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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 26-29

Heterogenous phenotypes of congenital nephrotic syndrome related to NPHS1 mutation

1 Paediatric Nephrology Centre, Hong Kong Children's Hospital; Department of Paediatric and Adolescent Medicine, Tuen Mun Hospital, Hong Kong, China
2 Paediatric Nephrology Centre, Hong Kong Children's Hospital, Hong Kong, China
3 Department of Pathology, Hong Kong Children's Hospital, Hong Kong, China

Date of Submission25-Apr-2020
Date of Decision18-Jul-2020
Date of Acceptance01-Apr-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Sze Wa Wong
Paediatric Nephrology Centre, Hong Kong Children's Hospital, Hong Kong
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_18_20

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We report the heterogeneous outcomes in congenital nephrotic syndrome (CNS) secondary to variants in NPHS1 gene. We retrospectively reviewed the records of all patients with genetically confirmed NPHS1-related CNS who presented to one center between 2000 and 2018. Four patients from three families were identified. Three progressed to kidney failure at 2–10 years and required kidney replacement therapy. Two patients with Arg1160Ter NPHS1 variant had slow disease progression, with one reaching only stage 2 chronic kidney disease in early adulthood. This report shows the phenotypic heterogeneity in CNS with NPSH1 variants indicating that genotype/phenotype correlations in NPHS1-related CNS are poor.

Keywords: Finnish nephrotic syndrome, nephrin, NPHS1

How to cite this article:
Wong SW, Hin Chan EY, Tak Ma AL, Ping Yuen LY, Lai WM. Heterogenous phenotypes of congenital nephrotic syndrome related to NPHS1 mutation. Asian J Pediatr Nephrol 2021;4:26-9

How to cite this URL:
Wong SW, Hin Chan EY, Tak Ma AL, Ping Yuen LY, Lai WM. Heterogenous phenotypes of congenital nephrotic syndrome related to NPHS1 mutation. Asian J Pediatr Nephrol [serial online] 2021 [cited 2022 Dec 2];4:26-9. Available from: https://www.ajpn-online.org/text.asp?2021/4/1/26/320180

  Introduction Top

Congenital nephrotic syndrome (CNS) is a rare disease, characterized by the onset of nephrotic syndrome within 3 months from birth.[1] Among different genetic causes, variations in NPHS1, which encodes nephrin, are the most common. Numerous variants of this gene have been described worldwide.[1],[2],[3] Due to poor patient and renal survival,[4] aggressive treatment with early kidney transplantation is advocated by some experts.[5] We share our experience in managing the four cases of NPHS1-related CNS, from three families, with highly variable clinical course and outcomes, highlighting CNS as a heterogeneous disease that merits individualized management.

  Methods Top

Among patients admitted or referred to one pediatric nephrology center for CNS between 2000 and 2018, we reviewed the records of those patients in whom the disease was considered to be secondary to variations in NPHS1 gene, as reported by the next-generation sequencing (NGS). The genes screened in the NGS panel included ACTN4, ADCK4, APOE, ARHGDIA, CD2AP, COL4A3, COL4A4, COL4A5, COQ2, DGKE, EMP2, FN1, INF2, LAMB2, LMX1B, MYH9, MYO1E, NPHS1, NPHS2, PAX2, PDSS2, PLCE1, PTPRO, SCARB2, SMARCAL1, TRPC6, and WT1. Gene variants were considered as disease causing if they were classified as pathogenic or likely pathogenic change based on their classification using 2015 criteria of the American College of Medical Genetics. All such variants were confirmed using Sanger sequencing.

  Results Top

Case 1

Patient 1 was a girl born to a consanguineous Pakistani couple and presented on day 18 of life with nephrotic syndrome. NGS confirmed homozygous variation for a known pathogenic variant, c.3478C>T [Table 1] and [Figure 1]a. She received regular albumin infusion, diuretics, angiotensin-converting enzyme inhibitor (ACE-I), indomethacin and warfarin, as prophylactic anticoagulant. Over time, proteinuria improved and there was good catch-up growth. Nonetheless, kidney function deteriorated and there was kidney failure by 10 years of age. Chronic hemodialysis was initiated.
Figure 1: Panel indicating the results of Sanger sequencing in the four patients with NPHS1-related nephrotic syndrome (NM_004646.3): (a) c.3478C>T variation in patients 1 and 2; (b) c.2944dupA in patient 3; and (c) c.809dupG and (d) c.712+2T >A in patient 4

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Table 1: Clinical characteristics of the four patients with NPHS1-related congenital nephrotic syndrome

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Case 2

Patient 2, the cousin of patient 1, was born to a nonconsanguineous Pakistani couple and first presented at 2.5 months old with generalized edema. Genetic testing was not available at that time. Kidney biopsy showed mesangial proliferation and global and diffuse effacement of podocyte foot processes. He was managed conservatively with ACE-I and indomethacin and was weaned off regular albumin infusions when 1-yr-old. The child remained stable, with disease relapse at the age of 7 years. Repeat kidney biopsy showed mild podocyte fusion. He was managed then as a minimal change disease with corticosteroids. Upon the diagnosis of steroid resistance, cyclosporine A was added, following which he achieved partial remission. Since the cousin had by then been diagnosed with NPHS1-related CNS, NGS was performed in him and showed the same pathogenic variation. Corticosteroids were discontinued but cyclosporine A was continued, for its effect of stabilizing the podocyte cytoskeleton, along with ACE-I. There were no disease relapses; however, there was progressive deterioration in kidney function leading to chronic kidney disease (CKD) stage 2 by 16 years old.

Case 3

Patient 3 was the only child of a consanguineous Pakistani couple. She presented with gross ascites on day 29 of life. NGS confirmed a homozygous known, pathogenic variation, c.2944dupA [Table 1] and [Figure 1]b. Both parents were heterozygous carriers of the variation. Despite optimizing medical treatment, there was persistent massive proteinuria and poor growth. With unilateral nephrectomy and institution of gastrostomy feeding, she demonstrated satisfactory catch-up growth. Even so, she developed kidney failure at 25 months of age and was initiated on hemodialysis in the preparation for kidney transplantation.

Case 4

Patient 4 was the first born of a nonconsanguineous Thai and Chinese couple. He presented at 2 months of age with generalized edema and respiratory distress. NGS revealed a known pathogenic variant, c.809dupG, and a novel variant of unknown significance, c.712+2T>A, in NPHS1 [Table 1] and [Figure 1]c, [Figure1]d. Allele segregation analysis to confirm the compound heterozygous nature of the variations could not be performed in parents' samples. Unilateral nephrectomy and gastrostomy were performed at 9 months of age for heavy proteinuria and poor growth. Despite symptomatic improvement, the child developed kidney failure by 3 years old, requiring automated peritoneal dialysis. Subsequently, he underwent deceased donor kidney transplantation at the age of 7 years and has had excellent graft function without disease recurrence.

  Discussion Top

All the four patients shared similar clinical features at presentation but demonstrated different histological characteristics and clinical course. Three patients had classical histological features of Finnish type CNS [Table 1]. However, patient 2 had mesangial proliferation in the first biopsy and showed minimal change disease upon repeat biopsy. Such differences in histological findings have been reported before.[6] Patients 1, 3, and 4 deteriorated at a variable rate and reached kidney failure at 2–10 years old. Patient 2 remained stable with stage 2 CKD until adolescence. The pathogenicity of one variant could not be demonstrated and the compound heterozygous nature of variants could not be confirmed for patient 4. However, the clinical course and histological changes in this and the other three patients were compatible with a podocytopathy and demonstrate heterogeneity in the phenotype of disease related to NPHS1 variations.

It is conventionally considered that CNS is invariably associated with poor outcomes including early deaths and kidney failure.[4] Similar to that reported previously, patients 3 and 4 developed kidney failure by 2–3 years of age.[7] However, milder course of disease and/or later onset, like that in patients 1 and 2, have also been reported.[6],[8] Notably, Wong et al. reported prolonged kidney survival, up to 37 years of age, in a few patients.[9] Such diverse clinical outcomes are shown to be unrelated to the underlying genotypic variations among patients. In a multi-center study conducted by the European Society of Pediatric Nephrology Dialysis Working Group in 2019,[10] the response to anti-proteinuric treatment and kidney and patient survival were independent of the type of NPHS1 variation. The findings of this case series echo that of previous reports, suggesting that genotype and phenotype correlation is poor in NPHS1-related CNS. To date, there is no definite explanation yet for this phenotypic heterogeneity.

The fact that patients 1 and 2 were cousins with identical variations but showed different rates of disease progression, suggests that NPHS1 variants show intrafamilal phenotypic heterogeneity. Specifically, in 2002, Koziell et al. reported that the Arg1160Ter variant in NPHS1, as in patients 1 and 2, is associated with slow progression of kidney failure in almost 50% of the cases with CNS.[2] A “tri-allelic hit” theory was previously proposed by Koziell et al. They suggested that the presence of a heterozygous NPHS-2 variant could modify histological phenotype in patients with NPHS-1 related CNS into congenital focal segmental glomerulosclerosis.[2] However, this theory was not supported in a subsequent study by Schultheiss et al.,[3] which showed that there was no difference in clinical manifestation and progression between patients with homozygous/compound heterozygous NPHS1 variants alone and those with an extra NPHS2 variant. Nonetheless, with a growing number of novel variants discovered over time, and expanding panel of genes covered by NGS, modifier genes may be identified in future.

The management of CNS is mainly supportive and includes optimizing nutrition, infusions of albumin, control of proteinuria with ACE-I, and nonsteroidal anti-inflammatory drugs such as indomethacin. However, anti-thrombotic prophylaxis still remains a controversy.[9] While bilateral nephrectomy followed by kidney transplantation has been widely adopted in the West,[5] a more conservative approach combining anti-proteinuric treatment with unilateral nephrectomy gained favor later, especially in those with milder disease.[10] Further studies are required to establish the predictive factors to guide patient management.

In conclusion, CNS due to NPHS1 variants can a have a wide spectrum of clinical manifestations and outcomes. There is no definite genotype-phenotype correlation. Given the rarity and heterogeneity of this disease, treatment should be individualized to best fit the patient's clinical picture.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Jalanko H. Congenital nephrotic syndrome. Pediatr Nephrol 2009;24:2121-8.  Back to cited text no. 1
Koziell A, Grech V, Hussain S, Lee G, Lenkkeri U, Tryggvason K, et al. Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet 2002;11:379-88.  Back to cited text no. 2
Schultheiss M, Ruf RG, Mucha BE, Wiggins R, Fuchshuber A, Lichtenberger A, et al. No evidence for genotype/phenotype correlation in NPHS1 and NPHS2 mutations. Pediatr Nephrol 2004;19:1340-8.  Back to cited text no. 3
Huttunen NP. Congenital nephrotic syndrome of Finnish type. Study of 75 patients. Arch Dis Child 1976;51:344-8.  Back to cited text no. 4
Holmberg C, Antikainen M, Rönnholm K, Ala Houhala M, Jalanko H. Management of congenital nephrotic syndrome of the Finnish type. Pediatr Nephrol 1995;9:87-93.  Back to cited text no. 5
Machuca E, Benoit G, Nevo F, Tête MJ, Gribouval O, Pawtowski A, et al. Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. J Am Soc Nephrol 2010;21:1209-17.  Back to cited text no. 6
Heeringa SF, Vlangos CN, Chernin G, Hinkes B, Gbadegesin R, Liu J, et al. Thirteen novel NPHS1 mutations in a large cohort of children with congenital nephrotic syndrome. Nephrol Dial Transplant 2008;23:3527-33.  Back to cited text no. 7
Philippe A, Nevo F, Esquivel EL, Reklaityte D, Gribouval O, Tête MJ, et al. Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2008;19:1871-8.  Back to cited text no. 8
Wong W, Morris MC, Kara T. Congenital nephrotic syndrome with prolonged renal survival without renal replacement therapy. Pediatr Nephrol 2013;28:2313-21.  Back to cited text no. 9
Dufek S, Holtta T, Trautmann A, Ylinen E, Alpay H, Ariceta G, et al. Management of children with congenital nephrotic syndrome: challenging treatment paradigms. Nephrol Dial Transplant 2019;34:1369-77.  Back to cited text no. 10


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