Geographic Chorioretinal Atrophy in Pseudoxanthoma Elasticum

SCOTT D. SCHOENBERGER AND ANITA AGARWAL

PURPOSE: To describe a series of patients with mutation is in subclass C of the ATP-binding cassette geographic atrophy independent of choroidal neovascula- transporter gene, where numerous mutations are re- rization (CNV) in pseudoxanthoma elasticum and to ported.2,3 Pathologic changes are most pronounced in the report progression over time. dermis, Bruch membrane, and blood vessels.1,4 DESIGN: Retrospective observational case series. Characteristic fundus lesions include angioid streaks, METHODS: Records of all Vanderbilt Eye Institute peau d’orange, optic disc drusen, pattern dystrophy, patients with pseudoxanthoma elasticum and at least 1 crystalline bodies, midperipheral ‘‘comet-tail’’ atrophic set of color fundus photographs were reviewed (41 eyes spots, and choroidal neovascularization (CNV).1 of 21 patients). Fluorescein angiography, fundus auto- Numerous retinal pigment epithelium (RPE) alterations fluorescence, and optical coherence tomography images have been described, including atrophy along angioid were reviewed, when available. In patients with streaks, atrophy associated with CNV, and pattern geographic atrophy and at least 1 year of follow-up, dystrophy.1,5 With CNV, RPE alterations include rips, atrophy was measured using fundus photographs. Main multilobular areas of atrophy, and broad areas of poorly outcome measures included incidence of geographic demarcated thinning/atrophy.3,6 atrophy, progression over time, and macular features The most common cause of vision loss is CNV and disci- associated with development or progression of geographic form scarring, which occurs in 68%-86% of cases.1,5 Little atrophy. has been reported regarding primary geographic atrophy in RESULTS: Eight eyes (20%) of 5 patients had the absence of CNV. Identified cases only exist in case geographic atrophy independent of CNV. Progression reports7 or hidden in larger studies.8–10 Longitudinal was documented in 6 eyes of 4 patients followed for at follow-up information and proposed mechanisms of patho- least 1 year (mean 3.5 years). Mean initial and final genesis of the atrophy are lacking. area was 2.9 and 9.5 mm2, respectively, and growth rate The purpose of the current study is to describe a series of was 1.7 mm2 per year. Of the 6 eyes, 3 had a final visual patients with geographic chorioretinal atrophy indepen- acuity of 20/20 and the other 3 ranged from 20/150 to 20/ dent of CNV in pseudoxanthoma elasticum. Serial photog- 400. All 8 eyes had pattern dystrophy, and 5 had linear raphy allowed for measuring progression rates of geographic pigment deposits that appeared to predict development atrophy. We also attempt to identify other clinical features or growth of atrophy. of pseudoxanthoma elasticum that may predict the devel- CONCLUSIONS: Isolated geographic atrophy indepen- opment or progression of geographic atrophy. dent of CNV can develop in pseudoxanthoma elasticum, causing significant vision loss. Linear pigmented pattern dystrophy appears to predate geographic atrophy. Progression is similar to age-related macular degenera- METHODS tion. Recognition of this feature is important, especially if therapies to slow or reverse geographic atrophy become PATIENT SELECTION: A retrospective observational available. (Am J Ophthalmol 2013;156:715–723. study was performed on all patients seen at the Vanderbilt Ó 2013 by Elsevier Inc. All rights reserved.) Eye Institute between 2002 and 2012 with a diagnosis of ‘‘angioid streaks’’ or ‘‘pseudoxanthoma elasticum’’ based on ICD-9 coding. Vanderbilt University Institutional SEUDOXANTHOMA ELASTICUM IS A SYSTEMIC Review Board approval was obtained for this retrospective disease that primarily affects the elastic tissue of review. Data were collected in accordance with compli- the skin, cardiovascular system, and eyes.1 Inheri- ance set forth by the Health Insurance Portability and P Accountability Act of 1996. The study adhered to the tance is usually autosomal recessive and the causative tenets of the Declaration of Helsinki. All patients with a diagnosis of ‘‘angioid streaks’’ or Accepted for publication May 23, 2013. ‘‘pseudoxanthoma elasticum’’ were identified. Only those From the Vanderbilt Eye Institute, Vanderbilt University School of with at least 1 set of digital color fundus photographs and Medicine, Nashville, Tennessee. Inquiries to Anita Agarwal, Vanderbilt Eye Institute. 2311 Pierce medical records were reviewed. Each patient’s diagnosis Avenue, Nashville, TN 37232; e-mail: [email protected] of pseudoxanthoma elasticum was made based on fundus

0002-9394/$36.00 Ó 2013 BY ELSEVIER INC.ALL RIGHTS RESERVED. 715 http://dx.doi.org/10.1016/j.ajo.2013.05.034 findings with or without a skin examination or biopsy. streaks (17 eyes, 41%), peau d’orange (16 eyes, 39%), Clinical findings, fundus photographs, fluorescein angiog- atrophy with CNV (15 eyes, 37%), disc drusen (10 eyes, raphy (FA), optical coherence tomography (OCT), and 24%), crystalline bodies (9 eyes, 22%), and comet-tail fundus autofluorescence (FAF) were reviewed. lesions (7 eyes, 17%). All eyes with pattern dystrophy had isolated pigment clumps consistent with fundus pulver- IDENTIFICATION AND MEASUREMENT OF GEOGRAPHIC ulentus. In addition, linear pigment deposits similar to the ATROPHY: Geographic atrophy was determined based on butterfly-type pattern dystrophy were present in 7 eyes of 4 fundus photography. Patients who had geographic atrophy patients. distinct from peripapillary atrophy or chorioretinal atrophy that followed angioid streaks were identified. Patients were GEOGRAPHIC ATROPHY: Geographic atrophy separate excluded if geographic atrophy was associated with CNV. from angioid streaks or CNV was identified in 8 eyes This was defined by the presence of subretinal hemorrhage, (20%) of 5 patients. Mean age of eyes when geographic lipid, fluid, subretinal fibrosis, or pigment epithelial hyper- atrophy was first identified was 50 years (range 37-53 years). plasia contiguous with geographic atrophy. Pattern dystrophy was present in all 8 eyes (100%), Geographic atrophy was measured on color fundus compared to 33% without this finding. The type of pattern photographs using OIS WinStation XP 5000 software dystrophy present was clumps of RPE distributed in (Ophthalmic Imaging Systems, Inc, Sacramento, Califor- a random fashion in the macula, typical of fundus pulveru- nia, USA). Fifty-degree images centered at the posterior lentus, and sometimes arranged in a linear pattern resem- pole were used in all cases, allowing for standardization of bling the butterfly type. Those with multiple sets of measurements. If present, FA and FAF were used to help photographs separated by at least 1 year (6 eyes of identify areas of atrophy, but they were not used for 4 patients) were measured for area of geographic atrophy. measurements. The magnification obtained on FAF images Two eyes of 1 patient with geographic atrophy had only does not conform to the standard magnification obtained 3-month follow-up and were excluded from measurement on fundus photographs; hence these images were not analysis. The mean initial and final area of the 6 eyes was used. The lesions were measured separately by each author 2.9 mm2 (range 0.3-8.1 mm2) and 9.5 mm2 (range (S.D.S., A.A.) and the mean value for each eye was used for 0.8-21.2 mm2), respectively, and mean growth rate was reporting. Growth per year was determined using the first 1.7 mm2 per year (range 0.4-2.5 mm2 per year). Of the and last digital fundus photograph showing geographic 6 eyes measured, 3 had visual acuity (VA) of 20/20 at atrophy. both initial and final visits. Three other eyes worsened over time, with initial VA ranging from 20/25 to 20/200 OTHER FEATURES OF PSEUDOXANTHOMA ELASTICUM: and final VA ranging from 20/150 to 20/400. Further char- In addition to geographic atrophy, photographs were also acteristics of the 6 eyes measured are described below and reviewed for angioid streaks, atrophy attributable to in the Table. CNV, atrophy along angioid streaks, disc drusen, peau d’orange, comet-tail lesions, pattern dystrophy, crystalline Patient 1. Patient 1 was a 50-year-old man with VA of bodies, and signs of CNV (subretinal hemorrhage, lipid, 20/20 associated with paracentral scotomas in both eyes. fluid, subretinal fibrosis, or pigment epithelial hyperplasia). Fundus photography at presentation showed angioid Patient demographics and other examination findings were streaks, pattern dystrophy, comet-tail lesions, and disc reviewed. Main outcome measures included the incidence drusen in both eyes (Figure 1, Top row). His left eye had of geographic atrophy without CNV, progression over a small patch of geographic atrophy in the macula, time, and other macular features associated with develop- measuring 2.50 mm2. He also had a ‘‘plucked chicken ment or progression of geographic atrophy. skin’’ appearance on his neck. Two years and five months later, the atrophy had enlarged in his left eye and he developed geographic atrophy in the macula of his right eye (1.50 mm2), but he retained 20/20 vision OU (not RESULTS shown). At his final visit, four years and five months after initial presentation, VA remained 20/20 OU. The PATIENTS: A total of 41 eyes (21 patients) were identi- atrophy continued to enlarge in both eyes, with an area fied with a clinical diagnosis of pseudoxanthoma elasticum of 6.51 mm2 OD and 7.13 mm2 OS (Figure 1, Bottom and at least 1 set of digital fundus photographs. One patient row). The atrophy had enlarged by 2.51 mm2 per year had photographs performed only in 1 eye but had bilateral OD and 1.05 mm2 per year OS. Isolated pigment clumps disease. Mean age of the 21 patients at initial photography (white arrows) and linear pigment deposits (black was 50 years (range 19-71 years). Signs of active or inac- arrowheads) were present. FAF revealed numerous tive CNV were present in 24 eyes (59%). Other findings intensely hyperautofluorescent areas scattered in the included angioid streaks (41 eyes, 100%), pattern dys- macula corresponding to isolated pigment clumps trophy (19 eyes, 46%), chorioretinal atrophy along angioid (Figure 2, Top row; white arrows). Temporal to

716 AMERICAN JOURNAL OF OPHTHALMOLOGY OCTOBER 2013 TABLE. Demographic Information and Ocular Features Over Time in 6 Eyes With Progressive Geographic Chorioretinal Atrophy Attributable to Pseudoxanthoma Elasticum

Initial Initial Area of Final Visual Final Area of Growth of Linear Pigment Patient (Eye) Age, Sex Visual Acuity Geographic Atrophy Length of Follow-up Acuity Geographic Atrophy Geographic Atrophy Deposits

1 (OD) 52, Ma 20/20 1.50 mm2 2 years 20/20 6.51 mm2 2.51 mm2/y Yes 1 (OS) 50, M 20/20 2.50 mm2 4 years, 5 months 20/20 7.13 mm2 1.05 mm2/y Yes 2 (OD) 53, F 20/200 8.07 mm2 6 years 20/400 21.20 mm2 2.19 mm2/y Yes 2 (OS) 53, F 20/60 3.14 mm2 6 years 20/150 17.47 mm2 2.39 mm2/y Yes 3 (OS) 41, M 20/25 1.92 mm2 15 months 20/200 3.71 mm2 1.43 mm2/y Yes 4 (OS) 37, M 20/20 0.34 mm2 15 months 20/20 0.80 mm2 0.37 mm2/y No

aThe right eye of Patient 1 developed geographic atrophy 2 years and 5 months after his initial evaluation, whereas atrophy was present in his left eye at initial evaluation.

FIGURE 1. Fundus photographs of a 50-year-old man (Patient 1) with pseudoxanthoma elasticum showing the evolution of pattern dystrophy with progressive non-neovascular geographic atrophy. (Top left and Top right) Images at presentation display angioid streaks, disc drusen, and pattern dystrophy that appeared in some areas as isolated pigment clumps (white arrows) and in other areas as linear pigment deposits (black arrowhead). Geographic atrophy is present in the left eye measuring 2.50 mm2. (Bottom left and Bottom right) Four years and 5 months later, the right eye has geographic atrophy (6.51 mm2), while the atrophy in the left eye is larger (7.13 mm2). Disappearance of the linear pigment deposits is observed with progression of the geographic atrophy.

geographic atrophy in both eyes were linear areas of mild outer nuclear layer corresponding to the linear pigment hyperautofluorescence corresponding to linear pigment deposits (Figure 2, Middle row and Bottom row, white deposits (black arrowheads). Infrared and spectral- arrowhead; magnified on left insets). Subretinal domain OCT imaging was performed on the right hyperreflectivity corresponding to RPE was present in (Figure 2, Middle row) and left (Figure 2, Bottom row) areas of isolated pigment clumps (Figure 2, Middle row eyes, which showed hyperreflectivity at the level of the and Bottom row, white asterisk; magnified on right insets).

VOL. 156,NO. 4 GEOGRAPHIC ATROPHY IN PSEUDOXANTHOMA ELASTICUM 717 FIGURE 2. Fundus autofluorescence (FAF), infrared, and spectral-domain optical coherence tomography (SDOCT) imaging of a 54-year-old man (Patient 1) with pseudoxanthoma elasticum showing multiple types of pattern dystrophy with non-neovascular geographic atrophy. (Top left and Top right) FAF shows geographic atrophy (hypoautofluorescence) and pattern dystrophy (hyperautofluorescence). The highly hyperautofluorescent areas correspond to pigment clumps (fundus pulverulentus, white arrows), while the linear pigment deposits are mildly hyperautofluorescent (butterfly-pattern dystrophy, black arrowheads). (Middle row and Bottom row) Infrared and SDOCT imaging show hyperreflectivity at the level of the outer nuclear layer corresponding to the linear pigment deposits (white arrowheads; magnified in left insets). Subretinal hyperreflectivity is present in areas of isolated pigment clumps (white asterisks; magnified in right insets).

Patient 2. Patient 2 was a 49-year-old woman with OS (Figure 3, Third row). The progression rate was angioid streaks, peau d’orange, pigment clumps, and 2.19 mm2 per year OD and 2.39 mm2 per year OS. linear pigment deposits in the macula consistent with FAF showed geographic atrophy to be distinct from pattern dystrophy in both eyes, without signs of CNV or peripapillary atrophy and angioid streaks (Figure 3, geographic atrophy (Figure 3, Top row; linear pigment Bottom row). FAF also showed extensive areas of hyper- deposits, black arrowheads). Visual acuity at that time and hypoautoﬂuorescence, indicative of widespread RPE was 20/30 OD and 20/40 OS. At age 53, her vision disease. Pigment clumps of pattern dystrophy were more worsened to 20/200 OD and 20/60 OS. Central easily seen on FAF than on the photographs (white arrows). geographic atrophy was present in both eyes, measuring 8.07 mm2 OD and 3.14 mm2 OS (Figure 3, Second row). Patient 3. Patient 3 was a 41-year-old man with VA of Over the next 6 years, VA declined to 20/400 OD and 20/20 OD and 20/25 OS. Angioid streaks, pattern 20/150 OS with enlargement of geographic atrophy in dystrophy, and midperipheral comet-tail lesions were both eyes, measuring 21.20 mm2 OD and 17.47 mm2 seen in both eyes on fundus photography. He had

718 AMERICAN JOURNAL OF OPHTHALMOLOGY OCTOBER 2013 FIGURE 3. Fundus photographs of a 49-year-old woman (Patient 2) with pseudoxanthoma elasticum showing the evolution of pattern dystrophy with progressive non-neovascular geographic atrophy. (Top left and Top right) Fundus photographs at presentation show pigment clumps (white arrows) and linear pigment deposits (black arrowheads) in both eyes without geographic atrophy. (Second row left and Second row right) Four years later there are large areas of geographic atrophy in both eyes, measuring 8.07 mm2 OD and 3.14 mm2 OS. (Third row left and Third row right) Photographs 6 additional years later demonstrate enlargement of atrophy in both eyes, measuring 21.20 mm2 OD and 17.47 mm2 OS. (Bottom left and Bottom right) Fundus autofluorescence shows hypoautofluorescence of the geographic atrophy. Pigment clumps are subtle on photography but more evident on autofluorescence (white arrows). The linear pigment deposits gradually disappear with enlargement of the geographic atrophy.

VOL. 156,NO. 4 GEOGRAPHIC ATROPHY IN PSEUDOXANTHOMA ELASTICUM 719 FIGURE 4. Fundus photographs and fundus autofluorescence (FAF) of a 37-year-old man (Patient 3) with pseudoxanthoma elasticum showing the evolution of pattern dystrophy with progressive non-neovascular geographic atrophy. (Top left) At initial presentation, the left eye has scattered patches of atrophy (black arrows). (Top right) FAF imaging shows the pigment clumps to be highly hyperautofluorescent (white arrows) and the linear pigment deposits to be mildly hyperautofluorescent (black arrowheads). (Bottom left) Fundus photograph 15 months later shows enlargement of the isolated patches of atrophy. (Bottom right) FAF confirms enlargement of atrophy. Some pigment clumps remain (white arrows), while the linear pigment deposits appear like a ring.

subfoveal fibrosis OD and several distinct areas of atrophy vision remained unchanged, but the area of atrophy OS measuring a total of 1.92 mm2 (Figure 4, Top left) increased to 0.80 mm2 (0.37 mm2 per year). Within the that were also seen on FAF (Figure 4, Top right). next year, he developed subretinal hemorrhage and subre- Intensely hyperautofluorescent pigment clumps (white tinal fibrosis from the laser scars that eventually extended arrows) and mildly hyperautofluorescent linear pigment into the area of atrophy. deposits were seen (black arrowhead). Fifteen months later, VA declined to 20/50 OD and 20/200 OS. Fundus photographs (Figure 4, Bottom left) and FAF (Figure 4, Bottom right) showed enlargement of geographic atrophy DISCUSSION in the left eye, now measuring a total of 3.71 mm2. The 2 rate of enlargement was 1.43 mm per year. Some GEOGRAPHIC ATROPHY MAY BE SEEN IN SEVERAL DISEASES, pigment clumps remained (white arrows), while the including age-related macular degeneration (AMD),11 linear pigment deposits evolved into a ring. maternally inherited diabetes and deafness,12 inherited pattern dystrophies,13 Stargardt macular dystrophy,14 Patient 4. Patient 4 was a 37-year-old man with VA of central areolar dystrophy,15 extensive macular atrophy 20/200 OD and 20/20 OS. Fundus photography showed with pseudodrusen-like appearance,16 late-onset retinal angioid streaks, disc drusen, peau d’orange, and pattern macular degeneration,17 and a resolved vitelliform lesion dystrophy. His right eye had a central disciform scar. His associated with cuticular drusen.18 There are scattered left eye had 2 localized subretinal scars from previous reports describing geographic atrophy in pseudoxanthoma thermal laser photocoagulation for CNV along an angioid elasticum in the absence of CNV.7–10 We describe streak running above the fovea. The left eye had an area of a series of eyes with geographic atrophy in patients with geographic atrophy separate from these scars in the nasal pseudoxanthoma elasticum, their rate of progression over macula that measured 0.34 mm2. Over 15 months, his time, and identification of risk factors. These latter

720 AMERICAN JOURNAL OF OPHTHALMOLOGY OCTOBER 2013 findings have not been previously reported and may aid in hyperautofluorescence of isolated pigment clumps. The understanding the pathogenesis of pseudoxanthoma latter clumps are located in the subretinal space and elasticum. correspond to engulfed fluorophores within native RPE The primary pathologic site in pseudoxanthoma elasti- cells remaining at their natural location. This more cum is the RPE–Bruch membrane complex.19 Several types common finding was seen in several eyes without of RPE alteration have been described, including changes geographic atrophy and appears less predictive of along angioid streaks and associated with CNV.1,3,6,20 geographic atrophy than linear pigment deposits. This Atrophy associated with disciform scarring may be quite suggests that disruption of the photoreceptor-RPE complex extensive, involving the entire macula and nasal to the and migration of RPE cells is a precursor for geographic optic nerve.3,6,19 Cases of geographic atrophy without atrophy. CNV are present in the literature but are limited to Rate of growth of geographic atrophy in pseudoxan- single reports or hidden in a larger series.7–10 Long-term thoma elasticum has not been previously reported and follow-up data were not presented and growth rates were approximates that in atrophic AMD. Using fundus photo- not measured. In addition, associated features and risk graphs, Lindblad and associates determined progression of factors for progression were not ascertained. 1.78 mm2 per year,23 and Sunness and associates reported In the current series, geographic atrophy was present in 8 a median enlargement rate of 2.1 mm2 per year in eyes of 5 patients. Pattern dystrophy was present in all 8 AMD.24 Mean progression in the current series was eyes, whereas in the remaining 33 eyes it was present in 1.7 mm2 per year. Differences were seen between the 2 11 eyes (33%). On our review of the images of the 4 etiologies, aside from what is evident on clinical examina- reported cases of geographic atrophy without CNV in the tion. A ring of hyperautofluorescence around geographic literature,7–10 3 were of adequate quality to determine atrophy may predict further extension in AMD, and is the presence of pattern dystrophy.7,9,10 All 3 had attributable to increased metabolic stress of the surrounding findings on fundus photography, FA, or FAF that were RPE cells.25 In the current study, FAF images were obtained consistent with pattern dystrophy. Pattern dystrophy in in 3 patients (Patients 1, 2, and 3), and none had a ring of pseudoxanthoma elasticum is a common finding, noted hyperautofluorescence. This finding was also absent with in 46% of eyes in this review and 59% of patients in our multilobular atrophy distinct from CNV and angioid previous report (4 patients included in both studies).5 streaks.6 Metabolic stress at the edge of geographic atrophy The presence of pattern dystrophy seems to be required does not appear to contribute in pseudoxanthoma elasticum. for geographic atrophy, though not all eyes with pattern The genetic defect in pseudoxanthoma elasticum dystrophy develop it. Geographic atrophy and pattern involves subclass C of the ATP-binding cassette trans- dystrophy in maternally inherited diabetes and deafness12 porter, which is involved in the metabolism and synthesis and familial pattern dystrophy13 resemble the current of the extracellular matrix.1,3 Genetic mutations may series, suggesting possible overlap in pathophysiology result in aberrant transport mechanisms in the retina, between these entities. leading to abnormal elastin accumulation in the RPE– Two types of hyperautofluorescence of the pigment Bruch membrane complex and impaired removal of waste lesions were seen: mild hyperautofluorescence of the linear products by the choriocapillaris.4 The Bruch membrane or radial pigment deposits and bright punctate hyperauto- becomes thickened and calcified and the number of fluorescence of the pigment clumps. The former likely pigment granules in the RPE decreases.26 The number of represents pigment epithelial migration into the retina, remaining RPE cells may be reduced and become dediffer- representing a disturbance of the interdigitation of the entiated.3,26 Retinal changes may occur because of changes photoreceptor/RPE complex. This may be the earliest in nutrient supply to photoreceptors across a diseased step prior to the development of visible photoreceptor Bruch membrane,8 resulting in full-thickness atrophy of and RPE atrophy. Linear pigment deposits were seen in 5 Bruch membrane, RPE, choriocapillaris, and photorecep- of 8 eyes that had, or developed, geographic atrophy tors.26 RPE dedifferentiation and intraretinal migration (Patients 1, 2, and 3), and its presence may predict devel- appears to precede atrophy of the RPE–Bruch membrane opment of, or worsening, atrophy. Two eyes of 1 patient complex. without geographic atrophy or CNV had linear pigment Although there are no currently approved treatments deposits, but follow-up imaging was not available so for geographic atrophy, several therapies are in clinical progression to atrophic or neovascular disease could not trials or preclinical testing. Ciliary neurotrophic factor be assessed. OCT imaging of 2 eyes in 1 patient (Patient delivered by encapsulated cell technology can slow 1) with geographic atrophy revealed pigment to be at the progressive vision loss attributable to geographic atrophy outer nuclear layer. Intraretinal pigment migration has in AMD.27 Stem cell technology and fenretinide have also been described in type II macular telangiectasia and also shown some promise in AMD.28,29 Clinical trials AMD, where migration occurs over areas of outer retinal are ongoing for doxycycline, sirolimus, and fluocinolone or RPE disruption.21,22 The imaging findings of linear acetonide intravitreal implants, among others.30–32 It is pigment deposits are in contrast to bright punctate important to recognize geographic atrophy as a cause of

VOL. 156,NO. 4 GEOGRAPHIC ATROPHY IN PSEUDOXANTHOMA ELASTICUM 721 severe vision loss in pseudoxanthoma elasticum. Findings atrophy. However, both FAF and color fundus photography such as pattern dystrophy and linear pigment deposits are reliable for measuring geographic atrophy in AMD.11 may represent high-risk features that may benefit from The incidence of atrophy may have been underestimated, earlier intervention, when available. However, it is as it could have preceded CNV in some eyes, which unclear if different pathophysiologic mechanisms of excluded the eye from our analysis. Finally, genotyping geographic atrophy formation in pseudoxanthoma elasti- was not performed on any patients in the study; cum and AMD would result in different treatment genotype-phenotype associations have been previously responses. It seems plausible that restoration of lost photo- described in pseudoxanthoma elasticum.33 receptors (ciliary neurotrophic factor, stem cells) would be In conclusion, geographic atrophy can develop in pseu- more successful in pseudoxanthoma elasticum than target- doxanthoma elasticum independent of CNV, resulting in ing AMD-based pathways (fenretinide). severe vision loss. Linear pattern dystrophy may predict There are limitations to this study. It is retrospective development of geographic atrophy. Progression is similar with variable follow-up. Aside from fundus photography, to AMD. Some of the future treatments that become avail- imaging was not uniform. In addition, atrophy was identi- able to slow or reverse geographic atrophy in AMD may fied and measured using fundus photography. FAF and also benefit patients with pseudoxanthoma elasticum. Early high-resolution OCT were not available until recently identification of this finding and predisposing factors may and were only used as adjunctive studies to aid in outlining be critical when such therapies become available.

BOTH AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF Interest. The authors report no ﬁnancial disclosures. This work was supported in part by an unrestricted grant from Research to Prevent Blindness to the Vanderbilt University School of Medicine Department of Ophthalmology and Visual Sciences. Author contributions: conception and design (S.D.S., A.A.); analysis and interpretation (S.D.S., A.A.); writing the article (S.D.S.); critical revision of the article (A.A.); ﬁnal approval of the article (S.D.S., A.A.); data collection (S.D.S., A.A.); provision of materials, patients, or resources (AA); obtaining funding (A.A.); literature search (S.D.S.); and administrative, technical, or logistical support (A.A.).

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