Familial juvenile hyperuricemia in early childhood in a boy with a novel gene mutation

Abstract

Familial juvenile hyperuricemic nephropathy (FJHN) is a rare autosomal dominant disease caused by mutations in the uromodulin (UMOD) gene. It is characterized by the development of gout, tubulointerstitial nephropathy, and end-stage renal disease. Here we report a case of FJHN that was diagnosed in early childhood in a boy with a novel gene mutation. At the age of 4 years, the patient was admitted with a diagnosis of purpura nephritis. He was discharged following symptom alleviation. However, hyperuricemia (7–9 mg/dL) and mild renal dysfunction [creatinine-estimated glomerular filtration rate (eGFR): 80–90 mL/min/1.73 m2] persisted after discharge. FJHN was suspected on the basis of a maternal family history of hyperuricemia, renal dysfunction, and dialysis. Direct sequence analysis performed at the age of 5 years revealed a novel missense mutation (c766T > G), p.Cys256Gly, in exon 3. Urate-lowering therapy was started, which provided good uric acid control (6.0 mg/dL). At the age of 8 years, persistent renal dysfunction was observed (eGFR: 80–90 mL/min/1.73 m2). Interestingly, cases of FJHN with c744C > G (p.Cys248Trp) mutations also exhibit a high incidence of juvenile onset, and identical disulfide bridges are considered responsible for the accumulation of mutant UMOD in the endoplasmic reticulum. Pediatricians should consider UMOD mutation analysis for families with autosomal dominant tubulointerstitial kidney disease (ADTKD) and a bland urinary sediment, even if hyperuricemia is mild. Also, sex and genotype are very important prognostic factors for ADTKD caused by UMOD mutations.

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References

  1. 1.

    Eckardt K-U, Alper SL, Antignac C, Bleyer AJ, Chauveau D, Dahan K, Deltas C, Hosking A, Kmoch S, Rampoldi L, Wiesener M. Kidney disease: improving global outcomes. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—a KDIGO consensus report. Kidney Int. 2015;88:676–83.

    CAS  Article  Google Scholar 

  2. 2.

    Duncan H, Dixon AS. Gout, familial hyperuricaemia, and renal disease. Q J Med. 1960;29:127–35.

    CAS  PubMed  Google Scholar 

  3. 3.

    Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet. 2002;39:882–92.

    CAS  Article  Google Scholar 

  4. 4.

    Bleyer AJ, Zivná M, Kmoch S. Uromodulin-associated kidney disease. Nephron Clin Pract. 2011;118:c31–6.

    Article  Google Scholar 

  5. 5.

    Dahan K, Fuchshuber A, Adamis S, Smaers M, Kroiss S, Loute G, Cosyns JP, Hildebrandt F, Verellen-Dumoulin CH, Pirson Y. Familial juvenile hyperuricemic nephropathy and autosomal dominant medullary kidney cystic disease type 2: two facets of the same disease? J Am Soc Nephrol. 2001;12:2348–57.

    CAS  PubMed  Google Scholar 

  6. 6.

    Moskowitz JL, Piret SE, Lhotta K, Kitzler TM, Tashman AP, Velez E, Thakker RV, Kotanko P. Association between genotype and phenotype in uromodulin-associated kidney disease. Clin J Am Soc Nephrol. 2013;8:1349–57.

    CAS  Article  Google Scholar 

  7. 7.

    Uemura O, Nagai T, Ishikura K, Ito S, Hataya H, Gotoh Y, Fujita N, Akioka Y, Kaneko T, Honda M. Creatinine-based equation to estimate the glomerular filtration rate in Japanese children and adolescents with chronic kidney disease. Clin Exp Nephrol. 2014;18:626–33.

    CAS  Article  Google Scholar 

  8. 8.

    Turner JJ, Stacey JM, Harding B, Kotanko P, Lhotta K, Puig JG, Roberts I, Torres RJ, Thakker RV. Uromodulin mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab. 2003;88:1398–401.

    CAS  Article  Google Scholar 

  9. 9.

    Liu M, Chen Y, Liang Y, Liu Y, Wang S, Hou P, Zhang H, Zhao M. Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking. Gene. 2013;531:363–9.

    CAS  Article  Google Scholar 

  10. 10.

    Nasr SH, Lucia JP, Galgano SJ, Markowitz GS, D’Agati VD. Uromodulin storage disease. Kidney Int. 2008;73:971–6.

    CAS  Article  Google Scholar 

  11. 11.

    Bernascone I, Janas S, Ikehata M, Trudu M, Corbelli A, Schaeffer C, Rastaldi MP, Devuyst O, Rampoldi L. A transgenic mouse model for uromodulin-associated kidney diseases shows specific tubulointerstitial damage, urinary concentrating defect, and renal failure. Hum Mol Genet. 2010;19:2998–3010.

    CAS  Article  Google Scholar 

  12. 12.

    Fairbanks LD, Cameron JS, Venkat-Raman G, Rigden SP, Rees L, Van’T Hoff W, Mansell M, Pattison J, Goldsmith DJ, Simmonds HA. Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. QJM. 2002;95:597–607.

    CAS  Article  Google Scholar 

  13. 13.

    Labriola L, Ki D, Pirson Y. Outcome of kidney transplantation in familial juvenile hyperuricaemic nephropathy. Nephrol Dial Transplant. 2007;22:3070–3.

    Article  Google Scholar 

  14. 14.

    Kemter E, Sklenak S, Rathkolb B, de Angelis MH, Wolf E, Aigner B, Wanke R. No amelioration of uromodulin maturation and trafficking defect by sodium-4-phenylbutyrate in vivo: studies in mouse models of uromodulin-associated kidney disease. J Biol Chem. 2014;289:10715–26.

    CAS  Article  Google Scholar 

  15. 15.

    Yang H, Wu C, Zhao S, Guo J. Identification and characterization of D8C, a novel domain present in liver-specific LZP, uromodulin and glycoprotein 2, mutated in familial juvenile hyperuricaemic nephropathy. FEBS Lett. 2004;578:236–8.

    CAS  Article  Google Scholar 

  16. 16.

    Wolf MT, Beck BB, Zaucke F, Kunze A, Misselwitz J, Ruley J, Ronda T, Fischer A, Eifinger F, Licht C, Otto E. The uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect. Kidney Int. 2007;71:574–81.

    CAS  Article  Google Scholar 

  17. 17.

    Goicoechea M, Garcia V, Verdalles U, Verde E, Macias N, Santos A, de Jose AP, Cedeño S, Linares T, Luño J. Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial. Am J Kidney Dis. 2015;65:543–9.

    CAS  Article  Google Scholar 

  18. 18.

    Takir M, Kostek O, Ozkok A, Elcioglu OC, Bakan A, Erek A, Mutlu HH, Telci O, Semerci A, Odabas AR, Afsar B. Lowering uric acid with allopurinol improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. J Invest Med. 2015;63:924–9.

    CAS  Article  Google Scholar 

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Acknowledgments

I would like to thank Dr. Norio Taniguchi of Tokyo Women’s Medical University for performing this genetic test.

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Correspondence to Daishi Hirano.

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Takemasa, Y., Hirano, D., Kawakami, Y. et al. Familial juvenile hyperuricemia in early childhood in a boy with a novel gene mutation. CEN Case Rep (2021). https://doi.org/10.1007/s13730-020-00566-7

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Keywords

  • Familial juvenile hyperuricemic nephropathy
  • Autosomal dominant tubulointerstitial kidney disease
  • Uromodulin
  • Disulfide bridges
  • Chaperone therapy