| Type, inheritance, gene, product | Cutaneous symptoms | Mucosal involvement | Nails and hair symptoms | Extracutaneous manifestations |
| Localized DDEB
(previously encompassing nails only, pretibial, and acral DDEB) AD COL7A1
(monoallelic missense, splice-site mutations with in-frame exon skipping; deletion mutations within triple helical domain) Type VII collagen | - Predominantly acral or pretibial skin fragility, usually from birth or early childhood (acral) or later childhood/adulthood (pretibial)
- Risk of cutaneous SCC
- EB nevi may occur
| | - Nails only variants with progressive dystrophy and loss (toenails)
| |
| Intermediate DDEB
(previously known as generalized DDEB) AD COL7A1
(monoallelic missense, splice-site, or deletion mutations; somatic mosaicism for a dominant glycine substitution mutation) Type VII collagen | - Generalized skin fragility, scarring, and milia from birth or early childhood, predilection for bony prominences (elbows, knees, ankles, and dorsa of the hands and feet)
- Increased risk of cutaneous SCC
- EB nevi may occur
| - Oral mucosa
- Oesophageal blistering
- Recurrent blistering and fissuring around anal margin, exacerbating constipation
- Involvement of the conjunctiva and cornea (corneal erosions, scarring, pannus, symblepharon formation, reduced visual acuity)
- Urethral strictures
| - Nail dystrophy and loss secondary to trauma
| - Nutritional impairment due to reduced intake (microstomia, dental caries, oesophageal stricture disease) in combination with increased metabolic demands because of chronic wounds, infection, inflammation
- Constipation (anal fissuring and blistering, exacerbated by poor intake of fiber-rich foods)
|
| Intermediate RDEB
(previously known as RDEB generalized intermediate, non-Hallopeau-Siemens RDEB) AR COL7A1
(biallelic missense, nonsense, deletion, insertion, small insertion/deletion, or splice-site mutations with compound heterozygosity for a loss-of-function mutation on one COL7A1 allele and a non-loss-of-function mutation on the second allele; revertant mosaicism [somatic mutation and intragenic crossover] and forward nonrevertant mosaicism [germline frameshift mutation and somatic splice-site mutation]) Type VII collagen | - Generalized skin fragility, scarring, and milia from birth or early childhood, predilection for bony prominences
- Mutilating deformities generally missing, mild flexion contractures of fingers and limited digital fusion in proximal digital web spaces possible
- Striate pattern of keratoderma
- Increased risk of cutaneous SCC
- EB nevi may occur
| - Oral mucosa
- Oesophageal blistering
- Recurrent blistering and fissuring around anal margin, exacerbating constipation
- Involvement of the conjunctiva and cornea
- Urethral strictures
| - Nail dystrophy and loss secondary to trauma
| - Nutritional impairment, growth retardation
- Anemia (iron deficiency, inflammation)
- Constipation (anal fissuring and blistering, exacerbated by poor intake of fiber-rich foods)
|
| Severe RDEB
(previously RDEB generalized severe, Hallopeau-Siemens RDEB) AR COL7A1
(biallelic nonsense, splice-site, deletion, insertion, small insertion/deletion, or missense mutations with homozygosity or compound heterozygosity, usually resulting in null alleles; revertant mosaicism [somatic mutation, intragenic crossover] and forward nonrevertant mosaicism with germline frameshift mutation and somatic splice-site mutation reported) Type VII collagen | - Widespread skin blistering from birth; from infancy, blistering is more marked over bony prominences
- Extensive scarring and flexion contractures of large joints and mitten deformities of hands and feet due to progressive pseudosyndactyly (digital fusion), flexion contractures, and distal resorption of digits; milia formation
- Congenital skin ulceration (uni- or bilateral, especially dorsomedial foot, ankle, medial lower leg)
- High risk for aggressive cutaneous SCC commonly arising in areas of repeated trauma, chronic wounds, and scarring from teen years onwards
- EB nevi may occur
| - Oral mucosa: microstomia, ankyloglossia; dental overcrowding, malalignment; secondary caries due to progressive scarring
- Oesophageal blistering, strictures limiting oral nutritional intake
- Protein-losing enteropathy
- Recurrent blistering and fissuring around anal margin, exacerbating constipation
- Involvement of conjunctiva and cornea
- Urethral strictures
| - Nail dystrophy and loss secondary to trauma during the first several years of life
- Scarring alopecia and crusting are common with increasing age
| - Nutritional impairment common, impaired growth, delayed puberty
- Constipation (anal fissuring and blistering, exacerbated by poor intake of fiber-rich foods)
- Anemia (iron deficiency, inflammation)
- Osteopenia, osteoporosis vertebral fractures (reduced mobility, chronic inflammation, vitamin D and calcium deficiency, pubertal delay)
- Renal impairment and failure (acute kidney injury, poststreptococcal glomerulonephritis, renal amyloid, or IgA nephropathy)
- Cardiomyopathy (micronutrient deficiency, iron overload, drugs, viral causes)
|
| DDEB, pruriginosa and RDEB, pruriginosa AD or AR COL7A1 (monoallelic or biallelic mutations; no specific genotype-phenotype correlation) Type VII collagen | - Presents initially as localized or intermediate DDEB or RDEB in childhood and early adulthood; characterized by intensely pruritic, excoriated, violaceous papules or linear plaques and scars, particularly on lower legs, thighs, arms; may become progressive with spreading more proximally and onto arms from adolescence through adulthood; may coexist with nonpruriginosa DEB within families
- Milia common
| | | |
| DDEB, self-improving and RDEB, self-improving
(also known as bullous dermolysis of the newborn) AD or AR COL7A1
(missense, in-frame deletion, premature termination codon, and alternative splicing mutations; self-improving associated with in-frame skipping of exons or with specific glycine substitutions) Type VII collagen Characteristic intraepidermal retention of type VII collagen on immunohistochemistry and stellate bodies in dilated, rough endoplasmic reticulum on transmission electron microscopy | - Skin blistering presents at or shortly after birth, usually on extremities, with scarring and milia formation; skin fragility improves spontaneously and may resolve completely over first year or two of life
- Aplasia cutis of the lower limbs may be present
| | - Nail dystrophy may persist throughout life
| |
| RDEB inversa AR COL7A1
(compound heterozygosity for loss-of-function and missense mutation; specific glycine and arginine substitution mutations may affect thermostability of type VII collagen) Type VII collagen | - Generalized skin blistering of intermediate severity in neonatal period and childhood; predilection for flexural sites (axillae, groins, perianal area, natal cleft) develops from adolescence to early adulthood
- Marked vulvovaginal and inframammary skin blistering in women
| | | - External auditory canal with narrowing or complete occlusion
|
| RDEB, localized AR Compound heterozygosity for COL7A1 missense, splice-site, and frameshift mutations Type VII collagen | - Skin fragility at or shortly after birth, rarely late onset in adulthood
- Limited blistering, predominantly of hands and feet or pretibial area
| - Oral and esophageal mucosal involvement mild or absent
| | |
| Dominant and recessive compound heterozygous DEB AD and AR COL7A1
(compound heterozygosity for a dominant glycine substitution mutation and a recessive mutation on second allele) Type VII collagen | - Severe skin fragility presenting from birth, indistinguishable from severe RDEB
| - Severe mucosal fragility presenting from birth, indistinguishable from severe RDEB
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