Asian Journal of Pediatric Nephrology

: 2020  |  Volume : 3  |  Issue : 1  |  Page : 15--20

Infantile nephropathic cystinosis: Clinical features and outcome

Sumantra Raut1, Priyanka Khandelwal1, Aditi Sinha1, Ritu Thakur1, Mamta Puraswani1, Thirumurthy Velpandian2, Pankaj Hari1, Arvind Bagga1,  
1 Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
2 Department of Ocular Pharmacology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Arvind Bagga
Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029


Background: Nephropathic infantile cystinosis, the most common cause of renal Fanconi syndrome, presents in early infancy with impaired growth, polyuria and polydipsia, and progresses to end stage renal disease during the first decade. Diagnosis is based on corneal examination for cystine crystals, leukocyte cystine content and genetic testing of the CTNS gene. Information on clinical features and genotype of Indian children with cystinosis is limited. Methods: We describe clinical features, renal outcomes and genetic variants in the CTNS gene in Indian children with cystinosis. Results: We included 19 patients with cystinosis from 17 families predominantly presenting with poor growth (95%), polyuria (84%) and refractory rickets (74%). Cystine crystals were present in 84%. Fanconi syndrome was common; two had nephrocalcinosis and 9 presented with eGFR <60 ml/ min/ 1.73 m2. Genetic analysis, performed in 11 families, (12 patients) showed 8 variants. Five were reported, pathogenic variants, one was likely pathogenic and two were rare or novel variants of unknown significance. Conclusion: The p.Thr7PhefsTer7 variant, common to five unrelated patients, might be a population hotspot. Eight (42%) patients have been initiated on therapy with cysteamine. Studies with prolonged follow-up are necessary to define renal and extrarenal outcomes and the effect of cysteamine in Indian children.

How to cite this article:
Raut S, Khandelwal P, Sinha A, Thakur R, Puraswani M, Velpandian T, Hari P, Bagga A. Infantile nephropathic cystinosis: Clinical features and outcome.Asian J Pediatr Nephrol 2020;3:15-20

How to cite this URL:
Raut S, Khandelwal P, Sinha A, Thakur R, Puraswani M, Velpandian T, Hari P, Bagga A. Infantile nephropathic cystinosis: Clinical features and outcome. Asian J Pediatr Nephrol [serial online] 2020 [cited 2020 Nov 24 ];3:15-20
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Full Text


Cystinosis is the most common cause of renal Fanconi syndrome in childhood and the first treatable lysosomal storage disease.[1],[2] Defect in the transport protein, cystinosin, encoded by CTNS, on chromosome 17p13, results in lysosomal accumulation of cystine, which forms crystals and causes progressive organ injury.[3] Infantile nephropathic cystinosis is the most common and severe form, accounting for 95% of all cases. Symptoms, beginning in early infancy, include impaired growth, polyuria, and polydipsia, and cause end-stage renal disease (ESRD) by the end of the first decade.[4] Due to limitations in diagnosis and therapy, there are few reports of the clinical profile and outcome of the disease from India.[5],[6],[7],[8] We describe our experience on the clinical features, management, and outcome of patients with cystinosis.

 Patients and Methods

We retrospectively reviewed the medical records of all patients, younger than 18-year-old, diagnosed with infantile nephropathic cystinosis at this center between 2009 and 2018. Cystinosis was diagnosed in the presence of proximal renal tubular acidosis (RTA), with or without Fanconi syndrome, and anyone of the following: (i) slit-lamp examination showing corneal cystine crystals; (ii) homozygous or compound heterozygous, pathogenic or likely pathogenic mutations in CTNS gene;[9] or (iii) family history of confirmed cystinosis.[10] While leukocyte cystine content >5 nmol of half-cystine/mg protein is a diagnostic criterion, we lacked access to this facility. The diagnosis of proximal RTA relied on presence of (i) normal anion gap metabolic acidosis, (ii) urine pH <5.3 (at bicarbonate level <15 mEq/L), and (iii) during bicarbonate loading, fractional excretion of bicarbonate >15% and urine to blood carbon dioxide gradient >20 mmHg.[11] Fanconi syndrome was diagnosed in the presence of one or more of the following: low molecular weight proteinuria, aminoaciduria, glucosuria, potassium and phosphate wasting, and hypercalciuria.

Clinical and biochemical details were recorded at diagnosis and at follow-up. Genomic DNA was amplified by polymerase chain reaction using primers for all exons of CTNS or clinical exome sequencing by next-generation sequencing using the Illumina platform, followed by Sanger sequencing. Rare or novel variants were those with minor allele frequency <1% or absent in public databases, 1000 Genomes project, and Genome Aggregation Database. Bioinformatic prediction of pathogenicity was by a Phred-scaled score > 10 by Combined Annotation Dependent Depletion version 1.4 (, Polyphen-2 ( 2/) and Mutation Taster ( Annotation of variants was done according to the American College of Medical Genetics and Genomics criteria.[9] Parental testing was done by Sanger sequencing at a commercial laboratory to confirm compound heterozygosity, where feasible and applicable.


Patient characteristics

Of 19 patients with cystinosis from 17 families, 15 were boys [Table 1]. Four families were consanguineous; four additional patients had 1–2 siblings each with a history of similar symptoms who had died without evaluation. Among patients with infantile nephropathic cystinosis, the median age at first clinical symptoms was 9 months (interquartile range, 6.5, 15.5) months, at presentation to this hospital was 3 (1.9, 5) years and at last follow-up was 5.3 (2.3, 7.0) years. The median time from symptom onset to diagnosis was 1.8 (1.1, 3.5) years. The chief symptoms were poor growth in 18 (94.7%) patients, polyuria and polydipsia in 16 (84.2%), refractory rickets in 14 (73.6%), salt preference in 13 (68%), and photophobia in 3 (15.8%) patients. All but one presented with short stature with median height standard deviation score (SDS) of − 5 (−6.7, −3.1). Cystine crystals in the cornea were present at diagnosis in 14 (73.6%) patients; two more patients showed crystals at 6-month and 2-year follow-up. The youngest age at which crystal deposition was detected was at 18 months (patient #4). Pigmented retinopathy was diagnosed in one child with nephropathic cystinosis.{Table 1}

Eleven (64.7%) patients had hypercalciuria, with median 24-hr urine calcium among hypercalciuric children being 10.9 (7.7, 15.5) mg/kg/day; 2 (10.5%) patients had nephrocalcinosis. The median tubular maximum for phosphate reabsorption/glomerular filtration rate (TmP/GFR) was 1.7 (1.0, 1.8) mg/dl; TmP/GFR was below the threshold in 18 children. The median blood level of phosphate was 2.5 (2.1, 3.2) mg/dl, and potassium was 3.0 (2.6, 3.5) mEq/L. The median level of urinary beta-2 microglobulin was 10597 (1156, 23016) ng/ml. Generalized urinary aminoaciduria was present in 85% of patients. Of 19 children, 9 (47.4%) presented with estimated GFR (eGFR) <60 ml/min/1.73 m 2. The median eGFR at diagnosis was 65 (44.5, 83.5) ml/min/1.73 m 2 at presentation. Hypothyroidism was present in 42% (6 children at initial evaluation and 2 additional patients during follow-up).

Genetic analysis

Genetic analysis for mutations in the CTNS gene, performed in 11 families (12 patients), showed eight different homozygous or compound heterozygous variants [Table 1] and [Figure 1]. Five variants were pathogenic and reported previously, including [3],[12],[13],[14] four frameshifts and one in-frame deletion. One deletion c.682-65_698del was classified as likely pathogenic since it was present in trans with a pathogenic variant. Two were variants of unknown significance comprising two substitutions (c.681+ 4A >G and c.934A>C). Six patients from five unrelated families showed a previously reported frameshift change of threonine to phenylalanine and premature truncation at position 7 (p. Thr7PhefsTer7) caused by either of the two variants c. 16_19delCTGA (n = 3 patients, 2 families), and c. 18_21delGATC (n = 3). The variants p. Gly258SerfsTer30, and p. Ser312Arg were common to three and two patients, respectively. Segregation analysis confirmed compound heterozygosity in patient #4. To avoid added cost, only mothers of patients #5 and #15 were tested and found to be heterozygous carriers.{Figure 1}

Therapy and response to cysteamine

Median daily bicarbonate and potassium dose requirement was 5.5 mEq/kg and 5 mEq/kg, respectively. The median daily phosphate replacement dose was 70 mg/kg.

Nearly one-third of the patients were on proton pump inhibitors or prokinetics. Oral cysteamine was administered to 8 (42%) patients, starting at a median age of 3.3 (2.0, 4.8) years for a median duration of 9 (2.8, 21) months. Cysteamine therapy was begun <2 years in three patients. The median daily dose of cysteamine was 1.3 (1.2, 1.5) g/m 2; dose was titrated as per clinical response due to the unavailability of leukocyte cystine estimation. Compliance to dose interval of cysteamine was uniformly poor. Cysteamine eye drop was used in three patients.

In four patients treated with cysteamine for over 6 months (median 28 months), the median height SDS was −3.5 at the start of therapy and −4.7 SDS at the last follow-up. Of patients who did not receive cysteamine, with follow-up of >6-months, the height SDS was −5.7 SDS and −6.8 SDS at baseline and last follow-up, respectively. The median eGFR at onset was 65 ml/min/1.73 m 2 in patients treated with cysteamine versus 58 ml/min/1.73 m 2 in untreated patients, and the median fall in eGFR by the last follow-up was 20.1% versus 0%, respectively.

Follow-up and outcome

Follow-up data were available for all, except one child, with a median duration of 2.1 (0.7, 4.9) years. Two patients showed radiological healing of rickets and underwent corrective osteotomy. One patient underwent a gastrostomy tube placement while none received growth hormone therapy. Hypercalciuria persisted at follow-up [spot calcium-creatinine ratio 0.6 (0.5, 0.7) mg/mg], without change from baseline [0.45 (0.24, 1.1) mg/mg; P = 0.71]. There was no evidence of diabetes mellitus (median HbA1c 4.9 %), neuromuscular disorders, myopathy, pancreatitis, or swallowing impairment at presentation or during follow-up; five patients (26.3%) had recurrent vomiting.

During follow-up, 6 (32%) patients required median 2.7 (1.3, 3.8) episodes of hospitalizations, among which four were for recurrent dehydration, three for hypokalemic weakness and two due to hypocalcemic spasm/seizure and acute kidney injury (not requiring renal replacement) each. Estimated GFR deteriorated till last follow-up to 46 (28, 77) ml/min/1.73 m 2 at the rate of median 3.5 (1.4–5.6) ml/1.73 m 2/min. Seven patients showed a decline in renal function and developed chronic kidney disease (CKD) stage 3 at a mean age of 2.6 years; 3 of them showed >25% decline in eGFR, but ESRD was not observed. Two patients succumbed at 1.8 years and 6.4 years of age after 8.9 months and 67.3 months of follow-up, respectively, due to dyselectrolytemia and sepsis.


The present report describes the phenotype and genotype of a cohort of Indian children with infantile nephropathic cystinosis. [Table 2] compares the characteristics of the present patients with those of large cohorts. While the median age of onset in our cohort was similar to other cohorts, the diagnosis was slightly delayed till 3 years of age compared to Brazilian, French, and Iranian cohorts (1–2.8 years) [Table 2].[15],[17],[18]{Table 2}

Growth retardation (95%), polyuria (82%), Fanconi syndrome (85%), and hypercalciuria (58%) were common, similar to other cohorts; rickets was more prevalent than the French cohort (41%).[15],[18] While hypokalemic paralysis (21%) and hypocalcemic tetany (32%) were common, few patients (10%) had nephrocalcinosis or nephrolithiasis despite the persistence of hypercalciuria. Hypothyroidism was present in 42% of children, similar to other reports.[1],[18] Given the short duration of follow-up (median 2.9 years), complications such as diabetes, hypogonadism, cardiovascular abnormality, myopathy, or ESRD were not detected.

Cysteamine is not available in India and is prohibitively expensive. This limited its use to 8 patients with delayed initiation of therapy, in sharp contrast to 76%–100% cysteamine usage in worldwide cohorts.[1],[17],[18] Vaisbich and Koch showed the benefit of initiation of cysteamine < 2-years of age on the progression of renal injury.[17] Delayed initiation of cysteamine, especially when renal function had already deteriorated, possibly caused unsatisfactory linear growth and progression of renal failure in the present cohort. In addition, lack of aggressive nutritional rehabilitation, with parental reluctance for nasogastric or gastrostomy tube placement might have perpetuated malnutrition, and affected cysteamine compliance and efficacy, in the present cohort.[22],[23]

The limited availability of leukocyte cystine assay in South Asia is a major barrier to the early diagnosis and titration of optimal therapy. Recently, with support from the Indian Council of Medical Research (ICMR) and with assistance from IKRIS Pharma Network, an attempt is being made to establish this assay at this center. Diagnosis in the current study was predominately by the detection of corneal cystine crystals, due to the cost and long turn-around time of genetic studies.

There is limited genotypic information in Indian patients with cystinosis. The 57-kb deletion is the most common mutation associated with cystinosis detected in 17%–75% European, 50% North American and 37% Brazilian patients; this mutation was not found in our study,[1],[18],[24] similar to reports from Middle Eastern cohorts and those with late-onset disease.[25],[26] In our limited experience, the previously reported p. Thr7PhefsTer7 variant [3] was found in six patients from five unrelated families, suggesting that this region might be a mutation hotspot. Most variations caused large deletions with premature truncation of the protein, which is expected to result in a more severe phenotype. Sequencing of the CTNS gene in a large number of patients with cystinosis is required to confirm the above findings. The current report is limited by a small number of patients and a relatively short duration of follow-up; paternal testing to complete segregation analysis could not be done in two patients.


Early diagnosis by leukocyte cystine assay/genetic sequencing along with prompt initiation of specific therapy with cysteamine, can effectively delay the progression of renal failure.[27] Management of cystinosis in developing countries is a challenge due to the lack of these basic diagnostic and therapeutic modalities. A high index of suspicion for diagnosis and a consolidated effort for creating laboratory expertise and facilitation of therapy is necessary. Longer follow-up studies are necessary to define renal and extra renal outcomes and the effect of cysteamine in Indian children.


Funding support by ICMR (Advanced Centre for Research in Pediatric Kidney Diseases; 5/7/1090/2013-RHN); and IKRIS Pharma Network.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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