Grand Rounds CYSTINOSIS Denis Jusufbegovic, M.D. University of Louisville Department of Ophthalmology and Visual Sciences 10/05/12
Subjective CC: bilateral ocular opacities x yrs HPI: : 11 yo WF referred to pediatric ophthalmology clinic by her nephrologist for re-evaluation of bilateral ocular opacities. These opacities were initially noted at 2 yrs of age, but have been getting worse over last 2-3 yrs. Pt. has no visual complaints, ocular pain, redness or photophobia. POH: : Mild hyperopic astigmatism PMH: : Fanconi syndrome, stage IV CKD, HTN, h/o Rickets, hypothyroidism
FH: : non-contributory Subjective MEDS: Enalapril, Amiloride, Calcitriol, Levocarnitine, Cystagon, Synthroid All: NKDA ROS: Negative
Objective VAsc 20/20 20/25 P 4 2 4 2 O RAPD, brisk OU T 14 16 EOM: Full OU, ortho
Objective SLE: OD OS Ext WNL OU C/S clear OU K diffuse iridescent crystals OU AC I/L no C/F OU wnl, clear OU
Anterior segment photo Anterior segment photo of the right eye shows iridescent corneal crystals. Left eye had similar findings.
Corneal photo This photo shows numerous iridescent corneal crystals involving entire cornea
Corneal photo This corneal photo shows iridescent corneal crystals
Corneal photo Slit-lamp beam showing corneal crystals in all corneal layers
Color fundus photos Color fundus photos of both eyes demonstrate mild optic disc drusen, otherwise it is unremarkable
Assessment 11 yo WF with bilateral corneal iridescent crystals, end-stage kidney disease, hypothyroidism and h/o rickets. Diagnosis: Infantile Cystinosis
Treatment Observation Topical cysteamine drops discussed as a therapeutic option
Cystinosis Metabolic disease characterized by an accumulation of cystine in different organs and tissues Three forms exist: infantile (nephropathic), intermediate (adolescent), adult (benign) Rare disorder affecting 1:100,000-200,000 children with incidence of 6 per 100,000 in Newfoundland, Canada
Pathogenesis Transmitted as an autosomal recessive trait Caused by mutation in CTNS gene on Chr 17p13 which codes for lysosomal membrane protein named cystinosin
Pathogenesis Cystine is derived from protein degradation within the lysosomes It is normally transported through the lysosomal membrane to the cytosol Defect in the transport system leads to the cellular accumulation of poorly soluble cystine crystals
Pathogenesis
Clinical Manifestations Infantile cystinosis: Clinical signs appear between 3-6 mo of age Renal disease (Fanconi syndrome) and extrarenal involvement of eyes, liver, pancreas, thyroid, brain, etc Intermediate cystinosis similar to infantile but starts after 8 yrs of age and milder involvement Adult generally asymptomatic but may have
Ocular manifestation Affects multiple ocular tissues Corneal crystals are the pathognomonic ophthalmic manifestation of cystinosis and are found in the epithelium, stroma, and endothelium Accumulation of crystals in the cornea starts in infancy and usually leads to photophobia and blepharospasms, but they don t affect visual acuity
A childhood nephropathic cystinosis patient displays typical fair features and photophobia. Krachmer: Cornea, 3rd ed. - 2010 - Mosby, An Imprint of Elsevier
Anterior segment SD-OCT of a patient with ocular cystinosis shows hyperreflective deposits in the stroma and endothelium likely representing cystine crystals Guignier, B etc. Archives of Ophthalmology, August 2012, p 1018
Ocular manifestation Crystals are also found in the conjunctiva, iris and ciliary body, choroid, fundus, and optic nerve Risk of glaucoma increases with age due to crystal accumulation in the ciliary body ( CB ) and trabecular meshwork ( TM ) Angle closure glaucoma can occur from plateau iris- like syndrome due to crystal deposition in the ( CB )
Ocular manifestation Retinal involvement is most commonly manifested by patches of depigmentation with pigmentary mottling Pigmentary abnormality is confined to the periphery in the early stages Fluorescein angiography shows window defects corresponding to the patches of depigmentation Posterior progression of pigmentary abnormalities can lead to vision loss in 15% of cases
Ophthalmic manifestations of infantile nephropathic cystinosis: corneal crystals (A), iris crystals (B), retinal crystals (C ), peripheral retinal pigmentary changes (D) Tsilou E, Zhou M, Gahl W, Sieving PC, Chan CC.Ophthalmic manifestations and histopathology of infantile nephropathic cystinosis: report of a case and review of the literature. Surv Ophthalmol. 2007 Jan- Feb;52(1):97-105.
Diagnosis Confirmed by determining the cystine content of peripheral blood leukocyte or fibroblasts form 5 to 15 nmol/mg protein in the infantile 3 to 6 in the intermediate less than 1 in heterozygous carriers less than 0.2 in normal individuals
Treatment of Corneal Involvement Cysteamine hydrochloride 0.55% (50 mm) solution with benzalkonium chloride 0.01% Used 10-12 times per day Reacts with cystine to produce cysteine, which is a soluble molecule that leaves lysosome Cysteamine is unstable and oxidizes rapidly Should be stored in the frozen state and used within one week at room temperature
Pharmacies National Institutes of Health (NIH)Eye Clinic Alana Temple, RN Clinical Trials Coordinator Phone: (301) 402-1369 Email: templeal@nei.nih.gov Premier Pharmacy Labs Inc. 8269 Commercial Way Spring Hill, FL 34639 Phone: (800) 752-7139 Fax: (800) 868-4978 www.rxnations.com Email: vet528@tampabay.rr.com Leiter's Pharmacy 1700 Park Avenue Suite 30 San Jose CA 95126 Toll free (800) 292-6773 or (408) 292-6772 www.leiterrx.com Aurora Pharmacy 3284 W. Main St. East Troy, WI 53120 Phone: (262) 642-5800 Hoosier Prescription Shop 3020 S. 7th St. Terre Haute, IN Phone: (812) 232-9646 Alberta Children's Hosptial in Calgary Phone: (403) 955-7303 Maryanne MacDonald for further information. Mark Drugs Pharmacy 384 E. Irving Park Road Roselle, IL 60172 Phone: (630) 529-3400 www.markdrugs.com 2012 Cystinosis Research Network
Thank you
References 1.Gahl WA, Thoene JG, Schneider J. Cystinosis. N Engl J Med.2002;347:111 121. 2.Kaiser-Kupfer MI, Caruso RC, Minkler DS, et al: Long-term ocular manifestations in nephropathic cystinosis. Arch Ophthalmol 104:706--11, 1986 3.Tsilou E, Zhou M, Gahl W, Sieving PC, Chan CC.Ophthalmic manifestations and histopathology of infantile nephropathic cystinosis: report of a case and review of the literature. Surv Ophthalmol. 2007 Jan-Feb;52(1):97-105. 4.Yamamoto GK, et al. Long-term ocular changes in cystinosis: observations in renal transplant recipients. J Pediatr Ophthalmol.1979;16:16 21. 5.Zimmerman TJ, Hood I, Gasset AF. Adolescent cystinosis: a case report and review of the literature. Arch Ophthalmol. 1974;92:265