Christine Okorn1, Anne Goertz1, Udo Vester1, Bodo B Beck2,3, Carsten Bergmann4, Sandra Habbig5, Jens König6, Martin Konrad6, Dominik Müller7, Jun Oh8, Nadina Ortiz-Brüchle9, Ludwig Patzer10, Raphael Schild8, Tomas Seeman11, Hagen Staude12, Julia Thumfart7, Burkhard Tönshoff13, Ulrike Walden14, Lutz Weber5, Marcin Zaniew15, Hildegard Zappel16, Peter F Hoyer1, Stefanie Weber17. 1. Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany. 2. Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany. 3. Cologne Center for Genomics (CCG) and Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. 4. Bergmann Laboratory, University Medical Center Freiburg, Freiburg, Germany. 5. Pediatric Nephrology, University Children's Hospital Cologne, Cologne, Germany. 6. Pediatric Nephrology, University Children's Hospital Münster, Münster, Germany. 7. Pediatric Nephrology, University Campus Virchow University Children's Hospital Berlin, Berlin, Germany. 8. Pediatric Nephrology, University Children's Hospital Hamburg, Hamburg, Germany. 9. Institute of Human Genetics, RWTH University Hospital Aachen, Aachen, Germany. 10. Children's Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany. 11. Pediatric Nephrology, University Children's Hospital Prague, Prague, Czech Republic. 12. Pediatric Nephrology, University Children's Hospital Rostock, Rostock, Germany. 13. Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg, Germany. 14. Children's Hospital Augsburg, Augsburg, Germany. 15. Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland. 16. University Children's Hospital Göttingen, Göttingen, Germany. 17. Pediatric Nephrology, University Children's Hospital Marburg, Baldingerstrasse 1, 35033, Marburg, Germany. Stefanie.weber@med.uni-marburg.de.
Abstract
BACKGROUND: HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult. METHODS: Longitudinal data of 62 children probands with genetically proven HNF1B nephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases. RESULTS: Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of - 0.33 ml/min/1.73m2 per year (± 8.9). In patients with an increase in cyst number, the annual GFR reduction was - 2.8 ml/min/1.73m2 (± 13.2), in the total cohort - 1.0 ml/min/1.73m2 (±10.3). A subset of HNF1B patients differs from this group and develops end stage renal disease (ESRD) at very early ages < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged child. Genetic analysis revealed no genotype-phenotype correlations but a significant parent-of-origin effect with a preponderance of 81% of maternal inheritance in dominant cases. CONCLUSIONS: In most children, HNF1B nephropathy has a non-progressive course of cyst development and a slow-progressive course of kidney function. A subgroup of patients developed ESRD at very young age < 2 years requiring special medical attention. The parent-of-origin effect suggests an influence of epigenetic modifiers in HNF1B disease.
BACKGROUND:HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult. METHODS: Longitudinal data of 62 children probands with genetically proven HNF1Bnephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases. RESULTS: Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of - 0.33 ml/min/1.73m2 per year (± 8.9). In patients with an increase in cyst number, the annual GFR reduction was - 2.8 ml/min/1.73m2 (± 13.2), in the total cohort - 1.0 ml/min/1.73m2 (±10.3). A subset of HNF1Bpatients differs from this group and develops end stage renal disease (ESRD) at very early ages < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged child. Genetic analysis revealed no genotype-phenotype correlations but a significant parent-of-origin effect with a preponderance of 81% of maternal inheritance in dominant cases. CONCLUSIONS: In most children, HNF1Bnephropathy has a non-progressive course of cyst development and a slow-progressive course of kidney function. A subgroup of patients developed ESRD at very young age < 2 years requiring special medical attention. The parent-of-origin effect suggests an influence of epigenetic modifiers in HNF1B disease.
Entities:
Keywords:
Cystic kidney disease; GFR decline; HNF1B; Hypomagnesemia; MODY
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