HNF1B Mutations Are Associated With a Gitelman-like Tubulopathy That Develops During Childhood

Abstract

Background: Mutations in the transcription factor hepatocyte nuclear factor 1B (HNF1B) are the most common inherited cause of renal malformations, yet also associated with renal tubular dysfunction, most prominently magnesium wasting with hypomagnesemia. The presence of hypomagnesemia has been proposed to help select appropriate patients for genetic testing. Yet, in a large cohort, hypomagnesemia was discriminatory only in adult, but not in pediatric patients. We therefore investigated whether hypomagnesemia and other biochemical changes develop with age.

Methods: We performed a retrospective analysis of clinical, biochemical, and genetic results of pediatric patients with renal malformations tested for HNF1B mutations, separated into 4 age groups. Values were excluded if concurrent estimated glomerular filtration rate (eGFR) was <30 ml/min per 1.73 m², or after transplantation.

Results: A total of 199 patients underwent HNF1B genetic testing and mutations were identified in 52 (mut+). The eGFRs were comparable between mut+ and mut- in any age group. Although median plasma magnesium concentrations differed significantly between mut+ and mut- patients in all age groups, overt hypomagnesemia was not present until the second half of childhood in the mut+ group. There was also a significant difference in median potassium concentrations in late childhood with lower values in the mut+ cohort.

Conclusions: The abnormal tubular electrolyte handling associated with HNF1B mutations develops with age and is not restricted to magnesium, but consistent with a more generalized dysfunction of the distal convoluted tubule, reminiscent of Gitelman syndrome. The absence of these abnormalities in early childhood should not preclude HNF1B mutations from diagnostic considerations.

Keywords: HNF1B; alkalosis; children; hypokalemia; hypomagnesemia; renal tubular function.

Figure 1

Funnel diagram of patient identification. Shown is the number (n) of patients included in the analysis. A total of 199 patients with renal malformations were identified that had testing for HNF1B performed. After exclusion of those without an available glomerular filtration rate (GFR; measured or estimated) and those with a GFR of <30 ml/min per 1.73 m², 30 mut+ and 89 mut− patients remained with biochemical values suitable for analysis. eGFR, estimated glomerular filtration rate.

Figure 2

Plasma electrolyte abnormalities in mut+ patients develop over time. Shown are box plots for the plasma concentrations of (a) magnesium (Mg), (b) potassium (K), (c) chloride (Cl), and (d) bicarbonate (TCO2) according to the 4 age groups. Box plot graphs represent the median and interquartile range (IQR); the upper and lower whiskers include data points within 1.5 × IQR. Outliers are plotted individually. The blue boxes represent the mut− group, and the red boxes represent mut+. The respective normal range is represented by the transparent blue boxes. Note the development with increasing age of a Gitelman-like tubulopathy with hypomagnesemia and hypokalemic, hypochloremic metabolic alkalosis in the mut+ group. For number of patients for each plot and results of statistical comparisons, see Table 1.

Figure 3

Magnesium levels in individual patients over time. Plotted are all plasma magnesium measurements included in the analysis with individual patients represented by colored lines, if more than 1 measurement was available. Note the decreasing plasma magnesium levels in the mut+ group, whereas no such trend is noticeable in the mut− group.