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Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by a malfunctioning of the protein cystinosin, which is encoded by the CTNS gene. This disorder is characterized by the accumulation of cystine within cellular lysosomes, leading to widespread organ involvement. In nephropathic or infantile cystinosis, renal issues are the primary cause of morbidity and mortality, and it is also the most common inherited cause of Fanconi syndrome in children. Cystinosis has 3 forms—infantile (nephropathic), juvenile (intermediate and late-onset), and adult (benign, ocular, and non-nephropathic). The infantile form is the most common and severe, accounting for about 95% of cases, and leads to end-stage renal disease (ESRD) by ages 10 to 12. The eyes and endocrine organs are also significantly affected, contributing to the condition's overall morbidity. Cysteamine, a cystine-depleting medication, is the cornerstone of treatment for cystinosis, significantly delaying disease progression and improving outcomes. Early diagnosis and prompt treatment with cysteamine are crucial for managing the disease and preventing complications, including the progression to ESRD. This activity covers the epidemiology, pathophysiology, molecular genetics, clinical presentation, and evaluation of cystinosis, along with the identification and management of common complications. This activity also highlights the role of the interprofessional healthcare team in the long-term management of cystinosis and in improving patient outcomes. Objectives: Identify the typical clinical presentations of cystinosis, including polyuria, polydipsia, and failure to thrive, particularly in infantile nephropathic cases. Implement cysteamine therapy early to delay disease progression and improve patient outcomes. Select appropriate diagnostic tools, including cystine levels and molecular genetic testing for pathogenic CTNS variants, to confirm diagnosis and assess disease severity. Collaborate with an interprofessional healthcare team to provide comprehensive care for cystinosis, addressing renal, ocular, endocrine, and neurological complications to optimize treatment and enhance patient quality of life. Access free multiple choice questions on this topic.

Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene, which encodes the cystinosin protein. This disorder affects an estimated 1 in 100,000 to 200,000 live births worldwide. Cystinosis is characterized by the accumulation of cystine within cellular lysosomes, ultimately affecting almost all organs.[1] Renal involvement, characterized by proximal tubulopathy, is the most common cause of morbidity and mortality in nephropathic or infantile cystinosis and eventually leads to renal failure. Cystinosis is also the most common inherited cause of Fanconi syndrome in children. The 3 known forms of cystinosis are infantile (nephropathic), juvenile (intermediate and late-onset), and adult (benign, ocular, and non-nephropathic). The infantile form is the most common and severe, accounting for about 95% of cases, and typically leads to end-stage renal disease (ESRD) by ages 10 to 12. Cysteamine, a cystine-depleting therapy, is the cornerstone of treatment for this disorder. Early recognition and treatment with cysteamine can delay the progression to ESRD and associated morbidities, resulting in improved overall outcomes.

Cystinosis is caused by a malfunctioning protein named cystinosin, which is encoded by the CTNS gene on chromosome 17p13.2. Cystinosin is a lysosomal membrane transporter responsible for transporting cystine out of lysosomes. Biallelic mutations in the CTNS gene result in defective cystinosin production. More than 140 pathogenic mutations have been identified as causing cystinosis.[2] Larger or truncating mutations are associated with a severe form of cystinosis. Patients with these mutations typically develop infantile (nephropathic) cystinosis. In contrast, those with juvenile or adult forms usually have milder mutations, which allow some cystine transport out of lysosomes.[3]

Cystinosis affects approximately 1 in 200,000 live births worldwide, although incidence varies significantly by geographical location.[1] Due to its autosomal recessive inheritance pattern, regions with high consanguinity or founder effects show much higher incidences. For instance, the incidence in Brittany, France, is as high as 1 in 26,000 live births, while in Quebec, Canada, it is 1 in 62,500 live births.[4] The highest known incidence of cystinosis is among the Pakistani ethnic group living in the West Midlands, UK, at 1 in 3600 births. Prevalence appears higher in regions where consanguineous marriages are more common, such as the Middle East and North Africa, although specific statistics are unavailable.[5]

Cystine is produced through protein catabolism in lysosomes and is a covalently linked dimer of the amino acid cysteine. Under normal conditions, cystinosin transports cystine out of lysosomes, allowing it to be reused by cells. In cystinosis, the defective cystinosin protein cannot transport cystine, causing it to accumulate in lysosomes. This results in cystine crystal buildup in cells across various organ systems. Cystine accumulation leads to cell injury and apoptosis due to increased oxidative stress, impaired chaperone-mediated autophagy, ATP depletion, and damage to other cellular transporters.[6] Cell damage and apoptosis ultimately result in dysfunction across multiple organ systems. A varying degree of loss of function of the same CTNS gene is responsible for the 3 forms of cystinosis. Large deletions or variants leading to significant protein truncation are associated with the most severe form, infantile cystinosis. In contrast, inheritance of a milder variant on one or both alleles leads to juvenile (intermediate and late-onset) and benign (adult, ocular, and non-nephropathic) cystinosis. Manifestations of underlying renal impairment are a key feature of cystinosis, with proximal tubulopathy caused by cystine crystal deposition leading to glycosuria, aminoaciduria, phosphaturia, bicarbonaturia, and other electrolyte losses. Animal studies suggest this is due to the loss of proximal tubular receptors such as megalin and cubilin, SGLT2, and NaPi-IIa transporters.[5] This solute loss and reduced concentrating ability of the proximal tubules result in polyuria, polydipsia, growth failure, and rickets. Over time, proteinuria and renal injury progress to ESRD. Ocular manifestations are caused by cystine crystal deposition in the cornea and conjunctiva, and they present as watery eyes, photophobia, and blepharospasm, with hemorrhagic retinopathy being a rare complication. Nearly all affected children develop corneal cystine crystals by 18 months of age. In addition to the kidneys, the eyes and endocrine organs are commonly affected, typically manifesting later than the renal signs and symptoms.[5]

This solute loss and reduced concentrating ability of the proximal tubules result in polyuria, polydipsia, growth failure, and rickets. Over time, proteinuria and renal injury progress to ESRD. Ocular manifestations are caused by cystine crystal deposition in the cornea and conjunctiva, and they present as watery eyes, photophobia, and blepharospasm, with hemorrhagic retinopathy being a rare complication. Nearly all affected children develop corneal cystine crystals by 18 months of age. In addition to the kidneys, the eyes and endocrine organs are commonly affected, typically manifesting later than the renal signs and symptoms.[5] The commonly affected endocrine organs include the thyroid, endocrine pancreas, and gonads.[7] Primary hypothyroidism and gonadal failure are more frequent than hypothalamic-pituitary involvement. Later in life, neuromuscular involvement—often characterized by difficulty swallowing and walking, metabolic bone disease, and premature vascular calcifications—can increase the morbidity of affected individuals. In addition, the accumulation of cystine crystals can cause coarsening of the facial features.[8]

Renal histopathological changes in infantile nephropathic cystinosis include severe proximal tubular lesions, multinucleated podocytes, and cystine crystal deposition, primarily in interstitial cells and podocytes. Under light microscopy, cystine crystals may appear as empty rectangular structures, although they are not always visible on biopsy. Focal and segmental global sclerosis is common and likely contributes to the significant proteinuria.[9]

Infantile Cystinosis This is by far the most common and severe presentation of cystinosis, accounting for up to 95% of cases. Infants typically present between 6 and 12 months of age with symptoms including failure to thrive, polyuria, polydipsia, electrolyte imbalances, dehydration, vomiting, and constipation. Phosphaturia, loss of vitamin D binding protein, and decreased activation of 25-vitamin D can lead to vitamin D–resistant rickets, as well as osteomalacia and osteoporosis by the second decade of life. Proteinuria is an early sign and may reach nephrotic levels.[5][10] One study showed that growth failure was the most common presentation of infantile cystinosis, occurring in 93% of cases.[11] By ages 3 to 4 in children, photophobia often develops due to progressive corneal crystal deposition. Serum creatinine levels typically remain normal until age 5, but without treatment, progression to ESRD can occur by ages 10 to 12. Additionally, children may develop hepatomegaly due to cystine deposition in Kupffer cells, which can lead to portal hypertension and splenomegaly. Hypothyroidism, hypogonadism, and diabetes are also common and typically present by the second decade of life. Neuromuscular dysfunction, such as difficulty walking and swallowing and legal blindness, may occur by the third decade of life.[7] Juvenile or Late-Onset Nephropathic Cystinosis This form comprises about 5% of cases. Initial symptoms often include ocular discomfort or photophobia. The presentation can vary widely, from mild proteinuria to overt nephrotic syndrome, with growth retardation typically not being a characteristic feature of this form.[5][9] Symptoms usually begin between ages 5 and 20, with less severe progression to ESRD by ages 15 to 30 years or later. Fanconi syndrome is less common in this late-onset form, even when renal involvement is present.[9] Adult (Ophthalmic) Cystinosis This form manifests as visual symptoms, primarily photophobia, from young adulthood to middle age. An eye examination will reveal corneal cystine accumulation, while other systemic symptoms are usually absent.[12] Ophthalmological Examination

This form comprises about 5% of cases. Initial symptoms often include ocular discomfort or photophobia. The presentation can vary widely, from mild proteinuria to overt nephrotic syndrome, with growth retardation typically not being a characteristic feature of this form.[5][9] Symptoms usually begin between ages 5 and 20, with less severe progression to ESRD by ages 15 to 30 years or later. Fanconi syndrome is less common in this late-onset form, even when renal involvement is present.[9] Adult (Ophthalmic) Cystinosis This form manifests as visual symptoms, primarily photophobia, from young adulthood to middle age. An eye examination will reveal corneal cystine accumulation, while other systemic symptoms are usually absent.[12] Ophthalmological Examination Eye abnormalities often represent one of the earliest extra-renal manifestations of cystinosis, making ophthalmological examination crucial for diagnosis. Corneal cystine accumulation with crystal formation is typically the first extra-renal finding and usually becomes apparent by 12 to 18 months of age, requiring a slit-lamp exam for visualization. This crystal formation can lead to photophobia and blepharospasm, generally occurring between mid-childhood and early adolescence. Superficial punctate and filamentary keratopathy are frequently observed in adolescent and adult patients. Band keratopathy, peripheral corneal neovascularization, and posterior synechiae with iridic thickening are often found in older individuals. Depigmentation of the peripheral retina with pigment epithelial mottling is a common posterior segment complication. Approximately 10% to 15% of patients may develop retinal blindness.[13][14][15] Neurological Examination Neurological findings are common and may include tremors, hypotonia, gross and fine motor impairment, speech delays, neurocognitive dysfunction, behavioral issues, idiopathic intracranial hypertension, and encephalopathy. Progressive distal muscle wasting and weakness are also frequently observed.[5] Other Physical Examination Findings Coarse facial features [8] Congenital hypopigmentation, including light skin and blond hair, due to impaired melanin production [16] Growth retardation Hepatomegaly Hypogonadism Premature skin aging [5]

Polyuria is often the first notable sign of cystinosis, defined as urine output of more than 2 L/m2/d. Once polyuria is confirmed, it is crucial to assess urinary electrolytes, bicarbonate, glucose, and protein levels. All patients with Fanconi syndrome at a young age should be evaluated for cystinosis unless another cause is known, as cystinosis is the most common hereditary cause of Fanconi syndrome in children. Common Diagnostic Findings in Cystinosis Serum electrolytes: Hypokalemia, hypophosphatemia, hypocalcemia, hyponatremia, and low bicarbonate levels [10] Urinalysis: Low osmolality, glycosuria, tubular proteinuria, phosphaturia, and bicarbonaturia Arterial blood gas: Non-anion gap metabolic acidosis Thyroid function: Evidence of hypothyroidism Hemoglobin A1c (HbA1c): Elevated, indicating persistent hyperglycemia Sex hormones: Low testosterone levels Liver function tests: Elevated alanine aminotransferase and aspartate aminotransferase Vitamin D (1,25-OH): Low with normal vitamin D (25-OH) Wrist radiography and dual-energy x-ray absorptiometry (DXA): Low bone mineral density, leading to rickets and osteoporosis Renal ultrasonography: Nephrocalcinosis Leukocyte cystine levels and molecular genetic testing for pathogenic CTNS variants are recommended to support a diagnosis of cystinosis. A comprehensive ophthalmological examination is also crucial and cannot be understated. Evaluation of leukocyte cystine levels requires a specialized laboratory. Results are expressed as half-cystine (with 1 molecule of cysteine being half of cystine) per milligram of protein. Generally, levels greater than 2 nmol half-cystine/mg of protein suggest cystinosis. Specifically, levels in the range of 5 to 15 nmol half-cystine/mg of protein indicate infantile cystinosis, while 3 to 6 nmol half-cystine/mg of protein suggest juvenile cystinosis. Patients without cystinosis typically have levels below 0.2 nmol half-cystine/mg of protein.[17]

Systemic Cysteamine Therapy Cysteamine is the primary treatment to lower cystine levels. This alkyl amine contains a thiol group that interacts with cystine in lysosomes, forming cysteine (half-cystine) and cysteine-cysteamine complexes. These complexes can be transported out of lysosomes via cysteine and lysine transporters, such as the PQLC2 transporter. Cysteamine therapy significantly delays disease progression and reduces morbidity and mortality across all forms of cystinosis.[10][18] Early treatment is essential, as it can significantly delay the progression to ESRD, improve growth, and reduce other complications of cystinosis. While cysteamine is generally considered non-curative and primarily delays symptom progression, patients still require aggressive hydration, nutrition, and electrolyte and bicarbonate replacement. However, a recent study demonstrated that early cysteamine treatment in infants can successfully preserve proximal tubular function, with normal electrolyte and bicarbonate levels observed into their second decade of life.[19] Cysteamine is available in both immediate-release and newer delayed-release formulations. The immediate-release formulation should be initiated at one-sixth of the target dose, given every 6 hours, up to 1.3 g/m²/d for children aged 12 or younger and 2 g/d for those aged 12 or older or with a body weight of more than 50 kg.[17] The delayed-release formulation can be administered every 12 hours with equal efficacy.[20] Transitioning from an immediate- to a delayed-release formulation typically results in a modest dose reduction. Leukocyte cystine levels should be monitored regularly, initially monthly and then less frequently as the condition stabilizes, to guide therapy. Cysteamine treatment aims to maintain a mean cystine level of less than 1 nmol/mg of protein in a blood sample taken 6 hours after the last cysteamine dose.[17] Common adverse reactions to cysteamine include nausea, vomiting, diarrhea, anorexia, abdominal pain, headache, bad breath, sulfuric body odor, hallucinations, nervousness, fever, and skin rash.

Leukocyte cystine levels should be monitored regularly, initially monthly and then less frequently as the condition stabilizes, to guide therapy. Cysteamine treatment aims to maintain a mean cystine level of less than 1 nmol/mg of protein in a blood sample taken 6 hours after the last cysteamine dose.[17] Common adverse reactions to cysteamine include nausea, vomiting, diarrhea, anorexia, abdominal pain, headache, bad breath, sulfuric body odor, hallucinations, nervousness, fever, and skin rash. Cysteamine increases gastric acid secretion, making gastrointestinal complications common and potentially leading to medication intolerance. Proton pump inhibitors can help alleviate these symptoms. Due to the metabolism of cysteamine into sulfur products, a bad odor may develop, which can sometimes be managed with riboflavin or chlorophyll supplements.[5] While rare, severe adverse reactions include seizures, neutropenia, and fibrosing colonopathy. Cysteamine therapy should be discontinued during pregnancy due to concerns about potential teratogenic effects.[21] Topical Ophthalmic Cysteamine Therapy Systemic therapy does not address corneal cystine deposition effectively. Topical ophthalmic cysteamine eye drops help prevent and reduce cystine accumulation in the cornea. However, adherence to this therapy is challenging due to the need for application 6 to 10 times daily.[22] The gel formulation offers a more sustainable option.[23] Prostaglandin Inhibitors Cysteamine therapy does not alleviate symptoms of established Fanconi syndrome. Indomethacin, a prostaglandin inhibitor, has shown variable success in treating conditions such as Bartter syndrome and arginine vasopressin resistance (formerly nephrogenic diabetes insipidus), which involve water and electrolyte loss, resulting in polyuria, polydipsia, and failure to thrive. In cystinosis, prostaglandin inhibitors, such as indomethacin at doses of 1 to 3 mg/kg/d, have been used with similar aims and yielded variable outcomes. Precautions are necessary during periods of dehydration, and indomethacin is typically discontinued during these times. Angiotensin-converting enzyme (ACE) inhibitors should be avoided with indomethacin, as their combined use can decrease glomerular filtration rate (GFR) and worsen renal insufficiency. Treatment of Complications and Comorbidities

Cysteamine therapy does not alleviate symptoms of established Fanconi syndrome. Indomethacin, a prostaglandin inhibitor, has shown variable success in treating conditions such as Bartter syndrome and arginine vasopressin resistance (formerly nephrogenic diabetes insipidus), which involve water and electrolyte loss, resulting in polyuria, polydipsia, and failure to thrive. In cystinosis, prostaglandin inhibitors, such as indomethacin at doses of 1 to 3 mg/kg/d, have been used with similar aims and yielded variable outcomes. Precautions are necessary during periods of dehydration, and indomethacin is typically discontinued during these times. Angiotensin-converting enzyme (ACE) inhibitors should be avoided with indomethacin, as their combined use can decrease glomerular filtration rate (GFR) and worsen renal insufficiency. Treatment of Complications and Comorbidities Adequate fluids, phosphate, potassium, and alkali replacement are essential to compensate for proximal tubular losses. High fluid intake is crucial during fevers, gastroenteritis, and summer months to prevent hypovolemia, which can worsen renal damage.[10][24] Cholecalciferol, calcitriol, phosphate, and alkali supplements help maintain bone health.[25] Growth failure is common in children affected by this condition.[11] Early initiation of growth hormone therapy is both safe and effective, regardless of growth hormone stimulation results or renal insufficiency.[26] Carnitine therapy has been investigated for muscle wasting but has not shown proven effectiveness. A high-calorie diet remains the primary treatment approach.[5] Thyroid hormone replacement should be administered as needed.

Growth failure is common in children affected by this condition.[11] Early initiation of growth hormone therapy is both safe and effective, regardless of growth hormone stimulation results or renal insufficiency.[26] Carnitine therapy has been investigated for muscle wasting but has not shown proven effectiveness. A high-calorie diet remains the primary treatment approach.[5] Thyroid hormone replacement should be administered as needed. Puberty may begin spontaneously; however, many boys experience gonadal failure in the second decade of life due to cystine deposition in various parts of the testes, which leads to decreased androgen and sperm production. Both nonobstructive and obstructive factors can cause azoospermia. As gonadal failure is primarily due to end-organ failure rather than hypothalamus-pituitary dysfunction, gonadotropin treatment is ineffective for cystinosis-induced hypogonadism. Testosterone replacement should be provided as needed. Fertility preservation, including sperm banking and the option of future assisted reproductive technology, should be offered to all males starting in adolescence. Unlike males, females with cystinosis usually have unaffected gonadal function. However, chronic kidney disease and immunosuppressive therapy for renal transplantation (if needed) can somewhat limit their childbearing potential. Splenectomy may be required for splenomegaly or complications of hypersplenism, such as pancytopenia or anemia. According to the Centers for Disease Control and Prevention (CDC), patients undergoing planned splenectomy should receive pneumococcal, meningococcal, and Haemophilus influenzae vaccines at least 14 days before surgery. Renal Transplantation As renal disease progresses toward ESRD, renal transplantation should be offered to patients. Although recipient monocytes may infiltrate donor kidneys with cystine crystals, renal tubular disease does not recur in the transplanted kidney. Renal transplantation generally has favorable long-term outcomes in cystinosis.[27] Long-term outcomes in cystinosis are generally considered superior to transplants for other etiologies.[5] Cysteamine must be continued after the transplant to manage nonrenal complications.[28] Future Therapies Hematopoietic stem cell transplantation shows promise for treating cystinosis,[29] although current experience with this therapy is still preliminary.[30][31]

As renal disease progresses toward ESRD, renal transplantation should be offered to patients. Although recipient monocytes may infiltrate donor kidneys with cystine crystals, renal tubular disease does not recur in the transplanted kidney. Renal transplantation generally has favorable long-term outcomes in cystinosis.[27] Long-term outcomes in cystinosis are generally considered superior to transplants for other etiologies.[5] Cysteamine must be continued after the transplant to manage nonrenal complications.[28] Future Therapies Hematopoietic stem cell transplantation shows promise for treating cystinosis,[29] although current experience with this therapy is still preliminary.[30][31] Inflammation plays a significant role in cystinosis pathology, with macrophages contributing to the inflammatory cycle. Galectin-3, an inflammatory mediator that attracts macrophages, has been used in animal models, and decreased expression of this molecule in humans is believed to be part of the therapeutic effect of indomethacin.[32] Other disease-modulating therapies, including mitochondrial oxygen scavengers such as Mito-TEMPO, have also been studied. Other proposed agents under evaluation include anakinra, an interleukin-1 antagonist, and leptin receptor blockers. However, none of these have been approved for clinical use.[10][32]

Other causes of Fanconi syndrome include: Tyrosinemia Galactosemia Glycogen storage disorders Wilson disease Lowe syndrome Hereditary fructose intolerance Mitochondrial disorders Monoclonal gammopathy Dent disease Heavy metal toxicities causing Fanconi syndrome include: Lead (in children) Cadmium Mercury Platinum Uranium Conditions causing growth retardation with renal symptoms or episodes of dehydration include: Renal tubular acidosis (proximal and distal) Bartter syndrome Gitelman syndrome Diuretic abuse Genetic causes of vitamin D-resistant rickets include vitamin D–dependent rickets types 1A, 1B, 2A, and 2B.

Previously, most patients with cystinosis died young due to complications, but early treatment with cysteamine now allows patients to survive to adulthood. Despite this, cystinosis continues to cause significant morbidity and increased mortality. While cysteamine therapy delays complications and reduces morbidity, no current treatment can offer a normal or near-normal life. Renal complications contribute to increased morbidity and often necessitate renal transplantation. In transplanted kidneys, cystine deposition does not recur. Gene therapy using hematopoietic stem cell transplantation shows future potential, but clinical experience remains limited.[31]

Cystinosis affects almost every organ system of the affected individual, with kidneys being the most commonly affected organ. Early signs include proximal renal tubular acidosis, characterized by multiple substance leaks, leading to Fanconi syndrome. Over time, GFR progressively declines, proteinuria often increases, and ESRD may develop, requiring renal replacement therapy. Renal complications: Fanconi syndrome, dehydration episodes, hypokalemia, acidosis, hypophosphatemic rickets, and ESRD. Ocular complications: Corneal cystine deposition causing watering, photophobia, blepharospasm, and hemorrhagic retinopathy. Endocrine complications: Growth retardation, hypothyroidism, diabetes mellitus, and hypogonadism. Neurological and neuromuscular complications: Progressive loss of speech, memory, and intellectual function; cerebral calcification; and progressive myopathy causing swallowing and walking difficulties. Skeletal complications: Rickets, osteoporosis, renal osteodystrophy, and fragility fractures.

Cystinosis is an autosomal recessive genetic disorder with a known locus and predictable clinical course, with a 25% recurrence risk in offspring. Raising awareness through genetic counseling is crucial for prevention within affected families and the broader community. In addition to prevention, early recognition and prompt cysteamine treatment significantly reduce morbidity and delay mortality. Effective management of comorbidities and timely renal transplant referrals, along with cysteamine therapy, have a profoundly positive impact on the lives of affected families.

Similar to many hereditary multisystem conditions, managing cystinosis and taking care of patients with this disorder require interprofessional team approach. Cystinosis is an inherited condition that often occurs in families with consanguineous unions. Patients or their families might seek help from general pediatricians and pediatric nephrologists or endocrinologists for symptoms such as polyuria, failure to thrive, or bony deformities. Ophthalmologists may be consulted for visual symptoms. Geneticists contribute to diagnosis through molecular genetic testing for CTNS variants and provide genetic counseling to affected families. Pediatric nephrology, pediatric endocrinology, ophthalmology, and neurology teams collaborate to manage the various manifestations of the condition. Physiotherapy and dietitian teams collaborate with specialists to address neuromuscular complications and manage special nutritional needs. The urology team assists in evaluating renal transplant requirements for patients with advanced renal failure. Care coordination is crucial for delivering seamless and efficient patient care. Physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals must collaborate closely from diagnosis through treatment and follow-up. This collaboration and teamwork minimizes errors, reduces delays, and enhances patient safety, ultimately leading to improved outcomes and patient-centered care that prioritizes the well-being and satisfaction of those affected by cystinosis.