Epidermolysis bullosa is a group of genetic disorders of the skin and mucous membranes characterized by skin fragility in response to minor trauma.1 Epidermolysis bullosa simplex is one sub-type of epidermolysis bullosa that may rarely occur in conjunction with muscular dystrophy. In these cases, progressive muscle weakness begins in childhood, adolescence, or adulthood.2,3 Epidermolysis bullosa simplex associated with muscular dystrophy is autosomal recessive and associated with mutations in PLEC1, which encodes a giant multifunctional cytolinker protein called plectin that stabilizes intermediate filament networks in cells.2,3 Pyloric atresia and cardiomyopathy have been associated with PLEC mutations.3,4 Ocular surface issues, especially recurrent corneal epithelial erosions, are known to occur in multiple types of epidermolysis bullosa.5,6 However, only one case report has been published in the ophthalmic literature describing a patient with epidermolysis bullosa simplex associated with muscular dystrophy, ptosis, and oculomotor dysfunction.7 Although muscular dystrophy associated with epidermolysis bullosa simplex has been well described by Shimizu et al.,8 ocular issues were not mentioned. Our report represents the largest ophthalmologic study of patients with epidermolysis bullosa simplex associated with muscular dystrophy.
Institutional review board approval for this study was granted by Cincinnati Children's Hospital Medical Center. In compliance with the U.S. Health Insurance Portability and Accountability Act, medical records of patients with epidermolysis bullosa evaluated from 2000 to 2015 were retrospectively reviewed.
Six patients with epidermolysis bullosa simplex associated with muscular dystrophy and documented eye examinations were identified. Three of the 6 patients had ocular abnormalities and the findings are presented in detail.
An 11-year-old boy with epidermolysis bullosa presented to the pediatric ophthalmology clinic for ocular surface evaluation. He had a history of intellectual disability but no delay in motor developmental. Uncorrected visual acuity was 20/25 in each eye. Blepharitis was present bilaterally, but the ocular surface was normal. Bilateral symmetric ptosis without anomalous head position was noted, but margin reflex distance was not documented. Ocular motility was moderately limited in both left and right gaze and was severely limited in up and down gaze. Alternating exotropia of 45 prism diopters was present in primary gaze. The remainder of the examination was unremarkable. The patient's family declined strabismus surgery.
The patient returned at age 13 years with a complaint of decreased vision. Examination revealed stable normal visual acuity but increased ptosis with compensatory chin-up head position, severe ophthalmoplegia, and stable exotropia. The patient was lost to follow-up for 4 years and was subsequently admitted to the hospital at age 17 years for poor oral intake, malnourishment, and progressive muscle weakness. He had been unable to climb stairs since age 14 years and started needing a wheelchair at age 16 years. Ocular findings were unchanged compared with the previous eye examination. Muscle weakness and dysphagia progressed despite systemic management and improved nutrition. He was evaluated for muscular dystrophy and found to have homozygous PLEC1 mutations, which confirmed a diagnosis of epidermolysis bullosa simplex associated with muscular dystrophy. By age 21 years, ptosis, exotropia, and ophthalmoplegia had increaseds compared with his findings at age 13 years (Figure 1 and Video 1, available in the online version of this article).
Case 1 at 21 years of age with progressive ptosis, exotropia, and ophthalmoplegia associated with epidermolysis bullosa simplex associated with muscular dystrophy and plectin deficiency.
A 4-year-old girl with a diagnosis of epidermolysis bullosa simplex associated with muscular dystrophy and PLEC1 mutation presented for ocular surface evaluation. Epidermolysis bullosa had been diagnosed at age 5 months. Developmentally, she was able to sit unsupported at 18 months and walked at 2 years of age. Her delay in gross motor development was initially attributed to prematurity, but a later evaluation for muscular dystrophy revealed PLEC1 mutations. The parents reported chronic neck weakness, difficulty bending over and standing up, fine motor delay, and language delay. Family history was significant for a 1-year-old sister who also had PLEC1 mutation.
The patient's initial eye examination at 4 years of age revealed periocular crusted skin blisters without blepharitis, bilaterally. Uncorrected visual acuity was 20/40 in each eye. The corneal and conjunctival epithelia were intact and showed no scarring bilaterally. Ocular motility was full and ocular alignment was orthophoria. When she returned 2 years later, uncorrected visual acuity was 20/25 in each eye. She had developed bilateral ptosis with a compensatory chin-up head position and bilateral limitation of abduction (Figure 2 and Video 1). Trichiasis was present but not sufficient to require treatment. The ocular surface remained normal. The patient's younger sister subsequently had normal eye examinations at 1 and 4 years of age with no signs of developmental delay or muscle weakness.
Case 2 at 6 years of age with ptosis, ophthalmoplegia, and epidermolysis bullosa simplex associated with muscular dystrophy and plectin deficiency.
A 6-year-old boy with epidermolysis bullosa simplex associated with muscular dystrophy and mutations in PLEC1 presented for ocular surface evaluation. Examination revealed uncorrected visual acuity of 20/25 in each eye. The eyelids were free of skin blisters and blepharitis. The corneal and conjunctival epithelia were intact and without scarring. Ocular motility was full and alignment was orthophoria. When he returned at age 12 years, mild acquired ptosis was present without an associated compensatory chin-up head position. The ocular surface, motility, and remainder of the examination were normal. The patient and his family denied symptoms of muscle weakness or developmental delay.
Corneal erosions and other ocular surface issues are common in various subtypes of epidermolysis bullosa.5,6 Interestingly, ocular surface disease was not present in our patients with epidermolysis bullosa simplex associated with muscular dystrophy. One of our patients had significant eyelid margin disease, which is common in patients with other subtypes of epidermolysis bullosa.6
Smith et al.9 reported a relatively high prevalence of strabismus, refractive errors, and decreased visual acuity in patients with a diagnosis of epidermolysis bullosa. However, neither ptosis nor limited motility was observed in their series and none of their patients had epidermolysis bullosa simplex associated with muscular dystrophy. Auringer et al.7 reported the only case in the ophthalmic literature of bilateral ptosis and limited ocular motility in a patient with epidermolysis bullosa simplex associated with muscular dystrophy.
Our study is the first to evaluate ocular manifestations in a series of patients with epidermolysis bullosa simplex associated with muscular dystrophy. We found ptosis in 3 of 6 patients and ophthalmoplegia in 2 patients. These findings are significant given the rarity of this condition. Oculomotor abnormalities and ptosis were similar to the patient described by Auringer et al.7; however, in our cases, the ocular findings were discovered at younger ages and as early as 6 years. In one of our patients, ptosis and ophthalmoplegia preceded the diagnosis of epidermolysis bullosa simplex associated with muscular dystrophy by genetic testing. In another patient, the ptosis and ophthalmoplegia developed early in the course of epidermolysis bullosa simplex associated with muscular dystrophy, before generalized muscle weakness was evident to the patient.
To our knowledge, case 1 was the first patient with epidermolysis bullosa simplex associated with muscular dystrophy who had been evaluated by our ophthalmology division. At his first two examinations at 11 and 13 years of age, we were not aware of a potential association between epidermolysis bullosa simplex associated with muscular dystrophy, ptosis, ophthalmoplegia, and muscular dystrophy. Consequently, genetic testing to diagnose epidermolysis bullosa simplex associated with muscular dystrophy was not recommended. When case 1 later developed extremity weakness, genetic testing was performed and epidermolysis bullosa simplex associated with muscular dystrophy was diagnosed. Strabismus surgery was not performed in case 1 due to the preferences of his parents. It is possible that surgery may have had limited value given that the oculomotor deficits and exotropia were both progressive.
Half of our patients with epidermolysis bullosa simplex associated with muscular dystrophy had ptosis, ophthalmoplegia, or both and the other half did not. Incomplete penetrance of ocular features of this genetic disorder may play a role, but a definitive reason remains unclear. Ptosis and ophthalmoplegia appear to be common in patients with epidermolysis bullosa simplex associated with muscular dystrophy.
- Fine JD, Bruckner-Tuderman L, Eady RA, et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol. 2014;70:1103–1126. doi:10.1016/j.jaad.2014.01.903 [CrossRef]
- Rezniczek GA, Walko G, Wiche G. Plectin gene defects lead to various forms of epidermolysis bullosa simplex. Dermatol Clin. 2010;28:33–41. doi:10.1016/j.det.2009.10.004 [CrossRef]
- Natsuga K. Plectin-related skin diseases. J Dermatol Sci. 2015;77:139–145. doi:10.1016/j.jdermsci.2014.11.005 [CrossRef]
- Villa CR, Ryan TD, Collins JJ, Taylor MD, Lucky AW, Jefferies JL. Left ventricular non-compaction cardiomyopathy associated with epidermolysis bullosa simplex with muscular dystrophy and PLEC1 mutation. Neuromuscul Disord. 2015;25:165–168. doi:10.1016/j.nmd.2014.09.011 [CrossRef]
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- Jones SM, Smith KA, Jain M, Mellerio JE, Martinez A, Nischal KK. The frequency of signs of meibomian gland dysfunction in children with epidermolysis bullosa. Ophthalmology. 2016;123:991–999. doi:10.1016/j.ophtha.2015.12.040 [CrossRef]
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- Shimizu H, Takizawa Y, Pulkkinen L, et al. Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature. J Am Acad Dermatol. 1999;41:950–956. doi:10.1016/S0190-9622(99)70252-5 [CrossRef]
- Smith KA, Jones SM, Nischal KK. Refractive and ocular motility findings in children with epidermolysis bullosa. Am Orthopt J. 2009;59:76–83. doi:10.3368/aoj.59.1.76 [CrossRef]