Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations

Abstract

HNF1B mutations, one of the most common causes of congenital anomalies of the kidney and urinary tract, manifest as various renal and extrarenal phenotypes. We analyzed the genotype-phenotype correlations in 14 pediatric patients with HNF1B mutations. Genetic studies revealed total gene deletion in six patients (43%). All patients had bilateral renal abnormalities, primarily multiple renal cysts. Twelve patients exhibited progressive renal functional deterioration, and six of them progressed to kidney failure. The annual reduction in estimated glomerular filtration rate was−2.1 mL/min/1.73 m2. Diabetes developed in five patients (36%), including one patient with new-onset diabetes after transplantation. Neurological deficits were noted in three patients (21%), one with total gene deletion and two with missense mutations. Pancreatic abnormalities were more frequent in patients with missense mutations than in patients with other types of mutations. Genotype showed no significant correlation with renal outcomes or other extrarenal manifestations. The HNF1B scores at the times of onset and genetic diagnosis were <8 in two patients and one patient, respectively. Diagnosis of HNF1B mutations is clinically difficult because of extreme phenotypic variability and incomplete penetrance. Furthermore, some phenotypes develop with age. Therefore, patient age should be taken into consideration to increase the diagnostic rate, because some phenotypes develop with age.

The Clinical Characteristics and Gene Mutations of Maturity-Onset Diabetes of the Young Type 5 in Sixty-One Patients

“…This led to underexpression of certain genes and indirectly reduced kidney damage (17). But another study showed no correlation between genotype and renal functional (9). Although renal malformations appeared to be the common manifestation of HNF1B mutations, progression to end-stage renal disease (ESKD) in patients with HNF1B mutations seemed to be rare (18).…”

Hyperuricemia Is an Early and Relatively Common Feature in Children with HNF1B Nephropathy but Its Utility as a Predictor of the Disease Is Limited

“…There is a concern that in a more severe CKD population, secondary hyperparathyroidism will distort this relationship. Importantly, the HNF1B score by Faguer et al [ 20 ] was developed for both adults and children, which makes this score imperfect, especially in young children, wrongly predicting the absence of a mutation [ 14 ]. In this respect, there is a need for revision of the existing score or creation of a new HNF1B score or a diagnostic algorithm that could be applicable specifically in children.…”

“…Its multi-organ expression results in a wide spectrum of renal and extra-renal manifestations in patients with HNF1B -associated disease, which includes renal cysts, multicystic dysplastic kidney, solitary kidney, agenesis of pancreas body and tail, maturity-onset diabetes in the young type 5, genital malformations, elevated liver enzymes, electrolyte abnormalities, primary hyperparathyroidism, gout, and epilepsy [ 4 , 5 ]. Hyperuricemia is a key hallmark of the disease that has been repeatedly reported in patients with HNF1B mutation [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Although this association is described in many studies, when compared to patients without HNF1B mutation, the frequency of hyperuricemia in patients with HNF1B mutation was not significantly different [ 10 , 11 ].…”

“…A search of the literature revealed that the frequency of hyperuricemia varies significantly, depending mostly on the severity of CKD and age of the cohorts [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Importantly, in studies for which a combined cohort (i.e., children and adults) has been studied, the authors used higher upper limits for sUA, usually those applicable for adult patients.…”

“…Importantly, in studies for which a combined cohort (i.e., children and adults) has been studied, the authors used higher upper limits for sUA, usually those applicable for adult patients. This could ultimately result in a low prevalence of hyperuricemia in children [ 10 , 14 ]. Others utilized reference data published in 1990, which are not reliable as these were generated from a small sample, and could be regarded as outdated [ 16 ].…”