| Type, inheritance, gene, product | Cutaneous symptoms | Mucosal involvement | Nails and hair symptoms | Extracutaneous manifestations |
| Intermediate JEB
(previously JEB generalized intermediate, non-Herlitz JEB) AR LAMA3, LAMB3, LAMC2
(biallelic missense, nonsense, frameshift, or splice-site [non-loss-of-function] pathogenic variants) COL17A1
(biallelic missense, nonsense, frameshift, or splice-site pathogenic variants; revertant mosaicism) Laminin-alpha-3 chain of laminin-332 Laminin-beta-3 chain of laminin-332 Laminin-gamma-2 chain of laminin-332 Type XVII collagen | - Generalized blistering from birth or shortly afterwards; rupture with erosions, usually without tendency for developing chronic granulation tissue; healing with atrophic scarring, milia formation, and variable hypo- or hyperpigmentation
- Areas of ulcerated skin may be present at birth (lower limbs, dorsa of feet and ankles)
- Development of cutaneous squamous cell carcinoma can occur in adulthood
- EB nevi may occur
| - Involvement of oral mucosa
- Corneal blistering, erosions, pannus formation, scarring, symblepharon
- Involvement of gastrointestinal, respiratory, and genitourinary tract (urethral stricture disease)
| - Nails usually lost or dystrophic with atrophy, thickening or ridging of nail plate
- Scarring or nonscarring alopecia and diffuse hair loss
| - Anemia
- Growth retardation
- Protein-losing enteropathy, diarrhea
- Dental enamel defects, caries
|
| Severe JEB
(previously JEB generalized severe, Herlitz JEB) AR LAMA3, LAMB3, or LAMC2
(biallelic loss of function with nonsense, frameshift, or splice-site pathogenic variants) COL17A1
(rarely) Laminin-alpha-3 chain of laminin-332 Laminin-beta-3 chain of laminin-332 Laminin-gamma-2 chain of laminin-332 Type XVII collagen | - Blistering from birth or shortly afterwards (buttocks, elbows, around nails), may be initially clinically mild; then, generalized, recurrent, often persistent blistering, erosions, and crusting covering not only particularly exposed skin areas (like palms and soles) but most or almost all of the body surface, develop from the first few weeks to months of age; blisters tend to rupture with extensive erosions; chronic wounds with bed of friable granulation tissue (periorificial, face, ears, distal digits; gluteal) develop over first months of life; healing with atrophic scarring and variable hypo- or hyperpigmentation
- Areas of ulcerated skin may be present at birth (lower limbs, dorsa of feet and ankles)
| - Involvement of oral and laryngeal mucosa (hoarseness, stridor, airway obstruction due to blistering, granulation tissue, scarring)
- Corneal blistering and erosions, pannus formation, scarring, symblepharon
- Involvement of gastrointestinal (protein-losing enteropathy, diarrhea) and genitourinary tract
| - Onychodystrophy and loss of all nails in first few months of life; development of friable granulation tissue and soft tissue swelling (periungual inflammation) of distal digits
- Scarring or nonscarring alopecia and diffuse hair loss
| - Profound failure to thrive
- Anemia common
- Dental enamel defects
- Death in the first 24 months due to failure to thrive, airway involvement, or sepsis
|
| JEB with pyloric atresia AR ITGA6
(biallelic loss-of-function, splice-site, or missense pathogenic variants result in severe and rapidly lethal phenotype) ITGB4
(biallelic loss-of-function or splice-site pathogenic variants result in loss of beta-4 integrin with severe and rapidly lethal phenotype; biallelic loss-of-function, missense, splice-site, or in-frame deletion mutations in ITGB4 that result in reduced beta-4 integrin expression result in milder form; biallelic mutations in ITGB4 may also result in JEB without pyloric atresia) Integrin alpha-6 beta-4 | - Gestational hydramnios
- Full thickness skin loss over extensive areas of the head, trunk, and limbs at birth, may cause deformities of ear/nose; subsequent severe skin fragility, atrophic scarring
| - Genitourinary tract involvement in milder, nonlethal forms with less severe skin and nail involvement
| | - Pyloric atresia evident within the first days to week of life; atresia at other gastrointestinal sites (eg, duodenal or anal) may be present
- Usually lethal within the first few weeks
|
| JEB localized AR Homozygous or compound heterozygous pathogenic variants in COL17A1, LAMA3, LAMB3, LAMC2, ITGB4, ITGA3
Type XVII collagen
Integrin beta-4
Laminin-alpha-3 chain of laminin-332
Laminin-beta-3 chain of laminin-332
Laminin-gamma-2 chain of laminin-332
Integrin alpha-3 subunit | - Limited cutaneous fragility and blistering, often only acral
| | - Variable nail dystrophy
- Normal hair
| - Variable dental enamel defects
|
| JEB inversa AR Pathogenic variants associated with residual expression of laminin 332 | - Onset of blistering at birth in flexural sites (overall extent exceeding that observed in localized JEB), atrophic scarring, milia, hypopigmentation, hyperpigmentation
| | | - Dental enamel abnormalities
|
| JEB late onset AR Biallelic pathogenic variants in COL17A1
Type XVII collagen | - Onset of skin fragility in childhood often starting acrally; progressive fragility with age; healing with skin atrophy and loss of dermatoglyphs; flexion contractures of fingers and reduction of mouth opening due to scarring occur with age
| | - Variable nail involvement
| - Variable enamel involvement
|
| JEB-LOC syndrome
(Shabbir syndrome) AR LAMA3A
(homozygous founder single nucleotide insertion mutation in exon 39 of LAMA3 specific to LAMA3A isoform; compound heterozygosity for mutations in LAMA3A and LAMA3 result in similar phenotype) Laminin-alpha-3a chain of laminin-332 | - High incidence in Punjab but Caucasian cases reported
- Onset of skin fragility at birth, blistered areas leaving erosions and prominent granulation tissue (much more than in severe JEB), with delayed healing, atrophic scarring, bleeding and anemia; predilection for face and neck
| - Conjunctival and eyelid granulation tissue leading to symblepharon, scarring, and impaired vision
- Laryngeal granulation tissue (altered cry) leading to respiratory obstruction that can be lethal
| - Nail dystrophy and loss with granulation tissue of nail beds
| - Profound anemia due to bleeding from over granulating wounds
- Enamel defects
|
| JEB with interstitial lung disease and nephrotic syndrome
(also known as ILNEB) AR ITGA3
(homozygous loss-of-function pathogenic variants; missense mutations in milder cases surviving to later childhood) Integrin alpha-3 | - Variable cutaneous features with absence or presence of skin fragility from infancy
| | - Nails may be dystrophic
- Hair may be sparse
| - Interstitial lung disease (tachypnea, respiratory distress, cyanosis in first days of life; secondary aspiration with respiratory tract infections) soon after birth
- Nephrotic syndrome/CAKUT (small kidneys, atrophic glomeruli, focal segmental glomerulosclerosis, diffuse interstitial fibrosis, tubular atrophy and loss) soon after birth
- Death in infancy or early childhood
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