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Last updated: 2/14/2024
Years published: 1986, 1987, 1988, 1990, 1991, 1993, 1994, 1995, 1997, 1998, 1999, 2007, 2011, 2014, 2017, 2020, 2024
NORD gratefully acknowledges William A. Gahl, MD, PhD, Senior Investigator, National Human Genome Research Institute, Director, NIH Undiagnosed Diseases Program, National Institutes of Health, for assistance in the preparation of this report.
Summary
Cystinosis is a rare, multisystem genetic disorder characterized by the accumulation of an amino acid called cystine in different tissues and organs of the body including the kidneys, eyes, muscles, liver, pancreas and brain. The kidneys and eyes are the two organs most often affected. Generally, cystinosis is broken down into three different forms known as nephropathic cystinosis, intermediate cystinosis and non-nephropathic (or ocular) cystinosis, although there is overlap among these arbitrary categories. The age of onset, symptoms and severity of cystinosis can vary greatly from one person to another. Nephropathic cystinosis begins in infancy and is the most common and severe form. Early detection and prompt treatment are critical in slowing the development and progression of symptoms associated with cystinosis. Individuals with nephropathic cystinosis and most people with intermediate cystinosis have ultimately required a kidney transplant. Non-nephropathic cystinosis affects only the corneas of the eyes, although cystine is stored in other tissues to a certain extent. Cystinosis is caused by variants in the CTNS gene and is inherited in an autosomal recessive pattern.
Introduction
Cystinosis was first described in the medical literature in 1903 by Abderhalden. Cystinosis is classified as a lysosomal storage disorder. Lysosomes are membrane bound compartments within cells that break down nutrients such as fats, proteins and carbohydrates. Lysosomes are the primary digestive unit within cells. Some enzymes within lysosomes break down (metabolize) these nutrients, while other proteins transport the leftover metabolic products (such as cystine) out of the lysosome. In people with cystinosis, the lack of this specific transporter causes cystine to accumulate in lysosomes of cells throughout the body. Cystine forms crystals (crystallizes) in many types of cells and slowly damages affected organs.
At one time, nephropathic cystinosis was fatal at a very young age. However, improvements in kidney transplantation and the development of a medication known as cysteamine (which lowers the levels of cystine in the cells of the body) have transformed cystinosis from a fatal kidney disorder to a chronic, multisystem disorder with a life expectancy well into adulthood.
The specific symptoms and severity of cystinosis vary greatly from one person to another based upon several factors including age of onset and whether the disorder is promptly diagnosed and treated. The progression of the disorder can be slowed by early diagnosis and treatment. Eventually, cystinosis can affect all tissues of the body. The age of onset for different symptoms varies greatly.
It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
NEPHROPATHIC CYSTINOSIS
Nephropathic, or infantile, cystinosis is the most frequent and most severe form of cystinosis. The symptoms of nephropathic cystinosis usually become apparent within the second half of the first year of life. Specific symptoms can be mild or severe based upon each individual case and the age when treatment is started.
Growth failure and renal Fanconi syndrome (see below) are usually the first noticeable complications of the disorder. Although infants appear normal at birth, by the age of one they generally fall into the third percentile for height and weight. In addition, affected infants may have episodes of vomiting, poor appetite and feeding difficulties that contribute (along with kidney dysfunction) to nutritional deficiency and failure to gain weight and grow at the expected rate (failure to thrive). On average, growth in untreated children with cystinosis is about 60% of the expected rate.
Infants with nephropathic cystinosis develop renal Fanconi syndrome, a rare disorder characterized by kidney dysfunction. The kidneys are two bean-shaped organs located just under the back of the ribcage. The kidneys have several functions, including filtering and excreting waste products from the blood and body, creating certain hormones and helping maintain the balance of certain chemicals in the body such as potassium, sodium, chloride, bicarbonate, calcium, magnesium and other minerals. In nephropathic cystinosis, the kidney tubules fail to reabsorb a variety of needed substances, including the compounds mentioned above as well as amino acids, water, phosphate, glucose, carnitine and certain proteins. Consequently, affected individuals have abnormally low levels of many of these substances in the body.
Symptoms of renal Fanconi syndrome usually become apparent between 6 and 12 months of age and may include excessive thirst (polydipsia), excessive production and passage of urine (polyuria), electrolyte imbalances, vomiting and dehydration with or without fever. Dehydration can be severe in some affected individuals.
The renal Fanconi syndrome can also cause hypophosphatemic rickets. In this disorder, because the kidneys are unable to reabsorb phosphate from the urine, the body leaches phosphate from the bones to maintain blood levels of phosphate; this results in progressive softening and weakening of the bone (rickets). Rickets can cause bone deformity and can delay walking because it is painful. Affected children may walk gingerly. Kidney dysfunction can also cause excessive amounts of calcium to be lost from the body through the urine (hypercalciuric hypocalcemia). Low levels of calcium can cause intermittent muscle spasms (tetany) and, rarely in cystinosis, seizures.
Besides reabsorbing important molecules from the urine, another function of the kidneys is to filter out, or remove, certain compounds. If left untreated, the filtering function of the kidney will continue to deteriorate, eventually progressing to kidney failure at about 10 years of age. Treatment with medications that lower cystine levels can slow or stop the progression of kidney disease and delay the need for a kidney transplant into the teen-age years, the 20s or later. Any existing kidney damage that occurs before diagnosis (and therefore before treatment) is irreversible.
Extrarenal Symptoms
Children with nephropathic cystinosis may also develop symptoms unrelated to the kidneys (extrarenal symptoms). Again, these findings are highly variable, and an affected child will not develop all the symptoms discussed below. Specific extrarenal symptoms vary greatly depending upon the age at which treatment is begun and the specific organs that become involved; organs can include the eyes, bone marrow, liver, pancreas, spleen, intestine, brain, thyroid, muscles and testes.
At any age, children may develop an abnormal sensitivity to light (photophobia) and irritation due to the formation of cystine crystals in the cornea. The severity of photophobia can vary. In some untreated individuals, pain and recurrent corneal erosions may develop.
By the age of 10, about half of affected children have developed deficiency of thyroid hormone production (hypothyroidism) due to cystine accumulation in the thyroid. The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid secretes hormones into the bloodstream that influence certain activities of the body such as growth, maturation and the rate of metabolism. Symptoms of hypothyroidism are highly variable, but may include fatigue, feeling cold, dry skin, constipation and depression.
As a group, children with nephropathic cystinosis do not produce normal amounts of tears, sweat or saliva. Tear production may be diminished causing the eyes to dry out. An impaired ability to sweat can potentially cause total exhaustion or collapse due to heat (heat prostration); this is unusual in cystinosis.
Puberty may be delayed by one or two years. Untreated males have hypogonadism, in which the testes produce reduced amounts of testosterone. Testosterone plays a key role in growth and the development of male secondary sexual characteristics during puberty. Males are generally infertile because of cystine accumulation in the testes.
Intelligence is usually normal, although many children experience learning disabilities. Some children may have problems with processing visual information, short-term visual memory, difficulties identifying common objects by touch (tactile recognition) and an inability to visually recognize the spatial relationships among objects (poor visuospatial skills). An example of visuospatial skills is distance and depth perception. Issues with motor speed and sustained attention have also been reported. Some affected children have behavioral and psychosocial issues, which are common in children dealing with chronic illnesses. IQ levels, while in the normal range, may be lower than would be expected based upon the IQ levels of parents and siblings.
Delayed dental development and delayed eruption of permanent teeth can also occur. Some affected individuals may develop increased pressure of cerebrospinal fluid within the brain (intracranial hypertension), which can cause headaches and swelling of the optic disc (papilledema).
Late-Onset Abnormalities
Individuals with nephropathic cystinosis are living longer and this has revealed additional complications affecting organs other than the kidneys later in life. These complications develop due to the chronic accumulation of cystine in individuals who have not been adequately treated with cysteamine, although they have had a kidney transplant. These additional complications generally develop between 20 and 40 years of age.
Accumulation of cystine in muscle tissue can cause muscle disease (myopathy) leading to progressive weakness and wasting of affected muscles. This usually begins in the hands and progresses to the arms, shoulders and neck. Impairment of muscles in the throat can lead to swallowing and feeding difficulties. Involvement of chest muscles can result in decreased lung function.
A wide variety of gastrointestinal symptoms can develop including enlargement of the liver (hepatomegaly), high blood pressure of the main vein of the liver (portal hypertension), enlargement of the spleen (splenomegaly), gastroesophageal reflux, ulcers, inflammation of the esophagus (esophagitis) and dysfunction of the muscles of the gastrointestinal tract (dysmotility). Unusual additional symptoms include poor fat absorption causing diarrhea and inflammatory bowel disease. Tearing of the bowel causing the contents of the intestines to flow into the abdominal cavity (bowel perforation) and inflammation of the peritoneum (peritonitis), which is the membrane that lines the abdominal wall and organs, can occur, sometimes related to chronic peritoneal dialysis for kidney failure.
High blood pressure (hypertension), coronary artery atherosclerosis and anemia are complications of the renal disease associated with cystinosis.
Additional findings can include metabolic bone disease and an inability to properly digest food due to a lack of digestive enzymes normally produced by the pancreas (pancreatic exocrine insufficiency). Adults with cystinosis may also develop eye abnormalities including spasm of the eyelids (blepharospasm), band keratopathy and pigmentary retinopathy. Band keratopathy refers to the accumulation of calcium deposits in a band across the central surface of the cornea, which can cause pain and decreased clarity of vision (visual acuity). Pigmentary retinopathy is characterized by progressive degeneration of the retina, the thin layer of nerve cells that line the inner surface of the back of the eyes. The retina senses light and converts it to nerve signals, which are then relayed to the brain through the optic nerve. Pigmentary retinopathy can impair night and color vision and, eventually, can contribute to overall reduced clarity of vision.
Although uncommon, brain dysfunction can occur in some older adults with cystinosis. The exact reason this occurs is unknown. Specific symptoms will vary, but some affected individuals may experience a decline in both motor and mental capabilities. In very rare cases, neurological dysfunction can progress to dementia. Brain MRI imaging studies can show atrophy and calcium deposits, but these findings do not usually indicate dysfunction.
Individuals with nephropathic cystinosis have a higher rate of diabetes than the general population because of destruction of the pancreas by cystine accumulation.
INTERMEDIATE CYSTINOSIS
Also known as nephropathic juvenile cystinosis or adolescent cystinosis, this form of cystinosis can be characterized by the signs and symptoms of nephropathic cystinosis described above. However, the onset and frequency of these symptoms does not occur until later, perhaps at 8-20 years of age. Generally, the symptoms are less severe than in the classical infantile nephropathic form and have a slower progression. If untreated, end-stage renal failure in intermediate cystinosis usually develops at some point between 15 and 25 years of age. There is a spectrum of disease severity in cystinosis, with overlap of the infantile and intermediate forms.
NON-NEPHROPATHIC CYSTINOSIS
Also known as ocular or โbenignโ cystinosis, this form usually affects adults during middle age; it was once called adult cystinosis. Kidney disease does not occur in these individuals. The disorder appears to affect only the eyes. Untreated individuals with non-nephropathic cystinosis eventually develop photophobia due to cystine crystal accumulation in the eyes.
All types of cystinosis are caused by disease-causing variants in the CTNS gene. The CTNS gene contains instructions for producing (encoding) a protein called cystinosin that is required to transport the amino acid cystine out of lysosomes and into the rest of a cell. Lysosomes break down (degrade) certain proteins into their component amino acids such as cystine. Cystine is then transported out of the lysosome by cystinosin. Deficient levels of functional cystinosin result in the accumulation of cystine in the lysosomes of various tissues and organs of the body, eventually damaging the affected organs. The accumulated cystine forms crystals in many cell types.
Cystinosis is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a variant in the same gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease and will not show symptoms. Carriers for cystinosis (e.g., parents of affected individuals) never have symptoms of the disease. The risk for two carrier parents to both pass the gene variant and, therefore, have an affected child is 25 percent with each pregnancy. The risk of having a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents is 25 percent. The risk is the same for males and females.
Cystinosis affects males and females in equal numbers. The disorder is estimated to occur in 1 in 100,000-200,000 people in the general population. Cystinosis has been reported worldwide, in all ethnic groups. Cystinosis is the most common cause of renal Fanconi syndrome in children and accounts for approximately 5 percent of all childhood cases of kidney failure.
A diagnosis of cystinosis is based upon identification of characteristic symptoms (e.g., symptoms of renal Fanconi syndrome), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A prompt diagnosis of cystinosis is critical to maximize the preventive and therapeutic benefits of cystine depleting medications.
A diagnosis of cystinosis can be confirmed by measuring cystine levels in certain white blood cells (โpolymorphonuclear leukocytesโ).
Urinary examination may reveal excess loss of nutrients including minerals, electrolytes, amino acids, carnitine and water, which is indicative of renal Fanconi syndrome.
A physician may use a special microscope called a slit lamp to view the eyes through high magnification, which can reveal cystine crystals in the cornea. This is diagnostic if performed by an experienced ophthalmologist.
A diagnosis of cystinosis can also be confirmed by molecular genetic testing, which can identify disease-causing variants in the CTNS gene. Molecular genetic testing is available through a commercial laboratory.
Treatment
The treatment of cystinosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), eye specialists (ophthalmologists), digestive disorder specialists (gastroenterologists), psychologists and other healthcare professionals may need to plan an affected childโs treatment systematically and comprehensively.
Nephropathic and intermediate cystinosis were once progressively fatal disorders, with a lifespan for the infantile form of less than 10 years. However, the development of cystine depleting therapies along with improvements in kidney transplantation have extended the lifespan well into adulthood.
Cystine Depleting Therapy
In 1994, the U.S. Food and Drug Administration (FDA) approved cysteamine bitartrate (Cystagon) for the treatment of individuals with cystinosis. In 2013, the FDA approved Procysb, an extended-release form of cysteamine. Cysteamine is a cystine-depleting agent that can greatly lower cystine levels within cells. Therapy with cysteamine slows the development and progression of kidney damage and enhances growth in children. Cysteamine can significantly delay the need for a kidney transplant. Some individuals who underwent early, diligent treatment with cysteamine were able to delay a kidney transplant into their 20โs or longer.
Therapy with cysteamine should begin immediately after diagnosis to prevent or slow kidney damage. Cysteamine should be continued throughout life because studies have shown that long-standing treatment can prevent many of the non-renal, late onset complications of cystinosis.
Cysteamine smells and tastes foul, which can be unpleasant for patients. Therapy with oral cysteamine can cause nausea, vomiting and gastrointestinal discomfort. Cysteamine also causes excess secretion of stomach acids. Some individuals taking cysteamine may need to take proton pump inhibitors such as omeprazole to reduce the production of stomach acid, helping to improve gastrointestinal symptoms.
Cysteamine is taken orally, but it does not reach the cornea effectively and, therefore, fails to eliminate cystine crystals from the cornea. Cysteamine ophthalmic (Cystaran and Cystadrops) are approved by the FDA to treat the corneal cystine crystal accumulation associated with cystinosis.
Symptomatic Therapy
Renal Fanconi syndrome is treated with a high intake of fluids to prevent excessive reduction of body water (dehydration). Sodium bicarbonate, sodium citrate, magnesium and potassium may be administered to help to maintain normal electrolyte balance. Angiotensin-converting enzyme (ACE) inhibitors are sometimes used to reduce the loss of proteins in the urine, with the hope of slowing the progression of the renal disease.
Indomethacin is an anti-inflammatory medication that is sometimes used to reduce urinary losses of water and electrolytes; it may help to improve growth rate if growth is being impaired by poor nutrition because of excessive water intake. If affected individuals take indomethacin, they must be closely monitored for renal function.
Phosphates and vitamin D are often given to correct impaired reabsorption of phosphate into the blood and prevent rickets. Carnitine may be prescribed for some pre-transplant individuals to improve muscle strength.
Proper nutrition is vitally important to ensure that affected infants and children maximize their growth potential. Growth hormone therapy has significantly improved growth in many patients. L-thyroxine is used to treat hypothyroidism, insulin is used to treat insulin-dependent diabetes and testosterone is used to treat males with underactive testicular function (hypogonadism) so that secondary sexual characteristics will develop. Infertility will not respond to testosterone treatment.
Ocular symptoms of cystinosis can be treated with avoidance of bright light, sunglasses and lubrication. In extremely rare cases, a corneal transplant may be necessary. This is usually required only for individuals with large band keratopathies or those suffering from pain due to repeated corneal erosions.
Some infants and children with cystinosis (e.g., those with dysphagia, poor nutrition and increased risk of aspiration) may require the implantation of a gastronomy tube. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food and/or medicine.
Renal Transplantation
Despite early and prompt treatment, individuals with infantile and intermediate cystinosis eventually develop end stage renal disease (ESRD), requiring a kidney transplant. Initially, an affected individual may undergo dialysis. Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney, filtering waste products from the bloodstream and helping to maintain proper levels of essential chemicals such as potassium. ESRD is not reversible so individuals will eventually require a kidney transplant. The rate of progression of kidney dysfunction to ESRD can vary greatly from one individual to another. Individuals with cystinosis generally respond very well to a kidney transplant, which can cure renal Fanconi syndrome because cystine does not accumulate in the donated kidney. However, cystine still accumulates in other tissues and organs of the body. The lifespan of a transplanted kidney varies but is increasing.
Speech and language therapy may be beneficial for some patients.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
Gahl WA, Adams DR, Markello TC, Toro C, Tifft CJ. Genetic Approaches to Rare and Undiagnosed Diseases. In: Nelson Textbook of Pediatrics (RM Kliegman, J St. Geme, NJ Blum, SS Shah, RC Tasker, KM Wilson, eds), Edition 21, chapter 101, pp. 683-7. Elsevier, Inc., Philadelphia, PA, 2019.
Gahl WA, Nesterova G. Cystinosis. In Pediatric Nephrology (ED Avner, WE Harmon, P Niaudet, N Yoshikawa, F Emma, S Goldstein, eds). Heidelberg: Springer-Verlag, 2016.
Trauner DA. Neurological and Cognitive Consequences of Nephropathic Cystinosis. In: Cognitive and Behavioral Abnormalities of Pediatric Diseases, Nass RD, Frank Y, eds. 2010 Oxford University Press, New York, NY. pp. 333-341.
Chadha V, Warady BA. Cystinosis. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:683.
JOURNAL ARTICLES
Brodin-Sartorius A, Tete MJ, Niaudet P, et al. Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults. Kidney Int. 2011; [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/21900880
Wilmer MJ, Schoeber JP, Lambertus P, van den Heuvel, Levtchenko EN. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol. 2011;26:205-215. http://www.ncbi.nlm.nih.gov/pubmed/20734088
Besouw MT, Hulstijn-Dirkmaat GM, van der Rijken RE, et al. Neurocognitive functioning in school-aged cystinosis patients. J Inherit Metab Dis. 2010;33:787-793. http://www.ncbi.nlm.nih.gov/pubmed/20814825
Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol. 2008;23:863-878. http://www.ncbi.nlm.nih.gov/pubmed/18008091
Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med. 2007;147:242-250. http://www.ncbi.nlm.nih.gov/pubmed/17709758
Ueda M, OโBrien K, Rosing DR, et al. Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. Clin J Am Soc Nephrol. 2006;1:555-562. http://www.ncbi.nlm.nih.gov/pubmed/17699259
Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347:111-121. http://www.ncbi.nlm.nih.gov/pubmed/12110740
Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. 1993; 328:1157-62.
INTERNET
Nesterova G, Gahl WA. Cystinosis. 2001 Mar 22 [Updated 2017 Dec 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1400/ Accessed Jan 30, 2024.
Elenberg E, Langman CB. Cystinosis. Medscape. Last Update Dec 5, 2020. Available at: http://emedicine.medscape.com/article/981650-overview Accessed Jan 30, 2024.
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