Bilateral Diffuse Iris Nodular Nevi Clinical and Histopathologic Characterization

Benjamin H. Ticho, MD,I-2 Mordechai Rosner, MD,2 Marilyn B. Mets, MD/ Mark 0. M. Tso, MD2

Background: Diffuse nodular nevus of the iris is an uncommon condition that pre­sents with multiple verrucous excrescences distributed diffusely on the iris surface.

Methods: The authors describe 30 patients with bilateral diffuse iris nodular nevi and report associations with bilateral congenital cataract, neurofibromatosis, oculodermal melanocytosis, congenital ptosis, morning glory anomaly, Axenfeld anomaly, or Peters anomaly.

Results: Iris nodules were uniform in size and distribution and were brown, as was the surrounding iris. Light and electron microscopy of iridectomy specimens from one patient showed elevated plaques composed of aggregates of plump, lightly pigmented nevoid cells interwoven with mature, densely pigmented spindle-shaped uveal mela­nocytes.

Conclusions: The authors report the largest clinical series and first ultrastructural description of bilateral diffuse iris nodular nevi, which represents a variant of neural crest development. No ocular complications could be attributed to the iris nodules, which should be differentiated from Lisch nodules and other pathologic iris lesions. Ophthalmology 1995;102:419-425

In 1912, both Coats' and Collins2 introduced the term iris melanosis to describe an uncommon condition char-

Originally received: October 14, 1993. Revision accepted: October 5, 1994. 1Department of Ophthalmology, The Children's Memorial Hospital, Chicago. 2 Ophthalmic Pathology Laboratory, Department of Ophthalmology and V1sual Sciences, University of Illinois at Chicago Eye and Ear Infirmary, Chicago. Presented in part as a poster at the American Academy of Ophthalmology Annual Meeting, Dallas, November 1992. Supported in part by core grant EY01792 from the National Eye Institute, Bethesda, Maryland: a grant from the Lions of Illinois Foundation, Hill­side. Illinois: and an unrestricted research grant from Research to Prevent Blindness. Inc, New York, New York. Dr. Mark 0 . M. Tso is a Research to Prevent Blindness Senior Scientific Investigator. Reprint requests to Mark 0. M. Tso, MD, Department of Ophthalmology & Visual Sciences, University of Illinois at Chicago, UIC Eye Center. 1855 W. Taylor St. Rm L217, Chicago, IL 60612.

acterized by multiple verrucous excrescences distributed diffusely on the iris surface. Early reports'-4 described unilateral cases, often associated with hyperpigmentation of the uvea (ocular melanosis). In 1987, Traboulsi and Maumenee5 described a patient with bilateral nodules distributed diffusely in brown irides without associated conjunctival, episcleral, or choroidal hyperpigmentation. They called this condition bilateral iris melanosis. Joon­deph and Goldberg6 described eight members of two His­panic pedigrees with bilateral diffuse iris nodules. They argued that the term melanosis was inappropriate, because they did not observe abnormal iris or other uveal hyper­pigmentation. Other terms used in the literature to de­scribe this entity include dotted Swiss iris6 and iris mam­illa/ions. 7·8 It has been suggested that the iris excrescences might be irregular thickening of the anterior iris surface tissue4 or aggregates of uveal melanocytes, as seen in ocular melanosis.6 Detailed histopathologic study of this con­dition has not been reported previously.

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We describe 30 patients with bilateral diffuse iris nod­ules associated with bilateral congenital cataracts, neu­rofibromatosis, oculodermal melanocytosis, congenital ptosis, morning glory anomaly, Axenfeld anomaly, or Pe­ters anomaly. We also present light and electron micro­scopic findings of bilateral iridectomy specimens from one patient. Based on our clinical and pathologic observations, we propose the term diffuse iris nodular nevi to describe this entity.

Materials and Methods

In September 1991, a patient with bilateral cataracts and iris nodules (case 1) presented to the Ophthalmology Clinic at The Children's Memorial Hospital, Chicago. In the 18-month period after this initial presentation, we ex­amined 29 additional patients with similar bilateral iris nodules, including five families with 15 affected members (Table 1 ). This series consists of 25 Hispanic patients, 3 African-American patients (cases 25, 26, and 30), and two Asian patients (cases 12 and 29). Affected children underwent a complete eye examination, including visual acuity determination, refraction, external examination, motility evaluation, slit-lamp examination, and dilated funduscopy. Available adult family members underwent slit-lamp examination.

Selected Case Reports

Case 1. A 4-year-old Hispanic girl presented after failing a school vision test. She had no other pertinent medical or ocular history. Best-corrected visual acuity (with -8.00 +2.00 X 90 correction) was 20/100 in both eyes. Nystagmus was not present. Results of slit-lamp examination showed numerous nodular, discrete excrescences distributed diffusely and symmetrically throughout both irides. These nodules were brown, as was the surrounding iris tissue. They were most prominent in the midperiphery but extended to the pupillary border (Fig I). Bilateral anterior and posterior subcapsular cataracts were noted. Results of dilated fundus examination were unremarkable, and there was no abnormal cutaneous, scleral, or choroidal pigmentation.

Peripheral iridectomy specimens were obtained at the time of bilateral uncomplicated lensectomy-anterior vitrectomy. Fragments from both iridectomy specimens were fixed in formalin, embedded in paraffin, stained with hematoxylin-eosin, and bleached with I% potassium permanganate. A portion of each iridectomy specimen was fixed in I% glutaraldehyde and 4% paraformaldehyde and processed for electron microscopic examination.

Postoperatively, the patient's best-corrected visual acuity was 20/30 in both eyes. Six family members underwent slit-lamp examination (Fig 2). The propositus' brother, mother, maternal aunt, and niece had variably prominent bilateral iris nodules.

Case 2. A 2-year-old Hispanic girl (case 7) had slate-gray periocular skin on the left side and scleral pigmentation char­acteristic of oculodermal melanocytosis since birth. There was

Table 1. Clinical Characteristics of Patients with Diffuse Iris Nodular Nevi

Case No.

1-6

7 8 9, 10

11 12 13-16

17 18 19

20 21 22, 23

24 25, 26 27, 28 29 30

Age (yrs)

4

2.5 9

14 6

17 7

NA 12 8

2 3

10

14 6 9 8

10

Associations

Bilateral cataract

Nevus ofOta Neurofibromatosis Neurofibroma Neurofibromatosis Peters anomaly Congenital ptosis; hearing loss;

abnormal ERG High myopia None Neurofibromatosis, optic nerve

glioma Chromosome 4-7 translocation PHPV Cerebral palsy; Axenfeld's anomaly;

bilateral microcornea Morning glory anomaly Mental retardation Neurofibromatosis None None

Family Involvement

Mother; 2 brothers; maternal aunt; 1 maternal cousin +DINN

Mother-DINN Parents -DINN Maternal aunt +DINN Parents; sister -DINN Mother -DINN Sister; 2 paternal third cousins +DINN;

mother; maternal great-aunt -DINN NA NA Mother - DINN

NA Mother, sister, maternal aunt -DINN Mother -DINN; brother +DINN

+Axenfeld's anomaly Mother; sister -DINN Sister + DINN; mother -DINN Mother +NF, -DINN; brother+ DINN NA Mother -DINN

DINN = diffuse iris nodular nevi; PHPV= persistent hyperplastic primary vitreous; NA =not available; NF =neurofibromatosis.

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Top left, Figure 1. Slit-lamp photograph of a 4-year old Hispanic girl (case 1) shows multiple nodules distributed diffusely on the iris surface.

Center left, Figure 2. Slit-lamp photograph of the mother of case 1 shows similar but slightly smaller iris nodules.

Bottom left, Figure 3. Slit-lamp photograph of right eye of a 2-year-old Hispanic girl (case 7) with right oculodermal melanocytosis shows multiple small nodules distributed diffusely across the iris surface.

Top right, Figure 4. Slit-lamp photograph of left eye of case 7 demon­strates diffuse iris nodules which are more prominent ipsilateral to her oculodermal changes.

Bottom right, Figure 5. Slit· lamp photograph of a 9-year-old Hispanic boy with neurofibromatosis type I shows multiple, scattered, yellow Lisch nodules as well as more numerous brown iris nodules uniform in size and distribution.

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no other pertinent medical, ocular, or family history. Fixation was central, steady, and maintained in both eyes. Multiple nod­ular excrescences were noted in both irides and were especially prominent in the midperipheral iris. The nodules were more numerous and slightly larger on the left iris (Figs 3 and 4). Slight iris heterochromia was noted. Results of dilated fundus exam­ination showed no melanosis oculi or choroidal nevi in either eye. Results of slit-lamp examination of her mother disclosed no iris nodules.

Case 3. A 9-year-old Hispanic boy (case 8) had received a diagnosis of neurofibromatosis type I at 2 years of age due to multiple cafe-au-lait spots noted since birth, with axillary and inguinal freckling. Results of neurologic examination were un­remarkable, but a magnetic resonance imaging scan showed a glioma of the right optic nerve without intracranial extension. Visual acuity was 20/25 in the right eye and 20/30 in the left. Pupils reacted equally to light and without afferent defect. Color vision testing was unremarkable in both eyes. Results of slit­lamp examination showed multiple fleshy Lisch nodules and more numerous discrete nodules diffusely distributed in both irides (Fig 5). These brown iris nodules matched the color of the surrounding iris tissue and easily were distinguished from the yellow Lisch nodules. Results ofdilated fundus examination showed no choroidal nevi and normal-appearing optic nerve heads. Goldmann applanation tonometry yielded pressures of 14 mmHg in both eyes. Cycloplegic refraction showed 2.50 diopters of hyperopia in both eyes.

Results

All affected patients had bilateral discrete nodules distrib­uted diffusely on the iris surface. The nodules were rela­tively uniform in size and distribution, extending from the iris root to the pupillary border; in some patients, they were more prominent in the midperipheral portion of the iris. In all patients, the nodules were uniformly brown, as was the surrounding iris. Two patients had asymmetric diffuse iris nodular nevi, with more prominent nodules in the eye with unilateral oculodermal melanocytosis (case 7) and morning glory anomaly (case 24). Pupillary reac­tion was normal in all patients with diffuse iris nodular nevi. In the affected pedigrees, we noted some variability in size of the iris nodules among family members. Only subtle differences in nodule size, distribution, and number were seen with increasing age. There was no known con­sanguinity in affected pedigrees. An autosomal dominant pattern was evident in two affected pedigrees. Conditions associated with the nevi in this series included neurofi­bromatosis ( 4 patients), isolated neurofibroma (I patient), oculodermal melanocytosis (I patient), bilateral congen­ital cataracts (I patient), congenital ptosis with decreased hearing and subnormal scotopic and photopic electroret­inographic responses ( 1 patient), morning glory anomaly ( 1 patient), Axenfeld anomaly with bilateral microcornea ( 1 patient), Peters anomaly ( 1 patient), high myopia ( 1 patient), persistent hyperplastic primary vitreous (I pa­tient), and q 4 to 7 chromosomal translocation ( 1 patient).

Histopathologic Findings The biopsy specimens consisted of portions of heavily pigmented iris tissue. Pigmented uveal melanocytes lined

the anterior surface of the iris, occasionally aggregating in plaques (Figs 6a and 6c). These uveal melanocytes had spindle-shaped nuclei and rare nucleoli (Fig 6d), inter­mingled with plumper nevoid melanocytes with oval nu­clei (Fig 6d). As seen on electron microscopy, the spindle­shaped cells were heavily loaded with mature melanin granules and contained few cytoplasmic organelles. Some of the plump cells had an infolded nuclear membrane (Fig 6e), relatively more abundant cytoplasm, fewer mel­anin granules, scattered mitochondria, and bundles ofcy­toplasmic filaments. Melanosomes in both the spindle­shaped and plump melanocytes varied in size from 0.1 to 0.6 ~min the long axis. Most of the melanosomes were mature and heavily melanized. Occasional melanin gran­ules had rodlike structures and were not fully melanized (Fig 6f). Rarely, larger spheroidal pigment granules (ap­proximately I ~m in diameter) were seen within phago­somes in the iris stroma (Figs 6g and 6h). However, no typical giant melanosomes were found in the sections ex­amined.

Deep in the iris stroma, the melanocytes were mostly spindle-shaped and were arranged around the iris capil­laries (Fig 6b). Morphologically, these melanocytes were comparable to the spindle-shaped uveal melanocytes found in the surface plaques. No nesting of the pigmented cells was seen within the iris stroma. No musculature or iris pigment epithelium and only occasional macrophages were seen in the sections examined.

Discussion

The 30 patients with bilateral diffuse iris nodular nevi could be categorized into two groups: familial and sporadic (occasionally asymmetric) associated with other disorders. Familial diffuse iris nodular nevi showed an autosomal dominant pattern of inheritance in two pedigrees. Family members with diffuse iris nodular nevi usually did not have associated ocular abnormalities. Disorders associated with nonfamilial diffuse iris nodular nevi included such putative neurocristopathies9 as neurofibromatosis, ocu­lodermal melanocytosis, Peters anomaly, and Axenfeld anomaly. Histologically, the iris nodules in the iridectomy specimens (case I) were characterized by hyperpigmented, elevated plaques composed ofaggregates ofspindle-shaped uveal melanocytes, and plump nevoid cells.

The differential diagnosis of multiple iris nodules in­cludes both benign and malignant disorders (Table 2). In particular, this condition should be distinguished from generalized ocular melanosis with or without associated dermatologic hyperpigmentation, iris nevus with surface plaque, Lisch nodules in neurofibromatosis type I, and Cogan-Reese (iris nevus) syndrome.

Traboulsi and Maumenee5 argued that iris melanosis may be a limited form of melanosis oculi. Diffuse iris nodular nevi may be differentiated from generalized ocular melanosis by its bilaterality, the nodules' diffuse distribution, and the absence of increased pigmentation of the iris, ciliary body, choroid, sclera, conjunctiva, or optic disc.4•10 Results of histopathologic examination

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Ticho et al Diffuse Nodular Nevi

Figure 6. a, photomicrograph (original magnification, x 250) ofanterior iris leaflet discloses nodular cluster of densely pigmented iris nevus cells surrounded by pigmented uveal melanocytes. b, elec­tron micrograph of iris stroma (original magnifica­tion, X500) shows scattered nevoid cells (N) clustered around capillary (C), with scattered uveal melanocytes (M). c, plump, oval nevoid celJs (N) are found clustered along the anterior iris surface, with spindle-shaped uveal melanocytes (M) found more posteriorly (electron micro­graph; original magnification, XlOOO). d, spindle-shaped uveal melanocytes (M) con­tain elongated nuclei and nu­merous heavily pigmented me!anosomes. e, ovoid ne­void celJs (N) have rounder indented nuclei with fewer melanosomes (electron mi­crograph; original magnifica­tion, X3000). f, cytoplasm of a nevoid cell is characterized by partially and fuJly melan­ized melanosomes (M) and numerous intracytoplasmic filaments (F) (electron micro­graph; original magnification, X37,000). g and h, larger (1­!Lm) fully melanized melano­somes (ml) are found adjacent to smaller (0.3-4 !Lm), more common melanosomes (m2)

within nevoid celJ cytoplasm (electron micrograph; original magnification, Xl7,000).

ping off" into the deeper iris stroma has been describedofocular melanosis generally shows increased numbers of heavily pigmented melanocytes without nevoid cells in oculodermal melanocytosis. 13 Giant melanosomes, or anterior nodule formation . 11 However, unilateral iris observed within iris nevus cells in ocular melanosis 12

nodules that are clinically similar in appearance to those and oculodermal melanocytosis, 13 were not observed in our patients have been described in conjunction with in our specimens. melanosis oculi. 1-

4 Histologically, the nevoid cells found Traboulsi and Maumenee5 noted that iris nodules as­within the surface plaques in our iridectomy specimens sociated with unilateral ocular melanosis may be detected were similar to those seen on light microscopy of iris more readily due to associated iris heterochromia. In our nevi associated with melanosis oculi 12 and oculodermal patient with oculodermal melanocytosis, iris nodules were melanocytosis. 13 The pattern of anterior clustering of more prominent ·ipsilateral to the increased uveal and nevus cells with more differentiated nevus cells "drop- dermal pigmentation.

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Table 2. Differential Diagnosis of Multiple Iris Nodules

Nevus 1. Diffuse iris nodular nevi

Familial; bilateral Isolated; bilateral/unilateral Associated with ocular abnormalities (ptosis, congenital cataract, morning glory anomaly) Associated with other neurocristopathies (neurofibromatosis, oculodermal melanocytosis, Axenfelds anomaly, Peters anomaly)

2. Melanosis oculi3-s/occulodermal melanocytosis5•6

•14

3. Spindle A nevus13

Intrastromal spindle cell nevus Spindle cell nevus with surface plaque Balloon cell nevus30

4. Epithelioid cell nevus of iris31 •32

5. Familial aggressive nevi of iris in childhood33

6. Neurofibromatosis Lisch nodules16- 20

7. Brushfield spots

Melanoma 1. Malignant melanoma of iris13

Spindle cell melanoma Epithelioid cell melanoma Mixed spindle/epithelioid cell melanoma

2. Tapioca melanoma34

Inflammatory Nodules 1. Granulomas

Sarcoidosis (Bussaca, Koeppe nodules) Tuberculosis (tuberculoma) Syphilis (gumma) Lepromatous leprosy (leprotic pearls)

2. Nodular iritis

Developmental Anomalies 1. lridocorneal endothelial syndromes35•36

Cogan-Reese iris nevus syndrome21 - 27

Essential iris atrophy37

2. Anterior segment dysgenesis Axenfeld-Rieger anomaly, syndrome Peters anomaly

3. Floccculus of the iris

(Adapted from Shields MB, et al. Arch Ophrhalmol 1976;94:406-10. Copyright © 1976, American Medical Association.)

Diffuse iris nodular nevi differs from typical iris nevi by the nodules' excrescent configuration, diffuse distri­bution, and absence of excess pigmentation compared with the surrounding iris. While most iris nevi consist of stromal nests of nevoid cells, surface plaques14 occasion­ally are noted.

Iris nevi are presumed to be derived from neural crest cells. 12

· 13 Dryja and Albert 15 reported bilaterally equal iris

nevus pigmentation in a patient with iris heterochromia and unilateral congenital Horner syndrome, suggesting that iris nevoid cells may be embryologically distinct from iris stromal melanocytes. In a previously described patient with diffuse iris nodular nevi, 5 a unilateral black flat iris "freckle" was noted to be different in configuration and color from the iris nodules, which were of similar pig­mentation as the surrounding iris tissue. The cells that form the nodules of these nevi are arguably developmen­tally distinct from those of typical iris freckles and nevi.

Four children (cases 8, II , 19, and 27) with diffuse iris nodular nevi had associated neurofibromatosis type I, in­cluding the presence oftypical Lisch nodules. One patient (case 9) with the condition also had an isolated cheek neurofibroma but did not have Lisch nodules and did not meet other diagnostic criteria for neurofibromatosis. The mother ofone patient (case 28) also had neurofibromatosis but did not have diffuse iris nodular nevi. The nodules of diffuse iris nodular nevi match the color of the surround­ing brown iris tissue and can be distinguished readily from Lisch nodules, which are typically less pigmented, often yellow or tan, and more variable in size, height, and dis­tribution. Lisch nodules usually have a characteristic fleshy or velvety texture and often have a glassy or trans­lucent appearance. Histologically, iris nodules in both dif­fuse iris nodular nevi and neurofibromatosis are composed of spindle-shaped melanocytes with slender dendritic processes intermixed with plumper, round cells. 16 How­ever, the iris nodules in neurofibromatosis have been de­scribed to be mainly intrastromal, whereas the prominent feature in diffuse iris nodular nevi is anterior superficial aggregates of melanocytes and nevoid cells. Furthermore, the melanocytes of iris nodules in neurofibromatosis 16

may be more metabolically active, with more immature melanosomes, mitochondria, cytoplasmic filaments, and polyribosome clusters, than melanocytes in diffuse iris nodular nevi, which rarely contain immature melano­somes and only a few mitochondria, scattered filaments, and other intracytoplasmic organelles. We believe that previous descriptions of ms hamartomas in neurofibromatosis 16

-20 may not always have distinguished

between the type oflesions we are describing in this report and true Lisch nodules.

On slit-lamp examination, the lesions seen in our pa­tients resemble somewhat those seen in the Cogan-Reese iridocorneal endothelial dysgenesis (iris-nevus) syndrome. The iris nodules in Cogan-Reese syndrome21 are unilat­eral, however, and histologically quite distinct. 21

-27

In our patients, no ocular complications could be at­tributed to the iris nodules. Open-angle glaucoma and ocular hypertension have been associated with iris nodules in diffuse iris nodular nevi6 and diffuse iris nevus.27 Ap­planation tonometry (10 patients), gonioscopy (3 pa­tients), and optic disc evaluation (19 patients) yielded normal findings in our patients.

When iris nevi are associated with diffuse uveal mel­anosis, as in melanosis oculi and oculodermal melano­cytosis, there is potential for malignant transformation . Growth or enlargement has been suggested to indicate malignant transformation of iris nevi. We noted only

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Ticho et al · Diffuse Nodular Nevi

subtle differences in nodule size, distribution, and number with increasing patient age.

Diffuse iris nodular nevi appear to be more common than previously reported. The autosomal dominant pat­tern of inheritance suggested a heritable variant of neural crest cell migration in familial cases. The nodules are not intrinsically harmful but should be differentiated from other iris lesions,28- 37 such as ocular melanosis and Lisch nodules. The frequency ofassociated ocular abnormalities in our series probably relates in part to the referral nature of our patient population. Further characterization of a possible association ofdiffuse iris nodular nevi with other neurocristopathies may be forthcoming with further study.

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