Hostname: page-component-586b7cd67f-l7hp2 Total loading time: 0 Render date: 2024-11-24T05:25:41.990Z Has data issue: false hasContentIssue false
  • English
  • Français

Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome

Published online by Cambridge University Press:  18 July 2012

Annika Winbo ,
Olof Sandström ,
Richard Palmqvist  and
Annika Rydberg
Annika Winbo*
Affiliation:
Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
Olof Sandström
Affiliation:
Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
Richard Palmqvist
Affiliation:
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
Annika Rydberg
Affiliation:
Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
*
Correspondence to: A. Winbo, MD, Department of Clinical Sciences, Pediatrics, Umeå University, SE 901 85 Umeå, Sweden. Tel: +46907852122; Fax: +46907852522; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Aim

We investigated extra-cardiac clinical symptoms and signs in the rare Jervell and Lange-Nielsen Syndrome, characterised by impaired KCNQ1 function, a gene essential for gastric acid secretion.

Methods

All Swedish Jervell and Lange-Nielsen cases with double KCNQ1 mutations (14 cases) were investigated by medical record review, an interview, and were offered laboratory testing for iron-deficiency anaemia and gastrointestinal markers.

Results

A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed. Previous endoscopy in five cases had revealed no case of coeliac or inflammatory bowel disease but three cases of mucosal hyperplasia/dysplasia. Current signs of anaemia or iron substitution were present in 9 of 12 tested cases. Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present. A significant correlation between elevated gastrin levels and concurrent iron-deficiency and/or anaemia was revealed (p-value 0.039).

Conclusions

A high frequency of extra-cardiac clinical symptoms and previous medical investigations was found. We propose that the Jervell and Lange-Nielsen Syndrome phenotypically includes gastrointestinal symptoms/signs and secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations. The resultant elevated gastrin level is a potential risk factor for later gastrointestinal cancer. Clinical monitoring with regard to developing anaemia and hypergastrinaemia should be considered in the Jervell and Lange-Nielsen Syndrome.

Keywords

GastrinKCNQ1 genemucosal hyperplasia/dysplasia
Type
Original Articles
Information
Cardiology in the Young , Volume 23 , Issue 3 , June 2013 , pp. 325 - 334
Copyright
Copyright © Cambridge University Press 2012 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Jervell, A, Lange-Nielsen, F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J 1957; 54: 59–68.Google Scholar
2. Schwartz, PJ, Spazzolini, C, Crotti, L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation 2006; 113: 783–790.Google Scholar
3. Goldenberg, I, Moss, AJ, Zareba, W, et al. Clinical course and risk stratification of patients affected with the Jervell and Lange-Nielsen syndrome. J Cardiovasc Electrophysiol 2006; 17: 1161–1168.Google Scholar
4. Splawski, I, Timothy, KW, Vincent, GM, Atkinson, DL, Keating, MT. Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med 1997; 336: 1562–1567.Google Scholar
5. Tyson, J, Tranebjaerg, L, Bellman, S, et al. IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum Mol Genet 1997; 6: 2179–2185.Google Scholar
6. Fraser, GR, Froggatt, P, Murphy, T. Genetical aspects of the cardio-auditory syndrome of Jervell and Lange-Nielsen (congenital deafness and electrocardiographic abnormalities). Ann Hum Genet 1964; 28: 133–157.Google Scholar
7. Jervell, A, Thingstad, R, Endsjo, TO. The surdo-cardiac syndrome: three new cases of congenital deafness with syncopal attacks and Q-T prolongation in the electrocardiogram. Am Heart J 1966; 72: 582–593.Google Scholar
8. Langslet, A, Sorland, SJ. Surdocardiac syndrome of Jervell and Lange-Nielsen, with prolonged QT interval present at birth, and severe anaemia and syncopal attacks in childhood. Br Heart J 1975; 37: 830–832.Google Scholar
9. Tranebjaerg, L, Bathen, J, Tyson, J, Bitner-Glindzicz, M. Jervell and Lange-Nielsen syndrome: a Norwegian perspective. Am J Med Genet 1999; 89: 137–146.Google Scholar
10. Jespersen, T, Grunnet, M, Olesen, SP. The KCNQ1 potassium channel: from gene to physiological function. Physiology (Bethesda) 2005; 20: 408–416.Google Scholar
11. Song, P, Groos, S, Riederer, B, et al. KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion. J Physiol 2009; 587: 3955–3965.Google Scholar
12. Takagi, T, Nishio, H, Yagi, T, et al. Phenotypic analysis of vertigo 2 Jackson mice with a Kcnq1 potassium channel mutation. Exp Anim 2007; 56: 295–300.Google Scholar
13. Waldegger, S. Heartburn: cardiac potassium channels involved in parietal cell acid secretion. Pflugers Arch 2003; 446: 143–147.Google Scholar
14. Grahammer, F, Herling, AW, Lang, HJ, et al. The cardiac K+ channel KCNQ1 is essential for gastric acid secretion. Gastroenterology 2001; 120: 1363–1371.Google Scholar
15. Rice, KS, Dickson, G, Lane, M, et al. Elevated serum gastrin levels in Jervell and Lange-Nielsen syndrome: a marker of severe KCNQ1 dysfunction? Heart Rhythm 2011; 8: 551–554.Google Scholar
16. Winbo A, Stattin EL, Diamant UB, Persson J, Jensen SM, Rydberg A. Prevalence, mutation spectrum, and cardiac phenotype of the Jervell and Lange-Nielsen syndrome in Sweden. Europace, 2012. Epub 28 April 2012, doi:10.1093/eurospace/eus111Google Scholar
17. Chouabe, C, Neyroud, N, Richard, P, et al. Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. Cardiovasc Res 2000; 45: 971–980.Google Scholar
18. Gouas, L, Bellocq, C, Berthet, M, et al. New KCNQ1 mutations leading to haploinsufficiency in a general population; defective trafficking of a KvLQT1 mutant. Cardiovasc Res 2004; 63: 60–68.CrossRefGoogle Scholar
19. Larsen, LA, Fosdal, I, Andersen, PS, et al. Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene. European Journal of Human Genetics 1999; 7: 724–728.Google Scholar
20. Napolitano, C, Priori, SG, Schwartz, PJ, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA 2005; 294: 2975–2980.Google Scholar
21. Neyroud, N, Tesson, F, Denjoy, I, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 1997; 15: 186–189.Google Scholar
22. Splawski, I, Shen, J, Timothy, KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102: 1178–1185.Google Scholar
23. Wei, J, Fish, FA, Myerburg, RJ, Roden, DM, George, AL Jr. Novel KCNQ1 mutations associated with recessive and dominant congenital long QT syndromes: evidence for variable hearing phenotype associated with R518X. Hum Mutat 2000; 15: 387–388.Google Scholar
24. Lee, MP, Ravenel, JD, Hu, RJ, et al. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J Clin Invest 2000; 106: 1447–1455.Google Scholar
25. Baird, IM, Wilson, GM. The pathogenesis of anaemia after partial gastrectomy. II. Iron absorption after partial gastrectomy. Q J Med 1959; 28: 35–41.Google Scholar
26. Baird, IM, Blackburn, EK, Wilson, GM. The pathogenesis of anaemia after partial gastrectomy. I. Development of anaemia in relation to time after operation, blood loss, and diet. Q J Med 1959; 28: 21–34.Google Scholar
27. Schade, SG, Cohen, RJ, Conrad, ME. Effect of hydrochloric acid on iron absorption. N Engl J Med 1968; 279: 672–674.Google Scholar
28. Conrad, ME, Schade, SG. Ascorbic acid chelates in iron absorption: a role for hydrochloric acid and bile. Gastroenterology 1968; 55: 35–45.Google Scholar
29. Catherine SC. Gastric acid secretion. In: Editor-in-Chief: Leonard J (ed.). Encyclopedia of Gastroenterology. Elsevier, New York, 2004, pp 105–116.Google Scholar
30. Graham JD. Gastrin. In: Editor-in-Chief: Luciano M (ed.). Encyclopedia of Endocrine Diseases. Elsevier, New York, 2004, pp 97–100.Google Scholar
31. Aly, A, Shulkes, A, Baldwin, GS. Gastrins, cholecystokinins and gastrointestinal cancer. Biochim Biophys Acta 2004; 1704: 1–10.Google Scholar
32. Ferrand, A, Wang, TC. Gastrin and cancer: a review. Cancer Lett 2006; 238: 15–29.Google Scholar
33. Hansen, OH, Pedersen, T, Larsen, JK, Rehfeld, JF. Effect of gastrin on gastric mucosal cell proliferation in man. Gut 1976; 17: 536–541.Google Scholar
34. Rivas, A, Francis, HW. Inner ear abnormalities in a Kcnq1 (Kvlqt1) knockout mouse: a model of Jervell and Lange-Nielsen syndrome. Otol Neurotol 2005; 26: 415–424.CrossRefGoogle Scholar
35. Friedmann, I, Fraser, GR, Froggatt, P. Pathology of the ear in the cardioauditory syndrome of Jervell and Lange-Nielsen (recessive deafness with electrocardiographic abnormalities). J Laryngol Otol 1966; 80: 451–470.Google Scholar
36. Vallon, V, Grahammer, F, Volkl, H, et al. KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc Natl Acad Sci U S A 2005; 102: 17864–17869.Google Scholar
37. Modlin, IM, Lawton, GP, Miu, K, et al. Pathophysiology of the fundic enterochromaffin-like (ECL) cell and gastric carcinoid tumours. Ann R Coll Surg Engl 1996; 78: 133–138.Google Scholar
38. Wang, TC, Dangler, CA, Chen, D, et al. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology 2000; 118: 36–47.Google Scholar
39. Elso, CM, Lu, X, Culiat, CT, et al. Heightened susceptibility to chronic gastritis, hyperplasia and metaplasia in Kcnq1 mutant mice. Hum Mol Genet 2004; 13: 2813–2821.Google Scholar
40. Ehrchen, JM, Sunderkotter, C, Foell, D, Vogl, T, Roth, J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 2009; 86: 557–566.Google Scholar
41. Roseth, AG, Kristinsson, J, Fagerhol, MK, et al. Faecal calprotectin: a novel test for the diagnosis of colorectal cancer? Scand J Gastroenterol 1993; 28: 1073–1076.Google Scholar
42. Kapplinger, JD, Tester, DJ, Salisbury, BA, et al. Spectrum and prevalence of mutations from the first 2500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm 2009; 6: 1297–1303.Google Scholar
43. Dipple, KM, McCabe, ER. Phenotypes of patients with “simple” Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 2000; 66: 1729–1735.Google Scholar