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Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 28-30

Nephropathic cystinosis: A cause of renal fanconi syndrome

1 Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital; Private Practice, Central Health Medical Practice; Paediatric Nephrology Centre, Hong Kong Children's Hospital, Hong Kong
2 Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital; Paediatric Nephrology Centre, Hong Kong Children's Hospital, Hong Kong
3 Department of Chemical Pathology, Prince of Wales Hospital; Department of Chemical Pathology, Hong Kong Children's Hospital, Hong Kong

Date of Submission20-Mar-2020
Date of Decision12-May-2020
Date of Acceptance07-Jun-2020
Date of Web Publication27-Jun-2020

Correspondence Address:
Euan Soo
Central Health Medical Practice, 3/F, Baskerville House, 13 Duddell Street, Central
Hong Kong
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_8_20

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We hereby describe a case of nephropathic cystinosis who presented as growth failure, polydipsia, and renal Fanconi syndrome. The diagnosis was based on demonstration of elevated leukocyte cystine content and mutations in CTNS. Management with oral cysteamine and cysteamine eyedrops along with adequate nutrition and appropriate supplements, was associated with improvement in growth and development.

Keywords: CTNS, cysteamine, cystine, proximal renal tubular acidosis

How to cite this article:
Soo E, Chan EY, Yuen YP, Ma AL. Nephropathic cystinosis: A cause of renal fanconi syndrome. Asian J Pediatr Nephrol 2020;3:28-30

How to cite this URL:
Soo E, Chan EY, Yuen YP, Ma AL. Nephropathic cystinosis: A cause of renal fanconi syndrome. Asian J Pediatr Nephrol [serial online] 2020 [cited 2022 Jul 7];3:28-30. Available from: https://www.ajpn-online.org/text.asp?2020/3/1/28/288154

  Introduction Top

Cystinosis is a rare autosomal recessive lysosomal storage disease with an estimated incidence of about 0.5–1.0/100,000 live births. The disease may be even rare in Chinese population.[1] The most common subtype, termed nephropathic cystinosis, presents with Fanconi syndrome, growth retardation, and rickets in the first year of life; milder forms that affect only extrarenal organs or become symptomatic later in life are possible. Extrarenal involvement may include the cornea, thyroid gland, pancreas, gonads, central nervous system, and muscles. If left untreated, death ensues by the age of 30 years.[2] We report the first case of cystinosis diagnosed in Hong Kong and its management.

  Case Report Top

A 6-month-old boy of Pakistani ancestry, first born of consanguineous marriage, was referred for failure to thrive. He was born by vaginal delivery at 37 weeks of gestation in Hong Kong, with a birth weight of 2.48 kg. The antenatal, perinatal, and family history for three generations were unremarkable.

Parents noted polyuria, polydipsia, and retarded growth at 3 months of age. On examination, weight (5.5 kg) and height (62 cm) were <3rd centile for age. Blood pressure, pulse, and respiratory rates were normal. The child had fair skin, hypopigmented hair and features of rickets, including frontal bossing, swelling of the wrists and bow legs [Figure 1]. Initial blood investigations revealed markedly elevated alkaline phosphatase (1153 U/L), hypokalemia (lowest potassium 2.5 mEq/L), hypophosphatemia (phosphate 0.53 mmol/L), and normal anion gap metabolic acidosis (bicarbonate 16.8 mEq/L). Serum levels of creatinine (25 μmol/L), 25-hydroxyvitamin-D and parathyroid hormone were within the normal range. The urine pH was 7.2; the urine anion gap was not measured. Urinalysis confirmed glucosuria, mild proteinuria, generalized aminoaciduria, and reduced tubular reabsorption of phosphate (58%; normal > 85%); the tubular maximum reabsorption of phosphate (TmP) indexed to glomerular filtration rate (GFR), TmP, was 0.33 mmol/L (normal 1.15–2.6 mg/dl). Wrist radiographs showed mild periosteal reaction and metaphyseal fraying. The slit lamp examination at 10 months of age was unremarkable. These findings were compatible with Fanconi syndrome with proximal renal tubular acidosis. The child was started on potassium citrate with sodium bicarbonate, supplements of phosphate, and alfacalcidol.
Figure 1: (a) Mild periosteal reaction at the right humeral head cortex; (b) Mild fraying of metaphysis at distal left radius and ulnar; (c) Slit lamp examination showing white specks indicating corneal deposits of cystine; (d) Poor height growth in height for age growth chart, with the arrow indicating the initiation of cysteamine therapy

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The child continued to have poor growth, and renal function deteriorated to an estimated GFR of 50 ml/1.73 m 2/min (modified Schwartz formula) by 15 months of age. Slit-lamp examination, repeated at this age, revealed corneal crystals, suggestive of cystinosis. Levels of leukocyte cystine, measured at an overseas laboratory, were elevated at >5 nmol half cystine/mg protein (normal 0–0.2 nmol/mg). Polymerase chain reaction failed to amplify the promoter and exon 1, 2 and 3 of the CTNS gene, suggesting a homozygous large deletion spanning this region. This deletion, considered pathogenic, was subsequently confirmed by a commercial laboratory using TaqMan copy number assay (ThermoFisher Scientific) and by Sanger sequencing, which did not reveal additional pathogenic variants in CTNS. Sequencing also confirmed that the parents were heterozygous carriers of the large deletion in CTNS.

Following a diagnosis of infantile nephropathic cystinosis, therapy with oral cysteamine was started and stepped up gradually to 1.3 g/m 2/day, along with cysteamine eye drops (one drop each in both eyes every 4 h), beginning at 18 months of age. To improve nutrition and therapy compliance, gastrostomy was performed. At last follow-up, polyuria had stabilized, and body weight improved to between 25th and 50th percentile; however, his height remained below 3rd percentile and features of Fanconi syndrome persisted. At last follow-up serum sodium was 142 mmol/L, potassium 3.5 mmol/L, creatinine 52 μmol/L and estimated GFR 68 ml/1.73 m 2/min.

  Discussion Top

Fanconi syndrome has many differential diagnoses, of which the most common inherited cause is cystinosis. Other causes include Lowe syndrome, mitochondrial disease, galactosemia, and Wilson disease in childhood, and multiple myeloma in adults.

Cystinosis is an autosomal recessive resulting from biallelic mutations in CTNS gene, which encodes the lysosomal cystine transporter cystinosin.[3] Three clinical subtypes are recognized, of which the most common form, infantile nephropathic cystinosis, is usually caused by truncating mutations. Milder mutations affecting only one allele result in less severe forms, namely juvenile nephropathic cystinosis and ocular non-nephropathic cystinosis. Large deletions, such as in our patients, are reported to lead to loss of protein function.[3] Clinical features of cystinosis are secondary to the accumulation of cystine in lysosomes. The kidney tubules are affected, resulting in renal Fanconi syndrome and end-stage renal disease by 10 years of age, if left untreated. Other organs affected include eyes (photophobia, blindness), pancreas (diabetes mellitus), thyroid (hypothyroidism), gonads (hypogonadism), muscles (swallowing difficulty, respiratory failure), and central nervous system (vertigo, memory loss, reduced motor function, speech impairment). Untreated, most patients die by the age of 30 years.

The diagnosis of cystinosis is made upon demonstration of either cystine crystals in the cornea on slit lamp examination (a finding that is seen beyond infancy), elevated cystine levels in leukocytes, or biallelic pathogenic mutations in CTNS. The test for leukocyte cystine level measurement is currently not available in Hong Kong, and was ordered from overseas laboratory. Genetic analysis of CTNS gene, which was readily available in Hong Kong, should include both sequence analysis and gene copy number assays so that large deletions are not missed.

Management aims at depleting intracellular cystine. Cysteamine, is an aminothiol that enters the lysosome to combine with cystine, forming a cysteamine-cystine disulfide molecule that can exit the lysosome via an alternative lysosomal protein PQLC2.[4] Therapy with cysteamine delays onset of end-stage renal disease, can prevent or delay extrarenal manifestations and avoid death.[2] Cysteamine eye drops are necessary to manage ocular manifestations since the oral drug does not penetrate the cornea. Despite its success, compliance with oral cysteamine is often poor due to the lack of access to therapy and high cost, particularly in developing regions, and the drug's foul odor, ascribed to its high sulfur content, that leads to anorexia and poor body image. Overdose with cysteamine can lead to cutaneous reactions (symmetric angioendotheliomatosis, striae rubrae), deformities of the long bones, and muscular or neurological symptoms.[5] Regular monitoring of leukocyte cystine levels is necessary to ensure that dosage is sufficient and not in the toxic range. Therapy also imposes the significant financial burden on the family; our patient's family spends over HK$ 18,000 each month for costs of oral drugs and the eye drops; requirements are expected to increase as the child grows older. Renal transplant is the mainstay of management once end-stage renal disease develops. However, patients continue to require therapy with cysteamine lifelong despite renal transplantation, to prevent extrarenal manifestations. Genetic counseling is important to prevent disease recurrence in siblings.

Our case illustrates the challenges faced when managing a patient with cystinosis. This systemic disease requires frequent multidisciplinary interactions to achieve satisfactory outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


Dr. Joannie Hui (Metabolic Paediatrician, The Chinese University of Hong Kong) for helping to liaise the testing of leukocyte cystine by Baylor College. Dr. Angie Fong Hon Chi (Hong Kong Eye Hospital) and Dr. Jason Yam Cheuk Sing (Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong) for their help in examination and slit-lamp images. Ms. Fiona Lai Fung Yee (clinical pharmacist, Princess Margaret Hospital) for her help in sourcing and working out the dosing of cysteamine.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Chuang YW, Wen MC, Wu MJ, Shu KH, Cheng CH, Yu TM, et al. Follow-up and treatment of renal transplantation with nephropathic cystinosis in central Taiwan. Transplant Proc 2012;44:80-2.  Back to cited text no. 1
Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, et al. Nephropathic cystinosis: An international consensus document. Nephrol Dial Transplant 2014;29 Suppl 4:iv87-94.  Back to cited text no. 2
Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore SA, 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. 3
Shams F, Livingstone I, Oladiwura D, Ramaesh K. Treatment of corneal cystine crystal accumulation in patients with cystinosis. Clin Ophthalmol 2014;8:2077-84.  Back to cited text no. 4
Besouw MT, Bowker R, Dutertre JP, Emma F, Gahl WA, Greco M, et al. Cysteamine toxicity in patients with cystinosis. J Pediatr 2011;159:1004-11.  Back to cited text no. 5


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