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Cystine Disease

Cystinosis is a genetic medical condition that results in excessive deposition of cystine crystals within lysosomes, leading to extensive organ dysfunction in the human body.

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Cystinosis can target multiple organs in the body and, thus, has a wide symptom presentation. Aside from kidney dysfunction, the disease can also present with thyroid dysfunction in the form of hypothyroidism, diabetes mellitus, swallowing difficulties and muscle wasting.

Infantile nephropathic cystinosis usually presents in children who otherwise are normal at birth. By the age of 10 months, patients start displaying symptoms particular to the disease such as growth stunting, frequent urination, irritability and increased thirst. Unlike healthy children, affected children are unable to walk or bear significant weight by 12 months of age. Infantile nephropathic cystinosis is considered the most severe form of the disease.

A characteristic signature of cystinosis is an associated Fanconi syndrome, defined by an inability to absorb many minerals and elements in the proximal renal tubules. The nutrients are subsequently excreted in the urine and, if not replaced, patients can suffer from severe electrolyte and acid-base abnormalities. Children generally have a poor appetite for certain foods, demand salt and display stunted growth. Without treatment, children suffering from this form of the disease can undergo kidney failure before the age of 10.

Other forms of cystinosis may first present in adolescence or even adulthood. Juvenile or adolescent cystinosis is characterized by renal and ocular symptoms. Adult cystinosis, on the other hand, is a benign condition in which the cornea of the eye is almost exclusively the site of cystine deposition.

  • Other signs and symptoms that may occur in untreated people, especially after adolescence, include muscle deterioration, blindness, inability to swallow, diabetes, thyroid and nervous system problems, and an inability to father children (infertility)[ghr.nlm.nih.gov]
  • Other complications of untreated cystinosis, especially after adolescence, may include muscle deterioration, blindness, difficulty swallowing, diabetes, thyroid and nervous system problems, and infertility (an inability to father children) in affected[leadiant.com]
  • Cystine deposits in various organs progressively lead to additional manifestations such as hypothyroidism, hypogonadism and male infertility, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, muscle involvement with distal muscle[orpha.net]
  • […] increased photophobia, thyroid insufficiency Adolescence (usually age 10-13 years): End-stage renal disease; good adherence to therapy slows down-progression of renal failure by several more years Delayed sexual maturation; in males, hypogonadism and infertility[emedicine.medscape.com]
Weight Loss
  • Since the age of five months, he developed symptoms of severe weight loss, vomiting, dehydration, and polyuria. He manifested the Toni Debré Fanconi syndrome.[sjkdt.org]
  • Excessive thirst and peeing (urination) Reduced appetite Weight loss Slow growth Softening or weakening of bones (rickets) Eventually, the damage caused by cystinosis causes the kidneys to fail completely, which can be treated only with dialysis (an artificial[procysbi.com]
  • We report a successful treatment of hypoventilation, due to diaphragm myopathy in a cystinosis patient, by nocturnal non-invasive positive pressure ventilation (NIPPV).[ncbi.nlm.nih.gov]
Respiratory Insufficiency
  • Respiratory insufficiency caused by overall respiratory muscle myopathy is a severely invalidating and sometimes a life-threatening complication of cystinosis.[ncbi.nlm.nih.gov]
Failure to Thrive
  • The history of muscle weakness, failure to thrive, polydipsia, and polyuria prompted subsequent clinical and laboratory evaluations, leading to the correct diagnosis of cystinosis.[ncbi.nlm.nih.gov]
  • Cystinosis is the major cause of inherited Fanconi syndrome, and should be suspected in young children with a failure to thrive and with signs of renal proximal tubular damage.[ncbi.nlm.nih.gov]
  • A 14-month-old girl was admitted to our clinic due to failure to thrive. Her weight and height were below the third percentile for age. Laboratory examination showed signs of alkalosis, hypokalemia, and hypochloremia.[ncbi.nlm.nih.gov]
  • A five-year-old boy was referred to our pediatric clinic for evaluation of failure to thrive, headache, intermittent high fever, restlessness, polyuria, and polydipsia. His weight and height measurements were under the 3rd percentile.[ncbi.nlm.nih.gov]
  • The disease results in deposition of crystals throughout the body; if untreated, it leads to failure to thrive, profound metabolic imbalance, early end-stage renal disease, thyroid failure, and multiorgan dysfunction.[doi.org]
  • Slow eating and dysphagia are common. Heterozygotes may have elevated levels of free cystine in leukocytes. The later onset juvenile form of cystinosis presents with kidney failure secondary to glomerular damage instead of tubular dysfunction.[disorders.eyes.arizona.edu]
  • A subset of patients may also suffer from dysphagia, malnutrition and frequent aspiration. These patients are usually treated with an implantation of a gastrostomy tube.[symptoma.com]
  • These include myopathy and dysphagia due to the accumulation of cystine in the muscles, endocrine involvement such as hypothyroidism and diabetes mellitus, hepatomegaly, hypersplenism and photophobia from the accumulation of cystine in the cornea.[sjkdt.org]
  • ., those with dysphagia, poor nutrition and increased risk of aspiration) may require the implantation of a gastronomy tube.[rarediseases.org]
Loss of Appetite
  • Children with this type of cystinosis often have short stature, changes in the retina (retinopathy), sensitivity to light (photophobia), vomiting, loss of appetite, and constipation.[verywellhealth.com]
  • Signs and symptoms of nephropathic infantile cystinosis include the following: Multiorgan involvement: May be mild to severe Polyuria, polydipsia, dehydration, vomiting, metabolic acidosis Hypophosphatemic rickets Constipation Failure to thrive, poor/loss[emedicine.medscape.com]
  • Cystine deposits in various organs progressively lead to hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, and muscle and cerebral involvement.[orpha.net]
  • Cystine deposits in various organs progressively lead to additional manifestations such as hypothyroidism, hypogonadism and male infertility, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, muscle involvement with distal muscle[orpha.net]
  • […] resulting in such complications as eye disease (eg, severe photophobia, corneal ulcerations, retinal blindness), delayed puberty, hypothyroidism, pancreatic disease (eg, exocrine insufficiency, insulin-dependent diabetes mellitus), liver disease (eg, hepatosplenomegaly[emedicine.medscape.com]
  • Systemic: Delayed puberty, growth failure, rickets, hyothyroidism, hepatosplenomegaly Symptoms Ocular: Photophobia, epiphora, foreign body sensation, blepharospasm Renal: Polyuria, polydypsia, vomiting, constipation, weakness Other: Nausea and vomiting[webeye.ophth.uiowa.edu]
  • Photophobia was relieved and IVCM obtained the decrease in size and density of corneal crystals 1 year after. Depth of corneal crystals did not change but crystal density score reduced with cysteamine treatment.[ncbi.nlm.nih.gov]
  • An 8-year-old boy with nephropathic cystinosis was experiencing debilitating and worsening photophobia from corneal crystal deposition.[ncbi.nlm.nih.gov]
  • We also evaluated photophobia, corneal cystine crystal scores (CCCSs), and cystine crystal depth measured by optical coherence tomography.[ncbi.nlm.nih.gov]
  • A 31-year-old woman who presented with photophobia was found to have bilateral corneal and conjunctival crystal deposition. Ocular cystinosis was diagnosed upon observation of typical crystals and lack of systemic involvement.[ncbi.nlm.nih.gov]
  • The untreated cornea is packed with crystals by age 3-4 years, leading to photophobia in early childhood.[emedicine.medscape.com]
Corneal Deposit
  • Cystine crystal deposition can be seen in the bone marrow earlier than corneal deposition, in patients with NC. METHODS: Ten patients with cystinosis diagnosis were enrolled in the study.[ncbi.nlm.nih.gov]
  • Topical cysteamine eye drops are also needed as systemic cysteamine has no effect on cystine corneal deposits. Prognosis Life expectancy has significantly improved with therapy. Cysteamine delays the need for renal replacement therapy.[orpha.net]
  • Topical cysteamine eye drops are also needed as systemic cysteamine has no effect on cystine corneal deposits. Prognosis Life expectancy is significantly improved with therapy.[orpha.net]
Retinal Damage
  • damage Third decade of life: Cerebral calcifications; muscular and swallowing difficulties Laboratory tests The following laboratory studies may be used to assess patients suspected of having cystinosis: Serum electrolyte levels: To detect the presence[emedicine.medscape.com]
Kidney Failure
  • If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.[en.wikipedia.org]
  • Untreated children will experience complete kidney failure by about the age of 10.[ghr.nlm.nih.gov]
  • Cystinosis can lead to permanent kidney damage and kidney failure. The disease is caused by mutations in the CTNS gene which can be passed down from parents to their children.[kidneyfund.org]
  • The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome.[ncbi.nlm.nih.gov]
  • At follow-up, the polyuria and hyponatremia were found to persist.[ncbi.nlm.nih.gov]
  • A 9-month-old boy was referred to our department for evaluation of polyuria and polydipsia. Clinical examination showed dehydration and enlarged wrists and rachitic rosaries.[ncbi.nlm.nih.gov]
  • The history of muscle weakness, failure to thrive, polydipsia, and polyuria prompted subsequent clinical and laboratory evaluations, leading to the correct diagnosis of cystinosis.[ncbi.nlm.nih.gov]
  • However, in view of the growth failure, fair hair and skin, proteinuria, polyuria and active rickets, cystinosis was considered. Bone marrow smear examination was normal, despite the existence of suspicious crystals in the cornea.[ncbi.nlm.nih.gov]
  • The presenting complaint was growth retardation in seven patients; polydipsia and polyuria in three patients; and vomiting in two patients.[ncbi.nlm.nih.gov]
Cerebral Calcification
  • calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).[emedicine.medscape.com]
Unable to Walk
  • Unlike healthy children, affected children are unable to walk or bear significant weight by 12 months of age. Infantile nephropathic cystinosis is considered the most severe form of the disease.[symptoma.com]
Unable to Walk
  • Unlike healthy children, affected children are unable to walk or bear significant weight by 12 months of age. Infantile nephropathic cystinosis is considered the most severe form of the disease.[symptoma.com]


The diagnosis of cystinosis is established after broad investigations that include the collection of pertinent history, performance of a physical exam and a range of testing modalities that help in elucidating the characteristic presenting symptoms as well as in conclusively diagnosing the disease. It is critical to diagnose the disease as early as possible, because prompt treatment can significantly improve prognosis and outcomes.

The presence of renal Fanconi Syndrome can be evaluated with urine analysis that identifies increased excretion of important minerals and compounds such electrolytes, water, carnitine and various amino acids [9]. Cystine crystals in the cornea of the eyes can be visualized with a slit lamp exam under high magnification. The slit lamp test may be sufficient for diagnosis when the test is done by an ophthalmologist.

Cystinosis can be also confirmed by assessing the levels of cystine in polymorphonuclear leukocytes, a particular type of white blood cells. Genetic testing may also help in identifying the responsible CTNS mutations for the disease. Such testing is usually provided by commercial laboratories.

Parents with known family history of the condition have the option of prenatal diagnosis. This can be performed through either sampling the fetal cells from the amniotic fluid or the chorionic villi. The latter are found on the placenta and may display high levels of cystine crystals that are characteristic of the disease.

  • Associated with nephrolithiasis (renal stones) [2] and renal failure. Autosomal recessive. [1] Mutation in cystinosin gene (CTNS). [3] [4] [5] Microscopic Kidney Multinucleation of podocytes. [6] [7] Images Case Cystinosis - intermed. mag.[librepathology.org]
  • Imaging features are non-specific and may include: rickets renal medullary nephrocalcinosis nephrolithiasis Treatment and prognosis The mainstay of treatment is cystine-depleting therapy with cysteamine 7.[radiopaedia.org]
  • Two patients were documented to have associated hypothy-roidism, while one patient each had nephrolithiasis and severe anemia. Three infants died due to metabolic disturbances and a six year old died due to end stage renal failure.[indianpediatrics.net]
  • The de Toni-Fanconi syndrome* is a clinical constellation characterized by resistant rickets, acidosis, glycosuria, hyperamino-aciduria, and organic aciduria.[doi.org]
  • All had nephropathic infantile-type cystinosis with evidence of proximal tubulopathy, with glycosuria and renal phosphate wasting. Diagnosis was confirmed in 19 cases by demonstrating an elevated cystine concentration in leukocytes.[ncbi.nlm.nih.gov]
  • Diagnostic methods The diagnosis is based on blood and urine analysis showing features of Fanconi syndrome (metabolic acidosis, hypokalemia, hyperaminoaciduria, glycosuria), detection of cystine crystals in the cornea and determination of elevated cystine[orpha.net]
  • Diagnostic methods The diagnosis is based on blood and urine analysis showing features of Fanconi syndrome (metabolic acidosis, hypokalemia, hyponatremia, hypophosphatemia, hyperaminoaciduria, glycosuria), detection of cystine crystals in the cornea by[orpha.net]
Liver Biopsy
  • Histologic examination of liver biopsy specimens from both patients showed changes characteristic of NRH with portal hypertension documented by measurement of pressure gradients.[ncbi.nlm.nih.gov]


Treatment is targeted at the wide range of symptoms and clinical manifestations associated with the disease. A team of physicians and healthcare professionals that includes pediatricians, ophthalmologists, nephrologists, gastroenterologists and psychologists who may be necessary for the adequate treatment and management of the patient.

Cysteamine bitartrate is one of the most important medications that were developed for the treatment of cystinosis. It was first approved in 1994 by the Food and Drug Administrations and, later in 2013, an extended form of the drug was also permitted on the market. It acts by depleting the level of cystine in the cells, thereby decreasing the rate of crystal formation. The end result is a significant reduction in growth stunting and kidney dysfunction. Prompt and intense therapy with cysteamine can delay the need for a renal transplant by more than 20 years compared to patients who did not receive any treatment. Furthermore, life-long treatment may also prevent complications that involve other organs in different stages of the disease. An eye drop solution of cysteamine was specifically designed to target crystal formation in the cornea because the oral ingested form of the drug is ineffective for ocular manifestations. The eye drop solution is the only FDA approved method of treatment for ocular cystinosis [10].

On the other hand, fluid intake and electrolyte replacements are recommended in the cases of Fanconi syndrome. Supplementation therapy with magnesium, potassium, sodium citrate and bicarbonate may also be necessary. Acetylcholinesterase inhibitors can additionally be effective in delaying the onset and progression of kidney failure. Another medication that can be employed for the management of Fanconi syndrome is indomethacin. It is an anti-inflammatory drug that decreases the excretion of water and various electrolytes and may assist in limiting growth failure. It is worth mentioning, however, that individuals taking indomethacin require frequent monitoring of their kidney function. Other treatment options targeted at the symptomatic manifestations of the disease include vitamin D and phosphates for the prevention of rickets, carnitine to increase muscle strength, L-thyroxine for hypothyroidism, growth hormone therapy for growth abnormalities, insulin for diabetes mellitus and testosterone for boys suffering from hypogonadism. The ocular manifestations of the diseases can be prevented by wearing sunglasses and avoiding intense sunlight. Extreme cases that are associated with frequent corneal erosions, pain and large band keratopathies may require corneal transplantation. A subset of patients may also suffer from dysphagia, malnutrition and frequent aspiration. These patients are usually treated with an implantation of a gastrostomy tube. This procedure is performed through the insertion of a thin tube in the stomach, where nutritious materials and medications are directly deposited.

Kidney transplant is usually recommended at some stage of the disease, even when patients are treated early and adequately. It can sometimes be preceded with dialysis, when kidney function sufficiently deteriorates. Renal transplants can completely resolve Fanconi syndrome and usually result in a good success rate in patients with cystinosis. Nonetheless, it does not affect the deposition of cystine crystals in other organs and systems.


Prognosis of cystinosis has improved dramatically in the last four decades due to significant advances in treatment options. Before the advance of cysteamine and renal transplantation, patients usually suffered from progressive renal failure and passed away before the age of 10. Nowadays, patients suffering from the disease can expect to live to their 50s. This is especially because of the ability of cysteamine to slow renal failure. Studies on renal transplantation also showed that, in a large European sample, 5 year survival increased from 86.1% to 100% in children diagnosed with infantile nephropathic cystinosis who had received a kidney transplant [8].


Cystinosis is caused by genetic mutations that target the CTNS gene. The gene normally codes for cystinosin, a transporter protein. Mutations within this gene are responsible for all types of cystinosis. Cystinosin acts to transport cystine to the outside of the lysosomes, the cellular compartments that function to rid the cells of harmful substances. When the protein is defected, cystine can build within the lysosomes and form crystals. This can ultimately result in damage to the eyes, kidneys and other organs.

Cystinosis is transmitted in an autosomal recessive fashion and was the first genetic disorder to be identified among diseases that affect lysosomal transport [5]. The type of mutations present can affect the phenotypic expression of the disease. Mutations in the G197R and IVS10-3C-G CTS genes can be mild or severe, with the latter being associated with ocular non-nephropathic cystinosis. Mild mutations do not completely inhibit the production of CTS mRNA, permitting the transport of lysosomal cystine and decreasing the levels of cystine within the cell [6].


Infantile nephropathic cystinosis has an incidence of 1 case in 100,000 to 200,000 live births in North America [7], with estimations indicating that there are around 400 patients affected with cystinosis in the United States. Each year, 15 new cases are diagnosed in the United States alone.

Internationally, cystinosis has a wider prevalence in specific locations. In Brittany, for example, 1 of every 25,909 individuals suffers from the disease. Nonetheless, incidence in France in total is far less frequent with 1 case in every 326,440 individuals.

Sex distribution
Age distribution


Cysteine is processed in the lysosome, where amino acids produced through the decomposition of ingested proteins are hydrolyzed in an acidic environment. Normally, cysteine undergoes an oxidization reaction and is converted to cystine and is then transported into the cytoplasm where it is re-transformed into cysteine with the help of reducing agents such as glutathione. Cytoplasmic cysteine can then be again inserted into a larger protein compound or it can undergo degradation and excretion outside the cell.

In cystinosis, cystinosin, the protein channel that is responsible for transporting cystine from the lysosome into the cytoplasm, is defective because of mutations that target the gene responsible for its expression. The end result is further accumulation of cystine within the lysosome, leading to the formation of various crystals that can be rectangular, birefringent or hexagonal.

Infantile nephropathic cystinosis is characterized by specific cystine crystal formation targeting kidney function, particularly in proximal tubular cells. Patients usually present between 6 and 12 months with a clinical phenotype corresponding to the Fanconi syndrome. This syndrome is known for salt and electrolyte wasting due to deficient absorption in the proximal tubule. The most commonly involved elements and compounds include magnesium, calcium, sodium, potassium, phosphate, bicarbonate and others. The resulting electrolyte imbalance and metabolic acidosis manifests clinically with growth abnormalities and is the most common form of Fanconi syndrome.


There are no current preventive measures for cystinosis.


Cystinosis is an inherited medical condition that results in an abnormal deposition of cystine in the various tissues and organs of the human body [1]. It is transmitted in an autosomal recessive fashion and results from mutations targeting the CTNS gene. This gene expresses a protein called cystinosin, that acts to transport cystine from the lysosome to the cytoplasm within the cell. A deficient cystine transporting channel leads to the abnormal formation of cystine crystals that can significantly damage cellular function. Cystinosis has a wide range of presenting symptoms, but is mostly characterized by kidney, ocular and growth abnormalities [2] [3]. Kidney dysfunction manifests with the Fanconi syndrome and can eventually lead to severe kidney failure and death if not treated. Ocular symptoms result from the deposition of cystine crystals within the cornea [4]. Treatment consists of medications that help deplete cells from cystine, kidney transplantation and various treatment options targeted specifically at symptomatic manifestations. For example, L-thyroxine is used for hypothyroidism, vitamin D and phosphate for rickets and insulin for insulin-dependent diabetes. Prognosis has markedly improved in the last four decades. With prompt and adequate treatment with cystine depleting drugs as well as kidney transplants, patients can expect to live up to their fifth decade of life.

Patient Information

Cystinosis is an inherited medical condition that results from the deposition of a particular organic compound called cystine. Excessive cystine can lead to the formation of crystals that ultimately disrupt the functioning of the cells and various organs. Cystinosis is transmitted in an autosomal recessive fashion. Normally, each individual has two copies of every gene, with each gene transmitted from one parent. A recessive genetic condition necessitates that mutations are present in both genes.

Cystinosis has various subtypes, although the most common and most severe subtype may present very early in childhood, by 10 months of age. Patients usually suffer from growth and ocular dysfunction as well as deterioration of the function of their kidneys. Variants that may present in adolescence or in early adulthood are much more benign and less likely to involve severe kidney dysfunction.

Treatment with medications such as cysteamine bitrate helps the body get rid of the excess cystine. Kidney transplantation may also be necessary to fully recover kidney function. Prognosis has significantly improved in the last four decades, and patients can now expect to live till their fifth decade.



  1. Middleton R, Bradbury M, Webb N, et al. Cystinosis. A clinicopathological conference. "From toddlers to twenties and beyond" Adult-Paediatric Nephrology Interface Meeting, Manchester 2001. Nephrol Dial Transplant 2003; 18:2492.
  2. Bois E, Feingold J, Frenay P, Briard ML. Infantile cystinosis in France: genetics, incidence, geographic distribution. J Med Genet 1976; 13:434.
  3. Manz F, Gretz N. Cystinosis in the Federal Republic of Germany. Coordination and analysis of the data. J Inherit Metab Dis 1985; 8:2.
  4. Levy M, Feingold J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 2000; 58:925.
  5. Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002 Jul 11;347(2):111-21.
  6. Anikster Y, Lucero C, Guo J, et al. Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations. Pediatr Res. 2000 Jan;47(1):17-23.
  7. Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol. 2008 Jun; 23(6):863-78.
  8. Van Stralen KJ, Emma F, Jager KJ, et al. Improvement in the renal prognosis in nephropathic cystinosis.Clin J Am Soc Nephrol. 2011 Oct; 6(10):2485-91.
  9. Bradarić N, Punda-Polić V. Cutaneous anthrax due to penicillin-resistant Bacillus anthracis transmitted by an insect bite. Lancet. 1992 Aug 1;340(8814):306-7.
  10. Gahl WA, Reed GF, Thoene JG, et al. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med. 1987 Apr 16;316(16):971-7.

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Last updated: 2019-07-11 22:32