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Br J Ophthalmol 1999;83:323–326 323

The eye in epidermolysis bullosa Br J Ophthalmol: first published as 10.1136/bjo.83.3.323 on 1 March 1999. Downloaded from

L Tong, P R Hodgkins, J Denyer, D Brosnahan, J Harper, I Russell-Eggitt, DSITaylor, D Atherton

Abstract Subsequent tissue involvement is diVerent in Aims—To describe the ophthalmic find- each subtype of EB.9 Simplex involves ings in a large cohort of epidermolysis the basal cells, junctional disease the lamina bullosa (EB) patients managed in one lucida. Dystrophic aVects the dermis below the large specialist centre. lamina densa at the level of the anchoring Methods—A case note review of consecu- fibrils. Among the diVerent subtypes there is tive patients seen at Great Ormond Street considerable variation in the severity of sys- Children’s Hospital. Data on the dermato- temic disease and ocular involvement. Ocular logical disease, ophthalmic history, and features previously described include corneal examination were collected and coded abrasions (three), corneal (two), corneal onto a data sheet. pannus (two), blisters (two), eyelid Results—181 patients: 50 (28%) simplex (two), conjunctival blisters (two), EB; 15 (8%) junctional EB; 28 (15%) auto- and symblepharon (two). Other ocular associa- somal dominant dystrophic EB; 72 (40%) tions reported in EB include (11), autosomal recessive dystrophic EB; nine plana and (12), refractive patients (5%) with dystrophic EB whose errors, , lacrimal duct obstruction, , subluxation, posterior vitreous inheritance could not be ascertained; and 2 seven cases (4%) of EB that could not be detachment, and Graves’ disease. classified. Ocular problems were found in This study aimed to describe the ophthalmic 12% (n=6) of simplex patients and 40% findings in a large cohort of EB patients who (n=6) of those with junctional disease. One have been carefully and systematically exam- patient (of 28) in the autosomal dominant ined in one large specialist centre. This is, firstly, to compare the incidence of complica- dystrophic group had ocular involvement tions with another large series and, secondly, to and 51% (37/72) of patients in the auto- indicate which patients are most at risk and somal recessive dystrophic group had therefore to assist in the management of these ophthalmic complications: corneal (25/ patients. 72), lid ectropions (3/72), lid blisters (5/72), and symblepharon (3/72).

Conclusion—Ophthalmic complications Methods http://bjo.bmj.com/ are common in EB overall but the inci- Consecutive patient names and hospital num- dence varies widely with subtype. Oph- bers were located from the database kept by the thalmic complications are the most severe specialist dermatology EB team coordinator. in the dystrophic recessive and junctional Between 1980 to 1996 at the Hospital for Sick Department of subtypes where there is a need for extra Children, Great Ormond Street, London, 181 , Great vigilance. The major treatment modality patients were seen. Records were located in all Ormond Street was use of ocular lubricants. cases. All patients had been seen by a consult- Hospital for Children (Br J Ophthalmol 1999;83:323–326) ant dermatologist and had undergone a stand- on September 24, 2021 by guest. Protected copyright. NHS Trust, Great Ormond Street, ard clinical examination consisting of: general London WC1N 3JH examination by the dermatologist, nutritional L Tong Epidermolysis bullosa (EB) is a term for a assessment by a dietitian, dental assessment, P R Hodgkins group of conditions associated with abnormali- physiotherapy assessment, and blood tests to D Brosnahan ties of the basement membrane zone of skin check nutritional status. Where indicated, I Russell-Eggitt and mucous membranes. Most frequently it is biopsy of unaVected skin was done and immu- DSITaylor genetically determined and congenital al- nohistochemistry and electron microscopy of though there is an acquired variety. The Department of the specimens performed. Dermatology, Great characteristic features are skin and mucosal All patients had also been seen by an Ormond Street fragility starting during infancy with a ten- ophthalmologist of at least senior registrar Hospital for Children dency to blister after even minor trauma. The level. Full ophthalmic examination was per- NHS Trust, Great involvement of the eye with conjunctival and formed consisting of: vision (visual acuity Ormond Street, corneal blistering can lead to progressive - where possible); refraction, ocular alignment London WC1N 3JH 1 J Denyer ring with reduced vision and even blindness. and ocular motility; slit lamp examination and J Harper There are several genetic subtypes: dystrophic tear film assessment. Details of the results of D Atherton (autosomal recessive and autosomal domi- this examination were recorded on to a data nant), junctional, and simplex. Even within sheet. The presence or absence of the following Correspondence to: these subtypes clinical variability has been rec- Mr P Hodgkins, lesions was coded together with their duration Southampton Eye Unit, ognised and further subcategorisation has been if known: punctate , corneal abrasion, Tremona Road, applied.2 Many of the subtypes of EB have now pannus or scar, conjunctival blister or sym- Southampton, SO16 6YD. been characterised by mutations of various blepharon, eyelid ectropion or . A 3–8 Accepted for publication genes aVecting diVerent elements of the history suggestive of corneal erosions (recur- 11 September 1998 basement membrane zone. rent with ) was also noted. 324 Tong, Hodgkins, Denyer, et al

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Table 1 Comparison of the results from Lin et al with the current study with any particular subtype of EB. Special pre- Br J Ophthalmol: first published as 10.1136/bjo.83.3.323 on 1 March 1999. Downloaded from cautions were taken with the pressure points Lin et al2 This study for glasses with sponge padding and for Total number of EB patients 204 181 patches soft tie on occlusion was used. Using Number of male EB patients * 100 this technique few problems were encountered Number of female EB patients * 81 Number of simplex EB patients 68 50 in treatment of the amblyopia by occlusion or Number of junctional EB patients 36 15 spectacle correction. Three patients had Number of recessive dystrophic EB patients 61 72 squints, including one with an A pattern and Number of dominant dystrophic EB patients 17 28 Number of dystrophic EB of unknown subtype 10 9 facial asymmetry. Among these, one patient Number of unclassified EB 22 7 had an alternating convergent squint of 80 Ocular complications in simplex EB patients 2 (3%) 6 (12%) Ocular complications in junctional EB patients 14 (39%) 6 (40%) prism dioptres without glasses and 30 prism Ocular complications in recessive dystrophic EB patients 31 (51%) 37 (51%) dioptres with glasses of +6.0 DS right and left. Ocular complications in dominant dystrophic EB patients 3 1 (4%) Subsequent squint was uneventful. Ocular complications as a whole 53 (26%) 50 (28%) /scar in recessive dystrophic EB patients 24 (39%) 17 (24%) Miscellaneous features noted were lacrimal Corneal pannus in recessive dystrophic EB patients 12 (20%) 13 (18%) punctal occlusion (one patient); punctal papil- Source of patients National EB Registry EB register loma on the eyelid (one patient); recurrent Country of study USA UK subconjunctival haemorrhage (one patient); *Not reported. pseudopterygia (four patients); microphthal- mos (one patient); anterior polar with Results (one patient). Records were found on all patients in the study The method of treatment in all our patients group (n=181). The study population included was conservative with frequent ocular lubri- 100 males—55% (mean age 9.6 (SD 5.6) cants, such as preservative-free hypromellose years) and 81 females—45% (mean age 10.5 drops in the daytime, which were as frequent as (6.0) years). The subtypes of EB were 50 hourly, and eye ointment at night. (28%) simplex EB; 15 (8%) junctional EB; 28 (15%) autosomal dominant dystrophic EB; 72 Discussion (40%) autosomal recessive dystrophic EB; nine We have reviewed the dermatological diagnosis patients (5%) with dystrophic EB of uncertain and ophthalmic examinations in a large group inheritance; and seven cases (4%) of unclassi- of patients with EB seen at one specialist Brit- fied EB. ish centre. Previously McDonnell10 studied a Autosomal dominant dystrophic EB (n=28): series of 11 patients with dystrophic EB and only one patient (4%) had significant ocular reported 73% of patients were noted to have involvement consisting of conjunctival blister- eye changes. In the largest series of patients ing without eyelid or corneal disease. published to date from the United States, ocu- Autosomal recessive dystrophic EB (n=72): lar complications were seen in 26% of the 204 14% (n=10) reported symptoms of recurrent patients . The results of this study by Lin et al 2 erosions but were normal on examination agree closely our results (Table 1).

while 51% (n=37) had eye complications on http://bjo.bmj.com/ examination. Ocular involvement consisted of: SIMPLEX EB 25/37 (68%) had corneal complications, in- Simplex EB has various subtypes such as cluding three cases of corneal abrasion, 13 Weber–Cockayne, Koebner, and Dowling, cases of corneal scarring and nine cases of cor- which diVer in their clinical features. In our neal pannus; 8% (3/37) had exposure keratitis study no ocular involvement was found in associated with upper and lower eyelid ectropi- patients with Weber–Cockayne and Koebner ons; 24% (9/37) of the patients had conjuncti- subtypes. Simplex patients with ocular involve- on September 24, 2021 by guest. Protected copyright. val complications; 14% (5/37) of the patients ment (eyelid blistering and corneal abrasion) had eyelid blisters. belonged exclusively to the Dowling–Meara Junctional EB (n=15): 40% (n=6) had eye subtype in which the skin disease is normally complications. Three had corneal scarring, two more severe.11–12 had severe , and one had Simplex EB is caused by mutations in the corneal abrasion. None of these patients had keratin 14 gene on chromosome 17 or keratin 5 symblepharon or conjunctival blistering. gene on chromosome 12.3 Keratin abnormali- Simplex EB (n=50): no ocular disease was ties lead to dysfunction in the intermediate found in 88% (n=44) of these patients. Periph- filaments.13 These keratins are not restricted to eral corneal vascularisation was seen in 12% of ocular tissue but are expressed by basal kerati- patients, all of whom had the Dowling subtype. nocytes in the skin elsewhere as well, hence was 6/12 or greater in 175 explaining the skin involvement of this condi- patients at their last visit. Uniocular testing and tion. On the other hand, mutations of cornea refractive correction were not always possible specific keratins (K3 and K12) as in Mees- in the clinic as many had been admitted mann’s only result in disease because of a flare up of their illness and were in the cornea, without concurrent systemic very unwell when seen. Vision was obtained disease.14 using a variety of techniques including Sheridan–Gardiner, CardiV cards, and linear JUNCTIONAL EB Snellen. There was one case of significant Junctional EB is a heterogeneous group, being hypermetropia, four cases of , and three conventionally subdivided into lethal and non- cases of marked astigmatism that required cor- lethal types. Ocular lesions were found in 40% rection with glasses. Amblyopia was detected (6/15) of our patients with corneal scarring in in only four cases (2%) and was not associated 20% (3/15) and exposure keratopathy in 33% The eye in epidermolysis bullosa 325

(n=5). These figures are very similar to those There is no statistical diVerence between these Br J Ophthalmol: first published as 10.1136/bjo.83.3.323 on 1 March 1999. Downloaded from reported by Lin et al 2 although they reported findings and both confirm the low level of ocu- many more cases of corneal abrasion among lar involvement. this group. The patients who wore glasses (n=7) did not Considerable molecular heterogeneity un- develop major problems despite the expected derlies cases of junctional EB. Mutations in six diYculty at the contact points on the nose and diVerent gene/protein systems have been de- ears. All our glasses were fitted by a specialist scribed including the three genes that encode fitter within the department able to make laminin 5 (LAMA3, LAMB3, and adaptable frames and use various amounts of LAMC2)4–7 15 the gene for the 180 kDa bullous additional sponge. No patient in this series pemphigoid antigen (BPAG2/ COL17A1) and wore contact lenses and no patient required the the alpha 6 beta 4 integrin genes use of soft bandage contact lenses for stubborn (ITGA6/ITGB4).16 17 corneal ulcers as has been reported.5 Despite 29 patients in our series having cor- DYSTROPHIC EB (AUTOSOMAL RECESSIVE) neal scars or pannus, no patient required Autosomal recessive dystrophic EB is the most corneal surgery. Lin et al 2 reported three common type of EB in our series (n=72). Ocu- patients who underwent lamellar keratectomy lar complications occurred in 51% with a with some visual improvement although this further 14% reporting symptoms suggestive of required many regrafts. This may reflect an recurrent corneal erosions but without signs at overall more conservative approach or alterna- examination. The ocular complications ranged tively greater success with conservative treat- from punctate keratitis, corneal pannus, cor- ment. There was one patient who underwent neal scarring, eyelid blisters, and symblepha- squint surgery that was not associated with any ron to eyelid ectropion. Symblepharon was problems. There was no precipitation of exces- found in this group of patients but not in other sive conjunctival or lid blistering and no exces- genetic types of EB. The recessive dystrophic sive scarring. type of EB results from mutations in both alle- les of the collagen VII gene on the short arm of chromosome 3.8 MANAGEMENT To some extent it is possible to explain the General Children suVering from EB, in particular those clinical phenotype by examining the specific with the recessive dystrophic variety, benefit mutation in dystrophic EB. Although both the from a multidisciplinary approach to care. recessive and dominant types of dystrophic EB Regular short admissions to a specialised are caused by mutations of the collagen VII centre aim to encourage the child to reach his gene, diVerent domains of the gene can be full potential and minimise disability. During aVected. As a result the abnormality may affect such admissions emphasis is placed on nutri- the function of the anchoring fibrils of the tional review, physiotherapy assessment, oph- basement membrane to diVerent extent. For thalmic and dental examinations and adjust- example, an amino acid substitution of methio- http://bjo.bmj.com/ ment of skin care regime. nine to lysine in position 2798 in the Intermittent surgery includes insertion of non-collagenous domain-2 aVects the intermo- gastrostomy buttons for those failing to thrive lecular disulphide bonding during assembly of or having severe dysphagia, plastic hand anchoring fibrils but clinical phenotype is mild surgery to release contractures and dental sur- (called the mitis/inversa type recessive dys- gery. Excellent healing and recovery has been trophic EB) because partial assembly of the observed following surgery for conditions not fibrils can take place. In patients with prema- arising from EB, such as appendicectomy, on September 24, 2021 by guest. Protected copyright. ture termination codons of translation in the orchidopexy and squint surgery. The main collagenous domain (from single base pair prognostic criterion for good healing after sur- deletion or insertion) the resulting collagen gery appears to be satisfactory nutritional polypeptides become truncated, this results in status. no functioning fibrils and the severe clinical phenotype called the Hallopeau–Simens type of recessive dystrophic EB is manifested. Ophthalmic Dystrophic EB may be complicated by cuta- The management of the EB patient should be neous squamous cell carcinomas18 although, as based on the severity and type of ocular far as we are aware, there have been no complication presented. The method of treat- documented case of squamous cell carcinomas ment in the majority of patients is conservative reported in the or eyelid of these with regular ocular lubricants. Care needs to patients. The tumorigenesis may be related to be taken not to hold the lids when applying the expression of mutant p53 gene in EB drops in children as this may damage the skin. patients.19 Mutant p53 protein may be ex- Patients with minimal disease, especially pressed in 26% of the squamous cell carcino- those with the simplex EB (except the mas from recessive dystrophic EB patients, and Dowling–Meara subtype) do not need regular it was believed that this expression correlated ophthalmic review, as long as the parents have with poor tumour diVerentiation. been advised what symptoms to look for and to seek the advice of an ophthalmologist when DYSTROPHIC EB (AUTOSOMAL DOMINANT) required. After the initial ophthalmic evalua- Ocular complications were rare with only one tion and advice on ocular lubricants, they can patient (4%) having any involvement while Lin be referred to the eye department again if fur- et al 2 reported 3/17 with ocular involvement. ther problems occur. 326 Tong, Hodgkins, Denyer, et al

3 McKenna KE, Hughes AE, Bingham EA, . Linkage of Patching using a soft tie on a patch and et al Br J Ophthalmol: first published as 10.1136/bjo.83.3.323 on 1 March 1999. Downloaded from epidermolysis bullosa simplex to keratin gene loci. JMed spectacle wear is not impossible but the Genet 1992;29:568–70. practitioner needs to monitor the patient care- 4 McGrath JA, Gatalica B, Christiano AM, et al. Mutations in the 180-kD bullous pemphigoid antigen (BPAG2), a fully for skin complications. Dispensing opti- hemidesmosomal transmembrane collagen (COL17A1), in cians should be aware of the problems and be generalized atrophic benign epidermolysis bullosa. Nat Genet 1995;11:83–6. ready to use large padded arms where neces- 5 Pulkkinen L, Gerecke DR, Christiano AM, et al. Cloning of sary. Ideally a person used to dealing with these the beta 3 chain gene (LAMB3) of human laminin 5, a candidate gene in junctional epidermolysis bullosa. Genom- types of problems would be best. Other meth- 1995; :192–8. 20 ics 25 ods of amblyopia therapy such as penalisation 6 Gedde-Dahl T Jr, Dupuy BM, Jonassen R, et al. Junctional can be considered; empirically, preservative- epidermolysis bullosa inversa (locus EBR2A) assigned to 1q31 by linkage and association to LAMC1. Hum Mol free drops should be used to minimise the risk Genet 1994;3:1387–91. of problems. 7 Vailly J, Pulkkinen L, Christiano AM, et al. Identification of a homozygous exon skipping mutation in the LAMC2 gene Patients with exposure keratitis are most dif- in a patient with Herlitz’s junctional epidermolysis bullosa. ficult to manage and require the most frequent J Invest Dermatol 1995;104:434–7. 8 Uitto J, Christiano AM. Molecular basis for the dystrophic follow up. Both ectropion and severe sym- forms of epidermolysis bullosa: mutations in the type VII blepharon can cause exposure or lagophthal- collagen gene. Arch Dermatol Res 1994;287:16–22. 9 Christiano AM, Uitto J. Molecular complexity of the mos. Some patients with blistering and indura- cutaneous basement membrane zone. Revelations from the tion of the upper lid have a mild paradigms of epidermolysis bullosa. Exp Dermatol 1996;5: 1–11. nocturnally. Once a dense corneal scar is 10 McDonnell PJ. The ocular signs and complications of EB.J formed little improvement can be obtained Roy Soc Med 1988;81:576–8. 11 Destro M, Wallow IHL, Brightbill FS. Recessive dystrophic with lubricants. Lamellar keratoplasty can be epidermolysis bullosa. Arch Ophthalmol 1987;105:1248. considered although its role has not been 12 Sharkey JA, Kervick GN, Jackson AJ, et al. Cornea plana proved here and management should be aimed and sclerocornea in association with recessive epidermoly- sis bullosa dystrophica. Cornea 1992;11:83–5. to prevent the development of this complica- 13 Hachisuka H, Morita M, Karashima T, et al. Keratin 14 tion. Tarsorrhaphy and ectropion surgery may gene point mutation in the Kobner and Dowling-Meara types of epidermolysis bullosa simplex as detected by the have to be considered. PASA method. Arch Dermatol Res 1995;287:142–5. Patients with squints and problems with 14 Irvine AD, Corden LD, Swensson O, et al. Mutations in cornea-specific keratin K3 or K12 genes cause Mees- should be assessed as for mann’s corneal dystrophy. Nat Genet 1997;16:184–7. other patients and surgery may be performed 15 Hovnanian A, de-Prost Y. [Hereditary epidermolysis bullosa: towards classification and genetic counseling based with the usual indications. upon identification of molecular defects (published erra- We conclude that ocular complications are tum appears in Arch Pediatr 1995;2:292)]. Arch Pediatr 1994;1:1028–33. common in EB overall although the incidence 16 Phillips RJ, Aplin JD, Lake BD. Antigenic expression of in the diVerent subtypes varies enormously. integrin alpha 6 beta 4 in junctional epidermolysis bullosa. Histopathology 1994;24:571–6. Ophthalmic complications are most severe in 17 Vidal F, Aberdam D, Miquel C, et al. Integrin beta 4 muta- the dystrophic recessive (46%) and junctional tions associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet 1995;10:229–34. group (40%) where there is a need for extra 18 Fourel E, Claudy AL. Squamous cell carcinoma and reces- ophthalmic vigilance. sive dystrophic epidermolysis bullosa. Ann Dermatol Vener- eol 1992;119:563–5. 19 Slater SD, McGrath JA, Hobbs C, et al. Expression of 1 Brodie SE. Ophthalmological aspects of epidermolysis bul- mutant p53 gene in squamous carcinoma arising in http://bjo.bmj.com/ losa. In: Lin AN, Carter DM, eds. Epidermolysis bullosa. patients with recessive dystrophic epidermolysis bullosa. Basic and clinical aspects. New York: Springer-Verlag, Histopathology 1992;20:237–41. 1992:185–90. 20 Simons K, Stein L, Sener EK, et al. Full time atropine, 2 Lin AN, Murphy F, Brodie SE, et al. Review of ophthalmic intermittent atropine, and optical penalization and binocu- findings in 204 patients with EB. Am J Ophthalmol lar outcome in treatment of strabismic amblyopia. Ophthal- 1994;118:384–90. mology 1997;104:2143–55. on September 24, 2021 by guest. Protected copyright.