Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies.

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. 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. 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. Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.

König J ，Kranz B ，König S ，Schlingmann KP ，Titieni A ，Tönshoff B ，Habbig S ，Pape L ，Häffner K ，Hansen M ，Büscher A ，Bald M ，Billing H ，Schild R ，Walden U ，Hampel T ，Staude H ，Riedl M ，Gretz N ，Lablans M ，Bergmann C ，Hildebrandt F ，Omran H ，Konrad M ，Gesellschaft für Pädiatrische Nephrologie (GPN) ... -  《-》

Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy.

Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children. Exploring the correlation between the phenotype and genotype of NPHP-RC is helpful for early diagnosis and management. We investigated the phenotype and genotype spectra of NPHP-RC in a Chinese multicentre cohort. Crosss-ectional and longitudinal data of 60 patients from 57 families with pathogenic NPHP-RC gene mutations distributed in 22 regions of China were collected into a unified, anonymous database. The mean observation time of this cohort was 3.5±3.1 years. Mutations in NPHP1 and NPHP3 were the most common genetic defects. Overall, 45% of patients presented with isolated nephronophthisis (NPH), and 55% exhibited the extrarenal phenotype, which frequently involved the liver (41.7%, n=25), central nervous system (26.7%, n=16), eyes (26.7%, n=16) and skeletal system (11.7%, n=7). Accidental detection of elevated serum creatinine and non-specific symptoms caused by chronic kidney disease occurred in 65% of patients. Patients carrying NPHP1 mutations mainly presented with isolated NPH (90%, 18/20) and progressed to ESRD at a mean age of 12.9±0.5 years. The mean age of ESRD onset in the non-NPHP1 group was lower than that in the NPHP1 group (6.2±1.4 years, p<0.001), especially for patients carrying NPHP3 mutations (3.1±1.2 years), showing a heterogeneous phenotype characterised by Bardet-Biedl syndrome (12.5%, n=5), Joubert syndrome (7.5%, n=3), COACH syndrome (2.5%, n=1), Mainzer-Saldino syndrome (2.5%, n=1), short-rib thoracic dysplasia (2.5%, n=1) and unclassified symptoms (32.5%, n=13). The Chinese Children Genetic Kidney Disease Database registry characterised the spectrum of the phenotype and genotype of NPHP-RC in the Chinese population. NPHP1 and NPHP3 were the most common pathogenic genes. Rapid progression to ESRD and liver involvement were noted in patients with NPHP3 mutations.

Tang X ，Liu C ，Liu X ，Chen J ，Fan X ，Liu J ，Ma D ，Cao G ，Chen Z ，Xu D ，Zhu Y ，Jiang X ，Cheng L ，Wu Y ，Hou L ，Li Y ，Shao X ，Zheng S ，Zhang A ，Zheng B ，Jian S ，Rong Z ，Su Q ，Gao X ，Rao J ，Shen Q ，Xu H ，Chinese Children Genetic Kidney Disease Database (CCGKDD) ，“Internet Plus” Nephrology Alliance of the National Center for Children’s Care ... -  《-》

Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience.

Soliman NA ，Hildebrandt F ，Otto EA ，Nabhan MM ，Allen SJ ，Badr AM ，Sheba M ，Fadda S ，Gawdat G ，El-Kiky H ... -  《-》

Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy.

Stokman MF ，van der Zwaag B ，van de Kar NCAJ ，van Haelst MM ，van Eerde AM ，van der Heijden JW ，Kroes HY ，Ippel E ，Schulp AJA ，van Gassen KL ，van Rooij IALM ，Giles RH ，Beales PL ，Roepman R ，Arts HH ，Bongers EMHF ，Renkema KY ，Knoers NVAM ，van Reeuwijk J ，Lilien MR ... -  《-》

Prospective Evaluation of Kidney Disease in Joubert Syndrome.

Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old). Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype.

Fleming LR ，Doherty DA ，Parisi MA ，Glass IA ，Bryant J ，Fischer R ，Turkbey B ，Choyke P ，Daryanani K ，Vemulapalli M ，Mullikin JC ，Malicdan MC ，Vilboux T ，Sayer JA ，Gahl WA ，Gunay-Aygun M ... -  《-》