Early Vitrectomy Effective for Norrie Disease

CLINICAL SCIENCES Early Vitrectomy Effective for Norrie Disease

Mark K. Walsh, MD, PhD; Kimberly A. Drenser, MD, PhD; Antonio Capone Jr, MD; Michael T. Trese, MD

Objective: To review our experience with Norrie dis- and/or a clear family history consistent with Norrie disease to determine if early vitrectomy abrogates the natu- ease (4 patients). All 14 boys with definite Norrie disease ral history of this rare disease; namely, bilateral no light had vitrectomy with or without lensectomy in at least 1 eye perception visual acuity and phthisis bulbi. prior to 12 months of age. Of the 14 boys with definite Nor- rie disease, 7 maintained at least light perception visual acu- Methods: We retrospectively reviewed the medical rec- ity in 1 eye and 3 had no light perception visual acuity bi- ords of all patients seen in our tertiary care pediatric reti- laterally; visual acuity data were not available for 4 patients. nal clinical practice from 1988 through 2008 with a po- Only 2 of 24 (8%) eyes became phthisical. tential diagnosis of Norrie disease. Inclusion required not only clinical findings consistent with Norrie disease but Conclusions: Historically, no treatment has been of- also genetics and/or a family history consistent with Nor- fered to mitigate the dismal natural history of Norrie dis- rie disease. ease. We recommend consideration of early vitrectomy in Norrie disease. Results: Medical record review revealed 14 boys with clinically diagnosed Norrie disease and either Norrie disease gene (NDP) mutations noted on genetic testing (13 patients) Arch Ophthalmol. 2010;128(4):456-460

ORRIE DISEASE IS A RARE, ease. Patient lists were generated using Interna- X-linked, recessive disor- tional Classification of Diseases, Ninth Revision der, the clinical manifes- (ICD-9) codes 7438 (Norrie disease; anomaly tations of which have of eye other specified), 74358 (persistent fetal been extensively charac- vasculature; tortuous retinal vessels congeni- 1-6 tal), and 74351 (persistent hyperplastic pri- terizedN by Warburg. Ocular manifesta- mary vitreous; vitreous opacities congenital). tions are invariably severe; approximately These searches yielded 15, 227, and 101 pa- one-third of patients develop hearing loss tients, respectively. Clinical diagnosis of Nor- and two-thirds have mental retardation. rie disease required the presence of bilateral dys- Boys with Norrie disease are blind (no light plastic retinae. Children with clinical findings perception [NLP]) from birth or shortly suggestive of Norrie disease but neither a fam- thereafter (most cases by 3 months of age) ily history consistent with the X-linked reces- secondary to severely dysplastic retinae. sive inheritance of Norrie disease nor a Norrie Findings in infancy include leukocoria, iris disease gene (NDP; OMIM 300658) mutation atrophy, retrolental fibroplasia, vitreous noted on genetic testing were classified as having bilateral persistent fetal vasculature syn- hemorrhage, dysplastic retinae with a gray drome (PFVS), not Norrie disease. or grayish-yellow pseudoglioma appearance, retinal folds, and retinal detach- ments (often hemorrhagic). These eyes sub- RESULTS sequently develop cataracts and opaque corneas and become phthisical within the Medical record review revealed 14 boys first decade of life. Historically, no treat- with clinically diagnosed Norrie disease ment has been offered. with NDP mutations noted on genetic testing (Table) and/or a family history of Nor- METHODS rie disease. All 14 boys had bilateral dysplastic retinae notable for abnormal and limited vasculature. Some had a charac- Author Affiliations: Associated Institutional review board (William Beaumont Retinal Consultants, PC, Hospital) approval was granted for this retro- teristic pseudoglioma that we have char- William Beaumont Hospital, spective study. We reviewed the medical rec- acterized as having a “pumpkin” appear- Royal Oak, Michigan. Dr Walsh ords of all patients seen in our tertiary care pe- ance (Figure 1) with an avascular is now with Retina Associates diatric retinal clinical practice from 1988 through peripheral retina. Frequently noted con- Southwest, Tucson, Arizona. 2008 with a potential diagnosis of Norrie dis- comitant findings included persistent stalk

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Patient Total Duration Final Visual Acuity No. Family History Surgery (Age at Time of Surgery) of Follow-up, mo (Age, mo) Phthisis 1 None LSV OD (3.5 mo); Lens/Vit OS (3.5 mo); 33 20/200 Teller acuity OD, Prephthisis OS repeat Vit OS (10 mo & 15 mo) ±LP OS (36) 2 None Lens/Vit OU (6 mo); repeat Vit OS (15 mo) 47 NLP OU (53) No 3 None Vit OS (3 mo), outside surgeon; Lens/Vit OD 61 NLP OU (64) Prephthisis OS (8 mo) 4 None LSV OS (4.5 mo); Lens/Vit OD (4.5 mo) 29 LP OS, NLP OD (33) No 5 None Lens/Vit OD (3 mo), outside surgeon; 69 LP OS, NLP OD (74) Prephthisis OD Lens/Vit OS (5 mo); repeat Lens/Vit OD (5 mo); repeat Vit OS (14 mo) 6 None Vit OS (4 mo), OD (5 mo); repeat Vit with Follow-up elsewhere ...... Lens OS (6 mo), all outside surgeon 7 Older brother with ND LSV OD (1 wk); Lens/Vit OS (1 wk); repeat 78 LP OD, NLP OS (78) Phthisis bulbi OS (patient 8) Vit OS (2 mo) 8 Younger brother with Vit OU (1 mo), outside surgeon; repeat Vit 90 NLP OD, LP OS (117) Phthisis bulbi OD ND (patient 7) OS (27 mo) 9 None Lens/Vit OU (3 mo) Follow-up elsewhere ...... 10 None Lens/Vit OU (1.5 mo) 3 LP OD, 20/400 Teller No acuity OS (4.5); at least LP OU (11.5) 11 None Lens/Vit OD (11.5 mo), OS (14 mo) 202 NLP OD, CF 2 ft OS (212) No 12 Older brother with ND Lens/Vit OS (1 mo), OD (1.5 mo) 6.5 . . . No (patient 13) 13 Younger brother with Lens/Vit OU (1 mo) 12 ±LP Prephthisis OD ND (patient 12) 14 None Lens/Vit OU (3 mo) 12 NLP OU (15) No

Abbreviations: CF, counting fingers; ellipses, unknown; Lens, lensectomy; Lens/Vit, lensectomy and vitrectomy; LP, light perception; LSV, lens-sparing vitrectomy; ND, Norrie disease; NLP, no light perception; OD, right eye; OS, left eye; OU, both eyes; Vit, vitrectomy. a Defined as bilateral dysplastic retinae and NDP mutation on genetic testing and/or family history of Norrie disease.

A B

Figure 1. Pumpkin lesions in Norrie disease. Severely dysplastic retinae in Norrie disease may have this pseudoglioma appearance. A, A Retcam photograph shows the preoperative appearance in the left eye of patient 4 (Table). Notice the vascularized dysplastic retinal mass located posteriorly with associated subretinal hemorrhage and lipid. A stalk of tissue extended from this mass to the posterior lens surface. The retina peripheral to the pumpkin lesion was avascular. The right eye had dense retrolental fibroplasia. B, A Retcam photograph shows the preoperative appearance in the right eye of patient 1. Compared with the left image, there is less subretinal lipid/blood. Also note, at the base of the pumpkin there are some retinal blood vessels seen posteriorly.

tissue extending from the dysplastic retina to the lens NDP gene secondary to an inability to amplify exon 2. He (noted surgically in all cases), retinal detachment, sub- was therefore classified as having bilateral PFVS. One boy retinal hemorrhage, and retrolental fibroplasia, often dense with clinical findings consistent with Norrie disease had a and thus yielding no posterior view, and often associ- half brother (same mother) with a history of bilateral PFVS, ated with total retinal detachment with large amounts of but had indeterminate genetic testing and therefore was clas- subretinal blood. sified as having bilateral PFVS. An additional 12 patients One additional boy had clinically suspected Norrie dis- (4 girls, 8 boys) had clinical findings consistent with Nor- ease but a negative family history and an indeterminate ge- rie disease but negative family history and genetic testing netic test that was suspicious for an exon 2 deletion in the and therefore were diagnosed as having bilateral PFVS. Two

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 2. Pumpkin lesion in bilateral persistent fetal vasculature syndrome. Retcam photographs show the preoperative appearance of this boy’s left eye at 3 months of age. Notice the highly dysplastic retinal pseudoglioma with associated subretinal hemorrhage and lipid and the retinal periphery devoid of retinal vessels. A stalk of tissue extended from the center of this lesion to the posterior lens surface.

such patients also were noted to have a pumpkin appear- that did not have surgery. Lev et al8 also referred to a pa- ance to their dysplastic retinae (Figure 2). Eight addi- tient with Norrie disease who had bilateral lensectomy tional patients (6 boys, 2 girls) had no genetic testing data and vitrectomy at 1 month of age but outcome data were in their medical records. The 22 patients with ocular find- not reported. We have found in all of our patients with ings consistent with Norrie disease but classified as hav- Norrie disease that there is residual stalk tissue (hyaloi- ing bilateral PFVS also had vitrectomy in at least 1 eye if dal vessel remnant) connecting the posterior lens to the there was evidence of at least light perception (LP) preop- dysplastic retina. Intraoperatively we have noted that, as eratively. There were 5 additional patients (3 male, 2 fe- this stalk tissue is transected (preferably early in the sur- male) with clinical characteristics consistent with Norrie gery9), significant traction on the retina is often re- disease without a family history or positive genetic test- leased. We feel that this release of traction on the retina ing, and thus classified as having bilateral PFVS, who did is likely to at least partly explain the benefit of vitrec- not have vitrectomy surgery at any point, for various rea- tomy for Norrie disease. Release of this traction not only sons, eg, NLP visual acuity or being an adult patient. Four allows the retina to settle posteriorly but also eliminates patients (3 girls, 1 boy) had clinical findings consistent with an anterior-posterior tether that likely restricts normal Norrie disease but genetic analysis was still pending so they ocular development. In cases in which there is a dense were not included in the Norrie disease cohort. retrolental plaque with total retinal detachment, we feel All 14 boys with definite Norrie disease (based on clini- that meticulously peeling away this tissue from the reti- cal diagnosis and genetic mutation) had vitrectomy with nal surface and ciliary processes not only allows the retina transection of stalk tissue exerting traction on the de- to gradually reattach but also decreases the likelihood of tached retina, with or without lensectomy, in at least 1 hypotony secondary to ciliary body traction. Given the eye prior to 12 months of age. Of the 14 boys with defi- natural history of the disease (NLP by 3 months of age nite Norrie disease, 7 maintained at least LP visual acu- in most cases), we perform vitrectomy as early as pos- ity in 1 eye (follow-ups 3, 29, 33, 69, 78, 90, and 202 sible. If there is significant lens opacity obscuring our view months) and 3 had NLP bilaterally (follow-ups 12, 47, of the fundus or significant retrolental fibroplasia inti- and 61 months) (Table). Visual acuity data were not avail- mately apposed to the lens, we often remove the lens in able for 4 of the 14 patients with Norrie disease. One child addition to performing a vitrectomy. Interestingly, de- developed 20/200 visual acuity in his better eye after lens- spite the presence of large areas of avascular retina (which sparing vitrectomy (Figure 3). Of the 7 patients with we do not treat with laser photocoagulation or cryo- at least LP in the better eye, the median age at time of therapy), we have not noted any neovascularization in vitrectomy in the better eye was 3.5 months (range, 1 week our patients. Perhaps the avascular retina is so dysgenic to 14 months; mean,4.3 months). The median age at the that it does not mount a significant vascular endothelial time of vitrectomy for the 3 patients with bilateral NLP growth factor response. was 4.5 months (range, 3-8 months; mean,4.8 months). This study has the inherent deficiencies of a noncon- trolled retrospective review. Despite this, we feel that we CONCLUSIONS provide convincing evidence that early vitrectomy effec- tively alters the natural course of Norrie disease. War- Norrie disease is rare but devastating. Historically, no treat- burg’s extensive study of Norrie disease only revealed rare ment options have been offered to these patients. Jack- cases with vision beyond infancy. Of 24 patients in her lin7 described a patient who had lensectomy and vitrec- series, all had NLP except for 1 who could count fingers tomy in 1 eye and found that the eye that had surgery until age 12, when LP was lost, and another boy who could avoided phthisis bulbi at 2 years of age, unlike the eye perceive light.4 In Warburg’s review of the literature,4 she

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C D

Figure 3. Preoperative and postoperative images showing improvement in retinal anatomy in a patient with Norrie disease. A, A preoperative Retcam photograph of patient 1’s (Table) right eye reveals significant elevation of the central dysplastic retina (out of focus). B, A 2-month postoperative Retcam image shows flattening/settling of the dysplastic pumpkin (retinal vessels and central dysplastic tissue now in the same plane of focus) after lens-sparing vitrectomy with transection of stalk tissue that had connected the pumpkin to the posterior lens. C, A 6-month postoperative Retcam image shows further flattening of the retina. D, A 22-month postoperative Retcam image shows significant flattening of the retina (note that choroidal and retinal vessels are in similar planes of focus) and resorption of subretinal hemorrhage and lipid.

identified an additional 106 patients with Norrie dis- to result in a pumpkin appearance to the dysplastic ease. Of these, only 6 were noted to have LP or pupillary retina that has also been referred to as a pseudoglioma. reactivity after 3 months of age. Three were from the same This phenotype may not be pathognomonic of Norrie Greek family. One could read large print with the right disease, though. Figure 2 shows a similar phenotype in eye and had LP in the left until 13 years of age, after which a child that we labeled as having bilateral PFVS. Al- he was amaurotic. A 3-year-old boy had ambulatory vi- though he had ocular features consistent with Norrie sion in the right eye and LP in the left. Another patient disease, he had neither a family history of Norrie dis- from this family had LP visual acuity. Three other pa- ease nor any abnormalities in his NDP gene revealed by tients from an American family had LP. In total, only 8 genetic testing. It is possible that he and other patients of 130 (6%) patients had some vision noted after the age that we have categorized as having bilateral PFVS have of 3 months. This is in stark contrast to our series of pa- mutations in the NDP gene (eg, intron mutation that af- tients with Norrie disease, 70% of whom maintained at fects splicing) not revealed by current protocols for ge- least LP visual acuity in 1 eye after vitrectomy. netic testing. Another possibility is that Norrie disease In this study, we have limited our definition of Nor- and bilateral PFVS with severe posterior findings are rie disease to patients who have both the ocular pheno- phenotypically similar. Our surgical experience with type of the disease (bilateral dysplastic retinae) and bilateral PFVS is remarkably similar to what we have either a clear family history consistent with the found in Norrie disease.11 X-linked transmission of Norrie disease or a mutation There are several reasons that we feel surgery to pre- of the NDP gene noted on genetic testing. We have pre- serve even rudimentary vision is worthwhile. Seaber et viously found that mutations that affect the cysteine- al12 found in their study involving vitrectomy for stage knot motif of the NDP gene product norrin result in se- V retinopathy of prematurity that only form vision is re- vere retinal dysgenesis.10 These mutations were found quired for ambulation using visual cues, not 5/200 vi-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 sual acuity as previously reported.13 They also noted that interpretation of the data, or in the preparation, review, even children with only LP objected strenuously to bi- or approval of the manuscript. lateral occlusion, suggesting that they value any residual vision. Light perception is also beneficial for the maintenance of normal circadian rhythms and sleep- REFERENCES wake cycles in children,14,15 which is likely important in maximizing the potential for attention and learning in 1. Warburg M. Norrie’s disease: a new hereditary bilateral pseudotumor of the retina. children with limited vision.15 It has also been our an- Acta Ophthalmol (Copenh). 1961;39:757-772. 2. Warburg M. Norie’s disease (atrofia bulborum hereditaria). Acta Ophthalmol ecdotal experience that NLP often results in behavioral (Copenh). 1963;41:134-146. disturbances in children (not shown). Additionally, the 3. Warburg M. Norrie’s disease. Trans Ophthalmol Soc U K. 1965;85:391-408. future holds promise for the development of technolo- 4. Warburg M. Norrie’s disease: a congenital progressive oculo-acoustico- gies for vision restoration. We feel that it is safe to as- cerebral degeneration. Acta Ophthalmol (Copenh). 1966(suppl 89):1-47. 5. Warburg M. Norrie’s disease. Birth Defects Orig Artic Ser. 1971;7(3):117-124. sume that a child with at least LP is likely to be in a bet- 6. Warburg M. Norrie’s disease: differential diagnosis and treatment. Acta Ophthal- ter position to benefit from these technologies than a child mol (Copenh). 1975;53(2):217-236. with no ability to perceive light. Thus, based on these 7. Jacklin HN. Falciform fold, retinal detachment and Norrie’s disease. Am J premises and our experience with Norrie disease, dur- Ophthalmol. 1980;90(1):76-80. ing the past 2 decades in particular, we recommend early 8. Lev D, Weigl Y, Hasan M, et al. A novel missense mutation in the NDP gene in a child with Norrie disease and severe neurological involvement including infan- vitrectomy for patients with Norrie disease. tile spasms. Am J Med Genet A. 2007;143A(9):921-924. 9. Shaikh S, Trese MT. Lens-sparing vitrectomy in predominantly posterior per- Submitted for Publication: June 25, 2009; final revi- sistent fetal vasculature syndrome in eyes with nonaxial lens opacification. Retina. sion received June 25, 2009; accepted October 8, 2009. 2003;23(3):330-334. 10. Wu WC, Drenser K, Trese M, Capone A Jr, Dailey W. Retinal phenotype-genotype Correspondence: Mark K. Walsh, MD, PhD, Retina As- correlation of pediatric patients expressing mutations in the Norrie disease gene. sociates Southwest, PC, 6561 E Carondelet Dr, Tucson, Arch Ophthalmol. 2007;125(2):225-230. AZ 85710 ([email protected]). 11. Walsh MK, Drenser KA, Capone A Jr, Trese MT. Early vitrectomy effective for Financial Disclosure: None reported. bilateral combined anterior and posterior persistent fetal vasculature syndrome. Funding/Support: This study was supported in part by Retina. In press. 12. Seaber JH, Machemer R, Eliott D, Buckley EG, deJuan E, Martin DF. Long-term the Alliance for Vision Research; the Ronald G. Michels visual results of children after initially successful vitrectomy for stage V reti- Fellowship Foundation (Dr Walsh); and the Heed Oph- nopathy of prematurity. Ophthalmology. 1995;102(2):199-204. thalmic Foundation (Dr Walsh). 13. Kalina RE. Treatment of retinal detachment due to retinopathy of prematurity: Role of the Sponsor: The Alliance for Vision Research, documented disappointment [editorial]. Ophthalmology. 1991;98(1):3-4. 14. Okawa M, Nanami T, Wada S, et al. Four congenitally blind children with circa- the Ronald G. Michels Fellowship Foundation, and the dian sleep-wake rhythm disorder. Sleep. 1987;10(2):101-110. Heed Ophthalmic Foundation had no role in the design 15. Davitt BV, Morgan C, Cruz OA. Sleep disorders in children with congenital an- and conduct of the study, in the collection, analysis, and ophthalmia and microphthalmia. J AAPOS. 1997;1(3):151-153.

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