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Disease definition

A rare disorder of renal tubular amino acid transport characterized by recurrent formation of kidney cystine stones.


Classification level: Disorder

  • Cystinuria-lysinuria syndrome

Prevalence: 1-5 / 10 000

Inheritance: Autosomal recessive, Semi-dominant

Age of onset: All ages

ICD-10: E72.0

ICD-11: 5C60.2

OMIM: 220100

UMLS: C0010691

MeSH: D003555

GARD: 6237

MedDRA: 10011778


Prevalence of cystinuria has high ethnogeographic variation, ranging from 1:2,500 in the Libyan Jewish population to 1:100,000 in Sweden. The mean global value is estimated at 1:7,000.

Clinical description

Cystinuria develops in patients of any age but renal colic due to cystine stone appears generally in the first two decades of life, with a median age of onset of 15 years. Male patients tend to present with more aggressive disease, and occurrence of renal stones before the age of 3 is more frequent in males. Urolithiasis is bilateral in more than 75% of cases and recurrence rate is over 60%, with a higher rate in male patients. Renal insufficiency is uncommon.


Cystinuria is due to mutations in SLC3A1 (2p21) and SLC7A9 (19q13.11). Both genes are expressed in the renal proximal tubules and the intestinal tract and code for subunits of trans-epithelial transporters for the dibasic amino acids cystine, ornithine, lysine and arginine. The transporter deficiency leads to accumulation of cystine in the urine and subsequent precipitation of cystine crystals or even stone formation. Classification of patients now relies on genetic criteria: type A and type B cystinuria are respectively associated with mutations in the genes SLC3A1 and SLC7A9. Heterozygotes with mutation in one SLC3A1 allele are unaffected, while those who carry mutation in a single SLC7A9 allele show moderately increased urine output of cystine and dibasic amino acids and have a higher risk of developing renal stones when compared to the general population.

Diagnostic methods

Diagnosis relies on physical examination, detection of cystine stones and assay of excreted cystine in urine, which in children and young infants may be normalized for urine creatinine. Analysis reveals urinary cystine excretion over 300 - 400 mg/day. Renal ultrasound imaging is the method of choice for stone detection and follow-up. Molecular genetics may confirm diagnosis.

Differential diagnosis

Differential diagnosis includes three syndromes in which cystinuria is present: 2p21 deletion syndrome, hypotonia-cystinuria syndrome (HCS) and atypical HCS.

Antenatal diagnosis

Detection of a hyperechoic colon at routine ultrasound scan before 36 weeks of gestation may suggest a possible diagnosis of cystinuria with a high positive predictive value (89%). In any case, confirmation of the diagnosis should be made after delivery.

Genetic counseling

Type A cystinuria has an autosomal recessive mode of inheritance, whereas dominant transmission with incomplete penetrance is typically observed in type B cystinuria.

Management and treatment

Treatment requires several approaches to prevent stone formation or growth: high hydration to reduce urinary cystine osmolality, urinary alkalinization to increase cystine solubility (mainly with potassium citrate), and pharmacological cystine-binding medications (alpha-mercaptopropionylglycine, or tiopronin, and D-Penicillamine) to lower free cystine levels in the urine. Measuring the free fraction of cystine in the urine enables titration of the treatment with cystine binding drugs. Side effects of D-Penicillamine and tiopronin, in particular proteinuria, are not uncommon and require routine monitoring with dipsticks and frequently lead to discontinuation of the treatment; they also require zinc, copper and/or vitamin B6 supplementation. Low protein diet in adults or even adolescents is not very effective. When a cystine stone is still small (under 12 mm), extracorporeal shock wave lithotripsy is feasible, but with low efficiency due to the consistency of cystine stones. Over this size, laser stone fragmentation or even percutaneous nephrolithotomy is necessary.


Prognosis is good but low patient compliance and recurrence of stone formation and subsequent interventions can very rarely induce renal insufficiency.

Last update: September 2019 - Expert reviewer(s): Dr Luca DELLO STROLOGO | ERKNet*

* European Reference Network

A summary on this disease is available in Français (2019) Logo ERN Español (2019) Logo ERN Deutsch (2019) Logo ERN Italiano (2019) Logo ERN Português (2012) Nederlands (2019) Logo ERN Suomi (2020.pdf) עברית (2020.pdf) Polski (2012.pdf) Ελληνικά (2012.pdf) Slovenčina (2012.pdf)
Detailed information
Clinical practice guidelines
English (2021) - Kidney Int Logo ERN
Disease review articles
Review article
English (2012) - Orphanet J Rare Dis
Genetic testing
Guidance for genetic testing
English (2011) - Eur J Hum Genet

Logo ERN: produced/endorsed by ERN(s) Logo FSMR: produced/endorsed by FSMR(s)

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