Are You Confident of the Diagnosis?
What you should be alert for in the history
Inherited dystrophic epidermolysis bullosa (DEB, including dominant [DDEB] and recessive [RDEB] subtypes) should be considered in any patient with a history of blistering present at or shortly after the time of birth, especially if there is a family history of lifelong blistering in any family members. DDEB patients almost always have a parent with similar or identical findings, since the rate of spontaneous mutation among DDEB patients is quite low. In contrast, family history is often negative in those with RDEB, although it is not uncommon for an RDEB patient to have an affected sibling.
Characteristic findings on physical examination
DEB should be at the top of any differential diagnosis in those patients having marked mechanical fragility of the skin, blisters, a generalized distribution of other cutaneous findings, to include atrophic scarring, milia, nail dystrophy, and mucous membrane involvement. Some of these typical cutaneous findings may not develop until an infant is at least several months old, making these findings by themselves insensitive surrogate markers of the disease in newborns and infants.
There are several clinically distinctive subtypes of DEB, to include both generalized and more localized variants (the latter to include acral, inverse, and centripetal distributions). Detailed clinical summaries of each major DEB subtype may be found in the 2014 Consensus Report on Diagnosis and Classification (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5).
Expected results of diagnostic studies
All forms of DEB are characterized by subepidermal blisters. Performance of routine histology is not recommended, since it may be difficult or impossible to accurately demonstrate the precise level of blister formation with this technique. The gold standards for diagnosis are antigenic immunofluorescence mapping, coupled with specific monoclonal antibody staining techniques and transmission electron microscopy, both performed on skin sampled from freshly induced blister sites.
The hallmark findings in RDEB are the presence of a sublamina densa cleavage plane, absence of type VII collagen staining along the dermoepidermal junction, and absence of detectable anchoring fibrils. Although DDEB skin also cleaves beneath the lamina densa of the skin basement membrane, relative expression of type VII collagen and the number of mature-appearing anchoring fibrils can vary considerably, especially within skin specimens from patients with more localized variants of DDEB.
There are no imaging or serologic tests for any form of inherited EB.
It is now possible to determine the site and type of mutation present within the type VII collagen gene (COL7A) in DEB patients and is the gold standard for prenatal diagnosis. Mutational confirmation, however, is not needed in every patient, especially in those with classic phenotypic features and positive family history, until the availability and affordability of gene therapy necessitates its determination. It is important to stress, however, that there may be considerable variability in phenotypic expression even within the same affected kindred, and that in any given patient the genotype alone cannot be reliably used by itself as an accurate prediction of clinical severity and disease course.
With rare exceptions, there is no significant differential diagnosis for adults with DEB except in those with late (ie, adulthood onset of disease manifestations), at which point the diagnosis of acquired EB should be entertained and excluded by direct and indirect immunofluorescence studies. In the setting of neonatal blistering, in the absence of a positive family history of DEB, 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?
The overall prevalence and incidence of inherited EB in the United States has been recently reported to be 11.1 per one million population and 19.6 per one million live births, respectively, based on data derived from the National (USA) EB Registry from 1986-2002. The prevalence of DDEB and RDEB is 1.49 and 1.35 per one million; corresponding incidence is 2.12 and 3.05 per one million live births, respectively.
There are no non-genetic risk factors for any form of inherited EB.
What is the Cause of the Disease?
Both major types and all subtypes of DEB are caused by mutations within the type VII collagen gene (COL7A). Those with DDEB have a mutation in only one allele whereas those with RDEB have both alleles affected. Although every possible type or combination of types of mutation(s) within this gene has been reported to result in DEB, in general the most severe subtype, known as generalized severe RDEB (formerly named Hallopeau-Siemens RDEB) is characterized by the presence of premature termination codons in both COL7A alleles.
The presence of COL7A mutations results in the production of variable amounts of mutated gene product. The absence of type VII collagen within the dermoepidermal junction is associated with a lack of anchoring fibrils, whereas the production of variable amounts of mutated type VII collagen leads to the presence of reduced amounts of mechanically unstable anchoring fibrils within the skin. In each situation, the end result is marked mechanical fragility of the skin, recurrent blister formation, and scarring.
There is also evidence of increased collagenolysis in the upper dermis of patients with generalized RDEB, further compromising the integrity of the dermoepidermal junction. Preliminary data suggest that modifying genes may play some role in the intrafamilial variability of clinical severity in patients with RDEB, especially in the relative expression of those genes involved in scarring.
Systemic Implications and Complications
Patients with both major types of DEB, especially those with generalized RDEB, are at risk of developing a number of extracutaneous complications that impact on functionality and quality of life. Organ systems that may be involved include the oral cavity, gastrointestinal and genitourinary tracts, musculoskeletal system, external eye, heart, and bone marrow. Some of these may develop within the first year of life, and most become increasingly prevalent with increasing age.
The most common manifestations in the oral cavity in DEB are painful blisters, erosions, and soft tissue scars. RDEB patients also are at risk for microstomia, ankyloglossia, excessive caries, loss of surface markings on the tongue, and early loss of dentition. The external eye may develop blisters and scarring, which infrequently may lead to blindness. The most common complications within the gastrointestinal tract are progressive esophageal strictures or webs and severe constipation. Patients with severe generalized RDEB are at risk for recurrent urethral erosions and strictures, as well as hydroureter and chronic renal insufficiency, the latter associated with renal amyloidosis or poststreptococcal glomerulonephritis.
A subset of infants with severe generalized RDEB may develop dilated cardiomyopathy, possibly related to selenium or carnitine deficiency. Progressive acral “mitten” or “glove” deformities (pseudosyndactyly) are the norm in RDEB but may also arise in some DDEB patients. Severe multifactorial anemia is one of the hallmarks of severe generalized RDEB, as is profound growth retardation, undoubtedly the result of chronic severe gastrointestinal disease activity, with loss of iron via intestinal bleeding, altered nutrient uptake by intestinal epithelium, and chronic systemic inflammation. Severe depression is also common among patients with generalized forms of EB, especially those with RDEB, and may result in suicidal ideation or attempts.
There is no decreased life expectancy in patients with DDEB. In contrast, a minority of children with generalized RDEB die within the first year of life, most often the result of sepsis or failure to thrive. Most patients with severe generalized RDEB, and to a lesser extent those with inverse or other subtypes of generalized EB, are at risk of death during adulthood, due to the development of eventually metastatic squamous cell carcinomas (SCCs). Other infrequent causes of death in adults with severe generalized RDEB are renal failure and progressive cardiomyopathy.
The most alarming long-term complication of RDEB is the development of multiple primary SCCs on the skin. These may very rarely arise as early as the middle of the first decade of life, although the earliest reports within the United States are at about age 12 or 13. The cumulative risk of SCC does not begin to dramatically rise until the mid-third decade and beyond.
Although each of these tumors is usually histologically well differentiated, the rates of local recurrence and regional and distant metastases are great. In general, about 80% of patients with severe generalized RDEB die within 5 years of the diagnosis of their first primary SCC, despite apparently successful removal by wide surgical excision. These tumors are also resistant to chemotherapy and radiotherapy.
At present there are no universally agreed-upon protocols for the surveillance for and workup of possible extracutaneous complications in patients with RDEB, although most EB experts suggest that baseline laboratory tests be conducted in early childhood to look for as yet clinically silent anemia and renal and cardiac disease. Recent recommendations have been published, however, for evaluation and treatment of squamous cell carcinomas arising in the setting of DEB. Awareness of the usual time of onset for early involvement of one or more organs usually dictates the timing of rigorous clinical surveillance and the pursuit of more elaborate diagnostic tests, if signs and symptoms suggest their need.
For example, there is only rarely any justification for pursuing upper gastrointestinal tract radiograms or endoscopy in asymptomatic infants, whereas these would be appropriate in older children or adults if there are sufficient symptoms present to suggest that intervention with esophageal dilatation would be indicated, were significant stricture formation present.
The mainstays of day-to-day care of any patient with inherited EB are prevention of trauma and infection of the skin, promotion of wound healing, and optimization of nutritional intake.
As yet there are no specific therapies for any type or subtype of inherited EB, although phase I clinical trials are now underway in DEB to explore the feasibility and possible benefits of ex vivo gene therapy transplantation of sheets of recombinant DNA corrected autologous keratinocytes, stem cell transplantation, and injections of allogeneic cells (fibroblasts). A recent phase I trial on injection of recombinant type VII collagen was halted due to safety concerns. A phase I trial of losartan in RDEB is underway to explore the possible benefit effect on a drug known to inhibit scar formation on modulation of cutaneous disease activity and, long-term, a possible positive impact on the risk of carcinogenesis in this patient population. There is also one report of decreased blister formation in DEB patients treated with intradermal G-CSF.
CURRENT THERAPEUTIC MODALITIES
Soft sterile bandages are placed around skin sites most prone to mechanical trauma, so as to cushion and protect them from further injury. Nonadherent synthetic dressings (ie, Mepitel; Mepilex; other) are applied to open wounds to promote reepithelialization. These can then be changed daily or every few days and, if still partially adherent, can be easily soaked off with tap water. Some authorities recommend prior application of a topical antibiotic (ie, Polysporin; Silvadene) to these wounds to reduce the risk of secondary infection. Potent topical antimicrobials (ie, Bactroban) are usually not for routine day to day care, since chronic use in EB patients 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 and/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 recessive dystrophic 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.
Aggressive nutritional support should be employed in any child with recessive dystrophic EB who has evidence of growth retardation, since malnutrition oftentimes arises in these patients as a result of chronic loss of blood and protein through nonhealing wounds on the skin and within the gut.
Patients with progressive webbing of the fingers should be referred to a hand surgeon experienced in the management of these complications, since degloving and separation of these webs may lead to temporary functional improvement. Unfortunately, these hand deformities frequently recur, requiring repeated surgical intervention to maintain optimal functionality. Similar pseudosyndactyly arising on the feet rarely require intervention, since they tend not to interfere significantly with ambulation.
Individuals with severe esophageal strictures who cannot be treated by dilatation may require transcolonic interposition.
Biopsy-proven squamous carcinomas need wide excision to ensure clear margins. In general I prefer to have these done by a surgical oncologist. Although there are robust data supporting the use of MOHS surgical technique for the treatment of SCCs in non-EB patients, so as to minimize unnecessary removal of uninvolved skin, there are no similar data that would convincingly argue that this is also true in the setting of inherited EB.
Rare patients with regional metastases of their SCCs may briefly benefit from surgical debulking of these tumors, particularly if they are painful, nonhealing, malodorous, and otherwise impairing movement of the limb. It is possible to treat nonhealing ulcerations of the skin with split-thickness skin grafts once it is proven by biopsy that those wounds do not instead represent SCC.
Urologic complications are uncommon in dystrophic EB. Any suggestion of their presence, however, merits evaluation by a urologist.
There are no data to suggest that radiotherapy has any clinical benefit in the management of patients with RDEB who develop metastatic SCC. Similarly, there are no published chemotherapeutic regimens that appear to be efficacious in the setting of RDEB.
Optimal Therapeutic Approach for this Disease
As noted above, the primary focus of dermatologic care in patients with RDEB 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. If any is seen, then the patient should be referred to an appropriate specialist for further evaluation and care. As discussed elsewhere, priorities in surveillance should be based upon knowledge of the time during which each of the major extracutaneous complications usually first arise. Recommendations regarding the latter may be found in a recently published review article on this subject.
Patients with dystrophic EB need close follow-up by both a dermatologist and a primary care physician. Additional specialists who can monitor for and treat extracutaneous complications need to be incorporated into the patient’s multidisciplinary team. During the first few years of life, EB children may need to be seen as frequently as every 1 to 2 months, until their parents are sufficiently comfortable enough about routine wound care that they can bring their children in for follow-up on a less frequent basis. Close collaboration with a pediatrician familiar with EB will be critical during infancy and early childhood, since it is likely that children with dystrophic EB may develop other illnesses unrelated to their underlying skin disease.
Several of the more severe extracutaneous manifestations of generalized EB, most notably external eye erosions and tracheolaryngeal and esophageal strictures, may begin as early as the first year of life. Identification of and intervention in these at an early stage may prevent more serious complications during later childhood or young adulthood. A more detailed discussion of the breadth and relative frequency of extracutaneous complications may be found in a recent review article.
Although SCCs have been reported as early as the middle of the first decade of life in rare children with severe generalized RDEB, these tumors usually do not first develop until early adolescence. The cumulative risk of a RDEB patient developing at least one squamous carcinoma, however, rises rapidly as he or she approaches the third and fourth decades of life. As a personal policy I tend not to discuss in great detail the risk of these tumors with parents of newborns or young children with RDEB, since I believe that these parents have far more important issues to deal with during the first few years of their children’s lives.
I do emphasize to them, however, that any new skin lesions that appear to look or feel differently to the patient, and particularly those that do not heal like other lesions on the same patient, need to be examined promptly by the patient’s dermatologist. Furthermore, any lesion in which a differential diagnosis of SCC is being entertained should be biopsied immediately rather than instead being observed serially, since SCCs arising in individuals with RDEB often present as otherwise nondescript nonhealing erosions rather than as the more prototypic scaly nodules that arise in adults who lack EB.
Close monitoring of weight and height will be important in children with RDEB, since marked growth retardation and often severe multifactorial anemia are common complications. A nutritionist experienced in managing EB children should be involved in their multidisciplinary care. Elective gastrostomy may be particularly helpful in children who are unable to correct their nutritional deficiencies by oral means.
Patients with inherited EB, particularly those with junctional and RDEB, commonly experience depression. Suicidal ideation has been documented in some cohorts of patients, emphasizing the need for psychiatric assistance with any EB patient having such complaints. Similarly, parents and unaffected siblings may also need psychological and psychiatric support, given the incredible burden that a child with RDEB places on the family unit. Assistance by physical therapy, vocational therapy, and social work may also be important in the overall management of the patient with inherited EB.
Unusual Clinical Scenarios to Consider in Patient Management
Two very uncommon complications in RDEB that need to be entertained include acute or chronic renal failure and progressive, if not eventually fatal, cardiomyopathy. Although there is no consensus as to how often routine laboratory testing should be done in patients with DEB, it would seem prudent to be monitoring hematologic and basic chemistries every 6 to 12 months until it is clear that the patient does not have significant anemia, malnutrition, or renal insufficiency. Although there are no data that could help recommend when to obtain electrocardiograms and echocardiograms in patients with RDEB, the patient’s primary care physician should be attuned to any clinical symptoms that might suggest early cardiac disease.
What is the Evidence?
Fine, J-D, Bauer, EA, McGuire, J, Alan, Moshell. “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. “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, J-D, 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, J-D, 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, J-D, 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, J-D, 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, J-D, 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, J-D, 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, J-D, 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, J-D, 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. 367-384.
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.)
Fine, JD, Manes, B, Frangoul, H. “Systemic granulocyte colony-stimulating factor (G-CSF) enhances wound healing in dystrophic epidermolysis bullosa (DEB): results of a pilot trial”. J Am Acad Dermatol. vol. 73. 2015. pp. 56-61. (Report of a novel treatment that may be of temporary benefit in some DEB patients having otherwise recalcitrant non-healing skin wounds.)
Mellerio, JE, Robertson, SJ, Bernardis, C. “Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines”. Br J Dermatol. vol. 174. 2016. pp. 56-67. (An international consensus report on recommendations for diagnosis and management of squamous cell carcinoma arising in patients with dystrophic EB.)
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