uncertain significance with a single submitter (section 2.3).

The second case, a 15-year-old boy with c.220del p.(Ala74HisfsTer30) and c.497dup p.(Val168GlyfsTer12), had about 60% of the body surface involved (40% with chronic wounds) and pseudosyndactyly of the hands and feet; at 12 and 16 months of treatment the target wound had reduced by 50%, with reopening of small wounds and only mild pruritus [54]. The third, a 25-year-old man with c.8075del (described as c.8074delG) p.(Gly2692AlafsTer94) and c.8505dup p.(Val2836ArgfsTer13), with more than 50 wounds and about 70% of the surface involved, had taken part in GEM-3 and the extension in the USA until October 2023, with healing of more than 60% of chronic wounds and wounds on the back closed since then [54]. He restarted treatment in Italy in October 2024 on the lower limbs; a wound on the posterior aspect of the right thigh, subject to pressure from the wheelchair, reopened three times and quickly re-epithelialised after each cycle; after 24 applications, the wounds were superficial, without signs of SCC, without procedural pain and with less time spent on dressings; treatment was interrupted from April to October 2025 because the medicine was unavailable and resumed afterwards [54].

Figure 1 of the article shows the dorsal wounds of cases 1 and 2 before treatment and at 12 and 16 months, and case 3 before, at 6 months and 15 months after discontinuation (https://pmc.ncbi.nlm.nih.gov/articles/PMC13456074/figure/f1-dic-2026-2-4/); Figure 2 shows the cycle of reopening and healing of the right thigh between October 2024 and April 2025 (https://pmc.ncbi.nlm.nih.gov/articles/PMC13456074/figure/f2-dic-2026-2-4/) [54]. The authors stress that the responses were more variable and smaller than in the trials, in wounds more than a decade old, with fibrosis and inflammation, and that inflammatory markers, anaemia, transfusions and the dressing routine did not change relevantly; cleansing was with saline and mild antiseptics (acetic acid), and 0.005% dilute bleach required rinsing before application [54]. The weekly hospital application in this report corresponds to an early access programme and not to the routine foreseen in the current labels, which allow home application; the target wound, not the patient, was the unit of assessment; and two of the authors declared relationships with the marketing authorisation holders of the therapies [29, 54, 109].

10.2. Kindler EB with carcinoma of the buccal mucosa

Akasaka, Nakano and Sawamura published in 2022 the case of a Japanese woman first seen at 24 years of age, in 1983, the second daughter of healthy non-consanguineous parents and without a family history, with traumatic blisters on the extremities from birth that stopped at 12 years, followed by progressive photosensitivity and atrophy [60]. At that time she had atrophy with depigmented patches on the abdomen, mottled pigmentation on the chest, labial erosions and scars, gingival atrophy with periodontitis and mild palmar hyperkeratosis; the diagnosis was purely clinical, because the gene was not yet known, and follow-up was interrupted [60]. Thirty-seven years later, at 61 years, she was admitted to oral surgery for chemoradiotherapy of a carcinoma of the left buccal mucosa; she had poikiloderma and cigarette-paper skin on the dorsa of the hands and feet, partial pseudosyndactyly with interdigital webs, mottled pigmentation on the back and mild diffuse plantar hyperkeratosis; she had lost all her teeth in the fourth decade and there were labial ulcers, atrophy of the oral mucosa and a white ulcerated tumour on the left buccal mucosa [60]. Biopsy of the dorsum of the hand showed a flattened epidermis, vacuolar change and dilated capillaries in the papillary dermis, and TEM showed duplication of the lamina densa and separation within basal keratinocytes and along the lamina lucida; FERMT1 sequencing identified c.1761T>A p.(Tyr587Ter) in the homozygous state [60]. The parents were not tested, so homozygosity for three neighbouring polymorphisms does not exclude a large deletion on the other allele [60]. The legends of Figures 1 to 3 (appearance in 1983, appearance at 61 years, histology, TEM and electropherogram) were consulted in the full text of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC9263402/). The case illustrates loss to follow-up in a form in which blistering improves in adolescence, the progression of poikiloderma and fibrosis with age, early tooth loss and oral SCC in the sixth decade, in agreement with the recommendation of intraoral screening from the fourth decade and lifelong surveillance [26, 60, 73].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The prognosis depends on the subtype. Patients with localised non-syndromic forms have a normal life expectancy, although with an impact on quality of life; severe RDEB is accompanied by multiple complications (sepsis, growth failure, severe anaemia, cancer) and reduced life expectancy [34]. In severe RDEB, metastatic SCC is the main cause of death: in the NEBR, the cumulative risk of death from SCC was 38.7% at 35 years, 70.0% at 45 and 78.7% at 55 years; in London, median survival after the first SCC was 2.4 years, and in the Dutch registry the median age at death was 37.5 years, versus more than 57.3 years in the other subtypes [25, 81, 82]. Other causes of death include dilated cardiomyopathy, renal failure, sepsis and malnutrition [2, 35, 56]. In intermediate DDEB, the disease tends to become less severe in adulthood and other organs are generally spared, although nail dystrophy and scarring persist [2]. In KEB, morbidity and mortality result from mucosal strictures, infections and SCC; in the series of 91 patients, 5 of 13 with SCC died of the tumour 2 to 7 years later, and in the Dutch registry one patient died at 67.7 years of an unknown cause [6, 22, 26]. Topical targeted therapies accelerate healing of the treated wounds, but there are no data showing an effect on survival, SCC or systemic complications (section 3.8).

11.2. Surveillance in DEB

11.3. Surveillance in Kindler EB

The French PNDS (2021) aligns oncological follow-up in KEB with that in RDEB, with particular surveillance of the mucous membranes, and provides for KEB the same frequency of multidisciplinary consultations as for RDEB [36]. GeneReviews (2022) recommends annual skin screening from adolescence, and the SCC guideline (2016) places KEB in the lower-risk groups, with screening from 20 years of age every 6–12 months [6, 39]. The Guerrero-Aspizua series (first SCC at 29 years; isolated cases at 16, 23 and 27 years; 14 of 22 patients with the first SCC between 40 and 59 years) supports lifelong surveillance that becomes more attentive with age, precisely when blisters are less evident and surveillance tends to slacken [26].

11.4. Follow-up after targeted treatment

Patients treated with beremagene geperpavec in the EU should be included in a multinational non-interventional long-term safety study, and wounds with suspected or confirmed SCC are not treated with the gel [29]. After prademagene zamikeracel, surveillance for neoplasms is lifelong [32]. With birch bark extract, treatment is suspended in the area of an SCC or other skin neoplasm, and the FOSteR study follows the incidence of neoplasms [31, 116]. Treated wounds may reopen: in the GEM-3 open-label extension, only 7 of 19 primary wounds remained closed throughout the study, and the others responded again to retreatment [89].

12. Summary and Final Considerations

DEB is a COL7A1 disorder in which the amount and function of residual collagen VII determine a spectrum ranging from isolated dominant nail dystrophy to severe RDEB, with mutilating scarring, oesophageal strictures, malnutrition, anaemia, osteoporosis, cardiomyopathy, glomerulonephritis and aggressive SCC. The 2020 classification describes the dominant subtypes (intermediate, localised, pruriginosa, self-improving), the recessive subtypes (severe, intermediate, inversa, localised, pruriginosa, self-improving) and the severe form due to compound heterozygosity, and recognises Kindler EB as the fourth classical type. In DEB, diagnosis rests on genetic testing, in the index case and the parents, because only the genotype defines inheritance, recurrence risk and access to topical gene therapy; IFM gives the rapid answer the newborn needs, and TEM is kept for inconclusive cases. The detection rates of the methods are proportions of known variants, and a negative test does not exclude the disease, especially in KEB, in which deep intronic variants and phenocopies due to CD151, USB1 and PLCG2 are known.

Treatment remains mainly supportive and preventive, organised in reference centres: shear-free handling from birth, non-adherent dressings without adhesives, control of colonisation, high-calorie nutrition with gastrostomy when necessary, IV iron and transfusion at defined thresholds, fluoroscopy-guided balloon oesophageal dilatation, hand surgery with expected recurrence, stepwise analgesia and intensive oncological surveillance from 9–10 years of age in severe RDEB. Since 2022 there have been three wound-directed therapies: birch bark extract (EU 2022, USA 2023), beremagene geperpavec (USA 2023, EU 2025, Japan 2025, extended in 2025 to all ages and to home application) and prademagene zamikeracel (USA 2025). The trials showed healing of selected wounds, but no effects on SCC, anaemia, strictures or survival, and cost and availability limit access, with no data in the sources consulted on Portugal and Brazil.

In Kindler EB, blistering improves in adolescence while poikiloderma, mucosal fibrosis, periodontitis and the risk of SCC of the hands and mouth increase with age; there are no authorised medicines for this form, and photoprotection, early periodontal care, dilatation of strictures and lifelong oncological surveillance are the basis of care. The 2021 French PNDS converges with the international guidelines and adds a follow-up schedule by EB type, a contact lens protocol with azithromycin for corneal lesions and a description of the French network of centres and social entitlements; it diverges on specific points (role of immunohistochemistry in diagnosis, interval and start of oncological surveillance in KEB, SCC excision margin, first dental appointment). In all forms, genetic counselling based on the familial genotype, prenatal or preimplantation diagnosis when desired and lifelong psychosocial support are part of treatment.

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