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

Pediatr Nephrol. 2018 Oct;33(10):1701-1712. doi: 10.1007/s00467-018-3958-7. Epub 2018 Jul 5.


Background: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling.

Methods: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis.

Results: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%).

Conclusions: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30.

Keywords: Ciliopathy; Clinical registry; Gene-phenotype association; Nephronophthisis; Pediatric kidney disease.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adolescent
  • Adult
  • Age of Onset
  • Biopsy
  • Child
  • Ciliopathies / complications
  • Ciliopathies / diagnosis*
  • Ciliopathies / genetics
  • Ciliopathies / pathology
  • Cytoskeletal Proteins
  • Delayed Diagnosis / prevention & control
  • Exome Sequencing
  • Female
  • Genetic Counseling*
  • Genetic Testing*
  • Humans
  • Kidney / diagnostic imaging
  • Kidney / pathology
  • Kidney Diseases, Cystic / complications
  • Kidney Diseases, Cystic / congenital*
  • Kidney Diseases, Cystic / diagnosis
  • Kidney Diseases, Cystic / genetics
  • Kidney Diseases, Cystic / pathology
  • Kidney Failure, Chronic / etiology
  • Kidney Failure, Chronic / prevention & control*
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Netherlands
  • Registries / statistics & numerical data
  • Time Factors
  • Ultrasonography
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Membrane Proteins
  • NPHP1 protein, human

Supplementary concepts

  • Nephronophthisis, familial juvenile