Clinical characteristics.

Dystrophic epidermolysis bullosa (DEB) is characterized by skin fragility manifested by blistering and erosions with minimal trauma. Many individuals also have dystrophic or absent nails. DEB is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB).

Clinical findings in severe RDEB include skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring. Blistering and erosions affecting the whole body may be present in the neonatal period. Oral involvement may lead to mouth blistering, fusion of the tongue to the floor of the mouth, and progressive diminution of the size of the oral cavity and mouth opening. Esophageal erosions can lead to webs and strictures that can cause severe dysphagia. Malnutrition with vitamin and mineral deficiency may lead to growth deficiency in young children. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring results in contractures and pseudosyndactyly. The lifetime risk of aggressive squamous cell carcinoma (SCC) is greater than 90%.

In contrast, the blistering in intermediate RDEB may be localized to hands, feet, knees, and elbows with or without involvement of flexural areas and the trunk, and without severe scarring.

In DDEB, blistering is often mild and limited to hands, feet, knees, and elbows, but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and may be the only manifestation of DDEB.

Diagnosis/testing.

The diagnosis of DEB is established in a proband with characteristic clinical findings and biallelic COL7A1 pathogenic variants (for RDEB) or a heterozygous pathogenic variant in COL7A1 (for DDEB) identified by molecular genetic testing. Skin biopsy using transmission electron microscopy and/or immunofluorescent antibody/antigen mapping can be considered in those with inconclusive molecular genetic testing or if genetic mutation analysis is not available.

Management.

Targeted therapies: Beremagene geperpavec-svdt topical therapy in those with molecularly confirmed DEB; birch triterpenes / birch bark extract topical therapy.

Supportive care: Minimize new blisters with education of caretakers, wrapping and padding extremities, and soft and loose-fitting clothing; vaginal delivery is the preferred method, but in certain circumstances, cesarian delivery may be recommended to prevent trauma of an affected fetus; encourage play that reduces risk of skin trauma; dressing and padding to protect bone prominences; new blisters should be lanced, drained, and in most cases dressed with nonadherent dressings, covered with padding for stability and protection, and secured with an elastic mesh-like wrap for integrity (e.g., burn net). Antibiotics and antiseptics for wound infection; appropriate footwear and physical therapy to preserve ambulation; topical, oral, and psychological therapies for pain and itch; specialized treatment of SCC; good dental care; dilation of esophageal strictures and webs to improve swallowing; management of constipation. Fluid and electrolyte management as needed; nutritional support including feeding gastrostomy tube, vitamin A, zinc, selenium, and carnitine supplementation. Anemia is treated with iron supplements and transfusions as needed. Eye lubricants and protective contact lenses may prevent corneal abrasions. Angiotensin-converting enzyme inhibitors for cardiomyopathy; treatment of urologic and kidney manifestations per urologist and nephrologist. Occupational and physical therapy may help prevent hand and other joint contractures. Surgical release of fingers often needs to be repeated. Calcium and vitamin D supplementation and bisphosphonates as needed for osteoporosis. Estrogen replacement as needed for delayed puberty; suppression of menses can prevent exacerbation of anemia; psychosocial support.

Surveillance: Thorough skin examination at each visit and as recommended by dermatologist; evaluation of crusted, non-healing, and painful lesions as well as those with exuberant scar tissue at least annually beginning at age ten years; biopsies of suspicious lesions for evidence of SCC. Assess oral mucosa, feeding, esophageal involvement, gastrointestinal manifestations, growth, nutrition, hand function, footwear, mobility, and family needs at each visit. Serum vitamin A, selenium, carnitine, zinc, 25-hydroxyvitamin D₃, complete blood count, iron studies, and urinalysis every six to 12 months; ophthalmology examinations as needed; annual echocardiogram to identify dilated cardiomyopathy starting at age two years; annual spine radiographs and DXA scan to assess for osteoporosis starting at age six years or earlier in those with unexplained pain and/or fractures; evaluation of pubertal status at each visit beginning at age ten to 12 years.

Agents/circumstances to avoid: Nasogastric tubes are discouraged because of oral and esophageal fragility; poorly fitting or coarse-textured clothing and footwear; activities/bandages that traumatize the skin.

Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives should be offered to permit early diagnosis and treatment in order to identify those who would benefit from management of trauma to the skin.

Genetic counseling.

DEB is inherited in either an autosomal dominant (DDEB) or autosomal recessive (RDEB) manner. Some COL7A1 pathogenic variants are associated with both DDEB and RDEB. Molecular characterization of the COL7A1 pathogenic variants is the only accurate method to determine mode of inheritance and recurrence risk; phenotype severity and skin biopsy findings alone are not sufficient.

DDEB: About 70% of individuals diagnosed with DDEB are reported to have an affected parent. If a parent of a proband with DDEB is affected and/or is known to be heterozygous for the COL7A1 pathogenic variant, the risk to the sibs is 50%. Each child of an individual with DDEB has a 50% chance of inheriting the pathogenic variant. Intrafamilial clinical variability and reduced penetrance have been observed among heterozygous family members.

RDEB: If both parents are known to be heterozygous for a COL7A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous sibs of a proband with RDEB are typically asymptomatic, although some pathogenic variants are associated with both DDEB and RDEB.

Once the COL7A1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Dystrophic epidermolysis bullosa (DEB) should be suspected in individuals with the following clinical findings:

• Fragility of the skin, manifested by blistering with minimal trauma that heals with milia and scarring
• Absent lingual papillae
• Blistering and erosions that may:
  • Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa);
  • Be present in the neonatal period;
  • Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms);
  • Lead to pseudosyndactyly of the hands and feet (severe forms);
  • Lead to oral and/or esophageal scarring and strictures;
  • Lead to corneal erosions, scarring, and loss of vision;
  • Predispose to squamous cell carcinoma.
• Dystrophic or absent nails, especially toenails

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity) or autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of DEB is established in a proband with suggestive findings and one of the following:

• Identification of biallelic pathogenic (or likely pathogenic) variants (recessive DEB; RDEB) in COL7A1 identified by molecular genetic testing (see Table 1)
• Identification of a heterozygous pathogenic (or likely pathogenic) variant (dominant DEB; DDEB) in COL7A1 identified by molecular genetic testing (see Table 1)
• Characteristic findings on skin biopsy examined via transmission electron microscopy (absent or abnormal anchoring fibrils) and/or immunofluorescent antibody/antigen mapping of the collagen alpha-1(VII) chain (COL7A1) protein consistent with DEB (See Skin Biopsy.)

Note: (1) Molecular genetic testing is the preferred diagnostic method [Phillips et al 2022]; skin biopsy for diagnostic purposes should only be considered if molecular results are inconclusive or molecular testing is not available. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (3) Identification of a heterozygous or biallelic variants of uncertain significance does not establish or rule out the diagnosis.

Clinical Description

Dystrophic epidermolysis bullosa (DEB) is characterized by increased skin fragility and dystrophic or absent nails; features are usually present at birth (see Figure 1). DEB is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB). Each type is further divided into clinical subtypes based on severity.

Figure 1.

Common findings of dystrophic epidermolysis bullosa (DEB) a, b. Scarring on knees and hands and dystrophic nails found in dominant DEB in an adult

Genotype-Phenotype Correlations

RDEB

• Severe RDEB is typically caused by biallelic pathogenic variants in COL7A1 that result in null or out-of-frame insertions/deletions, and splice site variants resulting in little to no functional protein. Recent analysis of 236 individuals with RDEB showed correlation with types of pathogenic variants and disease severity: individuals with loss-of-function variants had more significant cutaneous and extracutaneous symptoms [Pathmarajah et al 2025].
• Intermediate RDEB and less severe forms generally result from having at least one variant that allows for partially functional protein. This could include missense variants for both alleles, or one allele with a missense variant and the other with a higher-impact variant such as a splice site or other variant resulting in little to no functional protein [Chen et al 2023, So et al 2024, Pathmarajah et al 2025].

DDEB. Most DDEB results from dominant-negative amino acid substitutions of glycine in the collagenous triple helical domain of collagen VII, especially in exons 73, 74, and 75. The most common variants of these are p.Gly2043Arg and p.Gly2043Glu [Has et al 2020, Chen et al 2023]. Of note, a few splice site variants and other amino acid substitutions have been reported. Inter- and intrafamilial clinical variability has been reported [Natale et al 2022, Chen et al 2023].

See also Table 9 and Pathmarajah et al [2025].

Penetrance

Penetrance for DDEB is reduced; unaffected individuals have been identified [Almaani et al 2011].

Nomenclature

The nomenclature for DEB has changed five times in the last 20 years. A classification system was developed in 2014, referred to as the "onion skin" terminology, which considers the level of blistering, phenotypic characteristics including distribution and severity of cutaneous blisters and wounding, and associated gene [Fine et al 2014].

The most recent reclassification system for DEB and other skin fragility disorders was published following the 2019 international consensus meeting [Has et al 2020] (see Table 3). Further revisions in classification can be expected.

Prevalence

According to the National EB Registry, the overall prevalence of EB is 11.07 in one million live births [Fine 2016]. The prevalence of DDEB and RDEB, respectively, is 1.49 and 1.35 in one million live births.

The carrier frequency of RDEB in the US population has been estimated at one in 370 [Pfendner et al 2001].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DEB, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended.

Agents/Circumstances to Avoid

Nasogastric tubes are discouraged because of oral and esophageal fragility [Bageta et al 2024].

Poorly fitting or coarse-textured clothing and footwear should be avoided, as they can cause trauma.

In general, activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) should be avoided; affected individuals who are committed to participation in such activities should be encouraged to devise ways of protecting the skin.

Most persons with DEB cannot tolerate the use of ordinary medical tape or Band-Aids^®.

Evaluation of Relatives at Risk

Evaluation of an at-risk newborn for evidence of blistering is appropriate so that trauma to the skin can be avoided as much as possible.

Given the significant clinical variability that may be seen among family members with DEB, it is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the COL7A1 pathogenic variant(s) in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Data on pregnancy and DEB are limited, but a recent survey did not detect increased risk for pregnancy-related complications in women with various forms of epidermolysis bullosa [Intong et al 2017, Greenblatt et al 2022].

Therapies Under Investigation

There are several promising therapies currently being studied, including genetically corrected autologous epidermal grafts [Siprashvili et al 2016] and various stem cell therapies including bone marrow transplant, mesenchymal stem cells, stromal cells, induced pluripotent stem (IPS) cells [Tamai & Uitto 2016], and gene-corrected fibroblasts [Jacków et al 2016]. Stop codon read-through, exon skipping, COL7A1 protein therapy, and revertant mosaicism are being investigated.

A clinical trial has shown the efficacy of autologous transgenic keratinocyte cultures used to regenerate an entire, fully functional epidermis on a child age seven years suffering from severe JEB [Hirsch et al 2017]. Similar studies are under way for DEB [Siprashvili et al 2016, So et al 2022] and awaiting FDA approval.

There are many new approaches to therapy currently in trial. Clinical trials evaluating antifibrotic, anti-inflammatory, and antipruritic medications are in progress [Danescu et al 2024].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Dystrophic epidermolysis bullosa (DEB) is inherited in an autosomal recessive (RDEB) or autosomal dominant (DDEB) manner. Some COL7A1 pathogenic variants are associated with both DDEB and RDEB.

Determining the mode of inheritance in a simplex case (i.e., a single occurrence in a family). Molecular characterization of the COL7A1 pathogenic variants is the only accurate method of determining mode of inheritance and recurrence risk. Multiple individuals with one COL7A1 pathogenic variant associated with DDEB and a second COL7A1 pathogenic variant associated with RDEB (compound heterozygous DEB) have been reported, suggesting caution when predicting recurrence risk based on parental phenotype alone (i.e., without molecular genetic testing) [Varki et al 2007, Turczynski et al 2016].

Phenotypic severity and transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping findings alone are not sufficient to determine mode of inheritance and recurrence risk, as phenotypic variability is extreme in RDEB. An individual with a mild phenotype and no family history may have either autosomal dominant or autosomal recessive DEB; numerous descriptions of the spectrum of phenotypes in RDEB document that some are very mild and mimic DDEB.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Approximately 70% of individuals diagnosed with DDEB are reported to have an affected parent.
• About 30% of individuals diagnosed with DDEB may have the disorder as the result of a de novo COL7A1 pathogenic variant [Chen et al 2023]; however, these numbers may not reflect the true proportion of de novo pathogenic variants because of ascertainment bias. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced penetrance. Therefore, de novo occurrence of a COL7A1 pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the COL7A1 pathogenic variant.
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Maternal gonadal mosaicism has been reported [Cserhalmi-Friedman et al 2001, Fassihi et al 2006]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to be heterozygous for the COL7A1 pathogenic variant, the risk to sibs of inheriting the pathogenic variant is 50%. Intrafamilial clinical variability [Chen et al 2023] and reduced penetrance have been observed among heterozygous family members.
• If the COL7A1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Cserhalmi-Friedman et al 2001, Fassihi et al 2006].
• If the parents appear to be clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for DDEB because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with DDEB has a 50% chance of inheriting the COL7A1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the COL7A1 pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with RDEB are presumed to be heterozygous for a COL7A1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a COL7A1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygous parents of a proband with RDEB are typically asymptomatic.
  • Heterozygosity for a COL7A1 null variant does not result in DEB; parents heterozygous for this category of COL7A1 pathogenic variant are asymptomatic and are not at risk for developing DEB (see Molecular Pathogenesis).
  • Heterozygosity for a COL7A1 glycine substitution in the Gly-X-Y domain may or may not result in DEB; some parents heterozygous for this type of COL7A1 pathogenic variant are affected and some are asymptomatic. This variation can occur even within members of the same family [Almaani et al 2011].

Sibs of a proband

• If both parents are known to be heterozygous for a COL7A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygous sibs of a proband with RDEB are typically asymptomatic.
  • Heterozygosity for a COL7A1 null variant does not result in DEB; sibs heterozygous for this category of COL7A1 pathogenic variant are asymptomatic and are not at risk for developing DEB (see Molecular Pathogenesis).
  • Heterozygosity for a COL7A1 glycine substitution in the Gly-X-Y domain may or may not result in DEB; some sibs heterozygous for this type of COL7A1 pathogenic variant are affected and some are asymptomatic. This variation can occur even within members of the same family [Almaani et al 2011].

Offspring of a proband. The offspring of an individual with RDEB are obligate heterozygotes for a pathogenic variant in COL7A1.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a COL7A1 pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk relatives requires prior identification of the COL7A1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the COL7A1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

COL7A1 encodes collagen alpha-1(VII) chain, which is expressed in keratinocytes, including the basal keratinocytes of the epidermis, where the protein product is assembled into homotrimeric molecules with a helical triple collagen domain. The homotrimers then associate via disulfide bonds into homodimeric structures in the extracellular matrix below the lamina densa and form the anchoring fibrils that anchor the basement membrane to the underlying dermis. The anchoring fibrils are linked to the basement membrane through attachment to laminin-5 and the keratinocyte hemidesmosomes directly above. The intracellular keratin intermediate filament network is linked directly to the hemidesmosomes that anchor the keratinocytes to the basal lamina and to the desmosomes that lead to strong attachment of the keratinocytes to one another. These associations along with the network itself supply stability and resistance to stress that enable the keratinocytes to maintain their structural integrity during minor trauma and remain anchored to the basement membrane and dermis [Bruckner-Tuderman 1999].

Pathogenic variants in COL7A1 can lead to reduced resistance to minor trauma and the resulting blistering that is the hallmark of dystrophic epidermolysis bullosa (DEB). The type of pathogenic variant, the biochemical properties of the substituted amino acid, and its location in the protein determine the severity of the blistering phenotype (see Genotype-Phenotype Correlations) and inheritance pattern.

Mechanism of disease causation

• Recessive DEB (RDEB) usually results from the absence of collagen VII as a result of COL7A1 null variants, although some glycine substitutions and other amino acid substitutions have been described in RDEB.
• Dominant DEB (DDEB). Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) predominate (>75%) in DDEB and may result in abnormal triple helical coiling and a partially nonfunctional protein product.

Author Notes

GeneDx website

Cincinnati Children's Epidermolysis Bullosa Center website

Author History

Sarah Crawford, MMSc, CGC (2025-present)
Anne W Lucky, MD (2006-present)
Ellen G Pfendner, PhD; GeneDx, Inc (2006-2025)
Elena Pope, MD, MSc (2025-present)

Revision History

• 8 May 2025 (sc) Revision: Genotype-Phenotypes Correlations edits
• 27 March 2025 (sw) Comprehensive update posted live
• 13 September 2018 (ha) Comprehensive update posted live
• 26 February 2015 (me) Comprehensive update posted live
• 4 November 2010 (me) Comprehensive update posted live
• 21 August 2006 (me) Review posted live
• 27 December 2005 (ep) Original submission

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