Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Clinical manifestations, diagnosis, and treatment of nephronophthisis

Patrick Niaudet, MD
Section Editors
Tej K Mattoo, MD, DCH, FRCP
Ronald D Perrone, MD
Deputy Editor
Melanie S Kim, MD


Nephronophthisis (NPHP) is a clinical condition caused by a group of autosomal recessive cystic kidney disorders that typically progresses to end-stage renal disease (ESRD). It is caused by mutations in a large number of genes that encode proteins involved in the function of primary cilia, basal bodies, and centrosomes resulting in renal disease and extra-renal manifestations.

The clinical manifestations and management of NPHP will be reviewed here. The genetics and pathogenesis of NPHP are discussed separately. (See "Genetics and pathogenesis of nephronophthisis".)


Patients with NPHP have gene mutations that encode components of the ciliary apparatus [1]. These gene defects result in the following characteristic findings of NPHP (see "Genetics and pathogenesis of nephronophthisis"):

Autosomal recessive inheritance

Impaired urinary concentrating ability and sodium absorption resulting in polyuria and polydipsia


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Aug 2017. | This topic last updated: Sep 14, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Srivastava S, Sayer JA. Nephronophthisis. J Pediatr Genet 2014; 3:103.
  2. Hildebrandt F, Attanasio M, Otto E. Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 2009; 20:23.
  3. Burke JR, Inglis JA, Craswell PW, et al. Juvenile nephronophthisis and medullary cystic disease--the same disease (report of a large family with medullary cystic disease associated with gout and epilepsy). Clin Nephrol 1982; 18:1.
  4. Haider NB, Carmi R, Shalev H, et al. A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping. Am J Hum Genet 1998; 63:1404.
  5. Otto EA, Schermer B, Obara T, et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet 2003; 34:413.
  6. Gagnadoux MF, Bacri JL, Broyer M, Habib R. Infantile chronic tubulo-interstitial nephritis with cortical microcysts: variant of nephronophthisis or new disease entity? Pediatr Nephrol 1989; 3:50.
  7. Oud MM, van Bon BW, Bongers EM, et al. Early presentation of cystic kidneys in a family with a homozygous INVS mutation. Am J Med Genet A 2014; 164A:1627.
  8. Tory K, Rousset-Rouvière C, Gubler MC, et al. Mutations of NPHP2 and NPHP3 in infantile nephronophthisis. Kidney Int 2009; 75:839.
  9. Hoefele J, Nayir A, Chaki M, et al. Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion. Pediatr Nephrol 2011; 26:967.
  10. Hildebrandt F, Strahm B, Nothwang HG, et al. Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie. Kidney Int 1997; 51:261.
  11. Gretz N, Schärer K, Waldherr R, Strauch M. Rate of deterioration of renal function in juvenile nephronophthisis. Pediatr Nephrol 1989; 3:56.
  12. Bodaghi E, Honarmand MT, Ahmadi M. Infantile nephronophthisis. Int J Pediatr Nephrol 1987; 8:207.
  13. Blowey DL, Querfeld U, Geary D, et al. Ultrasound findings in juvenile nephronophthisis. Pediatr Nephrol 1996; 10:22.
  14. Garel LA, Habib R, Pariente D, et al. Juvenile nephronophthisis: sonographic appearance in children with severe uremia. Radiology 1984; 151:93.
  15. Olbrich H, Fliegauf M, Hoefele J, et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat Genet 2003; 34:455.
  16. Omran H, Fernandez C, Jung M, et al. Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. Am J Hum Genet 2000; 66:118.
  17. Georges B, Cosyns JP, Dahan K, et al. Late-onset renal failure in Senior-Loken syndrome. Am J Kidney Dis 2000; 36:1271.
  18. Mainzer F, Saldino RM, Ozonoff MB, Minagi H. Familial nephropathy associatdd with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med 1970; 49:556.
  19. Boichis H, Passwell J, David R, Miller H. Congenital hepatic fibrosis and nephronophthisis. A family study. Q J Med 1973; 42:221.
  20. Proesmans W, Van Damme B, Macken J. Nephronophthisis and tapetoretinal degeneration associated with liver fibrosis. Clin Nephrol 1975; 3:160.
  21. Witzleben CL, Sharp AR. "Nephronophthisis-congenital hepatic fibrosis": an additional hepatorenal disorder. Hum Pathol 1982; 13:728.
  22. Otto EA, Tory K, Attanasio M, et al. Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11). J Med Genet 2009; 46:663.
  23. Hoff S, Halbritter J, Epting D, et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet 2013; 45:951.
  24. Schueler M, Braun DA, Chandrasekar G, et al. DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling. Am J Hum Genet 2015; 96:81.
  25. Bergmann C, Fliegauf M, Brüchle NO, et al. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet 2008; 82:959.
  26. SENIOR B, FRIEDMANN AI, BRAUDO JL. Juvenile familial nephropathy with tapetoretinal degeneration. A new oculorenal dystrophy. Am J Ophthalmol 1961; 52:625.
  27. LOKEN AC, HANSSEN O, HALVORSEN S, JOLSTER NJ. Hereditary renal dysplasia and blindness. Acta Paediatr 1961; 50:177.
  28. Otto EA, Loeys B, Khanna H, et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 2005; 37:282.
  29. Caridi G, Dagnino M, Gusmano R, et al. Clinical and molecular heterogeneity of juvenile nephronophthisis in Italy: insights from molecular screening. Am J Kidney Dis 2000; 35:44.
  30. Caridi G, Murer L, Bellantuono R, et al. Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am J Kidney Dis 1998; 32:1059.
  31. Caridi G, Dagnino M, Rossi A, et al. Nephronophthisis type 1 deletion syndrome with neurological symptoms: prevalence and significance of the association. Kidney Int 2006; 70:1342.
  32. Parisi MA, Bennett CL, Eckert ML, et al. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 2004; 75:82.
  33. Tory K, Lacoste T, Burglen L, et al. High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. J Am Soc Nephrol 2007; 18:1566.
  34. Castori M, Valente EM, Donati MA, et al. NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders. J Med Genet 2005; 42:e9.
  35. Arts HH, Doherty D, van Beersum SE, et al. Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat Genet 2007; 39:882.
  36. Valente EM, Logan CV, Mougou-Zerelli S, et al. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 2010; 42:619.
  37. Davis EE, Zhang Q, Liu Q, et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 2011; 43:189.
  38. Huber C, Cormier-Daire V. Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet 2012; 160C:165.
  39. Heninger E, Otto E, Imm A, et al. Improved strategy for molecular genetic diagnostics in juvenile nephronophthisis. Am J Kidney Dis 2001; 37:1131.
  40. Stavrou C, Deltas CC, Christophides TC, Pierides A. Outcome of kidney transplantation in autosomal dominant medullary cystic kidney disease type 1. Nephrol Dial Transplant 2003; 18:2165.
  41. Hamiwka LA, Midgley JP, Wade AW, et al. Outcomes of kidney transplantation in children with nephronophthisis: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry. Pediatr Transplant 2008; 12:878.
  42. Harris CM, Hodgkins PR, Kriss A, et al. Familial congenital saccade initiation failure and isolated cerebellar vermis hypoplasia. Dev Med Child Neurol 1998; 40:775.
  43. Delous M, Baala L, Salomon R, et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 2007; 39:875.
  44. Baala L, Romano S, Khaddour R, et al. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet 2007; 80:186.
  45. Braun DA, Hildebrandt F. Ciliopathies. Cold Spring Harb Perspect Biol 2017; 9.
  46. Betz R, Rensing C, Otto E, et al. Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis. J Pediatr 2000; 136:828.
  47. Konrad M, Saunier S, Heidet L, et al. Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum Mol Genet 1996; 5:367.
  48. Halbritter J, Porath JD, Diaz KA, et al. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet 2013; 132:865.