An update on the ocular phenotype in patients with pseudoxanthoma elasticum
Martin Gliem, Julie De Zaeytijd, Robert P Finger, Frank G Holz, Bart P Leroy, Peter Charbel Issa, Martin Gliem, Julie De Zaeytijd, Robert P Finger, Frank G Holz, Bart P Leroy, Peter Charbel Issa
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.
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References
- Aessopos A., Farmakis D., Loukopoulos D. (2002). Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes. Blood. 99 30–35
- Agarwal A., Patel P., Adkins T., Gass J. D. (2005). Spectrum of pattern dystrophy in pseudoxanthoma elasticum. Arch. Ophthalmol. 123 923–928
- Audo I., Vanakker O. M., Smith A., Leroy B. P., Robson A. G., Jenkins S. A., et al. (2007). Pseudoxanthoma elasticum with generalized retinal dysfunction, a common finding? Invest. Ophthalmol. Vis. Sci. 48 4250–4256
- Baillif-Gostoli S., Quaranta-El Maftouhi M., Mauget-Faysse M. (2010). Polypoidal choroidal vasculopathy in a patient with angioid streaks secondary to pseudoxanthoma elasticum. Graefes Arch. Clin. Exp. Ophthalmol. 248 1845–1848
- Bergen A. A., Plomp A. S., Schuurman E. J., Terry S., Breuning M., Dauwerse H., et al. (2000). Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat. Genet. 25 228–231
- Böck J. (1938). Zur Klinik und Anatomie der gefäβähnlichen Streifen im Augenhintergrund. Z. Augenheilk. 95 1–49
- Britten M. J. (1966). Unusual traumatic retinal haemorrhages associated with angioid streaks. Br. J. Ophthalmol. 50 540–542
- Charbel Issa P., Finger R. P., Götting C., Hendig D., Holz F. G, Scholl H. P. N. (2010a). Centrifugal fundus abnormalities in pseudoxanthoma elasticum. Ophthalmology 117 1406–1414
- Charbel Issa P., Tröger E., Finger R., Holz F. G., Wilke R, Scholl H. P. N. (2010b). Structure–function correlation of the human central retina. PLoS ONE 5:e12864. 10.1371/journal.pone.0012864
- Charbel Issa P., Finger R. P., Holz F. G, Scholl H. P. N. (2009). Multimodal imaging including spectral domain OCT and confocal near infrared reflectance for characterisation of outer retinal pathology in pseudoxanthoma elasticum. Invest. Ophthalmol. Vis. Sci. 50 5913–5918
- Chassaing N., Martin L., Calvas P., Le B. M., Hovnanian A. (2005). Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J. Med. Genet. 42 881–892
- Chong N. H., Keonin J., Luthert P. J., Frennesson C. I., Weingeist D. M., Wolf R. L., et al. (2005). Decreased thickness and integrity of the macular elastic layer of Bruch’s membrane correspond to the distribution of lesions associated with age-related macular degeneration. Am. J. Pathol. 166 241–251
- Clarkson J. G., Altman R. D. (1982). Angioid streaks. Surv. Ophthalmol. 26 235–246
- De Zaeytijd J., Vanakker O. M., Coucke P. J., De Paepe A., De Laey J. J., Leroy B. P. (2010). Added value of infrared, red-free and autofluorescence fundus imaging in pseudoxanthoma elasticum. Br. J. Ophthalmol. 94 479–486
- Domke H., Tost M. (1964). Zur Histologie der “Angioid Streaks”. Klin.Mbl.Augenheilk. 145 18–29
- Doyne R. W. (1889). Choroidal and retinal changes the result of blows on the eyes. Trans. Ophthalmol. Soc. U.K. 9 128
- Dreyer R., Green W. R. (1978). The pathology of angioid streaks: a study of twenty-one cases. Trans. Pa Acad. Ophthalmol. Otolaryngol. 31 158–167
- Ellabban A. A., Hangai M., Yamashiro K., Nakagawa S., Tsujikawa A., Yoshimura N. (2012a). Tomographic fundus features in pseudoxanthoma elasticum: comparison with neovascular age-related macular degeneration in Japanese patients. Eye 26 1086–1094
- Ellabban A. A., Tsujikawa A., Matsumoto A., Ogino K., Hangai M., Ooto S., et al. (2012b). Macular choroidal thickness and volume in eyes with angioid streaks measured by swept source optical coherence tomography. Am. J. Ophthalmol. 153 1133–1143
- Federman J. L., Shields J. A., Tomer T. L. (1975). Angioid streaks. II. Fluorescein angiographic features. Arch. Ophthal. 93 951–962
- Finger R. P., Charbel Issa P., Holz F. G., Ladewig M. S, Scholl H. P. N. (2009a). Fundus autofluorescence in patients with pseudoxanthoma elasticum. Retina 29 1496–1505
- Finger R. P., Charbel Issa P., Ladewig M. S., Götting C., Szliska C., Scholl H. P. N., et al. (2009b). Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches. Surv. Ophthalmol. 54 272–285
- Finger R. P., Charbel Issa P., Schmitz-Valckenberg S., Holz F. G., Scholl H. N. (2011a). Long-term effectiveness of intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks in pseudoxanthoma elasticum. Retina 31 1268–1278
- Finger R. P., Fenwick E., Marella M., Charbel Issa P., Scholl H. P., Holz F. G., et al. (2011b). The relative impact of vision impairment and cardiovascular disease on quality of life: the example of pseudoxanthoma elasticum. Health Qual. Life Outcomes 9:113. 10.1186/1477-7525-9-113
- Francois J., De Rouck A. (1981). Electrophysiological studies in Grönblad–Strandberg syndrome. Doc. Ophthalmol. Proc. Ser. 23 19–25
- Gass J. D. (2003). “Comet”lesion: an ocular sign of pseudoxanthoma elasticum. Retina 23 729–730
- Gass J. D. M. (1967). Pathogenesis of disciform detachment of the neuroepithelium. Am. J. Ophthalmol. 63 689–711
- Gass J. D., Clarkson J. G. (1973). Angioid streaks and disciform macular detachment in Pagets disease (osteitis deformans). Am. J. Ophthalmol. 75 576–586
- Gills J. P., Paton D. (1965). Mottled fundus oculi in pseudoxanthoma elasticum: a report on two siblings. Arch. Ophthalmol. 73 792–795
- Gliem M., Brinkmann C. K., Holz F. G, Charbel Issa P. (2013). Treatment of choroidal neovascularizations due to angioid streaks – a comprehensive review. Retina 10.1097/IAE.0b013e3182914d2b
- Green W. R., Friedman-Kien A., Banfield W. G. (1966). Angioid streaks in Ehlers–Danlos syndrome. Arch. Ophthalmol. 76 197–204
- Grönblad E. (1929). Angioid streaks – pseudoxanthoma elasticum: Vorläufige Mitteilung. Acta Ophthalmol. 7 329
- Hagedoorn A. (1939). Angioid streaks. Arch. Ophthalmol. 21 746–774
- Hagedoorn A. (1975). Angioid streaks and traumatic ruptures of Bruch’s membrane. Br. J Ophthalmol. 59 267
- Hallopeau H. F., Laffitte P. (1903). Nouvelle note sur un cas de pseudoxanthome élastique. Ann. Dermatol. Syphiligr. (Paris) 4 595
- Holz F. G., Jubb C., Fitzke F. W., Bird A. C., Pope F. M. (1994). Dark adaptation and scotopic perimetry over ‘peau d’orange’ in pseudoxanthoma elasticum. Br. J. Ophthalmol. 78 79–80
- Hu X., Plomp A. S., Van Soest S., Wijnholds J., De Jong P. T., Bergen A. A. (2003). Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update. Surv. Ophthalmol. 48 424–438
- Jampol L. M., Acheson R., Eagle R. C., Jr., Serjeant G, O’grady R. (1987). Calcification of Bruch’s membrane in angioid streaks with homozygous sickle cell disease. Arch. Ophthalmol. 105 93–98
- Jensen O. A. (1977). Bruch’s membrane in pseudoxanthoma elasticum. Histochemical, ultrastructural, and x-ray microanalytical study of the membrane and angioid streak areas. Albrecht Von Graefes Arch. Klin. Exp. Ophthalmol. 203 311–320
- Jiang Q., Endo M., Dibra F., Wang K., Uitto J. (2008). Pseudoxanthoma elasticum is a metabolic disease. J. Invest. Dermatol. 129 348–354
- Jiang Q., Oldenburg R., Otsuru S., Grand-Pierre A. E., Horwitz E. M., Uitto J. (2010). Parabiotic heterogenetic pairing of Abcc6-/-/Rag1-/- mice and their wild-type counterparts halts ectopic mineralization in a murine model of pseudoxanthoma elasticum. Am. J. Pathol. 176 1855–1862
- Kalal I. G., Seetha D., Panda A., Nitschke Y., Rutsch F. (2012). Molecular diagnosis of generalized arterial calcification of infancy (GACI). J. Cardiovasc. Dis. Res. 3 150–154
- Klien B. A. (1947). Angloid streaks; a clinical and histopathologic study. Am. J. Ophthalmol. 30 955–968
- Knapp H. (1892). On the formation of dark angioid streaks as an unusual metamorphosis of retinal hemorrhage. Arch. Ophthalmol. 21 289–292
- Kofler A. (1917). Beiträge zur Kenntnis der Angioid streaks. Arch. Augenheilkd. 82 134–149
- Krill A. E., Klien B. A., Archer D. B. (1973). Precursors of angioid streaks. Am. J. Ophthalmol. 76 875–879
- Lafaut B. A., Leys A. M., Scassellati-Sforzolini B., Priem H, De Laey J. J. (1998). Comparison of fluorescein and indocyanine green angiography in angioid streaks. Graefes Arch. Clin. Exp. Ophthalmol. 236 346–353
- Li Q., Grange D. K., Armstrong N. L., Whelan A. J., Hurley M. Y., Rishavy M. A., et al. (2009a). Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes. J. Invest. Dermatol. 129 553–563
- Li Q., Jiang Q., Pfendner E., Varadi A., Uitto J. (2009b). Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms. Exp. Dermatol. 18 1–11
- Mansour A. M., Ansari N. H., Shields J. A., Annesley W. H., Jr., Cronin C. M., Stock E. L. (1993). Evolution of angioid streaks. Ophthalmologica 207 57–61
- Mansour A. M. (1998). Marked thickening of Bruch’s membrane in a 17-year-old patient with angioid streaks. Eye 12 898–900
- Matsuzaki Y., Nakano A., Jiang Q. J., Pulkkinen L., Uitto J. (2005). Tissue-specific expression of the ABCC6 gene. J. Invest. Dermatol. 125 900–905
- McWilliam R. J. (1951). On the histology of angioid streaks. Trans. Ophthalmol. Soc. U.K. 71 243–249
- Meislik J., Neldner K., Reeve E. B., Ellis P. P. (1979). Atypical drusen in pseudoxanthoma elasticum. Ann. Ophthalmol. 11 653–656
- Myung J. S., Bhatnagar P., Spaide R. F., Klancnik J. M., Jr., Cooney M. J., Yannuzzi L. A., et al. (2010). Long-term outcomes of intravitreal antivascular endothelial growth factor therapy for the management of choroidal neovascularization in pseudoxanthoma elasticum. Retina 30 748–755
- Nakagawa S., Yamashiro K., Tsujikawa A., Otani A., Tamura H., Ooto S., et al. (2013). The time course changes of choroidal neovascularization in angioid streaks. Retina. 10.1097/IAE.0b013e31826b0bbe [Epub ahead of print].
- Naouri M., Boisseau C., Bonicel P., Daudon P., Bonneau D., Chassaing N., et al. (2009). Manifestations of pseudoxanthoma elasticum in childhood. Br. J. Dermatol. 161 635–639
- Patnaik B, Malik S. R. K. (1971). Fluorescein fundus photography of angioid streaks. Br. J. Ophthalmol. 55 833–837
- Pierro L., Brancato R., Minicucci M., Pece A. (1994). Echographic diagnosis of drusen of the optic nerve head in patients with angioid streaks. Ophthalmologica 208 239–242
- Plange O. (1891). über streifenförmige Pigmentbildung mit sekundären Veränderungen der Netzhaut infolge von Hämorrhagien. Arch. Augenheilkd. 23 78–90
- Plomp A. S., Bergen A. A., Florijn R. J., Terry S. F., Toonstra J., Van Dijk M. R., et al. (2009). Pseudoxanthoma elasticum: wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6. Genet. Med. 11 852–858
- Plomp A. S., Florijn R. J., Ten Brink J., Castle B., Kingston H., Martin-Santiago A., et al. (2008). ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones. Mol. Vis. 14 118–124
- Plomp A. S., Toonstra J., Bergen A. A., Van Dijk M. R, De Jong P. T. (2010). Proposal for updating the pseudoxanthoma elasticum classification system and a review of the clinical findings. Am. J. Med. Genet. A 152A 1049–1058
- Pruett R. C., Weiter J. J., Goldstein R. B. (1987). Myopic cracks, angioid streaks, and traumatic tears in Bruch’s membrane. Am. J. Ophthalmol. 103 537–543
- Sawa M., Ober M. D., Freund K. B., Spaide R. F. (2006). Fundus autofluorescence in patients with pseudoxanthoma elasticum. Ophthalmology 113 814–820
- Scholz R. O. (1941). Angioid streaks. Arch. Ophthalmol. 26 677–695
- Shiraki K., Kohno T., Moriwaki M., Yanagihara N. (2001). Fundus autofluorescence in patients with pseudoxanthoma elasticum. Int. Ophthalmol. 24 243–248
- Smith J. L., Gass J. D. M., Justice J. (1964). Fluorescein fundus photography of angioid streaks. Br. J. Ophthalmol. 48 517–521
- Strandberg J. (1929). Pseudoxanthoma elasticum. Zbl. Haut Geschlkr. 31 689
- Uitto J., Bercovitch L., Terry S. F., Terry P. F. (2011). Pseudoxanthoma elasticum: progress in diagnostics and research towards treatment: summary of the 2010 PXE International Research Meeting. Am. J. Med. Genet. A 155A 1517–1526
- Verhoeff F. H. (1948). Histological findings in a case of angioid streaks. Br. J. Ophthalmol. 32 531–544
- von Winning C. H., Oosterhuis J. A. (1974). A fluorographic study of reticular patterns in the fundus. Am. J. Ophthalmol. 77 491–498
- Zweifel S. A., Imamura Y., Freund K. B., Spaide R. F. (2011). Multimodal fundus imaging of pseudoxanthoma elasticum. Retina 31 482–491
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