Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease

Abstract

Introduction: In humans, heterozygous mutations of hepatocyte nuclear factor 1beta (HNF1B) are responsible for a dominant inherited disease with both renal and extrarenal phenotypes. HNF1B nephropathy is the umbrella term that includes the various kidney phenotypes of the disease, ranging from congenital anomalies of the kidney and urinary tract (CAKUT), to tubular transport abnormalities, to chronic tubulointerstitial and cystic renal disease.

Methods: We describe 7 families containing 13 patients with ascertained HNF1B nephropathy. All patients underwent genetic testing and clinical, laboratory, and instrumental assessment, including renal imaging and evaluation of extrarenal HNF1B manifestations.

Results: Significant inter- and intrafamilial variability of HNF1B nephropathy has been observed. In our cohort, HNF1B pathogenic variants presented with renal cysts and diabetes syndrome (RCAD); renal cystic phenotype mimicking autosomal dominant polycystic kidney disease (ADPKD); autosomal dominant tubulointerstitial kidney disease (ADTKD) with or without hyperuricemia and gout; CAKUT; and nephrogenic diabetes insipidus (NDI). Of note, for the first time, we describe the occurrence of medullary sponge kidney (MSK) in a family harboring the HNF1B whole-gene deletion at chromosome 17q12. Genotype characterization led to the identification of an additional 6 novel HNF1B pathogenic variants, 3 frameshift, 2 missense, and 1 nonsense.

Conclusion: HNF1B nephropathy may present with a highly variable renal phenotype in adult patients. We expand the HNF1B renal clinical picture to include MSK as a potential new finding. Finally, we expand the allelic repertoire of the disease by adding novel HNF1B pathogenic variants.

Keywords: ADPKD; ADTKD; CAKUT; HNF1B; RCAD; cystic kidney disease; medullary sponge kidney; nephrogenic diabetes; tubulointerstitial nephritis.

Graphical abstract

Figure 1

Pedigrees of families showing affected and unaffected individuals and HNF1B testing results. In the lower part of the figure, the HNF1B gene variants for each family are listed.

Figure 2

(a) I-1, family 1: computed tomography (CT) scan showing enlarged bilateral cysitc kidneys, left renal stone. (b) II-1, family 1: magnetic resonance imaging (MRI) scan showing multiple small bilateral kidney cysts in normal sized kidneys. (c) II-1, family 2: CT scan showing bilateral small kidneys and few cysts. (d) I-1, family 3: MRI scan showing bilateral small kidneys and annular pancreas (white arrow). (e) III-1, family 5: CT scan showing bilateral normal sized kidneys and several cysts. (f) I-1, family 6: CT scan showing right kidney hypoplasia with cysts, including multiple cysts in the left kidney and annular pancreas (white arrow).

Figure 3

Computed tomography scan of (a) I-1 and (b) I-2 of family 6: insets show magnification of left kidney with nephrocalcinosis and cystic dilatation of the renal medullary collecting ducts.