Cystinuria: hexagonal crystals in a young stone former

Nephrolithiasismedium

A 17-year-old boy is evaluated for nephrolithiasis. Two weeks ago, CT for right flank pain showed a 4-mm right distal ureteral stone with mild hydronephrosis and a 1.2-cm staghorn calculus in the left kidney. He passed the stone 3 days ago; it is yellow and 3.5 mm long. His paternal grandfather had kidney stones. Potassium is 4.8 mEq/L, total CO₂ 24 mEq/L, creatinine 1.1 mg/dL, and calcium 9.1 mg/dL. Urinalysis shows pH 6.0, 2+ blood, and negative protein, leukocyte esterase, and nitrite. In addition to sending the stone for analysis, which finding would best establish the diagnosis?

  1. A.Anhidrosis and periumbilical angiokeratomas on skin exam
  2. B.Crystalline deposits in the cornea on eye exam
  3. C.Ash leaf spots and facial angiofibromas on skin exam
  4. D.Hexagonal crystals on urine microscopyCorrect

Explanation

Finding hexagonal crystals on urine microscopy would best establish the diagnosis of cystinuria. This adolescent has a staghorn calculus without infection, a passed yellow stone, and a family history of stones, a picture typical of cystinuria. Cystinuria is an autosomal recessive (occasionally incompletely recessive) disorder caused by pathogenic variants in SLC3A1 or SLC7A9, which encode the subunits of the proximal tubular transporter for cystine and the dibasic amino acids ornithine, lysine, and arginine. Cystine is poorly soluble at the usual urine pH, with solubility of about 250 mg/L at pH 7 and rising sharply only above pH 7.5, so affected patients form recurrent, often large and bilateral, stones from childhood or adolescence. Cystine stones are yellow to amber with a waxy appearance, are faintly radiopaque, and frequently form staghorn calculi. Flat hexagonal crystals on urine microscopy are pathognomonic, although they are seen in only about a quarter of patients; a positive cyanide-nitroprusside screen and quantitative 24-hour urine cystine excretion (typically above 400 mg/day in homozygotes) confirm the diagnosis. Treatment includes high fluid intake to keep cystine concentration below its solubility, urine alkalinization with potassium citrate to a pH of 7.0 to 7.5, sodium and protein restriction, and thiol drugs such as tiopronin when needed. Ash leaf spots and facial angiofibromas indicate tuberous sclerosis complex, which causes angiomyolipomas and cysts and occasionally uric acid or calcium stones, but not staghorn stones in this pattern. Corneal crystalline deposits are characteristic of nephropathic cystinosis, a lysosomal storage disease caused by CTNS variants. Despite the similar name, cystinosis causes Fanconi syndrome and progressive kidney failure in childhood, not cystine stones, and his normal bicarbonate, potassium, and creatinine argue against it. Anhidrosis and periumbilical angiokeratomas suggest Fabry disease, which causes proteinuric CKD, cardiomyopathy, and neuropathy rather than nephrolithiasis.

Why each option

A.
Anhidrosis and periumbilical angiokeratomas suggest Fabry disease, an X-linked lysosomal disorder causing proteinuric CKD, cardiomyopathy, and neuropathy rather than kidney stones.
B.
Corneal crystals indicate nephropathic cystinosis, a lysosomal disease causing Fanconi syndrome and childhood kidney failure, not cystine nephrolithiasis.
C.
Ash leaf spots and angiofibromas indicate tuberous sclerosis, which causes angiomyolipomas and cysts rather than recurrent staghorn stones in adolescence.
D.
Correct. A yellow passed stone and a staghorn calculus in an adolescent suggest cystinuria, and hexagonal urine crystals are pathognomonic for cystine.

Reference: Eisner BH, J Endourol 2020 (consensus statement on evaluation and medical management of cystine nephrolithiasis); Pearle MS, J Urol 2014 (AUA guideline on medical management of kidney stones)

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