Oral soft tissues in hereditary epidermolysis bullosa J. T. Wright, DDS,” J.-D. Fine, MD,b and L. B. Johnson, SCD,~ Birmingham, SCHOOLS OF DENTISTRY

AND MEDICINE,

THE UNIVERSITY

OF ALABAMA

Ala.

AT BIRMINGHAM

Epidermolysis bullosa (EB) is associated with diverse oral manifestations, which can potentially involve both hard and soft tissues, depending on the specific EB subtype. This study determined the frequency and extent of oral soft tissue involvement in the inherited forms of EB. Examination of 216 affected persons revealed significant differences in the oral soft tissue involvement among the various types of EB. The frequency of oral involvement was greater in the dominant dystrophic (6 1.1%) and simplex (generalized, 56.6%; localized, 34.7%) types than previously reported. The marked frequency of oral blistering was similar in both major subtypes of junctional (Herlitz, 63.3%; non-Herlitz, 9 1.6%) and recessive dystrophic EB (generalized, 100%; localized, 92.3%). Obliteration of the oral vestibule, ankyloglossia, and microstomia were consistent findings in generalized recessive dystrophic EB. Oral milia were present in all major EB categories, most prevalently in the dystrophic forms, but were not seen in all the distinct EB subtypes. These findings indicate that although there are no pathognomonic intraoral soft tissue manifestations in the various forms of inherited EB, there are predictable patterns of involvement associated with specific subtypes of this disease. Understanding the oral involvement associated with EB may aid clinicians in the development of more advanced therapeutic approaches that are compatible with and directed at the unique characteristics of each EB subtype.

(ORALSURGORALMEDORAL PATHOL1991;71:440-6)

U

nderstanding and managing the myriad of physical and oral manifestations associated with epidermolysis bullosa (EB) remains a challenge for the medical and dental professions. EB is characterized by the presenceof mechanical fragility and blistering of the skin, which may result in potentially incapacitating scar formation and contractures. Depending on the EB subtype, a variety of extracutaneous tissues may be involved, thereby adding to the debilitating nature of the disorder.’ Numerous variants of EB have been identified, each of which is classified into three major categories on the basis of the level of tissue cleavage after mechanical trauma to the skin: epidermolytic (EB simplex), lamina lucidolytic (junctional), and dermolytic (dystrophic) EB.2*3 Distinct EB subtypes within each of these categories are delineated on the basis of clinical features, expression

Supported in part by National Institutes of Health grants (NO1 AR62271 [J.-D.F.], R03 DE08420-01 [J.T.W.], and 2 MO1 RR00032 [General Clinical Research Center, University of Alabama at Birmingham]). BDepartment of Pediatric Dentistry. bDepartment of Dermatology. 7/13/20613 440

of specific basement membrane features, and pattern of inheritance. The clinical features seenin each EB subtype are related to the depth of tissue cleavage with deeper tissue separation and usually, but not always, translate to more severeclinical presentations.4 The preferred nosology of the EB conditions remains a topic of debate.2,5,6 The inherited forms of EB have consistently demonstrated mendeiian inheritance as either autosomal dominant or recessivetraits with the exception of the Mendes da Costa variant of EB simplex, which appears to be inherited as an X-linked recessive trait.2q5,7 In addition, an acquired form of EB that is considered to be of autoimmune origin has been recently well characterized; of interest, however, a specific HLA haplotype has been associated with this disorder.8,9 Although the exact etiology for each of the EB subtypes remains obscure, skin fragility and bulla formation have beenassociatedin selectedtypes with a variety of basement membrane and enzymatic defects.‘0-‘4 Milia are small epidermal cysts that classically present as white, pinhead-sized papules that are frequently seen on the skin of neonates and in specific forms of EB, as well as in other dermatologic disorders associated with disruption of the dermoepider-

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Oral manifestations of epidermolysis bullosa

ma1junction. l5 Extraoral milia are seen primarily in patients with dystrophic EB, whereas those with junctional and simplex forms of this diseaseare rarely affec&15 Oral milia have been reported in persons with dominant dystrophic EB but have not been previously described in the other forms of EB.16It is believed that intraoral milia result from the entrapment of epithelial cells during the processof blister formation and healing. 15,l6 The character and severity of oral involvement are known to vary greatly from one EB subtype to the next.i7-19 In its mildest form the oral affliction may entail only occasional blistering manifested as small, discrete vesicles that heal rapidly. At the other extreme, severe intraoral blistering with subsequent scar formation, obliteration of the oral vestibule, ankyloglossia, and perioral carcinomas may occur in recessive dystrophic EB. 20-23The frequency of oral blistering remains poorly defined and has not been described since Touraine’s report19in 1942. Although these prevalence data are frequently cited, they remain to be substantiated by current diagnostic criteria.20*21 Despite the ability of phenytoin therapy to reduce the frequency of cutaneous blistering in somepatients with recessivedystrophic EB, the treatment of inherited EB remains essentially palliative.24y25 Persons with certain forms of EB are predisposedto rapid attrition and rampant dental caries, thereby posing significant problems in treatment.26,27Generalized pitting enamel hypoplasia is seen in all junctional EB subtypes and often leads to a rapid breakdown of the dentition.27-29Becauseof the fragility of the oral mucosa and frequency of extensive dental involvement, many patients with severe EB require general anesthesia to receive dental treatment.30*31Although numerous case reports have described soft tissue and dental anomalies of EB, our knowledge concerning the oral manifestations associated with the distinct types of EB remains imprecise. This leavesclinicians unable to predict accurately the degree of expected oral involvement and therefore unable to formulate the best possible therapeutic approach for optimal dental health. The purpose of this investigation was to evaluate the prevalence and character of oral soft tissue involvement in a well-defined population representing both major and minor types of inherited EB.

Table

MATERIAL

AND METHODS

Persons participating in the Southern Clinical Center for the National Epidermolysis Bullosa Registry, a federally funded project, were prospectively examined for the present study. Participants from 17 states were referred to the registry by practicing dermatologists, pediatricians, or patients with this dis-

441

I. Distribution of population by EB diagnosis, sex, and race Sex EB diagnosis

Dystrophic Recessivelocalized Recessivegeneralized Dominant generalized Junctional Herlitz Non-Herlitz Simplex Localized Generalized Total EB population Control subjects

Race Black

White

12 12 24

3 0 7

10 27 30

3 2

1 4

5 5

39 56 16 13 94 122 5 20

1 2 21 6

94 24 195 19

n

M

F

13 27 37

1 15 13

63 97 95 29 216 25

ease. Detailed family, medical, and dental histories were obtained, and each subject classified as having a specific EB subtype on the basis of clinical morphologic findings, pedigree analysis, and the results of specialized skin biopsy studies (transmission electron microscopy, EB-specific monoclonal antibody studies, immunofluorescence “antigenic” mapping studies).32 All dental evaluations were conducted by one dental examiner. Each subject was examined with artificial light, a dental mirror, and a No. 11 dental explorer. Oral lesions were documented as to size, characteristics, and location. Microstomia was quantified by measuring the commissure-to-commissure distance with the mouth closed and at rest, and with the mouth maximally open. Clinical photographs were taken to document the soft tissue and dental manifestations of each case. A control population of 25 unaffected, healthy persons were recruited from the University of Alabama School of Dentistry and examined with the same methods and criteria as those used with the EB population. Statistical analyses of age and microstomia measures included regression analysis, analysis of variance, and Fisher’s protected least significant difference test. Ordinal data of lesion presencewas evaluated with contingency tables. All statistical analyses accepted an a! level of p < 0.05 as statistically significant. RESULTS

A total of 216 patients with EB from across the southern United States were prospectively examined for inclusion in this investigation. Study participants represent all three major EB categories and nearly all the known subtypes of this disease.The distribution of subjects by major EB category, sex, and racial composition are presented in Table I. Although the majority of the participants were white, blacks were

442

Wright, Fine, and Johnson Occurrence of Oral Lesions in EB

Fig. 2. Tongue of young adult with dominant dystrophic EB shows partial loss of papillae from recurrent lesions and well-circumscribed eroded ulcer.

Fig. 1. Graph indicates that oral lesions occur in virtually all persons with dystrophic and junctional EB, and, although less frequent, oral blistering is also seen in patients with EB simplex.

represented in all groups, indicating that the disorder is multiracial. Evaluation of inheritance revealed that transmission in most casesfollowed autosomal dominant and recessivepatterns as previously published; however, several exceptions have been recently noted, including variants of EB simplex with autosomal recessive inheritance.33,34 Considerable heterogeneity was noted among the various EB categories with regard to clinical course and disease severity. Despite this clinical variation, however, the majority of subjects included in this study did have clinical findings characteristic of their diagnostic category as indicated by skin biopsy studies. Intraoral soft tissue lesions were common in each of the EB categories; nearly all patients with the recessive dystrophic, dominant dystrophic, or junctional forms had a history and/or clinical evidence of oral involvement. The prevalence of oral lesions for each EB category and subtype is presented in Fig. 1. Lesions varied from small, discrete vesicles to large intraoral bullae that ruptured, leaving denudederoded areas (Figs. 2 and 3). Lesions were distributed over the entire oral cavity, with all the mucosal surfaces at

Fig. 3. This hemorrhagic vesicle (arrow) on attached gingiva of child with dominant dystrophic EB occurred as result of light pressure.

risk for lesion development. No site-specific pattern of involvement was established for the different EB categories or subtypes, such as blistering being limited to or absent from certain intraoral areas. In the present investigation 34.7% of the patients with localized (n = 95) and 58.6% with generalized (n = 29) EB simplex, respectively, had demonstrable intraoral soft tissue fragility that resulted in at least intermittent frank blister formation. Although oral involvement in EB simplex was reported by participants or their parents as being most common during the perinatal period, somedid have persistent blistering during early childhood or even later. In dominant dystrophic EB (n = 37) oral lesions were noted in 89.6% of the patients examined. However, oral involvement in this subtype did not lead to clinically significant scarring, because none of these cases showed evidence of either vestibular obliteration or ankyloglossia. Patients with recessivedystrophic EB had the most severe intraoral involvement, characterized by com-

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Number 4

Fig. 4. Five-year-old child with generalized recessive dystrophic EB shows complete loss of papillae and ankylosis of tongue and restriction of oral opening.

plete vestibular obliteration and adhesion and decreased mobility of the tongue (ankyloglossia) (Fig. 4). Normal tissue structures such as the palatal rugae and lingual papillae were unrecognizable as a result of continuous blistering and scarring (Fig. 5). This pattern of oral involvement was present in all patients with generalized recessivedystrophic EB (n = 27). In one patient the anterior two thirds of the tongue had been previously removed becauseof the development of a squamouscell carcinoma. In contrast, none of the patients with localized recessive dystrophic EB (n = 13) had as severe oral scarring, and only 54% had lingual loss of papillae and/or ankyloglossia. Patients with junctional EB did not exhibit vestibular obliteration and only rarely had evidence of severe intraoral scarring. However, other oral lesions (vesicles, erosions) did develop in 88.8%. Ankyloglossia was not seen, although extensive lingual bullae developed in one patient. The frequency and character of intraoral involvement was similar in both Herlitz (n = 6) and non-Herlitz (n = 12) junctional EB subtypes. The Herlitz subtype differed from all other types in its predisposition to develop severe perioral lesions, which in several casesinvolved large areas of the face and caused occlusion of the nares (Fig. 6). These latter lesions were noted in all the patients with Herlitz junctional EB but tended to resolve and disappear during or after late adolescence. Microstomia was most severein generalized recessive dystrophic EB as evidenced by significantly reduced commissure-to-commissure measurements compared with all other EB variants. Whereas the normal mean maximal opening, as measured from commissure to commissure, was 44.7 mm, mean values of only 33.6 and 39.2 mm were noted in patients with generalized recessive dystrophic and Herlitz

Fig. 5. Palatal tissues of &year-old child with generalized recessive dystrophic EB demonstrates complete destruction of normal anatomic structures and tractlike lesions that have developed during ongoing blistering and scarring process.

6. Herlitz subtype of junctional EB is characterized by presenceof pathognomonic perioral crusted granulation tissue that in somepatients may be so extensive as to involve most of face. Fig.

junctional EB, respectively. Measurements of oral opening and the results of statistical analysis of the data are presented in Table II. Regression analyses showed that there is a significant positive correlation between age and oral opening width (p < 0.05, r = 0.421) in the control group and for all EB patients except for those with generalized recessivedystrophic EB (p > 0.05, r = 0.156). Oral milia differed in size and appearanceand were seen primarily on the palatal mucosa (Fig. 7). The prevalence of intraoral and extraoral milium formation varied significantly among the different forms of EB (Table III). A significant positive correlation was noted between the presenceof extraoral and intraoral milia in EB when data were analyzed for the entire EB and control populations with the use of contingency tables. Oral milia were most prevalent in localized recessive dystrophic (53.8%) and dominant dys-

444

Wright, Fine, and Johnson

ORAL SURG ORAL

MED ORAL PATHOL April 1991

Table III. Oral and cutaneous milia iormation in EB and control patients No. of subjects (% J EB diagnosis

Fig. 7. Oral milia were seen in all major forms of EB but were most common in dystrophic subtypes. Intraoral milia were typically present on keratinized palatal mucosa (arTOW),as seen in this ‘I-year-old child with dominant dystrophic EB.

Table II. Width of oral opening in EB and control patients EB diagnosis

Dystrophic Recessivelocalized Recessivegeneralized Dominant generalized Junctional Herlitz Non-Herlitz Simplex Localized Generalized Control subjects

n

Mean C-C (mm)

SD

11

41.4a3b

24 27

33.6c 46.F b

4.6 6.4 8.9

5 8

39.2a*C 46.7b

8.7 7.5

45.9b 42.P 44.7a,b

6.1

79 23 25

8.8 6.5

C-C. Width of oral cavity from commissure to commissure with mouth maximally open. a,b,CMeans that are similar whereas all other means are significantly different at p < 0.05.

trophic (66.6%) EB and, where assessable,appear to occur with nearly the same frequency intraorally and extraorally. The only exception to the latter was noted in patients with generalized recessivedystrophic EB, where intraoral milia were not visualized despite their widespread prevalence on the skin and despite the presence of severe oral involvement. DtSCUSStON

Oral involvement in inherited EB ranges from mild and infrequent blistering to extreme debilitation. Although one may expect the degree of severity to worsen as the depth of tissue blisters deepens,this was not uniformly found to be the case. For example, personswith dominant dystrophic and localized recessive dystrophic EB did not have the severity of tongue in-

Dystrophic Recessivelocalized Recessivegeneralized Dominant generalized Junctional Herlitz Non-Herlitz Simplex Localized Generalized Control subjects

n

Oral

Cutaneous

13

7 (54)

27 37

0* 18 (49)

9 (69) 21 (78) 25 (68)

6

0

12

2 (17)

95 29 25

8 (81 6 (21) 0 (0)

1 (17) 0 l(1)

6 (21) 0

*Oral milia were not seen in generalized recessive dystrophic EB, presumably because of the severity of tissue alteration and sloughing, thereby obscuring their visualization.

volvement that was so characteristically observed in generalized recessivedystrophic EB, even though the tissue cleaves at the same level (i.e., just beneath the lamina densa of the dermoepidermal junction) in all three dystrophic EB subtypes, This diverse range of oral involvement seenin our study population with EB provides further evidenceasto the clinical and genetic heterogeneity of this collective group of diseases. Oral milia were seenin all the major EB categories but not in each of the phenotypically distinct EB subtypes. Intraoral and extraoral milia occurred with similar frequency in each EB subtype, with the exception of the generalized recessivedystrophic subtype. As noted, extraoral milia were frequent (78%) in recessivedystrophic EB, whereasno intraoral milia were seenin any of the personsexamined. We assume that this simply reflects the severity of other intraoral tissue changes (i.e., denudation) that alter tissue morphology to such a degree that intraoral milia are not distinguishable even when present. Although milia are classically associated with dystrophic EB, we have found that milia also occur in generalized EB simplex with some regularity (21%).15-17In contrast, milium formation, either intraorally or extraorally, was rarely observed in junctional EB as has been noted previously,i7 The results of this investigation show that patients with EB simplex and dominant dystrophic EB are more likely to have oral soft tissue involvement than has been reported previously. Whereas the most commonly cited figure for oral involvement in EB simplex is 2%, the present study reveals 40.3% (both localized and generalized subtypes) with oral lesions, as determined by history and/or examination.‘9V2’ The prevalence of oral blistering varies among the different EB simplex variants and, as has been previously

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Oral manifestations of epidermolysis bullosa

reported, may occur with regularity in specific EB simplex subtypes.35As we have shown, persons with generalized EB simplex have a greater likelihood of having oral lesions develop than patients with more localized disease. However, even when present in EB simplex, oral manifestations were mild and only in rare instances led to significant alterations in lifestyle. Twenty percent of patients with dominant dystrophic EB have been reported to have associatedoral lesions,whereasin the present study 89.6%were noted to be so involved.lg* 2oThese lesions were frequently reported by our study participants as resulting from mechanical or chemical trauma (e.g., dental prophylaxis, acidic foods) and were usually self-limiting. However, persons with dominant dystrophic EB may have intraoral blistering severe enough to cause changes in eating and oral hygiene habits. Clinicians providing oral care should obtain a thorough history of oral involvement and proceedwith caution until the extent of oral fragility is ascertained. In our experience most of these persons will still be able to receive routine dental care with little or no modification of the treatment approach. The propensity to develop intraoral soft tissue lesions was nearly universal in the dystrophic and junctional forms of EB, with the generalized recessive dystrophic subtype having the most severesoft tissue involvement. In all casesof generalized recessivedystrophic EB, intraoral soft tissue was so involved that normal tissue morphology and mobility were drastically altered. The oral vestibule was obliterated, with the soft tissue becoming tightly adherent to the labial surfacesof the teeth and the tongue showing complete loss of papillae and ankylosis-findings that are consistent with those previously reported for this specific EB subtype.“, l8 This particular pattern of oral involvement appears to be unique to the generalized and inversa forms of recessivedystrophic EB (the latter of which is classified for the purpose of this study as a localized dystrophic subtype).23 It is known that continuous oral blistering that leads to oral scarring, ankyloglossia, and vestibular obliteration may produce tissue changes with malignant potential. Squamous cell carcinomas have been reported at numerous extraoral and perioral sites in personswith generalized recessivedystrophic EB who survive to the secondand third decadesof life.2oy36In addition to the malignancy of the tongue reported in the present study, several previous cases of lingual carcinomas have been documented, illustrating the potential lethality of oral involvement associatedwith this disorder.34-38Because many persons with this subtype of EB are surviving to the third decadeof life and are prone to the development of intraoral carcinomas, periodic oral examinations must be considered

an important aspect of the routine examination of these patients. In more severe forms of EB, microstomia results from both intraoral and perioral blistering and subsequent scar formation. The reduction in this oral dimension results from progressive oral scarring, which usually begins in early childhood and apparently leads to alterations in the normal growth of the oral tissues. The probability of an abnormal growth mechanism in the development of such microstomia is supported by the insignificant positive relationship between age and oral width in generalized recessive dystrophic EB. Specifically, this means that the oral cavity width does not increase at a normal rate with growth and microstomia results. Microstomia associated with generalized recessive dystrophic EB appears to be the result of chronic severeintraoral blistering. In contrast, whereas the Herlitz variant of junctional EB also demonstrates microstomia, vestibular obliteration and tongue involvement are characteristically absent. Instead, this EB subtype is classically associated with severe, chronic perioral erosions and granulation tissue. We suspect that this latter perioral blistering appears to be a major etiologic factor associated with microstomia in the Herlitz variant of junctional EB. Soft tissue involvement and microstomia complicate the ability to render both preventative and restorative care. We have found, however, that special techniques (i.e., use of flat tissue retractors and of long, slender instruments to deliver crowns to posterior teeth) can be used to provide restorative care in EB patients with severe microstomia.31 Critical evaluation of the oral manifestations of each EB subtype has shown that the majority of personswith EB simplex and milder forms of dystrophic EB have little to no disability of the oral cavity. On the basis of the present study, differences clearly exist with regard to the prevalence and severity of oral involvement, including blister formation, scarring, microstomia, and tendency for oral malignant transformation among the different EB types. The exact role that intraoral and perioral involvement play in the development of dental caries and inhibition of normal oral prevention remain to be explored. Medical and dental practitioners must be cognizant of these differences so that clinical evaluations and treatment approaches are tailored to the special needs of this unique population. REFERENCES

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therapy of recessivedystrophic epidermolysis bullosa. N Engl J Med 1980;303:776-81. Cooper TW, Bauer EA. Therapeutic efficacy of phenytoin: a comparison of short- and long-term treatment. Arch Dermato1 1984;120:490-5. Nowak AJ. Oropharyngeal lesions and their management in epidermolysis bullosa. Arch Dermatol 1988;124:742-5. Wriaht JT. Cauos J. Fine JD. JohnsonLB. Dental caries variationin the diffeient epidermdlysis bullosa diseases[Abstract]. J Dent Res 1989;68:416. Koshiba H, Kimura 0, Nakata M. A clinical and histologic observation of enamel hypoplasia in a case of epidermolysis bullosa. ORAL S~RC ORAL MED ORAL PATnoL 1977;43:

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bullosa simplex: identification of a kindred with autosomal recessivetransmission of the Weber-Cockayne variety. Pediatr Dermatol 1988;6:1-5. Fine J-D, JohnsonL, Wright T. Epidermolysis bullosa simplex superficialis, a new variant of epidermolysis bullosa characterized by subcorneal skin cleavage mimicking peeling skin syndrome. Arch Dermatol 1989;125:633-8. Reed WB, College J Jr, Francis MJO, et al. Epidermolysis bullosa dystrophica with epidermal neoplasms. Arch Dermatol 1974;110:894-902. Klausner E. Zungenkrebs als Folgezustand bei einem Falle von Epidermolysis Bullosa. Arch Dermatol Syph I9 13;I 16:71-8. Schiller F. Zungencarcinom bei Epidermolysis Bullosa Dystrophica. Arch Klin Exp Dermatol 1960;209:643-51.

Reprinr requesrs to:

J. T. Wright, DDS Associate Professor Department of Pediatric Dentistry School of Dentistry, CB 7450 Brauer Hall The University of North Carolina at Chapel Hill Chapel Hill, NC 27599-7540