The Mystery of Pseudoxanthoma Elasticum

A 46-year-old Caucasian male saw his optometrist complaining of a two-month history of distortion in his left eye. There was no significant past ophthalmic or medical history. The patient’s brother was known to have an eye condition, but the diagnosis was unknown by the patient. No medications were being taken.

Visual acuity was 6/3.8 in the right eye and 6/9.5+2 (pinhole 6/6) in the left eye. Anterior segments were normal.
On fundus examination, bilateral subretinal dark grey concentric and radial lines were noted particularly around the optic nerve heads and maculae (Figure 1). These were identified as angioid streaks. Temporal to both maculae there was a dimpled appearance to the retina, identified as ‘peau d’orange’ (French, translating as ‘orange peel skin’).

The angioid streaks could be easily visualised using fundus autofluorescence (Figure 2). There was no optic disc hyperaufluorescence, that would be seen with buried disc drusen. On optical coherence tomography (OCT) the streaks were seen as disruptions in Bruch’s membrane with elevations of the retinal pigment epithelium (Figure 3). Further examination of the patient’s skin revealed waxy papules (‘plucked chicken’ appearance), especially behind the neck (Figure 4).

Although currently there is no treatment for the underlying ocular or systemic manifestations of PXE, gene therapy may offer the potential of a cure in the future

A diagnosis of pseudoxanthoma elasticum (PXE) was made. Involvement of the left fovea with an angioid streak was noted on OCT. However, there was no associated haemorrhage, lipid or subretinal or intraretinal fluid suggestive of a choroidal neovascularisation (CNV). The distortion was ascribed to the angioid streak alone and fluorescein angiography was not necessary. The patient was advised to avoid activities that could potentially lead to ocular trauma and to wear safety goggles if playing contact sports.

An Amsler grid was provided to monitor for distortion suggestive of CNV. Referrals were made via the patient’s general practitioner to a dermatologist, gastroenterologist and cardiologist to screen for systemic complications associated with pseudoxanthoma elasticum.

Comment

Angioid streaks represent calcification and dehiscences of Bruch’s membrane (lying below the retinal pigment epithelium).^1-3 Through these streaks, CNV can grow. This occurs in 76–82 per cent of eyes with angioid streaks, and is bilateral in over 70 per cent of cases.⁴ The development of CNV tends to occur at a younger age than for neovascular age-related macular degeneration and is associated with a thinner than normal choroid.⁴ All types of CNV can occur2 and treatment with intravitreal anti-VEGF agents has been shown to be useful.^1,5

The aetiology of angioid streaks is diverse, but can be easily remembered by the pnemonic ‘PEPSI’:

• Pseudoxanthoma elasticum
• Ehlers-Danlos syndrome
• Paget’s disease of the bone
• Sickle cell disease
• Idiopathic (no detectable systemic association)

Pseudoxanthoma elasticum (PXE OMIM# 264800) is the most common systemic association of angioid streaks, with a reported incidence of 59–87 per cent.² It is an autosomal recessive disorder caused by mutations in the ABCC6 gene with an estimated prevalence of one in 50,000.6 In PXE, elastic fibres undergo calcification and fragmentation. Skin biopsies showing such changes in the dermal layers can assist with confirming the diagnosis.⁷ Organ involvement includes the eyes, skin, cardiovascular and gastrointestinal systems. The combination of eye and skin changes has previously been named Grönbland-Strandburg syndrome.² Common manifestations are outlined below:^1,3,4,6,8,9

Eyes

• Angioid streaks
• Optic disc drusen
• Peau d’orange
• Peripheral fundus “comets”
• Pattern-like dystrophy
• Choroidal neovascularisation
• Geographic atrophy

Skin (particularly found on flexural skin):

• Peau d’orange
• Yellow papules (“plucked chicken” appearance)
• Inelastic skinfolds

Cardiovascular

• Accelerated atherosclerosis

Gastrointestinal

• Gastrointestinal haemorrhage

Fundus Autofluorescence

Fundus autofluorescence of patients with pseudoxanthoma elasticum is useful in highlighting the streaks and geographic atrophy (both hypoautofluorescent) as well as any buried optic disc drusen (hyperautofluorescent).³

Patients with PXE lose vision due to involvement of the fovea by a streak, CNV or geographic atrophy.^2,9 Minor trauma can cause choroidal rupture in patients with PXE and protective goggles are therefore recommended in patients playing contact sports. Systemic involvement may require referral to a physician. Although currently there is no treatment for the underlying ocular or systemic manifestations of PXE, gene therapy may offer the potential of a cure in the future.

Dr Adrian Fung, MMBS (Hons1), MMed (Ophthal Sci), MMed (Clin Epi), FRANZCO is a vitreoretinal surgeon and medical retinal specialist. He also has expertise in tumours of the retina and choroid. He trained at Sydney Eye Hospital before completing fellowships at the University of British Columbia, Vancouver, Canada; Manhattan Eye Ear & Throat Hospital, New York; Bascom Palmer Eye Institute, Miami and Wills Eye Hospital, Philadelphia, USA. He has published seven ophthalmic books or book chapters and over 40 peer-reviewed journal articles. Dr Fung is a Senior Clinical Lecturer at the University of Sydney and Macquarie University. He works privately at Retina & Macula Specialists (Miranda and Hurstville), Retina Associates (Chatswood, Bondi, Liverpool) and Macquarie University Hospital.

References
1. Finger RP, Charbel Issa P, Hendig D, Scholl HP, Holz FG. Monthly ranibizumab for choroidal neovascularizations secondary to angioid streaks in pseudoxanthoma elasticum: a one-year prospective study. American Journal of Ophthalmology 2011;152:695-703.
2. Nakagawa S, Yamashiro K, Tsujikawa A, et al. The time course changes of choroidal neovascularization in angioid streaks. Retina 2013;33:825-33.
3. Sawa M, Ober MD, Freund KB, Spaide RF. Fundus autofluorescence in patients with pseudoxanthoma elasticum. Ophthalmology 2006;113:814-20.e2.
4. Ellabban AA, Tsujikawa A, Matsumoto A, et al. Macular choroidal thickness and volume in eyes with angioid streaks measured by swept source optical coherence tomography. American Journal of Ophthalmology 2012;153:1133-43.e1.
5. Shah M, Amoaku WM. Intravitreal ranibizumab for the treatment of choroidal neovascularisation secondary to angioid streaks. Eye 2012;26:1194-8.
6. Campens L, Vanakker OM, Trachet B, et al. Characterization of cardiovascular involvement in pseudoxanthoma elasticum families. Arteriosclerosis, Thrombosis & Vascular Biology;33:2646-52.
7. Ko JH, Shih YC, Huang YH, Yang CH. Pseudoxanthoma elasticum. Lancet 2013;381:565.
8. Goldman DR, Lee GD, Shah CP, Heier JS. Initial presentation of pseudoxanthoma elasticum. JAMA Ophthalmology 2013;131:1352.
9. Schoenberger SD, Agarwal A. Geographic chorioretinal atrophy in pseudoxanthoma elasticum. American Journal of Ophthalmology 2013;156:715-23.