CLINICAL CHARACTERISTICS

Cystinosis comprises three allelic clinical phenotypes caused by pathogenic variants in . 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. 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. 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 identified by molecular genetic testing.

MANAGEMENT

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. 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. : 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. Dehydration; sun exposure if photophobia is present. Biochemical or molecular genetic testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment. 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 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 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.