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Chronic keratoconjunctivitis associated with congenital dyskeratosis and erythrokeratodermia variablis
Chronic Keratoconjunctivitis Associated with Congenital Dyskeratosis and Erythrokeratodermia Variablis Two Rare Genodermatoses Amyna
Merchant,
MD, Tong-Zheng Zhao, MD,
C. Stephen Foster, MD,
FACS
Objective: The purpose of the study was to report the ocular manifestations and immunohistopathologic description of two rare forms of genodermatosis: congenital dyskeratosis (CD) and erythrokeratodermia variabilis (EKV). Oesign: Case reports. Patiicipants: Two patients with CD and EKV presenting with chronic keratoconjunctivitis were studied. Intervention: Clinical photography to show ocular manifestations and dermatologic findings was performed. Conjunctival biopsy was performed to determine the histopathology and immunohistopathology. Results: In the patient with EKV, the eyelid skin was dry, erythematous, and thickened. The lid margins showed plugging of some of the Meibomian glands, madarosis, and occasional trichiasis. The epibulbar conjunctiva was injected and had a moderate papillary reaction. Both corneas had pronounced vascularization and stromal scarring. Conjunctival biopsy results disclosed a striking number of degranulating mast cells and moderate numbers of plasma cells. lmmunohistopathology showed pronounced immunoglobulin G (IgG)-positive cells in the stroma and immunoglobulin A (IgA) positivity in the epithelium. There was scattered immunoglobulin M (IgM) and moderate C3 and C4 positivity in the stroma. In CD, the patient had keratinized lid margins, entropion formation, trichiasis, cicatrizing conjunctivitis, and symblephra formation. The cornea1 surface was keratinized, with deep and superficial vascularization. Conjunctival biopsy specimens showed pronounced epithelial keratinization and squamous metaplasia. Degranulating mast cells and eosinophils were prominent in the stroma. lmmunohistopathology showed C4 and immunoglobulin D positivity on the keratinized epithelial surface with rare foci of immunoglobulin E-positive cells. Basal epithelial cells were positive for IgA and IgG, and a large number of IgA and IgG plasma cells were present in the substantia propria. Conclusion: To the authors’ knowledge, these case reports represent the first clinical description of the ocular manifestation of EKV and the first immunohistopathologic description of the affected conjunctiva in EKV and CD, both of which should be considered in the differential diagnosis of genodermatosis associated with chronic keratoconjunctivitis. Ophthalmology 1998; 705:72867291
Ocular involvement is common in dyskeratotic dermatologic disorders with variable multiorgan involvement. Affected structures may include the lids, conjunctiva, cornea, lens, or retina. The skin involvement is the common denominator resulting in hyperkeratosis, hyperpigmentation, and/or hypopigmentation. Mucous membrane, if affected, may be hypoplastic or hyperplastic. A variety of hair, nail, bone, and dental anomaliesoccur in somedisorders, whereas hearing loss or mental retardation may be conspicuous findings in other disorders. Congenital dyskeratosis (CD) and erythrokeratodermia Originally received: December 6, 1996. Revlslon accepted: December 23, 1997. From the Immunology Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Address correspondence to C. Stephen Foster, MD, FACS, Immunology Service, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.
variabilis (EKV) are two clinically impressive but rare forms of genodermatoses.Despite extensive ectodermal involvement, reports of cornea1 manifestations of these disorders have been rare. To our knowledge, ocular manifestations of EKV have not been reported in the literature; ocular findings reported in CD include bullous conjunctivitis, madarosis, and lacrimal duct atresia resulting in epiphora,’ and cornea1 scarring and neovascularization have been reported previously in two patients with CD’ in the genetics literature in 1986.2To our knowledge, the following casesrepresent the first clinical description of the ocular manifestation of EKV and the first immunohistopathologic description of the affected conjunctiva in both EKV and CD.
Case Reports Case 1. An 18-year-old white woman was first evaluated at our service in September 1984. She had a 17-year history of
Merchant et al * Chronic
Keratoconjunctivitis
photophobia, ocular irritation and chronic conjunctivitis, and keratitis in both eyes. Her vision had deteriorated progressively, secondary to bilateral cornea1 scarring and neovascularization. A lamellar keratoplasty in the right eye, performed in August 1983, had failed, with subsequent scarring and neovascularization. Her dermatologic history included dermatitis dating from birth, with erythematous hyperkeratosis involving most of her body surface area. The dermatologist who diagnosed the patient with EKV was of the opinion that she exhibited the classic skin features of EKV, with circumscribed erythematous plaques initially on the extensor surfaces, but with rapid progression to involve most of the skin, with rapid (6- to 4%hour) changes in color and appearance, and an apparent association with environmental temperature changes. Abdominal skin biopsy results disclosed slight epidermal hyperplasia with papillomatosis, marked hyperkeratosis, and ichthyosis-like changes that were consistent with histopathologic findings of EKV.’ The patient also suffered recurrent infections at various sites, including skin carbuncles, otitis, and pneumonia as a child. There was no history of atopy or eosinophilia, and the family history, including that of three siblings, was noncontributory. At the time of the patient’s first evaluation, her visual acuity was counting fingers at 6 inches in her right eye and counting fingers at 4 inches in her left eye. The skin of the eyelids was dry, erythematous, and thickened. Some of the Meibomian glands were plugged with keratin, and the lashes were reduced in number, with occasional trichitic lashes (Fig 1). There was a 2+ papillary reaction and 2+ injection of the superior epibulbar conjunctiva. There was no subepithelial fibrosis, fornix foreshortening, or symblephra formation. Both corneas showed pronounced vascularization and stromal scarring (Fig 1). A fine patina of inflammatory cells in advance of the leading leash of neovascular fronds was observed in the stroma of the left cornea. The anterior chambers were deep and quiet, and the rest of the examination was unremarkable. The cornea1 sensation was normal in both eyes. Schirmer testing after anesthetic showed 16 and 19 mm of wetting for the right eye and left eye, respectively. Tear osmolarity and tear evaporation rates were normal. Clinical examination of the skin showed erythematous, hyperkeratotic changes on the face (Fig 2), neck, hands, legs, and torso. Laboratory investigation, including a complete blood count with differential and a urine analysis, was normal. Results from the following tests were negative: fluorescent treponemal antibody absorption, Veneral Disease Research Laboratory, antinuclear antibody, rheumatoid factor, and antineutrophil cytoplasmic antibodies. The erythrocyte sedimentation rate was elevated to 128 mm/hour. Quantitative serum immunoglobulin A, E, G, and M levels, cryoglobulins, and serum complement and C4 levels were all within normal limits. Bulbar conjunctival biopsy results from the left eye disclosed a striking number of goblet cells in the epithelium. There were significant numbers of mast cells in the substantia propria, many of which were degranulating (Fig 3). Moderate numbers of plasma cells also were present in the stroma. Immunofluorescence microscopy showed positive epithelial and stromal staining for both immunoglobulin G (IgG) and immunoglobulin A (IgA). The IgG was more pronounced in the stroma and IgA in the epithelium. The basement membrane zone was negative for both immunoglobulins. Immunoglobulins D and E were not detected in any area, and there was some scattered staining for immunoglobulin M in the stroma. Both C3 and C4 showed 2+ stromal positivity. Albumin and fibrin control specimens were negative. Case 2. A 5%year-old man from Puerto Rico with a longstanding history of CD was referred to our service for evaluation
and CD and EKV
of chronic cicatrizing keratoconjunctivitis in June 1995. The patient had had problems with his eyes since 5 years of age. His symptoms included epiphora, photosensitivity, and chronic irritation in both eyes. Recently, progressively decreasing vision had developed, which was worse in the left eye. His nonocular history was remarkable for reticulate pigmentation of the skin, dystrophic nails, leukoplakia, alopecia, dental problems resulting in tooth loss, and thrombocytopenia. His family history was significant for an autosomal-dominant pattern of CD with variable penetration. The patient’s mother had a mild form of the disease with limited skin involvement, and his two brothers had significant skin pigmentation and nail dystrophy. One of the brothers also had a history of tongue cancer and epiphora. The patient’s two sisters were both healthy. The patient had one son who did not have any manifestation of the disease, but two of his three daughters had classic skin and nail findings of CD, and the other daughter had subtle skin findings. One of the patient’s grandsons, who was 17 years old, had early pigmentary skin changes and significant thrombocytopenia. At the time of presentation, the patient’s visual acuity was 20/60 in the right eye and counting fingers at 3 feet in the left eye. He had significant keratinization of the lid margins, entropion, and trichiasis that was more severe on the left side. There was significant cicatrizing conjunctivitis with fornix foreshortening, also greater on the left side (Fig 4). The cornea1 surface was keratinized with deep and superficial vascularization covering the entire left cornea1 surface (Fig 4); neovascularization and keratinization were limited to the periphery in the right cornea. The cornea1 sensation was decreased on the left side relative to the right. The anterior chambers were deep and quiet, and the intraocular pressure was 16 and 12 mmHg in the right and left eyes, respectively. Nonocular examination results showed reticulate skin pigmentation of the face (Fig 5), legs, hypoplastic nails (Fig 6), leukoplakia, alopecia, and tooth loss. A diagnostic conjunctival biopsy specimen obtained from the left eye showed pronounced keratinization and squamous metaplasia of the epithelium. A large amount of mucin was present in the superficial epithelium despite the reduced density of goblet cells on periodic acidSchiff staining. There was a striking number of eosinophils in the stroma and areas of focal chronic inflammation (Fig 7). Also present was a significant population of mast cells, many of which were degranulating (Fig 8). Immunofluorescence microscopy showed a very large number of IgA and IgG plasma cells in the substantia propria and IgA and IgG positivity at the basal lamella of the basal epithelial cells (Figs 9A, B). The C4 and immunoglobulin D positivity was seen on the keratinized surface of the epithelium (Figs lOA, B) with rare foci of brightly positive cells for immunoglobulin E. Ultrastructural studies showed a keratinized squamous epithelium. Occasional condensation of the tonofibrils was seen near the surface (Fig 1lA). Keratohyaline granules were dispersed throughout the anterior region of the epithelium, and aggregates of tonofilaments were dispersed through the cytoplasm (Fig 1lB). There was considerable flattening of the wing cells with widened intercellular spaces (Fig 12). Occasional lymphocytes were present in these spaces. The basal cells had lost their polygonal shape and were separated from the stroma by an intact basement membrane. The stroma consisted of tibroblasts, numerous blood vessels, an occasional mast cell, and loose and dense connective tissue (Fig 13). No goblet cells were seen.
Discussion To our knowledge, the cases reported herein represent the first clinical description of the ocular manifestation of
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Figure 1. Case 1 Dry, themat ous, and thtckened hd skm wtth madarosrs. Mc mian glands are clogged wit1 keratm. Cornea shows pro nounced vascularization and stromal scarrme. Figure 2. Case 1. Factal skm IS erythematoua and hyperkeratot1c.
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Figure 3. Case 1. Photomrcrograph of bulbar conjuncttval biopsy specimen shows striking number of degranulating mast cells m substantta propria (smm, Gtemsa; ortgtnal magnification, X20). Figure 4. Case 2. Crcatrtzmg conjunctlvitrs wtth formx foreshortenmg and symblephra formatron. Cornea1 surtace shows pronounced keratmrzatton and vascularizatton. Figure 5. Case 2. Patient’s facral skm shows classrc retrculate prgmentat*on seen m congemtal dyskeratosts. Figure 6. Case 2. Patient’s trophtc nads.
dys-
Figure 7. Case 2 Photomicrograph of bulbar conjuncttva showmg squamous metaplasta of the eptrheltum, pronounced keratmtzatron, and mucm m superior eprthelium. Focal chronic inflammation (stain, hematoxyhneostn; ortgtnal magnification, X20). Figure 8. Caac 2. Photomtcrograph of bulbar conjunctiva showing degranulating mast cells m the substantia proprta.
1288
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ulm G plasma cells m the 1 lamella of the qxthelmm m the auhstantla propna. A, case 2. Photomlf hulhar conlunctlva xnplement factor-4Ils ,n the kcrxmlzcd mm. B, cabe 2. Photomlh of hulhar conjuncnva owmg ~mmunoglohulm D10.
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Figure 12. Electron micro. graph from the middle regron OI coquncuval cplthclmm ahow! flattened wq cclla with W& mtercellular apaces (X) m hctween them. A large condensa~ non of tonofilaments (CTF) scattered lymphocyte
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Figure 11. A, Electron m~cm. graph (EM) from supcrfic~al ep ithelial layer of conlunctlv; showmg smface keratuuzatlon Surface cells have lost their cell structure. Aggregates of tonofi. laments (TF), keratohy&nc granules (KH). B, EM from the cplthehum below the surface layer with TF and KH dlaperacc throughout the cytoplasm; M = mmxhondna.
13. Electron micro graph from conlunctlval atrom shows collagen fiber\ (CO) blood vessel (RV), fihrohlas (FB); MC = mast cell.
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1289
t
Ophthalmology
Volume 105, Number 7, July 1998
Table 1. Differential Diagnosis of Congenital and Inherited Dermatologic Conditions Associated with Ocular Surface Disease Ectodermal dysplasia Ichthyosls simplex Ichthyosls vulgaris Rothmund’s syndrome Werner’s syndrome Keratltts, Ichthyosls, and deafness (KID) Keratosls palmaris et plantaris Keratosls follicularis Congenital ichthyosiform erythroderma Pitynasis rubra pilaris Pachyonychia congenita
syndrome
EKV and the first immunohistopathologic description of the affected conjunctiva in both EKV and CD. Erythrokeratodermia variabilis was first reported by Rille4 in 1922 and later described by Mendes da Costa in 1925.5 The diseaseonset is at birth or during the first year of life with equal gender predilection. The autosomal-dominant form is the most common mode of inheritance, but recessive transmission also has been described. The heredity in our patient with EKV is unknown, because she is the first in her family to be affected. The clinical course is lifelong, and the findings in the skin are characterized by two types of skin lesions: (1) symmetrical transient erythematous areas, often polycyclic or anular, that last from hours to a few days, occasionally weeks; and (2) darkly erythematous, well-demarcated hyperkeratotic plaques. These are relatively fixed and can involve any part of the body, but the face and extensor surface of the extremities and buttocks commonly are involved. Keratoderma of palms and soles also may occur.6*7There are no systemic findings, but several variants with specific central nervous system findings such as gait ataxia, dysarthria, nystagmus, and deafnesshave been described in the European literature.7 The histologic findings in the skin are not pathognomonic, but the presenceof marked laminated ichthyosiform orthohyperkeratosis, a granular zone of two to three layers, irregular acanthosis, and papillomatosis are characteristic features in the skin.3 The pathogenesisis unknown. It was postulated that EKV is a systemic ectodermal vascular dysplasia in which the abnormal vascular dilation leads to abnormal keratinization by some unknown mechanisms,7but this remains unproved. Gewirtzman et al8 have described linear deposits of IgG in the lower portion of the stratum corneum in the skin, either causedby a primary or secondary event to increase vascular permeability or inflammation. There is no specific therapy for EKV, but several investigators have tried retinoids and steroids with variable results,’ whereas others have reported oral retinoids to be highly effective in EKV.” Etretinate, 0.5 to 1.0 mg/kg per day, is the usual doseused. In addition, 5% lactic acid in hydrophilic ointment may provide skin clearing for several weeks.’ The scarring and neovascularization of the cornea in our patient probably was secondary to the chronic papillary conjunctivitis. The immunohistopathologic demonstration of IgA and IgG deposition in the stroma and basal epithelial cells of the affected conjunctiva of patients with
1290
EKV and CD, C3 and C4 components of the complement system in the stroma of the patient with CD, and C4 deposition on the epithelial surface of the patient with EKV suggestsa possible role for an immune mechanism in the pathogenesisof these disorders. Others previously have shown IgG deposition in the stratum corneum of the skin of patients with EKV, but it is not known whether this is the result of a primary event or an aftermath of the inflammation. Congenital dyskeratosis, also known as Zinsser-Cole-Engman syndrome, is another rare inherited diseasewith a wide spectrum of diverse clinical findings. Congenital dyskeratosis was first described by Zinsser in 1906.” The characteristic clinical findings include reticulate skin pigmentation, hypoplastic or absent nails, and mucosal leukoplakia, which is premalignant and often leads to squamous cell carcinoma. Bone marrow failure occurs in 50% of patients, and there is a predisposition to malignancy.” Congenital abnormalities of the skeletal system leading to a small stature and stricture formation in the esophagus,anus, urethra, and ureters are common. Dental abnormalities also are common, with early tooth loss, and hair tends to be sparse.Ocular findings include bullous conjunctivitis, madarosis, and lacrimal duct atresia, resulting in epiphora. One report described cornea1 scarring and neovascularization in two patients with CD.’ The onset occurs most frequently in the middle of the first decadewith skin pigmentation and nail findings being the first manifestations. Leukoplakia and epiphora appear later, and by the mid-teens, serious bone marrow failure and malignancy may develop. The male-to-female ratio for reported casesof this disorder is 8:1.13The X-linked recessive trait is the most common pattern of inheritance, and the gene has been assigned to the Xq28 locus.’ Autosomal-recessive and autosomal-dominant modes of inheritance also have been described. The clinical phenotype appears to vary with the mode of inheritance. The X-linked recessive and autosomal-recessivepatients are affected more severely than are the patients with autosomal-dominant modesof inheritance who have a mild variant of the syndrome.” The primary defect responsible for the diseaseremains unknown. Studies on CD fibroblasts have shown abnormalities in the morphology, increased growth rate, as well as numerous breaks and unbalanced chromosomal rearrangement.14Results of a few immunologic studies have shown inconsistent findings: raised and depressedimmunoglobulin levels, a reduced responseof lymphocytes to mitogens, impaired delayed skin hypersensitivity reactions, and reduced T-cell numbers. Thymic aplasia has been described in three patients with CD.‘2,‘5 The life expectancy of patients with CD may be decreased becauseof aplastic anemia or malignancy. Bone marrow transplants may be helpful in some cases.16Retinoid usehas been reported to causeregression of mucosal plaques.‘3 Ocular involvement can affect the conjunctiva, cornea, lens, and retina and has been described in many dyskeratotic disorders with variable multiorgan involvement. The keratopathy in our patient with CD may have occurred as a consequenceof the chronic cicatrizing conjunctivitis and lid margin keratinization, as well as a mucin-deficient
Merchant et al * Chronic
Keratoconjunctivitis
dry eye, as evidenced by the lack of conjunctival goblet cells. A differential diagnosis of dermatologic conditions resulting in cornea1 involvement’7 is listed in Table 1. We suggest that CD and EKV should also be considered in the differential diagnosis of patients presenting with chronic keratoconjunctivitis with relevant associated dermatologic or systemic findings or both. These case reports underscore the value of the dermatologic history and a careful examination of the skin and mucous membranes as essential parts of the work-up of patients presenting with chronic ocular disease of obscure cause. Tissue biopsy in such cases may prove valuable in determining a definitive pathologic diagnosis. A trial of treatment with retinoids and steroids early in the disease course may even be beneficial in preventing visually debilitating cornea1 changes associated with these disorders. In addition, given the striking number of mast cells present in histologic sections, topical mast-cell stabilizers may prove beneficial.
References 1. Bruanauer SR. Zur Sympatomatologie und histologie der kongenitalen dyskeratosen. Dyskeratosen. Dermat Ztschr Berl 1924;6-26. 2. Connor JM, Gatherer D, Gray FC, et al. Assignment of the gene for dyskeratosis congenita to Xq28. Hum Genet 1986;72:348-51. 3. Vandersteen PR, Muller SA. Erythrokeratodermia variabilis: an enzyme histochemical and ultrastructural study. Arch Dermatol 1971; 103:362-70. 4. Rille F. Krankenvorstellungen. Zbl Haut Geschlechtskr 1922-3;7:161.
and CD and EKV
5. Cram DL. Erythrokeratoderma variabilis and variable circinate erythrokeratodermas. Arch Derm 1970; 101:68-73. 6. Brown J, Kierland RR. Erythrokeratodermia variabilis. Report of three cases and review of the literature. Arch Dermato1 1966;93:194-201. 7. Coles RB. Erythemato-keratotic phacomatosis. Br J Dermato1 1954;66:225-6. 8. Gewirtzman GB, Winkler NW, Dobson RL. Erythrokeratoderma variabilis. A family study. Arch Dermatol 1978; 114:259-61. 9. Luy TJ, Jacobs AH, Nickoloff BJ. A child with erythematous and hyperkeratotic patches. Erythrokeratodermia variabilis. Arch Dermatol 1988; 124:1271-2. 10. Marks R, Finlay AY, Holt PJA. Severe disorders of keratinization: effects of treatment with Tigason (etretinate). Br J Dermatol 1981; 104:667-73. Il. Zinsser F. Atrophia cutis reticularis cum pigmentione, dystrophia unguium, et leukoplakia oris. Ikonogr Dermatol (Hyoto) 1906;5:219-23. 12. Sirinavin C, Trowbridge AA. Dyskeratosis congenita: clinical features and genetic aspects. Report of a family and review of the literature. J Med Genet 1975; 12:339-54. 13. Novice FM, Collison DW, Burgdorf WHC, Esterly NB. Handbook of Genetic Skin Disorders. Philadelphia: W.B. Saunders Co., 1994; 125-7. 14. Dokal I, Luzzatto L. Dyskeratosis congenita is a chromosomal instability disorder. Leuk Lymphoma 1994; 15:1-7. 15. Wiedemann HP, McGuire J, Dwyer JM, et al. Progressive immune failure in dyskeratosis congenita. Report of an adult in whom Pneumocystis carinii and fatal disseminated candidiasis developed. Arch Intern Med 1984; 144:397-9. 16. Phillips RJ, Judge M, Webb D, Harper JI. Dyskeratosis congenita: delay in diagnosis and successful treatment of pancytopenia by bone marrow transplantation. Br J Dermato1 1992; 127:278-80. 17. Wilson FM II, Grayson M, Pieroni D. Cornea1 changes in ectodermal dysplasia. Case report, histopathology, and differential diagnosis. Am J Ophthalmol 1973;75: 17-27.
1291
Merchant,
MD, Tong-Zheng Zhao, MD,
C. Stephen Foster, MD,
FACS
Objective: The purpose of the study was to report the ocular manifestations and immunohistopathologic description of two rare forms of genodermatosis: congenital dyskeratosis (CD) and erythrokeratodermia variabilis (EKV). Oesign: Case reports. Patiicipants: Two patients with CD and EKV presenting with chronic keratoconjunctivitis were studied. Intervention: Clinical photography to show ocular manifestations and dermatologic findings was performed. Conjunctival biopsy was performed to determine the histopathology and immunohistopathology. Results: In the patient with EKV, the eyelid skin was dry, erythematous, and thickened. The lid margins showed plugging of some of the Meibomian glands, madarosis, and occasional trichiasis. The epibulbar conjunctiva was injected and had a moderate papillary reaction. Both corneas had pronounced vascularization and stromal scarring. Conjunctival biopsy results disclosed a striking number of degranulating mast cells and moderate numbers of plasma cells. lmmunohistopathology showed pronounced immunoglobulin G (IgG)-positive cells in the stroma and immunoglobulin A (IgA) positivity in the epithelium. There was scattered immunoglobulin M (IgM) and moderate C3 and C4 positivity in the stroma. In CD, the patient had keratinized lid margins, entropion formation, trichiasis, cicatrizing conjunctivitis, and symblephra formation. The cornea1 surface was keratinized, with deep and superficial vascularization. Conjunctival biopsy specimens showed pronounced epithelial keratinization and squamous metaplasia. Degranulating mast cells and eosinophils were prominent in the stroma. lmmunohistopathology showed C4 and immunoglobulin D positivity on the keratinized epithelial surface with rare foci of immunoglobulin E-positive cells. Basal epithelial cells were positive for IgA and IgG, and a large number of IgA and IgG plasma cells were present in the substantia propria. Conclusion: To the authors’ knowledge, these case reports represent the first clinical description of the ocular manifestation of EKV and the first immunohistopathologic description of the affected conjunctiva in EKV and CD, both of which should be considered in the differential diagnosis of genodermatosis associated with chronic keratoconjunctivitis. Ophthalmology 1998; 705:72867291
Ocular involvement is common in dyskeratotic dermatologic disorders with variable multiorgan involvement. Affected structures may include the lids, conjunctiva, cornea, lens, or retina. The skin involvement is the common denominator resulting in hyperkeratosis, hyperpigmentation, and/or hypopigmentation. Mucous membrane, if affected, may be hypoplastic or hyperplastic. A variety of hair, nail, bone, and dental anomaliesoccur in somedisorders, whereas hearing loss or mental retardation may be conspicuous findings in other disorders. Congenital dyskeratosis (CD) and erythrokeratodermia Originally received: December 6, 1996. Revlslon accepted: December 23, 1997. From the Immunology Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Address correspondence to C. Stephen Foster, MD, FACS, Immunology Service, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.
variabilis (EKV) are two clinically impressive but rare forms of genodermatoses.Despite extensive ectodermal involvement, reports of cornea1 manifestations of these disorders have been rare. To our knowledge, ocular manifestations of EKV have not been reported in the literature; ocular findings reported in CD include bullous conjunctivitis, madarosis, and lacrimal duct atresia resulting in epiphora,’ and cornea1 scarring and neovascularization have been reported previously in two patients with CD’ in the genetics literature in 1986.2To our knowledge, the following casesrepresent the first clinical description of the ocular manifestation of EKV and the first immunohistopathologic description of the affected conjunctiva in both EKV and CD.
Case Reports Case 1. An 18-year-old white woman was first evaluated at our service in September 1984. She had a 17-year history of
Merchant et al * Chronic
Keratoconjunctivitis
photophobia, ocular irritation and chronic conjunctivitis, and keratitis in both eyes. Her vision had deteriorated progressively, secondary to bilateral cornea1 scarring and neovascularization. A lamellar keratoplasty in the right eye, performed in August 1983, had failed, with subsequent scarring and neovascularization. Her dermatologic history included dermatitis dating from birth, with erythematous hyperkeratosis involving most of her body surface area. The dermatologist who diagnosed the patient with EKV was of the opinion that she exhibited the classic skin features of EKV, with circumscribed erythematous plaques initially on the extensor surfaces, but with rapid progression to involve most of the skin, with rapid (6- to 4%hour) changes in color and appearance, and an apparent association with environmental temperature changes. Abdominal skin biopsy results disclosed slight epidermal hyperplasia with papillomatosis, marked hyperkeratosis, and ichthyosis-like changes that were consistent with histopathologic findings of EKV.’ The patient also suffered recurrent infections at various sites, including skin carbuncles, otitis, and pneumonia as a child. There was no history of atopy or eosinophilia, and the family history, including that of three siblings, was noncontributory. At the time of the patient’s first evaluation, her visual acuity was counting fingers at 6 inches in her right eye and counting fingers at 4 inches in her left eye. The skin of the eyelids was dry, erythematous, and thickened. Some of the Meibomian glands were plugged with keratin, and the lashes were reduced in number, with occasional trichitic lashes (Fig 1). There was a 2+ papillary reaction and 2+ injection of the superior epibulbar conjunctiva. There was no subepithelial fibrosis, fornix foreshortening, or symblephra formation. Both corneas showed pronounced vascularization and stromal scarring (Fig 1). A fine patina of inflammatory cells in advance of the leading leash of neovascular fronds was observed in the stroma of the left cornea. The anterior chambers were deep and quiet, and the rest of the examination was unremarkable. The cornea1 sensation was normal in both eyes. Schirmer testing after anesthetic showed 16 and 19 mm of wetting for the right eye and left eye, respectively. Tear osmolarity and tear evaporation rates were normal. Clinical examination of the skin showed erythematous, hyperkeratotic changes on the face (Fig 2), neck, hands, legs, and torso. Laboratory investigation, including a complete blood count with differential and a urine analysis, was normal. Results from the following tests were negative: fluorescent treponemal antibody absorption, Veneral Disease Research Laboratory, antinuclear antibody, rheumatoid factor, and antineutrophil cytoplasmic antibodies. The erythrocyte sedimentation rate was elevated to 128 mm/hour. Quantitative serum immunoglobulin A, E, G, and M levels, cryoglobulins, and serum complement and C4 levels were all within normal limits. Bulbar conjunctival biopsy results from the left eye disclosed a striking number of goblet cells in the epithelium. There were significant numbers of mast cells in the substantia propria, many of which were degranulating (Fig 3). Moderate numbers of plasma cells also were present in the stroma. Immunofluorescence microscopy showed positive epithelial and stromal staining for both immunoglobulin G (IgG) and immunoglobulin A (IgA). The IgG was more pronounced in the stroma and IgA in the epithelium. The basement membrane zone was negative for both immunoglobulins. Immunoglobulins D and E were not detected in any area, and there was some scattered staining for immunoglobulin M in the stroma. Both C3 and C4 showed 2+ stromal positivity. Albumin and fibrin control specimens were negative. Case 2. A 5%year-old man from Puerto Rico with a longstanding history of CD was referred to our service for evaluation
and CD and EKV
of chronic cicatrizing keratoconjunctivitis in June 1995. The patient had had problems with his eyes since 5 years of age. His symptoms included epiphora, photosensitivity, and chronic irritation in both eyes. Recently, progressively decreasing vision had developed, which was worse in the left eye. His nonocular history was remarkable for reticulate pigmentation of the skin, dystrophic nails, leukoplakia, alopecia, dental problems resulting in tooth loss, and thrombocytopenia. His family history was significant for an autosomal-dominant pattern of CD with variable penetration. The patient’s mother had a mild form of the disease with limited skin involvement, and his two brothers had significant skin pigmentation and nail dystrophy. One of the brothers also had a history of tongue cancer and epiphora. The patient’s two sisters were both healthy. The patient had one son who did not have any manifestation of the disease, but two of his three daughters had classic skin and nail findings of CD, and the other daughter had subtle skin findings. One of the patient’s grandsons, who was 17 years old, had early pigmentary skin changes and significant thrombocytopenia. At the time of presentation, the patient’s visual acuity was 20/60 in the right eye and counting fingers at 3 feet in the left eye. He had significant keratinization of the lid margins, entropion, and trichiasis that was more severe on the left side. There was significant cicatrizing conjunctivitis with fornix foreshortening, also greater on the left side (Fig 4). The cornea1 surface was keratinized with deep and superficial vascularization covering the entire left cornea1 surface (Fig 4); neovascularization and keratinization were limited to the periphery in the right cornea. The cornea1 sensation was decreased on the left side relative to the right. The anterior chambers were deep and quiet, and the intraocular pressure was 16 and 12 mmHg in the right and left eyes, respectively. Nonocular examination results showed reticulate skin pigmentation of the face (Fig 5), legs, hypoplastic nails (Fig 6), leukoplakia, alopecia, and tooth loss. A diagnostic conjunctival biopsy specimen obtained from the left eye showed pronounced keratinization and squamous metaplasia of the epithelium. A large amount of mucin was present in the superficial epithelium despite the reduced density of goblet cells on periodic acidSchiff staining. There was a striking number of eosinophils in the stroma and areas of focal chronic inflammation (Fig 7). Also present was a significant population of mast cells, many of which were degranulating (Fig 8). Immunofluorescence microscopy showed a very large number of IgA and IgG plasma cells in the substantia propria and IgA and IgG positivity at the basal lamella of the basal epithelial cells (Figs 9A, B). The C4 and immunoglobulin D positivity was seen on the keratinized surface of the epithelium (Figs lOA, B) with rare foci of brightly positive cells for immunoglobulin E. Ultrastructural studies showed a keratinized squamous epithelium. Occasional condensation of the tonofibrils was seen near the surface (Fig 1lA). Keratohyaline granules were dispersed throughout the anterior region of the epithelium, and aggregates of tonofilaments were dispersed through the cytoplasm (Fig 1lB). There was considerable flattening of the wing cells with widened intercellular spaces (Fig 12). Occasional lymphocytes were present in these spaces. The basal cells had lost their polygonal shape and were separated from the stroma by an intact basement membrane. The stroma consisted of tibroblasts, numerous blood vessels, an occasional mast cell, and loose and dense connective tissue (Fig 13). No goblet cells were seen.
Discussion To our knowledge, the cases reported herein represent the first clinical description of the ocular manifestation of
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Figure 1. Case 1 Dry, themat ous, and thtckened hd skm wtth madarosrs. Mc mian glands are clogged wit1 keratm. Cornea shows pro nounced vascularization and stromal scarrme. Figure 2. Case 1. Factal skm IS erythematoua and hyperkeratot1c.
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Figure 3. Case 1. Photomrcrograph of bulbar conjuncttval biopsy specimen shows striking number of degranulating mast cells m substantta propria (smm, Gtemsa; ortgtnal magnification, X20). Figure 4. Case 2. Crcatrtzmg conjunctlvitrs wtth formx foreshortenmg and symblephra formatron. Cornea1 surtace shows pronounced keratmrzatton and vascularizatton. Figure 5. Case 2. Patient’s facral skm shows classrc retrculate prgmentat*on seen m congemtal dyskeratosts. Figure 6. Case 2. Patient’s trophtc nads.
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Figure 7. Case 2 Photomicrograph of bulbar conjuncttva showmg squamous metaplasta of the eptrheltum, pronounced keratmtzatron, and mucm m superior eprthelium. Focal chronic inflammation (stain, hematoxyhneostn; ortgtnal magnification, X20). Figure 8. Caac 2. Photomtcrograph of bulbar conjunctiva showing degranulating mast cells m the substantia proprta.
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Figure 11. A, Electron m~cm. graph (EM) from supcrfic~al ep ithelial layer of conlunctlv; showmg smface keratuuzatlon Surface cells have lost their cell structure. Aggregates of tonofi. laments (TF), keratohy&nc granules (KH). B, EM from the cplthehum below the surface layer with TF and KH dlaperacc throughout the cytoplasm; M = mmxhondna.
13. Electron micro graph from conlunctlval atrom shows collagen fiber\ (CO) blood vessel (RV), fihrohlas (FB); MC = mast cell.
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t
Ophthalmology
Volume 105, Number 7, July 1998
Table 1. Differential Diagnosis of Congenital and Inherited Dermatologic Conditions Associated with Ocular Surface Disease Ectodermal dysplasia Ichthyosls simplex Ichthyosls vulgaris Rothmund’s syndrome Werner’s syndrome Keratltts, Ichthyosls, and deafness (KID) Keratosls palmaris et plantaris Keratosls follicularis Congenital ichthyosiform erythroderma Pitynasis rubra pilaris Pachyonychia congenita
syndrome
EKV and the first immunohistopathologic description of the affected conjunctiva in both EKV and CD. Erythrokeratodermia variabilis was first reported by Rille4 in 1922 and later described by Mendes da Costa in 1925.5 The diseaseonset is at birth or during the first year of life with equal gender predilection. The autosomal-dominant form is the most common mode of inheritance, but recessive transmission also has been described. The heredity in our patient with EKV is unknown, because she is the first in her family to be affected. The clinical course is lifelong, and the findings in the skin are characterized by two types of skin lesions: (1) symmetrical transient erythematous areas, often polycyclic or anular, that last from hours to a few days, occasionally weeks; and (2) darkly erythematous, well-demarcated hyperkeratotic plaques. These are relatively fixed and can involve any part of the body, but the face and extensor surface of the extremities and buttocks commonly are involved. Keratoderma of palms and soles also may occur.6*7There are no systemic findings, but several variants with specific central nervous system findings such as gait ataxia, dysarthria, nystagmus, and deafnesshave been described in the European literature.7 The histologic findings in the skin are not pathognomonic, but the presenceof marked laminated ichthyosiform orthohyperkeratosis, a granular zone of two to three layers, irregular acanthosis, and papillomatosis are characteristic features in the skin.3 The pathogenesisis unknown. It was postulated that EKV is a systemic ectodermal vascular dysplasia in which the abnormal vascular dilation leads to abnormal keratinization by some unknown mechanisms,7but this remains unproved. Gewirtzman et al8 have described linear deposits of IgG in the lower portion of the stratum corneum in the skin, either causedby a primary or secondary event to increase vascular permeability or inflammation. There is no specific therapy for EKV, but several investigators have tried retinoids and steroids with variable results,’ whereas others have reported oral retinoids to be highly effective in EKV.” Etretinate, 0.5 to 1.0 mg/kg per day, is the usual doseused. In addition, 5% lactic acid in hydrophilic ointment may provide skin clearing for several weeks.’ The scarring and neovascularization of the cornea in our patient probably was secondary to the chronic papillary conjunctivitis. The immunohistopathologic demonstration of IgA and IgG deposition in the stroma and basal epithelial cells of the affected conjunctiva of patients with
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EKV and CD, C3 and C4 components of the complement system in the stroma of the patient with CD, and C4 deposition on the epithelial surface of the patient with EKV suggestsa possible role for an immune mechanism in the pathogenesisof these disorders. Others previously have shown IgG deposition in the stratum corneum of the skin of patients with EKV, but it is not known whether this is the result of a primary event or an aftermath of the inflammation. Congenital dyskeratosis, also known as Zinsser-Cole-Engman syndrome, is another rare inherited diseasewith a wide spectrum of diverse clinical findings. Congenital dyskeratosis was first described by Zinsser in 1906.” The characteristic clinical findings include reticulate skin pigmentation, hypoplastic or absent nails, and mucosal leukoplakia, which is premalignant and often leads to squamous cell carcinoma. Bone marrow failure occurs in 50% of patients, and there is a predisposition to malignancy.” Congenital abnormalities of the skeletal system leading to a small stature and stricture formation in the esophagus,anus, urethra, and ureters are common. Dental abnormalities also are common, with early tooth loss, and hair tends to be sparse.Ocular findings include bullous conjunctivitis, madarosis, and lacrimal duct atresia, resulting in epiphora. One report described cornea1 scarring and neovascularization in two patients with CD.’ The onset occurs most frequently in the middle of the first decadewith skin pigmentation and nail findings being the first manifestations. Leukoplakia and epiphora appear later, and by the mid-teens, serious bone marrow failure and malignancy may develop. The male-to-female ratio for reported casesof this disorder is 8:1.13The X-linked recessive trait is the most common pattern of inheritance, and the gene has been assigned to the Xq28 locus.’ Autosomal-recessive and autosomal-dominant modes of inheritance also have been described. The clinical phenotype appears to vary with the mode of inheritance. The X-linked recessive and autosomal-recessivepatients are affected more severely than are the patients with autosomal-dominant modesof inheritance who have a mild variant of the syndrome.” The primary defect responsible for the diseaseremains unknown. Studies on CD fibroblasts have shown abnormalities in the morphology, increased growth rate, as well as numerous breaks and unbalanced chromosomal rearrangement.14Results of a few immunologic studies have shown inconsistent findings: raised and depressedimmunoglobulin levels, a reduced responseof lymphocytes to mitogens, impaired delayed skin hypersensitivity reactions, and reduced T-cell numbers. Thymic aplasia has been described in three patients with CD.‘2,‘5 The life expectancy of patients with CD may be decreased becauseof aplastic anemia or malignancy. Bone marrow transplants may be helpful in some cases.16Retinoid usehas been reported to causeregression of mucosal plaques.‘3 Ocular involvement can affect the conjunctiva, cornea, lens, and retina and has been described in many dyskeratotic disorders with variable multiorgan involvement. The keratopathy in our patient with CD may have occurred as a consequenceof the chronic cicatrizing conjunctivitis and lid margin keratinization, as well as a mucin-deficient
Merchant et al * Chronic
Keratoconjunctivitis
dry eye, as evidenced by the lack of conjunctival goblet cells. A differential diagnosis of dermatologic conditions resulting in cornea1 involvement’7 is listed in Table 1. We suggest that CD and EKV should also be considered in the differential diagnosis of patients presenting with chronic keratoconjunctivitis with relevant associated dermatologic or systemic findings or both. These case reports underscore the value of the dermatologic history and a careful examination of the skin and mucous membranes as essential parts of the work-up of patients presenting with chronic ocular disease of obscure cause. Tissue biopsy in such cases may prove valuable in determining a definitive pathologic diagnosis. A trial of treatment with retinoids and steroids early in the disease course may even be beneficial in preventing visually debilitating cornea1 changes associated with these disorders. In addition, given the striking number of mast cells present in histologic sections, topical mast-cell stabilizers may prove beneficial.
References 1. Bruanauer SR. Zur Sympatomatologie und histologie der kongenitalen dyskeratosen. Dyskeratosen. Dermat Ztschr Berl 1924;6-26. 2. Connor JM, Gatherer D, Gray FC, et al. Assignment of the gene for dyskeratosis congenita to Xq28. Hum Genet 1986;72:348-51. 3. Vandersteen PR, Muller SA. Erythrokeratodermia variabilis: an enzyme histochemical and ultrastructural study. Arch Dermatol 1971; 103:362-70. 4. Rille F. Krankenvorstellungen. Zbl Haut Geschlechtskr 1922-3;7:161.
and CD and EKV
5. Cram DL. Erythrokeratoderma variabilis and variable circinate erythrokeratodermas. Arch Derm 1970; 101:68-73. 6. Brown J, Kierland RR. Erythrokeratodermia variabilis. Report of three cases and review of the literature. Arch Dermato1 1966;93:194-201. 7. Coles RB. Erythemato-keratotic phacomatosis. Br J Dermato1 1954;66:225-6. 8. Gewirtzman GB, Winkler NW, Dobson RL. Erythrokeratoderma variabilis. A family study. Arch Dermatol 1978; 114:259-61. 9. Luy TJ, Jacobs AH, Nickoloff BJ. A child with erythematous and hyperkeratotic patches. Erythrokeratodermia variabilis. Arch Dermatol 1988; 124:1271-2. 10. Marks R, Finlay AY, Holt PJA. Severe disorders of keratinization: effects of treatment with Tigason (etretinate). Br J Dermatol 1981; 104:667-73. Il. Zinsser F. Atrophia cutis reticularis cum pigmentione, dystrophia unguium, et leukoplakia oris. Ikonogr Dermatol (Hyoto) 1906;5:219-23. 12. Sirinavin C, Trowbridge AA. Dyskeratosis congenita: clinical features and genetic aspects. Report of a family and review of the literature. J Med Genet 1975; 12:339-54. 13. Novice FM, Collison DW, Burgdorf WHC, Esterly NB. Handbook of Genetic Skin Disorders. Philadelphia: W.B. Saunders Co., 1994; 125-7. 14. Dokal I, Luzzatto L. Dyskeratosis congenita is a chromosomal instability disorder. Leuk Lymphoma 1994; 15:1-7. 15. Wiedemann HP, McGuire J, Dwyer JM, et al. Progressive immune failure in dyskeratosis congenita. Report of an adult in whom Pneumocystis carinii and fatal disseminated candidiasis developed. Arch Intern Med 1984; 144:397-9. 16. Phillips RJ, Judge M, Webb D, Harper JI. Dyskeratosis congenita: delay in diagnosis and successful treatment of pancytopenia by bone marrow transplantation. Br J Dermato1 1992; 127:278-80. 17. Wilson FM II, Grayson M, Pieroni D. Cornea1 changes in ectodermal dysplasia. Case report, histopathology, and differential diagnosis. Am J Ophthalmol 1973;75: 17-27.
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