Clinical characteristics.

Cystinosis comprises three allelic clinical phenotypes caused by pathogenic variants in CTNS.

Nephropathic (infantile) cystinosis: Characterized in untreated infants/children by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. This is the most common form (95% of individuals with cystinosis). The typical untreated child has short stature, rickets, and photophobia. Failure to gain weight is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months and progress to end-stage kidney disease within the first 12 years of life if untreated; corneal crystals can be present before age one year and are typically present after age 16 months. Laboratory findings include hypochloremic metabolic acidosis; increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, and tubular protein including β2-microglobulin; elevated serum alkaline phosphatase; and hypocalcemia, hypophosphatemia, and hypokalemia. Prior to cystine-depleting drug therapy and kidney transplantation the life span in nephropathic cystinosis was less than ten years. With these treatment interventions, some affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life.

Later-onset (juvenile) cystinosis: Characterized by the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in untreated affected individuals, usually between ages 15 and 25 years. This form accounts for ~5% of individuals with cystinosis.

Non-nephropathic adult (ocular) cystinosis: Characterized by photophobia resulting from corneal cystine crystal accumulation.

Diagnosis/testing.

The diagnosis of cystinosis is established in a proband with cystine crystals in the cornea identified on slit lamp examination, elevated cystine concentration in polymorphonuclear leukocytes, and/or demonstration of increased cystine content in cultured fibroblasts or in the placenta at the time of birth, and biallelic pathogenic variants in CTNS identified by molecular genetic testing.

Management.

Targeted therapies: Early treatment with cystine depletion therapy (cysteamine bitartrate) significantly delays progression of glomerular damage. Cysteamine ophthalmic drops can relieve photophobia. Kidney transplantation is indicated when other medical treatments are no longer effective.

Supportive care: Nutrition and feeding support; growth hormone therapy as needed; education regarding nutrition and avoidance of dehydration. Renal Fanconi syndrome is treated by replacement of tubular losses of electrolytes, bicarbonate, minerals, and other small-molecular-weight nutrients; children should have free access to water and bathroom privileges and supplementation with citrate to alkalinize the blood; fluid and nutrient replacement during episodes of dehydration. Phosphate replacement to prevent and treat rickets; vitamin D supplementation; treatment of skeletal deformities per orthopedist; additional treatment of renal glomerular disease include dialysis and kidney transplant; additional treatments for photophobia include sun avoidance, dark glasses and lubrication; anti-inflammatory agents or other local treatments for corneal complications; L-thyroxine as needed for hypothyroidism; diuretics or CSF drainage may be necessary for intracranial hypertension. Other treatments may include insulin for diabetes mellitus, testosterone for hypogonadism in males, and referral for fertility care; regular exercise and physical therapy for muscle deterioration; L-carnitine may improve muscle strength; treatment per pulmonologist for respiratory manifestations; proton pump inhibitors for gastric acid hypersecretion; treatment of other GI complications per gastroenterologist; treatment of cardiovascular and coagulation complications per cardiologist, vascular specialist, and/or hematologist; developmental and educational support; speech therapy, physical therapy, and occupational therapy for neurologic complications; treatment of immune dysfunction due to anti-rejection medications per transplant specialist; sunscreen and sun-protective clothing; dental care; psychosocial support.

Surveillance: Growth assessment every three to six months throughout childhood, including evaluations of weight, nutrition, and feeding difficulties; evaluation for progressive muscle weakness and swallowing difficulties in those with advanced disease; evaluation by a nephrologist including kidney function tests every three to six months, depending on the severity of kidney impairment; evaluation by metabolic specialist including serum electrolytes, calcium, phosphate, alkaline phosphatase, and intact parathyroid hormone annually or more frequently as needed; skeletal radiographs and DXA scan annually or as needed beginning at age two years; kidney ultrasound every one to two years beginning at age six years; dental exams every six months; detailed ophthalmologic evaluation every six to twelve months with fundoscopic examination to screen for increased intracranial pressure; endocrinology evaluation including thyroid function tests every six months; testosterone, inhibin B, luteinizing hormone, and follicle-stimulating hormone (in males) annually starting before puberty, then as indicated; fasting blood glucose concentration every six to 12 months beginning in adolescence. Neurologic, neurocognitive, and physical and occupational therapy evaluations include visual-motor integration, visual memory, planning, sustained attention, and motor speed every six to 12 months beginning at age seven to eight years. Brain CT or MRI for evaluation of cerebral atrophy or calcifications every two to three years in those with advanced disease. Electroneuromyography, six-minute walk test, and motor function measurement as recommended by neurologist; assess for respiratory manifestations annually; pulmonary function tests as needed; gastroenterologist evaluation every six to 12 months with liver and pancreatic function tests, clinical exam for hepatomegaly and splenomegaly, and assessment for symptoms of gastroesophageal reflux disease annually or more frequently as needed; abdominal ultrasound as needed; annual assessment for cardiac manifestations; chest CT and EKG for detection of coronary and other vascular calcification every two to three years in those with advanced disease; assess for signs and symptoms of coagulation disorder at each visit in adults; assess for signs and symptoms of immunodeficiency due to anti-rejection medications at each visit after kidney transplant; annual dermatology exam in adults especially following kidney transplant; psychosocial assessment including assessment for depression and anxiety annually or more frequently as needed.

Agents/circumstances to avoid: Dehydration; sun exposure if photophobia is present.

Evaluation of relatives at risk: Biochemical or molecular genetic testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment.

Pregnancy management: Pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored. Fluid and electrolyte status require careful management. Females should be counseled that they will need to stop cysteamine treatment during pregnancy. Pregnancy should be managed by an experienced obstetrician and nephrologist due to high incidence of polypharmacy and comorbidities associated with cystinosis, such as chronic kidney disease, hypothyroidism, hypertension, diabetes, and pulmonary and neuromuscular complications.

Genetic counseling.

Cystinosis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CTNS pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the CTNS pathogenic variants have been identified in an affected individual, carrier testing for at-risk family members and prenatal/preimplantation genetic testing for cystinosis are possible.

Suggestive Findings

Nephropathic cystinosis should be suspected in infants and young children with the following clinical, laboratory, and imaging features and family history.

Clinical features

• Typically, birth weight and initial growth are normal. Poor weight gain and growth deficiency occurs by age six to 12 months.
• Vomiting and feeding difficulties
• Severe polyuria, polydipsia, and dehydration
• Progressive rachitic skeletal changes; failure to walk at a normal age
• Tetany
• Corneal crystals, typically observed by slit lamp examination in most individuals by age 12 months and in virtually all individuals by age 18 months [Gahl et al 2000, Elmonem et al 2016] (See Figure 1b.)

Figure 1.

Findings on slit lamp examination of the cornea in individuals with cystinosis a. Band keratopathy in an individual age 33 years with cystinosis treated with cysteamine eye drops, which dissolved the cystine crystals, but not the calcified band (arrow) (more...)

Laboratory features

• Hypochloremic metabolic acidosis
• Renal Fanconi syndrome: increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, and tubular protein including β2-microglobulin
• Elevated serum alkaline phosphatase
• Hypocalcemia, hypophosphatemia, and hypokalemia
• Elevated cystine concentration in polymorphonuclear leukocytes, cultured fibroblasts, or placenta (See Establishing the Diagnosis, Other Testing.)

Imaging features

• Radiographic features of rickets including bowing of the long bones in the lower extremities, widened metaphyses, frayed epiphyses, and generalized osteopenia
• Renal ultrasound features including medullary nephrocalcinosis and/or increased echogenicity

Later-onset (juvenile) cystinosis should be suspected in individuals exhibiting proteinuria and mild renal tubular Fanconi syndrome combined with progressive chronic glomerular insufficiency.

Non-nephropathic (ocular) cystinosis should be suspected in adults with photophobia and/or cystine crystals in the cornea on slit lamp examination (see Figure 1b).

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of cystinosis is established in a proband with suggestive clinical and laboratory findings and biallelic pathogenic (or likely pathogenic) variants in CTNS identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic CTNS variants of uncertain significance (or of one known CTNS pathogenic variant and one CTNS variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Although phenotypes may overlap, three clinical phenotypes of cystinosis are recognized: nephropathic (the most severe form that presents in infancy), later-onset (juvenile), and non-nephropathic (ocular) cystinosis [Emma et al 2014].

Nephropathic Cystinosis

The clinical characteristics of untreated nephropathic cystinosis include poor weight gain, growth deficiency, renal tubular Fanconi syndrome, renal glomerular failure, and non-renal involvement of a variety of tissues and organ systems. Treatment with cysteamine allows depletion of lysosomal cystine in most tissues. Although cysteamine does not cure the disease, it dramatically improves the overall prognosis and life span [Emma et al 2014].

Growth. Infants with untreated nephropathic cystinosis typically have normal birth measurements. In undiagnosed or untreated individuals, initial failure to gain weight and later linear growth failure are generally noticed between ages six and nine months. Typically, infants are at the third centile for height at age one year [Gahl et al 2001, Gahl et al 2002]. Later, growth occurs at 60% of the normal rate. Bone age is usually delayed one to three years. Head circumference is normal for age.

A high frequency of vomiting (usually in the morning), poor appetite, and feeding difficulties, combined with renal losses of nutrients, causes poor nutrition and severe failure to gain weight. With the development of chronic kidney disease (CKD), there are marked alterations in linear growth and poor weight gain for height. Overall, linear growth was significantly more impaired in individuals with nephrogenic cystinosis compared to individuals with CKD due to other causes, suggesting there are additional factors that contribute to growth deficiency in nephrogenic cystinosis [Kluck et al 2022].

Early and optimal cystine-depleting therapy allows for a normal growth rate but does not provide catch-up growth. Treated infants and toddlers with nephropathic cystinosis have height in the 10th-25th centile for age and fall in the range of mid-parental constitutional growth. Growth hormone administration improves growth velocity in prepubertal children.

Renal tubular Fanconi syndrome. Infants with untreated nephropathic cystinosis show signs of renal tubular Fanconi syndrome – i.e., generalized proximal tubular dysfunction – as early as age six months. Fanconi syndrome involves failure of the renal tubules to reabsorb water, electrolytes (sodium, potassium, bicarbonate, phosphate, and calcium), glucose, carnitine, amino acids, and tubular proteins. Individuals with untreated cystinosis have severe polyuria (2-6 L/day), polydipsia, dehydration, and hypochloremic metabolic acidosis, sometimes requiring hospitalization because of life-threatening hypovolemia, particularly during a gastrointestinal illness.

Hypophosphatemic/calcipenic rickets, characterized by high excretion of phosphate and calcium, elevated serum alkaline phosphatase, and bone deformities, make walking painful enough to delay ambulation. Nutritional deficiencies of vitamin D and calcium may accompany rickets, leading to seizures and tetany.

Severe hypokalemia can cause cardiac conduction abnormalities. Occasionally, hyponatremia and hypomagnesemia also occur.

Diligent treatment with replacement of renal losses is required for resolution of rickets, tetany, acidosis, and laboratory abnormalities. Cystine-depleting therapy begun just after birth when tubular damage is not complete can attenuate renal tubular Fanconi syndrome [Kleta & Gahl 2004]. However, renal tubular damage present at the usual time of diagnosis (i.e., age ~1 year) is irreversible [Nesterova et al 2015].

Renal glomerular failure. In those with untreated nephropathic cystinosis, glomerular function gradually deteriorates, resulting in kidney failure at approximately age ten years [Gahl et al 2001, Gahl et al 2002]. Serum creatinine concentration may not exceed 1.0 mg/dL until age five years, but once it rises, it increases exponentially. Many affected individuals have significant proteinuria, sometimes in nephrotic ranges, along with granular casts and microhematuria.

Early treatment with cystine-depleting therapy (i.e., oral cysteamine) slows or stops the progression of glomerular damage and can delay or eliminate the need for kidney transplantation [Kleta & Gahl 2004].

Non-kidney involvement. Without optimal therapy, cystine accumulation occurs in virtually all organs and tissues, including bone marrow, liver, intestine, muscle, brain, spleen, eye, thyroid, pancreas, and testes. Without therapy, several complications of cystinosis occur prior to kidney transplantation:

• Children with cystinosis have mildly altered craniofacial morphology, reduced airway dimensions, and delayed dental development with delayed eruption of permanent teeth [Bassim et al 2010].
• Photophobia develops as the cornea becomes packed with cystine crystals, generally at the end of the first decade of life.
• Affected individuals typically develop hypothyroidism at the end of the first decade of life.
• Sweating is impaired and affected individuals can suffer heat prostration [Gahl et al 2001, Gahl et al 2002].
• Intracranial hypertension occasionally develops as the deposition of cystine in the meninges and arachnoid villi may reduce cerebrospinal fluid absorption [Martín-Begué et al 2017].
• Puberty is generally delayed one to two years. Females with cystinosis appear to have normal fertility, although complications secondary to the disease and kidney transplantation frequently occur during pregnancy [Servais et al 2022]. In contrast, most males with nephropathic cystinosis suffer from obstructive azoospermia, with intact spermatogenesis in early adulthood [Reda et al 2021]. It is currently not known whether diligent cysteamine treatment can prevent primary hypogonadism in males.

Late-onset abnormalities. After kidney transplantation (at age ~20-40 years) [Langman et al 2012], additional complications can occur from the long-standing accumulation of cystine crystals in organs other than the kidneys in individuals not treated with cysteamine [Servais et al 2008].

• Increased cystine content in the muscles causes vacuolar myopathy in 60% of individuals [Gahl et al 2007]. Generalized myopathy leads to progressive muscle wasting and weakness (Figure 2a, 2c, 2d) [Charnas et al 1994, Sadjadi et al 2020, Vill et al 2022]. Oral motor dysfunction causes swallowing and feeding difficulties [Sonies et al 2005, van Rijssel et al 2019]. Electromyography demonstrates a myopathic pattern.
• Extrinsic chest muscle impairment causes extraparenchymal restriction of ventilation leading to pulmonary insufficiency with decreased values of forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁) on pulmonary function tests [Anikster et al 2001].
• Gastrointestinal findings can include reflux, dysmotility, esophagitis, gastric/duodenal ulcers, hepatomegaly with nodular regenerating hyperplasia of the liver and portal hypertension, exocrine pancreatic insufficiency, inflammatory bowel disease, bowel perforation, and peritonitis [O'Brien et al 2006, Gahl et al 2007, Topaloglu et al 2020].
• Pancreatic endocrine insufficiency can result in diabetes mellitus, exacerbated by post-transplant steroid use as an anti-rejection medication.
• Cardiovascular manifestations can include arteriopathy caused by the combination of vascular calcifications, obstructive atherosclerosis with hypercholesterolemia (Figure 2e) [Ueda et al 2006], and end-stage kidney disease (ESKD); renin-dependent hypertension; dilated cardiomyopathy; and aortic aneurysms. These factors contribute to cardiovascular morbidity and increase the risk for myocardial infarction and neurovascular incidents.
• Metabolic bone disease develops because of direct deposition of cystine crystals in bone, mineral imbalance, and renal osteodystrophy prior to kidney transplantation [Florenzano et al 2018, Lahring et al 2025]. The term cystinosis metabolic bone disease (CMBD) was coined by an international guideline initiative to describe the complex bone phenotype in individuals with nephropathic cystinosis [Haffner et al 2022].
• Hypercoagulopathy or hypocoagulopathy can occur because of kidney failure and platelet aggregation dysfunction [Nesterova & Gahl 2008].
• Central nervous system (CNS) calcifications (Figure 2f), benign intracranial hypertension with non-absorptive hydrocephalus, and parenchymal deterioration of the CNS with cerebral atrophy can lead to various degrees of encephalopathy [Gahl et al 2001, Gahl et al 2002] and other CNS complications [Servais et al 2020]. Neurologic complications can include cognitive dysfunction, particularly in visual spatial and visual memory domains, difficulties with academic function, and motor incoordination [Trauner 2017, Trauner 2023]. Occasionally, cerebrovascular incidents with paresis or pseudobulbar palsy occur [Gahl et al 2007].
• Late ocular complications can include crystal deposition in the anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve that manifests as anterior and posterior segment problems [Tsilou et al 2007]; anterior segment problems that include crystals in the anterior lens surface, band keratopathy (Figure 1a), peripheral corneal neovascularization, and posterior synechiae; and posterior segment problems that include pigmentary retinopathy with degeneration of the photoreceptors, which contribute to impaired visual function in the late stage of the disease [Tsilou et al 2002].

Figure 2.

A man age 37 years with nephropathic cystinosis a. Thin habitus

Genotype-Phenotype Correlations

Some genotype-phenotype correlations have been reported (see Table 7):

• Truncating CTNS pathogenic variants and the 57-kb deletion result in nephropathic cystinosis when present in homozygous form [Topaloglu 2021].
• Individuals with apparent residual activity (and lower levels of cystine accumulation in leukocytes) often have missense pathogenic variants in CTNS [Attard et al 1999]. Individuals with later-onset (juvenile) cystinosis or non-nephropathic (ocular) cystinosis generally have one severe CTNS pathogenic variant, typical for nephropathic cystinosis, and one mild pathogenic variant. The mild pathogenic variants include c.589G>A (p.Gly197Arg) and c.853-3C>G [Anikster et al 1999].
• The pathogenic variant c.416C>T (p.Ser139Phe) may cause later-onset (juvenile) phenotype [Macías-Vidal et al 2009] when the other allele is a nonsense variant.

Nomenclature

Nephropathic cystinosis is also referred to as infantile nephropathic cystinosis.

Later-onset (juvenile) cystinosis is also referred to as intermediate cystinosis or adolescent (or juvenile) nephropathic cystinosis.

The terms "adult cystinosis" and "benign cystinosis" should be replaced by "ocular cystinosis," "non-nephropathic cystinosis," or "ocular non-nephropathic cystinosis."

Prevalence

Cystinosis occurs with a frequency of approximately one in 150,000 to 200,000 and has been found worldwide in all ethnic groups [Levtchenko et al 2022].

Cystinosis accounts for 5% of childhood kidney failure [Middleton et al 2003].

The 57-kb deletion represents more than 50% of CTNS pathogenic variants in affected individuals of northern European ancestry; however, it has not been reported in any individuals from the Middle East, Asia, and Africa, suggesting that it is a northern European founder variant [Emma et al 2014, David et al 2019, Topaloglu et al 2020] (see Table 7).

Evaluations Following Initial Diagnosis

Treatment of Manifestations

It is recommended that a multidisciplinary team that includes specialists in nephrology, metabolic disease, ophthalmology, neurology, gastroenterology, nutrition, and psychology manage individuals with cystinosis. A clinical care coordinator should be identified (e.g., nephrologist or metabolic disease specialist). There is no cure for cystinosis.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended. Clinical and laboratory examinations should be performed in individuals with nephropathic cystinosis according to disease severity and may include renal, endocrine, ophthalmologic, neurologic, and cardiac examinations [Levtchenko et al 2022].

Agents/Circumstances to Avoid

Avoid the following:

• Dehydration, which compromises remaining kidney function
• Sun exposure, which can exacerbate photophobia

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. Molecular genetic prenatal testing of a fetus at risk may be performed to facilitate institution of treatment at birth.

Newborn sib of a proband with cystinosis. If prenatal testing was not performed, prompt biochemical or molecular genetic testing of a newborn sib is recommended to allow for early diagnosis and treatment. Treatment of an affected newborn sib in the first two weeks of life is recommended to prevent life-threatening complications of cystinosis.

Older sibs of a proband with cystinosis. The genetic status of older sibs (even if asymptomatic) should be clarified by biochemical testing or molecular genetic testing so that treatment can be instituted in a timely manner.

See Genetic Counseling for issues related to testing at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored closely [Ramappa & Pyatt 2010]. For females who are post-transplantation, the abdominal kidney allograft creates mechanical issues. For females who have not undergone transplantation, fluid and electrolyte status require careful management.

One study demonstrated low amounts of cysteamine in breast milk. The authors concluded that these levels were unlikely to be clinically significant. This information may be reassuring for women with cystinosis who desire to breastfeed. However, additional data is needed to confirm the safety of cysteamine use in breastfeeding [Chan et al 2022].

Pregnancy should be managed by an experienced obstetrician and nephrologist due to high incidence of polypharmacy and comorbidities associated with cystinosis, such as chronic kidney disease, hypothyroidism, hypertension, diabetes, and pulmonary and neuromuscular complications.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Development of a newborn screening test for cystinosis will potentially allow broader therapeutic success [Nesterova & Gahl 2008, Hohenfellner et al 2022a]. Molecular-based screening in Germany has successfully identified newborns with cystinosis [Hohenfellner et al 2019].

Mode of Inheritance

Cystinosis is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a CTNS pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CTNS pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a CTNS pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an affected individual's reproductive partner also has cystinosis or is a carrier, offspring will be obligate heterozygotes (carriers) for a CTNS pathogenic variant.
• Rarely, families with two-generation involvement (sometimes called "pseudodominance") have been identified; two-generation involvement results from an affected individual having children with a partner who is heterozygous (i.e., a carrier) for a CTNS pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CTNS pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk family members requires prior identification of the CTNS pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with cystinosis, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see Table 7).
• Females with cystinosis have had successful pregnancies resulting in healthy newborns. However, pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored closely (see Pregnancy Management).
• Most males with nephropathic cystinosis suffer from obstructive azoospermia; thus, when they reach reproductive age they may benefit from fertility counseling and discussion of assistive reproductive technology options [Langman et al 2023].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the CTNS pathogenic variants have been identified in an affected family member, molecular genetic prenatal and preimplantation genetic testing for cystinosis are possible

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider the use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Cystinosin, the protein product of CTNS, transports the disulfide amino acid cystine out of the lysosome and into the cytoplasm [Gahl et al 2002, Kleta & Gahl 2002. Cystinosin deficiency results in lysosomal cystine accumulation and cystine crystal formation in virtually all tissues and organs. Loss of cystinosin has been associated with disrupted autophagy, accumulation of aberrant mitochondria, and increased oxidative stress, leading to abnormal proliferation and dysfunction of kidney cells [Jamalpoor et al 2021].

A 57-kb deletion that includes the promotor region, exons 1-9, and interrupts exon 10 is the most common pathogenic variant identified in individuals with cystinosis from northern Europe and North America; Germany is considered the country of origin of this suspected founder variant. This deletion accounts for 50%-70% of pathogenic variants identified in individuals from these regions [Hohenfellner et al 2022a]. This deletion also includes two upstream genes (although no clinical disorders related to deletion of these genes have been reported) [Emma et al 2014].

Mechanism of disease causation. Loss of function

Author Notes

William Gahl, MD, PhD (vog.hin.liam@wlhag), is a pediatrician, medical geneticist, and biochemical geneticist who performs clinical and basic research into rare diseases. He has seen approximately 300 individuals with cystinosis and published more than 85 articles and reviews on the subject.

Dr Gahl is actively involved in clinical research regarding individuals with cystinosis and would be happy to communicate with persons who have any questions regarding diagnosis of cystinosis or other considerations.

Acknowledgments

Cystinosis Research Network (CRN) for providing clinical and scientific information to patients.

Dr Francisco Emma (Pediatric Nephrology Division at Bambino Gesù Children's Hospital in Rome), Dr Katharina Hohenfeller (Department of Pediatrics, Pediatric Nephrology, RoMed Kliniken, Pettenkoferstr.10, 83022 Rosenheim, Germany), and Dr Elena Levtchenko (Amsterdam Gastroenterology Endocrinology Metabolism) for recent investigations in cellular pathophysiology of cystinosis, contributions to developing newborn screening, and coordination of guidelines for management.

Author History

William A Gahl, MD, PhD (2001-present)
Robert Kleta, MD, PhD; National Human Genome Research Institute (2001-2009)
Galina Nesterova, MD (2009-2025)

Revision History

• 14 August 2025 (sw) Comprehensive update posted live
• 6 October 2016 (sw) Comprehensive update posted live
• 30 January 2014 (me) Comprehensive update posted live
• 11 August 2011 (me) Comprehensive update posted live
• 9 April 2009 (me) Comprehensive update posted live
• 18 October 2005 (me) Comprehensive update posted live
• 6 June 2003 (ca) Comprehensive update posted live
• 22 March 2001 (me) Review posted live
• January 2001 (wg) Original submission

Published Guidelines / Consensus Statements

• Ariceta G, Camacho JA, Fernández-Obispo M, Fernández-Polo A, Gamez J, García-Villoria J, Lara Monteczuma E, Leyes P, Martín-Begué N, Oppenheimer F, Perelló M, Morell GP, Torra R, Santandreu AV, Güell A; Grupo T-CiS.bcn. Cystinosis in adult and adolescent patients: recommendations for the comprehensive care of cystinosis. Nefrologia. 2015;35:304-21. [PubMed]
• Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van't Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014;29 Suppl 4:iv87-94. [PubMed]
• Hohenfellner K, Rauch F, Ariceta G, Awan A, Bacchetta J, Bergmann C, Bechtold S, Cassidy N, Deschenes G, Elenberg E, Gahl WA, Greil O, Harms E, Herzig N, Hoppe B, Koeppl C, Lewis MA, Levtchenko E, Nesterova G, Santos F, Schlingmann KP, Servais A, Soliman NA, Steidle G, Sweeney C, Treikauskas U, Topaloglu R, Tsygin A, Veys K, V Vigier R, Zustin J, Haffner D. Management of bone disease in cystinosis: statement from an international conference. J Inherit Metab Dis. 2019;42:1019-29. [PubMed]
• Levtchenko E, Servais A, Hulton SA, Ariceta G, Emma F, Game DS, Lange K, Lapatto R, Liang H, Sberro-Soussan R, Topaloglu R, Das AM, Webb NJA, Wanner C. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clin Kidney J. 2022;15:1675-84. [PubMed]
• Stabouli S, Sommer A, Kraft S, Schweer K, Bethe D, Bertholet-Thomas A, Batte S, Ariceta G, Brengmann S, Bacchetta J, Emma F, Levtchenko E, Topaloglu R, Willem L, Haffner D, Oh J. Addressing the psychosocial aspects of transition to adult care in patients with cystinosis. Pediatr Nephrol. 2024;39:2861-74. [PubMed]

Literature Cited

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