Junctional Epidermolysis Bullosa

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Summary

Clinical 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 JEB generalized severe and JEB generalized intermediate. In JEB generalized severe, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In JEB generalized intermediate, 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.

The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2. Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping can be performed but is no longer the preferred method of diagnosis.

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; antibiotics and antiseptics as needed for wound care and infection; dilation of esophageal strictures (rare); tracheostomy if appropriate; gastrostomy tube if needed; standard treatment of gastroesophageal disease; appropriate footwear and physical therapy to promote/preserve ambulation; psychosocial support, including social services and psychological counseling; appropriate management of chronic pain; regular dental care; treatment of urologic and renal disease using standard treatments.

Prevention of secondary complications: Attention to fluid and electrolyte balance in severely affected infants (especially sodium levels); nutritional support including feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements.

Surveillance: Annual screening for iron-deficiency anemia, zinc deficiency, vitamin D deficiency; periodic bone mineral density scanning for 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 can traumatize the skin (e.g., hiking, mountain biking, contact sports).

Pregnancy management: 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 pathogenic variant. Carrier testing for family members at increased risk and prenatal testing for a pregnancy at increased risk are possible if both pathogenic variants have been identified in the family.

Diagnosis

Suggestive Findings

Junctional epidermolysis bullosa (JEB) should be suspected in individuals who have 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

Note: 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 1.

JEB generalized severe a. Extensive widespread blistering and granulation tissue on ear

Figure 2.

Figure 2.

JEB generalized intermediate e. Minor nail dystrophy in an older child

Establishing the Diagnosis

The diagnosis of JEB is established in a proband with one or both of the following:

  • Identification by molecular genetic testing of biallelic pathogenic variants in one of the genes listed in Table 1
  • Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (see Skin Biopsy)

Note: Genetic testing is the preferred diagnostic method. Skin biopsy for diagnostic purposes is no longer routinely performed unless molecular genetic testing is not conclusive.

Molecular Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, targeted molecular genetic testing) and comprehensive genomic testing (exome sequencing, genome sequencing, exome array) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of junctional epidermolysis bullosa is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with fragile skin and blistering, or presenting in the neonatal period before significant sequelae such as exuberant granulomatous tissue has developed, are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of junctional epidermolysis bullosa, molecular genetic testing approaches can include use of a multigene panel or targeted molecular testing [Lucky et al 2018].

A junctional epidermolysis bullosa multigene panel that includes COL17A1, ITGB4, LAMB3, LAMA3, LAMC2, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by skin fragility and blistering, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Junctional Epidermolysis Bullosa

Gene 1, 2Proportion of JEB Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
COL17A112%>98%<2% 6
ITGB4<1% 7~100%<1%
LAMA39%>98% 8<1% 6
LAMB370%>98%<2% 9
LAMC29%>98%<2% 6
1.

Genes are listed in alphabetic order.

2.

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

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

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

7.

Biallelic pathogenic variants in ITGB4 are a rare cause of JEB [Author, personal communication].

8.

Care must be taken to sequence the genomic region of the longest transcript of LAMA3 (NM_198129​.2) rather than one of the shorter transcript variants.

9.

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]

Skin Biopsy

Examination of a skin biopsy by (1) transmission electron microscopy (TEM) and/or (2) immunofluorescent antibody/antigen mapping is sometimes performed to establish the 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) blister or from 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:

  • For TEM
    • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test.
    • Formaldehyde-fixed samples cannot be used for electron microscopy.
  • For immunofluorescent antibody/antigen mapping
    • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test.
    • Some laboratories prefer flash-frozen tissue.
    • 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 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.
  • Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes 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; and the presence of microvesicles showing the tissue cleavage plane.

Findings on TEM in JEB include the following [Shinkuma et al 2011]:

  • 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.
  • JEB generalized severe. Hemidesmosomes are hypoplastic and reduced in number. Anchoring filaments are markedly reduced or absent.
  • JEB generalized intermediate. 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 pathogenic variants in LAMA3, LAMB3, or LAMC2 in JEB generalized severe or JEB generalized intermediate
  • Abnormal or absent staining with antibodies to collagen XVII in JEB caused by pathogenic variants 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 are often not 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.

Clinical Characteristics

Clinical Description

Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate and is based on severity and survival past the first years of life [Yuen et al 2013, Kelly-Mancuso et al 2014].

JEB generalized severe (previously called JEB Herlitz). Severe blistering is present at birth or becomes apparent in the neonatal period 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 some of the individuals with JEB generalized severe who survive [Fine et al 1999]. In one series, 73% of 71 children born in a five-year period died at an average age of five months [Kelly-Mancuso et al 2014].

In addition to cutaneous involvement, mucosal involvement of the mouth, upper respiratory tract, esophagus, bladder, urethra, and corneas can be seen. Amelogenesis imperfecta with pitting of tooth enamel is common. 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 autosomal recessive dystrophic EB.

Secondary complications common in JEB generalized severe include malnutrition and growth retardation, anemia, alopecia, cutaneous infection, sepsis, electrolyte imbalance, osteoporosis [Fewtrell et al 2006], dilated cardiomyopathy, squamous cell carcinoma [Yuen & Jonkman 2011], and dental enamel dysplasia with pitting [Krämer 2010, Stellingsma et al 2011].

Most children with JEB generalized severe do not survive past the first year of life.

JEB generalized intermediate (previously called JEB non-Herlitz) includes a spectrum of less severe clinical phenotypes than JEB generalized severe. 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 seen in individuals with JEB generalized severe are rare.

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

Additional manifestations of JEB generalized severe and JEB generalized intermediate include:

  • Congenital localized absence of skin (aplasia cutis congenita)
  • Exuberant granulation tissue
  • Nail dystrophy
  • Scarring alopecia
  • Squamous cell carcinoma in individuals with JEB generalized intermediate [Montaudié et al 2016]
  • Pseudosyndactyly and other contractures. Pseudosyndactyly is defined as the partial or complete loss of web spaces between any digits of the hands or feet (rare).
  • Milia (rare)
  • Scarring (rare)

Genotype-Phenotype Correlations

JEB generalized severe is the result of inactivating pathogenic variants on both alleles, which result in little or no functional protein [Varki et al 2006]. For frameshift variants, the severity may be related to where the stop codon is located and whether any functional (although truncated) protein is formed; the presence of some functional protein appears to be the most important factor in mitigating disease severity [Kiritsi et al 2013].

JEB generalized intermediate generally results from amino acid substitutions and splice-junction variants, although it is difficult to generalize because of the wide phenotypic variability and range of allelic variants that have 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 variants [McGrath et al 1999, Kowalewski et al 2016].

Nomenclature

Table 2.

Junctional Epidermolysis Bullosa Nomenclature

Current Nomenclature2008 Nomenclature2013 "Onion Skin"
Nomenclature		Other Specific JEB Designations
Used in the Past
JEB SubtypeAbbreviation
GeneralizedJEB, generalized severeJEB-gen sevHerlitz JEB
(H-JEB)		JEB generalized severe, laminin-332 absent, LAMA3, LAMB3, or LAMC2 pathogenic variants (specify type)
  • Epidermolysis bullosa letalis
  • Epidermolysis bullosa junctional Herlitz-Pearson
  • Junctional epidermolysis bullosa mitis
JEB, generalized intermediateJEB-gen intermedNon-Herlitz JEB
(NH-JEB)		JEB generalized intermediate, laminin-332 or collagen XVII reduced staining, LAMA3, LAMB3, LAMC2, or COL17A1 pathogenic (specify type)
  • Epidermolysis bullosa, generalized atrophic benign (GABEB)
  • Epidermolysis bullosa junctionalis, disentis type
  • Epidermolysis bullosa junctionalis, progressive
  • Epidermolysis bullosa junctionalis, severe non-lethal
JEB with pyloric atresiaJEB-PA
JEB-late onsetJEB-LO
JEB with respiratory and renal involvementJEB-RR
LocalizedJEB, localizedJEB-loc
JEB, inversaJEB-inv; JEB-I
JEB-LOC syndrome

Adapted from Fine et al [2014]

JEB = junctional epidermolysis bullosa

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 at between 3.59 and 6.7 per million per year with a 73% mortality rate [Kelly-Mancuso et al 2014, Hammersen et al 2016].

  • The prevalence of JEB generalized severe is estimated at 0.4 per million but may be underrepresented. JEB generalized severe incidence is also very low (0.41 per million), but is probably underestimated: many individuals with JEB generalized severe go unreported because infants succumb to the disease in the neonatal period (a mortality rate of 73% in infancy has been reported) [Kelly-Mancuso et al 2014].
  • JEB generalized intermediate incidence is 2.0 per million.
  • Carrier risk of all forms of JEB in the US population has been calculated as 1:270 [Author, personal communication].
  • Carrier risk of JEB generalized severe has been calculated as 1:781 [Nakano et al 2000, Pfendner et al 2001].

Differential Diagnosis

Epidermolysis bullosa (EB). According to the 2014 classification system, the four major types of EB, caused by pathogenic variants in 18 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome (KS) [Fine et al 2014]. Classification into major type is based on the location of blistering in relation to the dermal-epidermal junction of skin. Subtypes are predominantly determined by clinical features and supported by molecular diagnosis.

The four major types of EB share easy fragility of the skin (and mucosa in many cases), manifested by blistering with little or no trauma. Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring – especially in young children and neonates ‒ may not be established or significant enough to allow identification of EB type; thus, molecular genetic testing (or less commonly skin biopsy) is usually required to establish the most precise diagnosis. The ability to induce blisters with friction (although the amount of friction can vary) and to enlarge blisters by applying pressure to the blister edge is common to all; mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators.

Post-inflammatory changes, such as those seen in generalized severe EBS (EBS-gen sev), 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 damage the exposed surface. Congenital absence of the skin can be seen in any of the four major types of EB and is not a discriminating diagnostic feature.

Corneal erosions, esophageal strictures, and nail involvement may indicate either DEB or JEB. In milder presentations, scarring (especially of the dorsal hands and feet) suggests DEB. Pseudosyndactyly (mitten deformities) resulting from scarring of the hands and feet in older children and adults usually suggests DEB.

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin that results in nonscarring blisters caused by little or no trauma. The four most common clinical subtypes of EBS range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. The majority of individuals with EBS have heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14. More recently, variants in EXPH5, TGM5, DST, ITGA3, KLHL24, and CD151 have been described.

  • In EBS, localized (EBS-loc; previously known as Weber-Cockayne type), blisters are rarely present at birth and may occur on the knees and shins with crawling or on the feet at approximately age 18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant.
  • In EBS, generalized intermediate (EBS-gen intermed; previously known as Koebner type), 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-gen sev.
  • In EBS with mottled pigmentation type (EBS-MP), skin fragility is evident at birth and clinically indistinguishable from EBS-gen sev; over time, progressive brown pigmentation interspersed with depigmented spots develops on the trunk and extremities, the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur.
  • In EBS, generalized severe (EBS-gen sev; previously known as Dowling-Meara type), 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. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyperpigmentation and hypopigmentation can occur. Mucosal involvement in EBS-gen sev may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.

EB caused by pathogenic variants in PLEC (OMIM 601282) can vary from relatively mild, previously known as the Ogna form, to more severe and sometimes lethal. Up to 8% of EBS may be caused by PLEC pathogenic variants. In most individuals with PLEC pathogenic variants, the associated phenotypes (i.e., EB with muscular dystrophy [EB-MD], EB with pyloric atresia [EB-PA]) are more complex:

  • EB-MD (OMIM 226670). More than 50 individuals with EB-MD have been reported worldwide. Blistering occurs early and is generally mild. Muscular dystrophy may not appear until later childhood, adolescence, or adulthood, and can cause immobility and eventually death later in life. Pathogenic variants have been described throughout PLEC 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 variants 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). Inheritance is autosomal recessive.
  • EB-PA. In several US and Japanese families, EB-PA is associated with premature termination variants in PLEC. EB-PA is more commonly associated with ITGB4 pathogenic variants, and rarely ITGA6 pathogenic variants. Although disease course is severe and often lethal in the neonatal period, non-lethal forms have been described. Individuals with pathogenic variants in ITGB4 or ITGA6 may also have renal and ureteral anomalies, including dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, and absent bladder. 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.

Dystrophic EB (DEB). The blister forms below the basement membrane, in the superficial dermis. The basement membrane is attached to the blister roof, resulting in scarring when blisters heal. Pathogenic variants in COL7A1, the gene encoding type VII collagen, have been demonstrated in all forms of DEB, both dominant and recessive.

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 (if not performed as part of the evaluation that led to the diagnosis) 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
  • Consultation with a clinical geneticist and/or genetic counselor

Note: Clinical decision making in children who manifest sign and symptoms of severe JEB with a very poor prognosis has been debated and remains difficult [Hammersen et al 2016].

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., Conform® , Flexicon®) 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® or Tubifast®)

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

Other. The most common secondary complication in individuals with JEB 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 or other upper airway abnormalities. 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, discussions with the family and a hospital ethics committee often help 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