Phenotypic and genotypic characteristics of children with Bartter syndrome

Introduction. Bartter syndrome (BS) is a group of autosomal-recessive tubular disorders and it is classified into five genetic subtypes. BS can also be classified by phenotype (antenatal, classic). Patients with mutations in the same gene can present different phenotypes. In the present study, target gene sequencing was performed to evaluate the genotype-phenotype relationship. Methods. Biochemical, clinical and renal ultrasonography results were collected at presentation and the last clinic visit. Genetic analyses were performed. The findings of patients with classical BS (cBS) and antenatal BS (aBS) at presentation and the last visit were compared. Results. Our study included 21 patients (12 female, 57.1%) from 20 families with BS. The median age at diagnosis was 8 months and the median follow-up period was 39 months. The most frequent complaint was growth failure. We have found 18 different types of mutations in four genes, including nine in the CLCNKB gene, seven in the SLCA12A1 gene, one in the KCNJ1 gene and one in the BSND gene. In ten patients, nine different types of CLCNKB gene mutations were detected, five of them were novel. Seven different mutations in the SLC12A1 gene were detected in eight patients, five of them were novel. Compared to patients with aBS and cBS, prematurity was significantly higher in the group with aBS. Nephrocalcinosis was present in only one patient with cBS, all the ten hypercalciuric patients with aBS had nephrocalcinosis at the time of diagnosis and the last visit. The mean height standard deviation score (SDS) of patients with aBS were significantly lower than the cBS group at the time of presentation. The mean weight SDS at the time of presentation was worse in patients with aBS than in patients with cBS. The mean plasma potassium and chloride concentrations were significantly lower in the patients with cBS at the time of diagnosis. Conclusions. This investigation revealed the mutation characteristics and phenotype-genotype relationship of our patients and provided valuable data for genetic counseling.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Bartter FC, Pronove P, Gill JR Jr, MacCardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis: a new syndrome. Am J Med 1962; 33:811-828. https:// doi.org/10.1016/0002-9343(62)90214-0
2. Matsunoshita N, Nozu K, Shono A, et al. Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo-Bartter/Gitelman syndrome based on clinical characteristics. Genet Med 2016; 18: 180-188. https://doi.org/10.1038/gim.2015.56
3. Lee BH, Cho HY, Lee H, et al. Genetic basis of Bartter syndrome in Korea. Nephrol Dial Transplant 2012; 27: 1516-1521. https://doi.org/10.1093/ndt/gfr475
4. Laghmani K, Beck BB, Yang SS, et al. Polyhydramnios, Transient Antenatal Bartter’s Syndrome, and MAGED2 Mutations. N Engl J Med 2016; 374: 1853- 1863. https://doi.org/10.1056/NEJMoa1507629
5. Igarashi P, Vanden Heuvel GB, Payne JA, Forbush B 3rd. Cloning, embryonic expression, and alternative splicing of a murine kidney-specific Na- K-Cl cotransporter. Am J Physiol 1995; 269: 405-418. https://doi.org/10.1152/ajprenal.1995.269.3.F405
6. Simon DB, Karet FE, Rodriguez-Soriano J, et al. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 1996; 14: 152-156. https://doi.org/10.1038/ ng1096-152
7. Károlyi L, Konrad M, Köckerling A, et al. Mutations in the gene encoding the inwardly rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: Evidence for genetic heterogeneity. Hum Mol Genet 1997; 6: 17-26. https://doi.org/10.1093/hmg/6.1.17
8. Jeck N, Derst C, Wischmeyer E, et al. Functional heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney Int 2001; 59: 1803-1811. https://doi.org/10.1046/j.1523- 1755.2001.0590051803.x
9. Cunha T da S, Heilberg IP. Bartter syndrome: causes, diagnosis, and treatment. Int J Nephrol Renovasc Dis 2018; 11: 291-301. https://doi.org/10.2147/IJNRD. S155397
10. García Castaño A, Pérez de Nanclares G, Madariaga L, et al. Genetics of type III Bartter syndrome in Spain, proposed diagnostic algorithm. PLoS One 2013; 8: e74673. https://doi.org/10.1371/journal. pone.0074673
11. Rees L, Brogan PA, Bockenhauer D, Webb NJA, eds. Renal calculi and nephrocalcinosis. In: Paediatric nephrology. Oxford specialist handbooks in paediatrics (1st ed). Oxford, Oxford University Press, 2012: 177. https://doi.org/10.1093/ med/9780199601370.003.0079
12. Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009; 20: 629-637. https://doi. org/10.1681/ASN.2008030287
13. Neyzi O, Bundak R, Gökçay G, et al. Reference values for weight, height, head circumference, and body mass index in Turkish children. J Clin Res Pediatr Endocrinol 2015; 7: 280-293. https://doi. org/10.4274/jcrpe.2183
14. Dong Y, Ji G, Feng QW, Zeng XT, Jiang GR. A novel splicing mutation in CLCNKB in a Chinese patient with Bartter syndrome type III. Chin Med J 2010; 123: 3151-3153 https://doi.org/10.3760/ cma.j.issn.0366-6999.2010.21.037
15. Han Y, Lin Y, Sun Q, Wang S, Gao Y, Shao L. Mutation spectrum of Chinese patients with Bartter syndrome. Oncotarget 2017; 8: 101614-101622. https://doi.org/10.18632/oncotarget.21355
16. Messa HL, de Oliveira Achili Ferreira JC, Rangel- Santos A, Vaisbich MH. Genetic spectrum of Brazilian suspected Bartter Syndrome Patients. Research Square [Preprint]. https://doi.org/10.21203/ rs.3.rs-35560/v1
17. Seys E, Andrini O, Keck M, et al. Clinical and genetic spectrum of Bartter Syndrome type 3. J Am Soc Nephrol 2017; 28: 2540-2552. https://doi.org/10.1681/ ASN.2016101057
18. Tajima T, Nawate M, Takahashi Y, et al. Molecular analysis of the CLCNKB gene in Japanese patients with classic Bartter syndrome. Endocr J 2006; 53: 647-652. https://doi.org/10.1507/endocrj.k06-034
19. Bircan Z, Harputluoglu F, Jeck N. Deletion of exons 2-4 in the BSND gene causes severe antenatal Bartter syndrome. Pediatr Nephrol 2009; 24: 841-844. https:// doi.org/10.1007/s00467-008-1008-6
20. García-Nieto V, Flores C, Luis-Yanes MI, Gallego E, Villar J, Claverie-Martín F. Mutation G47R in the BSND gene causes Bartter syndrome with deafness in two Spanish families. Pediatr Nephrol 2006; 21: 643-648. https://doi.org/10.1007/s00467-006-0062-1
21. Ozlu F, Yapicioğlu H, Satar M, et al. Barttin mutations in antenatal Bartter syndrome with sensorineural deafness. Pediatr Nephrol 2006; 21: 1056-1057. https://doi.org/10.1007/s00467-006-0108-4
22. Zaffanello M, Taranta A, Palma A, Bettinelli A, Marseglia GL, Emma F. Type IV Bartter syndrome: report of two new cases. Pediatr Nephrol 2006; 21: 766-770. https://doi.org/10.1007/s00467-006-0090-x
23. Brum S, Rueff J, Santos JR, Calado J. Unusual adultonset manifestation of an attenuated Bartter’s syndrome type IV renal phenotype caused by a mutation in BSND. Nephrol Dial Transplant 2007; 22: 288-289. https://doi.org/10.1093/ndt/gfl493
24. Puricelli E, Bettinelli A, Borsa N, et al. Long-term follow-up of patients with Bartter syndrome type I and II. Nephrol Dial Transplant 2010; 25: 2976-2981. https://doi.org/10.1093/ndt/gfq119
25. Bockenhauer D, Bichet DG. Inherited secondary nephrogenic diabetes insipidus: concentrating on humans. Am J Physiol Renal Physiol 2013; 304: F1037- 42. https://doi.org/10.1152/ajprenal.00639.2012
26. Haycock GB. The influence of sodium on growth in infancy. Pediatr Nephrol 1993; 7: 871-875. https:// doi.org/10.1007/BF01213376
27. Buyukcelik M, Keskin M, Kilic BD, Kor Y, Balat A. Bartter syndrome and growth hormone deficiency: three cases. Pediatr Nephrol 2012; 27: 2145-2148. https://doi.org/10.1007/s00467-012-2212-y
28. Hochberg Z, Amit T, Flyvbjerg A, Dørup I. Growth hormone (GH) receptor and GH-binding protein deficiency in the growth failure of potassiumdepleted rats. J Endocrinol 1995; 147: 253-258. https://doi.org/10.1677/joe.0.1470253
29. Reinalter SC, Gröne HJ, Konrad M, Seyberth HW, Klaus G. Evaluation of long-term treatment with indomethacin in hereditary hypokalemic salt-losing tubulopathies. J Pediatr 2001; 139: 398-406. https:// doi.org/10.1067/mpd.2001.117007
30. Finer G, Shalev H, Birk OS, et al. Transient neonatal hyperkalemia in the antenatal (ROMK defective) Bartter syndrome. J Pediatr 2003; 142: 318-323. https://doi.org/10.1067/mpd.2003.100
31. Brochard K, Boyer O, Blanchard A, et al. Phenotype-genotype correlation in antenatal and neonatal variants of Bartter syndrome. Nephrol Dial Transplant 2009; 24: 1455-1464. https://doi. org/10.1093/ndt/gfn689
32. Mrad FCC, Soares SBM, de Menezes Silva LAW, Dos Anjos Menezes PV, Simões-E-Silva AC. Bartter’s syndrome: clinical findings, genetic causes and therapeutic approach. World J Pediatr 2021; 17: 31- 39. https://doi.org/10.1007/s12519-020-00370-4
33. Besouw MTP, Kleta R, Bockenhauer D. Bartter and Gitelman syndromes: Questions of class. Pediatr Nephrol 2020; 35: 1815-1824. https://doi.org/10.1007/ s00467-019-04371-y
34. García Castaño A, Pérez de Nanclares G, Madariaga L, et al. Poor phenotype-genotype association in a large series of patients with Type III Bartter syndrome. PLoS One 2017; 12: e0173581. https://doi. org/10.1371/journal.pone.0173581
35. Konrad M, Vollmer M, Lemmink HH, et al. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol 2000; 11: 1449-1459. https://doi.org/10.1681/ ASN.V1181449
36. Simon DB, Bindra RS, Mansfield TA, et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III. Nat Genet 1997; 17: 171- 178. https://doi.org/10.1038/ng1097-171
37. Sahbani D, Strumbo B, Tedeschi S, et al. Functional study of novel Bartter’s Syndrome mutations in ClC-Kb and rescue by the accessory subunit barttin toward personalized medicine. Front Pharmacol 2020; 11: 327. https://doi.org/10.3389/ fphar.2020.00327
38. Acar FA, Işik G, Mutlu M, Kader Ş, Aslan Y, Kalyoncu M. Antenatal Bartter Syndrome Caused by a Novel Homozygous Mutation in SLC12A1 Gene. Indian J Nephrol 2019; 29: 360-363. https://doi.org/10.4103/ ijn.IJN_175_18
39. Adachi M, Asakura Y, Sato Y, et al. Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1. Endocr J 2007; 54: 1003-1007. https://doi.org/10.1507/endocrj.k06-204

APA	Güven S, Gökce İ, Alavanda C, Cicek n, Demirci Bodur E, SAK M, Pul S, Türkkan Ö, Yıldız N, ATA P, ALPAY H (2022). Phenotypic and genotypic characteristics of children with Bartter syndrome. , 825 - 838. 10.24953/turkjped.2021.4697
Chicago	Güven Serçin,Gökce İbrahim,Alavanda Ceren,Cicek neslihan,Demirci Bodur Ece,SAK MEHTAP,Pul Serim,Türkkan Özde nisa,Yıldız Nurdan,ATA PINAR,ALPAY HARİKA Phenotypic and genotypic characteristics of children with Bartter syndrome. (2022): 825 - 838. 10.24953/turkjped.2021.4697
MLA	Güven Serçin,Gökce İbrahim,Alavanda Ceren,Cicek neslihan,Demirci Bodur Ece,SAK MEHTAP,Pul Serim,Türkkan Özde nisa,Yıldız Nurdan,ATA PINAR,ALPAY HARİKA Phenotypic and genotypic characteristics of children with Bartter syndrome. , 2022, ss.825 - 838. 10.24953/turkjped.2021.4697
AMA	Güven S,Gökce İ,Alavanda C,Cicek n,Demirci Bodur E,SAK M,Pul S,Türkkan Ö,Yıldız N,ATA P,ALPAY H Phenotypic and genotypic characteristics of children with Bartter syndrome. . 2022; 825 - 838. 10.24953/turkjped.2021.4697
Vancouver	Güven S,Gökce İ,Alavanda C,Cicek n,Demirci Bodur E,SAK M,Pul S,Türkkan Ö,Yıldız N,ATA P,ALPAY H Phenotypic and genotypic characteristics of children with Bartter syndrome. . 2022; 825 - 838. 10.24953/turkjped.2021.4697
IEEE	Güven S,Gökce İ,Alavanda C,Cicek n,Demirci Bodur E,SAK M,Pul S,Türkkan Ö,Yıldız N,ATA P,ALPAY H "Phenotypic and genotypic characteristics of children with Bartter syndrome." , ss.825 - 838, 2022. 10.24953/turkjped.2021.4697
ISNAD	Güven, Serçin vd. "Phenotypic and genotypic characteristics of children with Bartter syndrome". (2022), 825-838. https://doi.org/10.24953/turkjped.2021.4697

APA	Güven S, Gökce İ, Alavanda C, Cicek n, Demirci Bodur E, SAK M, Pul S, Türkkan Ö, Yıldız N, ATA P, ALPAY H (2022). Phenotypic and genotypic characteristics of children with Bartter syndrome. Turkish Journal of Pediatrics, 64(5), 825 - 838. 10.24953/turkjped.2021.4697
Chicago	Güven Serçin,Gökce İbrahim,Alavanda Ceren,Cicek neslihan,Demirci Bodur Ece,SAK MEHTAP,Pul Serim,Türkkan Özde nisa,Yıldız Nurdan,ATA PINAR,ALPAY HARİKA Phenotypic and genotypic characteristics of children with Bartter syndrome. Turkish Journal of Pediatrics 64, no.5 (2022): 825 - 838. 10.24953/turkjped.2021.4697
MLA	Güven Serçin,Gökce İbrahim,Alavanda Ceren,Cicek neslihan,Demirci Bodur Ece,SAK MEHTAP,Pul Serim,Türkkan Özde nisa,Yıldız Nurdan,ATA PINAR,ALPAY HARİKA Phenotypic and genotypic characteristics of children with Bartter syndrome. Turkish Journal of Pediatrics, vol.64, no.5, 2022, ss.825 - 838. 10.24953/turkjped.2021.4697
AMA	Güven S,Gökce İ,Alavanda C,Cicek n,Demirci Bodur E,SAK M,Pul S,Türkkan Ö,Yıldız N,ATA P,ALPAY H Phenotypic and genotypic characteristics of children with Bartter syndrome. Turkish Journal of Pediatrics. 2022; 64(5): 825 - 838. 10.24953/turkjped.2021.4697
Vancouver	Güven S,Gökce İ,Alavanda C,Cicek n,Demirci Bodur E,SAK M,Pul S,Türkkan Ö,Yıldız N,ATA P,ALPAY H Phenotypic and genotypic characteristics of children with Bartter syndrome. Turkish Journal of Pediatrics. 2022; 64(5): 825 - 838. 10.24953/turkjped.2021.4697
IEEE	Güven S,Gökce İ,Alavanda C,Cicek n,Demirci Bodur E,SAK M,Pul S,Türkkan Ö,Yıldız N,ATA P,ALPAY H "Phenotypic and genotypic characteristics of children with Bartter syndrome." Turkish Journal of Pediatrics, 64, ss.825 - 838, 2022. 10.24953/turkjped.2021.4697
ISNAD	Güven, Serçin vd. "Phenotypic and genotypic characteristics of children with Bartter syndrome". Turkish Journal of Pediatrics 64/5 (2022), 825-838. https://doi.org/10.24953/turkjped.2021.4697