Skip to main content
Springer Nature Link
Log in

Two novel mutations in seven Czech and Slovak kindreds with familial neurohypophyseal diabetes insipidus—benefit of genetic testing

  • Original Article
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Familial neurohypophyseal diabetes insipidus (FNDI) is a rare hereditary disorder with unknown prevalence characterized by arginine-vasopressin hormone (AVP) deficiency resulting in polyuria and polydipsia from early childhood. We report the clinical manifestation and genetic test results in seven unrelated kindreds of Czech or Slovak origin with FNDI phenotype. The age of the sign outset ranged from 2 to 17 years with remarkable interfamilial and intrafamilial variability. Inconclusive result of the fluid deprivation test in three children aged 7 and 17 years old might cause misdiagnosis; however, the AVP gene analysis confirmed the FNDI. The seven families segregated together five different mutations, two of them were novel (c.164C > A, c.298G > C). In addition, DNA analysis proved mutation carrier status in one asymptomatic 1-year-old infant.

Conclusions: The present study together with previously published data identified 38 individuals with FNDI in the studied population of 16 million which predicts a disease prevalence of 1:450,000 for the Central European region. The paper underscores that diagnostic water deprivation test may be inconclusive in polyuric children with partial diabetes insipidus and points to the clinical importance and feasibility of molecular genetic testing for AVP gene mutations in the proband and her/his first degree relatives.

What is Known:

• At least 70 different mutations were reported to date in about 100 families with neurohypophyseal diabetes insipidus (FNDI), and new mutations appear sporadically.

What is New:

• Two novel mutations of the AVP gene are reported

• The importance of molecular testing in children with polyuria and inconclusive water deprivation test is emphasized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AVP:

arginine vasopressin

CP:

copeptin

DI:

diabetes insipidus

FNDI:

familial neurohypophyseal diabetes insipidus

MRI:

magnetic resonance imaging

NPII:

neurophysin II

Posm :

osmolality of plasma

SP:

signal peptide

Uosm :

osmolality of urine

WDT:

water deprivation test

References

  1. Arima H, Morishita Y, Hagiwara D, Hayashi M, Oiso Y (2013) Endoplasmatic reticulum stress in vasopressin neurons of familial diabetes insipidus model mice: aggregate formation and mRNA poly(A) tail shortening. Exp Physiol 99:66–71. doi:10.1113/expphysiol.2013.072553

    Article  PubMed  Google Scholar 

  2. Birkegaard C, Christensen JH, Falorni A, Marzotti S, Minarelli V, Gregersen N, Rittig S (2013) A novel variation in the AVP gene resulting in familial neurohypophyseal diabetes insipidus in a large Italian kindred. Pituitary 16:152–157. doi:10.1007/s11102-012-0392-x

    Article  CAS  PubMed  Google Scholar 

  3. Boson WL, Sarubi JC, d’Alva CB, Friedman E, Faria D, De Marco L, Wajchenberg B (2003) A signal peptide mutation of the arginine vasopressin gene in monozygotic twins. Clin Endocrinol (Oxf) 58:108–110

    Article  CAS  Google Scholar 

  4. Bourdet K, Vallette S, Deladoëy J, Van Vliet G (2016) Early-onset Central diabetes insipidus due to compound heterozygosity for AVP mutations. Horm Res Pediatr 85:283–287. doi:10.1159/000441844

    Article  CAS  Google Scholar 

  5. Brownstein MJ, Russel JT, Gainer H (1980) Synthesis, transport and release of posterior pituitary hormones. Sci (Wash DC) 207:373–378

    Article  CAS  Google Scholar 

  6. Chitturi S, Harris M, Thomsett MJ, Bowling F, McGown I, Cowley D, Leong GM, Batch J, Cotterill AM (2008) Utility of AVP gene testing in familial neurohypophyseal diabetes insipidus. Clin Endocrinol (Oxf) 69:926–930. doi:10.1111/j.1365-2265.2008.03303.x

    Article  Google Scholar 

  7. Christensen JH, Kvistgaard H, Knudsen J, Shaikh G, Tolmie J, Cooke S, Pedersen S, Corydon TJ, Gregersen N, Rittig S (2013) A novel deletion partly removing the AVP gene causes autosomal recessive inheritance of early-onset neurohypophyseal diabetes insipidus. Clin Genet 83:44–52. doi:10.1111/j.1399-0004.2011.01833.x

    Article  CAS  PubMed  Google Scholar 

  8. Christensen JH, Rittig S (2006) Familial neurohypophyseal diabetes insipidus – an update. Semin Nephrol 26:209–223. doi:10.1016/j.semnephrol.2006.03.003

    Article  CAS  PubMed  Google Scholar 

  9. Christensen JH, Siggard C, Corydon TJ, deSanctis L, Kovacs L, Robertson GL, Gregersen N, Rittig S (2004) Six novel mutations in the arginine vasopressin gene in 15 kindreds with autosomal dominant familial neurohypophyseal diabetes insipidus give further insight into the pathogenesis. Eur J Hum Genet 12:44–51. doi:10.1038/sj.ejhg.5201086

    Article  CAS  PubMed  Google Scholar 

  10. Deniz F, Acar C, Saglar E, Erdem B, Karaduman T, Yonem A, Cagiltay E, Ay SA, Mergen H (2015) Identification of a novel deletion in AVP-NPII gene in a patient with central diabetes insipidus. Ann Clin Lab Sci 45:588–592

    CAS  PubMed  Google Scholar 

  11. Hagiwara D, Arima H, Morishita Y, Wenjun L, Azuma Y, Ito Y, Suga H, Goto M, Banno R, Sugimura Y, Shiota A, Asai N, Takahashi M, Oiso Y (2014) Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophyseal diabetes insipidus. Cell Death Dis 5, e1148. doi:10.1038/cddis.2014.124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hansen LK, Rittig S, Robertson GL (1997) Genetic basis of familial neurohypophyseal diabetes insipidus. Trends Endocrinol Metab 8:363–372

    Article  CAS  PubMed  Google Scholar 

  13. Ilhan M, Tiryakioglu NO, Karaman O, Coskunpinar E, Yildiz RS, Turgut S, Tiryakioglu D, Toprak H, Tasan E (2016) A novel AVP gene mutation in a Turkish family with neurohypophyseal diabetes insipidus. J Endocrinol Invest 39:285–290. doi:10.1007/s40618-015-0357-9

    Article  CAS  PubMed  Google Scholar 

  14. Ito M, Jameson JL, Ito M (1997) Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum. J Clin Invest 99:1897–1905. doi:10.1172/JCI119357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ito M, Oiso Y, Murase T, Kondo K, Saito H, Chinzei T, Racchi M, Lively MO (1993) Possible involvement of inefficient cleavage of preprovasopressin by signal peptidase as a cause for familial central diabetes insipidus. J Clin Invest 91:2565–2571. doi:10.1172/JCI116494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jendle J, Christensen JH, Kvistgaard H, Gregersen N, Rittig S (2012) Late-onset familial neurohypophyseal diabetes insipidus due to a novel mutation in the AVP gene. Clin Endocrinol 77:586–592. doi:10.1111/j.1365-2265.2012.04417.x

    Article  CAS  Google Scholar 

  17. Kanemitsu N, Kawauchi A, Nishida M, Tanaka Y, Mizitani Y, Shirahama S, Miki T (2002) Familial central diabetes insipidus detected by nocturnal enuresis. Pediatr Nephrol 17:1063–1065. doi:10.1007/s00467-002-0985-0

    Article  PubMed  Google Scholar 

  18. Kovács L, Robertson GL (1991) Diabetes insipidus. In: Conn RL (ed) Conn’s Current Diagnosis. W.B. Saunders, Philadelphia, pp 819–822

    Google Scholar 

  19. Lindenthal V, Mainberger A, Moris-Rosendahl DJ, Löning L, Mayer W, Müller HL (2013) Dilatative uropathy as a manifestation of neurohypophyseal diabetes insipidus due to a novel mutation in the arginine vasopressin-neurophysin-II gene. Klin Pediatr 225:407–412. doi:10.1055/s-0033-1354388

    Article  CAS  Google Scholar 

  20. McLeod JF, Kovács L, Gaskill MB, Rittig S, Bradley GS, Robertson GL (1993) Familial neurohypophyseal diabetes insipidus associated with a signal peptide mutation. J Clin Endocrinol Metab 77:599A–599G. doi:10.1210/jcem.77.3.8370682

    Article  CAS  PubMed  Google Scholar 

  21. Perrotta S, Di Iorgi N, Della Ragione F, Scianguetta S, Borriello A, Allegri AEM, Ferraro M, Santoro C, Napoli F, Calcagno A, Giaccardi M, Cappa M, Salerno MC, Cozzolino D, Maghnie M (2015) Early-onset central diabetes insipidus s associated with de novo arginine vasopressin-neurophysin II or Wolfram syndrome 1 gene mutations. Eur J Endocrinol 172:461–472. doi:10.1530/EJE-14-0942

    Article  CAS  PubMed  Google Scholar 

  22. Repaske DR, Browning JE (1994) A de novo mutation in the coding sequence for neurophysin-II (Pro24→Leu) is associated with onset and transmission of autosomal dominant neurohypophyseal diabetes insipidus. J Clin Endocrinol Metab 79:421–427. doi:10.1210/jcem.79.2.8045958

    CAS  PubMed  Google Scholar 

  23. Repaske DR, Medlei R, Gültekin EK, Krishnamani MR, Halaby G, Findling JW, Phillips JA 3rd (1997) Heterogeneity in clinical manifestation of autosomal dominant neurohypophyseal diabetes insipidus caused by a mutation encoding Ala−1→Val in the signal peptide of the arginine vasopressin/neurophysin II/copeptin precursor. J Clin Endocrinol Metab 82:51–56. doi:10.1210/jcem.82.1.3660

    CAS  PubMed  Google Scholar 

  24. Rittig S, Robertson GL, Siggard C, Kovács L, Gregersen N, Nyborg J, Pedersen EB (1996) Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus. Am J Hum Genet 58:107–117

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Siggaard C, Rittig S, Corydon TJ, Andreasen PH, Jensen TG, Andresen BS, Robertson GL, Gregersen N, Bolund L, Pedersen EB (1999) Clinical and molecular evidence of abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation. J Clin Endocrinol Metab 84:2933–2941. doi:10.1210/jcem.84.8.5869

    CAS  PubMed  Google Scholar 

  26. Siggard C, Christensen JH, Corydon TJ, Rittig S, Robertson GL, Gregersen N, Bolund L, Pedersen EB (2005) Expression of three different mutations in the arginine vasopressin gene suggests genotype-phenotype correlation in familial neurohypophyseal diabetes insipidus kindreds. Clin Endocrinol (Oxf) 63:207–216. doi:10.1111/j.1365-2265.2005.02327.x

    Article  Google Scholar 

  27. Srinivasan R, Ball S, Ward-Platt M, Bourn D, McAnulty C, Cheetham T (2013) Utility of genetic testing in suspected familial cranial diabetes insipidus. Endocrinol Diabetes Metab Case Rep 2013:130068. doi:10.1530/EDM-13-0068

    PubMed  PubMed Central  Google Scholar 

  28. Stephen MD, Fenwick RG, Brosnan PG (2012) Polyuria and polydipsia in a young child: diagnostic considerations and identification of a novel mutation causing familial neurohypophyseal diabetes insipidus. Pituitary 15:S1–S5. doi:10.1007/s11102-010-0230-y

    Article  PubMed  Google Scholar 

  29. Turkkaharaman D, Saglar E, Karaduman T, Mergen H (2015) AVP-NPII gene mutations and clinical characteristics of the patients with autosomal dominant familial central diabetes insipidus. Pituitary 18:898–904. doi:10.1007/s11102-015-0668z

    Article  Google Scholar 

  30. Van Lieburg AF, Knoers NVAM, Monnens LAH (1999) Clinical presentation and follow-up of 30 patients with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 10:1958–1964

    PubMed  Google Scholar 

  31. Wolf MT, Dötsch J, Metzler M, Holder M, Repp R, Rascher W (2003) A new missense mutation of the vasopressin-neurophysin II gene in a family with neurohypophyseal diabetes insipidus. Horm Res 60:143–147. doi: 72526.

  32. Yan Z, Hoffmann A, Kaiser EK, Grunwald WC Jr, Cool DR (2011) Misfolding of mutated vasopressin causes ER-retention and activation of ER-stress markers in neuro-2a cells. Open Neuroendocrinol J 4:136–146. doi:10.2174/1876528901104010136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Ministry of Health of the Slovak Republic under the project registration number 2012/5-UKBA-5, Slovak Research and Development Agency under the project registration number APVV-14-0234, Charles University in Prague under the project registration number PRVOUK P24/LF1/3 and P49/LF1/3 and Ministry of Health of the Czech Republic under the project registration number RVO-VFN 64165/2012.

Contributions

GN, VJ, and LK designed and wrote the manuscript. JK, JZ, VH, JL, DV, and ĽK made the clinical diagnosis and follow-up in described families. GN, JK, VH, and JL recorded the pedigrees. VJ conducted the water deprivation tests during the hospital admission in examined probands. GN, TD, and LK collected the clinical data. MČ and MT made the DNA testing and in silico analyses of the novel variants. All authors reviewed the manuscript. LK reviewed and edited the manuscript. All authors contributed to and have approved the final manuscript. GN and VJ contributed equally and are joint first authors.

Author information

Authors and Affiliations

  1. 2nd Department of Pediatrics, Faculty of Medicine, Comenius University in Bratislava and University Children’s Hospital Bratislava, Limbová 1, 833 40, Bratislava, Slovakia

    Gabriela Hrčková, Viktor Jankó, Michaela Čižmárová, Ľudmila Košťálová, Tomáš Dallos & László Kovács

  2. Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital Prague, Kateřinská 32, 121 08, Prague 2, Czech Republic

    Jitka Kytnarová, Markéta Tesařová & Jiří Zeman

  3. Department of Pediatrics, County Hospital Levice, SNP 19, 934 01, Levice, Slovakia

    Daniela Virgová

  4. 3rd Internal Clinic—Clinic of Endocrinology and Metabolism, First Faculty of Medicine, Charles University in Prague and General University Hospital Prague, Kateřinská 32, 121 08, Prague 2, Czech Republic

    Václav Hána

  5. Department of Pediatrics of the University Children’s Hospital in Motol and 2nd Faculty of Medicine of Charles University in Prague, V Úvalu 84, 150 06, Prague 5, Czech Republic

    Jan Lebl

Authors
  1. Gabriela Hrčková
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viktor Jankó
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jitka Kytnarová
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michaela Čižmárová
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Markéta Tesařová
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ľudmila Košťálová
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniela Virgová
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tomáš Dallos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Václav Hána
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jan Lebl
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jiří Zeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. László Kovács
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to László Kovács.

Ethics declarations

The study involves human participants. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Medical Ethical Committee of the University Children’s Hospital Bratislava, Slovakia has approved the study. Informed consent was obtained from all individual participants who were tested genetically.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Communicated by Beat Steinmann

Gabriela Hrčková and Viktor Jankó contributed equally.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hrčková, G., Jankó, V., Kytnarová, J. et al. Two novel mutations in seven Czech and Slovak kindreds with familial neurohypophyseal diabetes insipidus—benefit of genetic testing. Eur J Pediatr 175, 1199–1207 (2016). https://doi.org/10.1007/s00431-016-2759-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-016-2759-x

Keywords

Search

Navigation