Clinical characteristics: Cystinosis comprises three allelic phenotypes:
Nephropathic cystinosis in untreated children is characterized 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. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive 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; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life.
Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years.
The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.
Diagnosis/testing: The diagnosis of cystinosis is established in a proband by one of the following:
Identification of cystine crystals in the cornea on slit lamp examination
Identification of elevated cystine concentration in polymorphonuclear leukocytes
Demonstration of increased cystine content in cultured fibroblasts or in the placenta at the time of birth
Identification of biallelic pathogenic variants in CTNS on molecular genetic testing
Management: Treatment of manifestations: 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; phosphate replacement and vitamin D supplements are also used to prevent and treat rickets; skeletal deformities should be addressed early with the help of orthopedic specialists. Fluid and nutrient replacement is required during episodes of dehydration. For renal glomerular disease, oral cysteamine reduces cellular cystine; renal transplantation provides the ultimate treatment. Cysteamine eye drops relieve photophobia. Nutrition must be adequate to minimize failure to thrive in infants. Growth hormone replacement, L-thyroxine for hypothyroidism, insulin for diabetes mellitus, and testosterone for hypogonadism in males are all beneficial. Physical and speech therapy is helpful for the muscle deterioration and swallowing difficulties of older individuals.
Prevention of primary manifestations: Therapy with cystine-depleting agents begun as soon as the diagnosis is made or (if possible) shortly after birth will significantly slow the progression of glomerular damage; renal damage present at the time of diagnosis is irreversible. With optimal symptomatic and cystine-depleting therapy affected individuals grow at a normal rate but generally do not recover lost height unless human growth hormone is administered.
Prevention of secondary complications: Those who have undergone renal transplantation should be monitored for signs of immunodeficiency and infection; carnitine supplementation administered pre-transplant may improve muscle strength; treatment with proton pump inhibitors helps relieve cysteamine-induced gastric acid hypersecretion.
Surveillance: Evaluation by a nephrologist every three to six months depending on the severity of renal impairment; ophthalmologic evaluation every one to two years; assessment of bone mineralization throughout the disease course; fasting blood glucose concentration and testosterone concentration every two to three years (in males, starting before puberty); monitoring for late-onset complications by a multidisciplinary medical team.
Agents/circumstances to avoid: Dehydration; sun exposure if photophobia is present.
Evaluation of relatives at risk: Biochemical and/or molecular genetic testing (if the genetic status of the proband is known) allows for early diagnosis and treatment.
Genetic counseling: Cystinosis is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants have been identified in the family. For pregnancies at increased risk for nephropathic cystinosis, prenatal diagnosis is also possible biochemically, based on elevated cystine concentrations in both chorionic villi and amniocytes.
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