Dystrophic Epidermolysis Bullosa
Summary
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 diagnosis for DEB are possible.
Diagnosis
Dystrophic epidermolysis bullosa (DEB) is a genetic disorder affecting skin and nails that usually presents at birth. Currently, the classification of DEB is based on the publication of the consensus meeting of 2013 [Fine et al 2014]. Diagnosis is based on clinical suspicion in a patient with fragile skin, a family history of DEB, and diagnostic testing. Molecular genetic analysis is the most definitive test, but direct immunofluorescence (IF) and/or transmission electron microscopy (EM) may be helpful especially in classifying subtypes.
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 (see Nomenclature). Absence of a known family history of DEB does not preclude the diagnosis.
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 variants (RDEB) or a heterozygous 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.
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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of DEB molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of COL7A1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.Perform sequence analysis first. If no pathogenic variant is found or if only a single pathogenic variant is identified in an individual in whom recessive DEB is suspected, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- An epidermolysis bullosa multigene panel that includes COL7A1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by epidermolysis bullosa, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Dystrophic Epidermolysis Bullosa
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| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
|---|---|---|
| COL7A1 3 | Sequence analysis 4 | 95% 5 |
| Gene-targeted deletion/duplication analysis 6 | <2% 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Some pathogenic variants in COL7A1 have been described in both recessive and dominant inheritance patterns [Almaani et al 2011]. If two variants in COL7A1 are found, parental testing may be necessary to establish that the variants are biallelic.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Pathogenic variant detection rate by sequence analysis in individuals with biopsy-diagnosed DEB is 95% [Kern et al 2006, Bale & Pfendner 2014, Pfendner et al 2017].
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Proportion of probands with a pathogenic variant detectable by gene-targeted deletion/duplication analysis is <1% for dominant DEB and <2% for recessive DEB [Pfendner et al 2017].
Skin Biopsy
A definitive diagnosis of EB is made most directly by molecular genetic analysis. In the past, when only single-gene sequencing was available, it was imperative to perform a biopsy first to determine which single gene(s) to analyze. However, now that multigene panels are available [Lucky et al 2018], some clinicians prefer to avoid biopsy unless genetic analysis fails to yield a diagnosis [Pfendner 2015, Tenedini et al 2015].
If a biopsy is determined to be necessary for diagnosis, it should be taken from the leading edge of a fresh blister (<12 hours old) or of a mechanically induced blister and should include some normal adjacent skin; older blisters undergo changes that may obscure the diagnostic morphology. Elliptic 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 [Intong & Murrell 2010].
Light microscopy is inadequate and unacceptable for the accurate diagnosis of epidermolysis bullosa.
Immunofluorescence (IF). Examination of a skin biopsy by IF antibody/antigen mapping is an appropriate way to establish the diagnosis of DEB. Direct IF may reveal the level of clefting in the skin and help establish the broad category of EB type. Even without a split, presence or absence of specific proteins in the skin may also determine the type of EB. IF also has the advantage of a rapid turnaround time [Pohla-Gubo et al 2010, Meester et al 2018].
Characteristic findings:
- Staining of collagen VII using antibodies is diminished or absent.
- In milder forms of RDEB and in DDEB, staining for collagen VII may appear normal, but cleavage planes are below the lamina densa.
- Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) helps to confirm the diagnosis of DEB.
Transmission electron microscopy (TEM). Sometimes, especially in milder forms of EB, direct IF studies are not sufficient to make the diagnosis because near-normal antigen levels may be detected and no cleavage plane is observed. In such cases, TEM examination of the skin biopsy can be helpful in examining cellular structures [Eady & Dopping-Hepenstal 2010].
Characteristic findings:
- All DEB. Cleavage is observed below the lamina densa of the basement membrane zone.
- Recessive DEB (RDEB) severe generalized. Anchoring fibrils are markedly reduced, absent, or abnormal in morphology.
- Dominant DEB (DDEB), RDEB-gen and -loc
- Anchoring fibrils may appear reduced in number and/or 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.
Clinical Characteristics
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
Recessive DEB Severe Generalized (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, Murrell 2010, Li et al 2017].
Dermatologic and skin cancer risk
- Aplasia cutis congenita, especially of the extremities, which can occur in any type of EB, may be found in the newborn period.
- Blisters can affect the whole body including the skin, oral mucosa, esophageal mucosa, and corneas as early as the newborn period. Chronic nonhealing wounds and secondary infection are common, often with Staphylococcus, Pseudomonas, and Streptococcus.
- Blistering continues throughout life with scarring that may lead to disfigurement and orthopedic issues (see Orthopedic below).
- Many individuals develop large irregular brown patches that histologically comprise collections of nevus cells and are called EB nevi [Lanschuetzer et al 2010]. No instances of melanoma arising in these nevi have been reported to date.
- 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 [Mellerio et al 2016].
Oral, gastrointestinal, growth, and nutritional issues
- 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 and ultimately nutrition [Krämer et al 2012].
- Esophageal blisters and erosions as well as webs and strictures can cause severe dysphagia with resultant poor nutrition [Azizkhan et al 2006, Mortell & Azizkhan 2010]. Rarely, affected individuals can have esophageal disease with few or no skin manifestations. Gastroesophageal reflux disease is also common.
- Anal erosions, poor intake of fluid and fiber, and use of opioid analgesics contribute to frequent severe constipation.
- Malnutrition caused by poor intake and an increased nutritional demand for tissue healing can result in growth restriction in young children and absent or delayed puberty in older children.
- Vitamin and mineral deficiencies can occur especially with iron, zinc, carnitine, selenium, and vitamin D [Haynes 2010].
- Anemia results from poor iron intake and the anemia of chronic disease with bone marrow suppression.
- Zinc deficiency may impede proper healing of skin wounds.
- Carnitine and selenium deficiencies have been associated with cardiomyopathy in other conditions and may contribute to this finding in DEB.
- Osteopenia and osteoporosis is often associated with vitamin D deficiency, and results from poor nutrition, lack of exposure to adequate sunlight, and inactivity [Martinez & Mellerio 2010, Rodari et al 2017].
Ocular. Corneal erosions can lead to scarring and loss of vision [Matsumoto et al 2005].
Cardiac. Dilated cardiomyopathy, sometimes associated with selenium and carnitine deficiency, has been reported in RDEB and can be fatal in some cases [Lara-Corrales et al 2010, Ryan et al 2016].
Urologic/renal. Urethral erosions, strictures, bladder dysfunction, and glomerulonephritis can occur, sometimes leading to renal failure [Fine et al 2004].
Orthopedic. Individuals with RDEB tend to get contractures and pseudosyndactyly of the fingers resulting in a "mitten" or "cocoon" hand and consequent impairment of function and decreased quality of life [Eismann et al 2014]. Although fusion of the toes is not detrimental to function, painful blistering and progressive contractures of the foot and ankle as well as the larger joints (knees, hips, neck) can interfere with ambulation and function.
Psychosocial. Severe stress may affect the affected individual and family because of the complications of this disorder and the chronic pain endured by most individuals with EB. Quality of life can be decreased and psychosocial disorders including anxiety, depression, and drug dependence/abuse may occur in older persons [Frew & Murrell 2010] – although a recent study showed that pain in individuals with DEB is not correlated with anxiety or depression [Fortuna et al 2016].
Recessive DEB Generalized and Localized
Multiple clinical phenotypes make up the spectrum of RDEB, many of which are not as severe as RDEB-sev gen. The phenotype may be mild, with blistering localized to hands, feet, knees, and elbows as well as dystrophic nails, or relatively more widespread including flexural areas and trunk, but without the severe, mutilating scarring seen in RDEB-sev gen. Onset of blistering ranges from birth to childhood depending on type.
Some distinctive features of the less common RDEB-gen and -loc variants:
- RDEB inversa. Blistering and skin atrophy occurs on the trunk, neck, thighs, and legs while few 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.
- RDEB pretibial and pruriginosa often affect the shins. 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, small, white scars (albopapuloid skin lesions), and hypertrophic scars without pretibial predominance.
- RDEB generalized intermediate (RDEB-gen intermediate) exhibits widespread blistering with scarring, milia, and nevi. Pseudosyndactyly may occur along with oral lesions and damaged or absent nails. Growth retardation is possible but not as severe as with RDEB-sev gen. Squamous cell carcinoma also develops in some affected individuals.
- RDEB localized exhibits blistering with scarring which may be severe but is localized to the hands and feet. Other sites are not affected. The nails are often absent. Growth restriction and systemic illness are also absent. Squamous cell carcinoma has not been reported in individuals who have this subtype.
- RDEB centripetalis (RDEB-CE) is apparent at birth and involves the hands, feet, and pretibial areas only. Nails are absent. Growth retardation and systemic illness have not been reported. Squamous cell carcinoma has not been reported in individuals with this subtype.
- Bullous dermolysis of the newborn often has only transient blistering limited to the newborn period [Fassihi et al 2005]. Molecular genetic testing of these individuals reveals heterozygous COL7A1 pathogenic variants or (rarely) biallelic COL7A1 pathogenic variants [Frew et al 2011, Boccaletti et al 2015, Diociaiuti et al 2016].
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. The subtypes of DDEB resemble those of RDEB but may present with milder manifestations. There may be great clinical variability among members of the same family.
- DDEB generalized (DDEB-gen) is a milder form of EB in which a single pathogenic variant in COL7A1 results in a generalized blistering disease that affects most sites of friction in infancy but often evolves to less severe disease in adulthood. Blisters form with scarring and the nails are often absent. Other systems are generally unaffected and growth retardation and squamous cell carcinoma are rarely reported.
- DDEB pretibial and pruriginosa represent the same phenotypes as RDEB pretibial and pruriginosa (see above); however, heterozygous pathogenic variants in COL7A1 lead to an autosomal dominant pattern of inheritance.
- DDEB localized, nails only affects the nails, which are dystrophic and fragile. No skin findings are identified. Other family members, however, may have more severe manifestations.
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).
Table 2.
Comparison of 2008 DEB Nomenclature with Proposed "Onion Skin" Terminology – Representative Examples
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| Old Name 1 | 2014 Nomenclature |
|---|---|
| RDEB, severe generalized | RDEB generalized severe, collagen VII absent, COL7A1 pathogenic variants (specify type) |
| RDEB, generalized other | RDEB generalized intermediate, collagen VII reduced staining, COL7A1 pathogenic variants (specify type) |
| DEB-BDN | DEB-BDN, granular intraepidermal collagen VII staining, COL7A1 AD or AR pathogenic variants (specify) |
| DDEB generalized | DDEB generalized, normal collagen VII staining, COL7A1 pathogenic variant (specify) |
BDN = bullous dermolysis of newborn; DDEB = dominant dystrophic epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa
- 1.
Per 2008 recommendations
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].
Differential Diagnosis
The four major types of epidermolysis bullosa (EB) syndrome, caused by pathogenic variants in 20 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome (see Table 4). 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 Murrell [2010] for excellent clinical reviews and Fine et al [2014] (full text; note especially Tables I and VII) for the revised classification system.
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 further laboratory evaluation. Molecular genetic testing may be used to establish a diagnosis (see Establishing the Diagnosis). Alternatively, a fresh skin biopsy from a newly induced blister that is stained by indirect immunofluorescence for critical basement membrane protein components can be performed. 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.
The limitations of 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.
Table 3. Epidermolysis Bullosa Types
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| Clinical Features 1 | EB Type | EB Subtype | Gene | MOI | Skin Biopsy Findings (Level of Cleavage) | |||
|---|---|---|---|---|---|---|---|---|
| Extent of Blistering | Presence of Oral/ Other Mucous Membrane Lesions | Presence/Extent of Scarring | Other (Associated Gene) 1 | |||||
| Mild to severe depending on gene &/or variant | Mucous membrane involvement in severe forms |
|
| EBS 3 | EBS suprabasal | TGM5 | AR | In all EBS: a split above dermal-epidermal junction at ultrastructural level |
| DSP | ||||||||
| PKP1 | ||||||||
| JUP | ||||||||
| EBS basal | KRT5 | AD (AR 2) | ||||||
| KRT14 | ||||||||
| CD151 | ||||||||
| EXPH5 | AR | |||||||
| PLEC | ||||||||
| DST | ||||||||
| KLHL24 | ||||||||
| Moderate to severe depending on type of pathogenic variant |
| Granulation tissue formed on skin around oral & nasal cavities, fingers, & toes, & internally around upper airway & nails suggests JEB-GS. |
| JEB | JEB severe generalized | LAMA3 | AR | In all JEB: a split at level of lamina lucida, either:
|
| LAMB3 | ||||||||
| LAMC2 | ||||||||
| JEB generalized & localized | LAMA3 | |||||||
| LAMB3 | ||||||||
| LAMC2 | ||||||||
| COL17A1 | ||||||||
| ITGB4 | ||||||||
| JEB late onset | COL17A1 | |||||||
| JEB w/pyloric atresia | ITGB4 | |||||||
| ITGA6 | ||||||||
| JEB w/respiratory & renal involvement | ITGA3 | |||||||
| JEB-LOC syndrome 4 | LAMA3A | |||||||
| Extensive; predominantly on hands & feet | ||||||||