Congenital nephrotic syndrome of the finnish type in the Republic of Belarus: clinical case report and analysis of molecular genetic features

BACKGROUND. Congenital nephrotic syndrome (CNS) is a rare autosomal recessive kidney disorder that manifests within the first three months of life. It is characterized by massive proteinuria, hypoalbuminemia, hypercholesterolemia, edema, steroid resistance and inevitable progression to end-stage chronic kidney disease (ESCKD). In 85 % of cases CNS is a monogenic disease.

THE AIM: To present a clinical case of genetically confirmed CNS of the Finnish type in the Republic of Belarus.

PATIENTS AND METHODS. A male infant from the first pregnancy and first full-term birth was examined. On the third day after birth testicular hydrocele, proteinuria and hypoalbuminemia were diagnosed and persisted despite transfusions of 20 % albumin solution. Further examination revealed persistent arterial hypertension and elevated levels of thyroid-stimulating hormone. At the age of 5 months bilateral nephrectomy was performed, followed by various forms of renal replacement therapy (peritoneal dialysis, hemodialysis, and kidney transplantation from a deceased donor). Molecular genetic testing identified two mutations in the NPHS1 gene in a compound heterozygote.

RESULTS. Mutations of the NPHS1 gene are associated with CNS of the Finnish type (Nephrotic syndrome, type 1, OMIM 256300). The identified variants NM_004646: exon18:c.2335-1G>A and NM_004646:exon8:c.C847T:p.Q283* differ from the ‘Finnish mutations’ Fin-major and Fin-minor and are in trans. The patient was also found to be homozygous for the p.R229Q polymorphism at locus rs61747728 of the NPHS2 gene. Morphological examination of the nephrectomy materials revealed changes characteristic of CNS of the Finnish type.

CONCLUSIONS. In this clinical case a child with compound heterozygous mutation in the NPHS1 gene and a homozygous rare polymorphic variant in the NPHS2 gene exhibited a severe course of CNS of the Finnish type with rapid progression to ESCKD. Molecular genetic testing confirmed the diagnosis of CNS of the Finnish type and allowed avoiding the administration of immunosuppressive therapy. Additionally, the results of molecular genetic analysis of the parents should be taken into account when planning future pregnancies.

1. Sharma J, Saha A, Ohri A et al. New insights from the genetic work-up in early onset nephrotic syndrome: report from a registry in western India. Pediatr Nephrol 2024;39(7):2099–2104. doi:10.1007/s00467-024-06295-8

2. Preston R, Stuart HM, Lennon R. Genetic testing in steroidresistant nephrotic syndrome: why, who, when and how? Pediatr Nephrol 2019;34(2):195–210. doi:10.1007/s00467-017-3838-6

3. Savenkova ND. Hereditary Congenital and Infantile Nephrotic Syndrome in Children: Strategy of Management with New Possibilities for Genetic Diagnosis and Therapy. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2020;65(6):12–21. (In Russ.)] doi:10.21508/1027-4065-2020-65-6-12-21

4. Gu Y, Han B, Zhu X, Chen Y. Prenatal diagnosis of congenital nephrotic syndrome of the Finnish type in a Chinese family. Taiwan J Obstet Gynecol 2021;60(4):758–762. doi:10.1016/j.tjog.2021.05.030

5. Wong W, Morris MC, Kara T. Congenital nephrotic syndrome with prolonged renal survival without renal replacement therapy. Pediatr Nephrol 2013;28:2313–2321. doi:10.1007/s00467-013-2584-7-7

6. Bel'kevich AG, SHinkorenko YUL, Kozyro IA et al. Mutations in NPHS1 and NPHS2 genes in nephrotic syndrome in children. "Zdorovye deti – budushchee strany": Materialy VII Nacional'nogo kongressa s mezhdunarodnym uchastiem, (Sankt-Peterburg, 15–16 iyunya 2023 g.) FORCIPE 2023; 6(Supl.1):83–84. (In Russ.)]

7. Tory K, Menyhárd DK, Woerner S, et al. Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nat Genet 2014;46(3):299–304. doi:10.1038/ng.2898

8. Bierzynska A, McCarthy H, Soderquest K et al. Genomic and clinical profiling of a national Nephrotic Syndrome cohort advocates a precision medicine approach to disease management. Kidney International 2017;91(4):937–947. doi:10.1016/j.kint.2016.10.013

9. Ashton E, Bockenhauer D, Boustred C et al. (2020). ASHG 2013 Poster: Development of a rapid genetic testing service for nephrotic syndrome using next generation sequencing. Conference: American Society of Human Genetics, At Boston, USA 2013. available at https://www.researchgate.net/publication/258860074_ASHG_2013_Poster_Development_of_a_rapid_genetic_testing_service_for_nephrotic_syndrome_using_next_generation_sequencing; last accessed 21 February 2025

10. Koziell A, Grech V, Hussain S et al. Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic functional inter-relationship in glomerular filtration. Hum Mol Genet 2002;11:379–388. doi:10.1093/hmg/11.4.379

11. Kari JA, Montini G, Bockenhauer D et al. Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years. Pediatr Nephrol 2014;29(11):2173–2180. doi:10.1007/s00467-014-2856-x

12. Machuca E, Benoit G, Nevo F et al. Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. J Am Soc Nephrol 2010;21(7):1209–1217. doi:10.1681/ASN.2009121309

13. Lenkkeri U, Männikkö M, McCready P et al. Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 1999;64(1):51–61. doi:10.1086/302182

14. Pereira AC, Pereira AB, Mota GF et al. NPHS2 R229Q functional variant is associated with microalbuminuria in the general population. Kidney Int 2004;65(3):1026–1030. doi:10.1111/j.1523-1755.2004.00479.x

15. Yаtskiu HA, Nikitchenko NV, Bialkevich HH et al. The spectrum of polymorphic variants in exons and UTRs NPHS1 and NPHS2 genes in patients with nephrotic syndrome. Molekulyarnaya i prikladnaya genetika 2023;35:123–131. (In Russ.)]

16. Kerti A, Csohány R, Wagner L et al. NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis. Pediatr Nephrol 2013;28(10):2061–2064. doi:10.1007/s00467-013-2542-4

17. Patrakka J, Kestilä M, Wartiovaara J et al. Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. Kidney Int 2000;58(3):972–980. doi:10.1046/j.1523-1755.2000.00254.x

18. Savenkova ND, Chakhalian MI. Clinical-genetic features and therapy strategy of hereditary congenital and infantile nephrotic syndrome in children (literature review). Nephrology (Saint-Petersburg) 2019;23(5):17–28. (In Russ.)] https://doi.org/10.24884/1561-6274-2019-23-5-17-28

19. Klaassen I, Özgören B, Sadowski CE et al. Response to cyclosporine in steroid-resistant nephrotic syndrome: discontinuation is possible. Pediatr Nephrol 2015;30(9):1477–1483. doi:10.1007/s00467-015-3109-3

20. Milovanova AM, Pushkov AA, Savostyanov KV et al. A study of genetic causes of congenital and infantile nephrotic syndrome in children of Russian Federation. Nephrology and Dialysis.2021;23(1):57–72. (In Russ.)] https://doi.org/10.28996/2618-9801-2021-1-57-72

21. Patrakka J, Ruotsalainen V, Reponen P et al. Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin. Transplantation 2002;73(3):394–403. doi:10.1097/00007890-200202150-00013

22. Bérody S, Heidet L, Gribouval O et al. Treatment and outcome of congenital nephrotic syndrome. Nephrol Dial Transplant 2019; 34(3):458–467. doi:10.1093/ndt/gfy015