cystinosis: an “eye opener”

Cystinosis: An “eye opener”

Case Report

Cystinosis: An “eye opener”

Krishnan Swaminathan a,*, Murugan Jeyaraman b

aConsultant Endocrinologist, Department of Endocrinology, Apollo Specialty Hospital, 625 020 Madurai, IndiabConsultant Paediatrician, Department of Paediatrics, Apollo Specialty Hospital, 625 020 Madurai, India

a r t i c l e i n f o

Article history:

Received 3 January 2014

Accepted 21 January 2014

Available online xxx

Keywords:

Short stature

Cystinosis

Renal failure

a b s t r a c t

Amuch-quoted aphorism in medicine is “Listen to your patient and they are telling you the

diagnosis”. Most often, the history reveals the diagnosis and sometimes, it is all that is

required to make the diagnosis. Unfortunately, in this age of modern technology-based

medicine, many busy clinicians fail to get a proper history and miss important dots in

the history that connect to the diagnosis. This is clinically relevant, as a specific diagnosis

completely alters the nature of treatment and thereby improves prognosis. We present a

young boy with infantile cystinosis, who was evaluated in at least three tertiary referral

centers prior to our review and branded as having “renal rickets due to a posterior urethral

valve”. Two important clues from history that clinched a clinical diagnosis of infantile

cystinosis in this boy with renal rickets were the father’s comment that “His elder daughter

died at 7 years of age with a similar condition” and the mother’s complaint that “her son

cannot see television properly, his eyes become red and tears roll through his eyes”. Our

aim is to open the eyes of medical community to this rare but treatable condition, espe-

cially in young children presenting with renal rickets, photophobia and short stature.

Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved.

1. Case report

We report a 6-year-old boy born of consanguineous parents.

His birth history was normal. At nine months of age, he pre-

sented with polyuria and polydipsia, in the absence of hy-

perglycemia. For the next five years, he was investigated in

three different tertiary referral centers in South India for

stunted growth and renal rickets. He was finally branded as

having “renal osteodystrophy due to a posterior urethral

valve”. Treatment consisted of sodium bicarbonate tablets

and calcitriol 0.25 once daily, with poor compliance with both

the medications. At our clinic visit, we found a lethargic boy

with a height centile of <3% with features of renal rickets and

dryness of skin (Fig. 1). Abdomen was distended with mild

hepatomegaly. Further detailed family history revealed that

his elder sister had died at seven years of age with stunted

growth, rickets and renal failure. Another important piece of

history came from the boy’s mother who commented that

“the only pastime for him is to watch television but nowadays,

he gets severe irritation in his eyes with redness and persis-

tent watering”. A PubMed search with “short stature, renal

rickets and photophobia” gave three hits, all pointing towards

a diagnosis of infantile cystinosis.

Further lab work up revealed severe primary hypothy-

roidismwith a Thyroid stimulating hormone (TSH)> 150mIU/

L and undetectable free thyroxine (FT4). He had renal

impairment with low serum calcium, phosphate, grossly

elevated parathormone (PTH) and alkaline phosphatase.

* Corresponding author. Tel.: þ91 8526421150; fax: þ91 4522580199.E-mail address: [email protected] (K. Swaminathan).

Available online at www.sciencedirect.com

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Please cite this article in press as: Swaminathan K, Jeyaraman M, Cystinosis: An “eye opener”, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.01.002

0976-0016/$ e see front matter Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved.http://dx.doi.org/10.1016/j.apme.2014.01.002

Serum Insulin like Growth Factor-1 (IGF-1) was within normal

limits. An ophthalmologist referral revealed extensive corneal

micro deposits. Blood sampleswere sent formolecular genetic

analysis to Groupement Hospitalier Est, France. DNA was

extracted from leucocytes (Nucleon BACC3 kiteGE Health-

care). Screening for the common 57-kb deletion as well as

direct sequencing after PCR (Polymerase Chain Reaction)

amplification of the 12 exons of the CTNS gene was carried

out. The child was detected to have a mutation in an

apparently homozygous state in exon 7: c.422C > T respon-

sible for the replacement of serine by phenylalanine at posi-

tion 141 on the protein p.Ser141Phe (Fig. 2), in agreement with

a diagnosis of cystinosis.

The child was started on supportive measures, indometh-

acin, phosphate and increased dose of calcitriol. With great

difficulty, we managed to get Cysteamine (Cystagon), a drug

that directly treats the disease by reducing the intracellular

cystine content. This drug is very expensive, not available in

India and had to be imported from France (Orphan Europe,

http://www.orphan-europe.com). To this date, he has toler-

ated the drug well. Photophobia has improved remarkably

with Cysteamine eye drops (Cystagon 0.5%) six times per day.

He has been referred to the regional renal transplant team,

who have previous experience with a similar boy aged 7 years

with infantile cystinosis.

2. Discussion

We report a case of infantile cystinosis where themain clue to

the diagnosis was marked photophobia. An accurate diag-

nosis resulted in appropriate treatment with marked clinical

improvement, genetic counseling and a reason for the family

to be at peace to know the reason for their son’s illness and

their daughter’s death.

Cystinosis is a rare autosomal recessive metabolic disorder

characterized by defective lysosomal efflux of cystine.

This leads to accumulation of cystine in multiple organs,

Fig. 1 e Evidence of rickets and dryness of skin due to

severe primary hypothyroidism.

Fig. 2 e Mutation in an apparently homozygous state in exon 7: c.422C > T responsible for the replacement of serine by

phenylalanine at position 141 on the protein p.Ser141Phe.

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progressing to severe organ dysfunction, especially end-stage

renal failure.1 The first clinical signs usually appear at three to

six months of life and by six months, most children have full-

blown renal Fanconi syndrome (glycosuria, aminoaciduria,

phosphaturia,metabolic acidosis). The clinicalmanifestations

include polyuria, failure to thrive, growth retardation, devel-

opmental delay, rickets, constipation and acute dehydration

episodes.2

Predominant extra-renal organs affected by cystine depo-

sition are eyes, thyroid and liver. Cystine deposits in the

conjunctivae and cornea cause photophobia, blepharospasm

and watering of eyes. The deposits can be easily seen on slit

lamp examination. Hemorrhagic retinopathy and visual

impairment are late complications of this disease.3 Growth

retardation is a common feature of this condition. Thismay be

due in part to severe hypophosphatemia but hypothyroidism

may be an additional factor as well, especially in older chil-

dren,where the rates are close to 70% in childrenmore than 10

years of age. Enlarged Kupffer cells with cystine crystals

contribute to hepatomegaly and may lead to portal hyper-

tension.4 Muscular and neurological involvements are late

complications of the disease contributing to significant

morbidity. Such patients are usually older than twenty years.

Presenting features include pseudo bulbar palsy, cerebellar,

pyramidal signs and encephalopathy associated with stroke-

like episodes.5

The definitive treatment of infantile cystinosis includes

Cysteamine therapy and renal transplantation for end stage

renal disease. Cysteamine therapy should be started as soon

as the diagnosis is confirmed. This drug reduces cystine

accumulation in cells and when started early, delays the

development of renal failure, hypothyroidism and improves

growth.6,7 For children up to the age of 12 years, Cystagon

(cysteamine) dosing should be based on the body surface area,

the recommended dose being 1.30 g/m2/day of the free base

divided four times a day. In children over age 12 years and

>50 kg in weight, the recommended dose is 2 g/day divided

four times a day (Courtesy: Cystagon SPC leaflet, Orphan

Europe). The goal of therapy is to keep the leukocyte cystine

levels to <1 nmol hemicystine/mg protein. Unfortunately, we

do not have access to leukocyte cystine levels and therefore

have to continue treatment for our case based on clinical

response. It is important to remember not to exceed the dose

of cysteamine to higher than 1.95 gm/m2. Renal trans-

plantation is a definitive option for children with end stage

renal disease as cystine induced tubular dysfunction does not

recur on the graft. However, this has to be balanced against

long-term morbidity from immunosuppression and extra-

renal cystinosis.8

To summarize, infantile cystinosis can be easily missed.

We hope that this instructive case is an “eye opener” for the

medical community to think about this rare but treatable

disease in the appropriate clinical context.

Conflicts of interest

All authors have none to declare.

Acknowledgments

We wish to acknowledge Dr. Sujatha Jagadeesh, Consultant

Geneticist, Chennai and the molecular genetics work by Dr. C.

Vianey Saban and Dr. Cecile Acquaviva, France.

r e f e r e n c e s

1. Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med.2002;347(2):111.

2. Knoepfelmacher M, Rocha R, Salgado LR, et al. Nephropathiccystinosis: report of 2 cases and review of the literature. RevAssoc Med Bras. 1994;40(1):43.

3. Kaiser-Kupfer MI, Caruso RC, Minkler DS, Gahl WA. Long-termocular manifestations in nephropathic cystinosis. ArchOphthalmol. 1986;104(5):706.

4. Wilmer MJ, Schoeber JP, van den Heuvel LP, Levtchenko EN.Cystinosis: practical tools for diagnosis and treatment. PediatrNephrol. 2011 Feb;26(2):205e215.

5. Broyer M, Tete MJ, Guest G, Bertheleme JP, Labrousse F,Poisson M. Clinical polymorphism of cystinosisencephalopathy. Results of treatment with cysteamine. JInherit Metab Dis. 1996;19(1):65e75.

6. Markello TC, Bernardini IM, Gahl WA. Improved renal functionin children with cystinosis treated with cysteamine. N Engl JMed. 1993;328(16):1157.

7. Kimonis VE, Troendle J, Rose SR, Yang ML, Markello TC,Gahl WA. Effects of early cysteamine therapy on thyroidfunction and growth in nephropathic cystinosis. J ClinEndocrinol Metab. 1995;80(11):3257.

8. Ueda M, O’Brien K, Rosing DR, et al. Coronary artery and othervascular calcifications in patients with cystinosis after kidneytransplantation. Clin J Am Soc Nephrol. 2006;1(3):555.

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cystinosis: an “eye opener”

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