Grand Rounds. CYSTINOSIS Denis Jusufbegovic, M.D. University of Louisville Department of Ophthalmology and Visual Sciences 10/05/12
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1 Grand Rounds CYSTINOSIS Denis Jusufbegovic, M.D. University of Louisville Department of Ophthalmology and Visual Sciences 10/05/12
2 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
3 FH: : non-contributory Subjective MEDS: Enalapril, Amiloride, Calcitriol, Levocarnitine, Cystagon, Synthroid All: NKDA ROS: Negative
4 Objective VAsc 20/20 20/25 P O RAPD, brisk OU T EOM: Full OU, ortho
5 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
6 Anterior segment photo Anterior segment photo of the right eye shows iridescent corneal crystals. Left eye had similar findings.
7 Corneal photo This photo shows numerous iridescent corneal crystals involving entire cornea
8 Corneal photo This corneal photo shows iridescent corneal crystals
9 Corneal photo Slit-lamp beam showing corneal crystals in all corneal layers
10 Color fundus photos Color fundus photos of both eyes demonstrate mild optic disc drusen, otherwise it is unremarkable
11 Assessment 11 yo WF with bilateral corneal iridescent crystals, end-stage kidney disease, hypothyroidism and h/o rickets. Diagnosis: Infantile Cystinosis
12 Treatment Observation Topical cysteamine drops discussed as a therapeutic option
13 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 children with incidence of 6 per 100,000 in Newfoundland, Canada
14 Pathogenesis Transmitted as an autosomal recessive trait Caused by mutation in CTNS gene on Chr 17p13 which codes for lysosomal membrane protein named cystinosin
15 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
16 Pathogenesis
17 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
18 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
19 A childhood nephropathic cystinosis patient displays typical fair features and photophobia. Krachmer: Cornea, 3rd ed Mosby, An Imprint of Elsevier
20 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
21 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 )
22 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
23 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 Jan- Feb;52(1):
24 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
25 Treatment of Corneal Involvement Cysteamine hydrochloride 0.55% (50 mm) solution with benzalkonium chloride 0.01% Used 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
26 Pharmacies National Institutes of Health (NIH)Eye Clinic Alana Temple, RN Clinical Trials Coordinator Phone: (301) Premier Pharmacy Labs Inc Commercial Way Spring Hill, FL Phone: (800) Fax: (800) Leiter's Pharmacy 1700 Park Avenue Suite 30 San Jose CA Toll free (800) or (408) Aurora Pharmacy 3284 W. Main St. East Troy, WI Phone: (262) Hoosier Prescription Shop 3020 S. 7th St. Terre Haute, IN Phone: (812) Alberta Children's Hosptial in Calgary Phone: (403) Maryanne MacDonald for further information. Mark Drugs Pharmacy 384 E. Irving Park Road Roselle, IL Phone: (630) Cystinosis Research Network
27 Thank you
28 References 1.Gahl WA, Thoene JG, Schneider J. Cystinosis. N Engl J Med.2002;347: Kaiser-Kupfer MI, Caruso RC, Minkler DS, et al: Long-term ocular manifestations in nephropathic cystinosis. Arch Ophthalmol 104: , 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 Jan-Feb;52(1): Yamamoto GK, et al. Long-term ocular changes in cystinosis: observations in renal transplant recipients. J Pediatr Ophthalmol.1979;16: Zimmerman TJ, Hood I, Gasset AF. Adolescent cystinosis: a case report and review of the literature. Arch Ophthalmol. 1974;92:265
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