Clinical characteristics.

Dystrophic epidermolysis bullosa (DEB) is a genetic skin disorder affecting skin and nails that usually presents at birth. 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 multiple clinical subtypes. Absence of a known family history of DEB does not preclude the diagnosis.

Clinical findings in severe generalized RDEB include skin fragility manifest by blistering 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. Esophageal erosions can lead to webs and strictures that can cause severe dysphagia. Consequently, malnutrition and vitamin and mineral deficiency may lead to growth restriction in young children. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring fuses the digits into "mitten" hands and feet, with contractures and pseudosyndactyly. The lifetime risk of aggressive squamous cell carcinoma is higher than 90%.

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

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 the identification of biallelic pathogenic variants (RDEB) or a heterozygous pathogenic variant (DDEB) in COL7A1 by molecular genetic testing. The only gene in which pathogenic variants are known to cause DEB is COL7A1. If molecular genetic testing is not diagnostic, examination of a skin biopsy with direct immunofluorescence (IF) for specific cutaneous markers and/or electron microscopy (EM) may be necessary for diagnosis.

Management.

Treatment of manifestations: New blisters should be lanced, drained, and in most cases dressed with a nonadherent material, covered with padding for stability and protection, and secured with an elastic wrap for integrity. Infants and children with severe generalized RDEB and poor growth require attention to fluid and electrolyte balance and may require nutritional support, including feeding gastrostomy. Anemia is treated with iron supplements and transfusions as needed. Other nutritional supplements may include calcium, vitamin D, selenium, carnitine, and zinc. Occupational therapy may help prevent hand contractures. Surgical release of fingers often needs to be repeated.

Prevention of primary manifestations: If a fetus is known to be affected with any form of DEB, cesarean delivery may reduce trauma to the skin during delivery; age-appropriate play involving activities that cause minimal trauma to the skin is encouraged; dressings and padding are needed to protect bony prominences from blister-inducing impact.

Surveillance: Beginning in the second decade of life, biopsies of abnormal-appearing wounds that do not heal or have exuberant scar tissue are indicated for evidence of squamous cell carcinoma. Suggested regular testing includes screening for anemia and deficiencies of iron, zinc, vitamin D, selenium, and carnitine every 6-12 months. Yearly echocardiograms to identify dilated cardiomyopathy and bone mineral density studies to identify osteoporosis are recommended.

Agents/circumstances to avoid: Poorly fitting or coarse-textured clothing and footwear; activities/bandages that traumatize the skin.

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

Genetic counseling.

Dystrophic epidermolysis bullosa is inherited in either an autosomal dominant (DDEB) or autosomal recessive (RDEB) manner. Molecular characterization of pathogenic variants is the only accurate method to determine mode of inheritance and recurrence risk; phenotype severity and IF/EM 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, the risk to the sibs is 50%. Each child of an individual with DDEB has a 50% chance of inheriting the pathogenic variant.
• RDEB. Each sib of an affected individual whose parents are both carriers has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Once the COL7A1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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, manifest by blistering with minimal trauma that heals with milia and scarring
• Blistering and erosions that may:
  • Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities)
  • 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 mutilating pseudosyndactyly of the hands and feet (severe forms)
  • Lead to oral and/or esophageal scarring and strictures
  • Lead to corneal erosions with resulting scarring leading to loss of vision
  • Predispose to squamous cell carcinoma
• Dystrophic or absent nails, especially toenails
• Family history consistent with either an autosomal recessive or an autosomal dominant inheritance pattern

Establishing the Diagnosis

The diagnosis of DEB is established in a proband with characteristic clinical findings and either biallelic pathogenic (or likely pathogenic) variants (RDEB) or a heterozygous pathogenic (or likely pathogenic) variant (DDEB) in COL7A1 identified on molecular genetic testing (see Table 1). If molecular genetic testing is not diagnostic, examination of a skin biopsy (see Skin Biopsy) with direct IF for specific cutaneous markers and/or EM may be necessary. Routine histology is not useful.

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

It should be noted that not all clinicians have access to the diagnostic tools described in this section (molecular genetic testing, specialized tests on a skin biopsy). A recent study compared a matrix of clinical findings with genetic confirmation in 74 cases and found a high concordance to type and subtype of EB. This technique may be useful in developing countries [Yenamandra et al 2017].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DEB is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with epidermolysis bullosa (EB), or presenting at birth or in the neonatal period before more advanced disease progression has occurred, are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Before the molecular basis of dystrophic epidermolysis bullosa (DEB) was understood, types and subtypes were identified based primarily on clinical features, mode of inheritance, and the presence or absence of collagen VII and anchoring fibrils detected on skin biopsy. The current classification system is based on inheritance pattern (autosomal dominant DEB [DDEB] vs autosomal recessive DEB [RDEB]) and is further stratified by collagen VII staining and the specific COL7A1 pathogenic variant that is identified in a given affected individual (see Nomenclature) [Fine et al 2014]. For the purposes of this GeneReview the terms "recessive DEB severe generalized" (RDEB-sev gen), "recessive DEB generalized and localized" (which includes several further subtypes), and "dominant DEB" (DDEB) (which also includes further subtypes) have been used and are discussed below.

See Figure 1.

Figure 1.

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

Genotype-Phenotype Correlations

Recessive DEB (RDEB)

• The severest forms are caused by biallelic pathogenic variants in COL7A1 that result in either null or out-of-frame variants from insertions/deletions, single-base changes, and splice junction [Mellerio et al 1999a, Gardella et al 2002a, Gardella et al 2002b, Mallipeddi et al 2003]. The severity may be related to the position of the stop codon [Tamai et al 1999]; however, the presence or absence of some functional protein appears to be the most important factor in determining the disease severity.
• Moderately severe forms generally result from glycine substitution within the Gly-X-Y domain on one allele and a premature stop codon on the other allele; only a small amount of partially functional protein is made [Murata et al 2000, Dharma et al 2001, Varki et al 2007].
• Less severe forms generally result from other (non-glycine) amino acid substitutions and splice junction variants; there is wide phenotypic variability, and more than 700 pathogenic variants have been reported in the literature [Ashton et al 1999, Mellerio et al 1999b, Whittock et al 1999, Gardella et al 2002a, Murata et al 2004, Sawamura et al 2005, Varki et al 2007].

Dominant DEB (DDEB). Most DDEB results from dominant-negative amino acid substitutions of glycine in the collagenous triple helical domain of collagen VII, although a few splice junction and other amino acid substitutions have been reported. Phenotypes may show inter- and intrafamilial variability with the same pathogenic variant [Murata et al 2000, Vaccaro et al 2000, Mallipeddi et al 2003, Nakamura et al 2004, Wessagowit et al 2005].

Penetrance

Until recently, pathogenic variants in COL7A1 were considered to be 100% penetrant when family members were evaluated for mild features of the disease. However, in several families, an individual with DDEB and a known COL7A1 pathogenic variant had relatives with the same variant who had no signs of the disease. Penetrance therefore appears to be less than 100%, at least in DDEB [Almaani et al 2011; Authors, unpublished observations].

Nomenclature

Recessive DEB severe generalized (RDEB-sev gen) was originally called Hallopeau-Siemens type (RDEB-HS).

Recessive DEB generalized intermediate (RDEB-gen intermed) and RDEB localized (RDEB-loc) were originally called non-Hallopeau-Siemens type (RDEB-non-HS).

The nomenclature for DEB has changed four times in the last 15 years. The most recent classification system, referred to as the "onion skin" terminology, arose from an international consensus meeting, the recommendations of which were published in June 2014 [Fine et al 2014]. This classification system starts by dividing DEB into the inheritance pattern and follows with a histologic description of collagen VII staining, then the specific COL7A1 pathogenic variant that has been described in the affected individual (see Table 2).

For information on the newest nomenclature recommendations that pertain to epidermolysis bullosa simplex and junctional epidermolysis bullosa, see Table 3 (pdf).

Prevalence

According to the National EB Registry, the overall prevalence of EB is 11.07 per one million live births [Fine 2016]. The prevalence of DDEB and RDEB, respectively, is 1.49 and 1.35 per 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 dystrophic epidermolysis bullosa (DEB), the following evaluations are recommended if they have not already been completed.

Dermatologic and skin cancer risk

• Thorough evaluation of total skin surface for blisters, erosions, and infections
• Evaluation of crusted, nonhealing, or painful lesions in older individuals for squamous cell carcinoma (SCC)

Oral, gastrointestinal, and nutritional

• Examination of the mouth including mucosal blistering and erosions, dental caries, and crowding
• Barium swallow for esophageal strictures if there are symptoms of dysphagia
• Measurement of height, weight, and BMI to evaluate nutritional status and need for gastrostomy feeding
• Baseline laboratory examination for anemia and nutritional status (see Surveillance)
• Baseline DXA (dual-energy x-ray absorptiometry) scan for osteoporosis if diagnosis occurs in an older individual

Ocular. Ophthalmologic examination to evaluate for corneal abrasions and scars

Cardiac. Baseline echocardiogram

Urologic/renal. Baseline urinalysis to assess for hematuria and proteinuria

Orthopedic. Evaluation of hand function and mobility/dexterity status by a physical or occupational therapist

Gynecologic. Evaluation of pubertal status if individual is an adolescent at diagnosis

Psychosocial (psychology and social work)

• Evaluation by professional to assess for anxiety, depression, substance dependency and abuse
• Assistance with school-related issues
• Assistance with access to needed services, insurance, and handicapped accommodations

Genetics. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Dermatologic. Families must decide which of the many correct and effective methods of bandaging works for them: there is no "best" method. In general, however, blisters should be lanced and drained to prevent spread from fluid pressure [Denyer 2010, Pope et al 2012, El Hachem et al 2014].

In most cases, dressings for blisters and erosions involve three layers:

• Primary (base) layer. A primary nonadherent dressing that does not stick to the skin. Tolerance to different primary layers varies. Primary layers may include any of the following:
  • Nonstick products with or without silicone surfaces that are nonadhesive
  • Dressings impregnated or covered with an emollient (such as petrolatum) or a topical antiseptic (such as silver, medical-grade honey, or topical antibiotics if there is infection)
• Secondary layer. This layer provides stability for the primary layer and adds padding for protection. Rolls of soft gauze are commonly used.
• Tertiary layer. This layer usually has some elastic properties that secure the integrity of the primary and secondary dressings.

Nonhealing wounds may require coverage with biologic skin substitutes or temporary porcine or human cadaver skin grafts. New products involving gene-corrected autologous cells are currently in clinical trials (see Therapies Under Investigation).

Pain and itch are major factors affecting quality of life in individuals with DEB [Goldschneider et al 2014, Danial et al 2015]. A variety of topical, oral, and psychological therapies have been advocated.

Skin infection is common in DEB. All open wounds in EB eventually become colonized with bacteria. Clinical judgment must determine when there is significant infection that requires treatment. Many affected individuals become infected with resistant bacteria, most often methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Streptococcus. Both antibiotics and antiseptics need to be employed.

Squamous cell carcinoma (SCC). A variety of approaches to treatment of SCC are summarized in a 2016 publication [Mellerio et al 2016]. There is no well-accepted standard of care.

Oral, gastrointestinal, and nutritional. In infants and children with RDEB with more severe involvement, poor growth may be a problem, requiring additional nutritional support including a feeding gastrostomy when necessary to assure adequate caloric intake [Stehr et al 2008, Mortell & Azizkhan 2010, Hubbard 2016].

Esophageal strictures and webs can be dilated repeatedly to improve swallowing [Castillo et al 2002, Kay & Wyllie 2002, Azizkhan et al 2006].

Fluid and electrolyte problems, which can be significant and even life-threatening in the neonatal period and in infants with widespread disease, require careful management.

Anemia is a chronic problem with RDEB and can be treated with oral iron supplements, intravenous iron infusions, and/or red blood cell transfusions.

Treatment of other nutritional deficiencies includes:

• Calcium and vitamin D supplementation and intravenous bisphosphonates for osteopenia and osteoporosis;
• Selenium and carnitine replacement when levels are low to possibly help prevent dilated cardiomyopathy;
• Zinc replacement when levels are low to enhance wound healing.

Good dental care is essential to insure the ability to eat and to allow for adequate caloric intake [Harris et al 2001]. Extractions for dental caries and crowding may be needed.

Ocular. Prophylactic use of eye lubricants and, in some cases, protective contact lenses, may prevent corneal abrasions.

Cardiac. Refer to a cardiologist if cardiomyopathy is detected on echocardiogram; medical treatment with beta blockers and/or ACE inhibitors may be able to control or reverse it.

Urologic/renal. Refer to a urologist for urethral erosions, strictures, or bladder dysfunction or to a nephrologist when hematuria or proteinuria is present, as glomerulonephritis and renal failure may occur [Almaani & Mellerio 2010].

Orthopedic

• Occupational therapy may be helpful in preventing progressive hand contractures. Splinting of the hands can be problematic because of skin fragility.
• Surgical release of fingers by several methods has been described; it often needs to be performed repeatedly [Marín-Bertolín et al 1999, Glicenstein et al 2000]. Some centers advocate preservation of a functional thumb in preference to whole-hand releases.

Gynecologic. Delayed puberty is common in girls with poor nutrition.

• Estrogen replacement will initiate signs of puberty.
• Often menstrual periods are suppressed to prevent exacerbation of anemia.

Psychosocial. Psychosocial support including social services and psychological counseling is essential for managing affected individuals and their families.

Prevention of Primary Manifestations

If a fetus is known to be affected with any form of DEB, cesarean delivery may reduce trauma to the skin during delivery.

Age-appropriate play involving activities that cause minimal trauma to the skin is encouraged.

Dressings and padding are needed to protect bony prominences from blister-inducing impact.

Surveillance

Because the lifetime risk of metastatic squamous cell carcinoma is greater than 90% in individuals with RDEB, surveillance at least yearly in the second decade of life for wounds that do not heal, have exuberant scar tissue, or otherwise look abnormal is essential. Frequent biopsies of suspicious lesions may be necessary followed by local excision. Affected individuals are often unwilling to undress completely in the clinic setting and home photographs during dressing changes may have to suffice.

Agents/Circumstances to Avoid

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

Evaluating 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 intrafamilial clinical variability, 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 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 EB are limited, but a recent survey did not detect increased risk for pregnancy-related complications in women with EB [Intong et al 2017].

Therapies Under Investigation

There are several promising therapies under current investigation including genetically corrected autologous epidermal grafts [Siprashvili et al 2016], various stem cell therapies including bone marrow transplant, mesenchymal stem cells, and IPS cells [Tamai & Uitto 2016], and gene-corrected fibroblasts [Jacków et al 2016].

A recent expedited 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].

Using murine models of RDEB and murine wound models, it has been demonstrated that cultured dermal fibroblasts (either from unaffected human subjects or from individuals with RDEB, engineered to express the collagen 7 protein [C7]) can be injected into murine skin or transplanted RDEB skin equivalents and that the injected cells then secrete C7 into the papillary dermis. There, C7 incorporates into the dermal-epidermal junction (DEJ), forms new anchoring fibrils (AFs), and reverses the RDEB phenotype of poor epidermal-dermal adherence. It has also been shown that the cells could be administered intravenously (IV) at home to open wounds in the skin, promoting healing. This suggests that such cells, injected IV into an individual with RDEB, could localize within healing wounds and continually secrete C7 that could then incorporate into the DEJ and form new AFs that promote healing [Woodley et al 2013].

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 dominant or autosomal recessive manner.

Determining the mode of inheritance in a simplex case (i.e., a single occurrence in a family). Molecular characterization of pathogenic variants is the only accurate method of determining mode of inheritance and recurrence risk. Seven individuals with a combination of a recessive pathogenic variant on one allele and a dominantly inherited amino acid substitution on the other allele have been reported, suggesting caution when predicting recurrence risk based on parental phenotype alone (i.e., without molecular genetic testing) [Varki et al 2007].

Phenotypic severity and EM/IF findings alone are not sufficient to determine mode of inheritance and recurrence risk, as phenotypic variability is extreme in recessive DEB [Hashimoto et al 1999, Vaccaro et al 2000, Mallipeddi et al 2003]. 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 [Hashimoto et al 1999, Vaccaro et al 2000, Mallipeddi et al 2003, Varki et al 2007].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Approximately 70% of individuals diagnosed with dominant DEB (DDEB) are reported to have an affected parent.
• About 30% of probands may have the disorder as the result of a de novo COL7A1 pathogenic variant [Varki et al 2007]; however, these numbers may not reflect the true proportion of de novo pathogenic variants because of bias of ascertainment.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Maternal germline mosaicism has been reported [Cserhalmi-Friedman et al 2001, Fassihi et al 2006].
• Although 70% of individuals diagnosed with DDEB have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• 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 variant is 50%. Intrafamilial clinical variability and reduced penetrance have been observed.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low (~1 in 10⁶) but greater than that of the general population because germline mosaicism has been reported [Cserhalmi-Friedman et al 1999, Cserhalmi-Friedman et al 2001, Fassihi et al 2006].
• If the parents have not undergone molecular genetic testing but appear to be clinically unaffected, sibs of a proband are still presumed to be at increased risk for DDEB because of the possibility of reduced penetrance in a parent or parental germline 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 recessive dystrophic epidermolysis bullosa (RDEB) are obligate heterozygotes (i.e., carriers of one COL7A1 pathogenic variant).
• 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 variants 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

• At conception, each sib of an individual with RDEB whose parents are both carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are typically asymptomatic (see Parents of a proband).

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

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

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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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).

Prenatal Testing and Preimplantation Genetic Testing

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

Molecular Pathogenesis

COL7A1 is expressed in the keratinocytes including the basal keratinocytes of the epidermis where the protein products are 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 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. Intrafamilial phenotypic variability in dominant DEB suggests that other factors can affect the resistance of the cells to friction [Anton-Lamprecht & Gedde-Dahl 2002, Ortiz-Urda et al 2005].

Gene structure. The normal cDNA comprises 9.2 kb with an open reading frame of 8,833 nucleotides encoding 2,944 amino acids in 118 exons spanning 32 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) predominate (>75%) in DDEB. p.Gly2034Arg and p.Gly2043Arg are the most common DDEB-causing pathogenic variants, making up 50% of the dominant pathogenic variants reported in the largest US cohort [Varki et al 2007]. Glycine substitutions as well as other amino acid substitutions and splice junction variants outside of this region may also be found in dominant DEB; often, however, inheritance pattern cannot be predicted without determination of parental phenotype and corresponding genotype.

More than 700 COL7A1 recessive DEB-causing variants spanning the entire gene have been described for all forms of DEB [Ashton et al 1999, Mellerio et al 1999b, Whittock et al 1999, Gardella et al 2002a, Murata et al 2004, Sawamura et al 2005, Varki et al 2007]. Common pathogenic variants have been described in certain ethnic backgrounds – including c.497dupA [Ashton et al 1999, Gardella et al 2002a], c.2470dupG [Mellerio et al 1999b], p.Arg578Ter [Whittock et al 1999], c.3840delC [Whittock et al 1999], and c.4919delG [Whittock et al 1999] – and are recurrent in the US population. Each, however, accounts for no more than 1%-2% of the total number of pathogenic variants described. Null variants predominate in RDEB, though glycine substitutions and other amino acid substitutions have been described. Milder forms of RDEB are often caused by splice junction variants or other missense variants.

Normal gene product. Collagen VII is a monomer of 2,944 amino acids that associates into a homotrimer with a triple helical collagenous domain. The homotrimers then associate via disulfide bonds into homodimeric structures that form the anchoring fibrils.

Abnormal gene product. Recessive DEB usually results from the absence of the COL7A1 gene product as a result of premature termination codon variants on both alleles, or splicing variants leading to large deletions or out-of-frame gene products – although some glycine substitution variants have been demonstrated to have autosomal recessive as well as autosomal dominant inheritance and may lead presumably to an absent gene product (recessive) or defective gene product (dominant).

In dominant DEB, collagen VII with a glycine substitution in the collagenous domain (Gly-X-Y) may result in abnormal triple helical coiling and a partially nonfunctional protein product. These proteins may exhibit altered morphology on electron microscopy while immunofluorescent staining may be normal or slightly reduced in intensity, making diagnosis by immunofluorescent staining of a skin biopsy difficult unless a cleavage plane is present. In addition, in-frame exon skipping may serve to modulate disease severity in recessive disease and generate a partially functional gene product [McGrath et al 1999, Varki et al 2007].

Individuals with recessive DEB severe generalized (RDEB-sev gen) have a greater-than-90% lifetime risk of aggressive metastasizing squamous cell carcinoma. The reason for the elevated risk was not clear until the study of Ortiz-Urda et al [2005], which examined Ras-driven tumorigenesis in RDEB keratinocytes and found that cells lacking collagen VII did not form tumors in mice, whereas those retaining a specific collagen VII fragment (the amino-terminal noncollagenous domain NC1) were tumorigenic. Restoring NC1 expression restored tumorigenicity in collagen VII-deficient cells. They concluded that tumor-stroma interactions mediated by collagen VII promote neoplasia, and retention of NC1 sequences in a subset of individuals with RDEB may be a factor in their increased susceptibility to squamous cell carcinoma.

Literature Cited

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Author Notes

GeneDx website

Cincinnati Children's Epidermolysis Bullosa Center website

Revision History

• 13 September 2018 (ha) Comprehensive update posted live
• 26 February 2015 (me) Comprehensive update posted live
• 4 November 2010 (me) Comprehensive update posted live
• 4 October 2007 (cd) Revision: deletion/duplication analysis available on a clinical basis
• 21 September 2007 (cd) Revision: deletion/duplication analysis no longer available on a clinical basis
• 17 October 2006 (cd) Revision: deletion/duplication analysis available on a clinical basis
• 21 August 2006 (me) Review posted live
• 27 December 2005 (ep) Original submission