Epidermolysis Bullosa Recessive Dystrophic


Disease group Epithelial adhesion disorders
Synonymous None
Estimated prevalence 1.35/1.000.000
OMIM 226600
Inheritance Autosomal recessive
Gene (s) COL7A1 (120120)


Epidermolysis bullosa (EB) is a genetic skin blistering disease, where blisters and skin erosions form in response to (minor) injury, friction or spontaneous. Four major types are recognized: EB simplex, EB junctional, EB dystrophic and Kindler EB.

Recessive dystrophic Epidermolysis bullosa (RDEB) is the most severe type of dystrophic EB and is subdivided into further six subtypes with severe RDEB (RDEB-sev), being the most severe form of DEB (Table 1). All forms of RDEB are caused by mutations in the COL7A1 gene (3p.21.31).1


Table 1: RDEB subtypes.



Typical clinical features

Severe RDEB

Type VII collagen

Generalized, profound skin fragility; extensive scarring, milia formation; flexion contractures of large joints, mitten deformities of hands, feet (pseudosyndactyly); aplasia cutis; high risk for aggressive cutaneous SCC; EB nevi; oral involvement (microstomia, ankyloglossia, caries); oesophageal blistering and strictures; enteropathy; urethral strictures; conjunctiva and corneal involvement; scarring alopecia; anaemia, delayed puberty; constipation, osteopenia/-porosis); renal impairement/failure; cardiomyopathy

Intermediate RDEB

Generalized skin fragility, scarring, milia formation; presentation at birth or early childhood; predilection for bony prominences; no mutilating deformities; occasionally mild flexion contractures of fingers and digital fusion in proximal web spaces; risk for cutaneous SCC elevated; EB nevi; striate keratoderma; involvement of oral mucosa and gastrointestinal tract; ocular symptoms; Urethral strictures; nail dystrophy; anaemia, constipation;

RDEB inversa

Neonatal/childhood period: generalized blistering (intermediate severity), predilection for flexural sites (axillae, groins, perianal area, natal cleft) emerges from adolescent on; mucosal involvement (oral, oesophageal), nail dystrophy, external auditory canal (narrowing, obstruction)

RDEB pruriginosa

Initially localized RDEB; in childhood/early adulthood intensely prurituc violaceous papules, plaques, scars develop on lower legs (thighs, arms); milia; variable mucosal involvement; nail dystrophy common;

RDEB self-improving (bullous dermolysis of the newborn)

Skin blistering at birth or shortly thereafter (particular on extremities), scarring, milia formation; skin fragility improves spontaneously until 2nd year of life. Variable mucosal involvement; nail dystrophy (often persists whole life)

RDEB localized


Manifests shortly after birth or rarely late onset in adulthood; skin fragility limited to hands, feet or pretibial area; mild or absent oral/esophageal involvement; nail dystrophy common



Clinical Description

In severe RDEB, the skin is extremely fragile and blistering starts at birth, both spontaneously and secondary to often minor mechanical forces. Large lesions typically arise on trauma-exposed sites or over bony prominences and heal with scarring and hypo- or hyperpigmentation. Milia, i.e. keratin-filled cysts resulting from keratin that has become trapped under the epidermis, are pathognomonic. Likewise, repeated blistering with excessive scarring of hands and feet is common, resulting in mitten deformities with complete fusion of all of the individual digits to a keratinaceous cocoon-like, scarred mass (pseudosyndaktyly), contractures and – subsequently – muscle atrophy, bone absorption and progressive disablement including wheelchair dependency.2

Mucous membranes (e.g. oral, esophageal, genitourinary, ocular) are also affected with erosions and scarring. Perianal disease leads to painful stools and constipation. Dystrophic teeth, restricted mouth opening and tongue mobility due to scarring promote severe caries, and, together with esophageal strictures and protein-losing enteropathy lead to reduced food intake and nutritional deficiencies. The risk for early development of highly aggressive squamous cell carcinomas (SCC) is dramatically increased and requires rigorous monitoring.3, 4

Involvement of the nail apparatus causes peri- or subungual blistering, hemorrhages and nail bed hyperkeratosis with onycholysis, onychomadesis, nail dystrophy and loss.3

EB nevi are a frequent phenomenon especially in severe RDEB. They develop most commonly as acquired melanocytic nevi in infancy or adolescenc as flat, black to brown pigmented lesions. Later in life, melanocytes may descent into the deeper dermal layers and consequently the nevi may loose their pigment.  EB nevi typically arise in sites of former lesions, often with a darker rim at the borders of the preceding vesiculation. They frequently show clinical, histological and dermoscopic features highly suggestive of melanoma, which may be attributable to histoarchitectural changes in the background of a micromilieu of chronic skin wounding and regeneration. Malignant transformation of these moles, however, has hitherto not been reported.5, 6

Skin-derived squamous cell carcinoma (SCC) is a very common complication of particularly RDEB-severe. Tumors arise most commonly at sites of chronic wounding, regeneration or scarring, and as early as within the second decade of life - with further increasing frequency thereafter. This is complicated by a very aggressive course with high rates of metastasis as well as recurrence. Referring to statistics provided by the U.S. National EB Registry, advanced SCC is the primary cause of death in RDEB, occurring in the majority of patients with RDEB-sev.7 The cumulative risk of developing SCC and subsequent death in patients with RDEB-severe at age 55 is greater than 90% and 78%, respectively. Although data suggest repetitive tissue stress and remodeling, growth activation of keratinocytes, polymorphisms of matrix metalloproteinases and reduced activity of natural killer cells to promote malignant transformation either as a predisposing micro-environment or a distinct pathology, the exact pathogenic pathways involved in tumorigenicity hitherto remain largely unknown.8, 9

Extracutaneous involvement:

Virtually any organ lined or covered by epithelium may be affected by the pathogenic consequences occuring in EB. Blister formation, chronic non-healing wounds and scarring in extracutaneous tissues either primarily or secondarily result in significant morbidity and mortality. Time of onset and severity of extracutaneous complications vary considerably between the various DEB subtypes, and especially those patients suffering from RDEB-sev are most commonly and prominently affected by a multi-systemic disease.4

Extracutaneous involvement in RDEB includes:

* Oral cavity (e.g. microstomia, ankyloglossia, secondary tooth injury by excessive caries and premature loss).

* Eye (e.g. photophobia, corneal ulcerations; corneal pannus formation, limbal broadening; ectropion, symblephara and

* Gastrointestinal tract (e.g. esophageal webbing, stenoses and strictures, hernia, abnormal peristalsis, dysphagia, malabsorption
with nutritional compromise and growth retardation).

* Genitourinary tract (e.g. stenoses with dysuria, hypospadias, epispadias, glomerulonephritis, hydronephrosis, chronic renal

* Musculoskeletal system (e.g. acral deformities, muscular dystrophy, osteopenia and osteoporosis).

* Heart (e.g. cardiomyophathy due to malnutrition and micronutrient deficiency, chronic anemia).


In intermediate RDEB, blistering is less severe compared to severe RDEB and mutilating deformities do not (rarely) develop. The clinical picture is variable, with some patients displaying widespread disease, while in others blisters are limited primarily to the extremities. Skin lesions heal invariably with scars and milia. Oral, dental, nail and hair manifestations are similar to severe RDEB, but less extensive. Onset of disease is at birth. Life expectancy of intermediate RDEB is normal, but the risk of squamous cell carcinomas is elevated.8

In RDEB-inversa (RDEB-I), the disease starts at birth in a generalized fashion. During early childhood, blister formation tends to localize at intertriginous skin sites (skin folds), the neck and the lumbosacral area. The oral cavity, esophagus and the lowermost portion of the genitourinary tract are severely affected. Nail dystrophy shows variable severity among patients. Esophageal involvement may result in strictures and impairment of nutrient intake. Lesions of the genitourinary tract may lead to vaginal strictures and impairment of normal sexual function. RDEB-I patients may develop SCCs, but with a much lower cumulative risk, compared to severe and intermediate RDEB.2, 10



More than 600 distinct mutations in the COL7A1 gene have been identified in DEB that interfere with the structural and functional integrity of its proteinaceous product, the type VII collagen. The latter polymerizes to form anchoring fibrils (AF) that anchor the epidermal basement membrane with the dermis. Collagen VII in normal tissues is restricted to stratified squamous epithelia, with blistering affecting the skin, mucous membranes and upper third of the esophagus. Secondary systemic manifestations of DEB, such as anemia, renal failure and squamous cell carcinomas are downstream complications due to blood loss, infections and chronic inflammation. In DEB skin, collagen VII is either reduced or absent. Ultrastructurally, electron microscopy reveals paucity, rudimentary structure, or complete lack of AFs.11

In RDEB, compound heterozygosity for COL7A1 mutations is common. A functionally and/or structurally residual protein expression accounts for a generally milder phenotype.12 Different mutations and allelic combinations, however, generate a continuum of biological phenotypes. They often are family specific in each individual patient (“private mutations”). This makes phenotype-genotype correlations possible to provide the basis for more accurate genetic counseling and prenatal diagnosis for at-risk families.13

In severe RDEB, mutations that result in premature termination codons (PTC) in both alleles (i.e. nonsense mutations or deletion, insertion and splice site mutations with frame shift of translation) result in nonsense mediated mRNA decay or residual expression of truncated polypeptides that are degraded within the cell. 14 This leads to completely absent collagen type VII expression and total loss of AF, clinically manifesting with severe mutilating scarring and blistering.



Whenever possible, laboratory diagnosis should be performed in a specialized EB centre.

To determine the level of skin cleavage, immunomapping or transmission electron microscopy of skin biopsies (4-6mm) is recommended. The immunomapping has diagnostic accuracy similar to transmission electron microscopy, with the advantage of simple and fast execution and reading. The splitting of the skin occurs below the lamina densa, which can be visualized by electron microscopy. Electron microscopy shows cleavage area sub-lamina densa.

In parallel, blood sampling for the extraction of genomic DNA is recommended. Genetic testing is the gold standard since it provides a definite diagnosis and classification of the major EB type and in many cases the subtype. It also enables genetic counselling and DNA-based prenatal testing. RDEB cases are due to COL7A1 mutations. A next-generation sequencing (NGS) EB-gene panel is the method of choice as it encompasses all known pathogenic EB genes and shows good sequencing coverage. In addition, Sanger sequencing may be performed if the target gene is known and of small size, or to detect familial and recurrent genetic variants. Immunofluorescence findings and genetic analysis provide complementary information that enables precise and fast diagnosis but also prediction of consequences of novel sequence variants and genotype-phenotype correlations. The vast majority of EB cases can be genetically characterized with these methods. 1, 15



There is no cure for EB. Wound care as well as early recognition and treatment of complications (e.g. skin infections) remain the mainstays of management.

General measures: Prevention of blister formation in everyday life, e.g., by choosing appropriate foot wear and wide clothing without raised seams or labels as well as padding of trauma-exposed sites, should be routinely implemented. If palmar or plantar hyperkeratosis is present, regular debridement and/or keratinolytics will help reducing walking pain and preventing fissuring and infection under the thickened skin. Occurrence of pain should be regularly assessed and adequately treated, e.g. for mild pain with non-opioid analgesics (e.g. paracetamol in conjunction with nonsteroidal anti-inflammatory drug), for moderate to severe pain with opioid analgesics (e.g. codeine, morphine) and/or tricyclic antidepressants, gabapentin, pregabalin and non-pharmacologic practices. Cannabinoids (nonaddictive) either oral or topical have also some effectiveness in many patients. Pain may be inherent (blistering, wounds, erosions) or caused by manipulation or dressing changes. Management of pruritus is also a prominent, debilitating feature of RDEB and frequently challenging and includes pharmacologic interventions (e.g. antihistamines, antidepressants, gabapentin), topical emollients and psychological therapies like relaxation training, biofeedback or distraction. Regarding oral involvement, children should be referred to the dentist before the teeth erupt and preventative measures applied (e.g. oral hygiene, fluoride). Nutritional status (especially fluid and electrolyte balance in infants) should be checked regularly and special diets or vitamin supplements/micronutrients, if needed, introduced. Neonates with severe RDEB usually require enteral nutrition support. Many patients need iron supplementation (either orally or parenteral). Evaluation of bone mineral density should be regularly performed to screen for osteopenia and/or osteoporosis. Patients profit from physical therapy, starting early in life. Treatment of urologic and renal disease as well as other extracutaneous manifestations should be initiated as required.16, 17

Wound care: Large blisters can cause pain and should be carefully opened (e.g. with a sterile needle), in order to release the pressure from surrounding tissue. The blister roof can be left in place for a better healing. However, when it has been removed, special non adhesive dressings are needed to reduce the risk of wound infections and pain. The choice of the dressing should consider the wound characteristics (site, exudate, critical colonization/infection), size, patient age, patient/parent preferences). Adhesive dressings or tapes must be avoided as they can induce blistering. Surveillance for squamous cell carcinoma is recommended in the second decade of life.16 Systemic antibiotics, that cover common pathogens, may be needed if tissue infection (especially lymphadenopathy, malaise, fever) occurs.

Ocular involvement (e.g. corneal erosions, blistering, scarring, blepharitis, symblepharon, visual impairment, refractive errors, strabismus) requires regularly monitoring and experienced ophthalmologic evaluation and therapy. Topical lubricants are frequently helpful against mild symptoms and antibiotic ointments are regularly used for corneal erosions.18




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12. Christiano AM, Greenspan DS, Hoffman GG, et al. A missense mutation in type VII collagen in two affected siblings with recessive dystrophic epidermolysis bullosa. Nat Genet. 1993;4(1):62-66.

13. Varki R, Sadowski S, Uitto J, Pfendner E. Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J Med Genet. 2007;44(3):181-192.

14. Christiano AM, Anhalt G, Gibbons S, Bauer EA, Uitto J. Premature termination codons in the type VII collagen gene (COL7A1) underlie severe, mutilating recessive dystrophic epidermolysis bullosa. Genomics. 1994;21(1):160-168.

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18. Krämer S, Lucas J, Gamboa F. Clinical practice guidelines: Oral health care for children and adults living with epidermolysis bullosa. 2020;40 Suppl 1(Suppl 1):3-81.