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 the trachea. (See Figure 1, Figure 2.)

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 and tracheostomy (more...)

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 is usually required to establish the diagnosis, especially in infants.

Testing

Skin biopsy. Examination of a skin biopsy by transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping is the best way to reliably establish 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 mechanically induced blister and should include some normal adjacent skin. (Older blisters undergo change that may obscure the diagnostic morphology.)

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 marker antibodies of different layers of the basement membrane. A laboratory that has the 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.

(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 the 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-vessicles 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]:

• In all forms of JEB. Splitting 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 caused by mutations in COL17A1

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 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. Four genes are commonly associated with the two major phenotypes of JEB, Herlitz and non-Herlitz JEB [Fine et al 1999, Anton-Lamprecht & Gedde-Dahl 2002]:

• Mutations in LAMB3 account for 70% of all JEB.
• Mutations in COL17A1 account for 12% of all JEB.
• Mutations in LAMC2 account for 9% of all JEB.
• Mutations in LAMA3 account for 9% of all JEB.

Clinical testing

• Sequence analysis
  
  LAMB3. Sequencing of LAMB3 detects more than 98% of LAMB3 mutations overall. Large deletions (i.e., exonic and whole-gene deletions) have been identified in LAMB3 in fewer than 1% of cases [Pulkkinen et al 1995, Cserhalmi-Friedman et al 1998, Takizawa et al 2000b, Huber et al 2002, Micheloni et al 2004, Posteraro et al 2004].
  
  COL17A1. Sequencing of COL17A1 detects more than 98% of COL17A1 mutations overall.
  
  LAMC2. Sequencing of LAMC2 detects more than 98% of LAMC2 mutations overall.
  
  LAMA3. Sequencing of LAMA3 detects more than 98% of LAMA3 mutations overall.
  
  Note: Care must be taken to sequence all of LAMA3 rather than one of the shorter isoforms.

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

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Gene Symbol	Proportion of JEB Attributed to Mutations in This Gene 1	Test Method	Mutation Detection Frequency by Gene and Test Method 2 , 3	Test Availability
LAMB3	70%	Sequence analysis	>98% 4	Clinical
		Deletion analysis	<1% 5
		Targeted mutation analysis	See footnote 6
COL17A1	12%	Sequence analysis	>98%	Clinical
		Deletion analysis	<1% 5
LAMC2	9%	Sequence analysis	>98%	Clinical
		Deletion analysis	<1% 5
		Targeted mutation analysis	See footnote 6
LAMA3	9%	Sequence analysis	>98% 7	Clinical
		Deletion analysis	<1% 5
		Targeted mutation analysis	See footnote 6

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Varki et al [2006]

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. 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%; however, rare mutations in ITGB4 and PLEC1 have also resulted in a JEB-like phenotype (see EB-PA) and must be taken into consideration when no mutations are identified in either of the four genes included in this table [Inoue et al 2000, Kunz et al 2000, Charlesworth et al 2003].

4. Rarely, large deletions have been identified in LAMB3 which may result in a lower detection frequency [Pulkkinen et al 1995, Cserhalmi-Friedman et al 1998, Takizawa et al 2000b, Huber et al 2002, Micheloni et al 2004, Posteraro et al 2004].

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

6. One laboratory offers targeted mutation analysis for p.Arg42X, p.Gln243X, p.Arg635X, and p.957ins77 in LAMB3; p.Arg95X mutation in LAMC2; and p.Arg650X in LAMA3 with a 45% mutation detection frequency in individuals of European ancestry.

7. Care must be taken to sequence all of LAMA3 rather than one of the shorter isoforms.

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

Testing Strategy

Establishing the diagnosis in a proband

Skin biopsy. 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 studied with electron microscopy and/or indirect immunofluorescence for the basement membrane proteins to identify the affected proteins and suggest the appropriate genes to be tested.

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

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:

• European origin: LAMB3 (p.Arg635X, p.Gln243X)
• Hispanic and African American: LAMB3 (c.957ins77, p.Arg42X)
• Pakistani: LAMA3 (p.Arg650X) [McGrath et al 1996]
• Italian: LAMC2 (p.Arg95X) [Posteraro et al 2004]

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

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%

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

LAMB3 and LAMC2. No phenotypes other than JEB are associated with mutations in LAMB3 and LAMC2.

LAMA3. A related disorder, laryngoonychocutaneous (LOC or Shabbir) syndrome, or LOCS [OMIM 245660] is described in Punjabi Indians. LOCS has many phenotypic characteristics similar to NH-JEB [Figueira et al 2007, Pfendner et al 2007]. Skin fragility manifests as mild blistering and erosions of the hands and face that spreads to other parts of the body and heals with crusted lesions. Neonates may have a hoarse cry and later laryngeal abnormalities and growths, conjunctival disease, abnormal nails, and hypoplastic dental enamel. Eventually, conjunctival disease may cause blindness and laryngeal disease may cause life-threatening airway obstruction requiring tracheotomy.

The LAMA3 mutation c.151insG in exon 39, one of three LAMA3 isoforms, is causative [McLean et al 2003]. Inheritance is autosomal recessive.

Diagnosis of LOCS may be complicated by the lack of a definitive cleavage plane on TEM and reduced but not absent laminin 5 staining by immunofluorescence for the basement membrane proteins. Sequence analysis of all 76 exons of LAMA3, which encodes all three isoforms, is necessary to provide definitive diagnosis, especially in neonates.

COL17A1. Mutations in COL17A1 may also be associated with an epidermal keratinocyte cleavage plane usually associated with epidermolysis bullosa simplex (EBS) [Pasmooij et al 2004a].

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].

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

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 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 a 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.

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]
• Squamous cell carcinoma [Mallipeddi et al 2004]
• Enamel dysplasia with pitting of the teeth [Kirkham et al 2000, Nakamura et al 2006]

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 ameliorating 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.

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].

• H-JEB prevalence is estimated at 0.37 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.
• NH-JEB incidence is 0.07 per million.

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

• Carrier risk of H-JEB has been calculated as 1:781 [Nakano et al 2000, Pfendner et al 2001].

Evaluations Following Initial Diagnosis

To establish the extent of disease 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
• 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

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.

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 nonadherent 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].

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

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

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

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]

Iron-deficiency anemia, a chronic problem, can be treated with oral or intravenous iron infusions and red blood cell transfusions.

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 pick up early osteopenia and/ or osteoporosis. No guidelines have been established regarding the age at which this should begin.

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^®.

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.

Therapies Under Investigation

Several approaches to gene therapy for JEB have been proposed focused on retroviral modification of in vitro epidermal cells [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 a patient with LAMB3 mutations [Mavilio et al 2006]. Animal models include intra-amniotic prenatal laminin 332 delivery in the mouse [Muhle et al 2006] and a spontaneous form of JEB in the dog [Capt et al 2005, Spirito et al 2006].

The knockout mouse model for all JEB-related genes should facilitate the development of these therapeutic approaches [Jiang & Uitto 2005].

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

Other

Cesarean section is often recommended to reduce trauma to the skin of an affected fetus during delivery.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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.

Risk to Family Members

Parents of a proband

• The parents of an affected child are usually obligate heterozygotes and therefore each parent carries one mutant allele. Because germline mosaicism and uniparental isodisomy have been reported [Pulkkinen et al 1997, Takizawa et al 2000b, Cserhalmi-Friedman et al 2002, Fassihi et al 2005], carrier status of parents needs to be confirmed with molecular genetic testing.
• Heterozygotes (carriers) are asymptomatic except in a few rare cases of carriers of COL17A1 mutations where dental enamel hypoplasia and resulting caries have been reported [Nakamura et al 2006, Murrell et al 2007].

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 mutations where carriers may exhibit dental enamel pitting and caries [Nakamura et al 2006, Murrell et al 2007].

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 available on a clinical basis once the mutations have been identified in the family.

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 or 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal testing for pregnancies at increased risk for JEB is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 muco-cutaneous 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].

Literature Cited

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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 at www​.ommbid.com. Accessed 1-29-13.

Author Notes

Web: www.genedx.com

Web: www.cincinnatichildrens.org/eb-center

Revision History

• 22 February 2008 (me) Review posted to live Web site
• 10 May 2007 (egp) Original submission