Cystinosis

Background

• Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene, resulting in accumulation of the amino acid cystine within lysosomes of all cells.
• It is the most common inherited cause of Fanconi syndrome in children. Emergency physicians encounter cystinosis patients presenting with severe dehydration, electrolyte crises (hypokalemia, metabolic acidosis, hypophosphatemia), renal failure, hypoglycemia, and complications of chronic kidney disease and multiorgan involvement.
• Incidence approximately 1 in 100,000-200,000 live births
• Caused by loss-of-function mutations in CTNS (chromosome 17p13.2), encoding cystinosin, a lysosomal membrane cystine transporter
• Defective cystinosin → cystine cannot exit lysosomes → intralysosomal cystine accumulation → intracellular crystal formation → progressive cellular dysfunction and organ damage
• Kidneys are the first and most severely affected organ; proximal tubule cells are uniquely vulnerable
• Without treatment, end-stage renal disease (ESRD) by age 10-12 years
• With early cysteamine therapy, renal survival is significantly improved and many patients now survive into adulthood, though they develop progressive extrarenal complications
• Not the same as cystinuria (a separate disorder of renal cystine transport causing kidney stones)

Three clinical forms

Form	Frequency	Onset	Key features
Infantile (nephropathic)	~95%	6-12 months	Fanconi syndrome → ESRD by 10-12 yr; systemic disease
Juvenile (intermediate)	~5%	Late childhood/adolescence	Slower progression; may present with proteinuria alone
Adult (ocular/non-nephropathic)	Rare	Adulthood	Corneal crystals and photophobia only; no renal disease

Clinical features

What the EM physician will see

Infant/young child (most common ED presentation)

• Presentation typically at 6-18 months with features of Fanconi syndrome:
  • Polyuria, polydipsia (often severe)
  • Severe dehydration and volume depletion (the primary reason for ED visits in young children)
  • Recurrent vomiting
  • Failure to thrive, growth retardation
  • Unexplained fevers (from dehydration)
  • Constipation alternating with diarrhea
• Rickets: bowed legs, widened wrists, bone pain, pathologic fractures (from phosphate wasting + impaired vitamin D activation)
• Blonde hair and fair complexion — characteristically lighter pigmentation than siblings (impaired melanin synthesis from cystine accumulation)

Older child/adolescent/adult

• Chronic kidney disease — may present with complications of CKD/ESRD (fluid overload, hyperkalemia, uremia, pulmonary edema)
• Post-transplant complications — kidney transplant does NOT cure cystinosis; cystine continues to accumulate systemically
• Progressive extrarenal complications (see below)

Electrolyte emergencies (any age)

• Hypokalemia — may be severe and life-threatening (from Fanconi syndrome renal wasting)
• Metabolic acidosis — non-anion gap, hyperchloremic (proximal type 2 RTA)
• Hypophosphatemia
• Hyponatremia (from renal sodium wasting and free water excess)
• Hypoglycemia (especially in infants during intercurrent illness)

Extrarenal manifestations (progressive with age)

• Ocular: corneal cystine crystals visible on slit-lamp examination — pathognomonic finding that can clinch the diagnosis; photophobia, tearing, blepharospasm, retinal depigmentation
• Endocrine: hypothyroidism (most common; >70% of patients), insulin-dependent diabetes mellitus (pancreatic involvement), hypogonadism, delayed puberty
• Muscular: progressive distal myopathy, dysphagia and swallowing dysfunction (risk of aspiration pneumonia — a potentially lethal complication)
• Neurologic: encephalopathy, cognitive impairment, seizures, intracranial calcifications, cerebral atrophy
• Hepatic: hepatomegaly, portal hypertension (nodular regenerative hyperplasia)
• Pulmonary: restrictive lung disease from myopathy

Differential diagnosis

Infant with failure to thrive, polyuria, and dehydration

• Diabetes mellitus (type 1)
• Diabetes insipidus
• Bartter syndrome
• Other causes of Fanconi syndrome (see Fanconi syndrome#Differential diagnosis)
• Galactosemia
• Tyrosinemia
• Urinary tract infection/pyelonephritis
• Child abuse/neglect

Older child/adult with CKD

• Other causes of Chronic kidney disease
• IgA nephropathy
• Reflux nephropathy
• Focal segmental glomerulosclerosis

Renal tubular disorders

• Salt-wasting tubulopathies
  • Gitelman syndrome — distal convoluted tubule (NCC defect); hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis
  • Bartter syndrome — thick ascending limb (NKCC2/ROMK/ClC-Kb defect); hypokalemia, hypercalciuria, metabolic alkalosis
  • Liddle syndrome — collecting duct (ENaC gain-of-function); hypokalemia, hypertension, metabolic alkalosis
• Renal tubular acidosis
  • Renal tubular acidosis type I (distal) — hypokalemia, metabolic acidosis, nephrocalcinosis
  • Renal tubular acidosis type II (proximal) — hypokalemia, metabolic acidosis, Fanconi syndrome
  • Renal tubular acidosis type IV — hyperkalemia, metabolic acidosis, hypoaldosteronism
• Inherited disorders of tubular transport
  • Cystinuria — proximal tubule amino acid transport defect; recurrent cystine stones
  • Fanconi syndrome — proximal tubule generalized dysfunction; glucosuria, aminoaciduria, phosphaturia
  • Nephrogenic diabetes insipidus — collecting duct (aquaporin/V2R defect); polyuria, hypernatremia
  • Dent disease — proximal tubule (ClC-5 defect); low molecular weight proteinuria, nephrocalcinosis
• Acquired tubulopathies
  • Diuretic use/abuse (thiazide mimics Gitelman; loop mimics Bartter)
  • Aminoglycosides nephrotoxicity
  • Cisplatin nephrotoxicity
  • Amphotericin B nephrotoxicity
  • Lithium-induced nephrogenic DI

Evaluation

EM workup

• BMP: hypokalemia, hypophosphatemia, low bicarbonate (non-anion gap metabolic acidosis), elevated creatinine/BUN, hyponatremia
• Blood glucose: hypoglycemia (especially infants)
• ABG/VBG: non-anion gap metabolic acidosis (proximal RTA)
• Urinalysis:
  • Glycosuria with normal serum glucose (hallmark of Fanconi syndrome)
  • Generalized aminoaciduria, proteinuria (low-molecular-weight)
  • Phosphaturia
• CBC: may show anemia of CKD
• Calcium, magnesium, phosphate, uric acid, vitamin D, PTH
• TSH, free T4: hypothyroidism is common and may be undiagnosed
• ECG: if hypokalemia or hyperkalemia suspected

Diagnostic clue for the undiagnosed child

• Slit-lamp examination: corneal cystine crystals (refractile, needle-shaped crystals in the corneal stroma) — visible by approximately 1 year of age; pathognomonic for cystinosis
• If cystinosis is suspected, order white blood cell (WBC) cystine level — the gold standard diagnostic and monitoring test (normal <0.2 nmol half-cystine/mg protein; cystinosis patients typically 3-23 nmol)
• Confirmed by CTNS gene mutation analysis
• These confirmatory tests are NOT available in the ED but should be arranged via nephrology/genetics referral

When to suspect cystinosis in the ED

• Infant (6-18 months) with unexplained failure to thrive + polyuria + severe dehydration + metabolic acidosis
• Child with Fanconi syndrome (glycosuria + aminoaciduria + phosphaturia + bicarbonaturia) — cystinosis is the most common inherited cause
• Blonde child who is lighter than siblings with renal disease
• Any patient with corneal crystals on eye examination

Management

Acute ED management

• Dehydration: aggressive IV fluid resuscitation — cystinosis children can have massive free water losses from polyuria and may need large volumes
  • Use isotonic saline initially; switch to maintenance fluids with appropriate electrolyte composition once volume repleted
  • Caution: these patients may lose 2-3 L/m²/day of free water; calculate maintenance + ongoing losses carefully
• Hypokalemia:
  • IV and PO potassium repletion
  • May be refractory due to ongoing renal losses
  • Continuous cardiac monitoring if K⁺ <3.0 mEq/L
• Metabolic acidosis:
  • IV sodium bicarbonate for severe acidosis (pH <7.2)
  • Replete potassium FIRST or concurrently (bicarbonate worsens hypokalemia)
• Hypophosphatemia:
  • IV phosphate if severe (<1 mg/dL) or symptomatic
  • Oral phosphate supplementation for less acute presentations
• Hypoglycemia: IV dextrose
• Hypothyroidism: ensure patient is on levothyroxine if known cystinosis patient; do not discontinue
• Hyperkalemia/uremia/fluid overload (in ESRD patients): manage per standard CKD emergency protocols; dialysis if indicated

Disease-specific therapy

• Cysteamine (cysteamine bitartrate; Cystagon, Procysbi) — the only disease-modifying therapy
  • Depletes intralysosomal cystine by forming a mixed disulfide that can exit lysosomes via an alternative transporter
  • Do NOT discontinue cysteamine in the ED unless there is a specific contraindication — missed doses lead to cystine reaccumulation
  • If the patient cannot take oral medications (vomiting, intubation), contact their nephrologist/metabolic specialist for guidance on holding cysteamine
  • Common side effects: GI upset (nausea, vomiting, diarrhea), breath/body odor (sulfurous), skin rash
  • Cysteamine does not reverse established Fanconi syndrome; it slows progression to ESRD and delays extrarenal complications
• Cysteamine eye drops (Cystadrops): topical treatment for corneal cystine crystals; patients may present with ocular complaints if drops are missed
• Indomethacin (1-3 mg/kg/day): used in some patients to reduce polyuria/prostaglandin-mediated renal losses
  • Discontinue during acute dehydration or illness — can worsen renal function
  • Do NOT combine with ACE inhibitors — risk of acute GFR decline

Intercurrent illness ("sick day" management)

• Cystinosis patients are at high risk for rapid, severe dehydration during any intercurrent illness (gastroenteritis, febrile illness) due to their massive baseline renal water losses
• Low threshold for admission and IV fluids
• Monitor electrolytes frequently (q4-6 hours) during acute illness
• Hold indomethacin during dehydration
• Continue cysteamine if tolerated; if not, resume as soon as possible

Disposition

• Severe dehydration, significant electrolyte abnormalities, or hemodynamic instability: admit for IV resuscitation, continuous monitoring, serial electrolytes
• Infant with new-onset failure to thrive + Fanconi syndrome features: admit for evaluation and stabilization; nephrology and genetics consultation
• Known cystinosis patient with mild dehydration responding to IV fluids, stable electrolytes: may consider discharge with close follow-up if reliable caregiver, PO tolerance established, and outpatient team notified
• Any intercurrent illness in an infant/young child with cystinosis: low threshold for admission — these patients decompensate quickly
• ESRD complications (hyperkalemia, pulmonary edema, uremia): admit; nephrology/dialysis consultation
• Aspiration pneumonia (from progressive myopathy/dysphagia): admit; may need ICU if respiratory failure
• Ensure cysteamine is continued (or restarted ASAP)
• Communicate with the patient's nephrology/metabolic team — these patients are followed closely and their specialists should be notified of all ED visits

See Also

• Fanconi syndrome
• Fanconi anemia (a completely different condition)
• Renal tubular acidosis
• Hypokalemia
• Metabolic acidosis
• Chronic kidney disease
• Failure to thrive
• Cystinuria

External Links

• StatPearls — Cystinosis
• Orphanet J Rare Dis — Cystinosis: a review (2016)
• Nat Rev Nephrol — The renal Fanconi syndrome in cystinosis (2017)
• Cystinosis Research Network
• Fanconi Anemia Research Fund (for distinguishing from Fanconi anemia)