Yo Han Ahn1,2, Eu Jin Park1, Hee Gyung Kang1,3, Seong Heon Kim4, Hee Yeon Cho5, Jae Il Shin6, Joo Hoon Lee7, Young Seo Park7, Kyo Sun Kim8, Il-Soo Ha1,9, Hae Il Cheong10,11,12. 1. Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea. 2. Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea. 3. Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea. 4. Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea. 5. Department of Pediatrics, Samsung Medical Center, Seoul, Korea. 6. Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea. 7. Department of Pediatrics, Asan Medical Center, Seoul, Korea. 8. Department of Pediatrics, Konkuk University Hospital, Seoul, Korea. 9. Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea. 10. Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea. cheonghi@snu.ac.kr. 11. Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea. cheonghi@snu.ac.kr. 12. Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea. cheonghi@snu.ac.kr.
Abstract
BACKGROUND: WT1 is one of the genes commonly reported as mutated in children with steroid-resistant nephrotic syndrome (SRNS). We analyzed genotype-phenotype correlations in pediatric SRNS patients with WT1 mutations. METHODS: From 2001 to 2015, WT1 mutations were detected in 21 out of 354 children with SRNS by genetic screening (5.9 %). The patients were grouped into missense (n = 11) and KTS splicing (n = 10) mutation groups. RESULTS: Nine (82 %) patients with missense mutations presented with congenital/infantile nephrotic syndrome, while 8 (80 %) with KTS splicing mutations presented with childhood-onset SRNS. Progression to end-stage renal disease (ESRD) was noted in all patients with missense mutations (median age, 2.6 months; interquartile range [IQR], 0.8 months to 1.7 years) and in 5 patients with KTS splicing mutations (median, 9.3 years; IQR, 3.3-16.5 years). Disorders of sexual development (DSDs) were noted in all 12 patients with a 46, XY karyotype and in only 1 of the 8 patients with a 46, XX karyotype. One patient developed a Wilms tumor and another developed gonadoblastoma. Three patients had a diaphragmatic defect or hernia. CONCLUSIONS: WT1 mutations manifest as a wide spectrum of renal and extra-renal phenotypes. Genetic diagnosis is essential for overall management and to predict the genotype-specific risk of DSDs and the development of malignancies.
BACKGROUND:WT1 is one of the genes commonly reported as mutated in children with steroid-resistant nephrotic syndrome (SRNS). We analyzed genotype-phenotype correlations in pediatric SRNS patients with WT1 mutations. METHODS: From 2001 to 2015, WT1 mutations were detected in 21 out of 354 children with SRNS by genetic screening (5.9 %). The patients were grouped into missense (n = 11) and KTS splicing (n = 10) mutation groups. RESULTS: Nine (82 %) patients with missense mutations presented with congenital/infantile nephrotic syndrome, while 8 (80 %) with KTS splicing mutations presented with childhood-onset SRNS. Progression to end-stage renal disease (ESRD) was noted in all patients with missense mutations (median age, 2.6 months; interquartile range [IQR], 0.8 months to 1.7 years) and in 5 patients with KTS splicing mutations (median, 9.3 years; IQR, 3.3-16.5 years). Disorders of sexual development (DSDs) were noted in all 12 patients with a 46, XY karyotype and in only 1 of the 8 patients with a 46, XX karyotype. One patient developed a Wilms tumor and another developed gonadoblastoma. Three patients had a diaphragmatic defect or hernia. CONCLUSIONS:WT1 mutations manifest as a wide spectrum of renal and extra-renal phenotypes. Genetic diagnosis is essential for overall management and to predict the genotype-specific risk of DSDs and the development of malignancies.
Entities:
Keywords:
Diaphragmatic defect; Disorder of sexual development; Malignancy; Steroid-resistant nephrotic syndrome; WT1 gene
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