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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 3  |  Page : 436-442
Nephropathic cystinosis in children: An overlooked disease


1 Center of Pediatric Nephrology and Transplantation, Cairo University, Cairo, Egypt
2 Ophthalmology Research Institute, Cairo University, Cairo, Egypt

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   Abstract 

Nephropathic cystinosis is rare genetic disease characterized by defective lysosomal cystine transport and increased lysosomal cystine. Corneal Cystine Crystal Scoring (CCCS) for diagnosis of nephropathic cystinosis was studied in all suspected children with renal Fanconi syn­drome and siblings of diagnosed cases over a two year period. In addition to oral cysteamine, cys­teamine eye drops were provided to all diagnosed patients and CCCS was followed up on a quarterly basis. Of 33 screened cases, 14 had corneal cystine crystals. Crystals were absent in two cystinotic patients under the age of 20 months. The mean age at diagnosis was 52.7 months and five patients had ERSD. After six months of treatment, the mean CCCS did not increase from the initial value of 1.81; associated with a decrease of 0.5 in two cases and a similar increase in two others. Scores decreased in two other patients after 12 months. Compliance was generally inadequate due to the high frequency of administration and the need for multi-drug regimen. CCCS is a simple and reasonably sensitive method for diagnosis of nephropathic cystinosis above two years of age. To­pical treatment with cysteamine eye drops prevents progression of deposits and may decrease it with adequate compliance. Further follow up is still recommended to monitor long term effects of both systemic and topical cysteamine therapy.

Keywords: Corneal cystine crystal score, Cysteamine eye drops, Cystinosis, Diagnosis

How to cite this article:
Soliman NA, El-Baroudy R, Rizk A, Bazaraa H, Younan A. Nephropathic cystinosis in children: An overlooked disease. Saudi J Kidney Dis Transpl 2009;20:436-42

How to cite this URL:
Soliman NA, El-Baroudy R, Rizk A, Bazaraa H, Younan A. Nephropathic cystinosis in children: An overlooked disease. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 Nov 20];20:436-42. Available from: http://www.sjkdt.org/text.asp?2009/20/3/436/50775

   Introduction Top


Cystinosis is an autosomal recessive disorder of lysosomal transport of cystine [1] associated with mutations in CTNS gene coding the lyso­somal transport protein cystinosin. [2] More than 50 different mutations have been described. Nephropathic (infantile) cystinosis is the most common and the most severe clinical expre­ssion of the disease. [3] Defective export of cystine from the lysosomes results in widespread accu­mulation of cystine crystals in various tissues and associated organ dysfunction. [5],[6],[7] Recently, Park and Thoene suggested that increased lyso­somal membrane permeability to cystine early during apoptosis results in inappropriate commit­ment of cystinotic cells to apoptosis. [8]

Clinically, nephropathic cystinosis presents with infantile-onset renal tubular Fanconi syndrome and untreated cases progress to ESRD later in the first decade. [9] Ocular changes include photo­phobia associated with corneal deposits, as well as retinal changes. Corneal deposits are so pro­minent and typical that an early diagnosis can be achieved by an ophthalmologic examination before the nephropathic signs become evident. [10] Various other extra-renal complications may occur including hypothyroidism, male hypogo­nadism, pancreatic endocrine and exocrine insuf­ficiency, distal vacuolar myopathy, swallowing difficulties, decreased pulmonary function and neurological complications. [3],[11],[12],[13],[14],[15],[16],[17],[18],[19]

Classically, nephropathic cystinosis is diagnosed when leucocyte cystine is more than 2.0 nmol/ mg protein. [1] This test is not routinely available in Egypt. Unlike many other inherited disorders, cystinosis in amenable to specific treatment with oral cysteamine, which improves the export of cystine from lysosomes and prevents progre­ssion of the disease. [20] However, early initiation of treatment is important as oral cysteamine may not reverse established tubular pathology. [1] Like­wise, it does not reverse established corneal deposits [21] and hence the need for topical the­rapy in patients with such deposits. Early treatment is critical because approximately one year of maintainance of renal function is achieved for every month of early cysteamine therapy, i.e., treatment prior to 2 years of age. [22],[23],[24] Kleta and his co-workers reported that diligent cysteamine therapy can reverse some of the organ damage that accompanies nephropathic cysti­nosis and can produce catch-up growth. Other children with similarly well-treated cystinosis may not achieve such excellent outcomes. Kleta suggested that possible causes for this diver­gence are a different genetic back ground, with other gene alleles contributing to overall kidney function, and differences in pharmacokinetics and pharmacodynamics of cysteamine. [25]

The aim of this study is to assess the use of slit lamp examination for corneal cystine deposits in suspected cases for the diagnosis of nephropa­thic cystinosis, and the progress of such deposits with treatment.


   Methodology Top


This study was approved by the Institutional Review Board at Cairo University Children's Hospital. Selective screening for nephropathic cystinosis was conducted to all suspected pa­tients presenting to Center of Pediatric Nephro­logy and Transplantation or referred to Egyptian Group for Orphan Renal Diseases (EGORD), Cairo University over a period of two years between January 2005 and December 2006. Pa­tients were suspected on the basis of presen­tation with proximal renal tubular acidosis and or hypophosphatemic rickets, or chronic kidney disease associated with previous history sug­gestive of renal Fanconi Syndrome particularly in families reporting death of siblings due to a similar condition. In addition, siblings of diag­nosed cases were screened.

Evaluation of the patients included personal and family history, clinical examination, blood picture and measurement of blood urea, creati­nine, electrolytes, glucose, acid-base status, Free T4 and TSH. Additional investigations were performed in patients with anemia and those with renal impairment. Complete ophthalmologic examination was conducted for all patients at the Pediatric Ophthalmology unit, Ophthalmo­logy Research Institute, Cairo. This included fundus examination and slit lamp examination for corneal cystine crystals. When present, they were scored as described by Gahl et al. [10] Photo­phobia was subjectively described as absent, mild, moderate or severe. In patients younger than two years with negative slit lamp exami­nation, leucocyte cystine assay was carried out as confirmatory diagnostic test.

Diagnosed cases received oral cysteamine; nevertheless doses were lower than recom­mended due to cost, ranging from 20-45 mg/kg. In addition, cysteamine eyedrops were specifi­cally prepared for the investigators according to the formula described by Gahl et al [10] . Follow up included clinical and routine laboratory assessment as well as quarterly slit lamp exa­mination and scoring of corneal crystals.

Nominal data were expressed as frequency and percentage, while quantitative data were described using range, mean and standard deviation.


   Results Top


Thirty three patients from 24 families were screened and the diagnosis of nephropathic cystinosis was confirmed in 16 patients from 15 families [Figure 1]. Diagnosed patients included eight boys and eight girls with a mean age at diagnosis of 52.7 ± 39.2 months (10-112 months). Eleven patients (69%) were above two years at the time of diagnosis, including seven (44%) above five years of age. The age of onset of symptoms ranged from 3-36 months (8.4 ± 7.7 months), while the first reported symptoms were those of renal tubular acidosis (11 cases) and rickets (5 cases). Regarding family history, pa­rents were consanguineous in 12 families (80%) and sibling deaths were reported in six families (40%), including two with multiple sibling deaths. These deaths occurred at a mean age of 23.4 ± 26.5 months (8-90 months).

The ocular manifestations of the patients are shown in [Table 1], [Figure 2]. In addition, five pa­tients had end-stage renal disease and started hemodialysis at a mean age of 91.8 ± 16.6 months (72-110). Other features included failure to thrive [Table 2], hypothyroidism diagnosed in three patients at the age of 3.5, 6 and 10 years. Three patients died at the ages of 4, 7 and 9 years.

The mean dose of oral cysteamine used was 31.3 mg/kg/day (range 20-45). Apart from cysteamine, the most frequently used medications were L-carnitine (all cases), one alpha hydroxy vitamin D3 (all cases), oral or parenteral iron (all cases), phosphorous and sodium-potassium citrate (polycitra) supplements (9 cases) and oral calcium (8 cases). The mean number of medications received by each patient was 8.7.

[Figure 3] shows the progress of corneal cystine crystal scores with follow up in 11 out of 14 children who were on cysteamine eye drops for at least 3 months period. The mean CCCS at diagnosis was 1.95 (0-3). Follow up data for six months were available for six patients. Their mean score was 1.81 both at diagnosis and after six months, in association with a decrease of 0.5 point in two cases and a similar increase in two others. Scores decreased in two other patients by 12 months. The mean score at 9-12 months was 1.5. Compliance was generally inadequate.


   Discussion Top


Nephropathis cystinosis (OMIM 219800) is the most common inherited cause of the renal Fanconi syndrome. Diagnosis is made by measurement of leucocyte cystine; an assay which is not routinely available in Egypt. Demonstration of corneal cystine deposits by slit-lamp examina­tion is diagnostic. [10] Ocular examination missed two cases (12.5%) aged 10 and 19 months. It is expected that corneal deposits may still not be apparent in infants [10] and our findings suggest that negative ocular examinations in patients up to 20 months should be interpreted with cau­tion. Nevertheless, such examinations are simple and may be appropriate for screening sympto­matic cases. To the best of our knowledge, this is the first study aiming to diagnose and treat children with nephropathic cystinosis in Egypt. Cystinosis is significantly present in Egypt, given that a two-year surveillance by one center could diagnose 16 cases and that 15 new cases are diagnosed annually in the USA. 1 The rate of consanguineous marriage in Egypt is still high, [26] thus autosomal recessive inherited disorders are common as 80% of the families in this series had consanguineous marriage.

It is notable that whereas the mean age of onset of symptoms was 8.4 months; consistent with infantile onset, [4] the mean age at the time of diagnosis was above four years (52.7 months). Moreover, nearly half (44%) of patients were diagnosed after the age of five years and five patients already had ESRD when diagnosed con­trary to the recent recommendations for early diagnosis. [22],[23],[24] The need for improved awareness, screening of symptomatic patients and pre­symptomatic determination of leucocyte cystine in siblings of diagnosed cases is therefore em­phasized. The importance of early treatment was illustrated by Gahl and others, estimating that for every month of treatment prior to 3 years of age, 14 months' worth of later renal function were preserved. [23],[24]

Ocular manifestations include corneal crystal accumulation, and deposits in other areas of the eye; conjunctiva, anterior chamber, iris, ciliary body, choroid, fundus and optic nerve. [27] 14 pa­tients had corneal cystine crystals in addition, two had retinal, one each subretinal and sub­conjunctival deposits. Corneal crystals are ini­tially asymptomatic, but photophobia can deve­lop within the first few years of life [28] and half of our patients had photophobia. Retinal pig­mentary changes were present in about one third of cases, consistent with previous reports of such changes occurring as early as infancy. [29]

Although oral cysteamine provides the basis of treatment, there is sufficient evidence that strict compliance with six hourly dosing is needed for proper depletion of cystine. [9] In addition, oral therapy has no effect on the corneal crystal accumulation, most likely due to inadequate lo­cal concentrations. [1],[21] Nevertheless, adequate therapy decreases retinal infiltration, previously described as frequent and potentially blinding. [30] In the current study, CCCS did not change after six months of treatment and started to decrease after 9-12 months. This is consistent with Gahl et al [10] who reported that administration of 0.55% cysteamine eye drops 6 to 12 times per day re­sulted in dissolution only after 8-41 months. Given that compliance was not optimal, the effect of longer treatment on corneal deposits may reasonably be considered adequate. Com­pliance issues have been previously reported, even with oral cysteamine. [9] The monthly cost of oral cysteamine in a dose of 50 mg/kg/day for a child weighing 15 Kg is estimated at $490 and topical therapy has to be specially formu­lated with cumbersome storage measures to pre­serve its stability. Nevertheless, the cost of treat­ment is well justified considering the possibility of preventing the progression of renal and ocular problems as well as the occurrence of other com­plications. Though this study managed to diag­nose nephropathic cystinosis in 16 Egyptian children, it is strongly believed that more affect­ted children are still undiagnosed and overlooked. Hence the initiative of the awareness program carried by the Egyptian Group for Orphan Re­nal Diseases (EGORD). High index of suspi­cion in infants presenting with fluid and elec­trolyte loss, aminoaciduria, glycosuria, phospha­turia, renal tubular acidosis, rickets and growth retardation is greatly encouraged in this pro­gram aiming at early diagnosis and treatment.

In conclusion, the examination for corneal cystine crystals is a simple and specific diag­nostic test and proved very useful in diagnosing cystinosis. Nevertheless, leucocyte cystine assay is still needed for suspected children below 20 months who have negative ocular examination. Topical treatment with cysteamine eye drops prevents the progression of corneal deposits and may decrease them in well-compliant children and families. Long term follow up studies are still needed to assess the effects of both sys­temic and topical cysteamine on the renal and the extra-renal complications in these children.


   Acknowledgement Top


The authors acknowledge the valuable help of Dr. William Gahl and Isa Bernardini, National Institute of Health USA, in providing and per­forming leucocyte cystine assay for slit lamp negative children.

 
   References Top

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2.Town M, Jean G, Cherqui S, et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 1998;18:319-24.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
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4.Gahl WA, Thoene J, Schneider JA. Cystinosis: A disorder of lysosomal membrane transport. In: Seriver CR, Beaudet AL, Sly WS, editors. The metabolic and molecular bases of inherited disease. 8t h ed. New York: McGraw-Hill; 2001. p. 5085-108.  Back to cited text no. 4    
5.Mahoney C, Striker G. Early development of the renal lesions in infantile cystinosis. Pediatr Nephrol 2000;15:50-6.  Back to cited text no. 5    
6.Gahl WA, Bashan N, Tietze F, Bernardini I, Schulman JD. Lysosomal cystine transport is defective in cystinosis. Science 1982;217:1263-5.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
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8.Park MA, Thoene JG. Potential role of apop­tosis in development of the cystinotic pheno­type. Pediatr Nephrol. 2005;20(4):441-6.  Back to cited text no. 8    
9.Levtchenko EN, van Dael CM, de Graaf-Hess AC, et al. Strict cysteamine dose regimen is re­quired to prevent nocturnal cystine accumu­lation in cystinosis. Pediatr Nephrol. 2006;21 (1): 110-3.  Back to cited text no. 9    
10.Gahl WA, Kuehl EM, Iwata F, Lindblad A, Kaiser-Kupfer MI. Corneal crystals in nephro­pathic cystinosis: natural history and treatment with cysteamine eyedrops. Mol Genet Metab. 2000;71(1-2): 100-20.  Back to cited text no. 10    
11.Theodoropouios DS, Krasnewich D, Kaiser­Kupfer MI, Gahl WA. Classical nephropathic cystinosis as an adult disease. JAMA 1993;270: 2200-4.  Back to cited text no. 11    
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13.Sonies B, Ekman EF, Andersson H, et al. Swallowing dysfunction in nephropathic cysti­nosis. N Engl J Med 1990;323:565-70.  Back to cited text no. 13    
14.Fivush B, Green OC, Porter CC, Balfe JW, O'Regan S, Gahl WA. Pancreatic endocrine insufficiency in post transplant cystinosis. Am J Dis Child 1987;141:1087-9.  Back to cited text no. 14  [PUBMED]  
15.Fivush B, Flick JA, Gahl WA. Pancreatic exo­crine insufficiency in patient with nephropathic cystinosis. L Pediart 1988;112:49-51.  Back to cited text no. 15    
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17.Anikster Y, Lacbawan F, Brantly M, et al. Pulmonary dysfunction in adults patient with nephropathic cystinosis. Chest 2001;119:394­401.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Fink JK, Brouwers P, Barton N, et al. Neu­rologic complications in longstanding nephro­pathic cystinosis. Arch Neurol 1989;46:543-8.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: Natural history and effects of oral cysteamine therapy. Ann Intern Med. 2007;147:242-250.  Back to cited text no. 19    
20.Gahl WA, Charnas L, Markello TC, et al. Parenchymal organ cystine depletion with longterm cysteamine therapy. Biochem Med Metab Biol 1992;48:275-85.  Back to cited text no. 20    
21.Cantani A, Giardini O, Ciarnella Cantani A. Nephropathic cystinosis: ineffectiveness of cysteamine therapy for ocular changes. Am J Ophthalmol 1983;95:713-4.  Back to cited text no. 21    
22.Markello TC, Bernardini IM, Gahl WA. Im­proved renal function in children with cystinosis treated with cysteamine. N Engl J Med 1993; 328:1157-62.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Gahl WA. Early oral cysteamine therapy for nephropathic cystinosis. Eur J Pediatr 2003;162 Suppl 1:S38-41.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Kleta R, Gahl WA. Pharmacologic treatment of nephropathic cystinosis with cysteamine. Expert Opin Pharmacother 2004;(5)11:2255-62.  Back to cited text no. 24    
25.Kleta R, Bernardini I, Ueda M, et al. Long term follow-up of well treated nephropathic cystino­sis patients. J Pediatr 2004;145(4):555-60.  Back to cited text no. 25    
26.Hafez M, El-Tahan H, Awadalla M, El-Khayat H, Abdel-Gafa A, Ghoneim M. Consanguineous matings in the Egyptian population. J Med Genet 1983;20(1):58-60.  Back to cited text no. 26    
27.Tsilou E, Min Zhou, Gahl W, Sieving PC, Chan C. Ophthalmic Manifestations and Histopa­thology of Infantile Nephropathic Cystinosis: Report of a Case and Review of the Literature. Surv Ophthalmol 2007;52(1): 97-105.  Back to cited text no. 27    
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29.Tsilou ET, Rubin BI, Reed G, et al. Nephropa­thic cystinosis: Posterior segment manifesta­tions and effects of cysteamine therapy. Ophthalmology 2006;113(6):1002-9.  Back to cited text no. 29    
30.Dureau P, Broyer M, Dufier JL. Evolution of ocular manifestations in nephropathic cysti­nosis: a long-term study of a population treated with cysteamine. J Pediatr Ophthalmol Strabismus 2003;40(3):142-6.  Back to cited text no. 30    

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Correspondence Address:
Neveen A Soliman
Center of Pediatric Nephrology and Transplantation, Egyptian Group for Orphan Renal Diseases, Cairo University, Cairo
Egypt
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    Figures

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    Tables

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