Are You Confident of the Diagnosis?
Key historical features
The diagnosis of inherited junctional epidermolysis bullosa (EB) should be considered in any newborn or child with mechanically fragile skin and blisters. There are currently eight phenotypically and genotypically distinct JEB subtypes, three of which typically have relatively localized skin involvement. Junctional EB should be considered among the differential diagnoses in those children who have widespread skin involvement, particularly when arising at or shortly after birth. However, during the newborn period, as well as into infancy, there are no sufficiently reliable cutaneous findings that can differentiate among any of the many forms of inherited EB.
Characteristic findings on physical examination
The only pathognomonic finding seen in junctional EB is exuberant granulation tissue, a hallmark finding in the Herlitz variant of severe generalized junctional EB. However, this finding may not arise until at least the first year of life and may also disappear during mid or late adulthood, making it a rather specific, but still somewhat insensitive, diagnostic marker (Figure 1, Figure 2, Figure 3).
Enamel hypoplasia, manifested as variable surface pitting of teeth, is characteristically seen in all forms of junctional EB. It has also rarely been reported in epidermolysis bullosa simplex (EBS), although it is possible that the patients with EBS may have been misclassified. The end result of this symptom of JEB is excessive caries and early loss of dentition.
As is the case with recessive dystrophic EB, there are several subtypes of junctional EB which, when fully developed, have somewhat differing clinical findings.
The most severe form of generalized junctional EB, the Herlitz variant (JEB-H), is characterized by the presence of extensive blisters and erosions of the skin, as well as severe involvement of several extracutaneous sites, most notably the oral cavity (to include moderate microstomia), external eye, and upper airway, as well as the gastrointestinal and genitourinary tracts. These children are also characteristically short-statured and have moderate to severe multifactorial anemia and growth retardation.
The exuberant granulation tissue noted above typically arises within body folds, lumbosacral back, periungual folds, nape of the neck, and periorificial skin. It may also arise within the nares and both the upper throat and airway. These areas are red and moist, and are frequently associated with serosanguinous exudate.
Nails may be abnormal in shape and contour (dystrophic), identical to those seen typically in dystrophic EB. In contrast to recessive dystrophic EB, milia are rarely observed. Atrophic scarring may arise in all forms of inherited EB, but particularly so in junctional EB. Postinflammatory dyspigmentation may also occur.
Non-Herlitz junctional EB (JEB-nH, previously referred to as generalized atrophic EB [GABEB]), is also a generalized subtype of junctional EB. Skin findings resemble those of Herlitz disease, although exuberant granulation tissue is absent and the general severity of cutaneous disease activity is often much less. Although patients with JEB-nH run the same risk of upper airway strictures as do those with Herlitz disease, children with JEB-nH tend not to have clinically significant anemia or growth retardation.
The third major subtype of junctional EB is the inverse variant (JEB-I). It is characterized by usually severe cutaneous disease activity, primarily confined to body folds, most notably around the anus and genitalia, as well as within the oral cavity.
A rare but clinically striking subtype of junctional EB is the one associated with pyloric atresia (JEB-PA). As the name implies, occlusion of the pylorus is present at birth and can be readily diagnosed on clinical and radiologic grounds usually within the first day of life.
The typical symptoms of pyloric atresia are abdominal distension and vomiting following any attempt at feeding. The presence of air within the distended stomach can be confirmed at the bedside by simple percussion or via a flat upright film of the abdomen. Infants with this junctional EB subtype also frequently have urogenital congenital anomalies. The presence of these anomalies should be sought in any child with JEB-PA, given how commonly they arise within this particular EB subtype.
Expected results of diagnostic studies
The diagnosis of junctional EB is most easily and rapidly made by performing immunofluorescence antigenic mapping, coupled with EB-specific monoclonal antibody studies, on perilesional skin that has first been subjected to mild rotary traction. All JEB skin, regardless of subtype, will readily demonstrate the presence of a cleavage plane within the lamina lucida of the skin basement membrane zone.
JEB-H skin will fail to reveal any staining with antibodies to laminin-332, whereas weak staining is usually seen from those JEB-nH patients having underlying laminin-332 mutations. In those JEB-nH patients having mutations in the type XVII collagen gene (COL17A), antibody staining with its corresponding antibody is abnormal, as is staining of alpha-6 beta-4 integrin in the skin of those with JEB-PA.
Transmission electron microscopy reveals complete absence of hemidesmosomes, anchoring filaments, and sub-basal dense plates within the basement membrane zone of skin from patients with JEB-H, whereas hemidesmosomes appear rudimentary or embryonic and are present in reduced numbers in skin from those with JEB-nH. In JEB-PA, the hemidesmosome plaques are small and may be associated with attenuated sub-basal dense plates.
With rare exceptions, there is no significant differential diagnosis for adults with JEB, although any of the autoimmune bullous diseases may rarely present in early childhood. If there are clinical reasons to suspect the latter, then they may be easily excluded by direct and indirect immunofluorescence studies. Similarly, the presence of an inherited mechanobullous disease associated with exuberant granulation tissue should be diagnostic of Herlitz JEB.
In the setting of localized neonatal blistering, and in the absence of a positive family history of JEB (i.e. an identically affected sibling), the major differential diagnosis is neonatal herpes simplex infection. Additional diagnostic considerations in infants with blisters may include congenital porphyria, bullous mastocytosis, bullous impetigo, staphylococcal scalded skin syndrome, bullous congenital ichthyosiform erythroderma, ichthyosis bullosa of Siemens, acrodermatitis enteropathica, and pachyonychia congenita.
Who is at Risk for Developing this Disease?
With the exception of a single kindred having apparent autosomal dominant inheritance, all studied patients with junctional EB have had their disease transmitted in autosomal recessive fashion.
There are no known environmental risk factors associated with mutations for this disease, nor are there in any of the other inherited forms of EB. Since junctional EB is transmitted autosomal recessively, if neither parent of an affected child has clinical disease, then it must be assumed that both parents are silent carriers, and every further pregnancy from that couple is associated with a one in four risk of an affected child, a one in two risk of having a silent carrier, and a one in four chance of having a genetically normal infant.
The overall prevalence and incidence of junctional EB within the continental United States are 0.49 per one million and 2.68 per one million live births, respectively.
What is the Cause of the Disease?
Severe generalized junctional EB and inverse junctional EB arise as a result of mutations within any of the three genes encoding for laminin-332 (laminin-5), a 3-subunit extracellular matrix protein that is present within the lamina lucida of the skin basement membrane zone. This particular protein plays a critical role in maintaining attachment of the epidermis to the underlying dermis.
Each of the two laminin-332 alleles present in patients with severe generalized junctional EB contain premature termination codons, which lead to rapid degradation of mRNA and the absence of laminin-332 within the skin and other epithelial tissues. Whereas the majority of patients with JEB-nH also have mutations in the genes for laminin-332, a minority instead have mutations within the gene for type XVII collagen, which is another extracellular matrix protein that is normally present within the skin basement membrane.
JEB-nH patients who have laminin-332 mutations, as well as all JEB-I patients, may have combinations of any of a variety of different types of mutations within this gene, but since two premature termination codons do not arise in either of these non-Herlitz JEB subtypes, their overall clinical disease severity is less.
JEB-PA arises as the result of mutations within the gene encoding for alpha-6 beta-4 integrin, a 2-chained protein that is present within the region of the hemidesmosome.
A rare subtype of JEB, also referred to as laryngo-onycho-cutaneous syndrome (LOC), is associated with mutations in the alpha-3 chain of laminin-332.
Another rare subtype of JEB recently reported as JEB with respiratory and renal involvement involves the gene encoding for the integrin alpha-3 chain isoform.
Any of the above mutations will result in mechanically fragile skin, characterized by blister formation within the same ultrastructural level (i.e. intra-lamina lucida) in which the corresponding mutated proteins normally reside.
Systemic Implications and Complications
JEB-H children are at high risk of death during infancy and early childhood as a result of sepsis, failure to thrive, or acute upper airway occlusion.
Patients with either of the major subtypes of generalized JEB are at risk of tracheolaryngeal occlusion because of progressive stricture or stenosis of the airway. The cumulative risk for this complication plateaus by about age 6.
The earliest indication of disease activity in the upper airway is a hoarse cry. Later, the child may show signs of increasing dyspnea, including stridor. Since complete occlusion of the airway may be sudden, any JEB child with the above findings needs prompt evaluation by a pediatric otolaryngologist, and most end up requiring an elective tracheostomy, which must remain until the child is old enough to have the airway appliance safely removed.
As yet, there are no specific therapies for any type or subtype of inherited EB.
There has been one patient with JEB-nH in Europe who has been treated with a single skin graft prepared in vitro with his own genetically corrected cultured keratinocytes. After at least 3 years of follow-up, that solitary skin site has failed to blister further, suggesting the potential feasibility of gene therapy in this disease. Regulatory concerns within the European Union, however, have as yet prevented further patient enrollment.
CURRENT THERAPEUTIC MODALITIES
Soft sterile bandages are placed around skin sites most prone to mechanical trauma, to cushion and protect these areas from further injury. Nonadherent synthetic dressings (i.e. Mepitel, Mepilex, and others) are applied to open wounds to promote reepithelialization. These can then be changed daily or every few days and, if partially adherent, can be soaked off easily with tap water.
Some authorities recommend prior application of a topical antibiotic (i.e. Polysporin, Silvadene) to these wounds, to reduce the risk of secondary infection. Potent topical antimicrobials (i.e. Bactroban) are usually not routinely used, since chronic use may lead to superinfection with methicillin-resistant Staphylococcus aureus (MRSA). Some authorities also routinely use silver-impregnated dressings, although some concerns have been raised about the potential for excessive absorption of silver into the bloodstream from those dressings.
Nonhealing wounds, especially those with obvious purulence or odor, should be cultured to rule out secondary bacterial infection, and the choice of antibiotic should be based on the results of the culture.
Esophageal strictures may be at least temporarily improved by serial dilatation, performed by either a gastroenterologist or a pediatric surgeon experienced in the management of children with junctional EB. A variety of oral medications, to include lactulose, may be used in patients with moderate to severe constipation.
Patients with recurrent ocular erosions or scars should be referred to an ophthalmologist for optimal care.
Some JEB patients with mild upper airway disease activity can be managed with aerosolized medications.
Aggressive nutritional support should be employed in any child with JEB who has evidence of growth retardation, since malnutrition often arises in these patients as a result of chronic loss of blood and protein through nonhealing wounds on the skin and within the gut.
Nonhealing ulcerations of the skin of JEB patients have been successfully treated with split-thickness skin grafts. Autologous skin grafts employing cultured keratinocytes from JEB patients have also been used as biological coverings for these lesions.
Whereas gastrostomy is becoming standard of care for children severely affected with recessive dystrophic epidermolysis bullosa (RDEB), the procedure is still somewhat controversial, and it is questionable whether nutritional supplementation by this route has any beneficial effect on the long-term survival of children with JEB-H.
Urologic complications arise in infants with JEB-PA; these should be evaluated by a pediatric urologist.
Elective tracheostomy may be life-saving in JEB children who have progressive upper airway involvement, although this is still not considered standard of care by every EB expert.
Early dental intervention is important in JEB children (because of underlying enamel defects) so that permanent dentition is not lost as a result of severe caries formation. A variety of reconstructive dental procedures, to include crown placement, may be safely performed by an experienced pediatric dentist.
Optimal Therapeutic Approach for this Disease
As noted above, the primary focus of dermatological care in patients with junctional EB revolves around the prevention and treatment of wounds. Both the patient’s dermatologist and primary care physician need to be constantly attuned to the possibility of an extracutaneous complication, and the patient should be then referred to the appropriate specialist for further evaluation and care.
Priorities in surveillance should be based on knowledge of the usual time during which each of the major extracutaneous complications tend to first arise. Recommendations regarding the latter may be found in a recently published review article on this subject.
Patients with JEB, especially those with Herlitz disease, need very close follow-up by both a pediatric dermatologist and a pediatrician familiar with this disease. Parents of JEB-H children need to counseled as to the risk of death during infancy and early childhood, and also counseled about each of the medical and surgical options that may be available, in the event that correctable extracutaneous complications arise.
Although not universally accepted by all other EB experts, I tend to believe that aggressive interventions, to include renal dialysis, gastrostomy, and tracheostomy placement, should be pursued in any JEB child justifying such therapy, if the parents wish to do so. On the other hand, given the very high risk of mortality among JEB-H children, I do believe that parents have the right to refuse to pursue any of these options.
Unusual Clinical Scenarios to Consider in Patient Management
LOC, a rare subtype of JEB, is associated with mutations with the alpha-3 chain of laminin-332. The majority of these patients are from the Punjab region of Pakistan.
What is the Evidence?
Fine, J-D, Bauer, EA, McGuire, J, Moshell, A. “Epidermolysis bullosa: clinical, epidemiologic, and laboratory findings of the national epidermolysis bullosa registry”. 1999. (Peer-reviewed monograph containing original data on the first 1700 patients sequentially enrolled in the National EB Registry project, and the only published source of epidemiologic data on this unique patient cohort.)
Fine, JD, Johnson, LB, Weiner, M, Stein, A, Cash, S, DeLeoz, J. “Inherited epidermolysis bullosa (EB) and the risk of death from renal disease: experience of the National EB Registry”. Am J Kidney Dis. vol. 44. 2004. pp. 651-60. (Sixteen years of data on the frequency and cumulative risk of death from renal failure among the National EB Registry cohort, stratified by EB subtype.)
Fine, JD. “Inherited epidermolysis bullosa (EB): incidence and prevalence: estimates from the National EB Registry”. JAMA Dermatology. 2016. (Final estimates on the incidence and prevalence of inherited EB in the United States, based on 16 years of data collection on 3271 patients by the National EB Registry.)
Fine, JD, Johnson, LB, Weiner, M, Stein, A, Cash, S, DeLeoz, J. “Eye involvement in inherited epidermolysis bullosa (EB): experience of the National EB Registry”. Am J Ophthalmol. vol. 138. 2004. pp. 254-62. (Sixteen years of data on the frequency and cumulative risk of ocular complications among the National EB Registry cohort, stratified by EB subtype.)
Fine, JD, Johnson, LB, Weiner, M, Stein, A, Cash, S, DeLeoz, J. “Pseudosyndactyly and musculoskeletal deformities in inherited epidermolysis bullosa (EB): experience of the National EB Registry, 1986-2002”. J Hand Surg (British and European Volume). vol. 30B. 2005. pp. 14-22. (Sixteen years of data on the frequency and cumulative risk of hand and foot complications among the National EB Registry cohort, stratified by EB subtype.)
Fine, JD, Johnson, LB, Weiner, M, Suchindran, C. “Tracheolaryngeal complications of inherited epidermolysis bullosa: cumulative experience of the National EB Registry”. Laryngoscope. vol. 117. 2007. pp. 1652-60. (Sixteen years of data on the frequency and cumulative risk of tracheolaryngeal complications among the National EB Registry cohort, stratified by EB subtype.)
Fine, JD, Johnson, LB, Weiner, M, Suchindran, C. “Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National EB Registry”. J Ped Gastroenterol Nutr. vol. 46. 2008. pp. 147-58. (Sixteen years of data on the frequency and cumulative risk of gastrointestinal complications among the National EB Registry cohort, stratified by EB subtype.)
Fine, JD, Johnson, LB, Weiner, M, Suchindran, C. “Cause-specific risks of childhood death in inherited epidermolysis bullosa”. J Pediatr. vol. 152. 2008. pp. 276-80. (Sixteen years of data on the frequency and cumulative risk of cause-specific deaths among the National EB Registry cohort, stratified by EB subtype.)
Fine, JD, Hall, M, Weiner, M, Li, K-P, Suchindran, C. “The risk of cardiomyopathy in inherited epidermolysis bullosa”. Br J Dermatol. vol. 159. 2008. pp. 677-82. (Sixteen years of data on the frequency and cumulative risk of cardiomyopathy among the National EB Registry cohort, stratified by EB subtype.)
Fine, JD, Johnson, LB, Weiner, M, Li, K-P, Suchindran, C. “Inherited epidermolysis bullosa (EB) and the risk of life-threatening skin-derived cancers: experience of the National EB Registry, 1986-2006”. J Am Acad Dermatol. vol. 60. 2009. pp. 203-11. (Twenty years of data on the frequency and cumulative risk of first skin cancer and death from any skin cancer among the National EB Registry cohort, stratified by EB subtype.)
Fine, JD, Bruckner-Tuderman, L, Eady, RA. “Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification”. J Am Acad Dermatol. vol. 70. 2014. pp. 1103-26. (The most recent classification system for inherited EB, based on an international consensus meeting held in 2013, including summaries of clinical, ultrastructural, immunohistochemical, and molecular findings that are typically seen in each major EB subtype, including several not included in the 2008 consensus report.)
Fine, JD, Mellerio, J. “Extracutaneous manifestations and complications of inherited epidermolysis bullosa. Part I. Epithelial associated tissues”. J Am Acad Dermatol. vol. 61. 2009. pp. 367-84.
Fine, JD, Mellerio, J. “Extracutaneous manifestations and complications of inherited epidermolysis bullosa. Part II. Other organs”. J Am Acad Dermatol. vol. 61. 2009. pp. 387-402. (The above two review articles are focused on a critical review of the literature as pertains to extracutaneous complications arising in specific EB subtypes.)
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