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 m 2 , 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.

Inherited Tubulopathies of the Kidney

“…For instance, mutations impairing the function of the basolateral Na 1 -K 1 -ATPase seem to predominantly affect magnesium transport. Mutations in the a (ATP1A1) (53) or g (FXYD2) (54) subunit, or in their regulators, such as HNF1B (55), manifest primarily with hypomagnesemia, although a trend to a Gitelman-like tubulopathy may be observed (56). Presumably, this reflects the critical role of the DCT for magnesium homeostasis, whereas other segments may be able to compensate more with regards to sodium (57).…”

Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations

“…These electrolyte imbalances developed with age and became apparent in late childhood. In addition, abnormal tubular electrolyte handling associated with HNF1B mutations was not restricted to magnesium and potassium, but was rather consistent with a more generalized dysfunction of the distal convoluted tubule indicative of the Gitelman syndrome [ 11 ]. It is known that patients with HNF1B mutations usually exhibit a slowly progressive deterioration of renal function throughout adulthood, and it is known that progression to ESRD is rare in childhood [ 3 , 4 ].…”

“…A UK study validated the clinical utility of this score in a large number of referrals for HNF1B genetic testing and obtained a negative predictive value of 85% by applying a cutoff score of ≥8 [ 23 ]. In a follow-up UK study, HNF1B scores were recalculated after adjustment for the latest available magnesium concentration, and the percentage of patients with a score ≥ 8 increased to more than 90% in the older age group [ 11 ]. In our study, two patients (14%) at onset and one patient (7%) at the time of genetic diagnosis had a HNF1B score < 8 and would have been not eligible for genetic testing when a cutoff score of ≥8 was applied.…”

“…Cystic kidney disease, including cystic dysplasia, is the predominant form of CAKUT associated with HNF1B mutations [ 5 ]. Electrolyte imbalances, such as hypomagnesemia, hypokalemia, and hyperuricemia, are also a common feature of HNF1B mutations [ 3 , 10 , 11 ].…”

Bartter and Gitelman syndromes: Questions of class

“…Unfortunately, these questions are difficult to address, as such a phenotypic Bswitch^has not been described in the Clc-k2 (the murine orthologue of CLCNKB) knock-out mice or any other animal model [5,40]. Yet, clinical observations in other salt-wasting disorders have shown a similar development with time of the DCT phenotype, e.g., in EAST/ SeSAME syndrome and the HNF1B-related tubulopathy [41,42]. Further observations, coupled with investigations in the occasionally available biopsy tissue, or of Bliquid^biopsies, e.g., urinary exosomes, may provide further insights over time.…”