An update on the ocular phenotype in patients with pseudoxanthoma elasticum

Abstract

Pseudoxanthoma elasticum (PXE) is an inherited multi-system disorder characterized by ectopic mineralization and fragmentation of elastic fibers in the skin, the elastic laminae of blood vessels and Bruch's membrane in the eye. Biallelic mutations in the ATP-binding cassette (ABC) transporter gene ABCC6 on chromosome 16 are responsible for the disease. The pathophysiology is incompletely understood. However, there is consent that a metabolic alteration leads to dysfunction in extracellular calcium homeostasis and subsequent calcification of connective tissues rich in elastic fibers. This review summarizes and aims at explaining the variety of phenotypic ocular findings in patients with PXE. Specialized imaging techniques including white light fundus photography, blue light autofluorescence, near-infrared confocal reflectance imaging, high resolution optical coherence tomography, fluorescein and indocyanine green (ICG) angiography have revealed characteristic lesions at the ocular fundus of PXE patients. These include the classic signs of angioid streaks, peau d'orange, comet lesions, and choroidal neovascularizations (CNVs), but also the more recently recognized features such as chorioretinal atrophy, subretinal fluid independent from CNV, pattern dystrophy-like changes, debris accumulation under the retinal pigment epithelium, reticular drusen and a decreased fluorescence on late phase ICG angiography.

Keywords: Bruch’s membrane; angioid streaks; choroidal neovascularization; pseudoxanthoma elasticum; retina.

FIGURE 1

Clinical features of pseudoxanthoma elasticum on funduscopic examination. Peau d’orange is characterized by small dark spots on a whitish or opaque background (A–C) and likely represents the transition between calcified and non-calcified Bruch’s membrane. Peau d’orange appears to begin at the posterior pole (A), spreading peripherally over time (B,C,M). Peau d’orange is most pronounced temporaly but may be visible circular within the retinal periphery (M). Angioid streaks are reddish or brownish irregular lines that often form a peripapillary ring from where they radiate into the periphery (D–F,H,M). Small roundish chorioretinal atrophies are frequently found in the retinal periphery eccentric to peau d’orange, but may also occur closer to the optic nerve head. They often present with a tail pointing toward the optic nerve head, leading to the descriptive term of comet tail lesions (G). Not a pathognomonic but frequent finding are optic disc drusen (H). Angioid streaks may be complicated by the development of choroidal neovascularizations (D,I) leading to subsequent atrophy and scarring (J,K). Progressive chorioretinal atrophy may also enlarge without presence of active neovascularizations (J). The resistance of Bruch’s membrane to ocular trauma is reduced leading to extensive bleeding after minor traumata (L). PXE-associated fundus features are summarized in (M) with peau d’orange encompassing the circular periphery, comet tail lesions within the periphery, Angioid streaks not exceeding peau d’orange and central pattern dystrophy-like changes.

FIGURE 2

Features of pseudoxanthoma elasticum on optical coherence tomography. Calcification of Bruch’s membrane may be seen on OCT images. This is best illustrated within areas of peau d’orange, the transition zone between calcified and un-calcified Bruch membrane (A–E). The horizontal arrow in (A) and (B) indicates the placement of the OCT scan in (C). 2.5x magnifications of characteristic details in (C) are shown in (D,E). Area * corresponds to (D) and area # to (E). Areas of increased reflectivity within the outer zone of RPE-Bruch’s membrane complex (arrow heads in D) correlate to the whitish opaque fundus reflex on color images (A) and the increased signal on near-infrared reflectance images (B). Areas of lower reflectivity (E, arrows in D) correlate to the normal fundus reflex. Angioid streaks correlate to breaks within the thickened and hyperreflective Bruch’s membrane (F–H, arrows). Fibrovascular tissue may grow through such breaks (I,J). A typical complication of angioid streaks is the development of choroidal neovascularizations leading to retinal exsudation (K). Eventually, atrophy of the retinal pigment epithelium is associated with atrophic changes in the photoreceptor layer with (L) or without (M) cystoid retinal lesions. In some patients there may be persistent subretinal fluid independent of choroidal neovascularizations (N,Q). If longstanding, a vitelliform lesion may present with deposition of yellowish hyperautofluorescent material at the bottom of the lesion (O–Q). The green arrow in (P) indicates the placement of the OCT scan in (Q).

FIGURE 3

Features of pseudoxanthoma elasticum on fluorescein angiography. Angioid streaks typically show a variable staining on fluorescein angiography (A,B). Comet tail lesions appear as hyperfluorescent spots with their tail toward the optic disk (C,D). Choroidal neovascularizations are mostly classic membranes. Sometimes, their detection may be difficult due to adjacent staining of angioid streaks (E–H).

FIGURE 4

Comparison of clinical features on late phase fluorescein angiography, early and late phase ICG angiography, and funduscopy Late phase fluorescein angiography shows variable staining of angioid streaks (A,E,I) which corresponds well with findings on funduscopy (B,F,J). A characteristic finding on late phase ICG angiography is a centrally reduced fluorescence with a spotted transition zone to normal peripheral fluorescence (C,G,K). Angioid streaks are well visible within the dark non-fluorescent area. Note that there is no correlate on color images (B,F,J) or early ICG angiography frames (D,H,L). Comet tail lesions (J) usually are hyperfluorescent on late phase fluorescein angiograms (I) and hypofluorescent on ICG late phase angiogram (K).

FIGURE 5

Comparison of findings on late phase ICG angiography, NIR reflectance imaging and funduscopy. The transition zone from reduced to normal fluorescence on ICG angiography (A) is located more centrally relative to peau d’orange (B,C). Note that there is no correlate of this phenomenon on IR reflection imaging or funduscopy (D–F). Non-invasive near-infrared (NIR) reflectance imaging (B) often shows peau d’orange and angioid streaks with greater detail and contrast compared to fundus photography (C). Angioid streaks do not cross peau d’orange (G–I). (D–I) Represent a ×3.3 magnification of characteristic details of corresponding areas within (A–C). (D–F) Correspond to area #, (G–I) correspond to area *.

FIGURE 6

Near-infrared reflectance imaging and 488 nm fundus autofluorescence in pseudoxanthoma elasticum. Angioid streaks and peau d’orange are best and most reliably visible on NIR reflectance imaging (B,E,J) correlating well with findings on funduscopy (A,D,K). Peau d’orange is usually not discernible on 488 nm fundus autofluorescence images (C,F). Angioid streaks may present with a reduced autofluorescence (C,F) but may as well remain undetected on autofluorescence imaging (H,I). Note the reticular drusen on NIR reflectance and 488 nm autofluorescence which are sometimes associated with pseudoxanthoma elasticum (H,I).

FIGURE 7

Pattern dystrophy-like changes and atrophy in pseudoxanthoma elasticum on 488 nm fundus autofluorescence imaging. Atrophic lesions and pattern dystrophy-like changes are typical features of advanced pseudoxanthoma elasticum. Compared to funduscopic images (A,C,E,G) these lesions are best visible on 488 nm fundus autofluorescence images (B,D,F,H). Pattern dystrophy-like lesions encompass different patterns of increased autofluorescence. Depending on the stage of pattern dystrophy changes, atrophy of the retinal pigment epithelium with reduced autofluorescence may be present (B,D,F).