DiagnosisClinical DiagnosisDystrophic epidermolysis bullosa (DEB) includes three subtypes [Fine et al 2008]:Recessive DEB, severe generalized (RDEB-sev gen) (formerly called Hallopeau-Siemens type (RDEB-HS)Recessive DEB, generalized other (RDEB-O) (formerly called non-Hallopeau-Siemens type (RDEB-non-HS)Dominant DEB (DDEB)The diagnosis of DEB is suspected in individuals with fragility of the skin, manifest by blistering with little or no trauma. Blisters heal with milia and scarring that in the RDEB-sev gen, severest subtype of RDEB, can result in mutilating pseudosyndactyly of the hands and feet.Because the clinical features of all types of EB overlap significantly, clinical diagnosis is unreliable and examination of a skin biopsy is usually required to establish the diagnosis, especially in infants (see Figure 1).FigureFigure 1. Common findings of dystrophic epidermolysis bullosa:
a,b: Scarring on knees and hands and dystrophic nails found in dominant DEB in an adult
c: Aplasia cutis congenita in a newborn with recessive DEB
d: Generalized blistering (more...)TestingSkin biopsy. Examination of a skin biopsy by transmission electron microscopy and/or immunofluorescent antibody/antigen mapping is the best way to reliably establish the diagnosis of DEB. However, sometimes, especially in milder forms of EB, indirect immunofluorescent studies are not sufficient to make the diagnosis because near-normal antigen levels are detected and no cleavage plane is observed. In such cases, electron microscopic examination of the skin biopsy must be performed to examine the basement membrane zone structures — in particular, to determine the number and morphology of anchoring fibrils and the presence and morphology of hemidesmosomes, anchoring filaments, and keratin intermediate filaments.In DEB the blister forms below the basement membrane, which becomes attached to the blister roof, thus resulting in scarring when the blister heals.Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of EB.The biopsy should be taken from the leading edge of a fresh (less than 12 hours old) or mechanically induced blister and should include some normal adjacent skin; older blisters undergo change that may obscure the diagnostic morphology. Elliptical or shave excisions are often used. Although a punch biopsy can introduce confusing artifact, careful use of the punch can avoid loss of the epidermis.Findings on transmission electron microscopy (TEM)All DEB. Splitting is observed below the lamina densa of the basement membrane of the epidermis.Autosomal recessive DEB (RDEB), severe generalized type. Anchoring fibrils are markedly reduced or absent.Autosomal dominant DEB (DDEB) and RDEB-otherAnchoring fibrils may appear reduced in number and show altered morphology.Intracellular retention of collagen VII can be observed in some individuals.Collagen VII may be retained intracellularly within the basal keratinocytes instead of being transported to the basement membrane zone in some individuals who have transient blistering in the newborn period.Findings on immunofluorescent antibody/antigen mappingStaining of collagen VII using antibodies is diminished or absent. (In mild DEB, staining for collagen VII may appear normal, but cleavage planes in the form of vesicles or microvesicles can be observed below the lamina densa and below the collagen VII staining.)Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) confirms the diagnosis of DEB.Molecular Genetic TestingGene. The only gene known to be associated with dystrophic EB is COL7A1.Clinical testingSequence analysis
DDEB. When DDEB is suspected, a tiered testing approach with sequence analysis of exons 73, 74, and 75 of COL7A1, which detects approximately 75% of the dominant dystrophic EB-causing mutations, may be performed first. De novo and recurrent mutations, especially p.Gly2043Arg and p.Gly2034Arg in exon 73, have been described.
If no mutation is identified in exons 73-75, sequencing of the remaining coding exons is performed. Mutation detection rate in individuals with biopsy-diagnosed DEB is 95% [Kern et al 2006; Pfendner, unpublished observation].
RDEB. Sequencing of the entire coding region is usually necessary to identify both mutations in individuals with RDEB. Mutations may be nonsense, missense, splicing, or small insertions and deletions. Detection rate for sequencing of the entire COL7A1 gene is greater than 95%.
Note: Although sequencing of exons in which founder mutations are identified in individuals of certain ethnic backgrounds has been described in European populations, such an approach has not been fruitful in the US population, in which mutations can be found in any of the 118 exons of COL7A1.Deletion/duplication analysis. Using methods such as quantitative real-time PCR (see Table 1 footnote 4), deletions/duplications in COL7A1 may be detected.Table 1. Summary of Molecular Genetic Testing Used in Dystrophic Epidermolysis BullosaView in own windowGene SymbolDystrophic EB TypeTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityCOL7A1Dominant DEB Sequence analysis of select exons 2 Sequence variants 375% Clinical Sequence analysisSequence variants 395% Deletion / duplication analysis 4Partial- and whole-gene deletion 5UnknownRecessive DEBSequence analysisSequence variants 3>95% Deletion / duplication analysis 4Partial- and whole-gene deletion 5Unknown1. Proportion of individuals with biopsy-diagnosed DEB who have a mutation(s) as classified by DEB type and test method2. Exons 73, 74, 75; selected exons may vary by laboratory.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Extent of deletion detected may vary by method and by laboratory.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. A skin biopsy should be performed, especially in newborns, as soon as possible after initial evaluation and studied with indirect immunofluorescence to identify the intensity of basement membrane protein staining and the level of tissue cleavage.Molecular genetic testing is not usually used to establish the diagnosis of DEB except when the electron microscopy and/or immunofluorescence studies are not diagnostic, which sometimes occurs in the milder forms of DEB when a blister cannot be induced.Molecular genetic testing is used to establish inheritance pattern and to guide future reproductive decisions by enabling prenatal diagnosis for the affected person and his/her family members.Carrier testing for at-risk relatives for autosomal recessive forms of DEB requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.Genetically Related (Allelic) DisordersNo phenotypes other than DEB are known to be associated with mutations in COL7A1.}

Natural HistoryBefore the molecular basis of dystrophic epidermolysis bullosa (DEB) was understood, subtypes were identified (see Nomenclature) 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 includes the following three subtypes which are discussed below: recessive DEB, severe generalized; recessive DEB, generalized other; and dominant DEB [Fine et al 2008].Severe Generalized Recessive (RDEB-sev gen)In this classic severe form of RDEB, blisters are present at birth or become apparent in the neonatal period. Medical consequences of RDEB-sev gen have been recently reviewed [Fine & Mellerio 2009a, Fine & Mellerio 2009b].Blisters can affect the whole body including the oral mucosa, the esophageal mucosa, and the corneas as early as the newborn period. Secondary infection is common.Blistering continues throughout life with scarring that may lead to disfigurement. Scarring pseudosyndactyly of the hands and feet, a hallmark of this disorder, fuses the digits into "mitten" hands and feet with severe loss of function.Oral involvement may lead to fusion of the tongue to the floor of the mouth (ankyloglossia) and progressive diminution of the size of the oral cavity and mouth opening (microstomia) which, along with poor dental hygiene and caries, impairs food intake [Serrano-Martinez et al 2003, De Benedittis et al 2004].Esophageal erosions and esophageal webs and strictures can cause severe dysphagia with resultant poor nutrition [Castillo et al 2002, Azizkhan et al 2006]. Rarely, affected individuals can have esophageal disease with few or no skin manifestations [Zimmer et al 2002].Anal erosions can cause severe constipation. Gastroesophageal reflux disease (GERD) is common.Corneal erosions can lead to scarring and loss of vision [Matsumoto et al 2005].The lifetime risk of aggressive squamous cell carcinoma (SCC) is greater than 90% with significant metastatic potential [Fine et al 2009].SCC usually appears in the third decade but can appear as early as the second decade [Ayman et al 2002]. Affected individuals usually succumb to aggressive metastatic SCC.Many individuals develop large, irregular, brown patches that histologically comprise collections of nevus cells and are called EB nevi [Lanschuetzer et al 2010]Malnutrition caused by poor intake and an increased nutritional demand for tissue healing can result in growth retardation and failure to thrive in young children and absent or delayed puberty in older children.Anemia results from poor iron intake and the anemia of chronic disease with bone marrow suppression.Osteopenia and osteoporosis, often with vitamin D deficiency, result from poor nutrition, lack of exposure to adequate sunlight, and especially inactivityDilated cardiomyopathy can be fatal in some cases.Urethral erosions, strictures, bladder dysfunction, and a variety of renal diseases can occur [Fine et al 2004].Severe stress to the patient and family because of the complications of this disorder and the chronic pain endured by the most affected individuals often result in psychosocial disorders including anxiety, depression, and drug dependence and abuse in older persons.Generalized, Not Severe RDEB (RDEB-Other)Many clinical variants make up the spectrum of RDEB-O. The phenotype may be mild, with mild blistering localized to hands, feet, knees, and elbows and dystrophic nails, or relatively more widespread including flexural areas and trunk, but without the severe, mutilating scarring seen in RDEB-sev gen.In the variant known as DEB inversa, blistering and skin atrophy occurs on the trunk, neck, thighs, and legs while no changes are observed on the hands, feet, elbows, or knees. Otherwise, the phenotype resembles DEB types with blistering and resulting scarring. Blisters of the hands and feet may be present in infancy.Dominant DEB (DDEB)In this milder form of DEB, blistering is often limited to the hands, feet, knees, and elbows. Blistering may be relatively benign but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and loss of nails may occur. In the mildest forms, dystrophic nails may be the only characteristic noted [Dharma et al 2001, Sato-Matsumura et al 2002, Tosti et al 2003]. Blistering in DDEB often improves somewhat with age, possibly as a result of reduced physical activity.Manifestations Variably Present in Both RDEB and DDEBAlthough previously thought to be separate subtypes of DEB, the following manifestations are now recognized to be common to the three major subtypes as discussed in this entry:Congenital localized absence of skin (previously called DEB, Bart type). Congenital absence of the skin can be seen in any of the three major types of EB (i.e., epidermolysis bullosa simplex, or EBS; junctional epidermolysis simplex, or JEB; and DEB) and is not a discriminating diagnostic feature of any EB type or DEB subtype.Transient bullous dermolysis of the newborn. Mild to moderate skin fragility at birth diminishes with age but may not entirely disappear [Fassihi et al 2005].DEB, pretibial with lichenoid features. Pretibial blisters develop into prurigo-like hyperkeratotic lesions. The lesions occur predominantly on the pretibial areas, sparing the knees and other parts of the skin. Other findings include nail dystrophy, albopapuloid skin lesions, and hypertrophic scars without pretibial predominance.

Genotype-Phenotype CorrelationsRecessive DEB (RDEB)The severest forms are caused by mutations on both alleles that result in either null alleles or out-of-frame mutations 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 of some functional protein seems to be the most important factor in ameliorating the disease severity.Moderately severe forms result from glycine substitutions on one allele and a stop codon-forming mutation on the other allele, which result in the formation of only a small amount of partially functional protein [Murata et al 2000, Dharma et al 2001, Varki et al 2007].Less severe forms generally result from other amino acid substitutions and splice junction mutations, although it is difficult to generalize because of the wide phenotypic variability and range of mutations (over 500 reported in the literature) that have been identified [Ashton et al 1999, Mellerio et al 1999b, Whittock et al 1999, Gardella et al 2002a, Murata et al 2004, Sawamura et al 2005].Dominant DEB (DDEB). Most DDEB results from dominant-negative amino acid substitutions involving glycine substitution mutations in the collagenous triple helical domain of collagen VII, although a few splice junction and other amino acid substitution mutations have been reported. Phenotypes may show intra- and interfamilial variability with the same mutation [Murata et al 2000, Vaccaro et al 2000, Mallipeddi et al 2003, Nakamura et al 2004, Wessagowit et al 2005].

Differential DiagnosisThe four major types of epidermolysis bullosa syndrome, caused by mutations in 13 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome. While agreement exists as to diagnostic criteria for some types of epidermolysis bullosa, the validity of rarer subtypes and their diagnostic criteria are disputed. See Dermatologic Clinics (vol 28, 2010) (Suggested Reading) for excellent clinical reviews and Fine et al [2008] for the revised classification system, published after the Third International Consensus Meeting on Diagnosis and Classification of EB.The four major types of EB share fragility of the skin, manifested by blistering and/or erosions with little or no trauma. A positive Nikolsky sign (blistering of uninvolved skin after rubbing) is common to all types of EB. No clinical findings are specific to a given type; thus, establishing the EB type requires a fresh skin biopsy from a newly induced blister that is stained by indirect immunofluorescence for critical basement membrane protein components. The diagnosis is established by determining the cleavage plane and the presence/absence and distribution of these protein components. Electron microscopy is also diagnostic and often more useful in milder forms of EB.Clinical examination is useful in determining the extent of blistering, the presence of oral and other mucous membrane lesions, and the presence and extent of scarring.Limitations of the clinical findings in establishing the type of EB include the following:In young children and neonates, the extent and severity of blistering and scarring may not be established or significant enough to allow identification of EB type.Mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators.Post-inflammatory changes such as those seen in EBS, Dowling-Meara type (EBS-DM) are often mistaken for scarring or mottled pigmentation.Scarring can occur in EB simplex and junctional EB as a result of infection of erosions or scratching, which further damages the exposed surface.Congenital absence of the skin can be seen in any of the three major types of EB (i.e., EBS, JEB, DEB) and is not a discriminating diagnostic feature.Clinical findings that tend to be specific for a type of EB include the following:Corneal erosions, esophageal strictures, and nail involvement suggest DEB.Tooth enamel involvement suggests JEB.Scarring and milia of the hands and feet in milder cases suggests DEB rather than EBS.Pseudosyndactyly (mitten deformities) caused by scarring of the hands and feet in older children and adults usually suggests DEB.Epidermolysis bullosa simplex (EBS). The new criteria for EBS include subtypes in which skin blisters are rare; rather, fragility manifests by generalized oozing erosions (EBS superficialis, lethal acantholytic EBS, and plakophilin deficiency) in addition to the more common blistering forms (EBS localized; EBS, Dowling- Meara; and EBS other [non-Dowling-Meara]) [Fine et al 2008]. The severity of skin fragility in the EBS subtypes ranges from mild erosions or blisters to severe potentially fatal blistering (EBS Dowling-Meara) or sheet like erosions (lethal acantholytic EB).EBS localized (EBS-loc) (previously called Weber-Cockayne). Blisters are rarely present at birth and may occur on the knees and shins with crawling or on the feet at about age 18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet but can occur anywhere if trauma is significant.EBS, Dowling-Meara type (EBS-DM). Onset is usually at birth; great intra- and interfamilial variation in severity is observed. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical; hemorrhagic blisters are common. Improvement occurs in mid- to late childhood. EBS-DM appears to improve with fever in some individuals. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyperpigmentation and hypopigmentation can occur. Mucosal involvement in EBS-DM may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.EBS other generalized, non-Dowling Meara (EBS gen-nonDM) (previously called Koebner). Blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc but generally milder than in EBS-DM.EBS with mottled pigmentation (EBS-MP). Skin fragility is evident at birth and clinically indistinguishable from EBS-DM. Over time, progressive brown pigmentation interspersed with depigmented spots develops on the trunk and extremities, with pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur.EBS, autosomal recessive (EBS-AR). Patients tend to have more severe disease. Homozygous mutations in keratin 14 and plectin have been described.EBS with muscular dystrophy (EBS-MD) [OMIM 226670]. Some individuals with EB caused by PLEC1 mutations develop muscular dystrophy either in childhood or later in life [Charlesworth et al 2003, Koss-Harnes et al 2004, Schara et al 2004, Pfendner et al 2005]. Inheritance in this form of EBS is autosomal recessive.EBS with pyloric atresia (EBS-PA). In several US and Japanese families, EB-PA is associated with premature termination mutations in PLEC1 [Nakamura et al 2004, Pfendner & Uitto 2005]. Only lethal EBS-PA cases have been described in the literature.EBS, Ogna type (EBS-Og) [OMIM 131950], observed in one Norwegian and one German family, is caused by a site-specific missense mutation within the rod domain of PLEC1 [Koss-Harnes et al 2002]. Inheritance is autosomal dominant.EBS migratory circinate [OMIM 609352] is a rare form of AD EBS caused by keratin 5 mutations with the involvement of an unusual migratory circinate erythema with multiple vesicles on the area affected by the erythema. The lesions, which appeared from birth primarily on the hands, feet, and legs, heal with brown pigmentation but no scarring.Junctional EB (JEB). Separation occurs above the basement membrane of the dermis, within the lamina lucida of the dermal-epidermal junction, resulting in non-scarring blistering. Because atrophy may develop over time, the term "atrophicans" has been applied in Europe to individuals with some form of junctional EB.Classification of JEB includes:JEB Herlitz (JEB-H) and JEB other (JEB-O), based on severity and survival past the first years of life. JEB-O has been further subdivided into the following:JEB non-Herlitz localized (JEB-nH gen) (previously known as generalized atrophic benign EB or GABEB) JEB non-Herlitz localized (JEB-nH loc) JEB inversa (JEB-I)JEB late-onset (JEB-lo)Laryngo-oculo-dysplasia syndrome (LOC), previously known as Shabbir syndromeJEB is caused by mutations in the genes that encode the subunits of laminin 332 (LAMA3, LAMB3, LAMC2) and the gene that encodes type 17 collagen (COL17A1). JEB with pyloric atresia has been associated with mutations in ITGA6 and ITGB4 (α6β4 integrin) (see EB with Pyloric Atresia). Note that the new classification system of Fine et al [2008] separates EB-PA into the following:EBS-PA caused by plectin mutationsJEB-PA caused by alpha 6 and beta 4 integrin mutationsKindler syndrome. The classification of Fine et al [2008] identifies Kindler syndrome as a major type in the EB or bullous disorders. It is characterized by multiple cleavage planes; specifically epidermal, lamina lucida, and sub lamina densa. The presence of multiple cleavage planes is a characteristic that is unique to the mechanobullous disorders. The phenotype can be severe at birth but resolves later in life and includes poikiloderma and photosensitivity. Mutations in KIND1 (FERMT1) have been demonstrated; inheritance is autosomal recessive [Siegel et al 2003, Jobard et al 2003].

ManagementEvaluations Following Initial DiagnosisIn order to determine the extent of disease in an individual diagnosed with dystrophic epidermolysis bullosa (DEB), evaluation of the sites of blister formation including oral and esophageal blisters and erosions is recommended.Treatment of ManifestationsSkin. New blisters should be lanced and drained to prevent further spread from fluid pressure.Each family must decide which of the many correct and effective methods of bandaging works best for them. In most cases, dressings for blisters involve three layers:A primary non-adherent dressing that does not strip the top layers of the epidermis. Tolerance to different primary layers varies. Primary layers may include any the following:Ordinary Band-Aids^{®Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline® gauze, Adaptic®, Xeroform®)Non-stick products (e.g., Telfa® or N-terface®)Silicone-based products without adhesive (e.g., Mepitel® or Mepilex®)A secondary layer providing stability for the primary layer and adding padding to allow more activity. Rolls of gauze (e.g., Conform®, Kerlix®,) are commonly used.A tertiary layer (usually with some elastic properties) that ensures the integrity of the dressing (e.g., Tubifast®, Coban® or elasticized tube-gauze of varying diameters such as Band Net®)In infants and children with RDEB with more severe involvement, failure to thrive may be a problem, requiring additional nutritional support including a feeding gastrostomy when necessary to assure adequate caloric intake [Haynes et al 1996, Stehr et al 2008]. Esophageal strictures and webs can be dilated repeatedly to improve swallowing [Castillo et al 2002, Kay & Wyllie 2002, Azizkhan et al 2006].Other. 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 or intravenous iron infusions and red blood cell transfusions.Other nutritional deficiencies must also be addressed:Calcium and vitamin D supplementation for osteopenia and osteoporosisSelenium and carnitine replacement to help prevent dilated cardiomyopathyZinc replacement to enhance wound healingDental care is necessary to ensure adequate caloric intake [Harris et al 2001].Some children have delays or difficulty walking because of blistering and hyperkeratosis. Appropriate footwear and physical therapy are essential to preserve ambulation.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 [Marin-Bertolin et al 1999, Glicenstein et al 2000].Psychosocial support including social services and psychological counseling is essential.Prevention of Primary ManifestationsAge-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.If a fetus is known to be affected with any form of DEB, cesarean delivery may reduce trauma to the skin during delivery.Prevention of Secondary ComplicationsThe most common secondary complication is infection. In addition to wound care, treatment of chronic infection of wounds is a challenge. Many affected individuals become infected with resistant bacteria, most often methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Both antibiotics and antiseptics need to be employed.SurveillanceBecause the lifetime risk of metastatic squamous cell carcinoma is greater than 90% in individuals with RDEB, surveillance 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.Screening for anemia should be routine with complete blood counts and possibly measurement of serum iron concentration in order to provide iron supplementation when necessary.Screening for zinc deficiency by measurement of serum zinc concentration should be routine in order to provide zinc supplementation when necessary to enhance wound healing.Screening for predisposition to dilated cardiomyopathy secondary to selenium deficiency and carnitine deficiency is possible by measurement of serum concentrations of selenium and carnitine. Screening for dilated cardiomyopathy by transthoracic echocardiogram is also useful [Sidwell et al 2000]. No guidelines regarding the age at which such screening should begin have been established.Screening with bone mineral density scanning may pick up early osteopenia and/ or osteoporosis. No guidelines have been established regarding the age at which this should begin.Agents/Circumstances to AvoidPoorly 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 determined to participate in such activities should be encouraged to devise ways of protecting the skin.Most persons with DEB cannot use ordinary medical tape or Band-Aids®.Evaluation of Relatives at RiskEvaluating an at-risk newborn for evidence of blistering is appropriate so that trauma to the skin can be avoided as much as possible.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementCesarean section is often recommended to avoid vaginal delivery in a fetus at risk.Therapies Under InvestigationThe use of mouse models for EB has enhanced molecular therapies for the treatment of EB by mimicking the EB phenotypes and facilitating testing of a number of therapeutic approaches including the folloiwng:Gene replacement therapy [Ito et al 2009]Stem cell replacement therapy [Fujita et al 2010, Tolar et al 2009, Chino et al 2008]Allogenic transplantation of fibroblasts [Fritsch et al 2008]Transplantation of normal type VII collagen protein [Remington et al 2009]In addition, older approaches involving the use of viral vectors to transfer functional genes to cultured cells for transplant into humans are still being explored [Siprashvili et al 2010, Titeux et al 2010].Human trials for the treatment of EB that have just begun include the following:Local grafting of skin cells in which the genetic mutations have been corrected for treatment of human JEB [DeLuca et al 2009]Cell transfer-based treatment for DEB [Ortiz-Urda et al 2003; A Lane, Stanford University, personal communication]. One patient with JEB has had cell transfer treatment on the legs. A large Stanford University trial for DEB is planned (see ClinicalTrials.gov).Intradermal injections of large quantities of recombinant collagen 7 protein grown in vitro has shown efficacy in a murine model [Remington et al 2009]. Human clinical trials are likely to be under way in the near future.Intradermal injections of allogenic fibroblasts have reconstituted collagen 7 protein in the basement membrane. Although it appears that this “new” collagen 7 protein is identical to the mutant protein of the host, the increased quantities of collagen 7 seem to be clinically beneficial [Wong et al 2008].Bone marrow transplantation:Systemic use of allogenic stem cells has been shown in a murine model to have a clinically beneficial effect on blistering [Tolar et al 2009]. Currently trials of bone marrow and/or umbilical-cord stem cell transplants, using either conventional myeloablative or reduced intensity conditioning, are underway in two centers in the USA. See Wagner et al [2010] and ClinicalTrials.gov for details of the two EB trials at the University of Minnesota and Columbia University.Replacement of missing collagen 7 protein in RDEB has been accomplished using local injections of bone-marrow-derived mesenchymal stem cells. The clinical effect of healing of chronic wounds was noted in two patients; however, it lasted only four months [Conget et al 2010].Medical treatment of lesions suspicious for squamous cell carcinoma with agents such as topical imiquimod needs to be studied further.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.}

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Dystrophic Epidermolysis Bullosa: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCOL7A13p21​.31Collagen alpha-1(VII) chainCOL7A1 gene variants database
COL7A1 homepage - Mendelian genesCOL7A1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Dystrophic Epidermolysis Bullosa (View All in OMIM) View in own window 120120COLLAGEN, TYPE VII, ALPHA-1; COL7A1 131705TRANSIENT BULLOUS DERMOLYSIS OF THE NEWBORN; TBDN 131750EPIDERMOLYSIS BULLOSA DYSTROPHICA, AUTOSOMAL DOMINANT; DDEB 132000EPIDERMOLYSIS BULLOSA WITH CONGENITAL LOCALIZED ABSENCE OF SKIN AND DEFORMITY OF NAILS 226600EPIDERMOLYSIS BULLOSA DYSTROPHICA, AUTOSOMAL RECESSIVE; RDEB 226650EPIDERMOLYSIS BULLOSA, JUNCTIONAL, NON-HERLITZ TYPEMolecular Genetic PathogenesisThe COL7A1 gene 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. These molecules then assemble into homodimers that are found 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].Mutations in the COL7A1 gene can lead to reduced resistance to minor trauma and the resulting blistering that is the hallmark of DEB. The type of mutation, the biochemical properties of the substituted amino acid, and its location determine the severity of the blistering phenotype (see Genotype-Phenotype Correlations) and inheritance pattern. Missense mutations predominate in autosomal dominant forms of DEB and may affect the ability of the collagen VII to assemble into a triple helix (its secondary structure) and to form the intracellular network. Null mutations predominate in autosomal recessive forms of DEB and the absence of functional collagen VII and resulting absence of anchoring fibrils lead to the most severe forms of DEB. 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].Individuals with recessive DEB, severe generalized (RDEB-sev gen) (formerly known as Hallopeau-Siemens type (RDEB-HS) have a greater-than-90% lifetime risk of aggressive metastasizing squamous cell carcinoma. The reason for the elevated risk has not been clear until recently: Ortiz-Urda et al [2005] 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 non-collagenous domain NC1) were tumorigenic. Restoring NC1 expression restored tumorigenicity in collagen VII-deficient cells. They conclude 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.Normal allelic variants. The normal cDNA comprises 9.2 kbp with an open reading frame of 8,833 nucleotides encoding 2944 amino acids in 118 exons spanning 32 kb.Pathologic allelic variants. Glycine substitution mutations in the triple helical domain (especially in exons 73, 74, and 75) predominate (>75%) in DDEB. Mutations p.Gly2034Arg and p.Gly2043Arg are the most common DDEB-causing mutations, making up 50% of the dominant mutations reported in the largest US cohort [Varki et al 2007]. Glycine substitutions as well as other amino acid substitutions and splice junction mutations 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 400 recessive DEB-causing mutations 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 mutations have been described in certain ethnic backgrounds — including c.497dupA [Ashton et al 1999, Gardella et al 2002a], c.2470insG [Mellerio et al 1999b], p.Arg578* [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 mutation, however, accounts for no more than 1%-2% of the total number of mutations described. Null mutations predominate in RDEB, though glycine substitutions and other amino acid substitutions have been described. Milder forms of RDEB are often caused by splice junction mutations or other missense mutations.Table 2. Selected COL7A1 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.497dupA
(c.497insA)p.Val168Glyfs*12NM_000094​.3
NP_000085​.1c.1732C>Tp.Arg578*c.2470dupG
(c.2470insG)p.Asn825Lysfs*41c.3840delCp.Gly1281Valfs*44c.4919delGp.Gly1640Valfs*70c.6100G>Ap.Gly2034Argc.6127G>Ap.Gly2043ArgSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. Collagen VII is a monomer of 2944 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. In dominant DEB, collagen VII with a glycine substitution in the collagenous domain 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].