Development of a tool for predicting HNF1B mutations in children and young adults with congenital anomalies of the kidneys and urinary tract.

BACKGROUND: We aimed to develop a tool for predicting HNF1B mutations in children with congenital abnormalities of the kidneys and urinary tract (CAKUT). METHODS: The clinical and laboratory data from 234 children and young adults with known HNF1B mutation status were collected and analyzed retrospectively. All subjects were randomly divided into a training (70%) and a validation set (30%). A random forest model was constructed to predict HNF1B mutations. The recursive feature elimination algorithm was used for feature selection for the model, and receiver operating characteristic curve statistics was used to verify its predictive effect. RESULTS: A total of 213 patients were analyzed, including HNF1B-positive (mut + , n = 109) and HNF1B-negative (mut - , n = 104) subjects. The majority of patients had mild chronic kidney disease. Kidney phenotype was similar between groups, but bilateral kidney anomalies were more frequent in the mut + group. Hypomagnesemia and hypermagnesuria were the most common abnormalities in mut + patients and were highly selective of HNF1B. Hypomagnesemia based on age-appropriate norms had a better discriminatory value than the age-independent cutoff of 0.7 mmol/l. Pancreatic anomalies were almost exclusively found in mut + patients. No subjects had hypokalemia; the mean serum potassium level was lower in the HNF1B cohort. The abovementioned, discriminative parameters were selected for the model, which showed a good performance (area under the curve: 0.85; sensitivity of 93.67%, specificity of 73.57%). A corresponding calculator was developed for use and validation. CONCLUSIONS: This study developed a simple tool for predicting HNF1B mutations in children and young adults with CAKUT.

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

BACKGROUND: Hyperuricemia is recognized as an important feature of nephropathy, associated with a mutation in the hepatocyte nuclear factor-1B (HNF1B) gene, and could serve as a useful marker of the disease. However, neither a causal relationship nor its predictive value have been proven. The purpose of this study was to assess this in children with renal malformations, both with (mut+) and without HNF1B mutations (mut-). METHODS: We performed a retrospective analysis of clinical characteristics of pediatric patients tested for HNF1B mutations, collected in a national registry. RESULTS: 108 children were included in the study, comprising 43 mut+ patients and 65 mut- subjects. Mean sUA was higher and hyperuricemia more prevalent (42.5% vs. 15.4%) in HNF1B carriers. The two groups were similar with respect to respect to age, sex, anthropometric parameters, hypertension, and renal function. Renal function, fractional excretion of uric acid and parathyroid hormone level were independent predictors of sUA. The potential of hyperuricemia to predict mutation was low, and addition of hyperuricemia to a multivariate logistic regression model did not increase its accuracy. CONCLUSIONS: Hyperuricemia is an early and common feature of HNF1B nephropathy. A strong association of sUA with renal function and parathyroid hormone limits its utility as a reliable marker to predict HNF1B mutation among patients with kidney anomalies.

Four Cases of Maturity Onset Diabetes of the Young (MODY) Type 5 Associated with Mutations in the Hepatocyte Nuclear Factor 1 Beta (HNF1B) Gene Presenting in a 13-Year-Old Boy and in Adult Men Aged 33, 34, and 35 Years in Poland.

BACKGROUND Maturity onset diabetes of the young (MODY) usually presents in patients under the age of 25 years and is an autosomal dominant condition associated with mutations in the hepatocyte nuclear factor 1 alpha gene, glucokinase gene, or hepatocyte nuclear factor 4 alpha gene. This report is of a series of 4 cases from Poland of MODY type 5 associated with mutations in the hepatocyte nuclear factor 1 beta (HNF1B) gene, including a 13-year-old boy and adult men aged 33, 34, and 35 years. CASE REPORT Three cases were diagnosed late, in patients in their mid-thirties. In two patients, the initial presentation was symptomatic diabetes complicated by ketoacidosis and hyperglycemic hyperosmolar state. Renal cysts were found in all patients, and pancreatic hypoplasia in 3 patients. All patients except 1 were negative for autoantibodies; 1 presented with hypomagnesemia. Insulin therapy was instituted in all cases. The combination of family history, imaging study results, and biochemical characteristics led to the decision to perform genetic analysis, which was conducted in 2 cases at diagnosis, and in the 2 remaining patients at 1 month and 2 years after diagnosis, respectively. Follow-up data revealed hypomagnesemia and/or hypermagnesuria in all patients. CONCLUSIONS We present 3 young men over 25 years and 1 boy with HNF1B-MODY. Although rare, autosomal dominant gene associations should be considered in young patients with diabetes who present with renal/pancreatic anomalies and low serum magnesium. Unusual presentation and the presence of autoantibodies should not eliminate the possibility of a HNF1B defect.