AUTHOR INFORMATION

Section 1 of 12

Authored by Ewa Elenberg, MD, Assistant Professor, Department of Pediatrics, Renal Section, Texas Children's Hospital, Baylor College of Medicine

Ewa Elenberg, MD, is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, and American Society of Nephrology

Edited by Uri S Alon, MD, Director of Research and Education, Children's Mercy Hospital of Kansas City; Professor, Department of Pediatrics, Division of Pediatric Nephrology, University of Missouri at Kansas City; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Adrian Spitzer, MD, Professor, Department of Pediatrics, Albert Einstein College of Medicine; Director of NIH Training Program, Children's Hospital at Montefiore Medical Center; Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Professor, Department of Pediatrics, Division of Nephrology, Albert Einstein College of Medicine; and Craig B Langman, MD, Professor, Department of Pediatrics, Northwestern University School of Medicine; Head, Division of Kidney Diseases, Children's Memorial Hospital of Chicago

Author's Email:	Ewa Elenberg, MD
Editor's Email:	Uri S Alon, MD

eMedicine Journal, June 13 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 12

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, adolescent, and adult. Patients with the infantile nephropathic form of cystinosis (the most common and the most severe) develop symptoms early on in life and renal failure by late childhood.

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 a defective lysosomal integral membrane protein, cystinosin, which function is to transport cystine out of the lysosomes. Due to the defect in cystinosin, cystine cannot leave the lysosomes and is accumulated 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. This leads eventually to Fanconi syndrome, characterized by wasting of substances reabsorbed in this nephron segment, such as sodium, potassium, phosphate, calcium, magnesium, bicarbonate, and others. Metabolic acidosis and electrolyte disturbances ensue and contribute to the stunting in growth of children with cystinosis. Cystinosis is the most common inherited cause of Fanconi syndrome.

Frequency:

• In the US: In North America, the incidence of infantile nephropathic cystinosis is 1 case per 100,000-200,000 live births; an estimated 300-400 children in the United States have cystinosis.

• Internationally: The incidence of cystinosis is higher in certain subpopulations. France's Brittany province has an estimated incidence of 1 case out of 26,000 population, compared to incidence in the rest of France of 1 case per 326,440 population. The incidence rate of infantile and adolescent cystinosis in the former Federal Republic of Germany was reported at approximately 1 case per 179,000 live births.

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. 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 the linear growth of 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. Yet, many patients survive into the third or fourth decade of life and are able to pursue fulfilling lifestyles.

Race: Cystinosis is often considered a disease of fair-skinned individuals of European descent, but it is known to occur in blacks, Hispanics, and people of Middle Eastern descent. It has also been described in at least one Chinese and several Japanese patients.

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 adolescent form, symptoms are evident at the age of 8-12 years and the progression is slow. The adult form of cystinosis does not include renal involvement.

CLINICAL

Section 3 of 12

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 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 in children, 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 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 central nervous system involvement (eg, calcifications, atrophy, pseudotumor cerebri).
  
  
  
• Late-onset (intermediate) nephropathic cystinosis is a more indolent form of the disease. The first symptoms most commonly appear at 8-12 years of age. The features of Fanconi syndrome are less severe, and end-stage renal disease occurs after 15 years of age.



• 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 usually is not 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.

• 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 preferences that may already be evident by the age of 2 years.
  
  
  
• Initial presentation of late-onset nephropathic (intermediate) cystinosis


• • Most cases are diagnosed by 12 years of age.
  
  
  
  • 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 - A 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 3-4 years of age, leading to photophobia in early childhood.
  
  
  
  • By age 7-10 years, previously noted symptoms become more severe and patients develop renal failure, increased photophobia, and thyroid insufficiency.
  
  
  
  • Sexual maturation is almost always late.
  
  
  
  • 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 myopathy, cerebral calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).
  
  
  

Causes: 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 has been mapped to chromosome arm 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 either cause an absence of cystinosin or disruption of transmembrane domains and loss of protein function, leading to inhibition of cystine transport through the lysosomal membrane (which is carrier-dependent). So far, more than 80 different CTNS mutations (missense, nonsense, splice site, deletion, and promoter mutations) are described in nephropathic cystinosis patients, with the most common being 57 kb (~60% of the mutations in American patients).

Patients with a mild form of cystinosis that is diagnosed when patients are younger than 7 years or patients with late-onset (intermediate) cystinosis have mutations of CTNS that affect functionally unimportant regions of cystinosin, accounting for a milder clinical course. The variety of CTNS mutations can explain why the 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 the inheritance of a relatively less severe mutation in both alleles.

DIFFERENTIALS

Section 4 of 12

Other Problems to be Considered:

Cystinosis may initially be misdiagnosed as dehydration caused by vomiting and diarrhea, failure to thrive, fever of unknown origin, Bartter syndrome, diabetes mellitus, diabetes insipidus, dwarfism, rickets, or brain tumor.

WORKUP

Section 5 of 12

Lab Studies:

• Serum electrolyte measurements are used to detect the presence of acidosis (hyperchloremic, normal anion gap) and severity of hypokalemia, hyponatremia, hypophosphatemia, and low bicarbonate concentration.



• 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 1.0 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:

• 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:

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

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, becomes apparent during the first years of life and correlates with the clinical onset of the Fanconi syndrome, although this finding is not unique to cystinosis. A cystinotic kidney manifests different stages of destruction, with giant cell transformation of the glomerular visceral epithelium and occasional peculiar "dark" cells (unique to the cystinotic kidney) and cytoplasmic inclusions. 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.

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

TREATMENT

Section 6 of 12

Medical Care: In the past, the treatment of cystinosis was limited to replacement of substances lost in the urine and, later during the course of the disease, to the treatment of chronic renal failure. The availability of an effective drug, cysteamine, and of renal replacement therapy has drastically changed the management of these patients.

• 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. Particular care should be given to fluid and electrolyte therapy during episodes of fever, vomiting, or diarrhea.



• Manage dehydration
  • Initial management of dehydration in a cystinotic child requires administration of large amounts of fluids and electrolytes, often exceeding so-called acceptable limits. Fluid requirements may be more than twice that expected for the patient's size.

  • Urinary losses must be meticulously monitored and replaced during hospitalizations.

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

  • After rehydration is accomplished, maintaining free access to water or other fluids is important because cystinotic patients 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 eats well, restart the patient on a regular diet, supplementing individually determined amounts of sodium, potassium, bicarbonate, and phosphate to achieve reference range serum levels.



• Indomethacin
  • Indomethacin is used to treat cystinotic patients in Europe and is reported to relieve polyuria and polydipsia and to improve appetite, energy, and general well-being by reducing urinary losses of various substances.

  • Indomethacin therapy requires careful monitoring of renal function that may be decreased by the administration of this drug.

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

• Growth hormone
  • 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 the rise in creatinine independently of cysteamine treatment.

• Thyroid replacement is indicated in patients diagnosed with hypothyroidism.

• Renal transplantation for infantile cystinosis corrects renal failure and prolongs survival (the donor parenchymal cells are not homozygous for the genetic defect; therefore, they are able to transport cystine from the lysosomes). However, transplantation does not prevent progression of the disease in other nonrenal organs.

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

Consultations:

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



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



• 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.

Diet: Dietary recommendations should follow daily adult (RDA) 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

Section 7 of 12

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 cysteamine (Cystagon) therapy should be initiated within days of diagnosis. Topical cysteamine therapy to the anterior segment of the eye now is undergoing clinical trials.

Drug Category: Cystine-depleting agents -- Cysteamine is an aminothiol compound used to treat cystinosis. In addition to the PO product that is available, an ophthalmic product is currently investigational. Topical cysteamine therapy administered to the anterior segment of the eye is being studied to observe the results of decreasing corneal cystine crystals, which develop with nephropathic cystinosis.

Drug Name	Cysteamine (Cystagon) -- Approved by the FDA in August 1994, the sole distributor of this drug in the United States is CVS Procare (1-888-700-0024). Used as a cystine-depleting agent in cystinosis. Cysteamine 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 analog, phosphocysteamine, are very beneficial to patients with cystinosis, especially when started early in life. Cysteamine 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. In patients who tolerate cystine-depleting therapy, leukocyte cystine values have been reduced by almost 80%. Because of the offensive smell and taste of cysteamine-phosphocysteamine, some patients cannot tolerate it. Adverse effects may include nausea, vomiting, duodenal ulcer, seizures, rash, and leukopenia. 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. Available as 50-mg and 150-mg cap.
Adult Dose	>50 kg: Maintenance dose: 500 mg/dose PO q6h Administer 1/4 to 1/6 of maintenance dose initially; then increase gradually over 4-6 wk to avoid intolerance and achieve a leukocyte cystine level <1.0 nmol half-cystine/mg protein
Pediatric Dose	<12 years: Maintenance dose: 1.3-1.95 g/m2/d (about 60–90 mg/kg/d) PO divided q6h May sprinkle cysteamine cap contents over food >12 years and >50 kg: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported; can be administered with electrolyte and mineral and vitamin D and thyroid hormone replacements necessary for management
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Can cause occasional reversible leukopenia and abnormal liver function studies; monitor blood counts and perform liver function studies; because of adverse GI effects, therapy may have to be interrupted and the dose adjusted; may cause CNS symptoms (eg, seizures, lethargy, somnolence, depression, encephalopathy)

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• 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.

Further Outpatient Care:

• 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.
  
  
  
  • Blood chemistry should be monitored initially every other week for the first month and then monthly for 6 months and 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.
  
  
  

In/Out Patient Meds:

• A typical patient with cystinosis takes 2-11 medications daily. Most severely affected patients are treated with the following agents:


• • Cysteamine (oral form, ophthalmic drops - investigational)
  
  
  
  • Sodium chloride
  
  
  
  • Sodium bicarbonate
  
  
  
  • Potassium chloride
  
  
  
  • Phosphate supplements
  
  
  
  • Prokinetic agents and/or H2 blockers and/or dyspeptic agents
  
  
  
  • Vitamin D
  
  
  
  • Indomethacin
  
  
  
  • Growth hormone

  • Thyroid compounds
  
  
  

Complications:

• 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:

• In the early 1960s, nephropathic cystinosis was considered a fatal renal disease of childhood; patients died of progressive renal failure before the age of 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 the second and third decades of life. Cysteamine markedly slows the progression of renal failure.

Patient Education:

• 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 or Cystinosis Foundation to become familiar with the disease, to exchange their knowledge, and to bond their children with peers who also have cystinosis.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to consider a diagnosis of cystinosis in any young patient who presents with Fanconi syndrome, recurrent severe dehydration, or failure to thrive

Special Concerns:

• Pregnancy has been successful in a patient with cystinosis. Couples should have a consultation with a geneticist prior to conceiving to determine the partner's phenotype. Administration of cysteamine should be stopped during pregnancy because of the drug's unknown effect on the fetus.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A 10-month-old blond boy discharged from the hospital 3 days earlier is scheduled for a follow-up examination at his physician's office. The infant was hospitalized with his third episode of dehydration in the last 2 months. His mother seems to provide appropriate home care; the infant is at home with his mother and is fed baby food. The infant's mother considers him to be a picky eater, and, over the past few months, the infant has had frequent episodes of vomiting and irritability. He drinks juice eagerly, but his mother has been trying not to offer him too many liquids in order to improve his appetite for solid foods. A month ago, the physician noticed that the child had not gained weight since the previous visit at 6 months, which was attributed to recent episodes of dehydration related to acute gastroenteritis. Current serum electrolytes reveal hyponatremia, hypokalemia, and hypophosphatemia. Urinalysis reveals a specific gravity of 1.005, glucosuria, and proteinuria; the rest of the laboratory findings are normal. The child appears irritable but not dehydrated. To which of the following specialists should the physician refer this patient for further workup and diagnosis?

A: Gastroenterologist
B: Endocrinologist
C: Neurologist
D: Nephrologist
E: No need for further workup, current abnormalities are due to recent dehydration

The correct answer is D: A nephrologist should see this patient because the multiple electrolyte abnormalities suggest a renal cause. The patient presents with typical features of generalized dysfunction of the proximal tubule transport, Fanconi syndrome, which impairs reabsorption of sodium, potassium, phosphate, glucose, amino acids, and bicarbonate. Typically, patients with nephropathic cystinosis present clinically with episodes of recurrent dehydration, failure to thrive, and irritability due to thirst. No history of diarrhea suggests stool losses of above-mentioned electrolytes; thus, a visit to a gastroenterologist is not indicated until after cystinosis is diagnosed. A gastroenterologist should then treat the patient`s failure to thrive. Endocrinologists frequently treat these patients for hypothyroidism associated with cystinosis. Neurologists usually become involved later in the care of some of these patients to treat their distal myopathy or neuropathy.

CME Question 2: A 12-month-old blond patient is hospitalized for episodes of recurrent dehydration and failure to thrive. On chest examination, the physician notices rachitic rosaries. Blood and urine electrolytes suggest Fanconi syndrome. The physician suspects that the child may have cystinosis. Which of the following tests would be useful to perform during this hospitalization, prior to sending out the polymorphonuclear cells for cystine determination?

A: Urine cystine level
B: Abdominal radiography to rule out stones
C: Slit-lamp examination of cornea
D: Renal ultrasonography
E: ECG

The correct answer is C: Slit-lamp examination of the cornea can be performed by an experienced ophthalmologist. Corneal crystals are deposited early in cystinosis, and they can usually be detected in children younger than 12 months.

Pearl Question 1 (T/F): Nephropathic cystinosis is the most common cause of Fanconi syndrome in childhood.

The correct answer is True: Nephropathic cystinosis is the most common cause of Fanconi syndrome in childhood. Fanconi syndrome is characterized by a generalized dysfunction of proximal tubule transport, which impairs reabsorption of amino acids, glucose, sodium, potassium, phosphate, bicarbonate, and urate.

Pearl Question 2 (T/F): Typically, children with nephropathic cystinosis have blue eyes and blond hair.

The correct answer is True: Nephropathic cystinosis is commonly found in children with fair complexions, blue eyes, and blond hair, although it has also been described in Hispanics, blacks, and others.

Pearl Question 3 (T/F): The most common features of the clinical presentation of nephropathic cystinosis are failure to thrive, polydipsia, polyuria, and episodes of dehydration.

The correct answer is True: The most common features of clinical presentation of nephropathic cystinosis are failure to thrive, polydipsia, polyuria, and episodes of dehydration. These symptoms are caused by the large volume of water loss through the proximal tubule, leading to large water intake and suppressed appetite, thus causing lack of appropriate calorie intake and resulting in failure to thrive.

Pearl Question 4 (T/F): Metabolic acidosis, hypokalemia, hyponatremia, and hypophosphatemia are the 4 electrolyte abnormalities observed in nephropathic cystinosis.

The correct answer is True: The 4 electrolyte abnormalities that can be observed in nephropathic cystinosis are metabolic acidosis, hypokalemia, hyponatremia, and hypophosphatemia. They result from lack of reabsorption of these electrolytes by the abnormally functioning proximal tubule.

PICTURES

Section 11 of 12

Caption: Picture 1. An 8-month-old male infant at the time his cystinosis is diagnosed.
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Caption: Picture 2. Cystinosis. The same child as in Image 1, at 20 months of age, fed via gastric tube.
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Caption: Picture 3. Cystinosis. The same child as in Images 1-2, at age 3 years, fed via jejunal tube.
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Caption: Picture 4. Cystinosis. The same child as in Images 1-3, at age 4 years, on total parenteral nutrition via central line.
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Caption: Picture 5. Cystinosis. The same child as in Images 1-4, at age 9 years, off total parenteral nutrition for 1 year and tolerating oral intake.
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BIBLIOGRAPHY

Section 12 of 12

• Almond PS, Matas AJ, Nakhleh RE: Renal transplantation for infantile cystinosis: long-term follow-up. J Pediatr Surg 1993 Feb; 28(2): 232-8[Medline].
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