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Abstract：
OBJECTIVE: 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.
METHODS: 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.
METHODS: 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.
摘要：
目的：遗传异质性和表型变异性是家族性肾单位及相关纤毛病变的主要挑战。迄今为止,已鉴定出20种不同基因(NPHP1至-20)的突变可导致孤立的肾脏疾病或复杂的多器官疾病.在这项研究中,我们对152名特别关注肾外器官受累和ESRD长期发展的儿童进行了全面和详细的表征.
方法：我们建立了一个基于在线的注册表（www.Nephreg.de）以每年为基础评估肾病和相关纤毛病变患者的临床病程。收集横截面和纵向数据。平均观察时间为7.5±6.1年。
结果：总计，51%的儿童出现孤立的肾单位视情况,而其他49%表现出相关的纤毛病变。在152例患者中，有97例发现了单基因缺陷，89影响NPHP基因。八名患者携带与囊性肾病相关的其他基因突变。纯合NPHP1缺失是，到目前为止,最常见的遗传缺陷(n=60)。我们观察到肾外表现的患病率很高（NPHP1组23％[60个中的14个]，无NPHP1的儿童66％[92个中的61个]）。纯合的NPHP1缺失不仅导致幼年的肾phronophisis，而且能够表现为主要的神经系统表型。然而,无论最初的临床表现如何，所有携带NPHP1突变的患者的肾功能在8至16岁之间迅速下降，ESRD的平均年龄为11.4±2.4岁。相反，在非NPHP1组中，关于ESRD的发展没有统一的模式,包括早期发病的患者和其他在成年前保持正常肾功能的患者.
结论：NPHP基因的突变引起广泛的纤毛病变，多器官受累和不同的临床结局。
方法：我们建立了一个基于在线的注册表（www.Nephreg.de）以每年为基础评估肾病和相关纤毛病变患者的临床病程。收集横截面和纵向数据。平均观察时间为7.5±6.1年。
结果：总计，51%的儿童出现孤立的肾单位视情况,而其他49%表现出相关的纤毛病变。在152例患者中，有97例发现了单基因缺陷，89影响NPHP基因。八名患者携带与囊性肾病相关的其他基因突变。纯合NPHP1缺失是，到目前为止,最常见的遗传缺陷(n=60)。我们观察到肾外表现的患病率很高（NPHP1组23％[60个中的14个]，无NPHP1的儿童66％[92个中的61个]）。纯合的NPHP1缺失不仅导致幼年的肾phronophisis，而且能够表现为主要的神经系统表型。然而,无论最初的临床表现如何，所有携带NPHP1突变的患者的肾功能在8至16岁之间迅速下降，ESRD的平均年龄为11.4±2.4岁。相反，在非NPHP1组中，关于ESRD的发展没有统一的模式,包括早期发病的患者和其他在成年前保持正常肾功能的患者.
结论：NPHP基因的突变引起广泛的纤毛病变，多器官受累和不同的临床结局。
