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Inherited epidermolysis bullosa
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Inherited epidermolysis bullosa An update and suggested dental care considerations Javier F. Feijoo, MD, DDS, PhD; Juan Bugallo, DDS; Jacobo Limeres, DDS, PhD; David Peñarrocha, DDS; Miguel Peñarrocha, MD, DDS, PhD; Pedro Diz, MD, DDS, PhD
EPIDEMIOLOGY
EB affects both sexes and occurs in populations worldwide.6 The estimated prevalence of the disease in the United States is eight per 1,000,000 inhabitants and the incidence is 19 cases per 1,000,000 live births.6,7 Fine and Hintner8 suggested that these figures are underestimates subject to
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® Background. Epidermolysis bullosa (EB) is a skin disease characterized by epithelial fragility that leads to blistering A and erosion of the skin and mucosae. The 2 RT I C LE authors conducted a literature review to provide an update on oral manifestations and dental care of patients with EB. Literature Search. The authors reviewed the dental literature on EB in relation to clinical findings and provision of dental care. They searched textbooks and three databases: MEDLINE, Cochrane Library and Embase. The authors did not impose any date or publication status restrictions. They searched all databases up to August 2010. Results. The literature review revealed that four major groups and 32 subtypes of EB can be distinguished on the basis of the ultrastructural characteristics of skin cleavage, genetic mode of transmission and clinical phenotype. Oral manifestations differ in frequency and severity according to the disease subtype, but the most common are bullae, which leave painful ulcers on rupture, followed by scarring and tissue contraction. Although good oral health status is essential to maintaining oral function, dental treatment can induce new lesions and be hindered by the sequelae of existing lesions. Clinical Implications. Dental treatment in patients with EB requires a multidisciplinary approach. Dental procedures must be minimally traumatic, and the effectiveness of treatment is determined mainly by the patient’s general health, cooperation in the dental office and at home, oral hygiene and diet. Key Words. Epidermolysis bullosa; blistering; enamel hypoplasia; dental treatment. JADA 2011;142(9):1017-1025. T
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The objective of our review was to provide an update on oral manifestations and dental care of patients with EB. We searched textbooks and three databases: MEDLINE, Cochrane Library and Embase. We did not impose any date or publication status restrictions. We searched all databases up to August 2010.
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AB STRACT CON
enodermatoses constitute a highly heterogeneous group of clinical abnormalities. The conditions usually are inherited, and their principal manifestations affect the skin, hair and nails. Epidermolysis bullosa (EB) is a genodermatosis involving abnormal epithelial integrity. It is characterized by blistering and erosions of the skin and mucous membranes following slight mechanical trauma. In 1870, von Hebra1 provided probably the first description of a familial blistering disease, which he termed “hereditary pemphigus.” This soon was followed by other reports of patients with congenital blistering diseases.2-4 However, it was not until 1886 that Köbner5 gave the disease its present name and differentiated it from other bullous diseases.
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Dr. Feijoo is an assistant professor, Special Needs Unit, School of Medicine and Dentistry, Santiago de Compostela University, Spain. Dr. Bugallo is a graduate student, Special Needs Unit, School of Medicine and Dentistry, Santiago de Compostela University, Spain. Dr. Limeres is an associate professor, Special Needs Unit, School of Medicine and Dentistry, Santiago de Compostela University, Spain. Dr. D. Peñarrocha is a graduate student, Oral Surgery Unit, School of Medicine and Dentistry, Valencia University, Valencia, Spain. Dr. M. Peñarrocha is a professor, Oral Surgery Unit, School of Medicine and Dentistry, Valencia University, Valencia, Spain. Dr. Diz is an associate professor, Special Needs Unit, School of Medicine and Dentistry, Santiago de Compostela University, C./Entrerrios s/n, 15872 Santiago de Compostela, Spain, e-mail “[email protected]”. Address reprint requests to Dr. Diz.
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substantial bias in patient registries and that the true prevalence rate could be close to 45 patients per 1,000,000 inhabitants, and the true incidence rate could be close to 95 cases per 1,000,000 live births. Some authors have suggested that the overall U.S. rates are similar to those for Western Europe and probably can be generalized worldwide.9 However, researchers have observed marked differences between countries in reported prevalence, ranging from two to 56 patients per 1,000,000 inhabitants in South Africa10 and Scotland,11 respectively. These differences suggest incomplete enrollment in official EB databases, regional variations, differing genetic susceptibilities or a combination of these.11 CLASSIFICATION
In 1898, Hallopeau12 was the first, to our knowledge, to attempt to classify patients with EB on the basis of clinical criteria by using the French terms “simple” and “dystrophique.” This classification received much criticism and resulted in subsequent revisions. Almost 100 years later, in 1989, experts in EB held a consensus meeting regarding the diagnosis and classification of inherited EB.13 Those who participated in that meeting proposed a new classification system based on the ultrastructural level of skin cleavage. According to the new system, EB could be classified into one of three major groups: dEB simplex (EBS); djunctional EB (JEB); ddystrophic EB (DEB). According to the proposed system, EB was subclassified on the basis of the genetic mode of transmission and clinical phenotype. The third, and most recent, consensus meeting pertaining to the diagnosis and classification of EB took place in Vienna in 2007. The two main contributions from that meeting were the inclusion of a fourth major group of EB— Kindler syndrome—and the classification of the disease into 32 subtypes.14 MODES OF INHERITANCE, PATHOGENESIS AND PHENOTYPE
EBS. EBS is the most common of the major groups of EB.15 Inheritance can be dominant (DEBS) or recessive (REBS), but in all cases, intraepidermal blister formation is observed, most commonly appearing in early infancy. DEBS. DEBS is caused by mutations in the genes encoding keratin 5 and 14 in keratinocytes of the basal layer.16,17 Different phenotypes are observed according to the site at which the mutation occurs, and these have been grouped into three subtypes: Weber-Cockayne syndrome 1018
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or localized EBS, Dowling-Meara EBS, and Koebner or non-Dowling-Meara EBS.14 The localized subtype is the most common, accounting for two-thirds of cases of EBS,15 and it is characterized clinically by the preferential localization of the lesions on the palms and soles, although lesions may be precipitated by traumatic events at other sites. The Dowling-Meara subtype is the least frequent and the most severe of the three subtypes. Both the Dowling-Meara and Koebner subtypes are associated with widespread lesions. REBS. REBS is caused by mutations in the gene encoding plectin (HD1),18 a protein found in the hemidesmosomes and in skeletal muscle. Consequently, most patients experience widespread blistering and muscular dystrophy. A lethal variant exists (although some patients with milder cases have survived into childhood) associated with pyloric atresia.19 JEB. JEB follows a pattern of autosomaldominant inheritance and is characterized by the formation of blisters in the lamina lucida of the epithelial basement membrane that appear at birth or during the neonatal period. Three subtypes of JEB exist: Herlitz, non-Herlitz and a subtype involving pyloric atresia.14 Herlitz subtype. The Herlitz subtype has a severe phenotype and is produced by mutations in any of the three genes encoding the anchoring filament glycoprotein laminin 332 (previously called “laminin” or “laminin 5”).20 Affected patients have characteristic periorificial erosions and multisystem disease, and they are at increased risk of dying of sepsis. Thus, they usually do not survive for more than a few years.18 Non-Herlitz subtype. The non-Herlitz subtype is characterized by generalized blisters that predominate in sites exposed to friction, trauma or heat, and it accounts for 80 percent of cases of JEB.9 It is caused by point mutations in the genes encoding laminin 332 or by mutations in BPAg2, which encodes the BP180 polypeptide.21 Although non-Herlitz JEB generally is less severe than Herlitz JEB and many patients survive to adulthood, dying of the disease (especially in neonates) is not uncommon.22 Pyloric atresia. JEB pyloric atresia is caused by mutations in ITGA6 or ITGB4, genes encoding α6 integrin or β4 integrin (which form a ABBREVIATION KEY. DEB: Dystrophic epidermolysis bullosa. DDEB: Dominant dystrophic epidermolysis bullosa. DEBS: Dominant epidermolysis bullosa simplex. EB: Epidermolysis bullosa. EBS: Epidermolysis bullosa simplex. JEB: Junctional epidermolysis bullosa. RDEB: Recessive dystrophic epidermolysis bullosa. REBS: Recessive epidermolysis bullosa simplex.
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TABLE 1 glycoprotein complex found in hemidesmoPrevalence of oral findings in major types somes).23 It is characand subtypes of epidermolysis bullosa (EB).* terized by blistering with little or no MAJOR EB TYPES PERCENTAGE OF PATIENTS CARIES FREQUENCY AND SUBTYPES trauma, ureteral and Soft-Tissue Enamel Abnormalities Hypoplasia renal anomalies, and congenital pyloric EBS† atresia. The course Weber-Cockayne syndrome 25-50 10-25‡ Same as general population usually is severe and Koebner 50-75 10-25‡ Same as general population Dowling-Meara 25-50 10-25‡ Same as general population often lethal in the neonatal period. SurJEB§ vivors may experiHerlitz 50-75 75-100 Increased ence blistering with Non-Herlitz 75-100 75-100 Increased formation of granulaDEB¶ tion tissue, but some DDEB# 50-75 10-25‡ Same as general population patients experience RDEB** Hallopeau-Siemens 75-100 10-25‡ Increased little or no blistering RDEB non–Hallopeau-Siemens 75-100 25-50 Same as general population later in life.18 Kindler Syndrome Gingival Absent Same as general population hyperplasia DEB. DEB is characterized by intra* Sources: Fine,9 Fine and colleagues14 and Wright.28 † EBS: Epidermolysis bullosa simplex. dermal blisters, scar‡ Some authors consider the prevalence to be similar to that in control participants. ring and keratin§ JEB: Junctional epidermolysis bullosa. ¶ DEB: Dystrophic epidermolysis bullosa filled cysts below the # DDEB: Dominant dystrophic epidermolysis bullosa. epidermis (milia).18 ** RDEB: Recessive dystrophic epidermolysis bullosa. Inheritance can be dominant (DDEB) or recessive (RDEB).15 It is caused by mutations in COL7A1, which encodes collagen type VII (a component of hemidesmosome-anchoring filaments).24 The clinical manifestations of DDEB tend to be milder than those of the autosomal-recessive forms, with blistering often limited to hands, feet, knees and elbows. Two subtypes of RDEB have been described14: the Hallopeau-Siemens subtype—also termed the “severe generalized” form—and the non– Hallopeau-Siemens subtype. The HallopeauSiemens subtype is the most severe form and involves almost no expression of collagen VII in the basement membrane. The lifetime risk of developing aggressive squamous cell carcinoma in this subtype is more than 90 percent. In the Figure 1. Blister on the lower lip of a child with epidermolysis non–Hallopeau-Siemens subtype, there is some bullosa simplex. limited expression of collagen type VII, the clinORAL MANIFESTATIONS ical manifestations are milder and the distribution of lesions is similar to that in DDEB.9,14,18 The oral manifestations of EB can involve both Kindler syndrome. Kindler syndrome folsoft and hard tissues, and they differ in frequency lows a pattern of autosomal-recessive inheriand severity according to the EB subtype26,27 tance. Affected families have mutations in (Table 19,14,28). Although there are no pathognoKIND1 (FERMT1), which encodes Kindlin-1, a monic intraoral soft-tissue manifestations, the structural component of the actin cytoskeleton.25 most common oral finding is blistering (Figure 1). Defects in this protein compromise cell adhesion On rupture, bullae leave painful ulcers, followed in keratinocytes of the basal layer. Kindler synby scarring and tissue contraction.29 Other manidrome is characterized clinically by skin blisfestations include the appearance of milia, tering induced by trauma, poikiloderma, cutamicrostomia, ankyloglossia, severe periodontal neous atrophy, mucositis and varying degrees of disease, enamel hypoplasia, dental caries and photosensitivity.9,18 atrophy of the maxilla with mandibular prog27
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Figure 2. Enamel hypoplasia in a patient with junctional epidermolysis bullosa.
nathism.26,30,31 Patients with RDEB are at an increased risk of developing oral squamous cell carcinoma, which increases with age.26,32 Milia are tiny (1 to 4 millimeters) benign white papules that usually are located on the palate and correspond histologically to keratinfilled cysts. Oral milia are present in all major EB categories but are most prevalent in the dystrophic forms.26,33 The appearance of oral milia is not influenced by their occurrence on the skin or linked to the severity of oral involvement in different EB subtypes.26 Microstomia is a narrowing of the opening of the mouth caused by a constant process of blister formation and healing that results in scarring in the commissures and loss of vestibular space.34 It contributes to poor oral intake and makes access to the mouth and gastrointestinal tract difficult. The adhesions that form between the tongue and floor of the mouth give rise to ankyloglossia,30 which limits tongue movement and causes difficulties in eating and swallowing. Wright and colleagues35 reported dental anomalies ranging from mild to generalized enamel hypoplasia in patients with EB (Figure 2). Their clinical expression and prevalence vary according to the subtype.35 Azizkhan and colleagues34 described three enamel abnormalities in EBS and JEB: hypoplasia, hypomaturation and hypocalcification. In hypoplasia, the enamel does not achieve its normal thickness and has an irregular appearance, and teeth appear small. In hypomaturation, the enamel thickness is normal but the enamel has a mottled appearance, is fragile and is less radiolucent than is the dentin. In hypocalcification, the enamel thickness is normal, but the enamel is extremely soft with a yellow pigmentation, and the dentin often is left exposed. Wright and colleagues27,32 reported a high risk of caries development in patients with JEB or DEB (RDEB subtype). In contrast, Harris and colleagues36 reported that the prevalence of caries in patients with EBS or DDEB was similar to 1020 JADA 142(9)
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that in healthy control participants. Factors that favor caries formation in these patients include accumulation of dental plaque (as a result of poor oral hygiene due to the pain associated with toothbrushing and the fear of new lesions’ appearing), pseudosyndactyly, microstomia, diet consisting of soft foods that are rich in carbohydrates and reduced oral clearance.36 The mineral and chemical composition of dental enamel in patients with DEB is no different from that in normal enamel, but the developmentally compromised enamel found in JEB also could predispose patients to developing caries.37,38 Researchers have not determined whether salivary flow, salivary immunoglobulin levels or oral microflora are cofactors for caries susceptibility.32,36 EBS. One-third of patients with localized (that is, Weber-Cockayne syndrome) EBS have small numbers of localized blisters and erosions that are asymptomatic and generally are smaller than 1 centimeter in diameter.26,28,30 The blisters occur almost exclusively in childhood after the patient has experienced substantial trauma or traction, and they do not result in atrophic scarring or adhesion (Figure 1).27 The prevalence of enamel hypoplasia and caries is similar to that in the general population.32 JEB. Most patients with JEB have severe oral blisters (larger than 1 cm), with no specific localization, that leave scars on healing. As a result, microstomia and ankyloglossia are common,26,30 although some authors have reported that difficulties opening the mouth are minimal or do not occur.39,40 Although the oral manifestations are not as severe as those observed in RDEB,30 Fine and colleagues41 described cases of malignant transformation of JEB lesions into squamous cell carcinoma. The lesions can obstruct the salivary glands temporarily, but this obstruction resolves spontaneously without any need for specific treatment.30 The mutated genes in JEB encode proteins that are involved in cell adhesion in the odontogenic epithelium, which gives rise to ameloblasts, the cells that produce dental enamel. Dysfunctional ameloblast adhesion can result in leaking of serum fluids into the developing enamel, resulting in a retention of albumin and decreased mineralization.38 Consequently, the only clinical manifestation that is common to all subtypes of JEB is enamel hypoplasia, displayed as localized or more extensive thimblelike pitting of some or all of the tooth surfaces (Figure 2), most often in the primary teeth.27,30,35 Patients with JEB are at an increased risk of developing dental caries, probably the result of enamel defects that are difficult to clean and thus promote microbial growth
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CLINICAL
and dental plaque retention.30 DEB. Oral blisters develop relatively infrequently in patients with DDEB. They occur after mild trauma and heal by means of mucosal atrophy, but only one-half of affected patients have microstomia, ankyloglossia and loss of vestibular space. Almost all patients with RDEB have large blisters that can appear spontaneously.30 The most commonly affected site is the lingual mucosa, and the least commonly affected site is the buccal mucosa.42 The constant process of blister formation and healing leads to changes in the architecture of the oral epithelium, resulting in microstomia. The lingual papillae and the palatal folds ultimately can disappear.42 The structural changes in the lingual epithelium give rise to severe ankyloglossia.30 Patients with RDEB are at an increased risk of developing squamous cell carcinoma or malignant melanoma in adulthood.41 Milia are common in the palatal mucosa. Salivary secretion is normal in most people with DEB, whereas enamel hypoplasia is rare. Nevertheless, patients with DEB—particularly those with RDEB—are at a high risk of developing dental caries.30 Kindler syndrome. The gingival and oral mucosa commonly are affected in patients with Kindler syndrome.30 It manifests clinically as desquamative gingival hyperplasia with hyperkeratotic white plaques, atrophic areas and lip pigmentation.43 Clinical and microbiological findings in patients with Kindler syndrome suggest the existence of atypical periodontitis, with onset in the early teenage years and rapid progression.44 Tooth enamel usually is not affected, but caries is common owing to poor oral hygiene resulting from pain and bleeding during toothbrushing.9 DENTAL TREATMENT
General issues. Because of oral complications, patients with EB may have problems with nutritional intake and chewing and swallowing of food, and they may have a negative self-image because of their altered appearance and speech problems.45 Consequently, medical and dental treatment requires a multidisciplinary approach.27,46 Dental care is influenced by patients’ general health, their ability to cooperate in the dental office and at home, and their oral hygiene and diet, and it requires carefully performed, minimally traumatic procedures. Clinicians need to perform conservative and restorative treatments to maintain efficient masticatory function, because doing so reduces the risk of developing oral and esophageal lesions.27
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Additional care is necessary given the difficulty associated with opening the mouth and the fragility of the epithelial tissues. In patients who have reduced tongue mobility or difficulties opening their mouths, specific physiotherapy exercises are recommended.45 To reduce the risk of Figure 3. Oral ulcer after blister formation, aggressive compression of the researchers recomepithelium with a lip retractor. mend the use of lubricants (for example, petroleum jelly, glycerin and hydroxyethyl cellulose, methyl cellulose) on the patient’s lips and oral mucosa, as well as on gloves, radiographic film and instruments.28,30,46-49 For the same reason, clinicians should avoid using lateral traction and compressing the epithelium (Figure 3), and they should rest aspirators on hard tissues such as the teeth.31 If blisters form during dental treatment, clinicians should drain them with a sterile needle or scissors to limit blister growth (Figure 4).50 Because EB does not affect the immune system, dentists should prescribe antibiotics only when necessary.51 Preventive dentistry. Multiple factors associated with EB lead to an increased risk of developing caries. First, swallowing is difficult, and children tend to eat small quantities of pureed food throughout the day. Slow clearance also extends the contact time of food and drinks with the teeth. Physicians often supplement patients’ diets with cariogenic high-carbohydrate drinks to increase calorie intake. Thus, investigators48,51 strongly recommend use of pit-and-fissure sealants in these patients. Toothbrushing. Patients with EB experience difficulty brushing their teeth because blistering of the hands and fingers reduces their ability to hold a toothbrush. Microstomia and oral scarring also make toothbrushing difficult, and fear of new lesions’ forming limits oral hygiene practices. It is important to involve family members and caregivers in the supervision of effective, trauma-free brushing 51 and adherence to dietary recommendations.31,48 Investigators have recommended the use of soft toothbrushes with a small head27,28 and an arm adapted for patients with clawlike hands.51 Electric toothbrushes may be useful because the rotating brush cleans the teeth well and the patient does not have to make JADA 142(9)
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Figure 4. A blister is drained during dental treatment.
brushing movements with the hand.45 Mouthrinses. Mouthrinses should be alcohol free and without added flavorings.27 Chlorhexidine is the most potent oral antiseptic, and its use as a mouthrinse is recommended at concentrations of between 0.12 and 0.2 percent.52 Rinsing may be difficult for patients with severe oral disease because of microstomia and ankyloglossia, and they can use 0.2 percent chlorhexidine spray as an alternative.45 Neutral pH sodium fluoride mouthrinses are useful, whereas acidic fluoride preparations cause discomfort when oral ulceration occurs.53 Wright and colleagues32 recommended that patients receive topical applications of fluoride varnish every three to four months along with systemic fluoride supplements if fluoride is not present in the drinking water.54 Anesthesia. In most cases, dentists can perform treatment by using local anesthetic, although, on occasion, general anesthetic may be required because of a contracted mouth opening, lack of patient cooperation or the need to perform extensive treatments.31,55 They should inject the local anesthetic deeply and slowly to avoid separation of tissues and prevent blister formation.27,30,56 Clinicians should use peripheral venous lines when administering general anesthetic after applying topical disinfectant to regions free of lesions. During induction and intubation procedures, clinicians should apply lubricants such as petroleum jelly and hydrocortisone or triamcinolone creams to instruments and to areas in contact with the epithelium. Knab and colleagues57 recommended the use of petrolatum gauze for protection of the eyes and to pack the pharynx. Restorative and endodontic treatment. The use of resin-based composites is not contraindicated.28 Polishing and finishing of restorative materials are critically important, and restorations must be free of rough edges or surfaces that could cause trauma.48 Lesions caused by trauma during dental restorative procedures 1022 JADA 142(9)
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usually heal in one or two weeks without the need for any specific treatment.47,51,58 Wright28 and Serrano Martínez and colleagues50 reported successful treatment in pediatric patients with JEB and RDEB with the use of preformed steel crowns. Although tooth extraction was the treatment of choice for many years for patients with caries affecting the pulp,47,54 endodontic treatment is no longer contraindicated. Microstomia and limitations to mouth opening can present difficulties for clinicians introducing instruments.30,51 Krämer51 recently reported a series of 45 successful endodontic treatments performed in nine patients with RDEB. Orthodontic treatment. Most patients with EB tolerate orthodontic treatment well, but it is important to coat brackets with wax to minimize soft-tissue trauma.28 However, some authors27,28 have proposed the use of serial tooth extraction to treat malpositioned teeth in patients with RDEB. Periodontal treatment. Periodontal treatment is indicated in all patients with EB who have periodontal disease, including those with RDEB.53 However, clinicians should handle soft tissues with extreme care. Although lesions can appear as a consequence of intraoral manipulation, they generally heal in one or two weeks without any treatment.47,51,58 We could not find any consensus in the literature regarding the use of sutures. Some clinicians58 avoid their use to prevent the formation of blisters, whereas others46,51 report experiencing no complications associated with suturing. Prosthodontic restoration. Siqueira and colleagues48 reported the use of resin impression trays coated with petroleum jelly to minimize tissue trauma. We propose that a member of the dental team make a permanent model in type III dental plaster so that duplicates can be produced, especially when fabrication of a definitive prosthesis is expected to require multiple impressions. Removable gingiva-supported prostheses are not contraindicated, but several researchers have reported better tolerance with tooth- or implant-supported prostheses (Figure 5) because they allow reduced contact with the epithelium.48,49,59,60 In patients with RDEB, a fixed tooth- or implant-supported prosthesis is preferred.50,61 We found seven reports in the literature describing patients with EB who received dental implants49,59,60,62-65; together, they described 17 patients who received a total of 102 implants, with a success rate of between 97.7 and 100 percent (Table 249,59,60,62-65). Clinicians performed the procedures under both local49,59,60,62 and general63-65
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Figure 5. A. Palatal scarring and tissue contraction with severe maxillary atrophy. B. Fixed implant-supported prosthesis.
TABLE 2
Published reports of endosseous dental implants in patients with oral epidermolysis bullosa. SOURCE
NUMBER AGE RANGE, NUMBER FOLLOW-UP, SUCCESS RATE, TYPE OF OF YEARS OF MONTHS % OF CASES PROSTHESIS PATIENTS IMPLANTS
Peñarrocha-Diago and Colleagues,59 2000
4
26-35
15
12-58
100
Removable
Peñarrocha and Colleagues,60 2007
3
29-49
27
12-60
97.7
Fixed
Peñarrocha and Colleagues,49 2007
6
23-44
38
12-108
97.9
Fixed and removable
Lee and Colleagues,63 2007
1
29
8
Not reported
100
Fixed
Larrazabal-Morón and Colleagues,62 2009
1
52
2
12
100
Fixed
Oliveira and Colleagues,65 2010
1
13
2
24
100
Fixed
Müller and Colleagues,64 2010
1
20
10
48-60
100
Fixed
anesthesia. The main complications of the surgical interventions resulted from formation of bleeding blisters caused by minimal trauma, such as gingival incision, lifting of the flap or contact between the aspirator and the oral mucosa.59,60 In edentulous patients, clinicians typically place implants in the anterior region owing to accessibility problems caused by microstomia.48,59,60,62-64 These patients have severe maxillary atrophy (Figure 5A), and conventional drilling can destroy the residual bone and impair primary retention of the implants. Consequently, some clinicians have used endosseous implants to improve the implant bed in the maxilla and conserve as much bone as possible.49,59,60 An added advantage of using endosseous implants is that irrigation and aspiration are not required. Other authors, however, have reported using conventional drilling successfully in the maxilla.63-65 Clinicians must use surgical drills in all cases involving the mandible; they should drill using minimal irrigation and place the aspirator in contact with the bone rather than the soft tis-
sues to avoid blistering.49,59,60,62-65 In the cases published to date, investigators followed up patients for between 12 and 108 months. Several authors reported that a total of 13 patients (76.5 percent) developed ulcers in areas rubbed by the prosthesis, but they did not report effects on the mucosa surrounding the implant or the occurrence of blisters near the implant.49,59,60,62-65 Patients expressed high satisfaction, especially those who received fixed prostheses.49 In general, implant-supported prostheses are thought to have a high rate of success in patients with EB (Figure 5B).48,49 The improvements in esthetics and control of saliva that are achieved in this way enhance patients’ self-esteem and their quality of life.49,59,60 CONCLUSION
EB is a genodermatosis characterized by blistering of the skin and mucosae, usually involving the oral epithelium. In these patients, preventive dentistry (such as toothbrushing and regular use of antiplaque mouthrinses) plays a JADA 142(9)
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prominent role in reducing the need for dental care. Dental treatment must be minimally traumatic and is determined mainly on the basis of the general health of the patient, the patient’s cooperation in the dental office and at home, oral hygiene and diet. On the basis of the results of some published studies, endodontic treatment and dental implant placement may be performed successfully in these patients. ■ Disclosure. None of the authors reported any disclosures. 1. von Hebra F. Pemphigus. In: Ärztlicher Bericht des K.K. Allgemeinen Krankenhauses. Vienna: Tendler and Comp; 1870:362-364. 2. Fox T. Notes on unusual or rare forms of skin disease, IV: congenital ulceration of the skin (two cases) with pemphigus eruption and arrest of development generally. Lancet 1879;1:766-767. 3. Goldscheider A. Hereditäre Neigung zur Blasenbildung. Monatshefte Prakt Derm 1882;1:163-174. 4. Valentin A. Über hereditäre Dermatitis Bullosa und hereditäres acutes Oedem. Berl Klin Wchnschr 1885;22:150. 5. Köbner H. Hereditäre Anlage zur Blasenbildung. Dtsch Med Wochenschr 1886;12:21-22. 6. Fine JD. Rare disease registries: lessons learned from the National Epidermolysis Bullosa Registry. J Rare Dis 1996;2:5-14. 7. Fine JD, Johnson LB, Suchindran C, Moshell A, Gedde-Dahl T. The epidemiology of inherited EB: findings within American, Canadian and European study populations. In: Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999:101-113. 8. Fine JD, Hintner H. Life with Epidermolysis Bullosa: Etiology, Diagnosis, Multidisciplinary Care and Therapy. New York City: Springer; 2009:338. 9. Fine JD. Inherited epidermolysis bullosa. Orphanet J Rare Dis 2010;28:5-12. 10. Winship I. Epidermolysis bullosa in South Africa. In: Priestley GC, Tidman MJ, Weiss JB, Eady RA, eds. Epidermolysis Bullosa: A Comprehensive Review of Classification, Management and Laboratory Studies. Berkshire, England: Dystrophic Epidermolysis Bullosa Research Association; 1990:134-136. 11. Horn HM, Priestley GC, Eady RA, Tidman MJ. The prevalence of epidermolysis bullosa in Scotland. Br J Dermatol 1997;136(4): 560-564. 12. Hallopeau H. Nouvelle note sur la dermatose bulleuse hereditaire et traumatique. Ann Dermatol Syphiligr 1898;9:721-728. 13. Fine JD, Bauer EA, Briggaman RA, et al. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa: a consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry. J Am Acad Dermatol 1991;24(1):119-135. 14. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 2008;58(6):931-950. 15. Fine JD, Johnson LB, Suchindran C, Carter DM, Moshell A. The National Epidermolysis Bullosa Registry: organization, goals, methodologic approaches, basic demography, and accomplishments. In: Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999:79-100. 16. Lane EB, Rugg EL, Navsaria H, et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 1992;356(6366):244-246. 17. Chan YM, Yu QC, Fine JD, Fuchs E. The genetic basis of Weber-Cockayne epidermolysis bullosa simplex. Proc Natl Acad Sci U S A 1993;90(15):7414-7418. 18. Sawamura D, Nakano H, Matsuzaki Y. Overview of epidermolysis bullosa. J Dermatol 2010;37(3):214-219. 19. Pfendner E, Uitto J. Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. J Invest Dermatol 2005;124(1):111-115. 20. Aberdam D, Galliano MF, Vailly J, et al. Herlitz’s junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2)
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for the gamma 2 subunit of nicein⁄kalinin (LAMININ-5). Nat Genet 1994;6(3):299-304. 21. McGrath JA, Pulkkinen L, Christiano AM, Leigh IM, Eady RA, Uitto J. Altered laminin 5 expression due to mutations in the gene encoding the beta 3 chain (LAMB3) in generalized atrophic benign epidermolysis bullosa. J Invest Dermatol 1995;104(4):467-474. 22. Yancey KB, Hintner H. Non-Herlitz junctional epidermolysis bullosa. Dermatol Clin 2010;28(1):67-77. 23. Vidal F, Aberdam D, Miquel C, et al. Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet 1995;10(2):229-234. 24. Hilal L, Rochat A, Duquesnoy P, et al. A homozygous insertiondeletion in the type VII collagen gene (COL7A1) in Hallopeau-Siemens dystrophic epidermolysis bullosa. Nat Genet 1993;5(3):287-293. 25. Siegel DH, Ashton GH, Penagos HG, et al. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellularmatrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet 2003;73(1):174-187. 26. Wright JT, Fine JD, Johnson LB. Oral soft tissues in hereditary epidermolysis bullosa. Oral Surg Oral Med Oral Pathol 1991;71(4): 440-446. 27. Wright JT, Fine JD, Johnson L. Hereditary epidermolysis bullosa: oral manifestations and dental management. Pediatr Dent 1993; 15(4):242-248. 28. Wright JT. Oral manifestations of epidermolysis bullosa. In: Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999:236-257. 29. Sedano HO, Gorlin RJ. Epidermolysis bullosa. Oral Surg Oral Med Oral Pathol 1989;67(5):555-563. 30. Wright JT. Oral manifestations in the epidermolysis bullosa spectrum. Dermatol Clin 2010;28(1):159-164. 31. Stavropoulos F, Abramowicz S. Management of the oral surgery patient diagnosed with epidermolysis bullosa: report of 3 cases and review of the literature. J Oral Maxillofac Surg 2008;66(3):554-559. 32. Wright JT, Fine JD, Johnson L. Dental caries risk in hereditary epidermolysis bullosa. Pediatr Dent 1994;16(6):427-432. 33. Andreasen JO, Hjorting-Hansen E, Ulmansky M, Pindborg JJ. Milia formation in oral lesions in epidermolysis bullosa. Acta Pathol Microbiol Scand 1965;63:37-41. 34. Azizkhan RG, Denyer JE, Mellerio JE, et al. Surgical management of epidermolysis bullosa: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005. Int J Dermatol 2007;46(8):801-808. 35. Wright JT, Johnson LB, Fine JD. Developmental defects of enamel in humans with hereditary epidermolysis bullosa. Arch Oral Biol 1993;38(11):945-955. 36. Harris JC, Bryan RA, Lucas VS, Roberts GJ. Dental disease and caries related microflora in children with dystrophic epidermolysis bullosa. Pediatr Dent 2001;23(5):438-443. 37. Kirkham J, Robinson C, Strafford SM, et al. The chemical composition of tooth enamel in recessive dystrophic epidermolysis bullosa: significance with respect to dental caries. J Dent Res 1996; 75(9):1672-1678. 38. Kirkham J, Robinson C, Strafford SM, et al. The chemical composition of tooth enamel in junctional epidermolysis bullosa. Arch Oral Biol 2000;45(5):377-386. 39. Putnam JJ, Sferra GW. Dental aspects of epidermolysis bullosa. In: Lin N, Carter DM, eds. Epidermolysis Bullosa: Basic Research and Clinical Aspects. New York City: Springer-Verlag; 1992:198-209. 40. Winter GB. Dental problems in epidermolysis bullosa. In: Priestley GC, Tidman MJ, Weiss JB, Eady RA, eds. Epidermolysis Bullosa: A Comprehensive Review of Classification, Management and Laboratory Studies. Berkshire, England: Dystrophic Epidermolysis Bullosa Research Association; 1990:21-26. 41. Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol 2009;60(2): 203-211. 42. Serrano-Martínez MC, Bagán JV, Silvestre FJ, Viguer MT. Oral lesions in recessive dystrophic epidermolysis bullosa. Oral Dis 2003;9(5):264-268. 43. Chimenos Küstner E, Fernández Fresquet R, López López J, Rodríguez de Rivera Campillo E. Kindler syndrome: a clinical case. Med Oral 2003;8(1):38-44. 44. Wiebe CB, Penagos H, Luong N, et al. Clinical and microbiologic study of periodontitis associated with Kindler syndrome. J Peri-
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CLINICAL odontol 2003;74(1):25-31. 45. DEBRA International. EB dental problems and solutions. “www.debra-international.org/fileadmin/editor/docs/EB_Dental_ Problems_and_Solutions.pdf”. Accessed Aug. 4, 2011. 46. Harel-Raviv M, Bernier S, Raviv E, Gornitsky M. Oral epidermolysis bullosa in adults. Spec Care Dentist 1995;15(4):144-148. 47. Silva LC, Cruz RA, Abou-Id LR, Brini LN, Moreira LS. Clinical evaluation of patients with epidermolysis bullosa: review of the literature and case reports. Spec Care Dentist 2004;24(1):22-27. 48. Siqueira MA, de Souza Silva J, Silva FW, Díaz-Serrano KV, Freitas AC, Queiroz AM. Dental treatment in a patient with epidermolysis bullosa. Spec Care Dentist 2008;28(3):92-95. 49. Peñarrocha M, Larrazábal C, Balaguer J, Serrano C, Silvestre J, Bagán JV. Restoration with implants in patients with recessive dystrophic epidermolysis bullosa and patient satisfaction with the implant-supported superstructure. Int J Oral Maxillofac Implants 2007;22(4):651-655. 50. Serrano Martínez C, Silvestre Donat FJ, Bagán Sebastián JV, Peñarrocha-Diago M, Ali Ó, Sanz JJ. Hereditary epidermolysis bullosa: dental management of three cases. Med Oral 2001;6(1):48-56. 51. Krämer SM. Oral care and dental management for patients with epidermolysis bullosa. Dermatol Clin 2010;28(2):303-309. 52. Addy M, Jenkins S, Newcombe R. The effect of some chlorhexidine-containing mouthrinses on salivary bacterial counts. J Clin Periodontol 1991;18(2):90-93. 53. Olsen CB, Bourke LF. Recessive dystrophic epidermolysis bullosa: two case reports with 20-year follow-up. Aust Dent J 1997; 42(1):1-7. 54. Nowak AJ. Oropharyngeal lesions and their management in epidermolysis bullosa. Arch Dermatol 1988;124(5):742-745. 55. Endruschat AJ, Keenen DA. Anesthetic and dental management of a child with epidermolysis bullosa dystrophica. Oral Surg Oral Med Oral Pathol 1973;36(5):667-671. 56. Wright JT. Comprehensive dental care and general anesthetic management of hereditary epidermolysis bullosa: a review of fourteen cases. Oral Surg Oral Med Oral Pathol 1990;70(5):573-578. 57. Knab J, Schumann H, Kaltofen H, Steinmann D. Anaesthesia for children with epidermolysis bullosa (in German). Anasthesiol Intensivmed Notfallmed Schmerzther 2010;45(10):618-624. 58. Lindemeyer R, Wadenya R, Maxwell L. Dental and anaesthetic management of children with dystrophic epidermolysis bullosa. Int J Paediatr Dent 2009;19(2):127-134. 59. Peñarrocha-Diago M, Serrano C, Sanchis JM, Silvestre FJ, Bagán JV. Placement of endosseous implants in patients with oral epidermolysis bullosa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90(5): 587-590. 60. Peñarrocha M, Rambla J, Balaguer J, Serrano C, Silvestre J, Bagán JV. Complete fixed prostheses over implants in patients with oral epidermolysis bullosa. J Oral Maxillofac Surg 2007;65(7 suppl 1):103-106. 61. Brooks JK, Bare LC, Davidson J, Taylor LS, Wright JT. Junctional epidermolysis bullosa associated with hypoplastic enamel and pervasive failure of tooth eruption: oral rehabilitation with use of an overdenture. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105(4):e24-e28. 62. Larrazabal-Morón C, Boronat-López A, Peñarrocha-Diago M, Peñarrocha-Diago M. Oral rehabilitation with bone graft and simultaneous dental implants in a patient with epidermolysis bullosa: a clinical case
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report. J Oral Maxillofac Surg 2009;67(7):1499-1502. 63. Lee H, Al Mardini M, Ercoli C, Smith MN. Oral rehabilitation of a completely edentulous epidermolysis bullosa patient with an implant-supported prosthesis: a clinical report. J Prosthet Dent 2007;97(2):65-69. 64. Müller F, Bergendal B, Wahlmann U, Wagner W. Implantsupported fixed dental prostheses in an edentulous patient with dystrophic epidermolysis bullosa. Int J Prosthodont 2010;23(1):42-48. 65. Oliveira MA, Ortega KL, Martins FM, Maluf PS, Magalhães MG. Recessive dystrophic epidermolysis bullosa: oral rehabilitation using stereolithography and immediate endosseous implants. Spec Care Dentist 2010;30(1):23-26.
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Inherited epidermolysis bullosa An update and suggested dental care considerations Javier F. Feijoo, MD, DDS, PhD; Juan Bugallo, DDS; Jacobo Limeres, DDS, PhD; David Peñarrocha, DDS; Miguel Peñarrocha, MD, DDS, PhD; Pedro Diz, MD, DDS, PhD
EPIDEMIOLOGY
EB affects both sexes and occurs in populations worldwide.6 The estimated prevalence of the disease in the United States is eight per 1,000,000 inhabitants and the incidence is 19 cases per 1,000,000 live births.6,7 Fine and Hintner8 suggested that these figures are underestimates subject to
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® Background. Epidermolysis bullosa (EB) is a skin disease characterized by epithelial fragility that leads to blistering A and erosion of the skin and mucosae. The 2 RT I C LE authors conducted a literature review to provide an update on oral manifestations and dental care of patients with EB. Literature Search. The authors reviewed the dental literature on EB in relation to clinical findings and provision of dental care. They searched textbooks and three databases: MEDLINE, Cochrane Library and Embase. The authors did not impose any date or publication status restrictions. They searched all databases up to August 2010. Results. The literature review revealed that four major groups and 32 subtypes of EB can be distinguished on the basis of the ultrastructural characteristics of skin cleavage, genetic mode of transmission and clinical phenotype. Oral manifestations differ in frequency and severity according to the disease subtype, but the most common are bullae, which leave painful ulcers on rupture, followed by scarring and tissue contraction. Although good oral health status is essential to maintaining oral function, dental treatment can induce new lesions and be hindered by the sequelae of existing lesions. Clinical Implications. Dental treatment in patients with EB requires a multidisciplinary approach. Dental procedures must be minimally traumatic, and the effectiveness of treatment is determined mainly by the patient’s general health, cooperation in the dental office and at home, oral hygiene and diet. Key Words. Epidermolysis bullosa; blistering; enamel hypoplasia; dental treatment. JADA 2011;142(9):1017-1025. T
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The objective of our review was to provide an update on oral manifestations and dental care of patients with EB. We searched textbooks and three databases: MEDLINE, Cochrane Library and Embase. We did not impose any date or publication status restrictions. We searched all databases up to August 2010.
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AB STRACT CON
enodermatoses constitute a highly heterogeneous group of clinical abnormalities. The conditions usually are inherited, and their principal manifestations affect the skin, hair and nails. Epidermolysis bullosa (EB) is a genodermatosis involving abnormal epithelial integrity. It is characterized by blistering and erosions of the skin and mucous membranes following slight mechanical trauma. In 1870, von Hebra1 provided probably the first description of a familial blistering disease, which he termed “hereditary pemphigus.” This soon was followed by other reports of patients with congenital blistering diseases.2-4 However, it was not until 1886 that Köbner5 gave the disease its present name and differentiated it from other bullous diseases.
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Dr. Feijoo is an assistant professor, Special Needs Unit, School of Medicine and Dentistry, Santiago de Compostela University, Spain. Dr. Bugallo is a graduate student, Special Needs Unit, School of Medicine and Dentistry, Santiago de Compostela University, Spain. Dr. Limeres is an associate professor, Special Needs Unit, School of Medicine and Dentistry, Santiago de Compostela University, Spain. Dr. D. Peñarrocha is a graduate student, Oral Surgery Unit, School of Medicine and Dentistry, Valencia University, Valencia, Spain. Dr. M. Peñarrocha is a professor, Oral Surgery Unit, School of Medicine and Dentistry, Valencia University, Valencia, Spain. Dr. Diz is an associate professor, Special Needs Unit, School of Medicine and Dentistry, Santiago de Compostela University, C./Entrerrios s/n, 15872 Santiago de Compostela, Spain, e-mail “[email protected]”. Address reprint requests to Dr. Diz.
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substantial bias in patient registries and that the true prevalence rate could be close to 45 patients per 1,000,000 inhabitants, and the true incidence rate could be close to 95 cases per 1,000,000 live births. Some authors have suggested that the overall U.S. rates are similar to those for Western Europe and probably can be generalized worldwide.9 However, researchers have observed marked differences between countries in reported prevalence, ranging from two to 56 patients per 1,000,000 inhabitants in South Africa10 and Scotland,11 respectively. These differences suggest incomplete enrollment in official EB databases, regional variations, differing genetic susceptibilities or a combination of these.11 CLASSIFICATION
In 1898, Hallopeau12 was the first, to our knowledge, to attempt to classify patients with EB on the basis of clinical criteria by using the French terms “simple” and “dystrophique.” This classification received much criticism and resulted in subsequent revisions. Almost 100 years later, in 1989, experts in EB held a consensus meeting regarding the diagnosis and classification of inherited EB.13 Those who participated in that meeting proposed a new classification system based on the ultrastructural level of skin cleavage. According to the new system, EB could be classified into one of three major groups: dEB simplex (EBS); djunctional EB (JEB); ddystrophic EB (DEB). According to the proposed system, EB was subclassified on the basis of the genetic mode of transmission and clinical phenotype. The third, and most recent, consensus meeting pertaining to the diagnosis and classification of EB took place in Vienna in 2007. The two main contributions from that meeting were the inclusion of a fourth major group of EB— Kindler syndrome—and the classification of the disease into 32 subtypes.14 MODES OF INHERITANCE, PATHOGENESIS AND PHENOTYPE
EBS. EBS is the most common of the major groups of EB.15 Inheritance can be dominant (DEBS) or recessive (REBS), but in all cases, intraepidermal blister formation is observed, most commonly appearing in early infancy. DEBS. DEBS is caused by mutations in the genes encoding keratin 5 and 14 in keratinocytes of the basal layer.16,17 Different phenotypes are observed according to the site at which the mutation occurs, and these have been grouped into three subtypes: Weber-Cockayne syndrome 1018
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or localized EBS, Dowling-Meara EBS, and Koebner or non-Dowling-Meara EBS.14 The localized subtype is the most common, accounting for two-thirds of cases of EBS,15 and it is characterized clinically by the preferential localization of the lesions on the palms and soles, although lesions may be precipitated by traumatic events at other sites. The Dowling-Meara subtype is the least frequent and the most severe of the three subtypes. Both the Dowling-Meara and Koebner subtypes are associated with widespread lesions. REBS. REBS is caused by mutations in the gene encoding plectin (HD1),18 a protein found in the hemidesmosomes and in skeletal muscle. Consequently, most patients experience widespread blistering and muscular dystrophy. A lethal variant exists (although some patients with milder cases have survived into childhood) associated with pyloric atresia.19 JEB. JEB follows a pattern of autosomaldominant inheritance and is characterized by the formation of blisters in the lamina lucida of the epithelial basement membrane that appear at birth or during the neonatal period. Three subtypes of JEB exist: Herlitz, non-Herlitz and a subtype involving pyloric atresia.14 Herlitz subtype. The Herlitz subtype has a severe phenotype and is produced by mutations in any of the three genes encoding the anchoring filament glycoprotein laminin 332 (previously called “laminin” or “laminin 5”).20 Affected patients have characteristic periorificial erosions and multisystem disease, and they are at increased risk of dying of sepsis. Thus, they usually do not survive for more than a few years.18 Non-Herlitz subtype. The non-Herlitz subtype is characterized by generalized blisters that predominate in sites exposed to friction, trauma or heat, and it accounts for 80 percent of cases of JEB.9 It is caused by point mutations in the genes encoding laminin 332 or by mutations in BPAg2, which encodes the BP180 polypeptide.21 Although non-Herlitz JEB generally is less severe than Herlitz JEB and many patients survive to adulthood, dying of the disease (especially in neonates) is not uncommon.22 Pyloric atresia. JEB pyloric atresia is caused by mutations in ITGA6 or ITGB4, genes encoding α6 integrin or β4 integrin (which form a ABBREVIATION KEY. DEB: Dystrophic epidermolysis bullosa. DDEB: Dominant dystrophic epidermolysis bullosa. DEBS: Dominant epidermolysis bullosa simplex. EB: Epidermolysis bullosa. EBS: Epidermolysis bullosa simplex. JEB: Junctional epidermolysis bullosa. RDEB: Recessive dystrophic epidermolysis bullosa. REBS: Recessive epidermolysis bullosa simplex.
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TABLE 1 glycoprotein complex found in hemidesmoPrevalence of oral findings in major types somes).23 It is characand subtypes of epidermolysis bullosa (EB).* terized by blistering with little or no MAJOR EB TYPES PERCENTAGE OF PATIENTS CARIES FREQUENCY AND SUBTYPES trauma, ureteral and Soft-Tissue Enamel Abnormalities Hypoplasia renal anomalies, and congenital pyloric EBS† atresia. The course Weber-Cockayne syndrome 25-50 10-25‡ Same as general population usually is severe and Koebner 50-75 10-25‡ Same as general population Dowling-Meara 25-50 10-25‡ Same as general population often lethal in the neonatal period. SurJEB§ vivors may experiHerlitz 50-75 75-100 Increased ence blistering with Non-Herlitz 75-100 75-100 Increased formation of granulaDEB¶ tion tissue, but some DDEB# 50-75 10-25‡ Same as general population patients experience RDEB** Hallopeau-Siemens 75-100 10-25‡ Increased little or no blistering RDEB non–Hallopeau-Siemens 75-100 25-50 Same as general population later in life.18 Kindler Syndrome Gingival Absent Same as general population hyperplasia DEB. DEB is characterized by intra* Sources: Fine,9 Fine and colleagues14 and Wright.28 † EBS: Epidermolysis bullosa simplex. dermal blisters, scar‡ Some authors consider the prevalence to be similar to that in control participants. ring and keratin§ JEB: Junctional epidermolysis bullosa. ¶ DEB: Dystrophic epidermolysis bullosa filled cysts below the # DDEB: Dominant dystrophic epidermolysis bullosa. epidermis (milia).18 ** RDEB: Recessive dystrophic epidermolysis bullosa. Inheritance can be dominant (DDEB) or recessive (RDEB).15 It is caused by mutations in COL7A1, which encodes collagen type VII (a component of hemidesmosome-anchoring filaments).24 The clinical manifestations of DDEB tend to be milder than those of the autosomal-recessive forms, with blistering often limited to hands, feet, knees and elbows. Two subtypes of RDEB have been described14: the Hallopeau-Siemens subtype—also termed the “severe generalized” form—and the non– Hallopeau-Siemens subtype. The HallopeauSiemens subtype is the most severe form and involves almost no expression of collagen VII in the basement membrane. The lifetime risk of developing aggressive squamous cell carcinoma in this subtype is more than 90 percent. In the Figure 1. Blister on the lower lip of a child with epidermolysis non–Hallopeau-Siemens subtype, there is some bullosa simplex. limited expression of collagen type VII, the clinORAL MANIFESTATIONS ical manifestations are milder and the distribution of lesions is similar to that in DDEB.9,14,18 The oral manifestations of EB can involve both Kindler syndrome. Kindler syndrome folsoft and hard tissues, and they differ in frequency lows a pattern of autosomal-recessive inheriand severity according to the EB subtype26,27 tance. Affected families have mutations in (Table 19,14,28). Although there are no pathognoKIND1 (FERMT1), which encodes Kindlin-1, a monic intraoral soft-tissue manifestations, the structural component of the actin cytoskeleton.25 most common oral finding is blistering (Figure 1). Defects in this protein compromise cell adhesion On rupture, bullae leave painful ulcers, followed in keratinocytes of the basal layer. Kindler synby scarring and tissue contraction.29 Other manidrome is characterized clinically by skin blisfestations include the appearance of milia, tering induced by trauma, poikiloderma, cutamicrostomia, ankyloglossia, severe periodontal neous atrophy, mucositis and varying degrees of disease, enamel hypoplasia, dental caries and photosensitivity.9,18 atrophy of the maxilla with mandibular prog27
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Figure 2. Enamel hypoplasia in a patient with junctional epidermolysis bullosa.
nathism.26,30,31 Patients with RDEB are at an increased risk of developing oral squamous cell carcinoma, which increases with age.26,32 Milia are tiny (1 to 4 millimeters) benign white papules that usually are located on the palate and correspond histologically to keratinfilled cysts. Oral milia are present in all major EB categories but are most prevalent in the dystrophic forms.26,33 The appearance of oral milia is not influenced by their occurrence on the skin or linked to the severity of oral involvement in different EB subtypes.26 Microstomia is a narrowing of the opening of the mouth caused by a constant process of blister formation and healing that results in scarring in the commissures and loss of vestibular space.34 It contributes to poor oral intake and makes access to the mouth and gastrointestinal tract difficult. The adhesions that form between the tongue and floor of the mouth give rise to ankyloglossia,30 which limits tongue movement and causes difficulties in eating and swallowing. Wright and colleagues35 reported dental anomalies ranging from mild to generalized enamel hypoplasia in patients with EB (Figure 2). Their clinical expression and prevalence vary according to the subtype.35 Azizkhan and colleagues34 described three enamel abnormalities in EBS and JEB: hypoplasia, hypomaturation and hypocalcification. In hypoplasia, the enamel does not achieve its normal thickness and has an irregular appearance, and teeth appear small. In hypomaturation, the enamel thickness is normal but the enamel has a mottled appearance, is fragile and is less radiolucent than is the dentin. In hypocalcification, the enamel thickness is normal, but the enamel is extremely soft with a yellow pigmentation, and the dentin often is left exposed. Wright and colleagues27,32 reported a high risk of caries development in patients with JEB or DEB (RDEB subtype). In contrast, Harris and colleagues36 reported that the prevalence of caries in patients with EBS or DDEB was similar to 1020 JADA 142(9)
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that in healthy control participants. Factors that favor caries formation in these patients include accumulation of dental plaque (as a result of poor oral hygiene due to the pain associated with toothbrushing and the fear of new lesions’ appearing), pseudosyndactyly, microstomia, diet consisting of soft foods that are rich in carbohydrates and reduced oral clearance.36 The mineral and chemical composition of dental enamel in patients with DEB is no different from that in normal enamel, but the developmentally compromised enamel found in JEB also could predispose patients to developing caries.37,38 Researchers have not determined whether salivary flow, salivary immunoglobulin levels or oral microflora are cofactors for caries susceptibility.32,36 EBS. One-third of patients with localized (that is, Weber-Cockayne syndrome) EBS have small numbers of localized blisters and erosions that are asymptomatic and generally are smaller than 1 centimeter in diameter.26,28,30 The blisters occur almost exclusively in childhood after the patient has experienced substantial trauma or traction, and they do not result in atrophic scarring or adhesion (Figure 1).27 The prevalence of enamel hypoplasia and caries is similar to that in the general population.32 JEB. Most patients with JEB have severe oral blisters (larger than 1 cm), with no specific localization, that leave scars on healing. As a result, microstomia and ankyloglossia are common,26,30 although some authors have reported that difficulties opening the mouth are minimal or do not occur.39,40 Although the oral manifestations are not as severe as those observed in RDEB,30 Fine and colleagues41 described cases of malignant transformation of JEB lesions into squamous cell carcinoma. The lesions can obstruct the salivary glands temporarily, but this obstruction resolves spontaneously without any need for specific treatment.30 The mutated genes in JEB encode proteins that are involved in cell adhesion in the odontogenic epithelium, which gives rise to ameloblasts, the cells that produce dental enamel. Dysfunctional ameloblast adhesion can result in leaking of serum fluids into the developing enamel, resulting in a retention of albumin and decreased mineralization.38 Consequently, the only clinical manifestation that is common to all subtypes of JEB is enamel hypoplasia, displayed as localized or more extensive thimblelike pitting of some or all of the tooth surfaces (Figure 2), most often in the primary teeth.27,30,35 Patients with JEB are at an increased risk of developing dental caries, probably the result of enamel defects that are difficult to clean and thus promote microbial growth
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and dental plaque retention.30 DEB. Oral blisters develop relatively infrequently in patients with DDEB. They occur after mild trauma and heal by means of mucosal atrophy, but only one-half of affected patients have microstomia, ankyloglossia and loss of vestibular space. Almost all patients with RDEB have large blisters that can appear spontaneously.30 The most commonly affected site is the lingual mucosa, and the least commonly affected site is the buccal mucosa.42 The constant process of blister formation and healing leads to changes in the architecture of the oral epithelium, resulting in microstomia. The lingual papillae and the palatal folds ultimately can disappear.42 The structural changes in the lingual epithelium give rise to severe ankyloglossia.30 Patients with RDEB are at an increased risk of developing squamous cell carcinoma or malignant melanoma in adulthood.41 Milia are common in the palatal mucosa. Salivary secretion is normal in most people with DEB, whereas enamel hypoplasia is rare. Nevertheless, patients with DEB—particularly those with RDEB—are at a high risk of developing dental caries.30 Kindler syndrome. The gingival and oral mucosa commonly are affected in patients with Kindler syndrome.30 It manifests clinically as desquamative gingival hyperplasia with hyperkeratotic white plaques, atrophic areas and lip pigmentation.43 Clinical and microbiological findings in patients with Kindler syndrome suggest the existence of atypical periodontitis, with onset in the early teenage years and rapid progression.44 Tooth enamel usually is not affected, but caries is common owing to poor oral hygiene resulting from pain and bleeding during toothbrushing.9 DENTAL TREATMENT
General issues. Because of oral complications, patients with EB may have problems with nutritional intake and chewing and swallowing of food, and they may have a negative self-image because of their altered appearance and speech problems.45 Consequently, medical and dental treatment requires a multidisciplinary approach.27,46 Dental care is influenced by patients’ general health, their ability to cooperate in the dental office and at home, and their oral hygiene and diet, and it requires carefully performed, minimally traumatic procedures. Clinicians need to perform conservative and restorative treatments to maintain efficient masticatory function, because doing so reduces the risk of developing oral and esophageal lesions.27
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Additional care is necessary given the difficulty associated with opening the mouth and the fragility of the epithelial tissues. In patients who have reduced tongue mobility or difficulties opening their mouths, specific physiotherapy exercises are recommended.45 To reduce the risk of Figure 3. Oral ulcer after blister formation, aggressive compression of the researchers recomepithelium with a lip retractor. mend the use of lubricants (for example, petroleum jelly, glycerin and hydroxyethyl cellulose, methyl cellulose) on the patient’s lips and oral mucosa, as well as on gloves, radiographic film and instruments.28,30,46-49 For the same reason, clinicians should avoid using lateral traction and compressing the epithelium (Figure 3), and they should rest aspirators on hard tissues such as the teeth.31 If blisters form during dental treatment, clinicians should drain them with a sterile needle or scissors to limit blister growth (Figure 4).50 Because EB does not affect the immune system, dentists should prescribe antibiotics only when necessary.51 Preventive dentistry. Multiple factors associated with EB lead to an increased risk of developing caries. First, swallowing is difficult, and children tend to eat small quantities of pureed food throughout the day. Slow clearance also extends the contact time of food and drinks with the teeth. Physicians often supplement patients’ diets with cariogenic high-carbohydrate drinks to increase calorie intake. Thus, investigators48,51 strongly recommend use of pit-and-fissure sealants in these patients. Toothbrushing. Patients with EB experience difficulty brushing their teeth because blistering of the hands and fingers reduces their ability to hold a toothbrush. Microstomia and oral scarring also make toothbrushing difficult, and fear of new lesions’ forming limits oral hygiene practices. It is important to involve family members and caregivers in the supervision of effective, trauma-free brushing 51 and adherence to dietary recommendations.31,48 Investigators have recommended the use of soft toothbrushes with a small head27,28 and an arm adapted for patients with clawlike hands.51 Electric toothbrushes may be useful because the rotating brush cleans the teeth well and the patient does not have to make JADA 142(9)
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Figure 4. A blister is drained during dental treatment.
brushing movements with the hand.45 Mouthrinses. Mouthrinses should be alcohol free and without added flavorings.27 Chlorhexidine is the most potent oral antiseptic, and its use as a mouthrinse is recommended at concentrations of between 0.12 and 0.2 percent.52 Rinsing may be difficult for patients with severe oral disease because of microstomia and ankyloglossia, and they can use 0.2 percent chlorhexidine spray as an alternative.45 Neutral pH sodium fluoride mouthrinses are useful, whereas acidic fluoride preparations cause discomfort when oral ulceration occurs.53 Wright and colleagues32 recommended that patients receive topical applications of fluoride varnish every three to four months along with systemic fluoride supplements if fluoride is not present in the drinking water.54 Anesthesia. In most cases, dentists can perform treatment by using local anesthetic, although, on occasion, general anesthetic may be required because of a contracted mouth opening, lack of patient cooperation or the need to perform extensive treatments.31,55 They should inject the local anesthetic deeply and slowly to avoid separation of tissues and prevent blister formation.27,30,56 Clinicians should use peripheral venous lines when administering general anesthetic after applying topical disinfectant to regions free of lesions. During induction and intubation procedures, clinicians should apply lubricants such as petroleum jelly and hydrocortisone or triamcinolone creams to instruments and to areas in contact with the epithelium. Knab and colleagues57 recommended the use of petrolatum gauze for protection of the eyes and to pack the pharynx. Restorative and endodontic treatment. The use of resin-based composites is not contraindicated.28 Polishing and finishing of restorative materials are critically important, and restorations must be free of rough edges or surfaces that could cause trauma.48 Lesions caused by trauma during dental restorative procedures 1022 JADA 142(9)
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usually heal in one or two weeks without the need for any specific treatment.47,51,58 Wright28 and Serrano Martínez and colleagues50 reported successful treatment in pediatric patients with JEB and RDEB with the use of preformed steel crowns. Although tooth extraction was the treatment of choice for many years for patients with caries affecting the pulp,47,54 endodontic treatment is no longer contraindicated. Microstomia and limitations to mouth opening can present difficulties for clinicians introducing instruments.30,51 Krämer51 recently reported a series of 45 successful endodontic treatments performed in nine patients with RDEB. Orthodontic treatment. Most patients with EB tolerate orthodontic treatment well, but it is important to coat brackets with wax to minimize soft-tissue trauma.28 However, some authors27,28 have proposed the use of serial tooth extraction to treat malpositioned teeth in patients with RDEB. Periodontal treatment. Periodontal treatment is indicated in all patients with EB who have periodontal disease, including those with RDEB.53 However, clinicians should handle soft tissues with extreme care. Although lesions can appear as a consequence of intraoral manipulation, they generally heal in one or two weeks without any treatment.47,51,58 We could not find any consensus in the literature regarding the use of sutures. Some clinicians58 avoid their use to prevent the formation of blisters, whereas others46,51 report experiencing no complications associated with suturing. Prosthodontic restoration. Siqueira and colleagues48 reported the use of resin impression trays coated with petroleum jelly to minimize tissue trauma. We propose that a member of the dental team make a permanent model in type III dental plaster so that duplicates can be produced, especially when fabrication of a definitive prosthesis is expected to require multiple impressions. Removable gingiva-supported prostheses are not contraindicated, but several researchers have reported better tolerance with tooth- or implant-supported prostheses (Figure 5) because they allow reduced contact with the epithelium.48,49,59,60 In patients with RDEB, a fixed tooth- or implant-supported prosthesis is preferred.50,61 We found seven reports in the literature describing patients with EB who received dental implants49,59,60,62-65; together, they described 17 patients who received a total of 102 implants, with a success rate of between 97.7 and 100 percent (Table 249,59,60,62-65). Clinicians performed the procedures under both local49,59,60,62 and general63-65
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A
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B
Figure 5. A. Palatal scarring and tissue contraction with severe maxillary atrophy. B. Fixed implant-supported prosthesis.
TABLE 2
Published reports of endosseous dental implants in patients with oral epidermolysis bullosa. SOURCE
NUMBER AGE RANGE, NUMBER FOLLOW-UP, SUCCESS RATE, TYPE OF OF YEARS OF MONTHS % OF CASES PROSTHESIS PATIENTS IMPLANTS
Peñarrocha-Diago and Colleagues,59 2000
4
26-35
15
12-58
100
Removable
Peñarrocha and Colleagues,60 2007
3
29-49
27
12-60
97.7
Fixed
Peñarrocha and Colleagues,49 2007
6
23-44
38
12-108
97.9
Fixed and removable
Lee and Colleagues,63 2007
1
29
8
Not reported
100
Fixed
Larrazabal-Morón and Colleagues,62 2009
1
52
2
12
100
Fixed
Oliveira and Colleagues,65 2010
1
13
2
24
100
Fixed
Müller and Colleagues,64 2010
1
20
10
48-60
100
Fixed
anesthesia. The main complications of the surgical interventions resulted from formation of bleeding blisters caused by minimal trauma, such as gingival incision, lifting of the flap or contact between the aspirator and the oral mucosa.59,60 In edentulous patients, clinicians typically place implants in the anterior region owing to accessibility problems caused by microstomia.48,59,60,62-64 These patients have severe maxillary atrophy (Figure 5A), and conventional drilling can destroy the residual bone and impair primary retention of the implants. Consequently, some clinicians have used endosseous implants to improve the implant bed in the maxilla and conserve as much bone as possible.49,59,60 An added advantage of using endosseous implants is that irrigation and aspiration are not required. Other authors, however, have reported using conventional drilling successfully in the maxilla.63-65 Clinicians must use surgical drills in all cases involving the mandible; they should drill using minimal irrigation and place the aspirator in contact with the bone rather than the soft tis-
sues to avoid blistering.49,59,60,62-65 In the cases published to date, investigators followed up patients for between 12 and 108 months. Several authors reported that a total of 13 patients (76.5 percent) developed ulcers in areas rubbed by the prosthesis, but they did not report effects on the mucosa surrounding the implant or the occurrence of blisters near the implant.49,59,60,62-65 Patients expressed high satisfaction, especially those who received fixed prostheses.49 In general, implant-supported prostheses are thought to have a high rate of success in patients with EB (Figure 5B).48,49 The improvements in esthetics and control of saliva that are achieved in this way enhance patients’ self-esteem and their quality of life.49,59,60 CONCLUSION
EB is a genodermatosis characterized by blistering of the skin and mucosae, usually involving the oral epithelium. In these patients, preventive dentistry (such as toothbrushing and regular use of antiplaque mouthrinses) plays a JADA 142(9)
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prominent role in reducing the need for dental care. Dental treatment must be minimally traumatic and is determined mainly on the basis of the general health of the patient, the patient’s cooperation in the dental office and at home, oral hygiene and diet. On the basis of the results of some published studies, endodontic treatment and dental implant placement may be performed successfully in these patients. ■ Disclosure. None of the authors reported any disclosures. 1. von Hebra F. Pemphigus. In: Ärztlicher Bericht des K.K. Allgemeinen Krankenhauses. Vienna: Tendler and Comp; 1870:362-364. 2. Fox T. Notes on unusual or rare forms of skin disease, IV: congenital ulceration of the skin (two cases) with pemphigus eruption and arrest of development generally. Lancet 1879;1:766-767. 3. Goldscheider A. Hereditäre Neigung zur Blasenbildung. Monatshefte Prakt Derm 1882;1:163-174. 4. Valentin A. Über hereditäre Dermatitis Bullosa und hereditäres acutes Oedem. Berl Klin Wchnschr 1885;22:150. 5. Köbner H. Hereditäre Anlage zur Blasenbildung. Dtsch Med Wochenschr 1886;12:21-22. 6. Fine JD. Rare disease registries: lessons learned from the National Epidermolysis Bullosa Registry. J Rare Dis 1996;2:5-14. 7. Fine JD, Johnson LB, Suchindran C, Moshell A, Gedde-Dahl T. The epidemiology of inherited EB: findings within American, Canadian and European study populations. In: Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999:101-113. 8. Fine JD, Hintner H. Life with Epidermolysis Bullosa: Etiology, Diagnosis, Multidisciplinary Care and Therapy. New York City: Springer; 2009:338. 9. Fine JD. Inherited epidermolysis bullosa. Orphanet J Rare Dis 2010;28:5-12. 10. Winship I. Epidermolysis bullosa in South Africa. In: Priestley GC, Tidman MJ, Weiss JB, Eady RA, eds. Epidermolysis Bullosa: A Comprehensive Review of Classification, Management and Laboratory Studies. Berkshire, England: Dystrophic Epidermolysis Bullosa Research Association; 1990:134-136. 11. Horn HM, Priestley GC, Eady RA, Tidman MJ. The prevalence of epidermolysis bullosa in Scotland. Br J Dermatol 1997;136(4): 560-564. 12. Hallopeau H. Nouvelle note sur la dermatose bulleuse hereditaire et traumatique. Ann Dermatol Syphiligr 1898;9:721-728. 13. Fine JD, Bauer EA, Briggaman RA, et al. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa: a consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry. J Am Acad Dermatol 1991;24(1):119-135. 14. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 2008;58(6):931-950. 15. Fine JD, Johnson LB, Suchindran C, Carter DM, Moshell A. The National Epidermolysis Bullosa Registry: organization, goals, methodologic approaches, basic demography, and accomplishments. In: Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999:79-100. 16. Lane EB, Rugg EL, Navsaria H, et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 1992;356(6366):244-246. 17. Chan YM, Yu QC, Fine JD, Fuchs E. The genetic basis of Weber-Cockayne epidermolysis bullosa simplex. Proc Natl Acad Sci U S A 1993;90(15):7414-7418. 18. Sawamura D, Nakano H, Matsuzaki Y. Overview of epidermolysis bullosa. J Dermatol 2010;37(3):214-219. 19. Pfendner E, Uitto J. Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. J Invest Dermatol 2005;124(1):111-115. 20. Aberdam D, Galliano MF, Vailly J, et al. Herlitz’s junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2)
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for the gamma 2 subunit of nicein⁄kalinin (LAMININ-5). Nat Genet 1994;6(3):299-304. 21. McGrath JA, Pulkkinen L, Christiano AM, Leigh IM, Eady RA, Uitto J. Altered laminin 5 expression due to mutations in the gene encoding the beta 3 chain (LAMB3) in generalized atrophic benign epidermolysis bullosa. J Invest Dermatol 1995;104(4):467-474. 22. Yancey KB, Hintner H. Non-Herlitz junctional epidermolysis bullosa. Dermatol Clin 2010;28(1):67-77. 23. Vidal F, Aberdam D, Miquel C, et al. Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet 1995;10(2):229-234. 24. Hilal L, Rochat A, Duquesnoy P, et al. A homozygous insertiondeletion in the type VII collagen gene (COL7A1) in Hallopeau-Siemens dystrophic epidermolysis bullosa. Nat Genet 1993;5(3):287-293. 25. Siegel DH, Ashton GH, Penagos HG, et al. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellularmatrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet 2003;73(1):174-187. 26. Wright JT, Fine JD, Johnson LB. Oral soft tissues in hereditary epidermolysis bullosa. Oral Surg Oral Med Oral Pathol 1991;71(4): 440-446. 27. Wright JT, Fine JD, Johnson L. Hereditary epidermolysis bullosa: oral manifestations and dental management. Pediatr Dent 1993; 15(4):242-248. 28. Wright JT. Oral manifestations of epidermolysis bullosa. In: Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999:236-257. 29. Sedano HO, Gorlin RJ. Epidermolysis bullosa. Oral Surg Oral Med Oral Pathol 1989;67(5):555-563. 30. Wright JT. Oral manifestations in the epidermolysis bullosa spectrum. Dermatol Clin 2010;28(1):159-164. 31. Stavropoulos F, Abramowicz S. Management of the oral surgery patient diagnosed with epidermolysis bullosa: report of 3 cases and review of the literature. J Oral Maxillofac Surg 2008;66(3):554-559. 32. Wright JT, Fine JD, Johnson L. Dental caries risk in hereditary epidermolysis bullosa. Pediatr Dent 1994;16(6):427-432. 33. Andreasen JO, Hjorting-Hansen E, Ulmansky M, Pindborg JJ. Milia formation in oral lesions in epidermolysis bullosa. Acta Pathol Microbiol Scand 1965;63:37-41. 34. Azizkhan RG, Denyer JE, Mellerio JE, et al. Surgical management of epidermolysis bullosa: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005. Int J Dermatol 2007;46(8):801-808. 35. Wright JT, Johnson LB, Fine JD. Developmental defects of enamel in humans with hereditary epidermolysis bullosa. Arch Oral Biol 1993;38(11):945-955. 36. Harris JC, Bryan RA, Lucas VS, Roberts GJ. Dental disease and caries related microflora in children with dystrophic epidermolysis bullosa. Pediatr Dent 2001;23(5):438-443. 37. Kirkham J, Robinson C, Strafford SM, et al. The chemical composition of tooth enamel in recessive dystrophic epidermolysis bullosa: significance with respect to dental caries. J Dent Res 1996; 75(9):1672-1678. 38. Kirkham J, Robinson C, Strafford SM, et al. The chemical composition of tooth enamel in junctional epidermolysis bullosa. Arch Oral Biol 2000;45(5):377-386. 39. Putnam JJ, Sferra GW. Dental aspects of epidermolysis bullosa. In: Lin N, Carter DM, eds. Epidermolysis Bullosa: Basic Research and Clinical Aspects. New York City: Springer-Verlag; 1992:198-209. 40. Winter GB. Dental problems in epidermolysis bullosa. In: Priestley GC, Tidman MJ, Weiss JB, Eady RA, eds. Epidermolysis Bullosa: A Comprehensive Review of Classification, Management and Laboratory Studies. Berkshire, England: Dystrophic Epidermolysis Bullosa Research Association; 1990:21-26. 41. Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol 2009;60(2): 203-211. 42. Serrano-Martínez MC, Bagán JV, Silvestre FJ, Viguer MT. Oral lesions in recessive dystrophic epidermolysis bullosa. Oral Dis 2003;9(5):264-268. 43. Chimenos Küstner E, Fernández Fresquet R, López López J, Rodríguez de Rivera Campillo E. Kindler syndrome: a clinical case. Med Oral 2003;8(1):38-44. 44. Wiebe CB, Penagos H, Luong N, et al. Clinical and microbiologic study of periodontitis associated with Kindler syndrome. J Peri-
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CLINICAL odontol 2003;74(1):25-31. 45. DEBRA International. EB dental problems and solutions. “www.debra-international.org/fileadmin/editor/docs/EB_Dental_ Problems_and_Solutions.pdf”. Accessed Aug. 4, 2011. 46. Harel-Raviv M, Bernier S, Raviv E, Gornitsky M. Oral epidermolysis bullosa in adults. Spec Care Dentist 1995;15(4):144-148. 47. Silva LC, Cruz RA, Abou-Id LR, Brini LN, Moreira LS. Clinical evaluation of patients with epidermolysis bullosa: review of the literature and case reports. Spec Care Dentist 2004;24(1):22-27. 48. Siqueira MA, de Souza Silva J, Silva FW, Díaz-Serrano KV, Freitas AC, Queiroz AM. Dental treatment in a patient with epidermolysis bullosa. Spec Care Dentist 2008;28(3):92-95. 49. Peñarrocha M, Larrazábal C, Balaguer J, Serrano C, Silvestre J, Bagán JV. Restoration with implants in patients with recessive dystrophic epidermolysis bullosa and patient satisfaction with the implant-supported superstructure. Int J Oral Maxillofac Implants 2007;22(4):651-655. 50. Serrano Martínez C, Silvestre Donat FJ, Bagán Sebastián JV, Peñarrocha-Diago M, Ali Ó, Sanz JJ. Hereditary epidermolysis bullosa: dental management of three cases. Med Oral 2001;6(1):48-56. 51. Krämer SM. Oral care and dental management for patients with epidermolysis bullosa. Dermatol Clin 2010;28(2):303-309. 52. Addy M, Jenkins S, Newcombe R. The effect of some chlorhexidine-containing mouthrinses on salivary bacterial counts. J Clin Periodontol 1991;18(2):90-93. 53. Olsen CB, Bourke LF. Recessive dystrophic epidermolysis bullosa: two case reports with 20-year follow-up. Aust Dent J 1997; 42(1):1-7. 54. Nowak AJ. Oropharyngeal lesions and their management in epidermolysis bullosa. Arch Dermatol 1988;124(5):742-745. 55. Endruschat AJ, Keenen DA. Anesthetic and dental management of a child with epidermolysis bullosa dystrophica. Oral Surg Oral Med Oral Pathol 1973;36(5):667-671. 56. Wright JT. Comprehensive dental care and general anesthetic management of hereditary epidermolysis bullosa: a review of fourteen cases. Oral Surg Oral Med Oral Pathol 1990;70(5):573-578. 57. Knab J, Schumann H, Kaltofen H, Steinmann D. Anaesthesia for children with epidermolysis bullosa (in German). Anasthesiol Intensivmed Notfallmed Schmerzther 2010;45(10):618-624. 58. Lindemeyer R, Wadenya R, Maxwell L. Dental and anaesthetic management of children with dystrophic epidermolysis bullosa. Int J Paediatr Dent 2009;19(2):127-134. 59. Peñarrocha-Diago M, Serrano C, Sanchis JM, Silvestre FJ, Bagán JV. Placement of endosseous implants in patients with oral epidermolysis bullosa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90(5): 587-590. 60. Peñarrocha M, Rambla J, Balaguer J, Serrano C, Silvestre J, Bagán JV. Complete fixed prostheses over implants in patients with oral epidermolysis bullosa. J Oral Maxillofac Surg 2007;65(7 suppl 1):103-106. 61. Brooks JK, Bare LC, Davidson J, Taylor LS, Wright JT. Junctional epidermolysis bullosa associated with hypoplastic enamel and pervasive failure of tooth eruption: oral rehabilitation with use of an overdenture. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105(4):e24-e28. 62. Larrazabal-Morón C, Boronat-López A, Peñarrocha-Diago M, Peñarrocha-Diago M. Oral rehabilitation with bone graft and simultaneous dental implants in a patient with epidermolysis bullosa: a clinical case
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report. J Oral Maxillofac Surg 2009;67(7):1499-1502. 63. Lee H, Al Mardini M, Ercoli C, Smith MN. Oral rehabilitation of a completely edentulous epidermolysis bullosa patient with an implant-supported prosthesis: a clinical report. J Prosthet Dent 2007;97(2):65-69. 64. Müller F, Bergendal B, Wahlmann U, Wagner W. Implantsupported fixed dental prostheses in an edentulous patient with dystrophic epidermolysis bullosa. Int J Prosthodont 2010;23(1):42-48. 65. Oliveira MA, Ortega KL, Martins FM, Maluf PS, Magalhães MG. Recessive dystrophic epidermolysis bullosa: oral rehabilitation using stereolithography and immediate endosseous implants. Spec Care Dentist 2010;30(1):23-26.
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