Unmasking the Mimickers: HNF1B Variants in Pediatric Kidney Diseases

Introduction: Hepatocyte nuclear factor 1 beta (HNF1B) variants are associated with a spectrum of phenotypic manifestations including renal, pancreatic, and metabolic disorders. These variants can pose diagnostic dilemmas due to their diverse clinical presentations, often mimicking other congenital kidney conditions. Case Description: A retrospective case series of 12 pediatric patients (age 4 months to 10 years) referred to our Renal Genetics Clinic with varied kidney phenotypic findings ultimately attributed to heterozygous disease-causing HNF1B variants. Each case exhibited unique clinical features, including cystic and non-cystic renal abnormalities, early-onset diabetes, and abnormal liver tests. Table 1 lists the clinical, laboratory, and kidney imaging findings at clinical presentation. Genetic investigation revealed two types of HNF1B defects: (i) whole gene deletion (67%); and (ii) truncating or missense variant predicted to be pathogenic (33%), which were de novo in all cases but one. Discussion: Our findings highlight the importance of considering HNF1B variants in the differential diagnosis of pediatric patients presenting with structural kidney abnormalities with or without cystic kidney disease or specific multisystemic features. Despite disparate presentations, the genetic evaluation revealed a unifying etiology in all cases. Enhanced awareness of the protean nature of HNF1B-related disorders is valuable for accurate prognostication and optimization of multidisciplinary management strategies. Table 1 - Pt Variant Cystic Non-Cystic Abn LFT DM ↓ Mg ↑ U GD FH 1 c.494G>A: p.R165H - + + + - - + - 2 17q12 deletion + - - - - - - - 3 c.26C>T: p.Q9* + - - - - - - + 4 17q12 deletion + - - - - - - - 5 17q12 deletion - + - - + - - - 6 whole gene deletion + - - - - - - - 7 17q12 deletion - + - - - - - - 8 whole gene deletion + - - - - - + - 9 c.395A>G: p.H132R + - + - - - + - 10 c.826C>T: p.R276* - + - - - - + - 11 17q12 deletion + - - - + + - - 12 whole gene deletion - + - - - - - - Key: Cystic = cystic renal disease, Non-Cystic = non-cystic/functional renal disease, Abn LFT = abnormal liver test, DM = diabetes, ↓ Mg = hypomagnesemia, ↑ U = hyperuricemia, GD = growth delay, FH = family history