From Addenbrooke’s Hospital (VSA, KRM), Cambridge; and Moorfields Eye Hospital (PTK), London, United Kingdom.
Drs. Khaw and Martin received NIHR Biomedical Research Centre funding.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Keith R. Martin, MD, FRCOphth, Eye Department Box 41, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK. E-mail: firstname.lastname@example.org
Hereditary mucoepithelial dysplasia (HMD) is a rare desmosomal gap junction abnormality known to produce keratitis and cataracts in addition to multiple systemic problems. The visual prognosis of the eye disease is usually poor in published reports, with most patients becoming blind by adolescence.1–5
HMD should be considered in the differential diagnosis of red eyes and photophobia in children. HMD-associated eye disease usually presents with recurrent keratitis in infancy. Subsequent corneal scarring and cataracts often lead to amblyopia. Long-term use of steroids in the management of the condition is an additional risk for glaucoma. Frequent illnesses due to the underlying systemic abnormality can also affect the delivery of ophthalmic care. Nevertheless, timely interventions, a multidisciplinary approach, and parental involvement in care can achieve positive outcomes. We present a sporadic case of HMD with a good long-term visual outcome.
A 2-year-old girl was brought to the eye department with red eyes and photophobia. She was found to have bilateral corneal erosions, thin and brittle hair, alopecia, patchy eczema, and erythroderma. Examination by the dermatology team revealed follicular hyperkeratosis of the scalp and keratosis pilaris of the arms, legs, and face, but no frank ichthyosis (Figs. 1 and 2). Keratitis and loss of hair had followed a cyclical pattern with worsening in the winter. Family history was unremarkable.
Figure 1. Widespread Distribution of the Characteristic Skin Lesions of Hereditary Mucoepithelial Dysplasia (photograph Provided by Addenbrookes Hospital).
Figure 2. Keratosis Pilaris in Hereditary Mucoepithelial Dysplasia (photograph Provided by Addenbrookes Hospital).
A diagnosis of HMD was established by electron microscopic examination of the mucosal epithelium, which showed characteristic desmosomal gap junction abnormalities.
She was treated with regular preservative-free lubricants and bandage contact lenses, in addition to intermittent topical steroids and antibiotics for recurrent corneal erosions. Frequent examinations of the eyes under general anesthesia were required to monitor her condition. She developed myopia of the left eye and was given spectacles and patching. By the age of 5 years, she had bilateral corneal vascularization and bilateral lens opacities (Fig. 3). She underwent bilateral cataract extractions with lens implants at 6 years of age.
Figure 3. Corneal Vascularization and Scarring Reasonably Controlled by Long-Term Bandage Contact Lens Use.
Intraocular pressure (IOP) rose to 32 mm Hg in the right eye at the age of 5 years. IOP in the right eye responded well to topical timolol initially, but a Baerveldt glaucoma drainage device with mitomycin C application was required at age 7½ years because of IOP elevation resistant to topical therapy and progressive optic disc cupping. Subsequently, she also developed high IOP in the left eye. Having failed medical therapy and two cyclodiode laser treatments, she received Baerveldt implantation with mitomycin C application in the left eye at 10 years of age (Fig. 4). The postoperative course was uneventful. She had bilateral laser capsulotomies in the same year.
Figure 4. Baerveldt Implant with Overlying Bleb, Which Is Safer for Contact Lens Use than the Alternative of an Antimetabolite-Assisted Trabeculectomy Bleb.
Her general health throughout childhood was affected by repeated respiratory tract infections, constipation, perianal rashes, recurrent hair loss, and angular stomatitis. Her eye condition typically exacerbated in association with other symptoms and she was frequently treated in the eye department for corneal erosions, infections, and fluctuating vision. Her care was organized so that she always had access to senior ophthalmic and medical review immediately when new symptoms developed.
At her most recent visit at the age of 15 years, best-corrected visual acuity was 6/36 and 6/24 in her right and left eyes, respectively, improving to 6/18 with a pinhole. She retains good visual fields with good IOP control with no topical treatment and is a healthy and active student at a normal school making excellent educational progress.
HMD is an uncommon genetic disorder of the intercellular adhesion complexes resulting in defective assembly and formation of the desmosomal gap junction structures. The condition typically presents in infancy with photophobia and lacrimation due to recurrent keratitis.2 Corneal complications lead to scarring and cataracts by the first and second decades of life. Nystagmus, squint, and amblyopia are frequent associations. A variety of ocular features have been described in HMD, but the long-term clinical course of an ophthalmic case has not been reported.
Witkop et al. first described HMD as an autosomal dominant syndrome affecting oral, nasal, urethral, anal, vaginal, and conjunctival mucosa with the development of cataracts, follicular keratosis, nonscarring alopecia, and often fatal lung disease.1 The disease is accompanied by hair loss, diarrhea, occasional melena, enuresis, pyuria, and hematuria. Chronic rhinorrhea and repeated upper respiratory tract infections frequently progress to pneumonia, which can result in premature death. HMD is a rare condition and the diagnosis is often delayed.4 Histologically, the mucosal epithelium shows dyshesion, thinning of the epithelial layer, and dyskeratosis. Ultra-structurally, the mucosa is characterized by lack of keratohyalin granules, a paucity of desmosomes, intercellular accumulations, cytoplasmic vacuolization, and formation of filamentous structures resembling desmosomes and gap junctions in the cytoplasm.1
Ocular Features of HMD
A literature review by Boralevi et al. has reported the cumulative frequency of eye involvement in the condition as 77% with keratitis and cataract formation the most common features, occurring in almost all cases.4 The proportion of individuals with different types of eye disease is difficult to estimate due to incomplete ophthalmic examinations in many published reports, but it is clear that blindness occurs in the majority of patients.2–5
Although recurrent keratitis is recognized as the main ocular feature, its clinical course has not been reported in detail before. Our experience suggests that keratitis in HMD is due to recurrent corneal erosions. Our understanding of the disease process is that gap junction defects cause weak intercellular bonds that predispose the epithelial surfaces to shearing forces with frequent ruptures of the skin and mucosa. Corneal epithelium is particularly affected due to high cellular turnover. Intercellular junction anomalies are associated with poor wound healing resulting in corneal vascularization, inflammation, and scarring. Urban et al. has suggested that the severity of ocular involvement may vary in affected individuals due to variations in disease expressivity.6
Treating and preventing corneal epithelial erosions appears to be the vital step in reducing progressive corneal scarring and vascularization. Poorly adhesive epithelium and an unpredictable scarring response mean that surgical debridement and excimer laser treatment are problematic. In addition, corneal grafts carry a high risk of failure.1 Conservative therapy for recurrent corneal erosion in the acute phase consists of frequent lubrication and cycloplegia. Hypertonic saline solution (5% NaCl) during the day and ointment at bedtime for 6 to 12 months can promote proper epithelial attachment, although some patients find hypertonic medications unacceptably irritating.
In this case, we favored unpreserved ocular lubricants and long-term contact lens wear, which has proven to be successful in our patient. It is possible that bandage contact lens dependency from infancy may encourage corneal vascularization and increases the risk of infections. However, our experience suggests that contact lenses can make a major difference to the children’s quality of life, growth and development, and help in preventing dense amblyopia by allowing them to open their eyes comfortably. In our patient, contact lenses have also most likely minimized secondary corneal scarring and neovascularization by reducing the severity and frequency of epithelial erosions and inflammation, as evidenced by the increased problems when the lenses were not used. We used soft lenses with high water content, replaced every 6 weeks on average to prevent problems with build up of proteins.
Glaucoma has not been reported in HMD. It is not known whether gap junction anomalies affect the trabecular meshwork, Schlemm’s canal, and ciliary structures, thus potentially affecting aqueous production and drainage. The cause of glaucoma in our case is not clear, but may be a consequence of early cataract surgery and/or frequent use of topical steroids to control corneal inflammation. There may also be an underlying predisposition for the glaucoma development even if untreated with steroids. We believe that topical steroid use helped to reduce the amount of corneal scarring in this case and therefore contributed to the good visual outcome. However, steroids must always be used with caution and the risks and benefits properly balanced. Topical non-steroidal agents such as ketorolac may have been a useful adjunct to therapy without the risk of inducing secondary glaucoma. Where blepharitis is an additional problem, systemic antibiotics such as erythromycin or doxycycline may also be useful. Baerveldt glaucoma drainage devices have resulted in excellent long-term IOP control in this case and have also allowed the safer use of contact lenses compared with a trabeculectomy bleb.
Gap junction defects can produce early onset of cataracts because gap junctions are essential for normal lens metabolism. Early cataract surgery was required in the current case followed by vigilant assessment and management of amblyopia. Severe photophobia, corneal scarring, and cataracts are all risk factors for the development of amblyopia and all must be addressed to optimize the visual outcome.
We present a case of HMD where early diagnosis and careful management of ocular complications has resulted in an unusually good long-term visual outcome.
- Witkop CJ Jr, White JG, King RA, et al. Hereditary mucoepithelial dysplasia: a disease apparently of desmosome and gap junction formation. Am J Hum Genet. 1979;31:414–427.
- Witkop CJ Jr, White JG, Waring GO. Hereditary mucoepithelial dysplasia, a disease of gap junction and desmosome formation. Birth Defects Orig Artic Ser. 1982;18:493–511.
- Rogers M, Kourt G, Cameron A. Hereditary mucoepithelial dysplasia. Pediatr Dermatol. 1994;11:133–138. doi:10.1111/j.1525-1470.1994.tb00567.x [CrossRef]
- Boralevi F, Haftek M, Vabres P, et al. Hereditary mucoepithelial dysplasia: clinical, ultrastructural and genetic study of eight patients and literature review. Br J Dermatol. 2005;153:310–318. doi:10.1111/j.1365-2133.2005.06664.x [CrossRef]
- Scheman AJ, Ray DJ, Witkop CJ Jr, Dahl MV. Hereditary mucoepithelial dysplasia: case report and review of the literature. J Am Acad Dermatol. 1989;21:351–357. doi:10.1016/S0190-9622(89)80033-7 [CrossRef]
- Urban MD, Schosser R, Spohn W, et al. New clinical aspects of hereditary mucoepithelial dysplasia. Am J Med Genet. 1991;39:338–341. doi:10.1002/ajmg.1320390318 [CrossRef]
- Kersey JP, Broadway DC. Corticosteroid induced glaucoma: a review of the literature. Eye. 2006;20:407–416. doi:10.1038/sj.eye.6701895 [CrossRef]