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.[1] 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.[2]
  • Incidence approximately 1 in 100,000-200,000 live births[1]
  • 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[2]
  • 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[1]
  • 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)[3]
    • 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)[4]

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[2]
  • 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)[4]
  • 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

Older child/adult with CKD


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
  • 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[2]
  • 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)[1]
  • 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[3]
    • 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[1]
    • 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[1]

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[3]
  • 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[3]
  • 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

External Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Cystinosis. StatPearls. 2024. PMID: 39548762
  2. ↑ 2.0 2.1 2.2 2.3 Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347(2):111-121. doi:10.1056/NEJMra020552
  3. ↑ 3.0 3.1 3.2 3.3 Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol. 2008;23(6):863-878. doi:10.1007/s00467-007-0535-x
  4. ↑ 4.0 4.1 Elmonem MA, et al. Cystinosis: a review. Orphanet J Rare Dis. 2016;11:47. doi:10.1186/s13023-016-0426-y
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