Stage II: Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening Update History Stage 2 Status (Pediatric):Complete (Actionability curation complete.)

Condition: Cystinosis
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The population prevalence of cystinosis is 1–10/1,000,000 worldwide. The frequency of cystinosis in Brittany, France is 1/26,000. There are an estimated 500-600 children in the US with cystinosis with approximately 20 new cases identified each year.
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Clinical Features
(Signs / symptoms)
Cystinosis is a multisystemic lysosomal storage disease resulting from a defect in cystine transport out of lysosomes. This results in cystine accumulation affecting all tissues; the eyes and kidneys are the first organs to be affected. Cell damage and organ dysfunction are heterogeneous and vary in severity and progression. Cystinosis leads to severe renal Fanconi syndrome, characterized by polyuria, polydipsia, failure to thrive, vomiting, constipation, dehydration, impaired longitudinal growth, and/or hypophosphatemic/calcipenic rickets. Corneal crystals increase with age resulting in photophobia, corneal sensitivity, and reduced visual acuity if left untreated. Very rarely, patients not treated for ocular crystals may develop corneal lesions severe enough to require a corneal transplant.
Later in life, individuals can develop endocrine, cardiovascular, and neurological involvement as well as other non-specific symptoms (e.g., gastrointestinal involvement, heat intolerance, (hypophoresis) due to cystine buildup. Males generally develop hypergonadotropic hypogonadism with infertility invariably observed, while females usually have pubertal retardation but with less severely compromised gonadal function. Serious non-renal manifestations usually develop in the second decade of life.
There are three described clinical forms of the disease, which are a result of three allelic subtypes. The most severe and common subtype is infantile nephropathic cystinosis (95% of cases), followed by juvenile (or intermediate) nephropathic cystinosis (3% of cases), and a less severe subtype and adult non-nephropathic (ocular) cystinosis characterized clinically only by photophobia (unknown prevalence).
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Natural History
(Important subgroups & survival / recovery)
In infantile nephropathic cystinosis, failure to thrive is generally noticed after age six months. Signs of renal Fanconi syndrome appear as early as age six months, corneal crystals can be present before age one year and are always present after age 16 months. Ocular involvement usually appears after 3 years of age. Prior to the use of renal transplantation and cystine-depleting therapy, the disease progressed to end stage renal disease (ESRD) and death before the age of ten. The first symptoms of juvenile cystinosis appear around 6 – 8 years of age with a milder form of proximal tubulopathy and/or proteinuria with nephrotic syndrome. Progression to ESRD occurs later than in the infantile form. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years.
In the US, the mean age of first kidney transplant is 13.8 years (range 2-24 years). Despite successful renal transplantation, many patients do not survive past the age of 30 years if they have not been treated with cystine-depleting therapy. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. However, data is still accumulating on the effect of cysteine depleting agents on longevity due to its approval in the 1990s.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Following diagnosis individuals should undergo evaluation to establish the extent of disease and the needs in an individual:
-Height and weight plotted on an age-appropriate growth chart along with skeletal imaging
-Evaluation of the following: renal function and ultrasound; thyroid function; lipid panels; glucose tolerance; and serum testosterone and gonadotropins (for pre- and post-pubertal males)
-Ophthalmologic evaluation (including slit lamp examination of the cornea)
-Consultation with a clinical geneticists or genetic counselor (Tier 3)
Treatment should employ a team approach, including a pediatric nephrologist, a metabolic disease expert, a genetic counselor, and a local pediatrician or family practitioner. (Tier 2)
Regardless of kidney involvement, all patients should receive treatment with cysteamine (a cystine-depleting agent) which lowers the cystine content in muscles and other tissue. Treatment is lifelong and should be initiated at diagnosis under the supervision of a physician experienced in treatment of cystinosis. The best effects are seen if the drug is started at very young ages. A retrospective analysis of 86 adult patients (mean age 26.7; mean age at diagnosis 2.2 years) included 75 individuals who received cysteamine at a mean age of 9.9 years. Following a mean duration of treatment of 17.4 years, individuals who started cysteamine therapy before 5 years of age had a significant delay in onset of ESRD (13.4 years versus 9.5 years) and 8 patients who initiated treatment before 2.5 years of age did not reach ESRD by follow up. Treated individuals also had lower rates of later onset complications (e.g., hypothyroidism, diabetes (mean number of complications: 1.8 versus 3.8) compared with untreated individuals, with 5 treated individuals (mean age 21.4 years) developing no complications. For individuals starting treatment after age 5, there was no decrease in the incidence of ESRD and overall rate of complications; however, the development of diabetes and hypothyroidism was significantly delayed. Life expectancy was significantly improved among all individuals with cysteamine therapy, including both those who were treated before (p=0.03) and after (p<0.05) the age of five years. At time of follow up 5% of those treated prior to 5 years had died, compared with 43% of those treated after age 5, and 64% of those never treated. In a second retrospective study of 100 individuals (58 men and 42 women) aged 18 to 45 with nephropathic cystinosis (age at diagnosis not reported), individuals who had undergone long term cysteamine therapy (>8 years; mean 15.1 years) compared to those without long term treatment (0-8 years; mean 2.0 years) were found to have: later age at transplantation (14.8 years vs. 11 years), greater height (154.7 vs. 143.6 cm) and weight (53.2 vs. 45.3 kg), fewer complications (e.g., swallowing abnormalities, diabetes; [mean of 2.2 complications versus 4.0 complications]), and fewer deaths (8% vs. 30%) at follow up. (Tier 2)
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To prevent and treat eye complications, patients need to be treated topically with cysteamine hydrochloride eye drops that dissolve crystals and alleviate symptoms at all ages. A report of patients treated with cysteamine eyedrops in at least one eye for at least 1 year found that 37/98 (38%) of patients experienced a significant decrease in the corneal crystal accumulation (decreased by a 1.0 score of obstruction on a scale of 0-3.0). The remaining 62% of patients did not experience a reduction in crystal levels, which was attributed to noncompliance of treatment. (Tier 2)
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Treatment of chronic kidney disease (CKD) should follow international guidelines. Kidney transplantation is the treatment of choice for ESRD in cystinosis and is completely curative for the Fanconi syndrome. Overall, the results of kidney transplantation in cystinosis patients are better than in other patients undergoing transplantation. (Tier 2)
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Family planning is recommended in women of childbearing age. Pregnancies in women with cystinosis are at increased risk for premature delivery and must be monitored closely. (Tier 4)
Individuals should have annual ophthalmologic exams including: slit lamp biomicroscopy, intraocular pressure measurement, and dilated fundus examination. (Tier 2)
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Individuals should undergo routine monitoring for endocrine system involvement, including monitoring for signs of hypothyroidism, diabetes mellitus, impaired growth, hypogonadism, and fertility/pubertal development with treatment as needed. (Tier 2)
Individuals should undergo annual follow up for monitoring of neurological involvement including: monitoring functions of skeletal muscles, orofacial motor function (language) and swallowing, respiratory muscle function, central nervous system involvement, and neurocognitive alterations. (Tier 2)
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Circumstances to Avoid
Inhibitors of the renin-angiotensin system (ACEIs and ARBs) should be reduced or stopped during hot weather and high doses should always be avoided. (Tier 2)
Individuals should avoid dehydration, which can compromise remaining renal function. (Tier 3)
Sun exposure can exacerbate photophobia and should be avoided. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
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Prevalence of Genetic Mutations
No information on the prevalence of variants in CTNS was identified.
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on penetrance among individuals identified molecularly was found.
Current evidence indicates that cystinosis is a monogenic-recessive disease with
complete penetrance. (Tier 4)
The following age-related clinical characteristics of untreated nephropathic cystinosis, giving age of onset and prevalence, respectively, have been reported for clinically identified patients:
-Renal Fanconi syndrome, 6 to 12 months, 95%
-Hypothyroidism, 5 to 10 years, 50%
-Photophobia, 8 to 12 years, 50%
-Chronic renal failure, 8 to 12 years, 95%
-Myopathy, difficulty swallowing, 12 to 40 years, 20%
-Retinal blindness, 13 to 40 years, 10-15%
-Diabetes mellitus, 18 to 40 years, 5%
-Male hypogonadism, 18 to 40 years, 70%
-Pulmonary dysfunction, 21 to 40 years, 100%
-CNS calcifications, 21 to 40 years, 15%
-CNS symptomatic deterioration, 21 to 40 years, 2% (Tier 3)
Information on relative risk has not been reported.
Variation in clinical phenotype is generally linked to the type of variants present with those with the most severe form having truncating variants and those with less severe disease involvement generally having the at least one mild pathogenic variant. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Depending on the formula used, oral cysteamine dosing is required every 6-12 hours (which may include overnight doses). Side effects may include gastrointestinal disorders, characteristic sulphuric body odor, and halitosis. Non-compliance with treatment is frequent.
Cysteamine eye drops are taken 6-10 times a day and can cause eye burning.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Owing to the rarity of nephropathic cystinosis, the diagnosis is often delayed; some patients are diagnosed only when they present with ESRD. It is estimated that at least 50% of children worldwide are diagnosed beyond 1 year of age, unless there are other known affected family members. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
End-Stage Renal Disease (ESRD) / Oral cysteamine
Corneal crystals / Ophthalmic cysteamine
3D 1
1. Evidence level downgraded based on extrapolating corneal manifestations from photophobia likelihood.
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Ariceta G, Camacho JA, Fernandez-Obispo M, Fernandez-Polo A, Gamez J, Garcia-Villoria J, Lara Monteczuma E, Leyes P, Martin-Begue N, Oppenheimer F, Perello M, Morell GP, Torra R, Santandreu AV, Guell A. Cystinosis in adult and adolescent patients: recommendations for the comprehensive care of cystinosis. Nefrologia. (2015) 35(3):304-21.
2. Levtchenko E, van den Heuvel L, Emma F, Antignac C. Clinical utility gene card for: cystinosis. Eur J Hum Genet. (2014) 22(5).
3. G Nesterova, WA Gahl. Cystinosis. 2001 Mar 22 [Updated 2017 Dec 07]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from:
5. Nephropathic infantile cystinosis. Orphanet encyclopedia,
6. Juvenile nephropathic cystinosis. Orphanet encyclopedia,
7. Emma F, Nesterova G, Langman C, Labbe A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wuhl E, Niaudet P, Van't Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. (2014) 29 Suppl 4:iv87-94.
8. Kleta R, Kaskel F, Dohil R, Goodyer P, Guay-Woodford LM, Harms E, Ingelfinger JR, Koch VH, Langman CB, Leonard MB, Mannon RB, Sarwal M, Schneider JA, Skovby F, Sonies BC, Thoene JG, Trauner DA, Gahl WA. First nih/office of rare diseases conference on cystinosis: past, present, and future. Pediatr Nephrol. (2005) 20(4):452-4.
9. Ocular cystinosis. Orphanet encyclopedia,
10. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Cystinosis, nephropathic; ctns. MIM: 219800: 2016 Jul 09. World Wide Web URL:
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