Disk Drusen and Angioid Streaks in Pseudoxanthoma Elasticum

Disk Drusen and Angioid Streaks in Pseudoxanthoma Elasticum Kate Coleman, F.R.C.S.Ed., Monique Hope Ross, F.R.C.S., Mary Me Cabe, M.R.C.Path., Rosemary Coleman, M.R.C.P.I., and David Mooney, F.R.C.S. Visual field loss secondary to optic disk drusen became evident before the development of angioid streaks in a patient with pseudoxanthoma elasticum. The incidence of optic disk drusen in cases of pseudoxanthoma elasticum is 20 to 50 times greater than that in the healthy population. We postulate that the abnormal aggregation of macromolecules with a high affinity for calcium (resulting in abnormalities in elastin in cases of pseudoxanthoma elasticum) also develops at the cribriform plate, disrupting axonal flow and leading to disk drusen formation. Pseudoxanthoma elasticum is associated with marked cardiovascular and gastrointestinal morbidity. Moreover, macular hemorrhage and precipitation of angioid streaks have frequently been noted after trauma. Prompt diagnosis of pseudoxanthoma elasticum will allow necessary prophylaxis and must be considered in patients with optic disk drusen.

P

SEUDOXANTHOMA ELASTlCUM is an uncommon inherited disorder with a reported prevalence of one in 160,000 human beings.' It affects the elastin in the dermis, arterial walls, and Bruch's membrane, resulting in abnormal mineralization and deposition of phosphorus in the fibrils. Hemorrhage (usually gastrointestinal) is the primary life-threatening complication and affects up to 15% of patients with pseudoxanthoma elasticum, frequently before the onset of cutaneous or ocular symptoms." Eighty-

Accepted for publication May 20, 1991. From the Royal Victoria Eye and Ear Hospital, Dublin, Ireland (Drs. K. Coleman, Ross, and Mooney); Department of Pathology, Hume St. Hospital and St. Vincents Hospital, Dublin, Ireland (Dr. Mc Cabe); and Department of Dermatology, Addenbrooke's Hospital, Cambridge, England (Dr. R. Coleman). Reprint requests to Kate Coleman, F.R.C.S.Ed., The Orbital Center, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.

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five percent of the patients develop angioid streaks, usually in the second decade of life,2 and over 70% develop loss of central vision.v' Optic disk drusen are inherited in an irregular autosomal dominant fashion with a clinical incidence of 3.4/1,000 human beings.' Visual field loss is common. Both angioid streaks and optic disk drusen may be associated with subretinal and intraretinal hemorrhages. In this study, we evaluated the association between optic disk drusen and angioid streaks in a family of eight siblings with a history of pseudoxanthoma elasticum.

Patients A 23-year-old myopic male (Patient II-I) had reduced visual acuity and tunnel vision. On examination, corrected visual acuity was R.E.: 20/16 and L.E.: 20/16. He had bilateral optic disk drusen. Perimetry demonstrated rightfield constriction and a left inferonasal scotoma. He was also found to have convergence insufficiency which responded to orthoptic exercises. His old photographs were not available. Seventeen years later he was reviewed routinely at the Royal Victoria Eye and Ear Hospital. Corrected visual acuity was R.E.: 20/ 60 and L.E.: 20/16. He had developed bilateral peripapillary angioid streaks with peau d' orange mottling in the mid temporal peripheries. Results of a general physical examination disclosed the typical chicken-skin appearance of pseudoxanthoma elasticum on his neck. The diagnosis was confirmed by skin biopsy (Fig. 1). In view of these findings, the extended family was examined. A family tree was constructed (Fig. 2). Patient 1I-2 had bilateral angioid streaks associated with optic disk drusen and visual field loss. Patient 1I-4 had angioid streaks associated with peau d'orange mottling and short vertical retinal lines concentric to the disk margin, the

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which were detected by routine ophthalmoscopy when the patient was 40 years old. It was only after this discovery that the patient was examined for pseudoxanthoma elasticum, and cutaneous clinical signs were confirmed by skin biopsy.

Discussion

Fig. 1 (Coleman and associates). Photomicrograph of histologic section of skin of patient II-l showing the swollen clumped elastic fibers (arrow) of pseudoxanthoma elasticum (Verhoeff stain, x 250).

cracked-eggshell retinal changes described by Shields and associates.' Patients 11-3 and 11-7 had bilateral angioid streaks; Patient 11-7 also had peau d'orange mottling and early retinal pigment epithelial changes at the macula. Patient 11-5 had early macular degeneration. All siblings were examined clinically for pseudoxanthoma elasticum and it was decided that skin biopsies were not needed in view of the obvious ocular manifestations and confirmed diagnosis (Table). At initial examination, the propositus (Patient II-I) had visual field loss associated with optic disk drusen at the age of 23 years. This preceded the development of angioid streaks,

Pseudoxanthoma elasticum may be inherited as an autosomal dominant (type I and type II) or an autosomal recessive (type I and type II) disorder." Autosomal dominant (type I) is characterized by flexural skin lesions, severe cardiovascular disease, chorioretinal changes, and myopia. Type II autosomal dominant pseudoxanthoma elasticum is a milder variant characterized by focal skin lesions, hyperextensible skin, arched palate, angioid streaks, prominent choroidal vessels, and myopia with minimal vascular manifestations. Type I autosomal recessive pseudoxanthoma elasticum is of intermediate severity between type I and type II autosomal dominant pseudoxanthoma elasticum and shows flexural skin lesions, mild cardiovascular disease, and mild localized chorioretinal changes. Type II autosomal recessive pseudoxanthoma elasticum is the most uncommon variant and is characterized by generalized cutaneous laxity. Skin biopsies may confirm pseudoxanthoma elasticum when there are no clinical signs," Variable expressivity is common in dominantly inherited diseases. The clinical findings in the family suggest a type II autosomal dominant inheritance with incomplete penetrance. However, the lack of clinical signs in the parents would also support an autosomal recessive condition.

FAMILY TREE

II

Fig. 2 (Coleman and associates). Family tree showing ocular manifestations of pseudoxanthoma elasticum in eight siblings.

III

III Male not affected

f;J Angioid streaks

Q;) Female not affected

streaks, cutaneous pseudoxanlhoma elasticum • Angioid streaks, disc drusen and

X PelSOllally examined

< Propositus

!IIAllgioid

cutaneous pseudoxanthoma elasticum

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TABLE SUMMARY OF CLINICAL FINDINGS IN A FAMILY WITH PSEUDOXANTHOMA ELASTICUM PEDIGREE NO., AGE (YRS) GENDER

SYMPTOMS

OCULAR SIGNS

GENERAL CLINICAL SIGNS

11-1,40, M

Reduced visual acuity, tunnel vision

Pseudoxanthoma elasticum (neck) confirmed by skin biopsy, gastric ulcer

11-2,38, M

Glare, tunnel vision

11-3,36, M

None

Myopia; corrected visual acuity; RE., 20/16, L.E., 20/16; convergence insufficiency; right constricted field; left inferonasal scotoma at age 23; corrected visual acuity; RE., 20/60, L.E., 20/16; bilateral optic disk drusen; bilateral angioid streaks; peau d'orange mottling; no change in visual fields at age 40 Myopia; corrected visual acuity; RE., 20/20, L.E., 20/20; bilateral optic disk drusen; bilateral angioid streaks; constricted visual fields at age 29; No change at age 38 Myopia; corrected visual aCUity; R.E., 20/20, L.E., 20/20; bilateral angioid streaks

11-4.35,M

None

11-5,32, M

None

11-6,30.F

None

11-7,25, M

None

11-8,23, M 1-1,68, M

None None

1-2,65, F

None

Myopia; corrected visual aCUity; R.E., 20/20, L.E., 20/20; bilateral angioid streaks; bilateral peau d'orange mottling; cracked egg-shell appearance Emmetropia; visual acuity; R.E., 20/20, L.E., 20/20; macular degeneration; peripapillary atrophy Severe myopia; corrected visual acuity; RE., 20/20, L.E., 20/20; myopic degeneration; prominent choroidal vasculature Emmetropia; visual acuity; R.E., 20/20, L.E., 20/20; bilateral angioid streaks; peau d'orange mottling; macular pigment changes Emmetropia; visual acuity; RE., 20/16, L.E., 20/16 Presbyopia; corrected visual acuity; R.E., 20/20, L.E., 20/20 Severe myopia; corrected visual acuity; R.E., 20/20; L.E., 20/20; prominent choroidal vessels; increased myopia

Eighty-five percent of patients with pseudoxanthoma elasticum demonstrate angioid streaks." These angioid streaks usually develop after the second decade and may develop up to the fifth decade of life. Loss of visual acuity is common and over 60% have a visual acuity less than 20/200 after the age of 50 years. This results from foveal involvement by a streak or is because of the development of a subretinal neovascular membrane.v' Macular degeneration usually develops at a young age" and may precede the appearance of a streak.' Other ocular findings include peau d'orange mottling, cracked-eggshell appearance, salmon spots, and optic disk drusen. Disk drusen have been associated with these clinical signs before the development of angioid streaks" and have been well described in siblings of these patients.P:" They may, however, as demonstrated by the propositus, be the only ocular manifestation of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (neck), peptic ulcer

Pseudoxanthoma elasticum (neck). gastric ulcer None

None None

None

None None None

Optic disk drusen are inherited as an irregular autosomal dominant trait. Lorentzen" reported an incidence of 0.34% in a study of 3,200 eyes. In pseudoxanthoma elasticum, the incidence is between 6% (five of 86 eyes)" and 16% (ten of 112 eyes).' Visual field loss as a result of disk drusen develops in over 70% of patients with optic disk drusen and is usually in the form of nerve-fiber bundle defects or concentric constriction. Central vision is almost always spared,":" although vision may deteriorate suddenly because of direct compression of a vessel by the drusen.":" There is a high risk of visual field loss in patients with both angioid streaks (central loss) and optic disk drusen (peripheral loss). Patients with both conditions may be at an even greater risk of debilitating visual impairment. A review of the literature discloses that the combination of angioid streaks and optic disk drusen has been described exclusively in patients with

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pseudoxanthoma elasticum. We have recently seen both of these clinical signs in a patient with Waldenstrom's macroglobulinemia and believe that they may sometimes coexist in other diseases. Erkkila" hypothesized that the increased incidence of clinical disk drusen in patients with pseudoxanthoma elasticum may be because of enhanced expressivity of the disk drusen gene. Recent work, however, on the pathogenesis of pseudoxanthoma elasticum lends support to a probable common, genetically determined biochemical cause. Pseudoxanthoma elasticum was originally considered to be a result of a primary abnormality of elastin." Yamamura and San020 demonstrated mineralized elastic fibers in a granulomatous matrix composed of fibrinogen, collagenous protein, and glycoprotein. More recently, Walker, Frederickson, and Mayes" used immunocytochemistry and x-ray analysis to show that the earliest abnormality is the accumulation of polyanions in the pseudoxanthoma elasticum dermis. These polyanions have a high affinity for calcium and serve as the initiating factor in mineralization. They noted inconsistent collagen mineralization in addition to the elastin mineralization and hypothesize that the basic genetic abnormality is not one of elastin or calcium metabolism, but of glycoproteins or glycosaminoglycans. These abnormal macromolecules aggregate and then infiltrate and adhere to elastic fibers, resulting in mineralization and abnormal defects in collagen assembly. We believe that these macromolecules may also have a high affinity for the elastic fibers of the cribriform plate. Optic disk drusen are located in front of the lamina cribrosa.P-" Interference with axoplasmic transport at this point produces accumulations ofaxoplasmic material. 24 Ultrastructural studies by Tso25 have indicated that alteration in axonal transport, with abnormal axonal metabolism, leads to intracellular mitochondrial mineralization. Axonal rupture allows extrusion of these mitochondria into the extracellular space and mineralization of these microbodies continues to form drusen. We suggest that in patients with pseudoxanthoma elasticum, an abnormal accumulation of polyanions at the elastin of the cribriform plate results in disruption of axonal transport and subsequent formation of drusen. Disruption of axonal transport would account for the high clinical incidence of disk drusen in these patients. The actual incidence is probably much higher because over 80% of drusen are

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buried in the disk." We would support this hypothesis with histochemical and ultrastructural evidence comparing the connective tissue of the lamina cribrosa in the eyes of patients with pseudoxanthoma elasticum with agematched healthy eyes, but must await available material. From a practical point of view, as demonstrated by the propositus, optic disk drusen may be the earliest clinical manifestation in patients with pseudoxanthoma elasticum, with possible concomitant cardiovascular and gastrointestinal morbidity. It is well documented that ocular trauma in patients with pseudoxanthoma elasticum predisposes to the development of angioid streaks and subsequent visualloss. 7, l o,25.26 It is, therefore, our view that all patients with optic disk drusen should have a dermatologic assessment for evidence of pseudoxanthoma elasticum, so that prudent advice with regard to systemic symptoms and ocular trauma may be given.

References 1. Engelman, M. W., and Fliegelman, M. T.: Pseudoxanthoma elasticum. Cutis 216:837, 1978. 2. Goodman, R. M., Smith, E. W., Paton, D., Bergman, R. A., Siegel, C. L., Ottesen, O. E., Shelley, W. M., Pusch, and McKusick, V. A.: Pseudoxanthoma elasticum. A clinical and histopathological study. Medicine 42:297, 1963. 3. Clarkson, J. G., and Altman, R. D.: Angioid streaks. Surv. Ophthalmol. 26:235, 1982. 4. Shields, J. A., Federman, J. L., Tomer, T. L., and Annesley, W. H.: Angioid streaks. Ophthalmoscopic variations and diagnostic problems. Br. J. Ophthalmol. 59:257, 1975. 5. Lorentzen, S. E.: Drusen of the optic disc. A clinical and genetic study. Acta Ophthalmol. [Suppl.] (Copenh.) 90, 1966. 6. Pope, F. M.: Two types of autosomal recessive pseudoxanthoma elasticum. Arch. Dermatol. 110:209, 1974. 7. Percival, S. P. B.: Angioid streaks and elastorrhexis. Br. J. Ophthalmol. 52:297, 1968. 8. Mansour, A. M., Shields, J. A., Annesley, W. H., Jr., EI-Baba, F., Tasman, W., and Tomer, T. L.: Macular degeneration in angioid streaks. Ophthalmologica 197:36, 1988. 9. Krill, A. E., Klien, B. A., and Archer, D. B.: Precursors of angioid streaks. Am. J. Ophthalmol. 76:875, 1973. 10. Gills, J. P., and Paton, D.: Mottled fundus oculi in pseudoxanthoma elasticum. Arch. Ophthalmol. 73:792, 1965.

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11. Erkkila, H., Raitta, c., and Niemi, K. M.: Ocular findings in four siblings with pseudoxanthoma elasticum. Acta Ophthalmol. 61:589, 1983. 12. Meislik, J., Neldner, K., Basil Reeve, E., and Ellis, P. P.: Atypical drusen in pseudoxanthoma elasticum. Ann. Ophthalmol. 11:653, 1979. 13. Broderick, J. D.: Drusen of the disc and retinal hemorrhages. Br. J. Ophthalmol. 57:299, 1973. 14. Savino, P. J., Glaser, J. S., and Rosenberg, M. A.: Clinical analysis of pseudopapilledema. II. Visual field defects. Arch. Ophthalmol. 97:71, 1979. 15. Mustonen, E.: Pseudopapilledema with and without verified optic disc drusen. A clinical analysis. II. Visual fields. Acta Ophthalmol. 61:1057,1983. 16. Newman, N. J., Lessell, S., and Brandt, E. M.: Bilateral central retinal artery occlusions, disc drusen and migraine. Am. J. Ophthalmol. 107:236, 1989. 17. Sarkies, S. J. c.. and Sanders, M. D.: Optic disc drusen and episodic visual loss. Br. J. Ophthalmol. 71:537, 1987. 18. Erkkila, H.: Optic disc drusen in children. Acta Ophthalmol. [Suppl.] (Copenh.) 129,1977. 19. Martinet-Hernandez, A., and Huffer, W. E.: Pseudoxanthoma elasticum. Dermal polyanions and

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the mineralization of elastic fibers. Lab. Invest. 31:181,1974. 20. Yamamura, T., and Sano, S.: Ultrastructural and histochemical analysis of thready material in pseudoxanthoma elasticum. J. Cutan. Pathol. 11:282, 1984. 21. Walker, E. R., Frederickson, R. G., and Mayes, M. D.: The mineralization of elastic fibers and alterations of extracellular matrix in pseudoxanthoma elasticum. Arch. Dermatol. 125:70, 1989. 22. Rubenstein, K., and Ali, M.: Retinal complications of optic disc drusen. Br. J. Ophthalmol. 66:83, 1982. 23. Friedman, A. H., Gartner, S., and Modi, S. 5.: Drusen of the optic disc. A retrospective study in cadaver eyes. Br. J. Ophthalmol. 59:413, 1975. 24. Spencer, W. H.: Drusen of the optic disc and aberrant axoplasmic transport. Am. J. Ophthalmol. 85:1,1978. 25. Tso, M. O. M.: Pathology and pathogenesis of drusen of the optic nerve head. Ophthalmology 88: 1066, 1981. 26. Doyne, R. W.: Choroidal and retinal changes. The result of blows on the eyes. Trans. Ophthalmol. Soc. U.K. 9:128,1889.

OPHTHALMIC MINIATURE

Him and his two colors of eyes. I don't know what that particular ocular condition is called, maybe Crayola in the genes, but on Riley the unmatched hues were damn disconcerting-his way of looking at you in two tones, flat gray from one side and bright blue the other. Rampant right up to his irises. Ivan Doig, Ride With Me, Mariah Montana New York, Atheneum, 1990, p. 19