Oral manifestations

The presentation in the oral mucosa varies depending on the underlying type of eb, encompassing from few vesicles to large blisters with ulcerations and significant dental involvement.⁶

Blisters in simple eb tend to be mild, healing without scarring. Localized junctional eb is characterized by oral blister formation with minimal scarring, while patients with severe or widespread junctional eb may have blisters with extensive erosions and ulcerations of the oral mucosa and a tendency for scarring healing resulting in microstomia.⁷

Dominant dystrophic eb presents minimal oral blisters, but those with recessive dystrophic eb often have blister formation and scarring resulting in limitation of tongue mobility, loss of the vestibular sulcus, and microstomia.⁶ This inhibits food and dental plaque removal, predisposing to severe dental caries and complications such as dentoalveolar infections; gingivitis and pulpitis being the most frequent. Patients with recessive dystrophic eb are the most severely affected.⁸

Oral blisters in kindler syndrome tend to decrease with age, but are unique because the junctional epithelium that attaches the gingival tissues (gums) to the dental enamel is defective, and patients experience severe and early-onset periodontal disease, involving progressive loss of alveolar bone and tooth loss if not treated early.⁹

Overall, oral manifestations should be intentionally sought in patients with epidermolysis bullosa including vesicles, blisters, oral mucosal ulceration, loss of the vestibular sulcus, papillary atrophy, microstomia, ankyloglossia, caries, and enamel defects. No alteration of the salivary glands has been demonstrated.⁶ As for the site of involvement, gingival mucosa has been reported as the most common site in 80%, followed by buccal mucosa in 73%, lips in 64%, and palatal mucosa in 61%.^6,10,11

A retrospective study conducted in pediatric patients with eb found that the oral cavity was affected in 75% of patients, with blisters and vesicles being the most frequent lesions in 48.5% (figure 1), followed by ulcers in 20%. Dental caries is found in 86.6% of patients and it is mainly due to an increase in food contact time since there is limitation in tongue mobility, loss of the vestibular sulcus, presence of dental pits, and poor oral hygiene to avoid injuring the mucosa.5 The development of caries is not specific to any type of EB.¹²

Figure 1. Blister on the tongue.

Figure 2. Gingival inflammation

Figure 3. Dental enamel hypoplasia.

Figure 4. Subepidermal blister in a cutaneous lesion of rdbe.

Dental calculus has been reported in 80% of patients with eb and it is very similar in all subtypes, which is associated with periodontal disease. It is important to note that the presence of gingival bleeding cannot always be associated with periodontal disease since gingival bleeding may be due to inflammation from the underlying pathology.¹³

Gingivitis and periodontitis are more common in eb patients than in the general population (figure 2). They are infectious and inflammatory diseases characterized by marked inflammation that can lead to progressive destruction of soft and hard tissues supporting the tooth, causing loss of alveolar bone and even tooth loss.¹⁴

Enamel lesions is reported in 66% of patients with EB. ¹¹ It can range from pits to generalized hypoplasia resulting in a very thin layer of dental enamel15 (figure 3). It is noteworthy to compare by subtypes as Joseph et al. distinguished that 75% of patients with ueb had enamel damage compared to 12% in patients with deb and 8% in SEB. ¹¹

Dental malocclusion is reported in 75% of patients with eb. It is important an early to prevent recurrent trauma, and furthermore, dental treatment is more difficult later with the onset of microstomia.¹⁶

Patients with recessive dystrophic eb have been reported to have a higher frequency than the general population of oral mucosal changes suggestive of malignancy, and in most cases correspond to a carcinoma.¹⁷ Isolated cases of trismus have been reported.¹⁸

Papillary atrophy is reported in only 19% of patients, all of them with deb. Krämer et al. propose this finding as highly suggestive of DEB. ¹⁹

Microstomia is a decrease in mouth opening due to the formation of scar bands in the lining mucosa and skin of the lip region, mainly in the lip commissures. Ankyloglossia is a condition in which the lingual frenulum under the tongue is very thick, making its protrusion difficult and causing limited tongue movements.²⁰ Microstomia and ankyloglossia are mainly found in patients with DEB. ¹¹

Diagnosis

The clinical diagnosis of the subtype of EB is not simple, so we must rely mainly on complementary studies. Histopathologically, subepidermal blisters can be observed in all types of epidermolysis with minimal inflammation (figure 4). Although, in theory, simple eb presents with supraepidermal separation at the basal layer, it may not always be easily distinguishable from other subtypes using this method.¹ Electron microscopy allows visualization of the exact level of involvement, but it is a restricted study for certain centers, mainly research centers. Antigen mapping by immunofluorescence allows the use of antibodies to demonstrate the expression of a structural protein, but is scarce available. Genetic diagnosis, possibly the gold standard, requires complete genetic sequencing to identify the mutation because not all subtypes are associated with a point mutation, although commercially available panels with mutations known to date are already established.²¹

Fortuna et al. developed a severity score for oropharyngeal EB (EBOS) that can be used in all patients to establish the severity of oral involvement more objectively and monitor its evolution during subsequent consultations. It should be noted that the score is objective and does not include associated symptoms. Furthermore, it does not include parameters of caries, periodontal disease, or malignancy since it was considered that they are not directly related factors but rather secondary consequences. Up to this moment, no studies have been conducted to establish the usefulness of this scoring system. In other words, a classification for these scores that could define a need for specific treatment or other recommendations is lacking. Nevertheless, it is a score that can guide the clinician in subsequent evaluations regarding the overall status and progression of oral lesions to decide to implement early therapeutic management.²²

Treatment

Currently, there is no cure, and treatment is mainly symptomatic focusing on relieving symptoms and preventing complications.However, there are commercially available gene therapies, and multiple other gene, cellular, protein, and oligonucleotide therapies are in development.

Oral rehabilitation depends on the clinical manifestations and type of epidermolysis of the patient. The main objective is the preservation of teeth and preventing oral complications.²³ Treatment may include non-surgical approaches, such as scaling and root planning and antibiotics, or surgical measures such as reduction of the periodontal pocket or soft tissue and bone grafts.²

Patients with mild forms do not need major changes from the usual recommended oral hygiene except to be careful not to damage the mucosa.²⁴ General hygiene is recommended with toothbrushes with soft and short bristles. For caries control, the use of mouth rinses with chlorhexidine can be added, although its effectiveness compared to placebo has not shown substantial changes.^25,26 Some experts recommend the use of fluorides every three months to decrease the risk of caries or periodontal disease.²⁷ When a blister is found, it should be punctured with a sterile needle to drain its contents and prevent its expansion.¹⁸ In the case of frequent blisters and ulcers, the utility of sucralfate has been reported.^28,29 Some authors recommend sealing fissures and pits since oral hygiene and other preventive measures can be difficult to perform in those areas. However, some experts prefer to avoid it since the technique is very sensitive and may not be an option for some patients due to lack of cooperation and difficulty in follow-up. Patients with microstomia should perform daily exercises for 30 minutes to improve and maintain the best possible oral opening.²⁴ Extractions and surgical interventions are the treatment of choice in the most severe cases (figure 5). It should be noted that intraoral local anesthesia can cause tissue damage; it should be injected more deeply to avoid blister formation. Care should be taken in these patients, avoiding the use of suction equipment if possible, and covering the material with rubber and/or petrolatum Oral rehabilitation under general anesthesia is the preferred method for treatment, especially in patients with severe involvement.¹⁷ In the anesthetic management, consideration should be given to the limitation of oral opening and cervical flexion. It is recommended that all equipment in the upper airway be lubricated with petrolatum to minimize friction, as well as gauze with petrolatum beneath the anesthesiologist’s hands to avoid damaging the skin during mask ventilation. An alternative if available is to use transnasal humidified rapid insufflation ventilatory exchange (THRIVE) with the use of a high-flow nasal oxygen cannula placed over a petrolatum gauze, which reduces the risk of facial trauma due to mask ventilation and prolongs breathing time and safe apnea time during difficult intubation.¹⁷ Careful fiberoptic-guided intubation by an expert with a well-lubricated small endotracheal tube is the recommended technique to minimize trauma to the airways. Another alternative when mouth opening is sufficient is the use of a laryngeal mask, but it can be complicated by the formation of lingual blisters. It should also be noted that intubating a patient under general anesthesia can complicate the posterior airway after extubation with blister formation. The skin and oral mucosa where the endotracheal tube is fixed and passed should also be protected. For both the endotracheal tube and securing intravenous access, it is recommended to secure with non-adhesive dressing strips or soft silicone tape like Mepitac® and then wrap with self-adhesive wrap or gauze to secure it in place³⁰ (figure 6). Management is multidisciplinary, and patients require close follow-up by stomatology, dermatology, gastroenterology, nutrition, ophthalmology, and psychology. Dental check-ups are individualized depending on each patient, but generally, it is recommended to attend every three to six months for review.²⁴

Figure 5. Dental extractions in a patient with rdbe.

Figure 6. Avoid placing adhesives directly on any part of the skin

Conclusions

The stomatological manifestations of ea are very frequent and, in many cases, treatable to prevent later complications.

It is necessary to know the basic care that these patients require, provide and instruct parents and other healthcare professionals in their management, and have adequate multidisciplinary follow-up to optimize the quality of life of these patients. The dermatologist plays a key role in referring and promoting the evaluation of these patients.

Bibliografía

1.    1. Maldonado-Colín G, Durán-Mckinster C, Covarrubias O, López P, De Ocariz S y Romero G, Epidermólisis ampollosa: nuevos conceptos clínicos y moleculares para clasificación y diagnóstico, Dermatología cmq 2016; 14(4):289-98.
  
2.    2. Bardhan A, Bruckner-Tuderman L, Chapple ILC, Fine JD, Harper N, Has C et al., Epidermolysis bullosa, Nat Rev Dis Primers 2020; 6(1):78.
  
3.    3. Has C, Bauer JW, Bodemer C, Bolling MC, Bruckner-Tuderman L, Diem A et al., Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility, Br J Dermatol 2020; 183(4):614-27.
  
4.    4. Moghadam BK y Gier RE, Epidermolysis bullosa: oral management and case reports, asdc J Dent Child 1992; 59(1):66-9.
 
5.     5. Araiza-Atanacio MI, Gris-Calvo J, Piña-Ramírez MJ, Cadena-León JF, Ángeles ET, Varón-Munar D et al., Epidermolysis bullosa in children: a retrospective study in a reference hospital, Rev Med Inst Mex Seguro Soc 2020; 58(5):583-92.
 
6.     6. De Azevedo BLR, Roni GM, Dettogni RS, Torrelio RMF, Leal LF y Da Gama-de-Souza LN, Epidermolysis bullosa in oral health: clinical manifestations and salivary alterations, Clin Oral Investig 2023; 27(6):3117-24.
 
7.     7. Wright JT, Oral manifestations in the epidermolysis bullosa spectrum, Dermatol Clin 2010; 28(1):159-64.
 
8.     8. Torres-Iberico R, Palomo-Luck P, Torres-Ramos G y Lipa-Chancolla R, Epidermólisis bullosa en el Perú: estudio clínico y epidemiológico de pacientes atendidos en un hospital pediátrico de referencia nacional, 1993-2015, Rev Peru Med Exp Salud Publica 2017; 34(2):201.
   
9.   9. Wiebe CB, Penagos H, Luong N, Slots J, Epstein E Jr, Siegel D et al., Clinical and microbiologic study of periodontitis associated with Kindler syndrome, J Periodontol 2003; 74(1):25-31.
10.   10. Scheidt L, Sanabe ME y Diniz MB, Oral manifestations and dental management of epidermolysis bullosa simplex, Int J Clin Pediatr Dent 2015; 8(3):239-41.
11.   11. Joseph C, Marty M, Dridi SM, Verhaeghe V, Bailleul-Forestier I, Chiaverini C et al., Oral health status in patients with inherited epidermolysis bullosa: a comparative multicenter study, Quintessence Int 2023; 54(1):34-43.
12.   12.Wright JT, Fine JD y Johnson LB, Oral soft tissues in hereditary epidermolysis bullosa, Oral Surg Oral Med Oral Pathol 1991; 71(4):440-6.
13.   13.Chiaverini C, Marty M, Dridi SM, Campana SC, Canceill T, Bailleul-Forestier I et al., Oral status in patients with inherited epidermolysis bullosa: a multicentric observational study, J Am Acad Dermatol 2022; 87(4):872-4.
14.   14.Winstock D, Oral aspects of epidermolysis bullosa, Br J Dermatol 1962; 74:431-8.
15.   15.Brooks JK, Bare LC, Davidson J, Taylor LS y 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):e24-8.
16.   16. Lomelí-Valdez R, Lara-Barredes JC, Durán-Gutiérrez LA y García-Romero MT, Stomatological manifestations of epidermolysis bullosa, Acta Pediatr Mex 2025; 46(2):139-45.
17.   17. Pekiner FN, Yücelten D, Ozbayrak S y Sezen EC, Oral-clinical findings and management of epidermolysis bullosa, J Clin Pediatr Dent 2005; 30(1):59-65.
18.   18.Krämer S, Lucas J, Gamboa F, Peñarrocha-Diago M, PeñarrochaOltra D, Guzmán-Letelier et al., Clinical practice guidelines: oral health care for children and adults living with epidermolysis bullosa, Spec Care Dentist 2020; 40 (Suppl 1):3-81.
19.   19. Krämer S, Fuentes I, Yubero MJ, Encina C, Farfán J, Araya I et al., Absence of tongue papillae as a clinical criterion for the diagnosis of generalized recessive dystrophic epidermolysis bullosa types, J Am Acad Dermatol 2020; 83(6):1815-6.
20.   20.Portillo NE, De la Teja AE y Durán GA, Stomatologic management of dental malocclusion in patients with dystrophic epidermolysis bullosa using an interceptive guide of occlusion (igo): comparison of two cases, Rev Mex Ortodon 2014; 2(2):114-21.
21.   21. Cepeda-Valdés R, Pohla-Gubo G, Borbolla-Escoboza JR, Barboza-Quintana O, Ancer-Rodríguez J, Hintner H et al., Mapeo por inmunofluorescencia para el diagnóstico de epidermólisis ampollosa congénita, Actas Dermosifiliogr 2010; 101(8):673-82.
22.   22.Fortuna G, Chainani-Wu N, Lozada-Nur F, Aria M, Cepeda-Valdés R, Pollio A et al., Epidermolysis bullosa oropharyngeal severity (ebos) score: a multicenter development and reliability assessment, J Am Acad Dermatol 2013; 68(1):83-92.
23.   23.Barna BK, Eördegh G, Iván G, Piffkó J, Silló P y Antal M, Az epidermolysis bullosa szájüregi tünetei és annak ellátása [Epidermolysis bullosa: oral manifestations and their treatments], Orv Hetil 2017; 158(40):1577-83.
24.   24.Krämer SM, Serrano MC, Zillmann G, Gálvez P, Araya I, Yanine N et al., Oral health care for patients with epidermolysis bullosa, best clinical practice guidelines, Int J Paediatr Dent 2012; 22 Suppl 1:1-35.
25.   25.Polizzi A, Santonocito S, Patini R, Quinzi V, Mummolo S, Leonardi R et al., Oral alterations in heritable epidermolysis bullosa: a clinical study and literature review, Biomed Res Int 2022; 2022:6493156.
26.   26. James P, Worthington HV, Parnell C, Harding M, Lamont T, Cheung A et al., Chlorhexidine mouthrinse as an adjunctive treatment for gingival health, Cochrane Database Syst Rev 2017; 3(3):CD008676.
27.   27. Nowak AJ, Oropharyngeal lesions and their management in epidermolysis bullosa, Arch Dermatol 1988; 124(5):742-5.
28.   28.Yas¸ar S¸, Yas¸ar B, Cebeci F, Bayog˘lu D y Nuhog˘lu Ç, Topical sucralfate cream treatment for aplasia cutis congenita with dystrophic epidermolysis bullosa: a case study, J Wound Care 2018; 27(11):768-71.
29.   29.Agrawal A y Bhardwaj A, Sucralfate-based cream as a novel and cost-effective topical agent in poorly healing ulcers in junctional epidermolysis bullosa, Clin Exp Dermatol 2023; 48(2):138-40.
30.   30.Mittal BM, Goodnough CL, Bushell E, Turkmani-Bazzi S y Sheppard K, Anesthetic management of adults with epidermolysis bullosa, Anesth Analg 2022; 134(1):90-101.