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Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome
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Case report
Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome夽 David P. Kennedy, John W. Chandler, James P. McCulley ∗ Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9057, United States
a r t i c l e
i n f o
Article history: Received 4 November 2014 Received in revised form 3 February 2015 Accepted 3 February 2015 Keywords: Ocular surface disorders Ectrodactyly-ectodermal dysplasia-cleft syndrome Corneal epithelial stem cells Corneal stromal stem cells p63 mutations
a b s t r a c t Purpose: To present the ocular manifestation of 2 cases of ectrodactyly-ectodermal dysplasia-cleft syndrome, a multiple congenital anomaly syndrome caused by a single point mutation of the p63 gene that controls epidermal development and homeostasis and to present treatment options. Case reports and discussion: Patient 1 presented with mild signs and symptoms of dry eye and limbal stem cell deficiency with retention of 20/30 vision. Patient 2 presented with severe signs and symptoms of limbal stem cell deficiency with diffuse corneal scarring and counting fingers vision. This second patient’s course was complicated by allergic conjunctivitis and advanced steroid-induced glaucoma. The cause of visual loss in ectrodactyly-ectodermal dysplasia-cleft syndrome appears to be multifactorial and likely includes inflammation of the ocular surface, tear film abnormalities, eyelid abnormalities, and limbal stem cell deficiency. Treatment modalities including lubrication, contact lenses, and limbal stem cell transplantation are reviewed. Conclusions: The ophthalmic conditions seen in ectrodactyly-ectodermal dysplasia-cleft syndrome frequently lead to vision loss. Early correct diagnosis and appropriate therapy are paramount because p63 gene mutations have a critical role in maintaining the integrity of the ocular surface in the setting of limbal stem cell deficiency, especially if there are other ocular surface insults such as lid disease, meibomian gland dysfunction and toxicity from topical medications. Patients should be monitored at regular, frequent intervals; and particular attention should be taken to avoid adverse secondary effects of these conditions and medications. © 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction Ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome is a genetic disorder caused by mutations of the p63 gene, a transcription factor [1–3]. When a family history is present, EEC syndrome is an autosomal dominant disorder displaying variable phenotypic expression and reduced penetrance. Many of the reported EEC syndrome patients appear to have the condition as the result of spontaneous mutations. Ectrodactyly (lobster claw deformities) may involve hands, feet or both; ectodermal dysplasias may involve hair, teeth, nails, skin and sweat glands; and clefting may involve lip, palate or uvula to varying degrees. EEC syndrome prominently features a variety of ocular surface abnormalities that should prompt a diligent examination for other EEC syndrome features, especially in young patients [1,4,5].
Other described ectodermal dysplasias that appear to be associated with p63 gene mutations are hypohidrotic ectodermal dysplasia, ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, Rapp–Hodgkin syndrome and ectodermal dysplasiaectrodactyly-macular dystrophy syndrome (EEM) syndrome. All of these disorders may feature to some degree ophthalmic findings of the ocular surface [1]. This report describes two unrelated cases of EEC syndrome and discusses the importance of early, appropriate identification of the syndrome and extent of the ocular involvements, treatment of the underlying pathologic process, and recognition of common adverse effects of treatment regimens. 2. Case reports 2.1. Case 1
夽 Supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY. ∗ Corresponding author. Tel.: +1 214 648 0531; fax: +1 214 648 9061. E-mail address: [email protected] (J.P. McCulley).
A 21-year-old, orphaned male with cleft lip and palate and syndactyly presented with a 2-month history of bilateral conjunctival irritation and redness. There was a history of similar recurrent episodes in early childhood as well as life-long bilateral epiphora
http://dx.doi.org/10.1016/j.clae.2015.02.002 1367-0484/© 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kennedy DP, et al. Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.02.002
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Fig. 1. Slit lamp photos of Case 1, depicting absent meibomian glands.
without a history of dacryocystitis or probing of the nasolacrimal system. The recurrent irritation and redness subsided until the onset of the current episode. His medical history included only surgical repair of cleft lip and palate as an infant. He was not aware of any family history, and he took no medications. At initial presentation, his best-corrected visual acuity was 20/30 on the right and 20/40 on the left. The external examination detected several abnormalities including the absence of meibomian gland orifices and sparse lashes with some empty follicles bilaterally (Fig. 1). Salient features of slit-lamp biomicroscopy included punctate epithelial corneal erosions within the interpalpebral zones and 360◦ of superficial corneal neovascularization extending approximately 0.5 mm across the limbus of each eye. The palisades of Vogt were not identifiable on either cornea. The remainder of the examination of each eye was unremarkable including the conjunctivae, intraocular pressures and posterior poles. Tear production following topical anesthesia was 2 mm on the right and 4 mm on the left at 5 min. Irrigation and probing of the nasolacrimal system revealed bilateral obstructions. The patient achieved symptomatic relief after he was placed on chronic artificial tear replacement administered every 2 h. 2.2. Case 2 A 14 year-old male with EEC syndrome features including ectrodactyly and cleft palate was referred for evaluation and therapy of corneal scarring with a provisional referral diagnosis of StevensJohnson syndrome. The family history including parents and three siblings did not reveal any features of inherited EEC syndrome. The patient did not take any systemic medications. His relevant medical history included surgical repair of cleft palate and several relevant ocular items starting at birth. Symptoms of nasolacrimal obstructions were noted soon after birth and probing was performed at 6 and 18 months of age, however, the right side continued to be partially obstructed. Throughout early life he was considered to have chronic keratoconjunctivitis that was treated with neomycin–polymyxin–bacitracin ophthalmic ointment and prednisolone, 1% drops daily in each eye until age 11 when elevated intraocular pressures were discovered. After two years of glaucoma medical therapies, a trabeculectomy was performed on the left eye. At the time of surgery the visual acuity on the right was 20/60 and on the left was light perception. The corneas were clear enough to visualize the posterior pole of each eye. On the left there was extensive glaucomatous optic nerve damage and the visual acuity remained light perception after trabeculectomy. At age 12 a right conjunctivodacryocystorhinostomy with placement of a Jones tube was performed for management of the chronic dacryocystitis. Following surgery he was maintained on topical neomycin–polymyxin ophthalmic solution. Two years later at age 14, he was referred to the author’s clinic for management of chronic bilateral corneal scarring and
inflammation and was still being treated with the antibiotic combination. At this time the visual acuities were 3/200 on the right and light perception with accurate light projection in the superonasal quadrant on the left. Severe blepharospasm and photophobia were present. The external examination showed bilateral severe blepharitis with maceration of the lid margins. An eyelid speculum was required for examination of the ocular surface in each eye. All punctae appeared patent and meibomian gland orifices were stenetic or absent with difficult to express turbid secretions. The bulbar conjunctivae were moderately injected and the tarsal palpebral conjunctivae showed marked papillary hypertrophy. The filtering bleb was present on the left. The corneas had bilateral diffuse irregular epithelial surfaces, pannus formation and underlying stromal scarring (Fig. 2). The limbal palisades of Vogt were absent. These changes obscured the visual axis of each eye, however, the iris and lens appeared to be within normal limits but no details of the posterior pole of either eye could be seen. Intraocular pressures in the right and left eyes were 33 and 30 mmHg by pneumotonometer, respectively. Tear production with topical anesthetic was 15 mm on the right and 20 mm on the left at 5 min. Intradermal scratch skin testing performed with neomycin– polymyxin–bacitracin ointment and with neomycin–polymyxin solution revealed moderate and mild hypersensitivities, respectively. Conjunctival cultures were read as no growth and conjunctival scrapings for histology showed polymorphonuclear leukocytes and basophils. The combination topical antibiotics were discontinued and bilateral dexamethasone acetate, 1% solution five times daily and erythromycin ointment at bedtime were initiated. The patient was followed weekly, and his eyelid and conjunctival inflammation had significantly improved after 3 weeks, allowing examination without a speculum. Intraocular pressures were 18 and 16 mmHg, respectively. This improvement was felt to be due to improvement in blepharospasm. The vision in the right eye improved to 20/300 but was unchanged in the left eye (Fig. 3). The patient was maintained on erythromycin ointment at bedtime in each eye, but the dexamethasone drops were tapered and discontinued. Surgical intervention was discussed but the patient subsequently discontinued follow-up care. 3. Discussion Despite the multiple cosmetically obvious abnormalities of EEC syndrome, the ocular involvements are often the most lifealtering manifestations. Common ocular signs and symptoms include photophobia, blepharospasm, epiphora, and corneal neovascularization and scarring [6–8]. These two patients are examples of the extremes of the ocular involvements. The first case exhibits clinical findings of limbal stem cell deficiency (LSCD) and the ability of appropriate therapy to maintain an adequate ocular surface and preserve vision. In contrast, the second patient’s clinical
Please cite this article in press as: Kennedy DP, et al. Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.02.002
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Fig. 2. Slit lamp photos of Case 2 on presentation, showing severe corneal scarring and conjunctival inflammation. Note the lid speculum in place due to severe photophobia and blepharospasm.
course demonstrates the vulnerability of the ocular surface in EEC syndrome to insults associated with meibomian dysfunction and toxicity and sensitivity to topical medications. EEC syndrome is caused by a heterozygous missense mutation in the DNA-binding domain of p63, an important transcription factor during embryogenesis and stem cell differentiation of stratified epithelia [1,2,9]. The p63 gene is needed for regenerative proliferation in epithelial development and is expressed in limbal basal cells but not in the transient amplifying cells of the corneal surface [1]. Di Iorio et al. reported that 100% of 23 patients with EEC syndrome had one of 11 different missense mutations in the DNAbinding region of p63 and that these mutations were not found in unaffected family members or in 200 control chromosomes. The authors hypothesize that these p63 mutations result in LSCD, which in turn results in corneal changes and secondary visual impairment in EEC syndrome [1]. LSCD was seen in 14/23 (61%) patients, which led to a progressive keratopathy with corneal neovascularization and/or scarring in 13/23 patients (56.5%) [1]. LSCD was diagnosed by absence or abnormal appearance of limbal palisades on clinical exam, conjunctivalization producing fibrovascular pannus, and characteristic irregular fluorescein staining. In a small series, Felipe et al. reported 3 cases of EEC syndrome with variable ocular signs, including corneal neovascularization, perforation, and disabling symblephara. All cases demonstrated absence of limbal palisades of Vogt on clinical exam, and LSCD was thought to contribute to the corneal findings in each case [6]. Management of the ocular manifestations of EEC syndrome is challenging because of the chronic progressive nature of the ocular surface changes related to limbal stem cell deficiency and the rarity of the disease, which leads to misdiagnosis and mismanagement. If signs and symptoms are mild, conservative management with artificial tears may suffice, as it did in the case of patient 1. However, moderate to severe signs such as corneal neovascularization and epithelial defects may require more aggressive rehabilitation of the ocular surface. If a non-healing epithelial defect is present
with concern for perforation, amniotic membrane transplant by way of surgery or in-office placement of a commercially available ring should be considered. Corneal perforation can be managed with cyanoacrylate glue and bandage contact lens [6]. Rigid gaspermeable scleral contact lenses (GP-ScCL) have been reported useful in cases of severe ocular surface disease, particularly nonhealing epithelial defects [10,11]. In cases of ocular surface disease related to LSCD, the benefit is limited to symptomatic improvement of photophobia and pain rather than restoration of a normal ocular surface with corneal epithelium [9]. However, one report does claim that GP-ScCL may provide an environment for damaged but viable epithelial limbal stem cells to recover, restoring a physiologic corneal epithelium [10]. Further study is required to elucidate the role of GP-ScCL in the management of LSCD. If LSCD is severe enough that conjunctival epithelium has replaced corneal epithelium, the therapeutic approach includes either measures of palliation to maintain an intact epithelial surface or replacement of the limbal palisades of Vogt in hopes of visual rehabilitation. Autologous and allogeneic limbal stem cell therapies have been proven effective in various forms of LSCD [12,13]. However, reports are limited and have yielded varied results in patients with EEC syndrome. Daya et al. performed living related conjunctival limbal allograft in 1 patient with EEC syndrome and in 2 patients with ectodermal dysplasia, all of whom had improved visual acuity (from counting fingers to 20/80–20/200) and stabilization of the ocular surface postoperatively [14]. Ilari et al. reported a single case of EEC syndrome that underwent unsuccessful keratolimbal allograft transplantation from a cadaveric source [15]. Patients in both studies were treated with both systemic and topical steroids and systemic cyclosporine A. The conclusions of these studies suggest that severe ocular surface inflammation was a poor prognostic factor and that any surface reconstruction, such as symblepharon lysis or other lid abnormalities, should be performed prior to any limbal transplantation to increase the chances of success [14,15]. Living-related donor allograft is preferable to cadaveric
Fig. 3. Slit lamp photos of Case 2 after discontinuation of offending agents. Note improved conjunctival appearance and lack of need for speculum.
Please cite this article in press as: Kennedy DP, et al. Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.02.002
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keratolimbal allograft because of the higher possibility of HLAmatched tissue [13]. The future of EEC syndrome treatment may lie in stem cell therapy. Recent research has provided evidence that human-induced pluripotent stem cells (hiPSCs) may be derived from either hair follicle cells or skin fibroblasts [16,17]. Additionally, it has been shown that skin fibroblasts from EEC syndrome donors with characteristic p63 mutations can be reprogrammed into hiPSCs that can subsequently be treated with APR-246/Prima-1met , a small molecule compound that restores p53 functionality in human tumor cells, that revert p63 functionality and restore corneal epithelial lineage commitment and signaling [17,18]. Further refinements in these observations may lead to interventions in patients with EEC syndrome and functionally deficient or absent corneal epithelial stem cells prior to the inset of significant and vision-threatening complications. The first patient’s case had mild corneal neovascularization with either absent or abnormal palisades of Vogt on clinical exam, an abnormal basal tear secretion test, and absent meibomian gland orifices. The absence of meibomian glands has been previously confirmed in the literature; however, the role of this abnormality in EEC syndrome is unclear [7,8]. In this case, preservative-free artificial tears were sufficient to protect the ocular surface and resolve symptoms. The second patient presented with severe ocular signs and symptoms, which disrupted his functional status. LSCD associated with EEC syndrome was perhaps a precursor to his severe corneal scarring; however, the patient’s syndrome was not recognized at an early age, and lack of appreciation of the underlying pathologic process resulted in years of misdirected treatment regimens with severe consequences: advanced steroid-induced glaucoma and visually disabling corneal stromal scarring. The disparity in these two patients outcomes illustrates the point that correct, early diagnosis of EEC syndrome is critical to the sight of these patients. Mutations of the p63 gene make the ocular surface of these eyes vulnerable to the effects of other insults and leads to severe, irreversible sequelae if managed incorrectly. Even when placed on appropriate treatment, it is important to recognize and treat drug toxicity and/or hypersensitivity and also steroidinduced glaucomatous changes. Despite a guarded long-term visual prognosis, the progression of ocular manifestations and subsequent visual decline in EEC syndrome can be delayed by early identification of the syndrome, understanding of the pathologic processes at hand, and appropriate maintenance of the ocular surface, with regular follow-up to detect changes in disease progression and adverse effects of therapy.
Conflicts of interest The authors have no proprietary or commercial interests in any concept or product discussed in this article. References [1] Di Iorio E, Kaye SB, Ponzin D, Barbaro V, Ferrari S, Böhm E, et al. Limbal stem-cell deficiency and ocular phenotype in ectrodactyly-ectodermal dysplasia-clefting syndrome caused by p63 mutations. Ophthalmology 2012;119:74–83. [2] Clements SE, Techanukul T, Coman D, Mellerio JE, McGrath JA. Molecular basis of EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome: five new mutations in the DNA-binding domain of the TP63 gene and genotype-phenotype correlation. Br J Dermatol 2010;162:201–7. [3] Shalom-Feuerstein R, Serror L, Aberdam E, Müller FJ, van Bokhoven H, Wiman KG, et al. Impaired epithelial differentiation of induced pluripotent stem cells from ectrodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1met . Proc Natl Acad Sci U S A 2013;110:2152–6. [4] Buss PW, Hughes HE, Clarke A. Twenty-four cases of the EEC syndrome: clinical presentation and management. J Med Genet 1995;32:716–23. [5] Rodini ES, Richieri-Costa A. EEC syndrome: report on 20 new patients, clinical and genetic considerations. Am J Med Genet 1990;37:42–53. [6] Felipe AF, Abazari A, Hammersmith KM, Rapuano CJ, Nagra PK, Peiro BM. Corneal changes in ectrodactyly-ectodermal dysplasia-cleft lip and palate syndrome: case series and literature review. Int Ophthalmol 2012;32:475–80. [7] Mondino BJ, Bath PE, Foos RY, Apt L, Rajacich GM. Absent meibomian glands in the ectrodactyly, ectodermal dysplasia, cleft lip-palate syndrome. Am J Ophthalmol 1984;97:496–500. [8] Baum JL, Bull MJ. Ocular manifestations of the ectrodactyly, ectodermal dysplasia, cleft lip-palate syndrome. Am J Ophthalmol 1974;78:211–6. [9] Von Bokhoven H, Hamel BC, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PH, et al. p63 Gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 2001;69:481–92. [10] Romero-Rangel T, Stavrou P, Cotter J, Rosenthal P, Baltatzis S, Foster CS. Gas-permeable scleral contact lens therapy in ocular surface disease. Am J Ophthalmol 2000;130:25–32. [11] Schornack MM. Limbal stem cell disease: management with scleral lenses. Clin Exp Optom 2011;6:592–4. [12] Sharma S, Tandon R, Mohanty S, Sharma N, Sen S, M V, et al. Culture of corneal limbal epithelial stem cells: experience from benchtop to bedside in a tertiary care hospital in India. Cornea 2011;11:223–32. [13] Burman S, Sangwan V. Cultivated limbal stem cell transplantation for ocular surface reconstruction. Clin Ophthalmol 2008;3:489–502. [14] Daya SM, Ilari FA. Living related conjunctival limbal allograft for the treatment of stem cell deficiency. Ophthalmology 2001;108:126–33. [15] Ilari FA, Daya SM. Long-term outcomes of keratolimbal allograft for the treatment of severe ocular surface disorders. Ophthalmology 2002;109:1278–84. [16] Miyazaki S, Yamamoto H, Miyoshi N, Takahashi H, Suzuki Y, Haraguchi N, et al. Emerging methods for preparing iPS cells. Jpn J Clin Oncol 2012;42:773–9. [17] Shalom-Feuerstein R, Serror L, De La Forest Divonne S, Petit I, Aberdam E, Camargo L, et al. Pluripotent stem cell model reveals essential roles for miR450b-5p and miR-184 in embryonic corneal lineage specification. Stem Cells 2012;30:898–909. [18] Shen J, van den Bogaard EH, Kouwenhoven EN, Bykov VJ, Rinne T, Zhang Q, et al. APR-246/PRIMA-1met rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations. Proc Natl Acad Sci U S A 2013;110:2157–62.
Please cite this article in press as: Kennedy DP, et al. Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.02.002
ARTICLE IN PRESS
CLAE-779; No. of Pages 4
Contact Lens & Anterior Eye xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Contact Lens & Anterior Eye journal homepage: www.elsevier.com/locate/clae
Case report
Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome夽 David P. Kennedy, John W. Chandler, James P. McCulley ∗ Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9057, United States
a r t i c l e
i n f o
Article history: Received 4 November 2014 Received in revised form 3 February 2015 Accepted 3 February 2015 Keywords: Ocular surface disorders Ectrodactyly-ectodermal dysplasia-cleft syndrome Corneal epithelial stem cells Corneal stromal stem cells p63 mutations
a b s t r a c t Purpose: To present the ocular manifestation of 2 cases of ectrodactyly-ectodermal dysplasia-cleft syndrome, a multiple congenital anomaly syndrome caused by a single point mutation of the p63 gene that controls epidermal development and homeostasis and to present treatment options. Case reports and discussion: Patient 1 presented with mild signs and symptoms of dry eye and limbal stem cell deficiency with retention of 20/30 vision. Patient 2 presented with severe signs and symptoms of limbal stem cell deficiency with diffuse corneal scarring and counting fingers vision. This second patient’s course was complicated by allergic conjunctivitis and advanced steroid-induced glaucoma. The cause of visual loss in ectrodactyly-ectodermal dysplasia-cleft syndrome appears to be multifactorial and likely includes inflammation of the ocular surface, tear film abnormalities, eyelid abnormalities, and limbal stem cell deficiency. Treatment modalities including lubrication, contact lenses, and limbal stem cell transplantation are reviewed. Conclusions: The ophthalmic conditions seen in ectrodactyly-ectodermal dysplasia-cleft syndrome frequently lead to vision loss. Early correct diagnosis and appropriate therapy are paramount because p63 gene mutations have a critical role in maintaining the integrity of the ocular surface in the setting of limbal stem cell deficiency, especially if there are other ocular surface insults such as lid disease, meibomian gland dysfunction and toxicity from topical medications. Patients should be monitored at regular, frequent intervals; and particular attention should be taken to avoid adverse secondary effects of these conditions and medications. © 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction Ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome is a genetic disorder caused by mutations of the p63 gene, a transcription factor [1–3]. When a family history is present, EEC syndrome is an autosomal dominant disorder displaying variable phenotypic expression and reduced penetrance. Many of the reported EEC syndrome patients appear to have the condition as the result of spontaneous mutations. Ectrodactyly (lobster claw deformities) may involve hands, feet or both; ectodermal dysplasias may involve hair, teeth, nails, skin and sweat glands; and clefting may involve lip, palate or uvula to varying degrees. EEC syndrome prominently features a variety of ocular surface abnormalities that should prompt a diligent examination for other EEC syndrome features, especially in young patients [1,4,5].
Other described ectodermal dysplasias that appear to be associated with p63 gene mutations are hypohidrotic ectodermal dysplasia, ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, Rapp–Hodgkin syndrome and ectodermal dysplasiaectrodactyly-macular dystrophy syndrome (EEM) syndrome. All of these disorders may feature to some degree ophthalmic findings of the ocular surface [1]. This report describes two unrelated cases of EEC syndrome and discusses the importance of early, appropriate identification of the syndrome and extent of the ocular involvements, treatment of the underlying pathologic process, and recognition of common adverse effects of treatment regimens. 2. Case reports 2.1. Case 1
夽 Supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY. ∗ Corresponding author. Tel.: +1 214 648 0531; fax: +1 214 648 9061. E-mail address: [email protected] (J.P. McCulley).
A 21-year-old, orphaned male with cleft lip and palate and syndactyly presented with a 2-month history of bilateral conjunctival irritation and redness. There was a history of similar recurrent episodes in early childhood as well as life-long bilateral epiphora
http://dx.doi.org/10.1016/j.clae.2015.02.002 1367-0484/© 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kennedy DP, et al. Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.02.002
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Fig. 1. Slit lamp photos of Case 1, depicting absent meibomian glands.
without a history of dacryocystitis or probing of the nasolacrimal system. The recurrent irritation and redness subsided until the onset of the current episode. His medical history included only surgical repair of cleft lip and palate as an infant. He was not aware of any family history, and he took no medications. At initial presentation, his best-corrected visual acuity was 20/30 on the right and 20/40 on the left. The external examination detected several abnormalities including the absence of meibomian gland orifices and sparse lashes with some empty follicles bilaterally (Fig. 1). Salient features of slit-lamp biomicroscopy included punctate epithelial corneal erosions within the interpalpebral zones and 360◦ of superficial corneal neovascularization extending approximately 0.5 mm across the limbus of each eye. The palisades of Vogt were not identifiable on either cornea. The remainder of the examination of each eye was unremarkable including the conjunctivae, intraocular pressures and posterior poles. Tear production following topical anesthesia was 2 mm on the right and 4 mm on the left at 5 min. Irrigation and probing of the nasolacrimal system revealed bilateral obstructions. The patient achieved symptomatic relief after he was placed on chronic artificial tear replacement administered every 2 h. 2.2. Case 2 A 14 year-old male with EEC syndrome features including ectrodactyly and cleft palate was referred for evaluation and therapy of corneal scarring with a provisional referral diagnosis of StevensJohnson syndrome. The family history including parents and three siblings did not reveal any features of inherited EEC syndrome. The patient did not take any systemic medications. His relevant medical history included surgical repair of cleft palate and several relevant ocular items starting at birth. Symptoms of nasolacrimal obstructions were noted soon after birth and probing was performed at 6 and 18 months of age, however, the right side continued to be partially obstructed. Throughout early life he was considered to have chronic keratoconjunctivitis that was treated with neomycin–polymyxin–bacitracin ophthalmic ointment and prednisolone, 1% drops daily in each eye until age 11 when elevated intraocular pressures were discovered. After two years of glaucoma medical therapies, a trabeculectomy was performed on the left eye. At the time of surgery the visual acuity on the right was 20/60 and on the left was light perception. The corneas were clear enough to visualize the posterior pole of each eye. On the left there was extensive glaucomatous optic nerve damage and the visual acuity remained light perception after trabeculectomy. At age 12 a right conjunctivodacryocystorhinostomy with placement of a Jones tube was performed for management of the chronic dacryocystitis. Following surgery he was maintained on topical neomycin–polymyxin ophthalmic solution. Two years later at age 14, he was referred to the author’s clinic for management of chronic bilateral corneal scarring and
inflammation and was still being treated with the antibiotic combination. At this time the visual acuities were 3/200 on the right and light perception with accurate light projection in the superonasal quadrant on the left. Severe blepharospasm and photophobia were present. The external examination showed bilateral severe blepharitis with maceration of the lid margins. An eyelid speculum was required for examination of the ocular surface in each eye. All punctae appeared patent and meibomian gland orifices were stenetic or absent with difficult to express turbid secretions. The bulbar conjunctivae were moderately injected and the tarsal palpebral conjunctivae showed marked papillary hypertrophy. The filtering bleb was present on the left. The corneas had bilateral diffuse irregular epithelial surfaces, pannus formation and underlying stromal scarring (Fig. 2). The limbal palisades of Vogt were absent. These changes obscured the visual axis of each eye, however, the iris and lens appeared to be within normal limits but no details of the posterior pole of either eye could be seen. Intraocular pressures in the right and left eyes were 33 and 30 mmHg by pneumotonometer, respectively. Tear production with topical anesthetic was 15 mm on the right and 20 mm on the left at 5 min. Intradermal scratch skin testing performed with neomycin– polymyxin–bacitracin ointment and with neomycin–polymyxin solution revealed moderate and mild hypersensitivities, respectively. Conjunctival cultures were read as no growth and conjunctival scrapings for histology showed polymorphonuclear leukocytes and basophils. The combination topical antibiotics were discontinued and bilateral dexamethasone acetate, 1% solution five times daily and erythromycin ointment at bedtime were initiated. The patient was followed weekly, and his eyelid and conjunctival inflammation had significantly improved after 3 weeks, allowing examination without a speculum. Intraocular pressures were 18 and 16 mmHg, respectively. This improvement was felt to be due to improvement in blepharospasm. The vision in the right eye improved to 20/300 but was unchanged in the left eye (Fig. 3). The patient was maintained on erythromycin ointment at bedtime in each eye, but the dexamethasone drops were tapered and discontinued. Surgical intervention was discussed but the patient subsequently discontinued follow-up care. 3. Discussion Despite the multiple cosmetically obvious abnormalities of EEC syndrome, the ocular involvements are often the most lifealtering manifestations. Common ocular signs and symptoms include photophobia, blepharospasm, epiphora, and corneal neovascularization and scarring [6–8]. These two patients are examples of the extremes of the ocular involvements. The first case exhibits clinical findings of limbal stem cell deficiency (LSCD) and the ability of appropriate therapy to maintain an adequate ocular surface and preserve vision. In contrast, the second patient’s clinical
Please cite this article in press as: Kennedy DP, et al. Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.02.002
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Fig. 2. Slit lamp photos of Case 2 on presentation, showing severe corneal scarring and conjunctival inflammation. Note the lid speculum in place due to severe photophobia and blepharospasm.
course demonstrates the vulnerability of the ocular surface in EEC syndrome to insults associated with meibomian dysfunction and toxicity and sensitivity to topical medications. EEC syndrome is caused by a heterozygous missense mutation in the DNA-binding domain of p63, an important transcription factor during embryogenesis and stem cell differentiation of stratified epithelia [1,2,9]. The p63 gene is needed for regenerative proliferation in epithelial development and is expressed in limbal basal cells but not in the transient amplifying cells of the corneal surface [1]. Di Iorio et al. reported that 100% of 23 patients with EEC syndrome had one of 11 different missense mutations in the DNAbinding region of p63 and that these mutations were not found in unaffected family members or in 200 control chromosomes. The authors hypothesize that these p63 mutations result in LSCD, which in turn results in corneal changes and secondary visual impairment in EEC syndrome [1]. LSCD was seen in 14/23 (61%) patients, which led to a progressive keratopathy with corneal neovascularization and/or scarring in 13/23 patients (56.5%) [1]. LSCD was diagnosed by absence or abnormal appearance of limbal palisades on clinical exam, conjunctivalization producing fibrovascular pannus, and characteristic irregular fluorescein staining. In a small series, Felipe et al. reported 3 cases of EEC syndrome with variable ocular signs, including corneal neovascularization, perforation, and disabling symblephara. All cases demonstrated absence of limbal palisades of Vogt on clinical exam, and LSCD was thought to contribute to the corneal findings in each case [6]. Management of the ocular manifestations of EEC syndrome is challenging because of the chronic progressive nature of the ocular surface changes related to limbal stem cell deficiency and the rarity of the disease, which leads to misdiagnosis and mismanagement. If signs and symptoms are mild, conservative management with artificial tears may suffice, as it did in the case of patient 1. However, moderate to severe signs such as corneal neovascularization and epithelial defects may require more aggressive rehabilitation of the ocular surface. If a non-healing epithelial defect is present
with concern for perforation, amniotic membrane transplant by way of surgery or in-office placement of a commercially available ring should be considered. Corneal perforation can be managed with cyanoacrylate glue and bandage contact lens [6]. Rigid gaspermeable scleral contact lenses (GP-ScCL) have been reported useful in cases of severe ocular surface disease, particularly nonhealing epithelial defects [10,11]. In cases of ocular surface disease related to LSCD, the benefit is limited to symptomatic improvement of photophobia and pain rather than restoration of a normal ocular surface with corneal epithelium [9]. However, one report does claim that GP-ScCL may provide an environment for damaged but viable epithelial limbal stem cells to recover, restoring a physiologic corneal epithelium [10]. Further study is required to elucidate the role of GP-ScCL in the management of LSCD. If LSCD is severe enough that conjunctival epithelium has replaced corneal epithelium, the therapeutic approach includes either measures of palliation to maintain an intact epithelial surface or replacement of the limbal palisades of Vogt in hopes of visual rehabilitation. Autologous and allogeneic limbal stem cell therapies have been proven effective in various forms of LSCD [12,13]. However, reports are limited and have yielded varied results in patients with EEC syndrome. Daya et al. performed living related conjunctival limbal allograft in 1 patient with EEC syndrome and in 2 patients with ectodermal dysplasia, all of whom had improved visual acuity (from counting fingers to 20/80–20/200) and stabilization of the ocular surface postoperatively [14]. Ilari et al. reported a single case of EEC syndrome that underwent unsuccessful keratolimbal allograft transplantation from a cadaveric source [15]. Patients in both studies were treated with both systemic and topical steroids and systemic cyclosporine A. The conclusions of these studies suggest that severe ocular surface inflammation was a poor prognostic factor and that any surface reconstruction, such as symblepharon lysis or other lid abnormalities, should be performed prior to any limbal transplantation to increase the chances of success [14,15]. Living-related donor allograft is preferable to cadaveric
Fig. 3. Slit lamp photos of Case 2 after discontinuation of offending agents. Note improved conjunctival appearance and lack of need for speculum.
Please cite this article in press as: Kennedy DP, et al. Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.02.002
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keratolimbal allograft because of the higher possibility of HLAmatched tissue [13]. The future of EEC syndrome treatment may lie in stem cell therapy. Recent research has provided evidence that human-induced pluripotent stem cells (hiPSCs) may be derived from either hair follicle cells or skin fibroblasts [16,17]. Additionally, it has been shown that skin fibroblasts from EEC syndrome donors with characteristic p63 mutations can be reprogrammed into hiPSCs that can subsequently be treated with APR-246/Prima-1met , a small molecule compound that restores p53 functionality in human tumor cells, that revert p63 functionality and restore corneal epithelial lineage commitment and signaling [17,18]. Further refinements in these observations may lead to interventions in patients with EEC syndrome and functionally deficient or absent corneal epithelial stem cells prior to the inset of significant and vision-threatening complications. The first patient’s case had mild corneal neovascularization with either absent or abnormal palisades of Vogt on clinical exam, an abnormal basal tear secretion test, and absent meibomian gland orifices. The absence of meibomian glands has been previously confirmed in the literature; however, the role of this abnormality in EEC syndrome is unclear [7,8]. In this case, preservative-free artificial tears were sufficient to protect the ocular surface and resolve symptoms. The second patient presented with severe ocular signs and symptoms, which disrupted his functional status. LSCD associated with EEC syndrome was perhaps a precursor to his severe corneal scarring; however, the patient’s syndrome was not recognized at an early age, and lack of appreciation of the underlying pathologic process resulted in years of misdirected treatment regimens with severe consequences: advanced steroid-induced glaucoma and visually disabling corneal stromal scarring. The disparity in these two patients outcomes illustrates the point that correct, early diagnosis of EEC syndrome is critical to the sight of these patients. Mutations of the p63 gene make the ocular surface of these eyes vulnerable to the effects of other insults and leads to severe, irreversible sequelae if managed incorrectly. Even when placed on appropriate treatment, it is important to recognize and treat drug toxicity and/or hypersensitivity and also steroidinduced glaucomatous changes. Despite a guarded long-term visual prognosis, the progression of ocular manifestations and subsequent visual decline in EEC syndrome can be delayed by early identification of the syndrome, understanding of the pathologic processes at hand, and appropriate maintenance of the ocular surface, with regular follow-up to detect changes in disease progression and adverse effects of therapy.
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Please cite this article in press as: Kennedy DP, et al. Ocular surface involvements in ectrodactyly-ectodermal dysplasia-cleft syndrome. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.02.002