Hereditary xanthinuria (HX) is a rare autosomal recessive disorder of purine metabolism. It results from deficiency of the enzyme ‘xanthine dehydrogenase/oxidase (XDH/XO)’ which catalyzes the final two steps in the purine degradation pathway (conversion of hypoxanthine and xanthine to uric acid). The resultant plasma accumulation and excess urinary excretion of xanthine is responsible for the arthropathy, myopathy, crystal nephropathy, urolithiasis, and renal failure seen in this disorder. Most patients belong to Middle East or Mediterranean region, and the disorder is rare in other parts of the world [1,2]. Two types of HX have been described; type I and type II, based on distinct mutation loci. It is difficult to distinguish the two subtypes on clinical and biochemical grounds, and molecular testing is needed for accurate phenotyping [1].

A 13-month-old male child, presented with recurrent episodes of orange colored graveluria and hematuria since the age of nine months. The child was born of a second-degree consanguineous marriage and family history was negative. Examination revealed a healthy appearing child with length 78 cm (75th centile) and weight 8.8 kg (10th-25th centile). The general and systemic examination was unremarkable.

Investigations revealed serum calcium 10.2 mg/dL, phosphorus 5.6mg/dL, alkaline phosphatase 678 IU/L, creatinine 0.4 mg/dL, blood urea 10 mg/dL, hypouricemia (serum uric acid <0.01 mg/dL) and hypouricosuria (24 hour urinary uric acid 0.4 mg/day, normal 250-750 mg/day; 24 hour urinary creatinine 88 mg/day, normal 88-106 mg/day). Radiograph of kidney ureter and bladder was normal, while ultrasonography revealed two calculi in the urinary bladder and concretions in the lower pole of left kidney. In view of low serum and urinary uric acid levels and radiolucent nature of renal stones, xanthinuria was suspected. His hospital course was complicated by urethral obstruction which was relieved by catheterization followed by cystolithotomy at a later date. The bladder stones retrieved were subjected to X-ray diffraction study, revealing them to be of xanthine origin. A targeted gene sequencing revealed compound heterozygous mutation in the enzyme molybdenum cofactor sulfurase (MOCOS) gene [heterozygous two base pair deletion in exon 6 (chr18:33785104_33785105delCT) and heterozygous nonsense mutation in exon 11 (chr18:33831134T>G)]. Patient was diagnosed to be having HX type II and advised dietary purine restriction (avoidance of purine-rich foods including red and organ meat, shell fish, oily fish, seafood, sweetened beverages such as fruit juices and colas, yeast and mushroom, spinach, peas and whole pulses), and adequate oral hydration.

On follow-up, he had no further episodes of renal colic, graveluria or hematuria. The child maintained good compliance to dietary restrictions advised. His height and weight at nine years were 138.7cm (75th-97th percentile), and 32.1 kg (75th-97th percentile), respectively. Serial annual ultrasonography imaging and renal functions have remained normal with serum uric acid <0.01 mg/dL.

HX is a rare disorder of the purine metabolism that leads to urolithiasis. Renal stones can occur at any age, even in infancy [2]. The stones are radiolucent, and are seen in about 40-50% patients with this disorder. The diagnosis may be established with stone analysis, demonstration of an elevated urinary xanthine or hypoxanthine excretion, and measurement of XDH/XO activity in liver or intestinal biopsy sample. The finding of an orange-brown urinary sediment, orange-stained diapers, and profound hypouricemia are other important indicators. However, it is difficult to characterize the exact phenotype of the disorder (type I or II) based on these clinical and biochemical indicators alone, necessitating the use of molecular tests.

The mainstay of treatment is institution of a low-purine diet, and intake of plenty of oral fluids [3]. Urinary alkalinization is of minimal therapeutic value, as the solubility of xanthine is only minimally enhanced at alkaline pH. Our patient showed excellent treatment response over a long follow up of nine years, which is in line with the short-term follow-up response reported in the literature [4,5].

To conclude, HX is a rare disorder of purine metabolism which should be suspected in children presenting with orange colored graveluria, hypouricemia, hypouricosuria and radiolucent renal stones. Molecular testing is essential for exact phenotyping, and should be pursued in all cases. Such children show excellent response to treatment with low purine diet and increased oral hydration, as exemplified in the case described.

Contributors: SK: collected and analyzed the data and drafted the manuscript; AG: conceptualized the case report, drafted and edited the manuscript; RS: collected and analyzed the data, drafted and edited the manuscript. RK: conceptualized the case report and edited the manuscript.

Funding: None; Competing interest: None stated.

References

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2. Badertscher E, Robson WL, Leung AK, Trevenen CL. Xanthine calculi presenting at 1 month of age. Eur J Pediatr. 1993;152:252-54.

3. Gargah T, Essid A, Labassi A, Hamzaoui M, Lakhoua MR. Xanthine urolithiasis. Saudi J Kidney Dis Transpl. 2010; 21:328-31.

4. Fujiwara Y, Kawakami Y, Shinohara Y, Ichida K. A case of hereditary xanthinuria type I accompanied by bilateral renal calculi. Intern Med. 2012;51:1879-84.

5. Arikyants N, Sarkissian A, Hesse A, Eggermann T, Leumann E, Steinmann B. Xanthinuria type I: a rare cause of urolithiasis. Pediatr Nephrol. 2007;22:310-4.