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Ocular manifestations of keratitis– ichthyosis–deafness (KID) syndrome
Ocular Manifestations of Keratitis– Ichthyosis–Deafness (KID) Syndrome E. M. Messmer, MD,1 K. R. Kenyon, MD,2 O. Rittinger, MD,3 A. R. Janecke, MD,4 A. Kampik, MD1 Objective: Keratitis–ichthyosis– deafness (KID) syndrome is a rare congenital ectodermal dysplasia characterized by the association of hyperkeratotic skin lesions, moderate to profound sensorineural hearing loss and vascularizing keratitis. Mutations in the GJB2 gene coding for connexin 26, a component of gap junctions in epithelial cells, have been observed in several KID patients. Variable ocular manifestations of the disease in 3 patients with molecular genetically confirmed KID syndrome are reported. Design: Retrospective case series. Methods: Clinical examination and molecular genetic analysis for mutations in the GJB2 gene were performed in 3 patients with KID syndrome ages 5, 13, and 41 years. Results: Visual acuity ranged from normal to severe visual loss. The ocular signs included loss of eyebrows and lashes, thickened and keratinized lids, trichiasis, recurrent corneal epithelial defects, superficial and deep corneal stromal vascularization with scarring, keratoconjunctivitis sicca, and, in one patient, presumed limbal insufficiency. Whereas ocular surface integrity could be maintained with artificial tears in one patient, and an epithelial defect healed under conservative treatment in the second patient, multiple surgical procedures including superficial keratectomies, limbal allograft transplantation with systemic immunosuppression, amniotic membrane transplantation, lateral tarsorrhaphies, and lamellar keratoplasty could not preserve useful vision in the third patient. Conclusions: KID syndrome may affect the ocular adnexae and surface with variable severity independent of the age of the patient. Lid abnormalities, corneal surface instability, limbal stem cell deficiency with resulting corneal complications, and dry eye are the main ocular manifestations. Ophthalmology 2005;112:e1– e6 © 2005 by the American Academy of Ophthalmology.
In 1915, Burns described a patient with progressive corneal inflammatory disease, diffuse hyperkeratotic erythroderma, and neurosensory hearing loss.1 Subsequently, this syndrome was recognized as a specific congenital ectodermal disorder that affects not only the epidermis but also other ectodermal tissues such as the corneal epithelium and the inner ear. The acronym KID was coined by Skinner et al to represent the triad of keratitis, ichthyosiform erythroderma, and deafness.2 Other features of this syndrome include scarring alopecia, dystrophic nails, dental abnormalities, increased risk of developing squamous cell carcinoma, and increased susceptibility to bacterial and mycotic infections.3– 6 Most cases of KID syndrome are sporadic, but the existence of familial cases suggested a genetic etiology.7–10 Several patients with KID syndrome were shown to be heterozygous for distinct mutations in the connexin 26 – Originally received: May 11, 2004. Accepted: July 20, 2004. Manuscript no. 240359. 1 Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany. 2 Cornea Consultants International, Munich, Germany. 3 Klinische Genetik, Universitätsklinik für Kinder- und Jugendheilkunde, Paracelsus Medizinische Universität Salzburg, Salzburg, Austria. 4 Institute of Medical Biology and Human Genetics, Medical University, Innsbruck, Austria. Correspondence to E. Messmer, MD, Department of Ophthalmology, LudwigMaximilians-University, Mathildenstrasse 8, D-80336 Muenchen, Germany. © 2005 by the American Academy of Ophthalmology Published by Elsevier Inc.
coding gene GJB2.10 –13 Connexins are known to function as major gap junction proteins involved in intercellular communication in epithelial cells.14 Connexin 26, a 26kilodalton protein, consists of 226 amino acids and is encoded by the GJB2 gene, which is localized on chromosome 13.12 Corneal involvement is mainly reported as vascularizing keratitis, pannus formation, corneal neovascularization, or leucoma. Only recently, limbal stem cell deficiency was recognized as a possible major pathogenetic factor.7 Resultant ocular surface disease aggravated by severe dry eye may lead to major visual loss. We report on the ocular manifestations, the variable clinical course, and the therapeutic management of 3 KID patients.
Case Reports Case 1 At the age of 5 years, this male patient presented at our clinic with complaints of recurrent corneal epithelial defects, severe photophobia, and visual acuity (VA) of 20/200 in the right eye and 20/50 in the left eye. Ocular examination also disclosed the loss of eyebrows and eyelashes, hyperkeratotic lesions of the eyelids, a mild conjunctival injection, and corneal scarring with superficial vascularization in both eyes, reaching the optical zone in the right eye (Figs 1–3). ISSN 1549-4713/05/$–see front matter doi:10.1016/j.ophtha.2004.07.034
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Figure 1. Patient 1. Hyperkeratotic lid lesions and absence of lashes in keratitis–ichthyosis– deafness syndrome.
Figure 3. Left eye of patient 1 at first presentation. Conjunctivalization of the corneal surface.
The tear meniscus was nearly absent, and Schirmer test values were below 5 mm/5 minutes. The patient further exhibited profound sensorineural hearing loss since the age of 6 months, coarse, sparse, and hypopigmented hair, palmoplantar hyperkeratosis, dystrophic nails, and joint contractures, without mental retardation (Fig 4). Molecular analysis showed a heterozygous de novo mutation of connexin 26 in codon 50 and confirmed the diagnosis of KID syndrome. Neither topical corticosteroids nor artificial tears prevented progression of the ocular disease. Surgical procedures to improve visual function included superficial keratectomy, limbal allograft transplants from the HLA-related parents, amniotic membrane transplantation, and lateral tarsorrhaphies in both eyes under systemic immunosuppression with cyclosporin A. However, an aggressively regrowing pannus with recurrent epithelial defects rapidly limited VA again to counting fingers (CF) in the right eye and 1/50 in the left eye. Lamellar keratoplasty plus homologous limbal tissue and amniotic membrane transplantation was performed in the right eye. A persistent epithelial defect in the transplant necessitated a further amniotic membrane transplantation in the right eye. The most recent examination, at the age of 12, demonstrated the ocular surface to be stable, with corneal stromal scarring and superficial as well as deep vascularization (Figs 5, 6). Despite all therapeutic efforts, VA had decreased to CF in the right eye and 1/20 in the left eye.
Case 2
Figure 2. Right eye of patient 1 at first presentation. Conjunctivalization of the corneal surface.
Figure 4. Clinical appearance of patient 1. Coarse, sparse, hypopigmented hair and hearing aid for profound sensorineural hearing loss.
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This patient reported having ocular symptoms since the age of 26 years, and she had been treated for recurrent epithelial erosions and trichiatic lashes. At presentation in our clinic, the patient was 41
Messmer et al 䡠 Ocular Manifestations of KID Syndrome
Figure 5. Right eye of patient 1 at final presentation. Aggressive recurrent conjunctivalization of corneal surface and corneal stromal scarring after superficial keratectomy, limbal allograft transplantation, amniotic membrane transplantation, lateral tarsorrhaphies, and lamellar keratoplasty.
Figure 7. Right eye of patient 2 showing conjunctivalization of the corneal surface.
Case 3 and complained of photophobia and decreased vision. On examination, VA was reduced to 20/70 in both eyes. The ocular examination showed thickened lids without trichiasis in the upper lid, but completely epilated lashes in the lower lids of both eyes, mild conjunctival injection without signs of cicatrization, corneal subepithelial scarring, and superficial vascularization, as well as an epithelial defect in the left eye (Figs 7, 8). Corneal sensation was absent in both eyes. The inferior tear meniscus and Schirmer test values were within normal limits. Treatment with frequent artificial tears, a topical antibiotic, and a bandage contact lens was instituted. The epithelial defect in the left eye healed over 3 weeks. The patient history was remarkable for hyperkeratotic skin lesions since the age of 6 weeks, with subsequent development of palmoplantar and cubital hyperkeratosis (Fig 9), neurosensory hearing loss since childhood, hair loss, nail dystrophy (Fig 10), decreased ability to sweat, recurrent gingivitis with loosening of teeth, recurrent infections of the paranasal sinuses, and fistula formation in the anal region and the axilla. Molecular examination disclosed a heterozygous mutation of connexin 26 in codon 50, consistent with the diagnosis of KID syndrome.
Figure 6. Left eye of patient 1 at final presentation. Aggressive recurrent conjunctivalization of corneal surface and corneal stromal scarring after superficial keratectomy, limbal allograft transplantation, amniotic membrane transplantation, and lateral tarsorrhaphies.
This patient is the daughter of patient 2. Her fraternal twin brother is unaffected. At birth, erythematous scaly skin was evident, and the patient suffered from several episodes of cutaneous candida infections. Right-sided deafness and left-sided severe sensorineural hearing loss were noted in childhood (Fig 11). Since the age of 7 years, recurrent lower lid trichiasis has been treated by epilation. The ocular examination performed at the age of 13 revealed best-corrected VA of 20/20 in both eyes and was unremarkable except for keratotic lesions of the lids with minimal loss of lashes temporally in both eyes (Fig 12). Molecular analysis showed that she had inherited a heterozygous de novo mutation of connexin 26 in codon 50 with the disease from her mother.
Discussion KID syndrome is a congenital ectodermal disorder. In an extensive review of the literature by Caceres-Rios et al, 61 KID patients identified had cutaneous and auditory abnormalities, and 95% of patients showed ocular involvement. Vascularizing keratitis was seen in 79% of these patients.4
Figure 8. Left eye of patient 2 showing corneal stromal scarring with a persistent epithelial defect.
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Figure 9. Clinical appearance of patient 2 with palmoplantar hyperkeratosis.
Figure 11. Clinical appearance of patient 3 with hyperkeratotic skin lesions and hearing aid for severe sensorineural hearing loss.
Corneal abnormalities were noticed in 84% of 35 KID syndrome patients by Wilson et al.6 The KID acronym therefore does not always accurately define this entity, as keratitis may not be a prominent feature in the early course of the disease.4 As seen in our patients, eye disease associated with KID syndrome may be absent or mild, but may also cause severe ocular complications and visual loss. It seems that corneal involvement is not a primary inflammatory disease, as the expression “keratitis” implicates, but results from a generalized ectodermal disturbance with lid disease and limbal stem cell deficiency, with subsequent conjunctivalization, pannus formation, recurrent and persistent corneal erosions leading to ulceration, vascularization, and scarring. Keratoconjunctivitis sicca may be a prominent feature of KID syndrome.15,16 Lacrimal glands contain extensive arrays of gap junctions consisting of connexin 26 and connexin 32, and the integrity of these junctions seems to be essential for normal glandular secretory function. Loss of gap junctions or alterations in their regulation may therefore lead to keratoconjunctivitis sicca.17 Two of our patients with mild to moderate ocular disease, however, showed a normal tear meniscus, normal Schirmer test results, and an appropriate tear breakup time. Interestingly, Miteva re-
ported on a KID patient with absent lacrimal puncta and no corneal involvement.18 An intact lacrimal film may prevent the severe forms of ocular KID syndrome. We saw trichiasis of the lower lid in 2 of our patients without obvious lid deformity or conjunctival cicatrization. Cells of the outer root sheath of human hair follicles are known to be rich in connexin 26, and it seems to be required for the proper differentiation, migration, and proliferation of keratinocytes.19 Moreover, connexin 26 is known to upregulate E-cadherin, which is involved in the regulation of hair growth.13 Hyperkeratotic lesions of the lids with concurrent disturbance of the lash follicles may be responsible for this thus far unpublished ocular manifestation of KID syndrome. Molecular analysis and counseling should be considered in cases of suspected KID syndrome. De novo mutations in the gene encoding connexin 26 have been reported by several authors to be associated with KID syndrome.10 –13 A familial occurrence of KID syndrome is rare, and vertical transmission, as seen in our patients 2 and 3, confirming the autosomal-dominant pattern of inheritance of this disorder, has been reported in only 3 families7–9
Figure 10. Clinical appearance of patient 2 with palmoplantar hyperkeratosis and nail dystrophy.
Figure 12. Patient 3. Hyperkeratotic lid lesions with minimal loss of lashes temporally.
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Messmer et al 䡠 Ocular Manifestations of KID Syndrome Hexamers of connexins form gap junctions, which are tightly packed aggregations of channels directly connecting the cytoplasms of adjacent cells. They allow the transfer of ions, metabolites, and messenger molecules ⬍⬃1 kilodalton in size. Moreover, they may function as tumor suppressors.20 Connexin 26 is found at high levels within the inner ear and plays a critical role in the recycling of K⫹ necessary for the normal functioning of hair cells, thus explaining the deafness in KID syndrome.21 In the eye, animal studies suggest that certain connexins are important during retinal development22 and in electrical synapses in horizontal cells,23 in lens metabolism (connexin 46 or connexin 50 knockout mice develop early cataracts),14,24,25 and for the differentiation and healing of the corneal epithelium (connexins 43, 50, and 26).26 –30 In rabbit corneas, connexin 26 was localized on the baso-lateral cell membranes between basal epithelial cells, whereas connexin 43 was evenly distributed along the apex of basal cells, in corneal keratocytes, and in endothelial cells.29 In a wound-healing model, both connexins were expressed throughout the corneal epithelium.29 In human corneal specimens, a punctate pattern of connexin 26 labeling was observed in all cell layers of the epithelium; however, subpopulations of limbal basal epithelial cells lacked detectable fluorescence signals for connexin 26 and connexin 43 and did not develop functional gap junctions when cultured on amniotic membrane.30 Matic et al have shown previously that limbal epithelial stem cells lack distinct differentiationassociated connexin and do not form functional gap junctions.26 These laboratory data may explain the failure of homologous limbal grafting to restore epithelial integrity in our first patient. When caring for infants with KID syndrome, it is important to be aware of an increased susceptibility to bacterial, fungal, and viral infections, as well as scabies infestations.5 Infections may be limited to mucous membranes and skin, but may also progress to life-threatening systemic infections. Vigilant skin care to avoid the formation of cracks, fissures, erosions, and subsequent microbial colonialization is recommended.5 In addition to an increased danger of infections, the occurrence of squamous cell carcinoma has been reported in 11% of KID patients and may probably be considered as a manifestation of the disease.9,31 This is in line with the function of connexin 26 as a tumor suppressor. Thus, special vigilance is necessary to recognize precancerous lesions. The overall treatment of patients with KID syndrome is disappointing. Therapy for the skin manifestations of KID syndrome includes salicylic acid 2%, lactic acid 5%, urea 20%, mild soaps, various moisturizers, and vitamin A given systemically. Chronic oral ketoconazole therapy improved the ichtyosiform dermatosis and stabilized the corneal disease in a patient with KID syndrome described by Hazen et al.32 Aromatic retinoids such as acitretin are able to clear hyperkeratotic ichthyotic skin lesions in these patients, however, with little effect on the cornea or hearing.3,9,33 Isotretinoin may even exacerbate corneal neovascularization.34 Tazarotene gel, along with triamcinolone cream, is able to control associated irritation and pruritus.35 Treat-
ment of the ocular signs of KID patients has not been evaluated in a larger series. Artificial tears and antiinflammatory agents including topical corticosteroids and topical cyclosporin A have been tried, with variable success.7,15,16,35 The results of surgical procedures in KID patients have not been reported, except for unsuccessful removal of the corneal pannus6 and several failed corneal grafts.7,8,36 In this regard, our experience with multiple surgeries in our case 1 with KID-associated complete limbal stem cell deficiency was frustrating, as superficial keratectomies, limbal allografts, amniotic membrane transplantation, and lamellar keratoplasty could not prevent severe visual loss.
References 1. Burns FS. A case of generalized congenital keratoderma, with unusual involvement of the eyes, ears, and nasal and buccal mucous membranes. J Cutan Dis 1915;33:255– 60. 2. Skinner BA, Greist MC, Norins AL. The keratitis, ichthyosis, and deafness (KID) syndrome. Arch Dermatol 1981;117: 285–9. 3. Langer K, Konrad K, Wolff K. Keratitis, ichthyosis and deafness (KID)-syndrome: report of three cases and a review of the literature. Br J Dermatol 1990;122:689 –97. 4. Caceres-Rios H, Tamayo-Sanchez L, Duran-Mckinster C, et al. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology. Pediatr Dermatol 1996;13:105–13. 5. Gilliam A, Williams ML. Fatal septicemia in an infant with keratitis, ichthyosis, and deafness (KID) syndrome. Pediatr Dermatol 2002;19:232– 6. 6. Wilson GN, Squires RH Jr, Weinberg AG. Keratitis, hepatitis, ichthyosis, and deafness: report and review of KID syndrome. Am J Med Genet 1991;40:255–9. 7. Gicquel JJ, Lami MC, Catier A, et al. Limbal stem cell deficiency associated with KID syndrome, about a case [in French]. J Fr Ophtalmol 2002;25:1061– 4. 8. Nazzaro V, Blanchet-Bardon C, Lorette G, Civatte J. Familial occurrence of KID (keratitis, ichthyosis, deafness) syndrome. Case reports of a mother and daughter. J Am Acad Dermatol 1990;23:385– 8. 9. Grob JJ, Breton A, Bonafe JL, et al. Keratitis, ichthyosis, and deafness (KID) syndrome. Vertical transmission and death from multiple squamous cell carcinomas. Arch Dermatol 1987;123:777– 82. 10. Alvarez A, del Castillo I, Pera A, et al. De novo mutation in the gene encoding connexin-26 (GJB2) in a sporadic case of keratitis-ichthyosis-deafness (KID) syndrome. Am J Med Genet 2003;117A:89 –91. 11. Richard G, Rouan F, Willoughby CE, et al. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet 2002;70:1341– 8. 12. Yotsumoto S, Hashiguchi T, Chen X, et al. Novel mutations in GJB2 encoding connexin-26 in Japanese patients with keratitis-ichthyosis-deafness syndrome. Br J Dermatol 2003;148: 649 –53. 13. van Steensel MA, van Geel M, Nahuys M, et al. A novel connexin 26 mutation in a patient diagnosed with keratitisichthyosis-deafness syndrome. J Invest Dermatol 2002;118: 724 –7.
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Ophthalmology Volume 112, Number 2, February 2005 14. Simon AM, Goodenough DA. Diverse functions of vertebrate gap junctions. Trends Cell Biol 1998;8:477– 83. 15. Derse M, Wannke E, Payer H, et al. Successful topical cyclosporin. A in the therapy of progressive vascularising keratitis in keratitis-ichthyosis-deafness (KID) syndrome (Senter syndrome) [in German]. Klin Monatsbl Augenheilkd 2002;219: 383– 6. 16. Sonoda S, Uchino E, Sonoda KH, et al. Two patients with severe corneal disease in KID syndrome. Am J Ophthalmol 2004;137:181–3. 17. Walcott B, Moore LC, Birzgalis A, et al. Role of gap junctions in fluid secretion of lacrimal glands. Am J Physiol Cell Physiol 2002;282:C501–7. 18. Miteva L. Keratitis, ichthyosis, and deafness (KID) syndrome. Pediatr Dermatol 2002;19:513– 6. 19. Wiszniewski L, Limat A, Saurat JH, et al. Differential expression of connexins during stratification of human keratinocytes. J Invest Dermatol 2000;115:278 – 85. 20. Lee SW, Tomasetto C, Paul D, et al. Transcriptional downregulation of gap-junction proteins blocks junctional communication in human mammary tumor cell lines. J Cell Biol 1992;118:1213–21. 21. Kikuchi T, Kimura RS, Paul DL, et al. Gap junction systems in the mammalian cochlea. Brain Res Brain Res Rev 2000; 32:163– 6. 22. Becker DL, Bonness V, Catsicas M, Mobbs P. Changing patterns of ganglion cell coupling and connexin expression during chick retinal development. J Neurobiol 2002;52: 280 –93. 23. Pottek M, Hoppenstedt W, Janssen-Bienhold U, et al. Contribution of connexin26 to electrical feedback inhibition in the turtle retina. J Comp Neurol 2003;466:468 –77. 24. Gong X, Li E, Klier G, et al. Disruption of alpha3 connexin gene leads to proteolysis and cataractogenesis in mice. Cell 1997;91:833– 43. 25. White TW, Goodenough DA, Paul DL. Targeted ablation of connexin50 in mice results in microphthalmia and zonular pulverulent cataracts. J Cell Biol 1998;143:815–25.
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26. Matic M, Petrov IN, Chen S, et al. Stem cells of the corneal epithelium lack connexins and metabolite transfer capacity. Differentiation 1997;61:251– 60. 27. Matic M, Petrov IN, Rosenfeld T, Wolosin JM. Alterations in connexin expression and cell communication in healing corneal epithelium. Invest Ophthalmol Vis Sci 1997;38:600 –9. 28. Dong Y, Roos M, Gruijters T, et al. Differential expression of two gap junction proteins in corneal epithelium. Eur J Cell Biol 1994;64:95–100. 29. Ratkay-Traub I, Hopp B, Bor Z, et al. Regeneration of rabbit cornea following excimer laser photorefractive keratectomy: a study on gap junctions, epithelial junctions and epidermal growth factor receptor expression in correlation with cell proliferation. Exp Eye Res 2001;73:291–302. 30. Hernandez Galindo EE, Theiss C, Steuhl KP, Meller D. Gap junctional communication in microinjected human limbal and peripheral corneal epithelial cells cultured on intact amniotic membrane. Exp Eye Res 2003;76:303–14. 31. Madariaga J, Fromowitz F, Phillips M, Hoover HC Jr. Squamous cell carcinoma in congenital ichthyosis with deafness and keratitis. A case report and review of the literature. Cancer 1986;57:2026 –9. 32. Hazen PG, Walker AE, Stewart JJ, et al. Keratitis, ichthyosis, and deafness (KID) syndrome: management with chronic oral ketoconazole therapy. Int J Dermatol 1992;31:58 –9. 33. Sahoo B, Handa S, Kaur I, et al. KID syndrome: response to acitretin. J Dermatol 2002;29:499 –502. 34. Hazen PG, Carney JM, Langston RH, Meisler DM. Corneal effect of isotretinoin: possible exacerbation of corneal neovascularization in a patient with the keratitis, ichthyosis, deafness (“KID”) syndrome [letter]. J Am Acad Dermatol 1986;14: 141–2. 35. Chastain MA, Russo GG, Boh EE. KID syndrome: report of a case and support for its reclassification as an ectodermal dysplasia [letter]. Pediatr Dermatol 2000;17:244 –5. 36. Carey AB, Burke WA, Park HM. Malignant fibrous histiocytoma in keratosis, ichthyosis, and deafness syndrome [letter]. J Am Acad Dermatol 1988;19:1124 – 6.
In 1915, Burns described a patient with progressive corneal inflammatory disease, diffuse hyperkeratotic erythroderma, and neurosensory hearing loss.1 Subsequently, this syndrome was recognized as a specific congenital ectodermal disorder that affects not only the epidermis but also other ectodermal tissues such as the corneal epithelium and the inner ear. The acronym KID was coined by Skinner et al to represent the triad of keratitis, ichthyosiform erythroderma, and deafness.2 Other features of this syndrome include scarring alopecia, dystrophic nails, dental abnormalities, increased risk of developing squamous cell carcinoma, and increased susceptibility to bacterial and mycotic infections.3– 6 Most cases of KID syndrome are sporadic, but the existence of familial cases suggested a genetic etiology.7–10 Several patients with KID syndrome were shown to be heterozygous for distinct mutations in the connexin 26 – Originally received: May 11, 2004. Accepted: July 20, 2004. Manuscript no. 240359. 1 Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany. 2 Cornea Consultants International, Munich, Germany. 3 Klinische Genetik, Universitätsklinik für Kinder- und Jugendheilkunde, Paracelsus Medizinische Universität Salzburg, Salzburg, Austria. 4 Institute of Medical Biology and Human Genetics, Medical University, Innsbruck, Austria. Correspondence to E. Messmer, MD, Department of Ophthalmology, LudwigMaximilians-University, Mathildenstrasse 8, D-80336 Muenchen, Germany. © 2005 by the American Academy of Ophthalmology Published by Elsevier Inc.
coding gene GJB2.10 –13 Connexins are known to function as major gap junction proteins involved in intercellular communication in epithelial cells.14 Connexin 26, a 26kilodalton protein, consists of 226 amino acids and is encoded by the GJB2 gene, which is localized on chromosome 13.12 Corneal involvement is mainly reported as vascularizing keratitis, pannus formation, corneal neovascularization, or leucoma. Only recently, limbal stem cell deficiency was recognized as a possible major pathogenetic factor.7 Resultant ocular surface disease aggravated by severe dry eye may lead to major visual loss. We report on the ocular manifestations, the variable clinical course, and the therapeutic management of 3 KID patients.
Case Reports Case 1 At the age of 5 years, this male patient presented at our clinic with complaints of recurrent corneal epithelial defects, severe photophobia, and visual acuity (VA) of 20/200 in the right eye and 20/50 in the left eye. Ocular examination also disclosed the loss of eyebrows and eyelashes, hyperkeratotic lesions of the eyelids, a mild conjunctival injection, and corneal scarring with superficial vascularization in both eyes, reaching the optical zone in the right eye (Figs 1–3). ISSN 1549-4713/05/$–see front matter doi:10.1016/j.ophtha.2004.07.034
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Figure 1. Patient 1. Hyperkeratotic lid lesions and absence of lashes in keratitis–ichthyosis– deafness syndrome.
Figure 3. Left eye of patient 1 at first presentation. Conjunctivalization of the corneal surface.
The tear meniscus was nearly absent, and Schirmer test values were below 5 mm/5 minutes. The patient further exhibited profound sensorineural hearing loss since the age of 6 months, coarse, sparse, and hypopigmented hair, palmoplantar hyperkeratosis, dystrophic nails, and joint contractures, without mental retardation (Fig 4). Molecular analysis showed a heterozygous de novo mutation of connexin 26 in codon 50 and confirmed the diagnosis of KID syndrome. Neither topical corticosteroids nor artificial tears prevented progression of the ocular disease. Surgical procedures to improve visual function included superficial keratectomy, limbal allograft transplants from the HLA-related parents, amniotic membrane transplantation, and lateral tarsorrhaphies in both eyes under systemic immunosuppression with cyclosporin A. However, an aggressively regrowing pannus with recurrent epithelial defects rapidly limited VA again to counting fingers (CF) in the right eye and 1/50 in the left eye. Lamellar keratoplasty plus homologous limbal tissue and amniotic membrane transplantation was performed in the right eye. A persistent epithelial defect in the transplant necessitated a further amniotic membrane transplantation in the right eye. The most recent examination, at the age of 12, demonstrated the ocular surface to be stable, with corneal stromal scarring and superficial as well as deep vascularization (Figs 5, 6). Despite all therapeutic efforts, VA had decreased to CF in the right eye and 1/20 in the left eye.
Case 2
Figure 2. Right eye of patient 1 at first presentation. Conjunctivalization of the corneal surface.
Figure 4. Clinical appearance of patient 1. Coarse, sparse, hypopigmented hair and hearing aid for profound sensorineural hearing loss.
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This patient reported having ocular symptoms since the age of 26 years, and she had been treated for recurrent epithelial erosions and trichiatic lashes. At presentation in our clinic, the patient was 41
Messmer et al 䡠 Ocular Manifestations of KID Syndrome
Figure 5. Right eye of patient 1 at final presentation. Aggressive recurrent conjunctivalization of corneal surface and corneal stromal scarring after superficial keratectomy, limbal allograft transplantation, amniotic membrane transplantation, lateral tarsorrhaphies, and lamellar keratoplasty.
Figure 7. Right eye of patient 2 showing conjunctivalization of the corneal surface.
Case 3 and complained of photophobia and decreased vision. On examination, VA was reduced to 20/70 in both eyes. The ocular examination showed thickened lids without trichiasis in the upper lid, but completely epilated lashes in the lower lids of both eyes, mild conjunctival injection without signs of cicatrization, corneal subepithelial scarring, and superficial vascularization, as well as an epithelial defect in the left eye (Figs 7, 8). Corneal sensation was absent in both eyes. The inferior tear meniscus and Schirmer test values were within normal limits. Treatment with frequent artificial tears, a topical antibiotic, and a bandage contact lens was instituted. The epithelial defect in the left eye healed over 3 weeks. The patient history was remarkable for hyperkeratotic skin lesions since the age of 6 weeks, with subsequent development of palmoplantar and cubital hyperkeratosis (Fig 9), neurosensory hearing loss since childhood, hair loss, nail dystrophy (Fig 10), decreased ability to sweat, recurrent gingivitis with loosening of teeth, recurrent infections of the paranasal sinuses, and fistula formation in the anal region and the axilla. Molecular examination disclosed a heterozygous mutation of connexin 26 in codon 50, consistent with the diagnosis of KID syndrome.
Figure 6. Left eye of patient 1 at final presentation. Aggressive recurrent conjunctivalization of corneal surface and corneal stromal scarring after superficial keratectomy, limbal allograft transplantation, amniotic membrane transplantation, and lateral tarsorrhaphies.
This patient is the daughter of patient 2. Her fraternal twin brother is unaffected. At birth, erythematous scaly skin was evident, and the patient suffered from several episodes of cutaneous candida infections. Right-sided deafness and left-sided severe sensorineural hearing loss were noted in childhood (Fig 11). Since the age of 7 years, recurrent lower lid trichiasis has been treated by epilation. The ocular examination performed at the age of 13 revealed best-corrected VA of 20/20 in both eyes and was unremarkable except for keratotic lesions of the lids with minimal loss of lashes temporally in both eyes (Fig 12). Molecular analysis showed that she had inherited a heterozygous de novo mutation of connexin 26 in codon 50 with the disease from her mother.
Discussion KID syndrome is a congenital ectodermal disorder. In an extensive review of the literature by Caceres-Rios et al, 61 KID patients identified had cutaneous and auditory abnormalities, and 95% of patients showed ocular involvement. Vascularizing keratitis was seen in 79% of these patients.4
Figure 8. Left eye of patient 2 showing corneal stromal scarring with a persistent epithelial defect.
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Figure 9. Clinical appearance of patient 2 with palmoplantar hyperkeratosis.
Figure 11. Clinical appearance of patient 3 with hyperkeratotic skin lesions and hearing aid for severe sensorineural hearing loss.
Corneal abnormalities were noticed in 84% of 35 KID syndrome patients by Wilson et al.6 The KID acronym therefore does not always accurately define this entity, as keratitis may not be a prominent feature in the early course of the disease.4 As seen in our patients, eye disease associated with KID syndrome may be absent or mild, but may also cause severe ocular complications and visual loss. It seems that corneal involvement is not a primary inflammatory disease, as the expression “keratitis” implicates, but results from a generalized ectodermal disturbance with lid disease and limbal stem cell deficiency, with subsequent conjunctivalization, pannus formation, recurrent and persistent corneal erosions leading to ulceration, vascularization, and scarring. Keratoconjunctivitis sicca may be a prominent feature of KID syndrome.15,16 Lacrimal glands contain extensive arrays of gap junctions consisting of connexin 26 and connexin 32, and the integrity of these junctions seems to be essential for normal glandular secretory function. Loss of gap junctions or alterations in their regulation may therefore lead to keratoconjunctivitis sicca.17 Two of our patients with mild to moderate ocular disease, however, showed a normal tear meniscus, normal Schirmer test results, and an appropriate tear breakup time. Interestingly, Miteva re-
ported on a KID patient with absent lacrimal puncta and no corneal involvement.18 An intact lacrimal film may prevent the severe forms of ocular KID syndrome. We saw trichiasis of the lower lid in 2 of our patients without obvious lid deformity or conjunctival cicatrization. Cells of the outer root sheath of human hair follicles are known to be rich in connexin 26, and it seems to be required for the proper differentiation, migration, and proliferation of keratinocytes.19 Moreover, connexin 26 is known to upregulate E-cadherin, which is involved in the regulation of hair growth.13 Hyperkeratotic lesions of the lids with concurrent disturbance of the lash follicles may be responsible for this thus far unpublished ocular manifestation of KID syndrome. Molecular analysis and counseling should be considered in cases of suspected KID syndrome. De novo mutations in the gene encoding connexin 26 have been reported by several authors to be associated with KID syndrome.10 –13 A familial occurrence of KID syndrome is rare, and vertical transmission, as seen in our patients 2 and 3, confirming the autosomal-dominant pattern of inheritance of this disorder, has been reported in only 3 families7–9
Figure 10. Clinical appearance of patient 2 with palmoplantar hyperkeratosis and nail dystrophy.
Figure 12. Patient 3. Hyperkeratotic lid lesions with minimal loss of lashes temporally.
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Messmer et al 䡠 Ocular Manifestations of KID Syndrome Hexamers of connexins form gap junctions, which are tightly packed aggregations of channels directly connecting the cytoplasms of adjacent cells. They allow the transfer of ions, metabolites, and messenger molecules ⬍⬃1 kilodalton in size. Moreover, they may function as tumor suppressors.20 Connexin 26 is found at high levels within the inner ear and plays a critical role in the recycling of K⫹ necessary for the normal functioning of hair cells, thus explaining the deafness in KID syndrome.21 In the eye, animal studies suggest that certain connexins are important during retinal development22 and in electrical synapses in horizontal cells,23 in lens metabolism (connexin 46 or connexin 50 knockout mice develop early cataracts),14,24,25 and for the differentiation and healing of the corneal epithelium (connexins 43, 50, and 26).26 –30 In rabbit corneas, connexin 26 was localized on the baso-lateral cell membranes between basal epithelial cells, whereas connexin 43 was evenly distributed along the apex of basal cells, in corneal keratocytes, and in endothelial cells.29 In a wound-healing model, both connexins were expressed throughout the corneal epithelium.29 In human corneal specimens, a punctate pattern of connexin 26 labeling was observed in all cell layers of the epithelium; however, subpopulations of limbal basal epithelial cells lacked detectable fluorescence signals for connexin 26 and connexin 43 and did not develop functional gap junctions when cultured on amniotic membrane.30 Matic et al have shown previously that limbal epithelial stem cells lack distinct differentiationassociated connexin and do not form functional gap junctions.26 These laboratory data may explain the failure of homologous limbal grafting to restore epithelial integrity in our first patient. When caring for infants with KID syndrome, it is important to be aware of an increased susceptibility to bacterial, fungal, and viral infections, as well as scabies infestations.5 Infections may be limited to mucous membranes and skin, but may also progress to life-threatening systemic infections. Vigilant skin care to avoid the formation of cracks, fissures, erosions, and subsequent microbial colonialization is recommended.5 In addition to an increased danger of infections, the occurrence of squamous cell carcinoma has been reported in 11% of KID patients and may probably be considered as a manifestation of the disease.9,31 This is in line with the function of connexin 26 as a tumor suppressor. Thus, special vigilance is necessary to recognize precancerous lesions. The overall treatment of patients with KID syndrome is disappointing. Therapy for the skin manifestations of KID syndrome includes salicylic acid 2%, lactic acid 5%, urea 20%, mild soaps, various moisturizers, and vitamin A given systemically. Chronic oral ketoconazole therapy improved the ichtyosiform dermatosis and stabilized the corneal disease in a patient with KID syndrome described by Hazen et al.32 Aromatic retinoids such as acitretin are able to clear hyperkeratotic ichthyotic skin lesions in these patients, however, with little effect on the cornea or hearing.3,9,33 Isotretinoin may even exacerbate corneal neovascularization.34 Tazarotene gel, along with triamcinolone cream, is able to control associated irritation and pruritus.35 Treat-
ment of the ocular signs of KID patients has not been evaluated in a larger series. Artificial tears and antiinflammatory agents including topical corticosteroids and topical cyclosporin A have been tried, with variable success.7,15,16,35 The results of surgical procedures in KID patients have not been reported, except for unsuccessful removal of the corneal pannus6 and several failed corneal grafts.7,8,36 In this regard, our experience with multiple surgeries in our case 1 with KID-associated complete limbal stem cell deficiency was frustrating, as superficial keratectomies, limbal allografts, amniotic membrane transplantation, and lamellar keratoplasty could not prevent severe visual loss.
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