Grand Rounds Grand Rounds CYSTINOSIS CYSTINOSIS Denis Jusufbegovic, M.D. Denis Jusufbegovic, M.D. University of Louisville University of Louisville Department of Ophthalmology and Visual Sciences Department of Ophthalmology and Visual Sciences 10/05/12 10/05/12
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Grand Rounds CYSTINOSIS Denis Jusufbegovic, M.D. University of Louisville Department of Ophthalmology and Visual Sciences 10/05/12.
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Grand RoundsGrand Rounds
CYSTINOSISCYSTINOSIS
Denis Jusufbegovic, M.D.Denis Jusufbegovic, M.D.
University of LouisvilleUniversity of Louisville
Department of Ophthalmology and Visual SciencesDepartment of Ophthalmology and Visual Sciences
10/05/1210/05/12
SubjectiveSubjectiveCC:CC: “bilateral ocular opacities x yrs ” “bilateral ocular opacities x yrs ”
HPIHPI: 11 yo WF referred to pediatric ophthalmology : 11 yo WF referred to pediatric ophthalmology clinic by her nephrologist for re-evaluation of clinic by her nephrologist for re-evaluation of bilateral ocular opacities. These opacities were bilateral ocular opacities. These opacities were initially noted at 2 yrs of age, but have been initially noted at 2 yrs of age, but have been getting worse over last 2-3 yrs. Pt. has no visual getting worse over last 2-3 yrs. Pt. has no visual complaints, ocular pain, redness or photophobia. complaints, ocular pain, redness or photophobia.
KK diffuse iridescent diffuse iridescent crystals OUcrystals OU
ACAC no C/F OUno C/F OU
I/LI/L wnl, clear OUwnl, clear OU
Anterior segment photoAnterior segment photo
Anterior segment photo of the right eye shows iridescent corneal crystals. Left eye had similar findings.
Corneal photoCorneal photo
This photo shows numerous iridescent corneal crystals involving entire cornea
Corneal photoCorneal photo
This corneal photo shows iridescent corneal crystals
Corneal photoCorneal photo
Slit-lamp beam showing corneal crystals in all corneal layers
Color fundus photosColor fundus photos
Color fundus photos of both eyes demonstrate mild optic disc drusen, otherwise it is unremarkable
Assessment Assessment
11 yo WF with bilateral corneal 11 yo WF with bilateral corneal iridescent crystals, end-stage kidney iridescent crystals, end-stage kidney disease, hypothyroidism and h/o disease, hypothyroidism and h/o rickets. rickets.
Diagnosis: Diagnosis:
Infantile Cystinosis Infantile Cystinosis
TreatmentTreatment
Observation Observation
Topical cysteamine drops discussed Topical cysteamine drops discussed as a therapeutic optionas a therapeutic option
Cystinosis Cystinosis
Metabolic disease characterized by an Metabolic disease characterized by an accumulation of cystine in different organs and accumulation of cystine in different organs and tissuestissues
Three forms exist: infantile (nephropathic), Three forms exist: infantile (nephropathic), intermediate (adolescent), adult (benign) intermediate (adolescent), adult (benign)
Rare disorder affecting 1:100,000-200,000 Rare disorder affecting 1:100,000-200,000 children with incidence of 6 per 100,000 in children with incidence of 6 per 100,000 in Newfoundland, Canada Newfoundland, Canada
Pathogenesis Pathogenesis
Transmitted as an autosomal Transmitted as an autosomal recessive trait recessive trait
Caused by mutation in CTNS gene Caused by mutation in CTNS gene on Chr 17p13 which codes for on Chr 17p13 which codes for lysosomal membrane protein lysosomal membrane protein named cystinosin named cystinosin
Pathogenesis Pathogenesis
Cystine is derived from protein Cystine is derived from protein degradation within the lysosomesdegradation within the lysosomes
It is normally transported through the It is normally transported through the lysosomal membrane to the cytosol lysosomal membrane to the cytosol
Defect in the transport system leads to Defect in the transport system leads to the cellular accumulation of poorly the cellular accumulation of poorly soluble cystine crystals soluble cystine crystals
Pathogenesis Pathogenesis
Clinical Manifestations Clinical Manifestations Infantile cystinosisInfantile cystinosis:: Clinical signs appear between 3-6 mo of ageClinical signs appear between 3-6 mo of age Renal disease (Fanconi syndrome) and extrarenal Renal disease (Fanconi syndrome) and extrarenal
involvement of eyes, liver, pancreas, thyroid, brain, involvement of eyes, liver, pancreas, thyroid, brain, etcetc
Intermediate cystinosis Intermediate cystinosis – similar to infantile similar to infantile but starts after 8 yrs of age and milder involvementbut starts after 8 yrs of age and milder involvement
Adult Adult – generally asymptomatic but may have photophobia
Corneal crystals are the pathognomonic Corneal crystals are the pathognomonic ophthalmic manifestation of cystinosis and ophthalmic manifestation of cystinosis and are found in the epithelium, stroma, and are found in the epithelium, stroma, and endotheliumendothelium
Accumulation of crystals in the cornea Accumulation of crystals in the cornea starts in infancy and usually leads to starts in infancy and usually leads to photophobia and blepharospasms, but they photophobia and blepharospasms, but they don’t affect visual acuitydon’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 Ocular manifestation
Crystals are also found in the conjunctiva, iris Crystals are also found in the conjunctiva, iris and ciliary body, choroid, fundus, and optic and ciliary body, choroid, fundus, and optic nervenerve
Risk of glaucoma increases with age due to Risk of glaucoma increases with age due to crystal accumulation in the ciliary body ( CB ) crystal accumulation in the ciliary body ( CB ) and trabecular meshwork ( TM ) and trabecular meshwork ( TM )
Angle closure glaucoma can occur from Angle closure glaucoma can occur from plateau iris-like syndrome due to crystal plateau iris-like syndrome due to crystal deposition in the ( CB )deposition in the ( CB )
Ocular manifestation Ocular manifestation Retinal involvement is most commonly manifested Retinal involvement is most commonly manifested
by patches of depigmentation with pigmentary by patches of depigmentation with pigmentary mottlingmottling
Pigmentary abnormality is confined to the Pigmentary abnormality is confined to the periphery in the early stagesperiphery in the early stages
Fluorescein angiography shows window defects Fluorescein angiography shows window defects corresponding to the patches of depigmentationcorresponding to the patches of depigmentation
Posterior progression of pigmentary abnormalities Posterior progression of pigmentary abnormalities can lead to vision loss in 15% of casescan lead to vision loss in 15% of cases
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.
DiagnosisDiagnosis
Confirmed by determining the cystine Confirmed by determining the cystine content of peripheral blood leukocyte content of peripheral blood leukocyte or fibroblastsor fibroblasts
5 to 15 nmol/mg protein in the 5 to 15 nmol/mg protein in the infantile forminfantile form
3 to 6 in the intermediate 3 to 6 in the intermediate less than 1 in heterozygous carriersless than 1 in heterozygous carriers less than 0.2 in normal individuals less than 0.2 in normal individuals
Treatment of Corneal Treatment of Corneal InvolvementInvolvement
Used 10 -12 times per dayUsed 10 -12 times per day
Reacts with cystine to produce cysteine, which is a Reacts with cystine to produce cysteine, which is a soluble molecule that leaves lysosome soluble molecule that leaves lysosome
Cysteamine is unstable and oxidizes rapidly Cysteamine is unstable and oxidizes rapidly
Should be stored in the frozen state and used within Should be stored in the frozen state and used within one week at room temperatureone week at room temperature
Pharmacies Pharmacies National Institutes of Health (NIH)Eye National Institutes of Health (NIH)Eye
ClinicClinic
Alana Temple, RN Clinical Trials Alana Temple, RN Clinical Trials Coordinator Coordinator Phone: (301) Phone: (301)
Leiter's Pharmacy 1700 Park Avenue Leiter's Pharmacy 1700 Park Avenue Suite 30 San Jose CA 95126 Toll free Suite 30 San Jose CA 95126 Toll free (800) 292-6773 or (408) 292-6772 (800) 292-6773 or (408) 292-6772 www.leiterrx.comwww.leiterrx.com
Aurora Pharmacy 3284 W. Main St. Aurora Pharmacy 3284 W. Main St. East Troy, WI 53120 Phone: (262) East Troy, WI 53120 Phone: (262) 642-5800642-5800
Mark Drugs Pharmacy 384 E. Irving Mark Drugs Pharmacy 384 E. Irving Park Road Roselle, IL 60172 Phone: Park Road Roselle, IL 60172 Phone: (630) 529-3400 www.markdrugs.com(630) 529-3400 www.markdrugs.com
Premier Pharmacy Labs Inc. 8269 Premier Pharmacy Labs Inc. 8269 Commercial Way Spring Hill, FL Commercial Way Spring Hill, FL 34639 Phone: (800) 752-7139 Fax: 34639 Phone: (800) 752-7139 Fax: (800) 868-4978 (800) 868-4978 www.rxnations.com Email: [email protected] Email: [email protected]
Hoosier Prescription Shop 3020 S. 7th Hoosier Prescription Shop 3020 S. 7th St. Terre Haute, IN Phone: (812) 232-St. Terre Haute, IN Phone: (812) 232-96469646
Alberta Children's Hosptial in Calgary Alberta Children's Hosptial in Calgary Phone: (403) 955-7303 Maryanne Phone: (403) 955-7303 Maryanne MacDonald for further information.MacDonald for further information.
1.1.Gahl WA, Thoene JG, Schneider J. Cystinosis. N Engl J Med.2002;347:111–Gahl WA, Thoene JG, Schneider J. Cystinosis. N Engl J Med.2002;347:111–121.121.
2.2.Kaiser-Kupfer MI, Caruso RC, Minkler DS, et al: Long-term ocular Kaiser-Kupfer MI, Caruso RC, Minkler DS, et al: Long-term ocular manifestations in nephropathic cystinosis. Arch Ophthalmol 104:706--11, 1986manifestations in nephropathic cystinosis. Arch Ophthalmol 104:706--11, 1986
3.3.Tsilou E, Zhou M, Gahl W, Sieving PC, Chan CC.Tsilou E, Zhou M, Gahl W, Sieving PC, Chan CC.Ophthalmic manifestations Ophthalmic manifestations and histopathology of infantile nephropathic cystinosis: report of a case and and histopathology of infantile nephropathic cystinosis: report of a case and review of the literature. Surv Ophthalmol. 2007 Jan-Feb;52(1):97-105.review of the literature. Surv Ophthalmol. 2007 Jan-Feb;52(1):97-105.
4.4.Yamamoto GK, et al. Long-term ocular changes in cystinosis: observations in Yamamoto GK, et al. Long-term ocular changes in cystinosis: observations in renal transplant recipients. J Pediatr Ophthalmol.1979;16:16–21.renal transplant recipients. J Pediatr Ophthalmol.1979;16:16–21.
5.5.Zimmerman TJ, Hood I, Gasset AF. ‘Adolescent’ cystinosis: a case report and Zimmerman TJ, Hood I, Gasset AF. ‘Adolescent’ cystinosis: a case report and review of the literature. Arch Ophthalmol. 1974;92:265review of the literature. Arch Ophthalmol. 1974;92:265