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Autosomal-dominant Anomalies of the Iris Pigment Epithelium
Autosomal--dominant Anomalies of the Iris Pigment Epithelium Brian L. Lee, MD, Andrea B. Lanier , MD, J. Bronwyn Bateman, MD Purpose: The authors document two families in which anomalies of the iris pigment epithelium occur as an autosomal dominant trait. Methods: Eyes of members of two families were examined for the presence of anomalies of the iris pigment epithelium. Results: In both families, anomalies characterized by iris pigment epithelial cysts and peripupillary ruffles were observed in successive generations. In one family, the proband was 3 months of age, and both cysts and ruffles were present in affected individuals. Conclusions: Anomalies of the iris pigment epithelium can be inherited in an autosomal-dominant pattern. The cystic and ruffled phenotypes represent variable expressivity and may be evident in infancy. Ophthalmology 1996; 103:1696-1699
Primary anomalies of the iris pigment epithelium include cysts contiguous with the posterior face of the iris 1- 10 and ruffles visible at the pupillary margin. 1-4 These dysplastic lesions have been documented as incidental findings in both children and adults, but generally have been reported without description of involvement in additional family members. There are only three reports of these iris pigment epithelial anomalies in sequential generations of a single pedigree. I - 3 We present two pedigrees in which cystic or ruffled anomalies of the iris pigment epithelium occur in sequential generations and show that both forms of dysplasia can be present in a single pedigree. We propose an autosomal-dominant form of inheritance and postulate that iris pigment epithelial cysts and peri pupillary ruffles represent variable expressivity of a single gene.
Originally received: November 9, 1995. Revision accepted: May 28, 1996. From the Vision Genetics Center, Department of Ophthalmology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles. Presented in part at the ARVO Annual Meeting, Ft. Lauderdale, April 1996. Supported in part by National Institutes of Health grant EY088282 (Dr. Bateman), a Research to Prevent Blindness, Inc, William and Mary Greve International Scholar Award, New York, New York (Dr. Bateman), and the Karl Kirchgessner Foundation (Dr. Bateman). Reprint requests to J. Bronwyn Bateman, MD, Department of Ophthalmology, University of Colorado, Box B204, 4200 East 9th Ave, Denver, CO 80262.
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Methods We studied two patients from unrelated families who were referred for further evaluation of iris anomalies. One patient was referred for consultation and examination under anesthesia to assess the possibility of deprivation amblyopia; the other patient was referred for consultation to exclude the possibility of melanoma. The living members of the immediate families of both patients were invited to be examined by the authors.
Case Reports Family 1. The proband was noted to have an irregular left pupil at 3 months of age (Fig 1). Results of examination under anesthesia 2 months later showed two large cystic masses protruding through the undilated left pupil; transillumination demonstrated total obstruction of the pupillary axis. The right pupil was 3 mm and round. Dilation showed two additional lesions emanating from behind the right pupil and multiple additional lesions emanating from behind the left pupil. Transillumination showed a crescent of open visual axis in the left eye (Fig 2A); the right visual axis was clear. The remaining results of the examination were unremarkable. The father of the proband had a corrected visual acuity of 20/20 in each eye. Results of slit-lamp biomicroscopy showed multiple cystic masses at the pupillary margin in each undilated eye; the visual axis was open (Fig 2B). The remaining results of of the examination were unremarkable. The two older siblings of the proband each had uncorrected
Lee et al . Autosomal-dominant Anomalies of the Iris Pigment Epithelium Family 1
Family 2
o /
female
D
male
proband
+
examined
~rUffies
Figure 1. Pedigrees of families 1 and 2. Anomalies of the iris pigment epithelium in both pedigrees are inherited in an autosomal-dominant pattern.
visual aCUItIes of 20/20 in each eye. Results of slit-lamp biomicroscopy performed with and without dilation on both siblings showed ruffles of the pupillary margins in both eyes (Figs 2C and 2D). The remaining results of of the ocular examinations in these two individuals were unremarkable. Family 2. The proband, 55 years of age, was noted by his optometrist to have bilateral retroiridal masses (Fig 1). Two years
later, he was treated for a rhegmatogenous retinal detachment in the left eye and a retinal tear in the right eye. Evaluation with a gonioscopic prism shortly after retinal surgery showed a confluence of inferior retroiridal cystic masses of the right eye and multiple superonasal retroiridal cystic masses of the left eye. Both fundi showed changes consistent with prior retinal surgery. The remaining results of the ocular examination were unremarkable.
Figure 2. Family 1 has abnormalities of the iris epithelium in four members. A, left eye of the proband has multiple cysts of the iris pigment epithelium, including a single large cyst which occludes the visual axis. B, left eye of the proband's father has multiple cysts of the iris pigment epithelium contiguous with the posterior plane of the iris. C, left eye of the proband's brother has a ruffled pupillary margin. D, left eye of the proband's sister has a ruffled pupillary margin.
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Ophthalmology
Volume 103, Number 10, October 1996
Figure 3. Left eye of the daughter of the proband in family Z shows multiple large fusiform cysts of the iris pigment epithelium contiguous with the posterior plane of the iris.
By history, the proband's parents and siblings were not known to have iris anomalies. One of his four daughters was available for examination. She had been previously treated with laser retinopexy for a retinal tear in the left eye. Slit-lamp biomicroscopy showed cystic masses in the temporal aspects of the iris in each eye (Fig 3). The fundi showed changes consistent with laser treatment to the left eye. The remaining results of the examination were unremarkable. Ultrasonography showed iris thickening temporally in the right eye and cystic masses occupying 4 clock hours temporally in the left eye. Results of the physical examination of both the proband and his daughter were significant for an inverted dome-shaped palate. However, the palatal anomaly, retinal tear, and iris cysts do not co-segregate; by history, the proband's father had the same palatal anomaly, whereas the proband's mother had a retinal detachment.
Discussion The two primary InS pigment epithelial anomalies are cysts contiguous with the posterior iris plane'-10 and ruffles visible at the pupillary margin.'-4 These primary lesions are phenotypically and etiologically different from congenital iris ectropion, which is a condition arising from developmental abnormalities involving neural-crestderived cells; eyes with congenital iris ectropion display sheet-like ectropion of iris pigment epithelium, as well as findings suggestive of anterior segment dysgenesis. II The primary cystic lesions are generally believed to consist of separations of the two layers of iris epithelium5- 7 ; canine studies have suggested that they arise from abnormal proliferation of the inner layer of iris epithelium alone. 8 The primary ruffled lesions were termed flocculi in early reports 1-4 and, histologically, are hyperplasia and
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hypertrophy of the posterior layer of the iris pigment epithelium at the pupillary margin. 4 No etiologic mechanisms have been demonstrated to account for either of these iris pigment epithelial anomalies. However, the clinical appearance of these lesions, with support by histologic data, have led to several hypotheses. In 1936, Von Szily and Gallemaerts, as cited by Cowan,' suggested that both "flocculi" and cysts are a result of primary failure of closure in the anterior portion of the optic cup. In 1951, Vail and Merz9 postulated that a malapposition of the outer and inner layers of the optic cup caused by zonular traction results in the development of a cyst. However, despite the prevailing view that these lesions are developmental in nature, previous reports show only a single infant with a primary iris dysplastic anomaly; this infant had concomitant retinoblastoma. 5.6 Evidence for a single gene as the basis of iris pigment epithelial anomalies is rare. All published series of iris cysts fail to describe familial clustering of iris cysts or ruffles. Shields and colleagues,5.6 in describing clinical features of 53 cysts contiguous with the iris pigment epithelium, do not report the existence of similar iris abnormalities in family members. Series of 16 patients with iris epithelial anomalies by Scheie lO and of 12 patients with iris epithelial anomalies by Reese? also fail to identify familial clustering. There are only three reports of iris pigment epithelial anomalies occurring within families. No lesion is described congenitally. In 1936, Cowan' described and illustrated multiple cysts protruding through each pupil in two sisters and a son and a daughter of one of the sisters; the youngest patient in the report was 15 years of age. In the 1969 German literature, Meyer2 reported a three-generation pedigree in which multiple cysts were present bilaterally in seven members and unilaterally in two; the ages of the family members were not listed. In 1985, BalaccoGabrieli and associates 3 documented multiple cysts along the pupillary border in four women in three generations; the ages of the family members were not listed. Among the pedigrees reported by Cowan' and by Meyer were certain individuals with both cysts and' 'flocculi." These two anomalies occurred in the same eye in some individuals and in different eyes in other individuals. The mode of familial clustering seen in our two families, in conjunction with the three prior reports, provides convincing evidence that primary anomalies of the iris pigment epithelium can be inherited as an autosomaldominant trait. The presence of cysts in an infant, as seen in one of our probands, documents that such anomalies can be congenital. In addition, the presence of both ruffles and cysts in the same individual1. 2 and the observation of ruffles in one offspring and cysts in another (family 1 of this report) supports variable expressivity. The paucity of literature documenting the heritability of anomalies of the iris pigment epithelium may represent underreporting. A peripheral posterior cyst is often difficult to visualize and ruffles at the pupillary margin may easily be overlooked. However, awareness of the heritable nature of anomalies of the iris pigment epithelium may have clinical implications. Careful examina-
Lee et al . Autosomal-dominant Anomalies of the Iris Pigment Epithelium tion for iris cysts in an infant of a patient with iris pigment epithelial anomalies may be warranted to detect a visually obstructive lesion that may lead to deprivation amblyopia. In addition, the rarity and often surprising appearance of an iris cyst may initiate an evaluation for the possibility of melanoma 5,6,1O; such an evaluation may be unwarranted in a family with documented iris pigment epithelial anomalies,
References 1. Cowan A. Congenital and familial cysts and flocculi of the iris. Am J OphthalmoI1936;19:287-91. 2. Meyer HJ. Dominant vererbte pupillarpigmentzysten [in Gennan]. Klin Monatsbl Augenheilkd 1969; 154:158-66. 3. Balacco-Gabrieli C, Castellano L, Palmisano C, et al. Iris cysts in three generations conveyed by means of a genetic process connected with sex. Ophthalmic Paediatr Genet 1985;6:79-84.
4. Fuchs A. Contribution to the anatomy of congenital ectropium uveae (flocculi iridis). Am J Ophthalmol1931 ; 14:8658. 5. Shields JA, Kline MW, Augsburger D. Primary iris cysts: a review of the literature and report of 62 cases. Br J Ophthalmol 1984;68:152-66. 6. Shields JA. Primary cysts of the iris. Trans Am Ophthalmol Soc 1981;79:771-809. 7. Reese AB. Spontaneous cysts of the ciliary body simulating neoplasms. Trans Am Ophthalmol Soc 1949;47:138-46. 8. Kozart OM, Scheie HG. Spontaneous cysts of the ciliary epithelium. Trans Am Acad Ophthalmol Otolaryngol 1970; 74:534-47. 9. Vail D, Merz EH. Embryonic intra-epithelial cyst of the ciliary processes. Trans Am Ophthalmol Soc 1951;49:16783. 10. Scheie HG. Gonioscopy in the diagnosis of tumors of the iris and ciliary body, with emphasis on intraepithelial cysts. Trans Am Ophthalmol Soc 1953;51:313-31. II . Wilson ME. Congenital iris ectropion and a new classification for anterior segment dysgenesis. J Pediatr Ophthalmol Strabismus 1990; 27:48-55.
Centennial Advertisement From the Illustrated Catalogue of Spectacles & Eye Glasses, George Culver, Ltd. Penton ville, London, 1898. Steel Canadian Folders. *
FIg. 060.
175. Steel Frame, Canadian pattern, plain spring, cork placquets, chamfered eyes and fancy handle, nickel plated. Fig. 060 176 Steel Frame, Canadian pattern, light for grooved lenses. Fig. 060
2
3
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* Centennial advertisement provided courtesy of the Museum of Ophthalmology, Foundation of the American Academy of Ophthalmology, San Francisco, California
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Primary anomalies of the iris pigment epithelium include cysts contiguous with the posterior face of the iris 1- 10 and ruffles visible at the pupillary margin. 1-4 These dysplastic lesions have been documented as incidental findings in both children and adults, but generally have been reported without description of involvement in additional family members. There are only three reports of these iris pigment epithelial anomalies in sequential generations of a single pedigree. I - 3 We present two pedigrees in which cystic or ruffled anomalies of the iris pigment epithelium occur in sequential generations and show that both forms of dysplasia can be present in a single pedigree. We propose an autosomal-dominant form of inheritance and postulate that iris pigment epithelial cysts and peri pupillary ruffles represent variable expressivity of a single gene.
Originally received: November 9, 1995. Revision accepted: May 28, 1996. From the Vision Genetics Center, Department of Ophthalmology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles. Presented in part at the ARVO Annual Meeting, Ft. Lauderdale, April 1996. Supported in part by National Institutes of Health grant EY088282 (Dr. Bateman), a Research to Prevent Blindness, Inc, William and Mary Greve International Scholar Award, New York, New York (Dr. Bateman), and the Karl Kirchgessner Foundation (Dr. Bateman). Reprint requests to J. Bronwyn Bateman, MD, Department of Ophthalmology, University of Colorado, Box B204, 4200 East 9th Ave, Denver, CO 80262.
1696
Methods We studied two patients from unrelated families who were referred for further evaluation of iris anomalies. One patient was referred for consultation and examination under anesthesia to assess the possibility of deprivation amblyopia; the other patient was referred for consultation to exclude the possibility of melanoma. The living members of the immediate families of both patients were invited to be examined by the authors.
Case Reports Family 1. The proband was noted to have an irregular left pupil at 3 months of age (Fig 1). Results of examination under anesthesia 2 months later showed two large cystic masses protruding through the undilated left pupil; transillumination demonstrated total obstruction of the pupillary axis. The right pupil was 3 mm and round. Dilation showed two additional lesions emanating from behind the right pupil and multiple additional lesions emanating from behind the left pupil. Transillumination showed a crescent of open visual axis in the left eye (Fig 2A); the right visual axis was clear. The remaining results of the examination were unremarkable. The father of the proband had a corrected visual acuity of 20/20 in each eye. Results of slit-lamp biomicroscopy showed multiple cystic masses at the pupillary margin in each undilated eye; the visual axis was open (Fig 2B). The remaining results of of the examination were unremarkable. The two older siblings of the proband each had uncorrected
Lee et al . Autosomal-dominant Anomalies of the Iris Pigment Epithelium Family 1
Family 2
o /
female
D
male
proband
+
examined
~rUffies
Figure 1. Pedigrees of families 1 and 2. Anomalies of the iris pigment epithelium in both pedigrees are inherited in an autosomal-dominant pattern.
visual aCUItIes of 20/20 in each eye. Results of slit-lamp biomicroscopy performed with and without dilation on both siblings showed ruffles of the pupillary margins in both eyes (Figs 2C and 2D). The remaining results of of the ocular examinations in these two individuals were unremarkable. Family 2. The proband, 55 years of age, was noted by his optometrist to have bilateral retroiridal masses (Fig 1). Two years
later, he was treated for a rhegmatogenous retinal detachment in the left eye and a retinal tear in the right eye. Evaluation with a gonioscopic prism shortly after retinal surgery showed a confluence of inferior retroiridal cystic masses of the right eye and multiple superonasal retroiridal cystic masses of the left eye. Both fundi showed changes consistent with prior retinal surgery. The remaining results of the ocular examination were unremarkable.
Figure 2. Family 1 has abnormalities of the iris epithelium in four members. A, left eye of the proband has multiple cysts of the iris pigment epithelium, including a single large cyst which occludes the visual axis. B, left eye of the proband's father has multiple cysts of the iris pigment epithelium contiguous with the posterior plane of the iris. C, left eye of the proband's brother has a ruffled pupillary margin. D, left eye of the proband's sister has a ruffled pupillary margin.
1697
Ophthalmology
Volume 103, Number 10, October 1996
Figure 3. Left eye of the daughter of the proband in family Z shows multiple large fusiform cysts of the iris pigment epithelium contiguous with the posterior plane of the iris.
By history, the proband's parents and siblings were not known to have iris anomalies. One of his four daughters was available for examination. She had been previously treated with laser retinopexy for a retinal tear in the left eye. Slit-lamp biomicroscopy showed cystic masses in the temporal aspects of the iris in each eye (Fig 3). The fundi showed changes consistent with laser treatment to the left eye. The remaining results of the examination were unremarkable. Ultrasonography showed iris thickening temporally in the right eye and cystic masses occupying 4 clock hours temporally in the left eye. Results of the physical examination of both the proband and his daughter were significant for an inverted dome-shaped palate. However, the palatal anomaly, retinal tear, and iris cysts do not co-segregate; by history, the proband's father had the same palatal anomaly, whereas the proband's mother had a retinal detachment.
Discussion The two primary InS pigment epithelial anomalies are cysts contiguous with the posterior iris plane'-10 and ruffles visible at the pupillary margin.'-4 These primary lesions are phenotypically and etiologically different from congenital iris ectropion, which is a condition arising from developmental abnormalities involving neural-crestderived cells; eyes with congenital iris ectropion display sheet-like ectropion of iris pigment epithelium, as well as findings suggestive of anterior segment dysgenesis. II The primary cystic lesions are generally believed to consist of separations of the two layers of iris epithelium5- 7 ; canine studies have suggested that they arise from abnormal proliferation of the inner layer of iris epithelium alone. 8 The primary ruffled lesions were termed flocculi in early reports 1-4 and, histologically, are hyperplasia and
1698
hypertrophy of the posterior layer of the iris pigment epithelium at the pupillary margin. 4 No etiologic mechanisms have been demonstrated to account for either of these iris pigment epithelial anomalies. However, the clinical appearance of these lesions, with support by histologic data, have led to several hypotheses. In 1936, Von Szily and Gallemaerts, as cited by Cowan,' suggested that both "flocculi" and cysts are a result of primary failure of closure in the anterior portion of the optic cup. In 1951, Vail and Merz9 postulated that a malapposition of the outer and inner layers of the optic cup caused by zonular traction results in the development of a cyst. However, despite the prevailing view that these lesions are developmental in nature, previous reports show only a single infant with a primary iris dysplastic anomaly; this infant had concomitant retinoblastoma. 5.6 Evidence for a single gene as the basis of iris pigment epithelial anomalies is rare. All published series of iris cysts fail to describe familial clustering of iris cysts or ruffles. Shields and colleagues,5.6 in describing clinical features of 53 cysts contiguous with the iris pigment epithelium, do not report the existence of similar iris abnormalities in family members. Series of 16 patients with iris epithelial anomalies by Scheie lO and of 12 patients with iris epithelial anomalies by Reese? also fail to identify familial clustering. There are only three reports of iris pigment epithelial anomalies occurring within families. No lesion is described congenitally. In 1936, Cowan' described and illustrated multiple cysts protruding through each pupil in two sisters and a son and a daughter of one of the sisters; the youngest patient in the report was 15 years of age. In the 1969 German literature, Meyer2 reported a three-generation pedigree in which multiple cysts were present bilaterally in seven members and unilaterally in two; the ages of the family members were not listed. In 1985, BalaccoGabrieli and associates 3 documented multiple cysts along the pupillary border in four women in three generations; the ages of the family members were not listed. Among the pedigrees reported by Cowan' and by Meyer were certain individuals with both cysts and' 'flocculi." These two anomalies occurred in the same eye in some individuals and in different eyes in other individuals. The mode of familial clustering seen in our two families, in conjunction with the three prior reports, provides convincing evidence that primary anomalies of the iris pigment epithelium can be inherited as an autosomaldominant trait. The presence of cysts in an infant, as seen in one of our probands, documents that such anomalies can be congenital. In addition, the presence of both ruffles and cysts in the same individual1. 2 and the observation of ruffles in one offspring and cysts in another (family 1 of this report) supports variable expressivity. The paucity of literature documenting the heritability of anomalies of the iris pigment epithelium may represent underreporting. A peripheral posterior cyst is often difficult to visualize and ruffles at the pupillary margin may easily be overlooked. However, awareness of the heritable nature of anomalies of the iris pigment epithelium may have clinical implications. Careful examina-
Lee et al . Autosomal-dominant Anomalies of the Iris Pigment Epithelium tion for iris cysts in an infant of a patient with iris pigment epithelial anomalies may be warranted to detect a visually obstructive lesion that may lead to deprivation amblyopia. In addition, the rarity and often surprising appearance of an iris cyst may initiate an evaluation for the possibility of melanoma 5,6,1O; such an evaluation may be unwarranted in a family with documented iris pigment epithelial anomalies,
References 1. Cowan A. Congenital and familial cysts and flocculi of the iris. Am J OphthalmoI1936;19:287-91. 2. Meyer HJ. Dominant vererbte pupillarpigmentzysten [in Gennan]. Klin Monatsbl Augenheilkd 1969; 154:158-66. 3. Balacco-Gabrieli C, Castellano L, Palmisano C, et al. Iris cysts in three generations conveyed by means of a genetic process connected with sex. Ophthalmic Paediatr Genet 1985;6:79-84.
4. Fuchs A. Contribution to the anatomy of congenital ectropium uveae (flocculi iridis). Am J Ophthalmol1931 ; 14:8658. 5. Shields JA, Kline MW, Augsburger D. Primary iris cysts: a review of the literature and report of 62 cases. Br J Ophthalmol 1984;68:152-66. 6. Shields JA. Primary cysts of the iris. Trans Am Ophthalmol Soc 1981;79:771-809. 7. Reese AB. Spontaneous cysts of the ciliary body simulating neoplasms. Trans Am Ophthalmol Soc 1949;47:138-46. 8. Kozart OM, Scheie HG. Spontaneous cysts of the ciliary epithelium. Trans Am Acad Ophthalmol Otolaryngol 1970; 74:534-47. 9. Vail D, Merz EH. Embryonic intra-epithelial cyst of the ciliary processes. Trans Am Ophthalmol Soc 1951;49:16783. 10. Scheie HG. Gonioscopy in the diagnosis of tumors of the iris and ciliary body, with emphasis on intraepithelial cysts. Trans Am Ophthalmol Soc 1953;51:313-31. II . Wilson ME. Congenital iris ectropion and a new classification for anterior segment dysgenesis. J Pediatr Ophthalmol Strabismus 1990; 27:48-55.
Centennial Advertisement From the Illustrated Catalogue of Spectacles & Eye Glasses, George Culver, Ltd. Penton ville, London, 1898. Steel Canadian Folders. *
FIg. 060.
175. Steel Frame, Canadian pattern, plain spring, cork placquets, chamfered eyes and fancy handle, nickel plated. Fig. 060 176 Steel Frame, Canadian pattern, light for grooved lenses. Fig. 060
2
3
0 0
* Centennial advertisement provided courtesy of the Museum of Ophthalmology, Foundation of the American Academy of Ophthalmology, San Francisco, California
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