Clinical journal of the American Society of Nephrology : CJASN · 2017
Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies.
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König Jens, Kranz Birgitta, König Sabine, Schlingmann Karl Peter, Titieni Andrea, Tönshoff Burkhard, Habbig Sandra, Pape Lars, Häffner Karsten, Hansen Matthias, Büscher Anja, Bald Martin, Billing Heiko, Schild Raphael, Walden Ulrike, Hampel Tobias, Staude Hagen, Riedl Magdalena, Gretz Norbert, Lablans Martin, Bergmann Carsten, Hildebrandt Friedhelm, Omran Heymut, Konrad Martin, Gesellschaft für Pädiatrische Nephrologie (GPN)
Аннотация
BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years.
RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood.
CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years.
RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood.
CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.
Предметные рубрики MeSH
Adaptor Proteins, Signal TransducingAdolescentAnemiaAntigens, NeoplasmCalmodulin-Binding ProteinsCarrier ProteinsCell Cycle ProteinsChildCiliopathiesCross-Sectional StudiesCytoskeletal ProteinsFemaleGlomerular Filtration RateHomozygoteHumansKidneyKidney Diseases, CysticKidney Failure, ChronicKinesinsLongitudinal StudiesMaleMembrane ProteinsNeoplasm ProteinsNervous System DiseasesPhenotypePolyuriaProteinsUltrasonographyYoung Adult