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

Area of Science:

• Nephrology
• Genetics
• Pediatric Medicine

Background:

• Mutations in hepatocyte nuclear factor 1B (HNF1B) are a primary genetic cause of congenital kidney malformations.
• HNF1B mutations are linked to renal tubular dysfunction, notably magnesium wasting and hypomagnesemia.
• Hypomagnesemia's utility in diagnosing HNF1B mutations is age-dependent, being less reliable in pediatric patients.

Purpose of the Study:

• To investigate the age-dependent development of hypomagnesemia and other biochemical abnormalities in pediatric patients with HNF1B mutations.
• To determine if biochemical changes associated with HNF1B mutations manifest differently across pediatric age groups.

Main Methods:

• Retrospective analysis of clinical, biochemical, and genetic data from pediatric patients with renal malformations undergoing HNF1B mutation testing.
• Patients were stratified into four age groups to assess age-related biochemical changes.
• Data were excluded for patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m² or post-transplantation.

Main Results:

• HNF1B mutations were identified in 52 out of 199 pediatric patients.
• While plasma magnesium differed significantly between mutation-positive (mut+) and mutation-negative (mut-) groups across all ages, overt hypomagnesemia was only evident in the latter half of childhood in the mut+ group.
• Significant differences in median potassium concentrations, with lower values in the mut+ cohort, were observed in late childhood.

Conclusions:

• Abnormal tubular electrolyte handling in HNF1B mutations progresses with age, indicating a generalized distal convoluted tubule dysfunction.
• The findings suggest a phenotype similar to Gitelman syndrome.
• The absence of hypomagnesemia or other electrolyte abnormalities in early childhood should not exclude HNF1B mutations from diagnostic consideration.