Hypouricemia and hyperuricosuria in a pubescent girl: Answers

Hypouricemia, defined as serum uric acid (UA) levels < 2 mg/dl, can result from decreased UA production, but is more commonly due to decreased renal tubular UA reabsorption. The fractional excretion of uric acid (FE-UA) can be used to evaluate the mechanism of hypouricemia. Decreased FE-UA means that UA production has declined, while an increased FE-UA indicates decreased reabsorption or increased renal excretion of UA. Hypouricemia caused by defects in the purine degradation pathway (hereditary xanthinuria) is characterized by normal or low FE-UA together with elevated excretion of xanthine in urine.

In this case, the decreased serum UA together with markedly elevated FE-UA led us to suspect renal hypouricemia (RHUC), or secondary causes such as Fanconi syndrome, cystinosis, and/or inappropriate antidiuretic hormone secretion syndrome. These secondary conditions could be ruled out using various clinical and biochemical tests. Both hereditary conditions, RHUC and xanthinuria, are characterized by extremely low concentrations of UA.

Initially, the diagnosis of RHUC is determined based on hypouricemia with elevated FE-UA. Secondly, RHUC is confirmed by molecular genetic analysis of the SLC22A12 (RHUC type 1, OMIM no. 220150) and SLC2A9 genes (RHUC type 2, OMIM no. 612076) [1, 2]. Dysfunctional variants in the SLC22A12 gene, encoding the renal tubular uric acid transporter URAT1, are the major cause of renal hypouricemia (> 90%). In addition, unpublished allelic variants in URAT1 and GLUT9 (encoded by SLC2A9) proteins have usually been confirmed as pathogenic RHUC variants through in vitro functional studies using the Xenopus oocyte expression system [3].

RHUC patients have been described in different ethnic groups and in geographically noncontiguous countries. To date, more than 150 patients with loss-of-function variants in the SLC22A12 gene have been reported, most of whom are Asian: the predominant dysfunctional variant p.W258X has been associated with RHUC1 in Japanese and Korean patients with high frequencies 2.30–2.37% [4, 5]. However, two other dysfunctional SLC22A12 variants, c.1245_1253del (p.L415_G417del) and c.1400C>T (p.T467M), associated with RHUC1, are frequently found in the Roma populations of Czech Republic, Slovakia, and Spain, with frequencies of 1.92 and 5.56%, respectively [6‐8]. In detail, a Slovakian cohort of 802 subjects showed a frequency of 1.48% for deletion c.1245_1253del and 5.62% for the c.1400C>T substitution; a Czech cohort of 154 subjects showed frequencies of 2.78% for deletion c.1245_1253del and 3.51% for the c.1400C>T substitution; and a Spanish cohort of 60 subjects showed frequencies of 4.17% for deletion c.1245_1253del and 9.17% for the c.1400C>T substitution. These dysfunctional variants were not detected in a control cohort of 640 individuals (non-Roma Czech population) [7].

No treatment is available; however, allopurinol has been recently used to prevent recurrence of acute kidney injury episodes, and oral supplementation with antioxidants is also recommended [9]. Patients should be advised to avoid vigorous exercise and to drink plenty of fluids after exercise.