Cystinosis 

Updated: Aug 31, 2015
Author: Ewa Elenberg, MD, MEd; Chief Editor: Craig B Langman, MD 

Overview

Practice Essentials

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.

The image below depicts an infant at the time his cystinosis is diagnosed.

An 8-month-old male infant at the time his cystino An 8-month-old male infant at the time his cystinosis is diagnosed.

Signs and symptoms

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, if left untreated, develop end-stage kidney failure by late childhood.

Signs and symptoms of nephropathic infantile cystinosis include the following:

  • Multiorgan involvement: May be mild to severe

  • Polyuria, polydipsia, dehydration, vomiting, metabolic acidosis

  • Hypophosphatemic rickets

  • Constipation

  • Failure to thrive, poor/loss of appetite

  • Craves salty and hot and spicy foods; prefers specific food textures

  • May have recurrent bouts of fever and manifestations of heat intolerance

  • Left untreated, renal failure develops by age 7-10 years

Signs and symptoms of late-onset (intermediate) nephropathic cystinosis include the following:

More indolent disease than infantile form of the disease

  • Manifests most commonly in early adolescence; most diagnosed by age 12 years

  • Symptoms usually restricted to kidneys and eyes

  • Often doesn’t develop complete Fanconi syndrome, but renal function deteriorates

  • End-stage renal disease within a few years of diagnosis, after age 15 years

The major complication of nephropathic cystinosis in patients older than 20 years is legal blindness, distal vacuolar myopathy, cerebral calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).

Nonnephropathic cystinosis is considered a benign variant and is usually diagnosed by an ophthalmologist treating patients for photophobia, which may not begin until middle age and is not usually as debilitating as in the nephropathic form of the disease.

See Clinical Presentation for more detail.

Diagnosis

A typical cystinotic patient has pale blond hair and blue eyes, although the disease also occurs among dark-haired individuals with brown eyes. Examination in patients with nephropathic cystinosis (progressive disease) may also reveal the following features:

  • Children younger than 1 year: Usually growth retardation, rickets, metabolic acidosis, and other chemical evidence of renal tubular abnormalities (eg, increased renal excretion of glucose, amino acids, phosphate, and potassium)

  • As children age: Prominent failure to thrive; without specific therapy, children remain below the third percentile in both height and weight throughout life

  • By age 1-2 years: Corneal crystals

  • By age 3-4 years: Untreated, cornea packed with crystals, causing early photophobia

  • By age 7-10 years: Previously noted symptoms now more severe; increased proteinuria, progressive renal failure, increased photophobia, thyroid insufficiency

  • Adolescence (usually age 10-13 years): End-stage renal disease; good adherence to therapy slows down-progression of renal failure by several more years

  • Delayed sexual maturation; in males, hypogonadism and infertility

  • Second or third decade of life: Retinal damage

  • Third decade of life: Cerebral calcifications; muscular and swallowing difficulties

Laboratory tests

The following laboratory studies may be used to assess patients suspected of having cystinosis:

  • Serum electrolyte levels: To detect the presence of acidosis (hyperchloremic, normal anion gap) and severity of hypokalemia, hyponatremia, hypophosphatemia, and low bicarbonate concentration

  • Blood gases: To detect metabolic acidosis and the degree of respiratory compensation

  • Urine testing: Findings include low osmolality, glycosuria, and tubular proteinuria (including generalized amino aciduria)

  • Urine electrolyte levels: To detect the loss of bicarbonate and phosphaturia

  • Cystine levels in polymorphonuclear leukocytes or cultured fibroblasts (for fetuses: chorionic villi or cultured amniotic fluid cells): Confirms diagnosis of cystinosis

Other studies used in the evaluation of patients with suspected cystinosis include the following:

  • Slit-lamp examination of the eyes: Corneal and conjunctival crystals (pathognomonic)

  • Funduscopic examination: Possible presence of peripheral retinopathy that is more severe on the temporal side than on the nasal side

  • Biopsy of the kidney with histologic examination: Changes vary with disease stage

Imaging studies

  • Renal ultrasonography: Obtain in patients with elevated urine calcium excretion to rule out nephrocalcinosis

  • Radiography of kidneys, ureters, and bladder: To evaluate possible urinary tract calcifications in patients with hypercalciuria or as a diagnostic evaluation of severe abdominal pain

  • Computed tomography scanning and magnetic resonance imaging: To evaluate adult patients with infantile nephropathic cystinosis with central nervous system symptoms

See Workup for more detail.

Management

Cysteamine blunts the decline in renal function and improves the linear growth of children with nephropathic cystinosis, despite the fact that it does not ameliorate the defect in renal tubule transport. Oral therapy should be initiated as soon as the diagnosis is made.

Pharmacotherapy

Cysteine-depleting agents are used in the management of nephropathic cystinosis. Oral cysteamine therapy postpones the need for renal transplantation, whereas ophthalmic cysteamine is used to manage ocular complications such as corneal cystine crystals.

Indomethacin may limit water losses in patients with nephropathic cystinosis by both reducing the glomerular filtration rate and by sensitizing the collecting duct to the effects of antidiuretic hormone. It has been used to treat patients with cystinosis more commonly in Europe than in the United States. Careful monitoring of kidney function is required for this agent, because the glomerular filtration rate may be worsened by its administration. The ulcerogenic potential of indomethacin is its major drawback for treating cystinosis.

Treatment with recombinant human growth hormone improves growth velocity in young children with nephropathic cystinosis prior to renal replacement therapy. Growth hormone treatment is less effective for peripubertal/adolescent patients on renal replacement therapy.

Thyroid replacement is indicated in patients diagnosed with hypothyroidism.

Supportive therapy

Supportive care in the management of nephropathic cystinosis includes the following:

  • Replacement of urinary losses (eg, hydration, potassium and bicarbonate supplementation, vitamin D and phosphate supplementation; carnitine)

  • Management of volume depletion/dehydration states

Surgery

Kidney transplantation in patients with infantile cystinosis corrects kidney failure and prolongs survival (the donor parenchymal cells are not homozygous for the genetic defect and are therefore able to transport cystine from the lysosomes). However, transplantation does not prevent progression of the disease in other nonrenal organs, and therapy with oral cysteamine is indicated in patients after kidney transplantation. Management of cystinosis with oral cysteamine must be initiated as soon as diagnosis of cystinosis is made.

Some patients with severe gastroesophageal reflux and cystinosis may require gastric/jejunal tube placement or Nissen fundoplication to achieve optimal nutrition.

See Treatment and Medication for more detail.

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 cystino An 8-month-old male infant at the time his cystinosis is diagnosed.
The same child as in the previous image, at age 20 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 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 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 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 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, presenting as Fanconi syndrome, usually between age 6-12 months. Proximal tubules are particularly susceptible to the adverse effects of cystine accumulation. Fanconi syndrome is characterized by wasting of substances not reabsorbed in the proximal tubule, 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.

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 400 individuals 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 other races around the globe.

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).

 

Presentation

History

Cystinosis is classified into 2 general phenotypes: nephropathic and nonnephropathic cystinosis (benign variant).

  • Nephropathic cystinosis is further subdivided into infantile and late-onset (intermediate cystinosis), based on the age at presentation.

    • Nephropathic infantile cystinosis is the most common and most severe variant.

      • Symptoms of multiorgan involvement may be mild to severe, depending on the patient's age at diagnosis, the age when treatment was instituted and genetic factors.

      • Early in the natural history of infantile nephropathic cystinosis, clinical involvement follows a fairly predictable chronology. Patients usually present during the first year of life with polyuria, polydipsia, dehydration, metabolic acidosis (normal anion gap hyperchloremic acidosis), hypophosphatemic rickets, failure to thrive, and laboratory findings consistent with Fanconi syndrome. If untreated, renal failure develops by age 7-10 years.

      • Oral cysteamine therapy postpones the need for renal transplantation.

      • Renal transplantation has prolonged the lives of children with cystinosis. Renal transplantation is highly successful, disease does not recur in the graft, but cystine continues to accumulate in other tissues, resulting in such complications as eye disease (eg, severe photophobia, corneal ulcerations, retinal blindness), delayed puberty, hypothyroidism, pancreatic disease (eg, exocrine insufficiency, insulin-dependent diabetes mellitus), liver disease (eg, hepatosplenomegaly, nodular degenerative hyperplasia), distal vacuolar myopathy, swallowing difficulties, and CNS involvement (eg, calcifications, atrophy, pseudotumor cerebri).

    • Late-onset (intermediate) nephropathic cystinosis is a more indolent form of the disease. The age at manifestation is later; most commonly in early adolescence. Symptoms are usually restricted to kidneys (eg, less severe form of Fanconi syndrome, proteinuria) and eyes (eg, photophobia). Progression of the disease is slower; end-stage renal disease (ESRD) occurs after age 15 years.

  • Nonnephropathic cystinosis is considered a benign variant and is usually diagnosed by an ophthalmologist treating patients for photophobia. Photophobia may not begin until middle age and is not usually as debilitating as in the nephropathic form of the disease. Slit-lamp examination reveals corneal crystal deposits. In addition to the eye, cystine crystals are present in the bone marrow and leukocytes but are absent in the kidney and the retina.

Physical

A typical cystinotic patient has pale blond hair and blue eyes, although the disease also occurs among dark-haired individuals with brown eyes.

  • Initial presentation of infantile nephropathic cystinosis

    • The initial symptoms include polydipsia, polyuria, vomiting, loss of appetite, constipation, and failure to thrive.

    • The first signs may go unrecognized for several months until the patient develops severe dehydration, electrolyte imbalance, and metabolic acidosis during a mild illness. Some children may have recurrent bouts of fever and manifestations of heat intolerance (becoming red like beets) caused by a defect in sweat production.

    • Patients typically have short stature and renal Fanconi syndrome.

    • They have poor appetite, crave salty and hot and spicy foods, and prefer specific food textures. Each patient has specific food preferences that may already be evident by age 2 years.

  • Initial presentation of late-onset nephropathic (intermediate) cystinosis

    • Most cases are diagnosed by age 12 years.

    • Complete Fanconi syndrome often does not develop in late-onset cystinosis, but renal function deteriorates as in infantile nephropathic cystinosis, and patients often experience end-stage renal failure within a few years of diagnosis.

  • Nephropathic cystinosis (progressive disease)

    • Children younger than 1 year usually show growth retardation, rickets, metabolic acidosis, and other chemical evidence of renal tubular abnormalities, such as increased renal excretion of glucose, amino acids, phosphate, and potassium. They may require frequent hospital admissions because of dehydration.

    • As children age, failure to thrive is prominent. Without specific therapy, children remain below the third percentile in both height and weight throughout life.

    • Corneal crystals are apparent by age 1-2 years. The untreated cornea is packed with crystals by age 3-4 years, leading to photophobia in early childhood.

    • By age 7-10 years, previously noted symptoms become more severe, and patients develop increased proteinuria, progressive renal failure, increased photophobia, and thyroid insufficiency.

    • ESRD develops in adolescence, usually at age 10-13 years. The good adherence to therapy slows down the progression of renal failure by several more years.

    • Sexual maturation is delayed.

    • Males have hypogonadism and are infertile.

    • Retinal damage does not occur until the second or third decade of life.

    • Cerebral calcifications and muscular and swallowing difficulties cluster around the third decade of life.

    • The major complication of cystinosis in patients older than 20 years is legal blindness, distal vacuolar myopathy, cerebral calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).

Causes

See the list below:

  • All forms of cystinosis have autosomal recessive patterns of inheritance. Cystinosis is caused by a defect in transport of cystine across the lysosomal membrane due to defective function of the lysosomal membrane protein cystinosin, resulting from mutations of the cystinosis gene (CTNS). CTNS resides on chromosome 17p13. The CTNS gene has 12 exons, the last 10 of which code for cystinosin.

  • Cystinosin (an integral lysosomal membrane protein) has 367 amino acids and 7 transmembrane domains. In nephropathic cystinosis patients, CTNS mutations can cause either an absence of cystinosin or a disruption of transmembrane domains and loss of protein function, leading to inhibition of cystine transport through the lysosomal membrane (which is carrier-dependent). More than 80 different CTNS mutations (missense, nonsense, splice-site, deletion, and promoter mutations) are described in patients with nephropathic cystinosis; the most common are 57 kilobases (kb) (approximately 60% of the mutations in US patients).

  • Mutations of CTNS that affect functionally unimportant regions of cystinosin account for a milder clinical course. The various CTNS mutations can explain why patients have a wide spectrum of clinical symptomatology.

  • The parents of patients with cystinosis are obligate heterozygotes for cystinosis; they each carry a single gene for the disease. Individuals heterozygous for cystinosis have never been reported to have cystine crystals in any tissue or cell. Despite the clinically normal appearance of individuals who are heterozygous for cystinosis, their polymorphonuclear cells contain an increased amount of cystine.

  • Late-onset (intermediate) cystinosis appears to be due to the inheritance of a mutation known to cause infantile disease in one allele and a relatively less clinically severe mutation in the other or due to the inheritance of a relatively less severe mutation in both alleles.

 

Workup

Laboratory Studies

See the list below:

  • Serum electrolyte measurements are used to detect the presence of acidosis (hyperchloremic, normal anion gap [see the Anion Gap calculator]) and severity of hypokalemia, hyponatremia, hypophosphatemia, and low bicarbonate concentration in patients with cystinosis.

  • Blood gases may be used to detect metabolic acidosis and the degree of respiratory compensation.

  • Urine testing reveals low osmolality, glucosuria, and tubular proteinuria (including generalized amino aciduria).

  • Measurements of urine electrolytes serve to detect the loss of bicarbonate and phosphaturia.

  • Diagnosis of cystinosis is confirmed by measuring cystine levels in polymorphonuclear leukocytes or cultured fibroblasts. Cystine concentrations in individuals who are homozygous for cystinosis are 5-10 nmol half-cystine/mg cell protein; in heterozygous individuals, the levels are less than 1 nmol half-cystine/mg cell protein. Reference range levels are below 0.2 nmol half-cystine/mg cell protein.

  • When a fetus is at risk for cystinosis, the cystine level can be measured in chorionic villi or cultured amniotic fluid cells.

Imaging Studies

See the list below:

  • Renal ultrasonography should be obtained in patients with elevated urine calcium excretion to rule out nephrocalcinosis.

  • Radiography for kidneys, ureters, and bladder (KUB) may be needed to evaluate possible urinary tract calcifications in patients with hypercalciuria or as a diagnostic evaluation of severe abdominal pain.

  • CT scanning and MRI are used to evaluate adult patients with infantile nephropathic cystinosis who have CNS symptoms.

Other Tests

See the list below:

  • Slit-lamp examination of the eyes reveals corneal and conjunctival cystine crystals (pathognomonic for cystinosis) as early as age 1 year, although photophobia does not usually become apparent until age 3-6 years.

  • Examination of the eye fundi may reveal the presence of peripheral retinopathy that is more severe on the temporal than on the nasal side. In some patients, retinopathy may lead to blindness.

Histologic Findings

See the list below:

  • The kidney appears particularly susceptible to the adverse effects of cystine accumulation in cystinosis. The morphologic changes in the kidney vary with the stage of the disease.

  • Early in the course of the disease, renal tubules are disorganized and poorly developed, even before the clinical onset of Fanconi syndrome. A "swan neck" deformity, or thinning of the first part of proximal convoluted tubule develops after age 6 months and becomes apparent during the first years of life, correlating with the clinical onset of the Fanconi syndrome; however, this finding is not unique to cystinosis.

  • Swan neck lesions are characterized by thinning of the tubular epithelial cells and progression to glomerulo-tubular disconnection, leading to formation of atubular glomeruli. Disconnection of glomeruli from the tubules leads to failure of filtration from that nephron. Widespread atubular glomeruli result in progressive failure of filtration. Progressive formation of atubular glomeruli may explain slow progression to end-stage renal disease.

  • A cystinotic kidney manifests different stages of destruction, depending on the stage of chronic kidney injury. Giant cell transformation of the glomerular visceral epithelium with occasional peculiar "dark" cells (unique to the cystinotic kidney) and cytoplasmic inclusions may be seen. Hyperplasia and hypertrophy of the juxtaglomerular apparatus may correlate with functional alterations of the renin-angiotensin system. With the help of polarizer attachment to the light microscope, birefringent rectangular to polygonal crystals of cystine are readily apparent, especially in interstitial cells, but they have also been observed in glomerular and tubular cells.

  • Later in the course of cystinosis, in the uremic phase, varying degrees of global and segmental sclerosis, tubular atrophy and degeneration, chronic interstitial nephritis, interstitial fibrosis, and abundant crystal deposition are pronounced. The kidneys are small, echodense, and have a tendency to form cysts. Kidneys from patients with late-onset nephropathic disease resemble those with advanced changes in the infantile form.

  • In order to see cystine crystals, the biopsy sample must be fixed in ethanol, not in an aqueous solution, because water dilutes crystals. In general, a kidney biopsy is not necessary in cystinosis, unless the renal disease deviates from the expected course.

  • Kidneys from patients with benign adult cystinosis do not demonstrate any abnormalities.

 

Treatment

Medical Care

In the past, the treatment of cystinosis was limited to treating metabolic acidosis and, often, replacing electrolytes lost in the urine; later during the course of the disease, chronic kidney disease (CKD) was treated.[2] Today, the wide availability of an effective drug, phosphocysteamine, and kidney replacement therapy with transplantation has dramatically improved the outlook for patients and altered management strategies.

  • Replacement of urinary losses: The child must be well-hydrated and administered supplements of potassium and bicarbonate, as needed. Rickets should be treated with vitamin D and phosphate supplementation. Carnitine may also be needed because its excretion is particularly elevated in the urine, and muscle levels have been documented to be reduced. Particular care should be given to fluid and electrolyte therapy during intercurrent episodes of fever, vomiting, or diarrhea.

  • Management of volume depletion/dehydration states

    • Initial management of volume depletion in a child with cystinosis requires administration of large amounts of fluids and electrolytes, often exceeding conventionally defined limits. Fluid requirements may be more than twice that expected for the patient's size.

    • Urinary losses must be carefully monitored and replaced during hospitalization.

    • The rehydration fluid should contain glucose, sodium, potassium, and bicarbonate (in amounts generously exceeding the standard intravenous fluid composition). The concentration of these substances should be adjusted on the basis of frequently measured serum laboratory values.

    • After rehydration is accomplished, maintaining free access to water or other fluids is important because patients with cystinosis easily become dehydrated. For example, place a water container at the bedside during the night.

    • When the patient becomes free of acute GI symptoms (ie, no longer having frequent episodes of vomiting, gagging, abdominal pain, or diarrhea) and is able to eat well, restart the patient on a regular diet, supplementing individually determined amounts of sodium, potassium, bicarbonate, and phosphate to achieve reference range serum levels.

  • Cysteamine therapy

    • Delayed-release cysteamine bitartrate (Procysbi) is available for the management of nephropathic cystinosis, the most severe form of the rare genetic disorder cystinosis, in patients aged 2 years and older. Its approval was based on a study that showed the delayed-release formulation (q12h) was as effective as the immediate-release formulation (Cystagon) (q6h) in controlling cystine levels in 43 children aged 6 years or older and adults with nephropathic cystinosis. An extension of this trial enrolled 13 children aged 2-6 years who converted from immediate-release cysteamine to delayed-release. Mean WBC cystine decreased from 1.4 nmol to 1.13 nmol. Seven of the 13 patients achieved < 1 nmol.[3]

  • Indomethacin therapy

    • Indomethacin may limit water losses in patients with nephropathic cystinosis by both reducing the glomerular filtration rate (GFR) and by sensitizing the collecting duct to the effects of antidiuretic hormone. It has been used to treat patients with cystinosis more commonly in Europe than in the United States. In uncontrolled clinical reports, indomethacin has been shown to relieve polyuria and polydipsia and to improve appetite, energy, and general well-being by reducing urinary losses of water and other various substances.

    • Indomethacin therapy requires careful monitoring of kidney function because the GFR may be worsened by the administration of this drug.

    • The ulcerogenic potential of indomethacin is its major drawback for treating cystinosis.

  • Growth hormone therapy

    • Treatment with recombinant human growth hormone improves growth velocity. Long-term recombinant human growth hormone treatment in young children with nephropathic cystinosis prior to renal replacement therapy is safe and efficient.

    • Growth hormone treatment is less effective for peripubertal or adolescent patients on renal replacement therapy.

    • Treatment with recombinant human growth hormone does not accelerate a decline in kidney function in children with chronic kidney disease.

  • Thyroid replacement: This is indicated in patients diagnosed with hypothyroidism.

  • Kidney transplantation: Kidney transplantation in patients with infantile cystinosis corrects kidney failure and prolongs survival (the donor parenchymal cells are not homozygous for the genetic defect and are therefore able to transport cystine from the lysosomes). However, transplantation does not prevent progression of the disease in other nonrenal organs, and therapy with oral cysteamine is indicated in patients after kidney transplantation. Management of cystinosis with oral Cystagon must be initiated as soon as diagnosis of cystinosis is made.

  • Management of corneal cystine crystals

    • Ocular complications associated with deposition of corneal cystine crystals include photophobia, eye pain, squinting, corneal haziness and foreign body sensations. Severe cystine crystal accumulation can damage the cornea, resulting in serious vision difficulties. Oral cysteamine is not distributed into the eye and thus has no impact on corneal crystal accumulation.

    • Cysteamine ophthalmic solution 0.44% (Cystaran) was approved by the US Food and Drug Administration (FDA) in October 2012 for corneal cystine crystal accumulation in patients with cystinosis.[4] Corneal crystals reaccumulate if cysteamine ophthalmic solution is discontinued.

Images demonstrating the course of cystinosis are shown below.

An 8-month-old male infant at the time his cystino An 8-month-old male infant at the time his cystinosis is diagnosed.
The same child as in the previous image, at age 20 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 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 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 The same child as in the previous images, at age 9 years, off total parenteral nutrition for 1 year and tolerating oral intake.

Surgical Care

See the list below:

  • Some patients with severe gastroesophageal reflux may require gastric/jejunal tube placement or Nissen fundoplication to achieve optimal nutrition.

Consultations

See the list below:

  • Nephrologists usually diagnose cystinosis as the cause of Fanconi syndrome.

  • The patient must be referred to an ophthalmologist upon initial evaluation and at subsequent regular intervals.

  • Regular follow-up by pediatric nutritionist is recommended in patients with poor growth.

  • A pediatric endocrinologist may provide follow-up care for the patient related to growth hormone therapy, thyroid insufficiency, or diabetes mellitus.

  • Patients with recurrent abdominal pain, poor feeding, or vomiting and/or diarrhea should be evaluated by a gastroenterologist to diagnose the nature of GI abnormalities (eg, swallowing dysfunction, gastroesophageal reflux, delayed gastric emptying, gastric/duodenal ulcer, pseudo-obstruction).

  • Some children may require follow-up care by a behavioral therapist or a dietitian, depending on the child's needs.

  • Because of various neuromuscular problems, patients in late adolescence require follow-up by a neurologist.

  • Patients should be referred to an early intervention program to evaluate and treat common fine-motor movement and coordination delays.

Diet

See the list below:

  • Dietary recommendations should follow daily Dietary Reference Intake (DRI) requirements (ie, 60% carbohydrate, 10% protein, 30% lipids), and caloric intake should aim to achieve weight gain. If the patient is a poor eater and oral feeding is unsuccessful, high-calorie oral supplements should be administered. If the patient does not take supplements or has an inappropriately low intake because of poor appetite or vomiting, gastric tube placement can help.

  • Total parenteral nutrition is indicated if a cystinotic patient cannot tolerate any form of enteral feeding. Some patients may need additional therapy with agents improving GI kinetics or antagonists of acid production.

Activity

Because of the chronic nature of the disorder, parents should try to accommodate the child's medical needs, while allowing the child to grow and develop similar to healthy children. Parents should encourage play and group participation.

 

Medication

Medication Summary

Cysteamine, introduced in the 1980s, blunts the decline in renal function and improves the linear growth of these children, despite the fact that it does not ameliorate the defect in renal tubule transport. Oral therapy should be initiated as soon as the diagnosis is made. The delayed-release capsule (Procysbi) allows twice daily dosing (ie, q12h), whereas the immediate-release capsule (Cystagon) has to be administered every 6 hours, including throughout the night, to prevent nocturnal accumulation of cystine.

Some cystinosis patients treated with high dose cysteamine are reported to develop skin, vascular, neurologic, muscular, and bone lesions. These lesions improved after dose reduction.[5]

Cysteamine ophthalmic solution 0.44% (Cystaran) must be administered to each eye every hour while awake.

Cystine-depleting agents

Class Summary

Cysteamine is an aminothiol compound used to treat cystinosis. Various cysteamine salts are used. Cysteamine HCl has an unpleasant taste and odor, and, therefore, other forms have been developed. Cysteamine bitartrate (Cystagon, Procysbi) are available in the United States. Another form, phosphocysteamine, is the phosphorothioester of cysteamine and is rapidly converted to cysteamine in the gut. Phosphocysteamine is designated as an orphan drug in the United States. Much of the clinical data refers to cysteamine HCl or phosphocysteamine.

In addition to the oral products that are available, an ophthalmic product was approved by the FDA in October 2012 to decrease corneal cystine crystals, which develop with nephropathic cystinosis.[4]

Cysteamine (Cystagon, Procysbi)

Used as a cystine-depleting agent in cystinosis. It is a weak base that enters the cystinotic lysosome and reacts with cystine, forming a mixed disulfide of half-cystine and cysteamine. This mixed disulfide rapidly exits the lysosome via the transport system for cationic amino acids, which is normal in cystinosis. Cysteamine and its prodrug analog, phosphocysteamine, are very beneficial to patients with cystinosis, especially when started early in life. Therapy does not prevent or affect Fanconi syndrome. Diagnosis of cystinosis as early as possible is important because efficacy of cysteamine or phosphocysteamine treatment clearly relates to age at which the drugs are started.

Goal of therapy is to keep leukocyte cystine levels < 1 nmol/half-cystine/mg protein measured 5-6 h following administration of cysteamine. Check cystine levels after maintenance dose is achieved; then check every 3 mo; if cysteamine is poorly tolerated initially because of GI tract symptoms or transient rashes, temporarily stop therapy; restart at lower dose and gradually increase to proper dose. Dose is expressed as free base of drug. Cystagon (immediate-release) was approved by the FDA in August 1994. The sole distributor of this drug in the United States is CVS Procare (888-700-0024). Procysbi (delayed-release) was approved in April 2013 and will also be distributed by a specialty pharmacy service (Raptor Cares).

Cysteamine ophthalmic (Cystaran)

Cysteamine ophthalmic is a cystine-depleting agent indicated for corneal cystine crystal accumulation in patients with cystinosis. It converts cystine to cysteine-cysteamine mixed disulfides and reduces corneal cystine crystal accumulation.

 

Follow-up

Further Outpatient Care

See the list below:

  • Most patients receive follow-up care by a pediatric nephrologist, who usually undertakes the role of primary care provider because of the complexity of problems.

  • Patients should be seen on a regular basis, depending on the age of the patient and the spectrum of multisystem involvement. The visits should be coordinated with other subspecialists involved in the care.

    • The leukocyte cystine content should be measured every 3 months, depending on the previous levels. The goal is less than 1-2nmol/half-cystine/mg cell protein .

    • Blood chemistry should be monitored initially every other week for the first month and then monthly for 6 months; when chemistry remains stable, laboratory follow-up testing can be done less frequently, every 2-3 months.

    • During the office visits, the patient should be monitored for growth and weight gain, possible electrolyte abnormalities, renal function, and for nonrenal complications of cystinosis.

    • Ophthalmic examination should be performed every year to monitor corneal crystals and to rule out idiopathic intracranial hypertension.

    • If the linear growth velocity is not improved within a year of therapy and the height remains below the third percentile, recombinant human growth hormone therapy should be considered.

    • Thyroid function should be monitored to detect hypothyroidism.

Further Inpatient Care

See the list below:

  • Patients with nephropathic cystinosis may require many hospitalizations as a result of severe electrolyte imbalance during recurrent episodes of dehydration from vomiting, diarrhea, or infection. Some patients may also have severe failure to thrive, requiring total parenteral nutrition if gastric tube feedings are not tolerated.

Inpatient & Outpatient Medications

A typical patient with cystinosis takes 2-11 medications daily.

  • All patients with cystinosis require lifetime therapy with cysteamine (oral form, ophthalmic drops).

  • Patients with Fanconi syndrome require urine losses replacements, including the following:

    • Sodium replacement

    • Bicarbonate replacement

    • Potassium replacement

    • Phosphate supplements

  • In addition, the following agents are commonly used:

    • Prokinetic agents and/or dyspeptic agents

    • Vitamin D

    • Indomethacin

    • Growth hormone

    • Thyroid compounds

    • Carnitine

Patients who have renal transplants, require immunosuppressive therapy and need to continue oral cysteamine and ophthalmic drops

Late complications of cystinosis need to be treated accordingly.

Complications

See the list below:

  • Before renal transplantation, nonrenal complications of infantile cystinosis include photophobia, corneal crystals, hypothyroidism, and short stature.

  • After renal transplantation, nonrenal complications include photophobia, corneal crystals, hypothyroidism, polyneuropathy, distal myopathy, CNS abnormalities, renal stones, and diabetes mellitus. Among the more unusual complications noted in the literature are pulmonary fibrosis, nodular degenerative hyperplasia of the liver, and hearing loss.

Prognosis

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  • In the early 1960s, nephropathic cystinosis was considered a fatal renal disease of childhood; patients died of progressive renal failure before age 10 years. The natural history of the disease has changed dramatically since the introduction of cysteamine and renal transplantation. Patients with infantile cystinosis now survive into even the fifth decade of life. Cysteamine markedly slows the progression of renal failure.

  • The study results from a large European cohort showed improved survival of renal function and better patient and graft survival in children with nephropathic cystinosis who received renal replacement therapy compared with those who did not. The 5-year survival rate after the start of renal replacement therapy improved from 86.1% (prior to 1990) to 100% (since 2000).[6]

Patient Education

See the list below:

  • Because of the chronic and rare nature of the disease, allowing the parents of patients with cystinosis full access (eg, handouts to take home, library card) to current articles on the disease is critical. Parents may also join the Cystinosis Research Network, the Cystinosis Research Foundation, or the Cystinosis Foundation to become familiar with the disease, to exchange their knowledge, and to bond their children with peers who also have cystinosis.