Transcript Grand Rounds - University of Louisville Ophthalmology

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
Subjective

FH: non-contributory

MEDS: Enalapril, Amiloride, Calcitriol, Levocarnitine,
Cystagon, Synthroid

All: NKDA

ROS: Negative
Objective
20/20
VAsc
20/25
14
T
16
P
4
2
4
2
EOM: Full OU, ortho
O RAPD, brisk OU
Objective
SLE:
OD
Ext
C/S
K
AC
I/L
OS
WNL OU
clear OU
diffuse iridescent crystals OU
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
photophobia
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
Tsilou E, Zhou M, Gahl W, Sieving PC, Chan
Ophthalmic manifestations of infantile nephropathic
CC.Ophthalmic manifestations and histopathology
of infantile nephropathic cystinosis: report of a
case and review of the literature. Surv Ophthalmol.
cystinosis: corneal crystals (A), iris crystals (B),
2007 Jan-Feb;52(1):97-105.
retinal crystals (C ), peripheral retinal pigmentary changes (D)
Diagnosis





Confirmed by determining the cystine content
of peripheral blood leukocyte or fibroblasts
5 to 15 nmol/mg protein in the infantile form
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: [email protected]

Premier Pharmacy Labs Inc. 8269 Commercial
Way Spring Hill, FL 34639 Phone: (800) 752-7139
Fax: (800) 868-4978 www.rxnations.com Email:
[email protected]

Leiter's Pharmacy 1700 Park Avenue Suite 30 San
Jose CA 95126 Toll free (800) 292-6773 or (408)
292-6772 www.leiterrx.com

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.

Aurora Pharmacy 3284 W. Main St. East Troy, WI
53120 Phone: (262) 642-5800

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
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Gahl WA, Thoene JG, Schneider J. Cystinosis. N Engl J Med.2002;347:111–121.
Kaiser-Kupfer MI, Caruso RC, Minkler DS, et al: Long-term ocular manifestations in nephropathic
cystinosis. Arch Ophthalmol 104:706--11, 1986
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.
Yamamoto GK, et al. Long-term ocular changes in cystinosis: observations in renal transplant
recipients. J Pediatr Ophthalmol.1979;16:16–21.
Zimmerman TJ, Hood I, Gasset AF. ‘Adolescent’ cystinosis: a case report and review of the
literature. Arch Ophthalmol. 1974;92:265