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Junctional Epidermolysis Bullosa

Includes: COL17A1-Related Junctional Epidermolysis Bullosa, LAMA3-Related Junctional Epidermolysis Bullosa, LAMB3-Related Junctional Epidermolysis Bullosa, LAMC2-Related Junctional Epidermolysis Bullosa

, PhD and , MD.

Author Information
, PhD
Director, EBDx Program
GeneDx, Inc
Gaithersburg, Maryland
, MD
Director, Cincinnati Children's Epidermolysis Bullosa Center
Cincinnati Children's Hospital
Cincinnati, Ohio

Initial Posting: ; Last Update: January 2, 2014.

Summary

Disease characteristics. Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. Broad classification of JEB includes Herlitz JEB (aka lethal) and non-Herlitz JEB (aka non-lethal). In Herlitz JEB, the classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In non-Herlitz JEB, the phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, pseudosyndactyly, and other contractures.

Diagnosis/testing. Because the clinical features of all types of EB overlap significantly, examination of a skin biopsy by transmission electron microscopy (TEM) and/ or immunofluorescent antibody/antigen mapping is usually required to establish the diagnosis of JEB, especially in infants. The four genes in which mutations are known to cause JEB are LAMB3 (70% of all JEB), COL17A1 (12%), LAMC2 (9%), and LAMA3 (9%).

Management. Treatment of manifestations: Lance and drain new blisters and dress with three layers (primary: non-adherent; secondary: for stability and protection; third: elastic properties to ensure integrity). Protect skin from shearing forces; teach caretakers proper handling of infants and children; treatment of granulation tissue with high-potency topical steroids, silver nitrate, electrocautery, or autologous skin grafts; dilation of esophageal strictures; standard treatment of gastroesophageal disease; tracheostomy if appropriate; regular dental care; appropriate footwear and physical therapy to promote/preserve ambulation; psychosocial support, including social services and psychological counseling; appropriate management of chronic pain; treatment of urologic and renal disease using standard treatments.

Prevention of secondary complications: Antiseptics to treat wound infections; attention to fluid and electrolyte balance in severely affected infants; additional nutritional support including feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements.

Surveillance: Routine screening for iron-deficiency anemia, zinc deficiency, osteopenia and/or osteoporosis; periodic echocardiograms to evaluate for dilated cardiomyopathy; in the second decade of life, surveillance for squamous cell carcinoma is appropriate.

Agents/circumstances to avoid: Ordinary medical tape or Band-Aids®, poorly fitting or coarse-textured clothing and footwear, activities that in general traumatize the skin (e.g., hiking, mountain biking, contact sports).

Other: Consider cesarean section delivery to reduce trauma to the skin of an affected fetus.

Genetic counseling. JEB is inherited in an autosomal recessive manner. The parents of an affected child are usually obligate heterozygotes (i.e., carriers). Because germline mosaicism and uniparental isodisomy have been reported, carrier status of parents needs to be confirmed with molecular genetic testing. At conception, each sib of an affected individual 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. The offspring of an individual with autosomal recessive JEB are obligate heterozygotes (carriers) for a disease-causing mutation. Carrier testing for family members at increased risk and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

The diagnosis of junctional epidermolysis bullosa (JEB) is suspected in individuals with fragility of the skin with:

  • Blistering with little or no trauma. Blistering may be mild or severe; however, blisters generally heal with no significant scarring.
  • Significant oral and mucous membrane involvement

Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally in and around the upper airway and the trachea. (See Figure 1, Figure 2.)

Figure 1

Figure

Figure 1. Herlitz JEB

a. Extensive widespread blistering and granulation tissue on ear
b. Hand of a child showing aplasia cutis congenital
c. Foot of an affected child
d. Exuberant perioral granulation tissue (more...)

Figure 2

Figure

Figure 2. Non-Herlitz JEB

e. Minor nail dystrophy in an older child
f. Multiple blisters on the hands of an active toddler
g. Non-scarring superficial axillary erosions

Because the clinical features of all types of epidermolysis bullosa (EB) overlap significantly (see Differential Diagnosis), clinical diagnosis is unreliable and examination of a skin biopsy or molecular genetic testing is usually required to establish the diagnosis, especially in infants.

Testing

Until recently, skin biopsies were needed to direct the clinician toward appropriate gene targets for mutation analysis. See Testing Strategy for discussion of molecular genetic testing options to confirm a diagnosis in an individual suspected of having JEB.

Skin biopsy. Examination of a skin biopsy by transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping is one way to reliably establish a diagnosis of JEB. A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) or a mechanically induced blister and should include some normal adjacent skin. Older blisters undergo change that may obscure the diagnostic morphology and can be misleading.

Note:

1.

For TEM:

a.

Specimens must be placed in fixation medium (such as gluteraldehyde) as designated by the laboratory performing the test.

b.

Formaldehyde-fixed samples cannot be used for electron microscopy

2.

For immunofluorescent antibody/antigen mapping:

a.

Specimens should be sent in sterile carrying medium (such as Michel's of Zeus) as specified by the laboratory performing the test.

b.

Some laboratories prefer flash-frozen tissue.

c.

In some laboratories the mapping only designates the level of the cleavage by using various antibodies which mark different layers of the basement membrane. A specialized laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. Caution should be exercised NOT to send specimens labeled simply “for immunofluorescence” to a routine laboratory which is likely to stain for immunoglobulins and complement, both of which are irrelevant for the diagnosis of EB.

3.

Light microscopy is inadequate and unacceptable for the accurate diagnosis of EB.

Transmission electron microscopy (TEM) is used to examine the number and morphology of basement membrane zone structures — in particular, the number and morphology of anchoring fibrils, the presence of and morphology of hemidesmosomes, anchoring filaments, and keratin intermediate filaments as well as the presence of micro-vesicles showing the tissue cleavage plane.

Findings on TEM include the following [Kunz et al 2000, Jonkman et al 2002, Charlesworth et al 2003, Pasmooij et al 2004a, Shinkuma et al 2011]:

  • In all forms of JEB. Splitting is seen in the lamina lucida of the basement membrane of the epidermis or just above the basement membrane at the level of the hemidesmosomes in the lowest level of the keratinocytes layer.
  • In Herlitz JEB (H-JEB). Hemidesmosomes are reduced in number and hypoplastic. Anchoring filaments are markedly reduced or absent.
  • In non-Herlitz JEB (NH-JEB). Anchoring filaments may be reduced; hemidesmosomes may be reduced or hypoplastic.

Immunofluorescent antibody/antigen mapping. Findings include the following:

  • Abnormal or absent staining with antibodies to laminin 332 (aka LAM5) [Aumailley et al 2005] resulting from mutations in LAMA3, LAMB3, or LAMC2 in Herlitz or non-Herlitz forms of JEB
  • Abnormal or absent staining with antibodies to collagen XVII in JEB is caused by mutations in COL17A1

Note: Mutations in ITGB4, ITGA6, and PLEC1 are causative of epidermolysis bullosa with pyloric atresia (EB-PA).

Normal staining for other antigens (e.g., collagen VII, keratins 5 and 14) confirms the diagnosis of JEB.

Note: Especially in milder forms of EB, indirect immunofluorescent studies may not be sufficient to make the diagnosis because near-normal antigen levels are detected and no cleavage plane is observed. In these cases electron microscopic examination of the skin biopsy must be performed. Alternatively, rebiopsy allowing more time (several hours) between rubbing of the skin (or the patient performing an activity that induces fresh blistering) and blister formation prior to biopsy for IFM or EM may be required.

Molecular Genetic Testing

Genes. LAMB3, COL17A1, LAMC2, and LAMA3 are the four genes in which mutations are known to cause the two major phenotypes of JEB: Herlitz and non-Herlitz JEB [Fine et al 1999, Anton-Lamprecht & Gedde-Dahl 2002]:

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Junctional Epidermolysis Bullosa

Gene 1 Proportion of JEB Attributed to Mutations in This Gene 2 Test MethodMutations Detected 3, 4
LAMB3 70% Sequence analysis Sequence variants 5
Deletion/duplication analysis 6Exonic/whole gene deletions 7
Targeted mutation analysis Targeted variants 8
COL17A1 12% Sequence analysis Sequence variants 5
Deletion/duplication analysis 6 Exonic/whole gene deletions 7
LAMC2 9% Sequence analysis Sequence variants 5
Deletion analysis 6Exonic/whole gene deletions 7
Targeted mutation analysis Targeted variants 8
LAMA3 9% Sequence analysis Sequence variants 5, 9
Deletion analysis 6Exonic/whole gene deletions 7
Targeted mutation analysis Targeted variants

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. Varki et al [2006]

3. See Molecular Genetics for information on allelic variants.

4. Sequencing of all four genes results in a mutation detection frequency of 98%. Large deletions and intronic variations that alter splicing are thought to be responsible for the other 2%.

5. 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. For issues to consider in interpretation of sequence analysis results, click here.

6. 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.

7. Pulkkinen et al [1997], Takizawa et al [2000b], Fassihi et al [2005], Varki et al [2006]

8. Targeted mutation analysis should be the first step for individuals of specific ethnic groups (see Targeted molecular genetic testing).

9. Care must be taken to sequence the genomic region of the longest transcript of LAMA3 rather than one of the shorter transcript variants.

Testing Strategy

To confirm/establish the diagnosis in a proband

Skin biopsy is one way to reliably establish a diagnosis of JEB and to direct the clinician toward the appropriate genes to target for mutation analysis. Especially in newborns, a skin biopsy from a newly induced blister should be performed as soon as possible after initial evaluation. The skin biopsy should be analyzed for morphology by electron microscopy and/or for the basement membrane proteins by indirect immunofluorescence to suggest the appropriate genes to be tested.

Note: Lethal forms of JEB resulting from COL17A1 mutations have been described [Varki et al 2006, Murrell et al 2007]; thus the strict criteria of a lethal versus non-lethal form of JEB are not sufficient to define the order of molecular genetic testing.

Targeted molecular genetic testing. When any form of JEB is suspected, targeted mutation analysis should be the first step for individuals of the following ethnic groups:

These mutations may account for up to 45% of JEB-causing mutations.

Sequential gene sequence analysis. If neither or only one mutation is identified in an individual with biopsy-proven Herlitz JEB following targeted mutation analysis, sequence analysis of the four known genes has the following mutation detection frequencies [Varki et al 2006]:

  • LAMB3: 25%
  • LAMC2: 9%
  • LAMA3: 10%
  • COL17A1: 8%

If neither or only one mutation is identified in an individual with biopsy-proven non-Herlitz JEB following targeted mutation analysis, sequence analysis of the four known genes has the following mutation detection frequencies [Varki et al 2006]:

  • LAMB3: 25%
  • COL17A1: 25%
  • LAMC2: 3%
  • LAMA3: 8%

If no mutations are identified in the four genes listed above, it is appropriate to consider molecular genetic testing of genes that lead to a JEB-like phenotype (including ITGB4 and PLEC1; see Differential Diagnosis, EB-PA) [Inoue et al 2000, Kunz et al 2000, Charlesworth et al 2003] or a multi-gene panel that includes genes known to lead to JEB and JEB-like phenotypes.

Multi-gene panel analysis. An alternative to skin biopsy with targeted genetic testing and sequential genetic testing is use of a multi-gene panel. Multi-gene panels can be used for simultaneous analysis of multiple genes known to be involved in the pathogenesis of EB and related conditions. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual also varies.

Carrier testing for at-risk relatives (in families with autosomal recessive inheritance) 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 diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Clinical Description

Natural History

Before the molecular basis of junctional epidermolysis bullosa (JEB) was understood, subtypes were identified (see Nomenclature) based primarily on clinical features, mode of inheritance, and the presence or absence of laminin 5 and anchoring filaments on skin biopsy. Broad classification of JEB includes H-JEB (aka lethal) and NH-JEB (aka non-lethal) and is based on severity and survival past the first years of life [Fine et al 1999, Pulkkinen & Uitto 1999, Irvine & McLean 2003, Uitto & Richard 2005, Kelly-Mancuso et al 2013, Yuen et al 2013].

Herlitz JEB (H-JEB). In this classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period [Laimer et al 2010].

Blistering is very severe and may lead to large regions of affected skin with significant granulation tissue. Granulation tissue characteristically appears around the nose, mouth, ears, and tips of the fingers and toes as well as in areas subject to friction such as the buttocks and the back of the head. Persistent plaques on the face can be challenging to treat. The granulation tissue manifests as large eroded patches and plaques often with serpiginous or annular borders that are friable and bleed easily and profusely. There can be extensive loss of blood, fluid, and protein. Such erosions are often life threatening because they make these infants susceptible to electrolyte imbalance and infection including sepsis and sudden death. If the infant survives, blistering may continue throughout life, generally without scarring unless there has been severe secondary infection. Scarring pseudosyndactyly of the hands and feet fusing the digits into "mitten" hands and feet with severe loss of function has been seen in the very few individuals with H-JEB who survive [Fine et al 1999].

In addition to cutaneous involvement, mucosal involvement of the mouth, upper respiratory tract, esophagus, bladder, urethra, and corneas can be seen. Accumulation of granulation tissue surrounding the airway is usually subglottic and the first manifestation is a weak, hoarse cry. Eventually, compression and obstruction of the airway result in stridor and respiratory distress. Unless tracheostomy is performed, many children succumb from respiratory complications. However, managing a tracheostomy in a child with such fragile skin is difficult [Ida et al 2012].

Bladder and urethral epithelial involvement can cause dysuria, urinary retention, urinary tract infections, and eventual renal compromise. Renal and ureteral anomalies that can be seen include dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, and absent bladder [Puvabanditsin et al 1997, Kambham et al 2000, Nakano et al 2000, Wallerstein et al 2000, Fine et al 2004, Varki et al 2006, Pfendner et al 2007].

Esophageal narrowing has been reported, but is less common than in children with recessive dystrophic EB (RDEB).

Secondary complications common in H-JEB include the following:

  • Growth retardation from malnutrition as a result of poor intake and an increased nutritional demand for tissue healing
  • Anemia
  • Alopecia
  • Cutaneous infection
  • Sepsis
  • Electrolyte imbalance
  • Osteoporosis [Fewtrell et al 2006]
  • Dilated cardiomyopathy
  • Urologic and renal complications
  • Squamous cell carcinoma [Yuen & Jonkman 2011]
  • Enamel dysplasia with pitting of the teeth [Krämer 2010, Stellingsma et al 2011]

Most children with H-JEB do not survive past the first year of life.

Non-Herlitz JEB (NH-JEB). A spectrum of JEB clinical phenotypes, all of which are less severe than classic H-JEB, comprises NH-JEB. The phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal, ureteral, or esophageal involvement or relatively more widespread including flexural areas and trunk.

Some children virtually never blister after the newborn period. The severe granulation tissue and respiratory compromise of H-JEB are rare.

Varying degrees of alopecia and onychodystrophy as well as tooth pitting remain hallmarks of this type of JEB.

Manifestations that can occur in H-JEB, NH-JEB, and EB with pyloric atresia (EB-PA) as well as dystrophic epidermolysis bullosa (DEB) and epidermolysis bullosa simplex (EBS). The following manifestations are now recognized to be found in the major EB types as described in the findings of the National EB Registry [Fine et al 1999]:

  • Congenital localized absence of skin (aplasia cutis congenita) can be seen in any of the major types of EB and is not a discriminating diagnostic feature of any of these types of EB in general or any subtype of JEB. Congenital absence of skin on the extremities had been classified as Bart syndrome [OMIM 132000] but currently is considered a manifestation of all types of EB.
  • Milia are small white-topped papules; they are often confused with epidermal cysts and are not confined to any type of EB, although they are most common in individuals with DEB.
  • Nail dystrophy is defined as changes in size, color, shape, or texture of nails and is not confined to any one form of EB.
  • Scarring alopecia is defined as complete loss of scalp hair follicles as a result of scarring and loss of hair follicles. Scarring alopecia is more prevalent in JEB and DEB but is not confined solely to any one form of EB.
  • Hypotrichosis is defined as reduction in the number of hair follicles in a given area compared to the number of hair follicles in the same area of a normal individual of the same gender. Hypotrichosis is not confined to any one form of EB.
  • Pseudosyndactyly and other contractures. Pseudosyndactyly is defined as the partial or complete loss of web spaces between any digits of the hands or feet. "Other contractures" refers to loss of mobility of any other joints as a result of fibrous tissue scars. Although these changes are more prevalent in DEB, they have also been observed occasionally in the other forms of EB.
  • Scarring is not confined to any form of EB and has been observed in 30% of those with EBS, 76% of those with JEB, and up to 98% of those with DEB.
  • Exuberant granulation tissue, previously thought to be confined to those with JEB (23%), has now been observed in a small percentage of those with DEB (≤12%) and EBS (0.7%). This finding is misleading because it does not usually appear until the affected child is a few years old and most children with H-JEB do not survive that long.

Genotype-Phenotype Correlations

H-JEB. The severest forms of H-JEB are a result of inactivating mutations on both alleles, which result in little or no functional protein [Varki et al 2006]. For frameshift mutations, the severity may be related to the position of the stop codon; however, the presence of some functional protein seems to be the most important factor in mitigating disease severity.

Less severe forms of H-JEB 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 that has been identified [Varki et al 2006]. In addition, moderation of phenotypes expected to be severe has occurred through in-frame skipping of exons containing nonsense or frameshift mutations [McGrath et al 1999].

Penetrance

Mutations in LAMB3, LAMA3, LAMC2, and COL17A1 are 100% penetrant in individuals who have two mutations on different alleles in the same gene.

Anticipation

Genetic anticipation is not observed in junctional epidermolysis bullosa.

Nomenclature

The following hierarchy includes as synonyms specific designations for JEB that have been used in the past. Designations in current use are in boldface:

  • Junctional epidermolysis bullosa, Herlitz (synonyms: epidermolysis bullosa letalis; epidermolysis bullosa junctional Herlitz-Pearson; junctional epidermolysis bullosa mitis)
    In descending order of frequency:
    • LAMB3-related junctional epidermolysis bullosa
    • LAMC2-related junctional epidermolysis bullosa
    • LAMA3-related junctional epidermolysis bullosa
    • COL17A1-related junctional epidermolysis bullosa
  • Junctional epidermolysis bullosa, non-Herlitz (synonyms: epidermolysis bullosa, generalized atrophic benign (GABEB); epidermolysis bullosa junctionalis, disentis type; epidermolysis bullosa junctionalis, progressive; epidermolysis bullosa junctionalis, severe non-lethal)
    In descending order of frequency:
    • LAMB3-related junctional epidermolysis bullosa
    • COL17A1-related junctional epidermolysis bullosa
    • LAMC2-related junctional epidermolysis bullosa
    • LAMA3-related junctional epidermolysis bullosa

Generalized atrophic benign EB (GABEB), originally described as a separate clinical entity caused by mutations in COL17A1, is now included within the NH-JEB category because of significant phenotypic overlap.

Prevalence

According to the National EB Registry, prevalence of all types of JEB is 0.44 per million in the US population [Fine et al 1999]. Recent data estimate the incidence of JEB to be at least 3.59 per million per year with a 73% mortality rate.

  • H-JEB prevalence is estimated at 0.4 per million but may be underrepresented. JEB incidence is also very low (0.41 per million), but is probably underestimated: many Herlitz cases go unreported because infants succumb to the disease in the neonatal period. H-JEB prevalence is also low because most affected children die in early infancy.
  • NH-JEB incidence is 2.0 per million.

Carrier risk of all forms of JEB in the US population has been calculated as 1:350.

Differential Diagnosis

The four major types of EB, caused by mutations in 14 different genes, are epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), dystrophic epidermolysis bullosa (DEB), and Kindler syndrome. The diagnostic criteria describing the major types and rarer subtypes of EB have recently been expanded to include Kindler syndrome, Laryngo-oculo-cutaneous syndrome, and a number of rare forms of EBS [Fine et al 2009, Intong & Murrell 2012]. The diagnostic criteria are designed to encompass other new blistering disorders as they are discovered. Excellent clinical reviews include the chapter on EB in Principles and Practice of Medical Genetics [Anton-Lamprecht & Gedde-Dahl 2002] and Fine's Revised Classification System [Fine et al 1999, Fine et al 2000, Fine et al 2008].

The four major types of EB share fragility of the skin, manifested by blistering 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 type of EB requires either a fresh skin biopsy from a newly induced blister that is stained by indirect immunofluorescence for critical basement membrane protein components or molecular genetic confirmation of the diagnosis. When using skin biopsy, the diagnosis is established by determining the cleavage plane on TEM and the presence/absence of these protein components by immunofluorescent antibody/antigen mapping and their distribution. 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 (see Clinical Description).
  • 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 EBS and JEB 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 types of EB and is not a discriminating diagnostic feature (see Clinical Description).

Clinical findings that tend to be characteristic for a specific type of EB include the following:

  • Corneal erosions, esophageal strictures, and nail involvement may indicate DEB.
  • Blistering and scarring limited to the hands and feet in milder cases suggests autosomal dominant DEB (DDEB).
  • Pseudosyndactyly (mitten deformities) and contractures in older children and adults usually suggests autosomal recessive DEB (RDEB).
  • Hoarseness and respiratory distress suggest H-JEB.
  • Granulation tissue suggests JEB.
  • Hyperkeratosis of the palms and soles suggests EBS, especially the DM type.

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that results in nonscarring blisters caused by little or no trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 12 minor subtypes of EBS; all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are:

  • EBS, localized (EBS-loc; previously known as Weber-Cockayne type)
  • EBS, Dowling-Meara type(EBS-DM)
  • EBS, other generalized (EBS, gen-nonDM; previously known as Koebner type)
  • EBS-with mottled pigmentation (EBS-MP)

The phenotypes for these four subtypes of EBS range from relatively mild blistering of the hands and feet to more generalized blistering and extensive hyperkeratosis, which can be fatal.

  • In EBS-loc, blisters are rarely present or minimal at birth and may occur on the knees and shins with crawling or on the feet at approximately age18 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.
  • In EBS, gen-non DM, 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.
  • In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-DM; over time, progressive brown pigmentation interspersed with hypopigmented spots develops on the trunk and extremities, with the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur.
  • In EBS-DM, onset is usually at birth; severity varies greatly, both within and among families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. EBS-DM appears to improve with warmth 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 hyper- 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.

Other subtypes of EB simplex (EBS). The current classification system divides EBS into two subtypes based on the location of blistering in the epidermis. In the suprabasal forms of EBS, blistering occurs above the basal keratinocytes. The suprabasal forms of EBS are extremely rare and include: EBS superficialis; EBS, plakophilin-1 deficiency (also called ectodermal dysplasia/skin fragility syndrome); and EBS, lethal acantholytic.

  • EBS, plakophilin-1 deficiency is characterized by mild skin fragility associated with perioral cracking and cheilitis, hypotrichosis or alopecia, and a painful and fissured palmoplantar keratoderma; it is caused by loss-of-function mutations in PKP1 (for review, see McGrath & Mellerio [2010]).
  • EBS, lethal acantholytic is caused by mutations in the tail region of DSP, which encodes desmoplakin [Jonkman et al 2005, Bolling et al 2010, Hobbs et al 2010]. Affected neonates present with progressive erosions without blistering, alopecia, and loss of nails. Death within the first days after birth secondary to profound fluid and electrolyte imbalance is common.

Hemidesmosomal EB. Pulkkinen & Uitto [1999] proposed that EB with muscular dystrophy (EB-MD) and EB with pyloric atresia (EB-PA) be considered "hemidesmosomal JEB" because the involved proteins are located in the hemidesmosomes. Within basal keratinocytes, plectin is localized to the inner plaques of the hemidesmosomes, which are hypoplastic and show poor association with keratin filaments. Electron microscopy of skin biopsies reveals a plane of cleavage (level of separation) within the bottom layer of the basal keratinocytes, just above the hemidesmosomes. (See EB-PA.)

However, "hemidesmosomal epidermolysis bullosa" is not a universally accepted designation and is not included in the 2008 classification of EB; the following three types typically have been included either with EBS (caused by biallelic mutations in PLEC1, ITGA6, or ITGB4) or with JEB (caused by biallelic mutations in ITGA6 or ITGB4):

  • EB-MD [OMIM 226670]. Approximately 50 cases of EB-MD have been reported worldwide. Some persons with EB as a result of PLEC1 mutations develop muscular dystrophy [Smith et al 1996, Charlesworth et al 2003, Koss-Harnes et al 2004, Schara et al 2004, Pfendner et al 2005]. Blistering occurs early and is generally mild. Muscular dystrophy may not appear until later childhood, adolescence, or in some cases adulthood, and can cause immobility and eventually death later in life. Mutations have been described throughout PLEC1 but seem to cluster in the two long open reading frames containing exons in the 3' end of the gene. Nonsense, missense, insertion/deletion, and splice-junction mutations have been described. The mildest phenotypes are usually associated with in-frame insertions or deletions, which do not alter the reading frame of the microRNA (mRNA) [Pfendner et al 2005]. Inheritance is autosomal recessive.

    A lethal case of autosomal recessive EBS as a result of PLEC1 mutations has also been described [Charlesworth et al 2003]. Kunz et al [2000] also described a case of EBS with severe mucous membrane involvement as a result of mutations in PLEC1.

    EBS caused by mutations in PLEC1 can vary from relatively mild, previously known as the Ogna form [OMIM 131950] [Koss-Harnes et al 2002], to more severe and sometimes lethal [Kunz et al 2000, Charlesworth et al 2003]. Recent data indicates that up to 8% of EBS cases may be caused by mutations in PLEC1 [Bolling et al 2014].
  • EB-PA. In several US and Japanese families, EB with pyloric atresia is associated with premature termination mutations in PLEC1 [Nakamura et al 2005, Pfendner & Uitto 2005], and more commonly, the gene encoding β4 integrin (ITGB4). Rare cases of EB-PA are associated with mutations in the α6 integrin gene (ITGA6). Although disease course is severe and often lethal in the neonatal period, non-lethal forms have been described. Individuals with mutations in the genes encoding α6 or β4 integrin may also show renal and ureteral anomalies, including dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, and absent bladder [Puvabanditsin et al 1997, Kambham et al 2000, Nakano et al 2000, Wallerstein et al 2000, Varki et al 2006, Pfendner et al 2007]. Occasionally, pyloric atresia may be suspected during gestation as a result of oligohydramnios, with or without elevated alpha-fetoprotein and acetylcholinesterase levels, and echogenic material in the amniotic fluid [Dolan et al 1993, Azarian et al 2006].

Dystrophic EB (DEB). The blister forms below the basement membrane, and the basement membrane is attached to the blister roof, resulting in scarring when blisters heal. Mutations in COL7A1, the gene encoding type VII collagen, have been demonstrated in all forms of DEB, both dominant and recessive [Varki et al 2007].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with junctional epidermolysis bullosa (JEB), the following evaluations are recommended:

  • Evaluation of the sites of blister formation, including mouth, esophagus, and airway in a child with progressive hoarseness or stridor
  • Direct examination of the airway by an experienced otolaryngologist with appropriately small and lubricated instruments to determine the extent of airway compromise so that decisions regarding tracheostomy can be discussed with the family
  • Evaluation for gastroesophageal reflux disease which may cause additional trauma to the upper airway [Ida et al 2012]
  • Evaluation for existing osteopenia through skeletal radiographs or DEXA scan
  • Evaluation for cardiomyopathy by clinical evaluation and/or echocardiogram [Fine et all 2008]
  • Measurements of hemoglobin and electrolytes to evaluate for anemia and electrolyte imbalance
  • Skin bacterial cultures and blood cultures in clinically ill infants to decide appropriate antibiotic treatment
  • Medical genetics consultation

Treatment of Manifestations

Skin. The skin needs to be protected from shearing forces and caretakers need to learn how to handle the child with EB [Denyer 2010, Pope et al 2012].

New blisters should be lanced and drained to prevent further spread from fluid pressure. 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 include the following:
    • Ordinary Band-Aids®
    • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline® gauze, Adaptic®, Xeroform®)
    • Nonstick products (e.g., Telfa®, N-terface®)
    • Silicone-based products without adhesive (e.g., Mepitel®, Mepilex®)
  • A secondary layer that provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g., Kerlix®) are commonly used.
  • A tertiary layer that usually has some elastic properties and ensures the integrity of the dressing (e.g., Coban® or elasticized tube gauze of varying diameters such as Band Net®)

Other. The 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.

Esophageal strictures and webs can be dilated repeatedly to improve swallowing [Azizkhan et al 2007].

A hoarse cry in an infant should alert to the possibility of airway obstruction with granulation tissue. Decisions about tracheostomy should involve the family and take into consideration the medical condition of the infant. Because of the poor prognosis and severe pain and discomfort experienced by these infants, a discussion with the family and hospital ethics committee often helps to determine the type of intervention and comfort care to provide [Yan et al 2007, Ida et al 2012].

Gastroesophageal reflux disease, when present, should be treated as in the general population.

Some children have delays or difficulty walking because of blistering and hyperkeratosis. Appropriate footwear and physical therapy are essential to preserve ambulation.

Treatment of granulation tissue can be attempted with high-potency topical steroids, silver nitrate, electrocautery, or autologous skin grafts.

Psychosocial support, including social services and psychological counseling, is essential [Lucky et al 2007].

Pain management becomes an important part of daily care [Goldschneider & Lucky 2010]. In those with difficult-to-control pain, referral to a pain management specialist can be considered.

Dental care is necessary because of inherent enamel abnormalities [Kirkham et al 2000, Krämer et al 2012].

Urologic and renal problems may be serious in this population [Kajbafzadeh et al 2010]. For those affected individuals who survive, referral to a urologist may be considered.

Prevention of Secondary Complications

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.

In infants and children with JEB 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 2006].

In children who survive the newborn period, nutritional deficiencies must also be addressed when they are identified:

  • Calcium and vitamin D replacement for osteopenia and osteoporosis
  • Zinc supplementation for wound healing [Mellerio et al 2007]
  • Treatment of iron-deficiency anemia (a chronic problem) with oral or intravenous iron infusions and red blood cell transfusions

Wound infections should be treated with the appropriate antiseptic or antimicrobial medication.

Surveillance

Screening for iron-deficiency anemia should be routine, with complete blood counts and measurement of serum iron concentration to provide iron supplementation when necessary.

Screening for zinc deficiency by measuring serum zinc concentration should be routine to provide zinc supplementation when necessary to enhance wound healing.

Screening with bone mineral density scanning may detect early osteopenia and/or osteoporosis. No guidelines have been established regarding the age at which this should be initiated.

Screening for dilated cardiomyopathy can be accomplished with regular echocardiograms [Lara-Corrales et al 2010].

Because of the risk for squamous cell carcinoma, 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 followed by local excision may be necessary.

Agents/Circumstances to Avoid

Most persons with JEB cannot use ordinary medical tape or Band-Aids®. Silicone-based products provide a good substitute for tape.

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

Activities that, in general, 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 find creative ways to protect their skin.

Evaluation of Relatives at Risk

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

Pregnancy Management

Cesarean section may be recommended to reduce trauma to the skin of an affected fetus during delivery.

Therapies Under Investigation

Several approaches to gene therapy for JEB, focused on retroviral modification of in vitro epidermal cells, have been proposed [Robbins et al 2001, Ortiz-Urda et al 2003]. One successful clinical trial has been conducted using transplantation of sheets of genetically modified epidermal stem cells in one affected individual with biallelic LAMB3 mutations [Mavilio et al 2006, Di Nunzio et al 2008]. Animal models include intra-amniotic prenatal laminin 332 delivery in mouse [Mühle et al 2006] and a spontaneous form of JEB in dog [Capt et al 2005, Spirito et al 2006].

Natural gene therapy is being investigated using autologous revertant cells cultured from patches of non-blistering skin [Pasmooij et al 2012].

The knockout mouse model for all JEB-related genes should facilitate the development of these therapeutic approaches [Jiang & Uitto 2005]. Animal models that have been used to study EB were reviewed in Natsuga et al [2010].

Induced pleuripotent stem cells (IPS) are being studied in several laboratories around the world to address the treatment of other types of EB [Tolar et al 2013, Osborn et al 2013].

Protein replacement therapy with LAMB3 has been studied in vitro [Igoucheva et al 2008] with promising results.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Junctional epidermolysis bullosa (JEB) is inherited in an autosomal recessive manner.

There is no evidence to date that a single (i.e., heterozygous) mutation in LAMA3, LAMB3, LAMC2, or COL17A1 results in JEB. However dental anomalies have been reported in individuals who have a single LAMB3 or COL17A1 mutation [McGrath et al 1996, Almaani et al 2009, Poulter et al 2014].

Risk to Family Members

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual 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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic except in the case of COL17A1 or LAMB3 mutations where carriers may exhibit dental enamel hypoplasia and/or pitting and caries [Nakamura et al 2006, Murrell et al 2007, Kim et al 2013, Poulter et al 2014].

Offspring of a proband. The offspring of an individual with autosomal recessive JEB are obligate heterozygotes (carriers) for a disease-causing mutation.

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

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Fetoscopy. Electron microscopic evaluation of fetal skin biopsies obtained by fetoscopy is also diagnostic in JEB. Fetoscopy carries a greater risk to pregnancy than CVS or amniocentesis and is performed relatively late (18-20 weeks) in gestation. Prenatal diagnosis for JEB using fetoscopy is not currently available in the US, but may be available in Europe.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • DEBRA International
    Am Heumarkt 27/3
    Vienna 1030
    Austria
    Phone: +43 1 876 40 30-0
    Fax: +43 1 876 40 30-30
    Email: office@debra-international.org
  • DebRA of America, Inc. (Dystrophic Epidermolysis Bullosa Research Association)
    16 East 41st Street
    3rd Floor
    New York NY 10017
    Phone: 866-332-7276 (toll-free); 212-868-1573
    Email: staff@debra.org
  • DebRA UK
    DebRA House
    13 Wellington Business Park
    Crowthorne Berkshire RG45 6LS
    United Kingdom
    Phone: +44 01344 771961
    Fax: +44 01344 762661
    Email: debra@debra.org.uk
  • Medline Plus
  • EBCare Registry
    The EBCare Registry is a resource for individuals and families affected by all forms of epidermolysis bullosa (EB) and qualified researchers working on approved EB research projects.
    Phone: 866-332-7276
    Fax: 888-363-0790
    Email: coordinator@EBCare.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Junctional Epidermolysis Bullosa: Genes and Databases

Data 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 Junctional Epidermolysis Bullosa (View All in OMIM)

113811COLLAGEN, TYPE XVII, ALPHA-1; COL17A1
150292LAMININ, GAMMA-2; LAMC2
150310LAMININ, BETA-3; LAMB3
226650EPIDERMOLYSIS BULLOSA, JUNCTIONAL, NON-HERLITZ TYPE
226700EPIDERMOLYSIS BULLOSA, JUNCTIONAL, HERLITZ TYPE
600805LAMININ, ALPHA-3; LAMA3

Molecular Genetic Pathogenesis

The proteins encoded by LAMA3, LAMB3, and LAMC2 assemble into the laminin 332 heterotrimer (aka LAM5 [Aumailley et al 2005]). A mutation in these genes can lead to reduced resistance to minor trauma and the resulting mucocutaneous blistering that is the hallmark of junctional epidermolysis bullosa (JEB). The type of mutation, the biochemical properties of the substituted amino acid, if present, and its location determine the severity of the blistering phenotype (see Genotype-Phenotype Correlations). Nonsense mutations predominate in the severe forms of JEB and result in the absence of one of the three proteins that assemble into laminin 332. Missense mutations in key positions of the protein subunits affect the ability of the laminin α3, β3, and γ2 polypeptides to assemble into a trimeric molecule, its secondary structure, and its ability to form the intracellular anchoring fibrils of the lamina densa.

Collagen XVII forms an integral part of the hemidesmosome and has an intracellular as well as extracellular component. There is evidence that it interacts with alpha-6 integrin within the hemidesmosome. The hemidesmosomes – structures made up of several protein components including COLXVII, alpha-6 beta-4 integrin, BPAG1, and plectin – anchor the epidermal cells to the underlying dermis. The type and position of mutations in COL17A1 determine whether some partially functional protein is made and also affect the level of the cleavage plane of the skin. In some cases, mutations affecting the intracellular domain result in a cleavage plane within the lowest level of the basal keratinocytes usually associated with EBS [Charlesworth et al 2003].

LAMA3

Gene structure. All of LAMA3 is encoded in 76 exons spanning 318 kb on chromosome 18q11.2. Transcript variants are produced by alternative splicing (see Normal gene product).

Pathogenic allelic variants. Nonsense, missense, splicing, and insertion/deletion mutations have been reported [Nakano et al 2002a, Varki et al 2006]. Premature termination codon mutations on both alleles result in the severe (Herlitz) form of JEB in most instances. A few mildly affected individuals with JEB with premature termination codon mutations have been reported [Nakano et al 2002a]. Amino acid substitutions and splicing mutations may result in a milder phenotype [Posteraro et al 1998, Nakano et al 2002a]. The common hot spot mutations are reportedly present in approximately 45% of H-JEB cases in the US (see Testing Strategy). These mutations invariably result in premature termination codons and when found on both alleles result in H-JEB. Overlapping phenotypes may exist in which mutations in LAMA3 result in skin fragility with eye and laryngeal involvement [Varki et al 2006, Figueira et al 2007].

Table 2. LAMA3 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.151insG 1p.Val51GlyfsTer3AY327114​.1
AAQ72569​.1
c.1948A>Tp.Arg650Ter

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. See Genetically Related Disorders.

Normal gene product. There are three isoforms (LAMA3a, LAMA3b1, and LAMA3b2) produced by alternative splicing. Of the two LAMA3b isoforms, LAMA3b1 encodes a longer protein of 3,333 amino acids in 75 exons (exons 1-38 and 40-76 of the gene); the shorter isoform LAMA3b2 encodes a protein of 3289 amino acids in 74 exons (exons 1-9, 11-38, and 40-76 of the gene) and differs from LAMA3b1 in that exon 10 is removed by alternative splicing. The shorter LAMA3a isoform of 1724 amino acids is encoded in 38 exons (exons 39-76 of LAMA3) and is unique in that exon 39 is expressed.

The laminin A3 protein associates with laminin B3 and C2 proteins to form the laminin 332 heterotrimer that comprises the anchoring fibrils in the epidermis. The anchoring fibrils hold the layers of the basal lamina together and form associations with collagen VII on the dermal side and plectin and α6 β4 integrin in the hemidesmosomes on the epidermal side. This interaction allows the formation of the protein network of the epidermis, which results in a flexible and resilient barrier to resist trauma.

Abnormal gene product. See Molecular Genetic Pathogenesis. In all three genes (LAMB3, LAMC2, and LAMA3), amino acid substitutions, splicing mutations, and in-frame deletions and insertions may result in the formation of some partially functional protein that results in a milder phenotype. Specific amino acid substitutions, such as replacement of cysteine residues, inhibit the formation of disulfide bonds, result in altered laminin 332 intra- and intermolecular associations, and may result in a more severe phenotype. Usually, on a skin biopsy studied with immunofluorescence, if synthesis of one of the proteins is disrupted, the staining for the other two proteins will also be affected.

LAMB3

Gene structure. The normal LAMB3 cDNA has an open reading frame of 3516 nucleotides in 23 exons spanning 29 kb.

Pathogenic allelic variants. Nonsense, missense, splicing, and insertion/deletion mutations have been reported [Nakano et al 2002b, Varki et al 2006]. A few mildly affected persons with premature termination codon mutations have been reported [Pulkkinen et al 1998, Nakano et al 2002a]. Amino acid substitutions and splicing mutations may result in a milder phenotype [Mellerio et al 1998, Posteraro et al 1998, Nakano et al 2002a].

Table 3. LAMB3 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.124C>Tp.Arg42TerNM_000228​.2
NP_000219​.2
c.727C>Tp.Gln243Ter
c.957ins77p.Glu320Ter
c.1903C>Tp.Arg635Ter

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The laminin B3 protein has 1,172 amino acids. It associates with laminin A3 and C2 proteins to form the laminin 332 heterotrimer that comprises the anchoring fibrils in the epidermis.

Abnormal gene product. See Molecular Genetic Pathogenesis. In all three genes (LAMB3, LAMC2, and LAMA3), amino acid substitutions, splicing mutations, and in-frame deletions and insertions may result in the formation of some partially functional protein that results in a milder phenotype. Specific amino acid substitutions, such as replacement of cysteine residues, inhibit the formation of disulfide bonds, result in altered laminin 332 intra- and intermolecular associations, and may result in a more severe phenotype. Usually, on a skin biopsy studied with immunofluorescence, if synthesis of one of the proteins is disrupted, the staining for the other two proteins will also be affected. Reversion by LAMB3 mosaicism to a normal phenotype has been described and has implications for treatment [Pasmooij et al 2007].

LAMC2

Gene structure. Two LAMC2 transcripot variants result from alternative splicing. The longer is expressed in the epidermis; the epidermal LAMC2 cDNA has an open reading frame of 3573 nucleotides encoding 1191 amino acids in 23 exons spanning 55 kb. The shorter transcript variant terminates two codons past exon 22 and is expressed in the cerebral cortex, lung, and distal tubules of the kidney.

Pathogenic allelic variants. Nonsense, missense, splicing, and insertion/deletion mutations have been reported [Castiglia et al 2001, Nakano et al 2002b, Varki et al 2006]. Amino acid substitutions and splicing mutations may result in a milder phenotype [Posteraro et al 1998, Castiglia et al 2001, Nakano et al 2002a].

Table 4. LAMC2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.283C>Tp.Arg95TerNM_005562​.2
NP_005553​.2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The laminin C2 protein associates with laminins A3 and C2 to form the laminin 332 heterotrimer that makes up the anchoring fibrils in the epidermis.

Abnormal gene product. See Molecular Genetic Pathogenesis. In all three genes (LAMB3, LAMC2, and LAMA3), amino acid substitutions, splicing mutations, and in-frame deletions and insertions may result in the formation of some partially functional protein that results in a milder phenotype. Specific amino acid substitutions, such as replacement of cysteine residues, inhibit the formation of disulfide bonds, result in altered laminin 332 intra- and intermolecular associations, and may result in a more severe phenotype. Usually, on a skin biopsy studied with immunofluorescence, if synthesis of one of the proteins is disrupted, the staining for the other two proteins will also be affected.

COL17A1

Gene structure. The cDNA has an open reading frame of 5610 nucleotides encoding 1497 amino acids in 56 exons.

Benign allelic variants. There is one alternatively spliced mRNA variant [Ruzzi et al 2001].

Pathogenic allelic variants. Mutations in COL17A1, which encodes the collagen XVII protein, a component of the hemidesmosome, result in typically less severe forms of JEB (non-Herlitz) [Gatalica et al 1997, Pulkkinen et al 1999, Takizawa et al 2000a, van Leusden et al 2001, Pasmooij et al 2004b], although a few cases of lethal JEB resulting from COL17A1 mutations have been reported [Varki et al 2006, Murrell et al 2007]. All types of mutations, including premature termination codon, nonsense, insertion/deletion, splice junction, and missense, distributed throughout the gene have been described. The type and location of the mutations and the response of the cells to the mutations determines the phenotype, which can range from mild to severe and in some cases lethal. Reversion to a normal phenotype has been described [Pasmooij et al 2005].

Normal gene product. Collagen XVII (also known as BP180) is composed of intracellular and extracellular domains separated by a transmembrane domain that distinguishes collagen XVII from other collagen family members. The intracellular domain is localized within the basal keratinocyte; the ectodomain is localized outside the cell and serves as an association point with other components of the basement membrane zone. The carboxy-terminal half of collagen XVII, a stretch of 916 amino acids, consists of 15 collagen domains of variable length (15 to 242 amino acids) that are separated by short stretches of non-collagen sequences. The collagenous domains associate to form a homotrimeric triple helical segment of the molecule characteristic of all collagen family members.

Abnormal gene product. Premature termination codon mutations that result in a null allele cause skin fragility, dental abnormalities, and alopecia usually found in patients with NH-JEB. Other mutations may result in varying phenotypic severity. Although COL17A1 mutations do not usually result in lethality, several cases of a neonatal lethal phenotype were recently described [Varki et al 2006, Murrell et al 2007]. Mutations that affect the intracellular domain may result in a cleavage plane more consistent with EBS and be misleading in terms of diagnosis based on electron microscopy biopsy results. Mutations that affect the transmembrane domain may result in intracellular accumulation of collagen XVII protein. Although glycine substitutions in COL17A1 have been described, no autosomal dominant mutations resulting in skin fragility have been identified. Heterozygote carriers of a glycine substitution [Nakamura et al 2006] or other COL17A1 mutations [Murrell et al 2007] may exhibit dental enamel pitting and this characteristic may be diagnostic for COL17A1 mutations in a family with an affected child [Murrell et al 2007].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Almaani N, Liu L, Dopping-Hepenstal PJ, Lovell PA, Lai-Cheong JE, Graham RM, Mellerio JE, McGrath JA. Autosomal dominant junctional epidermolysis bullosa. Br J Dermatol. 2009;160:1094–7. [PubMed: 19120338]
  2. Anton-Lamprecht I, Gedde-Dahl T. Epidermolysis bullosa. In: Rimoin DL, Connor MJ, Pyeritz RE, Korf BR, Emery AEH, eds. Emery and Rimoin’s Principles and Practice of Medical Genetics. 4 ed. London, UK: Churchill Livingstone Publishers; 2002:3810-97.
  3. Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, Engel J, Engvall E, Hohenester E, Jones JC, Kleinman HK, Marinkovich MP, Martin GR, Mayer U, Meneguzzi G, Miner JH, Miyazaki K, Patarroyo M, Paulsson M, Quaranta V, Sanes JR, Sasaki T, Sekiguchi K, Sorokin LM, Talts JF, Tryggvason K, Uitto J, Virtanen I, von der Mark K, Wewer UM, Yamada Y, Yurchenco PD. A simplified laminin nomenclature. Matrix Biol. 2005;24:326–32. [PubMed: 15979864]
  4. Azarian M, Dreux S, Vuillard E, Meneguzzi G, Haber S, Guimiot F, Muller F. Prenatal diagnosis of inherited epidermolysis bullosa in a patient with no family history: a case report and literature review. Prenat Diagn. 2006;26:57–9. [PubMed: 16378325]
  5. Azizkhan RG, Denyer JE, Mellerio JE, González R, Bacigalupo M, Kantor A, Passalacqua G, Palisson F, Lucky AW. Surgical management of epidermolysis bullosa: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile. Int J Dermatol. 2007;46:801–8. [PubMed: 17651160]
  6. Bolling MC, Veenstra MJ, Jonkman MF, Diercks GF, Curry CJ, Fisher J, Pas HH, Bruckner AL. Lethal acantholytic epidermolysis bullosa due to a novel homozygous deletion in DSP: expanding the phenotype and implications for desmoplakin function in skin and heart. Br J Dermatol. 2010;162:1388–94. [PubMed: 20302578]
  7. Bolling MC, Jongbloed JD, Boven LG, Diercks GF, Smith FJ, McLean WH, Jonkman MF. Plectin mutations underlie epidermolysis bullosa simplex in 8% of patients. J Invest Dermatol. 2014;134:273–6. [PubMed: 23774525]
  8. Capt A, Spirito F, Guaguere E, Spadafora A, Ortonne JP, Meneguzzi G. Inherited junctional epidermolysis bullosa in the German Pointer: establishment of a large animal model. J Invest Dermatol. 2005;124:530–5. [PubMed: 15737193]
  9. Castiglia D, Posteraro P, Spirito F, Pinola M, Angelo C, Puddu P, Meneguzzi G, Zambruno G. Novel mutations in the LAMC2 gene in non-Herlitz junctional epidermolysis bullosa: effects on laminin-5 assembly, secretion, and deposition. J Invest Dermatol. 2001;117:731–9. [PubMed: 11564184]
  10. Charlesworth A, Gagnoux-Palacios L, Bonduelle M, Ortonne JP, De Raeve L, Meneguzzi G. Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin. J Invest Dermatol. 2003;121:1344–8. [PubMed: 14675180]
  11. Cohn HI, Murrell DF. Laryngo-onycho-cutaneous syndrome. Dermatol Clin. 2010;28:89–92. [PubMed: 19945620]
  12. Cserhalmi-Friedman PB, Anyane-Yeboa K, Christiano AM. Paternal germline mosaicism in Herlitz junctional epidermolysis bullosa. Exp Dermatol. 2002;11:468–70. [PubMed: 12366701]
  13. Cserhalmi-Friedman PB, Baden H, Burgeson RE, Christiano AM. Molecular basis of non-lethal junctional epidermolysis bullosa: identification of a 38 basepair insertion and a splice site mutation in exon 14 of the LAMB3 gene. Exp Dermatol. 1998;7:105–11. [PubMed: 9583749]
  14. Denyer JE. Wound management for children with epidermolysis bullosa. Dermatol Clin. 2010;28:257–64. [PubMed: 20447488]
  15. Di Nunzio F, Maruggi G, Ferrari S, Di Iorio E, Poletti V, Garcia M, Del Rio M, De Luca M, Larcher F, Pellegrini G, Mavilio F. Correction of laminin-5 deficiency in human epidermal stem cells by transcriptionally targeted lentiviral vectors. Mol Ther. 2008;16:1977–85. [PubMed: 18813277]
  16. Dolan CR, Smith LT, Sybert VP. Prenatal detection of epidermolysis bullosa letalis with pyloric atresia in a fetus by abnormal ultrasound and elevated alpha-fetoprotein. Am J Med Genet. 1993;47:395–400. [PubMed: 7510931]
  17. Fassihi H, Wessagowit V, Ashton GH, Moss C, Ward R, Denyer J, Mellerio JE, McGrath JA. Complete paternal uniparental isodisomy of chromosome 1 resulting in Herlitz junctional epidermolysis bullosa. Clin Exp Dermatol. 2005;30:71–4. [PubMed: 15663509]
  18. Fewtrell MS, Allgrove J, Gordon I, Brain C, Atherton D, Harper J, Mellerio JE, Martinez AE. Bone mineralization in children with epidermolysis bullosa. Br J Dermatol. 2006;154:959–62. [PubMed: 16634901]
  19. Figueira EC, Crotty A, Challinor CJ, Coroneo MT, Murrell DF. Granulation tissue in the eyelid margin and conjunctiva in junctional epidermolysis bullosa with features of laryngo-onycho-cutaneous syndrome. Clin Experiment Ophthalmol. 2007;35:163–6. [PubMed: 17362460]
  20. Fine JD, Bauer EA, McGuire J Moshell A, eds. Epidermolysis Bullosa; Clinical Epidemiologic, and Laboratory Advances and the Findings of the National Epidermolysis Bullosa Registry. Baltimore, MD: Johns Hopkins University Press; 1999.
  21. Fine JD, Eady RA, Bauer EA, Briggaman RA, Bruckner-Tuderman L, Christiano A, Heagerty A, Hintner H, Jonkman MF, McGrath J, McGuire J, Moshell A, Shimizu H, Tadini G, Uitto J. Revised classification system for inherited epidermolysis bullosa: Report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Dermatol. 2000;42:1051–66. [PubMed: 10827412]
  22. Fine JD, Hall M, Weiner M, Li KP, Suchindran C. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008;159:677–82. [PMC free article: PMC2592258] [PubMed: 18616785]
  23. Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol. 2009;60:203–11. [PubMed: 19026465]
  24. Fine JD, Johnson LB, Weiner M, Stein A, Cash S, DeLeoz J, Devries DT, Suchindran C. National Epidermolysis Bullosa Registry.; Inherited epidermolysis bullosa and the risk of death from renal disease: experience of the National Epidermolysis Bullosa Registry. Am J Kidney Dis. 2004;44:651–60. [PubMed: 15384016]
  25. Gatalica B, Pulkkinen L, Li K, Kuokkanen K, Ryynänen M, McGrath JA, Uitto J. Cloning of the human type XVII collagen gene (COL17A1), and detection of novel mutations in generalized atrophic benign epidermolysis bullosa. Am J Hum Genet. 1997;60:352–65. [PMC free article: PMC1712405] [PubMed: 9012408]
  26. Goldschneider KR, Lucky AW. Pain management in epidermolysis bullosa. Dermatol Clin. 2010;28:273–82. [PubMed: 20447492]
  27. Haynes L. Nutritional support for children with epidermolysis bullosa. Br J Nurs. 2006;15:1097–101. [PubMed: 17170656]
  28. Hobbs RP, Han SY, van der Zwaag PA, Bolling MC, Jongbloed JD, Jonkman MF, Getsios S, Paller AS, Green KJ. Insights from a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa. J Invest Dermatol. 2010;130:2680–3. [PMC free article: PMC3061313] [PubMed: 20613772]
  29. Huber M, Floeth M, Borradori L, Schäcke H, Rugg EL, Lane EB, Frenk E, Hohl D, Bruckner-Tuderman L. Deletion of the cytoplasmatic domain of BP180/collagen XVII causes a phenotype with predominant features of epidermolysis bullosa simplex. J Invest Dermatol. 2002;118:185–92. [PubMed: 11851893]
  30. Ida JB, Livshitz I, Azizkhan RG, Lucky AW, Elluru RG. Upper airway complications of junctional epidermolysis bullosa. J Pediatr. 2012 Apr;160:657-61.e1. [PubMed: 22050875]
  31. Igoucheva O, Kelly A, Uitto J, Alexeev V. Protein therapeutics for junctional epidermolysis bullosa: incorporation of recombinant beta3 chain into laminin 332 in beta3-/- keratinocytes in vitro. J Invest Dermatol. 2008;128:1476–86. [PMC free article: PMC3357058] [PubMed: 18079746]
  32. Inoue M, Tamai K, Shimizu H, Owaribe K, Nakama T, Hashimoto T, McGrath JA. A homozygous missense mutation in the cytoplasmic tail of beta4 integrin, G931D, that disrupts hemidesmosome assembly and underlies Non-Herlitz junctional epidermolysis bullosa without pyloric atresia? J Invest Dermatol. 2000;114:1061–4. [PubMed: 10792571]
  33. Intong LR, Murrell DF. Inherited epidermolysis bullosa: new diagnostic criteria and classification. Clin Dermatol. 2012;30:70–7. [PubMed: 22137229]
  34. Irvine AD, McLean WH. The molecular genetics of the genodermatoses: progress to date and future directions. Br J Dermatol. 2003;148:1–13. [PubMed: 12534588]
  35. Jiang QJ, Uitto J. Animal models of epidermolysis bullosa--targets for gene therapy. J Invest Dermatol. 2005;124:xi–xiii. [PubMed: 15812910]
  36. Jonkman MF, Pas HH, Nijenhuis M, Kloosterhuis G, Steege G. Deletion of a cytoplasmic domain of integrin beta4 causes epidermolysis bullosa simplex. J Invest Dermatol. 2002;119:1275–81. [PubMed: 12485428]
  37. Jonkman MF, Pasmooij AM, Pasmans SG, van den Berg MP, Ter Horst HJ, Timmer A, Pas HH. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet. 2005;77:653–60. [PMC free article: PMC1275614] [PubMed: 16175511]
  38. Kajbafzadeh AM, Elmi A, Mazaheri P, Talab SS, Jan D. Genitourinary involvement in epidermolysis bullosa: clinical presentations and therapeutic challenges. BJU Int. 2010;106:1763–6. [PubMed: 20477826]
  39. Kambham N, Tanji N, Seigle RL, Markowitz GS, Pulkkinen L, Uitto J, D'Agati VD. Congenital focal segmental glomerulosclerosis associated with beta4 integrin mutation and epidermolysis bullosa. Am J Kidney Dis. 2000;36:190–6. [PubMed: 10873890]
  40. Kelly-Mancuso G, Kopelan B, Azizkhan RG, Lucky AW. Junctional epidermolysis bullosa incidence and survival: 5-year experience of the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA) Nurse Educator. Pediatr Dermatol. 2013 [PubMed: 23721227]
  41. Kim JW, Seymen F, Lee KE, Ko J, Yildirim M, Tuna EB, Gencay K, Shin TJ, Kyun HK, Simmer JP, Hu JC. LAMB3 mutations causing autosomal dominant amelogenesis imperfecta. J Dent Res. 2013;92:899–904. [PMC free article: PMC3775375] [PubMed: 23958762]
  42. Kirkham J, Robinson C, Strafford SM, Shore RC, Bonass WA, Brookes SJ, Wright JT. The chemical composition of tooth enamel in junctional epidermolysis bullosa. Arch Oral Biol. 2000;45:377–86. [PubMed: 10739859]
  43. Koss-Harnes D, Høyheim B, Anton-Lamprecht I, Gjesti A, Jørgensen RS, Jahnsen FL, Olaisen B, Wiche G, Gedde-Dahl T. A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol. 2002;118:87–93. [PubMed: 11851880]
  44. Koss-Harnes D, Høyheim B, Jonkman MF, de Groot WP, de Weerdt CJ, Nikolic B, Wiche G, Gedde-Dahl T. Life-long course and molecular characterization of the original Dutch family with epidermolysis bullosa simplex with muscular dystrophy due to a homozygous novel plectin point mutation. Acta Derm Venereol. 2004;84:124–31. [PubMed: 15206692]
  45. Krämer SM, Serrano MC, Zillmann G, Gálvez P, Araya I, Yanine N, Carrasco-Labra A, Oliva P, Brignardello-Petersen R, Villanueva J. DEBRA International. Oral health care for patients with epidermolysis bullosa--best clinical practice guidelines. Int J Paediatr Dent. 2012;22 Suppl 1:1–35. [PubMed: 22937908]
  46. Krämer SM. Oral care and dental management for patients with epidermolysis bullosa. Dermatol Clin. 2010;28:303–9. [PubMed: 20447495]
  47. Kunz M, Rouan F, Pulkkinen L, Hamm H, Jeschke R, Bruckner-Tuderman L, Bröcker EB, Wiche G, Uitto J, Zillikens D. Mutation reports: epidermolysis bullosa simplex associated with severe mucous membrane involvement and novel mutations in the plectin gene. J Invest Dermatol. 2000;114:376–80. [PubMed: 10652001]
  48. Laimer M, Lanschuetzer CM, Diem A, Bauer JW. Herlitz junctional epidermolysis bullosa. Dermatol Clin. 2010;28:55–60. [PubMed: 19945616]
  49. Lara-Corrales I, Mellerio JE, Martinez AE, Green A, Lucky AW, Azizkhan RG, Murrell DF, Agero AL, Kantor PF, Pope E. Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study. Pediatr Dermatol. 2010;27:238–43. [PubMed: 20609141]
  50. Lucky AW, Pfendner E, Pillay E, Paskel J, Weiner M, Palisson F. Psychosocial aspects of epidermolysis bullosa: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile. Int J Dermatol. 2007;46:809–14. [PubMed: 17651161]
  51. Mavilio F, Pellegrini G, Ferrari S, Di Nunzio F, Di Iorio E, Recchia A, Maruggi G, Ferrari G, Provasi E, Bonini C, Capurro S, Conti A, Magnoni C, Giannetti A, De Luca M. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med. 2006;12:1397–402. [PubMed: 17115047]
  52. McGrath JA, Ashton GH, Mellerio JE, Salas-Alanis JC, Swensson O, McMillan JR, Eady RA. Moderation of phenotypic severity in dystrophic and junctional forms of epidermolysis bullosa through in-frame skipping of exons containing non-sense or frameshift mutations. J Invest Dermatol. 1999;113:314–21. [PubMed: 10469327]
  53. McGrath JA, Mellerio JE. Ectodermal dysplasia-skin fragility syndrome. Dermatol Clin. 2010;28:125–9. [PubMed: 19945625]
  54. McGrath JA, Kivirikko S, Ciatti S, Moss C, Christiano AM, Uitto J. A recurrent homozygous nonsense mutation within the LAMA3 gene as a cause of Herlitz junctional epidermolysis bullosa in patients of Pakistani ancestry: evidence for a founder effect. J Invest Dermatol. 1996;106:781–4. [PubMed: 8618022]
  55. McLean WH, Irvine AD, Hamill KJ, Whittock NV, Coleman-Campbell CM, Mellerio JE, Ashton GS, Dopping-Hepenstal PJ, Eady RA, Jamil T, Phillips R, Shabbir SG, Haroon TS, Khurshid K, Moore JE, Page B, Darling J, Atherton DJ, Van Steensel MA, Munro CS, Smith FJ, McGrath JA. An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. Hum Mol Genet. 2003;12:2395–409. [PubMed: 12915477]
  56. Mellerio JE, Eady RA, Atherton DJ, Lake BD, McGrath JA. E210K mutation in the gene encoding the beta3 chain of laminin-5 (LAMB3) is predictive of a phenotype of generalized atrophic benign epidermolysis bullosa. Br J Dermatol. 1998;139:325–31. [PubMed: 9767254]
  57. Mellerio JE, Weiner M, Denyer JE, Pillay EI, Lucky AW, Bruckner A, Palisson F. Medical management of epidermolysis bullosa: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile. Int J Dermatol. 2007;46:795–800. [PubMed: 17651159]
  58. Micheloni A, De Luca N, Tadini G, Zambruno G, D'Alessio M. Intracellular degradation of beta4 integrin in lethal junctional epidermolysis bullosa with pyloric atresia. Br J Dermatol. 2004;151:796–802. [PubMed: 15491419]
  59. Mühle C, Neuner A, Park J, Pacho F, Jiang Q, Waddington SN, Schneider H. Evaluation of prenatal intra-amniotic LAMB3 gene delivery in a mouse model of Herlitz disease. Gene Ther. 2006;13:1665–76. [PubMed: 16871230]
  60. Murrell DF, Pasmooij AM, Pas HH, Marr P, Klingberg S, Pfendner E, Uitto J, Sadowski S, Collins F, Widmer R, Jonkman MF. Retrospective diagnosis of fatal BP180-deficient non-Herlitz junctional epidermolysis bullosa suggested by immunofluorescence (IF) antigen-mapping of parental carriers bearing enamel defects. J Invest Dermatol. 2007;127:1772–5. [PubMed: 17344927]
  61. Nakamura H, Sawamura D, Goto M, Nakamura H, Kida M, Ariga T, Sakiyama Y, Tomizawa K, Mitsui H, Tamaki K, Shimizu H. Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta. Int J Mol Med. 2006;18:333–7. [PubMed: 16820943]
  62. Nakamura H, Sawamura D, Goto M, Nakamura H, McMillan JR, Park S, Kono S, Hasegawa S, Paku S, Nakamura T, Ogiso Y, Shimizu H. Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). J Mol Diagn. 2005;7:28–35. [PMC free article: PMC1867514] [PubMed: 15681471]
  63. Nakano A, Chao SC, Pulkkinen L, Murrell D, Bruckner-Tuderman L, Pfendner E, Uitto J. Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. Hum Genet. 2002a;110:41–51. [PubMed: 11810295]
  64. Nakano A, Lestringant GG, Paperna T, Bergman R, Gershoni R, Frossard P, Kanaan M, Meneguzzi G, Richard G, Pfendner E, Uitto J, Pulkkinen L, Sprecher E. Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families. J Am Acad Dermatol. 2002b;46:510–6. [PubMed: 11907499]
  65. Nakano A, Pfendner E, Hashimoto I, Uitto J. Herlitz junctional epidermolysis bullosa: novel and recurrent mutations in the LAMB3 gene and the population carrier frequency. J Invest Dermatol. 2000;115:493–8. [PubMed: 11023379]
  66. Natsuga K, Shinkuma S, Nishie W, Shimizu H. Animal models of epidermolysis bullosa. Dermatol Clin. 2010;28:137–42. [PubMed: 19945627]
  67. Ortiz-Urda S, Lin Q, Yant SR, Keene D, Kay MA, Khavari PA. Sustainable correction of junctional epidermolysis bullosa via transposon-mediated nonviral gene transfer. Gene Ther. 2003;10:1099–104. [PubMed: 12808440]
  68. Osborn MJ, Starker CG, McElroy AN, Webber BR, Riddle MJ, Xia L, DeFeo AP, Gabriel R, Schmidt M, von Kalle C, Carlson DF, Maeder ML, Joung JK, Wagner JE, Voytas DF, Blazar BR, Tolar J. TALEN-based gene correction for epidermolysis bullosa. Mol Ther. 2013;21:1151–9. [PMC free article: PMC3677309] [PubMed: 23546300]
  69. Pasmooij AM, Nijenhuis M, Brander R, Jonkman MF. Natural gene therapy may occur in all patients with generalized non-Herlitz junctional epidermolysis bullosa with COL17A1 mutations. J Invest Dermatol. 2012;132:1374–83. [PubMed: 22318390]
  70. Pasmooij AM, Pas HH, Bolling MC, Jonkman MF. Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3. J Clin Invest. 2007;117:1240–8. [PMC free article: PMC1857245] [PubMed: 17476356]
  71. Pasmooij AM, Pas HH, Deviaene FC, Nijenhuis M, Jonkman MF. Multiple correcting COL17A1 mutations in patients with revertant mosaicism of epidermolysis bullosa. Am J Hum Genet. 2005;77:727–40. [PMC free article: PMC1271383] [PubMed: 16252234]
  72. Pasmooij AM, van der Steege G, Pas HH, Smitt JH, Nijenhuis AM, Zuiderveen J, Jonkman MF. Features of epidermolysis bullosa simplex due to mutations in the ectodomain of type XVII collagen. Br J Dermatol. 2004a;151:669–74. [PubMed: 15377356]
  73. Pasmooij AM, van Zalen S, Nijenhuis AM, Kloosterhuis AJ, Zuiderveen J, Jonkman MF, Pas HH. A very mild form of non-Herlitz junctional epidermolysis bullosa: BP180 rescue by outsplicing of mutated exon 30 coding for the COL15 domain. Exp Dermatol. 2004b;13:125–8. [PubMed: 15009107]
  74. Pfendner E, Rouan F, Uitto J. Progress in epidermolysis bullosa: the phenotypic spectrum of plectin mutations. Exp Dermatol. 2005;14:241–9. [PubMed: 15810881]
  75. Pfendner E, Uitto J, Fine JD. Epidermolysis bullosa carrier frequencies in the US population. J Invest Dermatol. 2001;116:483–4. [PubMed: 11231335]
  76. Pfendner E, Uitto J. Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. J Invest Dermatol. 2005;124:111–5. [PubMed: 15654962]
  77. Pfendner EG, Bruckner A, Conget P, Mellerio J, Palisson F, Lucky AW. Basic science of epidermolysis bullosa and diagnostic and molecular characterization: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile. Int J Dermatol. 2007;46:781–94. [PubMed: 17651158]
  78. Pope E, Lara-Corrales I, Mellerio J, Martinez A, Schultz G, Burrell R, Goodman L, Coutts P, Wagner J, Allen U, Sibbald G. A consensus approach to wound care in epidermolysis bullosa. J Am Acad Dermatol. 2012;67:904–17. [PMC free article: PMC3655403] [PubMed: 22387035]
  79. Posteraro P, De Luca N, Meneguzzi G, El Hachem M, Angelo C, Gobello T, Tadini G, Zambruno G, Castiglia D. Laminin-5 mutational analysis in an Italian cohort of patients with junctional epidermolysis bullosa. J Invest Dermatol. 2004;123:639–48. [PubMed: 15373767]
  80. Posteraro P, Sorvillo S, Gagnoux-Palacios L, Angelo C, Paradisi M, Meneguzzi G, Castiglia D, Zambruno G. Compound heterozygosity for an out-of-frame deletion and a splice site mutation in the LAMB3 gene causes nonlethal junctional epidermolysis bullosa. Biochem Biophys Res Commun. 1998;243:758–64. [PubMed: 9501007]
  81. Poulter JA, El-Sayed W, Shore RC, Kirkham J, Inglehearn CF, Mighell AJ. Whole-exome sequencing, without prior linkage, identifies a mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta. Eur J Hum Genet. 2014;22:132–5. [PMC free article: PMC3865405] [PubMed: 23632796]
  82. Pulkkinen L, Bruckner-Tuderman L, August C, Uitto J. Compound heterozygosity for missense (L156P) and nonsense (R554X) mutations in the beta4 integrin gene (ITGB4) underlies mild, nonlethal phenotype of epidermolysis bullosa with pyloric atresia. Am J Pathol. 1998;152:935–41. [PMC free article: PMC1858243] [PubMed: 9546354]
  83. Pulkkinen L, Bullrich F, Czarnecki P, Weiss L, Uitto J. Maternal uniparental disomy of chromosome 1 with reduction to homozygosity of the LAMB3 locus in a patient with Herlitz junctional epidermolysis bullosa. Am J Hum Genet. 1997;61:611–9. [PMC free article: PMC1715967] [PubMed: 9326326]
  84. Pulkkinen L, Marinkovich MP, Tran HT, Lin L, Herron GS, Uitto J. Compound heterozygosity for novel splice site mutations in the BPAG2/COL17A1 gene underlies generalized atrophic benign epidermolysis bullosa. J Invest Dermatol. 1999;113:1114–8. [PubMed: 10636730]
  85. Pulkkinen L, McGrath JA, Christiano AM, Uitto J. Detection of sequence variants in the gene encoding the beta 3 chain of laminin 5 (LAMB3). Hum Mutat. 1995;6:77–84. [PubMed: 7550237]
  86. Pulkkinen L, Uitto J. Mutation analysis and molecular genetics of epidermolysis bullosa. Matrix Biol. 1999;18:29–42. [PubMed: 10367729]
  87. Puvabanditsin S, Garrow E, Samransamraujkit R, Lopez LA, Lambert WC. Epidermolysis bullosa associated with congenital localized absence of skin, fetal abdominal mass, and pyloric atresia. Pediatr Dermatol. 1997;14:359–62. [PubMed: 9336805]
  88. Robbins PB, Lin Q, Goodnough JB, Tian H, Chen X, Khavari PA. In vivo restoration of laminin 5 beta 3 expression and function in junctional epidermolysis bullosa. Proc Natl Acad Sci U S A. 2001;98:5193–8. [PMC free article: PMC33186] [PubMed: 11296269]
  89. Ruzzi L, Pas H, Posteraro P, Mazzanti C, Didona B, Owaribe K, Meneguzzi G, Zambruno G, Castiglia D, D'Alessio M. A homozygous nonsense mutation in type XVII collagen gene (COL17A1) uncovers an alternatively spliced mRNA accounting for an unusually mild form of non-Herlitz junctional epidermolysis bullosa. J Invest Dermatol. 2001;116:182–7. [PubMed: 11168815]
  90. Schara U, Tücke J, Mortier W, Nüsslein T, Rouan F, Pfendner E, Zillikens D, Bruckner-Tuderman L, Uitto J, Wiche G, Schröder R. Severe mucous membrane involvement in epidermolysis bullosa simplex with muscular dystrophy due to a novel plectin gene mutation. Eur J Pediatr. 2004;163:218–22. [PubMed: 14963703]
  91. Shinkuma S, McMillan JR, Shimizu H. Ultrastructure and molecular pathogenesis of epidermolysis bullosa. Clin Dermatol. 2011;29:412–9. [PubMed: 21679868]
  92. Smith FJ, Eady RA, Leigh IM, McMillan JR, Rugg EL, Kelsell DP, Bryant SP, Spurr NK, Geddes JF, Kirtschig G, Milana G, de Bono AG, Owaribe K, Wiche G, Pulkkinen L, Uitto J, McLean WH, Lane EB. Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet. 1996;13:450–7. [PubMed: 8696340]
  93. Spirito F, Capt A, Del Rio M, Larcher F, Guaguere E, Danos O, Meneguzzi G. Sustained phenotypic reversion of junctional epidermolysis bullosa dog keratinocytes: Establishment of an immunocompetent animal model for cutaneous gene therapy. Biochem Biophys Res Commun. 2006;339:769–78. [PubMed: 16316622]
  94. Stellingsma C, Dijkstra PU, Dijkstra J, Duipmans JC, Jonkman MF, Dekker R. Restrictions in oral functions caused by oral manifestations of epidermolysis bullosa. Eur J Dermatol. 2011;21:405–9. [PubMed: 21609900]
  95. Takizawa Y, Hiraoka Y, Takahashi H, Ishiko A, Yasuraoka I, Hashimoto I, Aiso S, Nishikawa T, Shimizu H. Compound heterozygosity for a point mutation and a deletion located at splice acceptor sites in the LAMB3 gene leads to generalized atrophic benign epidermolysis bullosa. J Invest Dermatol. 2000a;115:312–6. [PubMed: 10951252]
  96. Takizawa Y, Pulkkinen L, Chao SC, Nakajima H, Nakano Y, Shimizu H, Uitto J. Mutation report: complete paternal uniparental isodisomy of chromosome 1: a novel mechanism for Herlitz junctional epidermolysis bullosa. J Invest Dermatol. 2000b;115:307–11. [PubMed: 10951251]
  97. Tolar J, Xia L, Lees CJ, Riddle M, McElroy A, Keene DR, Lund TC, Osborn MJ, Marinkovich MP, Blazar BR, Wagner JE. Keratinocytes from induced pluripotent stem cells in junctional epidermolysis bullosa. J Invest Dermatol. 2013;133:562–5. [PMC free article: PMC3514565] [PubMed: 22931927]
  98. Uitto J, Richard G. Progress in epidermolysis bullosa: from eponyms to molecular genetic classification. Clin Dermatol. 2005;23:33–40. [PubMed: 15708287]
  99. van Leusden MR, Pas HH, Gedde-Dahl T, Sonnenberg A, Jonkman MF. Truncated typeXVII collagen expression in a patient with non-herlitz junctional epidermolysis bullosa caused by a homozygous splice-site mutation. Lab Invest. 2001;81:887–94. [PubMed: 11406649]
  100. Varki R, Sadowski S, Pfendner E, Uitto J. Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. J Med Genet. 2006;43:641–52. [PMC free article: PMC2564586] [PubMed: 16473856]
  101. Varki R, Sadowski S, Uitto J, Pfendner E. Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J Med Genet. 2007;44:181–92. [PMC free article: PMC2598021] [PubMed: 16971478]
  102. Wallerstein R, Klein ML, Genieser N, Pulkkinen L, Uitto J. Epidermolysis bullosa, pyloric atresia, and obstructive uropathy: a report of two case reports with molecular correlation and clinical management. Pediatr Dermatol. 2000;17:286–9. [PubMed: 10990577]
  103. Yan EG, Paris JJ, Ahluwalia J, Lane AT, Bruckner AL. Treatment decision-making for patients with the Herlitz subtype of junctional epidermolysis bullosa. J Perinatol. 2007;27:307–11. [PubMed: 17363907]
  104. Yuen WY, Huizinga J, Jonkman MF. Punch grafting of chronic ulcers in patients with laminin-332-deficient, non-Herlitz junctional epidermolysis bullosa. J Am Acad Dermatol. 2013;68:93–7. [PubMed: 22633040]
  105. Yuen WY, Jonkman MF. Risk of squamous cell carcinoma in junctional epidermolysis bullosa, non-Herlitz type: report of 7 cases and a review of the literature. J Am Acad Dermatol. 2011;65:780–9. [PubMed: 21624701]

Suggested Reading

  1. Van Coster R, Pulkkinen L. Epidermolysis bullosa: the disease of the cutaneous basement membrane zone. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 222. Available online. Accessed 12-18-13.

Chapter Notes

Revision History

  • 2 January 2014 (me) Comprehensive update posted live
  • 22 February 2008 (me) Review posted to live Web site
  • 10 May 2007 (egp) Original submission
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