Ocular Manifestations of Juvenile Paget Disease

CLINICAL SCIENCES Ocular Manifestations of Juvenile Paget Disease

Nathan M. Kerr, MBChB; Hamilton R. Cassinelli, MD; Linda A. DiMeglio, MD, MPH; Cristina Tau, MD; Beyhan Tüysüz, MD, PhD; Tim Cundy, MD; Andrea L. Vincent, MBChB

Objectives: To determine the prevalence and spec- 12 patients in the literature. Retinal abnormalities in- trum of retinal changes in juvenile Paget disease. cluded mottling of the retinal pigment epithelium, peripapillary atrophy, angioid streaks, and choroidal Methods: Observational case series and literature re- neovascularization. Cumulative number of retinal ab- view with analysis. Patients with clinical and molecular normalities was strongly associated with increasing age. evidence of juvenile Paget disease were recruited by members of the International Hyperphosphatasia Collabora- Conclusions: Juvenile Paget disease is associated with tive Group. Participants underwent ophthalmic exami- progressive retinopathy characterized by the develop- nations consisting of at least best-corrected Snellen visual ment of angioid streaks, which may be complicated by acuity and dilated fundal examination or color fundus choroidal neovascularization, the predominant cause of photography. A MEDLINE literature search was per- visual loss. Osteoprotegerin or its signaling pathway may formed, and all identified case reports were reviewed for have a role in calcification of Bruch membrane and in information regarding ocular phenotype. the pathogenesis of angioid streaks. Retinopathy in patients with juvenile Paget disease may be a sign of a more Results: Fourteen eyes from 7 patients were examined. The mean (SD) patient age was 22 (8) years, and 4 pa- generalized vascular disorder. tients were female. Retinal abnormalities were evident in 12 of 14 eyes and were reported among an additional Arch Ophthalmol. 2010;128(6):698-703

UVENILE PAGET DISEASE, OR IDIO- have received little attention. Retinal pathic hyperphosphatasia, is a changes and blindness have been de- rare recessively inherited disor- scribed in some patients,1,6-9 but the lit- der characterized by greatly erature regarding ocular manifestations of accelerated bone turnover juvenile Paget disease is limited, and most J throughout the skeleton. Since case reports do not indicate whether the the condition was first de- eyes were examined. The objectives of this scribed in 1956, approximately 50 cases study were to determine the prevalence have been reported worldwide.1 Affected and natural history of retinopathy in ju- Author Affiliations: individuals are healthy at birth but mani- venile Paget disease and to characterize the Departments of Ophthalmology, fest progressive long-bone deformity, ky- spectrum of retinal changes. New Zealand National Eye phoscoliosis, growth impairment, and frac- Centre (Drs Kerr and Vincent) tures in infancy or early childhood.2 The and Medicine (Dr Cundy), skull is also involved, and patients typi- METHODS Faculty of Medical and Health Sciences, University of cally have massive thickening of the cal- Auckland, Auckland, New varia and sensorineural hearing loss. Life Patients with juvenile Paget disease were re- Zealand; Endocrinología, expectancy is reduced largely because of cruited by members of the International Hy- Hospital de Ninõs severe restrictive lung disease secondary perphosphatasia Collaborative Group in Ar- (Dr Cassinelli), and to chest wall deformity. Bony changes are gentina, Turkey, the United States, and New Endocrinologıá,Hospital de the consequence of increased activity of Zealand. The sole inclusion criterion was clini- PediatrıáGarrahan (Dr Tau), osteoblasts (bone-forming cells) and os- cal and molecular diagnosis of juvenile Paget Buenos Aires, Argentina; teoclasts (bone-resorbing cells). Juvenile disease. There were no exclusion criteria. The Department of Pediatrics, Riley Paget disease results from deletions or loss- age at diagnosis, presence or absence of visual Hospital for Children, Indiana of-function mutations in the TNFRSF11B symptoms, duration of visual symptoms, ex- University School of Medicine, traocular phenotypic features, and a detailed Indianapolis (Dr DiMeglio); and gene (OMIM *602643), which encodes the family history were obtained for each patient. Department of Pediatrics, protein osteoprotegerin, a key regulator of Ophthalmic examinations consisted of at least 3-5 Cerrahpas¸a Medical Faculty, bone turnover. best-corrected Snellen visual acuity and di- Istanbul University, Istanbul, Because skeletal features predomi- lated binocular indirect ophthalmoscopy by an Turkey (Dr Tüysüz). nate, other manifestations of the disorder ophthalmologist (N.M.K. and A.L.V.) or color

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Patient No./ Parental TNFRSF11B Sex/Age, y Country of Origin Consanguinity Fracture Deformity Deafness Mutation 1/F/13 Turkey • • • • C56R 2/F/14 Argentina • • • F117L 3/F/15a Iraq • • • • delA182 4/M/24 Argentina • • C87Y 5/M/27 United States • • • • T76P 6/F/28a Iraq • • • • delA182 7/M/31a Iraq • • • • delA182

Abbreviations: F, female; M, male. a Siblings.

Table 2. Ophthalmic Features of Study Patients

Best-Corrected Visual Acuity, Snellen Equivalents Retinal Findings Patient No. OD OS Optic Nerve Pallor Peripapillary Atrophy Mottling of RPE Angioid Streaks CNVM 1 20/20 20/20 2 20/20 20/20 • • 3 20/20 20/20 • • • • 4 20/30 20/30 • • 5 20/25 20/20 • • 6 20/20 20/25 • • • • 7 20/20 20/20 • • • • •

Abbreviations: CNVM, choroidal neovascular membrane; RPE, retinal pigment epithelium. fundus photography through pharmacologically dilated pu- TNFRSF11B. Details of the skeletal and genetic findings pils. At a minimum, fields were required from the posterior pole in 6 of these patients have been published previously.3 and the peripheral retina. Because of skeletal manifestations of The ophthalmic findings are summarized in Table 2. this disorder, specifically limited cervical flexion and exten- All patients had best-corrected visual acuity of 20/30 sion, standardized photography was not practical. Where possible, patients underwent full examination by an ophthalmolo- Snellen or better. Results of optic nerve function clini- gist consisting of best-corrected Snellen visual acuity, visual fields cal tests (visual fields to confrontation, brightness sense, to confrontation, brightness sense, red perception, pseudoiso- red perception, pseudoisochromatic color Ishihara plates, chromatic color Ishihara plates, pupillary assessment, slit- and pupillary assessment) and slitlamp examinations of lamp biomicroscopy, Goldmann applanation tonometry, and the anterior segment were normal in patients 3, 6, and dilated funduscopy. All patients provided peripheral blood 7. Slitlamp examination could not be performed in pa- 3 samples for genomic DNA analysis as reported previously. In- tients 1 and 2. formed consent was obtained from all participants, and the study All patients underwent dilated fundal examination by complied with the tenets of the Declaration of Helsinki. A literature search was performed using MEDLINE (Janu- an ophthalmologist or color fundus photography of the ary 1, 1950, to present) for the terms juvenile Paget* disease, posterior pole and peripheral retina through pharmaco- osteoprotegerin deficiency, and idiopathic hyperphosphatasia. All logically dilated pupils. The fundus was normal in only identified case reports were reviewed for information regard- 1 patient examined. Optic nerve pallor was evident in 4 ing the ocular phenotype. patients, and 4 patients had peripapillary atrophy. Five patients had mottling of the retinal pigment epithelium, RESULTS and an equal number had angioid streaks. These changes are shown in Figure 1. In patient 7 (Table 2), angioid Seven patients with juvenile Paget disease were identi- streaks were complicated by peripapillary choroidal neo- fied, and all but 1 had retinal abnormalities. Three pa- vascularization. Shortly after undergoing retinal exami- tients were siblings (patients 3, 6, and 7); clinical details nation as part of this study, patient 4 was seen with signs of all study patients are summarized in Table 1. The mean of cavernous sinus syndrome, including bilateral che- age at presentation was 5 years; most patients mani- mosis and convergent strabismus secondary to bilateral fested difficulty in walking and long-bone deformities with sixth nerve palsies. Magnetic resonance imaging re- or without fractures. The mean (SD) patient age at the vealed large bilateral intracavernous aneurysms of the in- time of study was 22 (8) years (age range, 13-31 years). ternal carotid artery (Figure 2). All patients had sensorineural hearing loss and biochemi- We identified 40 case reports of juvenile Paget dis- cal evidence of increased bone turnover. All were homo- ease describing 55 patients in the literature. Ocular mani- zygous for probable loss-of-function mutations in festations were described in 12 patients, including se-

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Figure 1. Retinal changes associated with juvenile Paget disease. A, Peripapillary atrophy. B, Mottling of the retinal pigment epithelium. C, Angioid streaks. rial follow-up in 3 patients (Table 3).1,6-11 Angioid streaks were the most common ocular abnormality. They were found in almost all patients by the end of the second decade of life and seemed to be a precursor to the development of choroidal neovascularization, which occurred in more than half of those with angioid streaks. Subsequent involvement of the macula by disciform scarring was the predominant cause of visual loss. Two patients with long- term serial follow-up developed blindness due to choroidal neovascularization and disciform scarring.1,8 The nonspecific finding of mottling of the retinal pigment epithelium was observed less frequently and was more common in older patients. Peripapillary atrophy and optic nerve pallor were less frequent observations across all age groups. Electrophysiologic studies were under- taken in 4 patients, and all results were abnormal, showing diminished photoreceptor function. There was a strik- ing correlation between cumulative number of retinal abnormalities and increasing age (Figure 3).

COMMENT Figure 2. Coronal magnetic resonance image showing large bilateral intracavernous aneurysms of the internal carotid artery. To our knowledge, this is the largest systematic study of ophthalmic manifestations of juvenile Paget disease re- meric glycoprotein, secreted by osteoblasts and osteoblast ported to date. It confirms that juvenile Paget disease is precursors, that has an important role in regulating bone associated with distinctive retinopathy that is detect- turnover. Osteoprotegerin is a decoy receptor for recep- able in most patients by the end of the second decade of tor activator of nuclear factor-␬B ligand (RANKL), which life. Cumulative number of retinal abnormalities is dampens the stimulus to bone resorption; therefore, os- strongly associated with older age, suggesting that this teoprotegerin deficiency is characterized by unre- is a progressive disorder. The earliest changes seem to strained bone remodeling activity.12 be optic nerve pallor and mottling of the retinal pig- Patients with juvenile Paget disease have greatly ex- ment epithelium. This is followed by the development panded skull bones, so it is possible that the optic nerve of angioid streaks, choroidal neovascularization, and ul- pallor and atrophy we observed could result from bony timately disciform scarring and visual loss. Among pa- compression of the optic nerve at the orbital apex. Mot- tients in whom electrophysiologic studies were under- tling of the retinal pigment epithelium seems to be an taken, this seems to correlate with altered retinal function. early sign and may represent changes in underlying Bruch Two published case reports1,9 of patients studied seri- membrane. Angioid streaks were a common finding. These ally provide evidence that severe visual loss can occur. are linear gray or dark red lesions that typically extend Both patients had mild skeletal phenotypes. Because they radially from the optic disc and run beneath the retinal have the longest life expectancy, such patients may para- vessels.13 They are seen in a wide variety of systemic con- doxically be at greatest risk of visual loss. ditions and are of significance because they may be com- Juvenile Paget disease results from deletions of or loss- plicated by choroidal neovascularization in up to 86% of of-function mutations in TNFRSF11B, which encodes os- cases.14 Although recognized as breaks or dehiscence in teoprotegerin. Osteoprotegerin is a soluble homodi- a thickened, calcified, and abnormally brittle Bruch mem-

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Best-Corrected Retinal Findings Visual Acuity, Snellen Equivalents Optic Sex/ Visual Nerve Mottling Angioid Patient/Source Age, y OD OS Fields Pallor PPA of RPE Streaks CNVM Other ERG A/Iancu et al,7 1978 F/5 20/40 20/40 . . . Normal ... B/Bakwin and Eiger,10 F/5 ...... 1956 C/Iancu et al,7 1978 M/7 ...... • • ...... D/Thompson et al,11 M/9 Normal Normal . . . Normal . . . 1969 E/Mitsudo,8 1971 M/9 ...... Narrowing and ... increased tortuosity of the vessels, questionable small exudates at the disc margins F/Bakwin et al,6 1964 F/11 20/90 20/90 Normal • Hyaline refractile Diminished scotopic bodies and photopic potentials G/Bakwin et al,6 1964 F/14 ...... Grossly Early macular Grossly diminished constricted degeneration scotopic and with relative photopic central potentials scotomas H/Thompson et al,11 F/19 20/70 20/200 . . . • • White areas ... 1969 surrounded by pigment obliterating the macula I/Mitsudo,8 1971 M/17 Diminished Diminished . . . •• ...... M/18 Diminished Diminished . . . • • Several breaks and ... basophilia in Bruch membrane, equivocal increase in choroidal connective tissue, intimal sclerosis and marked calcification of retinal and ciliary arteries on autopsy J/Sharif et al,9 1989 M/10 20/20 20/20 . . . • • ...... M/13 20/20 HM . . . •• ...... M/18 20/60 20/120 . . . •• ...... K/Whyte et al,1 2007 M/31 20/16 20/120 . . . • ...... M/late 30s ...... ••• . . . Reduced activity M/41 20/30 20/80 Generalized • • • • Midperipheral and Subnormal constriction peripheral white of visual speckled retinal fields, lesions paracentral relative scotomas M/60 Legally Legally Central •••• ...... blind blind scotoma

Abbreviations: CNVM, choroidal neovascular membrane; ellipses, not reported; ERG, electroretinogram; F, female; HM, hand motion; M, male; PPA, peripapillary atrophy; RPE, retinal pigment epithelium. brane, their exact pathogenesis remains unknown. There- have not been described in the analogous bone condi- fore, osteoprotegerin deficiency may provide new insights tion of familial expansile osteolysis, which results from about pathogenesis of angioid streaks. Osteoprotegerin constitutive activation of RANK due to tandem duplica- is expressed in many tissues, including the eye and vas- tions within its TNFRSF11A gene.5 This suggests that os- cular endothelium.15 Animal investigations have shown teoprotegerin deficiency causes angioid streaks through that osteoprotegerin-deficient mice develop calcifica- a system independent of RANK activation. Osteopro- tion of the internal elastic lamina of the aorta and renal tegerin may prevent vascular calcification by inhibiting arteries, suggesting that osteoprotegerin acts as an in- apoptosis of endothelial cells caused by tumor necrosis hibitor of calcification of elastic fibers.16 Angioid streaks factor–related apoptosis-inducing ligand (TRAIL).17 In-

(REPRINTED) ARCH OPHTHALMOL / VOL 128 (NO. 6), JUNE 2010 WWW.ARCHOPHTHALMOL.COM 701 Downloaded from www.archophthalmol.com at , on September 8, 2010 ©2010 American Medical Association. All rights reserved. proven. Given the rarity of this disease, it is unlikely 6 there will ever be an “evidence-based” treatment. Based on our findings, we recommend that patients 5 with juvenile Paget disease be examined by an ophthal- 4 mologist at diagnosis and then on a regular basis accord- ing to the severity of ocular involvement. Patients should 3 be warned about the risk of visual loss and should be ad-

2 vised to immediately report any changes in vision. Fur- Patients from the literature thermore, patients with angioid streaks should be in- 1 Study patients formed of the possibility of subretinal hemorrhage after Patient K even minor ocular trauma.29 The regular use of a macu- Cumulative No. of Retinal Abnormalities 0 lar Amsler grid to screen for metamorphopsia, which may 0 10 20 30 40 50 60 70 Age, y be the first sign of choroidal neovascularization, may be beneficial. Prophylactic laser treatment of angioid streaks is discouraged by some authorities because of the risk of Figure 3. Cumulative number of retinal abnormalities. Patient K is listed in 30 Table 3. choroidal neovascular membrane formation. We conclude that juvenile Paget disease is associated with progressive retinopathy characterized by optic nerve deed, it has been shown that osteoprotegerin protects en- pallor, mottling of the retinal pigment epithelium, and dothelial cells from apoptosis induced by serum with- subsequent development of angioid streaks. The latter drawal and nuclear factor-␬B inactivation.17 Therefore, may be complicated by choroidal neovascularization, the osteoprotegerin deficiency may lead to angioid streaks predominant mechanism of visual loss. Retinal changes through loss of inhibition of calcification in the are evident by the end of the second decade of life, and elastin-rich middle elastic layer of Bruch membrane, the severity of retinopathy increases with age. Paradoxi- with subsequent formation of cracks.18,19 Whether sus- cally, patients with a mild skeletal phenotype may be at ceptibility of the choriocapillaris endothelium to apop- greatest risk of ocular complications. With early use of tosis20 contributes to this process requires further potent bisphosphonates, amelioration of the skeletal dis- investigation. ease could lengthen the lifespan of affected patients, in- Angioid streaks may be a marker or indicator of calci- creasing the risk of retinal disease development. Reti- fication in the systemic vasculature. Association between nopathy associated with juvenile Paget disease seems to juvenile Paget disease and vascular calcification has been be part of a more generalized vascular disorder, suggest- clinically observed. Mitsudo8 reported that calcium de- ing that osteoprotegerin or its signaling pathway has an posits were found in the intima of all muscular arteries at important role in inhibition of vascular calcification. the time of autopsy in a 17-year-old boy with juvenile Paget disease who died of intracerebral hemorrhage. Further- Submitted for Publication: June 29, 2009; final revision more, a temporal artery biopsy specimen from a 6-year- received November 3, 2009; accepted November 5, 2009. old boy with the disease revealed calcification of the in- Correspondence: Andrea L. Vincent, MBChB, Depart- 21 ternal elastic lamina. These findings are in keeping with ment of Ophthalmology, Faculty of Medical and Health results of animal investigations showing that osteopro- Sciences, University of Auckland, Private Bag 92019, tegerin-deficient mice develop early arterial calcifica- Auckland Mail Centre, Auckland 1142, New Zealand 22 tion. In our study, a patient investigated for signs of cav- ([email protected]). ernous sinus syndrome was found to have intracavernous Financial Disclosure: None reported. internal carotid artery aneurysms that were identical to those recently described by Allen et al23 in an 11-year-old REFERENCES boy with a severe form of juvenile Paget disease due to com- plete deletion of TNFRSF11B. Compared with extracra- 1. Whyte MP, Singhellakis PN, Petersen MB, Davies M, Totty WG, Mumm S. Ju- nial arteries, intracranial arteries have an attenuated tu- venile Paget’s disease: the second reported, oldest patient is homozygous for nica media and lack an external elastic lamina, rendering the TNFRSF11B “Balkan” mutation (966_969delTGACinsCTT), which elevates cir- them vulnerable to aneurysm formation.24 culating immunoreactive osteoprotegerin levels. J Bone Miner Res. 2007;22 Results of studies25,26 indicate that the skeletal phe- (6):938-946. 2. Whyte MP, Obrecht SE, Finnegan PM, et al. 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(REPRINTED) ARCH OPHTHALMOL / VOL 128 (NO. 6), JUNE 2010 WWW.ARCHOPHTHALMOL.COM 702 Downloaded from www.archophthalmol.com at , on September 8, 2010 ©2010 American Medical Association. All rights reserved. 8. Mitsudo SM. Chronic idiopathic hyperphosphatasia associated with pseudo- tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) levels in xanthoma elasticum. J Bone Joint Surg Am. 1971;53(2):303-314. atherosclerosis. Atherosclerosis. 2006;184(2):446-447. 9. Sharif KW, Doig WM, Kinsella FP. Visual impairment in a case of juvenile Pag- 20. McGonigle JS, Giachelli C, Scatena M. Osteoprotegerin and RANKL differen- et’s disease with pseudoxanthoma elasticum: an eleven-year follow-up. J Pedi- tially regulate angiogenesis and endothelial cell function. Angiogenesis. 2009; atr Ophthalmol Strabismus. 1989;26(6):299-302. 12(1):35-46. 10. Bakwin H, Eiger MS. Fragile bones and macrocranium. J Pediatr. 1956;49(5):558- 21. Silve C, Grosse B, Tau C, et al. Response to parathyroid hormone and 1,25-

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