Pediatric Nephrology

, Volume 27, Issue 10, pp 1989–1993 | Cite as

Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation

  • Paraskevas Iatropoulos
  • Erica Daina
  • Caterina Mele
  • Ramona Maranta
  • Giuseppe Remuzzi
  • Marina Noris
Brief Report



Renal coloboma syndrome (RCS) is a highly variable syndrome characterized by renal and ocular abnormalities. It is associated in about 50 % of cases with mutations of PAX2, a gene encoding a transcription factor required during development.


The case study involves two monozygotic twin sisters with RCS showing highly discordant phenotypes. Twin 1 was antenatally diagnosed with multiple cysts in the right kidney. She had complicated vacuum-assisted delivery with acute renal failure. She developed proteinuria at age 4 years, followed by a progressive rise in serum creatinine requiring renal replacement therapy at age 22. No ocular abnormalities have been detected. Twin 2 experienced rapidly reversible acute renal failure without renal morphological abnormalities at birth. At age 2 years, complete visual acuity loss of the left eye secondary to an optic disc coloboma was diagnosed. No significant events occurred until the age of 20, when clinical proteinuria was detected. Proteinuria remission was obtained by multidrug treatment. In both patients, a novel de novo mutation of PAX2 was detected, which leads to the substitution of a highly conserved cysteine (p.C52Y).


The patients described provide an extreme example of clinical variability in RCS. The role of environmental, genetic, and epigenetic factors is discussed.


Renal coloboma syndrome Papillorenal syndrome PAX2 Twins Phenotypic discordance Rare diseases 



The authors wish to thank the patients and their parents for the availability to participate in the study. C.M. and R.M. are recipients of fellowships from Fondazione ART per la Ricerca sui Trapianti ONLUS (Milan, Italy) and from Fondazione Aiuti per la Ricerca sulle Malattie Rare (ARMR), Bergamo, Italy, respectively. The authors also wish to thank Mrs. Sara Gamba for her contribution in the management of the patients and Dr. Irene van der Meer for carefully reading and editing the manuscript.

Supplementary material

467_2012_2205_MOESM1_ESM.doc (195 kb)
ESM 1 (DOC 195 kb)


  1. 1.
    Sanyanusin P, Schimmenti LA, McNoe LA, Ward TA, Pierpont ME, Sullivan MJ, Dobyns WB, Eccles MR (1995) Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nat Genet 9:358–364PubMedCrossRefGoogle Scholar
  2. 2.
    Schimmenti LA, Cunliffe HE, McNoe LA, Ward TA, French MC, Shim HH, Zhang YH, Proesmans W, Leys A, Byerly KA, Braddock SR, Masuno M, Imaizumi K, Devriendt K, Eccles MR (1997) Further delineation of renal-coloboma syndrome in patients with extreme variability of phenotype and identical PAX2 mutations. Am J Hum Genet 60:869–878PubMedGoogle Scholar
  3. 3.
    Fletcher J, Hu M, Berman Y, Collins F, Grigg J, McIver M, Jüppner H, Alexander SI (2005) Multicystic dysplastic kidney and variable phenotype in a family with a novel deletion mutation of PAX2. J Am Soc Nephrol 16:2754–2761PubMedCrossRefGoogle Scholar
  4. 4.
    Bower M, Salomon R, Allanson J, Antignac C, Benedicenti F, Benetti E, Binenbaum G, Jensen UB, Cochat P, DeCramer S, Dixon J, Drouin R, Falk MJ, Feret H, Gise R, Hunter A, Johnson K, Kumar R, Lavocat MP, Martin L, Morinière V, Mowat D, Murer L, Nguyen HT, Peretz-Amit G, Pierce E, Place E, Rodig N, Salerno A, Sastry S, Sato T, Sayer JA, Schaafsma GC, Shoemaker L, Stockton DW, Tan WH, Tenconi R, Vanhille P, Vats A, Wang X, Warman B, Weleber RG, White SM, Wilson-Brackett C, Zand DJ, Eccles M, Schimmenti LA, Heidet L (2012) Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. Hum Mutat 33:457–466PubMedCrossRefGoogle Scholar
  5. 5.
    Dressler GR (2011) Patterning and early cell lineage decisions in the developing kidney: the role of Pax genes. Pediatr Nephrol 26:1387–1394PubMedCrossRefGoogle Scholar
  6. 6.
    Thomas R, Sanna-Cherchi S, Warady BA, Furth SL, Kaskel FJ, Gharavi AG (2011) HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr Nephrol 26:897–903PubMedCrossRefGoogle Scholar
  7. 7.
    Favor J, Sandulache R, Neuhauser-Klaus A, Pretsch W, Chatterjee B, Senft E, Wurst W, Blanquet V, Grimes P, Spörle R, Schughart K (1996) The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Proc Natl Acad Sci USA 93:13870–13875PubMedCrossRefGoogle Scholar
  8. 8.
    Porteous S, Torban E, Cho NP, Cunliffe H, Chua L, McNoe L, Ward T, Souza C, Gus P, Giugliani R, Sato T, Yun K, Favor J, Sicotte M, Goodyer P, Eccles M (2000) Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of Pax2(1Neu) +/− mutant mice. Hum Mol Genet 9:1–11PubMedCrossRefGoogle Scholar
  9. 9.
    Amiel J, Audollent S, Joly D, Dureau P, Salomon R, Tellier AL, Augé J, Bouissou F, Antignac C, Gubler MC, Eccles MR, Munnich A, Vekemans M, Lyonnet S, Attié-Bitach T (2000) PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism. Eur J Hum Genet 8:820–826PubMedCrossRefGoogle Scholar
  10. 10.
    Xu W, Rould MA, Jun S, Desplan C, Pabo CO (1995) Crystal structure of a paired domain-DNA complex at 2.5 A resolution reveals structural basis for Pax developmental mutations. Cell 80:639–650PubMedCrossRefGoogle Scholar
  11. 11.
    Ruggenenti P, Perticucci E, Cravedi P, Gambara V, Costantini M, Sharma SK, Perna A, Remuzzi G (2008) Role of remission clinics in the longitudinal treatment of CKD. J Am Soc Nephrol 19:1213–1224PubMedCrossRefGoogle Scholar
  12. 12.
    Proesmans W, Van Dyck M, Devriendt K (2009) Nail-patella syndrome, infantile nephrotic syndrome: complete remission with antiproteinuric treatment. Nephrol Dial Transplant 24:1335–1338PubMedCrossRefGoogle Scholar
  13. 13.
    Machin G (2009) Non-identical monozygotic twins, intermediate twin types, zygosity testing, and the non-random nature of monozygotic twinning: a review. Am J Med Genet C Semin Med Genet 151C:110–127PubMedCrossRefGoogle Scholar
  14. 14.
    Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2012

Authors and Affiliations

  • Paraskevas Iatropoulos
    • 1
  • Erica Daina
    • 1
  • Caterina Mele
    • 1
  • Ramona Maranta
    • 1
  • Giuseppe Remuzzi
    • 1
    • 2
  • Marina Noris
    • 1
  1. 1.Mario Negri Institute for Pharmacological ResearchClinical Research Center for Rare Diseases Aldo e Cele DaccòRanica (BG)Italy
  2. 2.Department of Nephrology and DialysisAzienda Ospedaliera Ospedali Riuniti di BergamoBergamoItaly

Personalised recommendations