Background
Nephropathic cystinosis is an inherited (autosomal recessive) lysosomal storage disorder caused by defective transport of the amino acid cystine out of lysosomes. The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage.
Three types of cystinosis have been described based on the age at diagnosis and magnitude of cellular cystine deposition: infantile onset, adolescent onset, and adult onset. Patients with the infantile nephropathic form of cystinosis (the most common and the most severe) develop symptoms early in life and develop end-stage kidney failure by late childhood, if untreated.
Specific therapy with a drug that allows for removal of cystine from its lysosomal accumulation has been associated with marked improvement in the outlook for kidney function and quality of life in patients with nephropathic cystinosis.
An 8-month-old male infant at the time his cystinosis is diagnosed. 
The same child as in the previous image, at age 20 months, fed via gastric tube. 
The same child as in the previous images, at age 3 years, fed via jejunal tube. 
The same child as in the previous images, at age 4 years, on total parenteral nutrition via central line. 
The same child as in the previous images, at age 9 years, off total parenteral nutrition for 1 year and tolerating oral intake. Pathophysiology
Ingested protein enters the lysosome, where acid hydrolases degrade it to its component amino acids, including cysteine. Within the lysosome, cysteine is readily oxidized to cystine (a disulfide of the amino acid cysteine). In healthy individuals, both cystine and cysteine can normally enter the cytoplasm, where cystine is rapidly converted to cysteine by the reducing agent glutathione. Cytoplasmic cysteine is incorporated into protein or degraded to inorganic sulfate for excretion.
Cystinosis is caused by one of several mutations in the gene that encodes cystinosin, the cystine-lysomal exporter. Because of the defect in cystinosin, cystine cannot leave the lysosomes and is accumulated there as birefringent, hexagonal, or rectangular crystals within cells of various organ systems.
In the infantile nephropathic form of cystinosis, the kidney is affected early in life by cystine crystals deposited in proximal tubule cells. This leads eventually to a Fanconi syndrome, characterized by wasting of substances reabsorbed in this nephron segment, including sodium, potassium, phosphate, calcium, magnesium, bicarbonate, and others. Metabolic acidosis and electrolyte disturbances ensue and contribute to the stunting of growth in children with cystinosis. Cystinosis is the most common inherited cause of Fanconi syndrome.
Epidemiology
Frequency
United States
In North America, the incidence of infantile nephropathic cystinosis is 1 case per 100,000-200,000 live births;[1] an estimated 300-400 children in the United States have cystinosis. Approximately 15 new cases of cystinosis are diagnosed each year in the United States.
International
The incidence of cystinosis is higher in certain subpopulations. France's Brittany province has an estimated incidence of 1 case per 25,909 population; the incidence in the rest of France is 1 case per 326,440 population.
Mortality/Morbidity
Medical perceptions regarding the complications and outcome of cystinosis have changed over the years. Prior to the availability of renal transplantation, infantile cystinosis was considered a fatal disease, with a lifespan of approximately 10 years. By the early 1970s, the salutary effects of renal transplants had been recognized.
Cysteamine, introduced in the early 1980s, was shown to blunt the decline in renal function and improve linear growth in these children, despite the fact that it does not ameliorate the defect in renal tubule transport. However, the increased life expectancy afforded by the progress in medical and surgical treatment was accompanied by the development of serious complications due to the continuous accumulation of cystine in nonrenal organs, including the eye, thyroid, brain, liver, pancreas, and muscle. However, many patients survive into the third or fourth decade of life, some even survive into the fifth decade of life and are able to pursue fulfilling lifestyles.
Race
Cystinosis is often considered a disease of fair-skinned individuals of European descent; however, it is known to occur in blacks, Hispanics, and people of Middle Eastern descent. It has also been described in at least one Chinese patient and in several Japanese patients.
Sex
The male-to-female ratio among cystinotic children has been reported to be 1.4:1.
Age
Patients with infantile nephropathic cystinosis develop initial symptoms in infancy, frequently when younger than 1 year. In the late-onset (adolescent) form, symptoms are evident by age 8-12 years, and the progression is slower. The adult form of cystinosis does not include renal involvement and is limited to the eye (ocular cystinosis).
Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol. Jun 2008;23(6):863-78. [Medline].
[Guideline] Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of chronic kidney disease. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2008. [Full Text].
Besouw MT, Bowker R, Dutertre JP, et al. Cysteamine toxicity in patients with cystinosis. J Pediatr. Dec 2011;159(6):1004-11. [Medline].
Van Stralen KJ, Emma F, Jager KJ, et al. Improvement in the renal prognosis in nephropathic cystinosis. Clin J Am Soc Nephrol. Oct 2011;6(10):2485-91. [Medline].
Andrews PA, Sacks SH, van't Hoff W. Successful pregnancy in cystinosis. JAMA. Nov 2 1994;272(17):1327-8. [Medline].
Almond PS, Matas AJ, Nakhleh RE. Renal transplantation for infantile cystinosis: long-term follow-up. J Pediatr Surg. Feb 1993;28(2):232-8. [Medline].
Baum M. The Fanconi syndrome of cystinosis: insights into the pathophysiology. Pediatr Nephrol. Aug 1998;12(6):492-7. [Medline].
Bendavid C, Kleta R, Long R, et al. FISH diagnosis of the common 57-kb deletion in CTNS causing cystinosis. Hum Genet. Nov 2004;115(6):510-4. [Medline].
Dohil R, Newbury RO, Sellers ZM, et al. The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine. J Pediatr. Aug 2003;143(2):224-30. [Medline].
Elenberg E, Norling LL, Kleinman RE, Ingelfinger JR. Feeding problems in cystinosis. Pediatr Nephrol. Jun 1998;12(5):365-70. [Medline].
Facts and Comparisons. Cysteamine bitartrate. In: Drug Facts and Comparisons. 5th ed. St. Louis, MO: Facts and Comparisons; 2000:590-1.
Foreman JW. Metabolic disorders. In: Pediatric Nephrology. Baltimore, MD: Lippincott Williams & Wilkins; 1994:537- 57.
Gahl WA. Cystinosis coming of age. Adv Pediatr. 1986;33:95-126. [Medline].
Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med. Aug 21 2007;147(4):242-50. [Medline]. [Full Text].
Gahl WA, Reed GF, Thoene JG. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med. Apr 16 1987;316(16):971-7. [Medline].
Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. Jul 11 2002;347(2):111-21. [Medline].
Jonas AJ, Schulman JD, Matalon R, et al. Cystinosis in non-caucasian children. Johns Hopkins Med J. Sep 1982;151(3):117-21. [Medline].
Kleta R, Kaskel F, Dohil R, et al. First NIH/Office of Rare Diseases Conference on Cystinosis: past, present, and future. Pediatr Nephrol. Apr 2005;20(4):452-4. [Medline].
Levtchenko EN, van Dael CM, de Graaf-Hess AC, Wilmer MJ, van den Heuvel LP, Monnens LA. Strict cysteamine dose regimen is required to prevent nocturnal cystine accumulation in cystinosis. Pediatr Nephrol. Jan 2006;21(1):110-3. [Medline].
Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. Apr 22 1993;328(16):1157-62. [Medline].
Saleem MA, Milford DV, Alton H, et al. Hypercalciuria and ultrasound abnormalities in children with cystinosis. Pediatr Nephrol. Feb 1995;9(1):45-7. [Medline].
Schneider JA, Katz B, Melles RB. Update on nephropathic cystinosis. Pediatr Nephrol. Nov 1990;4(6):645-53. [Medline].
Smolin LA, Clark KF, Schneider JA. An improved method for heterozygote detection of cystinosis, using polymorphonuclear leukocytes. Am J Hum Genet. Aug 1987;41(2):266-75. [Medline]. [Full Text].
Sonies BC, Almajid P, Kleta R, Bernardini I, Gahl WA. Swallowing dysfunction in 101 patients with nephropathic cystinosis: benefit of long-term cysteamine therapy. Medicine (Baltimore). May 2005;84(3):137-46. [Medline].
Swinford RD, Elenberg E, Ingelfinger JR. Persistent renal disease. In: Nutritrition in Pediatrics: Basic Science and Clinical Applications. Hamilton, Ontario: BC Decker; 1996:493-515.
The Cystinosis Collaborative Research Group. Linkage of the gene for cystinosis to markers on the short arm of chromosome 17. Nat Genet. Jun 1995;10(2):246-8. [Medline].
Theodoropoulos DS, Krasnewich D, Kaiser-Kupfer MI, Gahl WA. Classic nephropathic cystinosis as an adult disease. JAMA. Nov 10 1993;270(18):2200-4. [Medline].
Wuhl E, Haffner D, Gretz N, et al. Treatment with recombinant human growth hormone in short children with nephropathic cystinosis: no evidence for increased deterioration rate of renal function. The European Study Group on Growth Hormone Treatment in Short Children with Nephropathic Cy. Pediatr Res. Apr 1998;43(4 Pt 1):484-8. [Medline].
Wuhl E, Haffner D, Offner G, et al. Long-term treatment with growth hormone in short children with nephropathic cystinosis. J Pediatr. Jun 2001;138(6):880-7. [Medline].
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