Врожденный нефротический синдром

Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) are disorders of podocytes in the slit diaphragm. CNS manifests during the first three months of life, and INS between 3-12 months, with severe proteinuria due to mutations in the NPHS1 and NPHS2 genes. This study aimed to establish specific genotype-phenotype characteristics of CNS and INS in the North American population. Eleven Pediatric Nephrology Research Consortium (PNRC) sites retrospectively reviewed charts of 36 patients born between 1998-2019 who had CNS or INS and underwent genetic testing. The genetic database confirmed the variant's pathogenicity. NPHS1 mutations were more frequently seen in CNS patients, while variant mutations in the WT1 and NPHS2 genes were more common in the INS group. Like c.2335-1 G > A splice mutation, the frequent compound heterozygous mutations of the NPHS1 gene were associated with more severe proteinuria (112.4 ± 135.6 vs. 53.9 ± 57.3). Additionally, NPHS1/WT1 and NPHS1/NPHS2 digenic inheritance featuring biallelic or tri-allelic hits were associated with patient transplantation, regardless of the disease onset. Identification of compound heterozygous mutations in the NPHS1 gene as an indicator of an aggressive course of CNS in infants. This finding could lead to earlier and targeted interventions of patients, through a precision therapeutic approach IMPACT: Variations at splice sites, particularly the c.2335-1 G > A mutation, alongside compound heterozygous mutations in the gene NPHS1 and digenic inheritance involving both NPHS1/WT1 or NPHS1/ NPHS2 with a triallelic hit, have been linked to a more severe progression of Congenital Nephrotic Syndrome (CNS) in infants. The presence of a variant involving the digenic inheritance of the NPHS1 gene among children in North America suggests earlier indicators for the severity of the kidney disease. This knowledge can transform the management of Congenital Nephrotic Syndrome in children's healthcare settings, and lead to the development of early diagnosis biomarkers for the disease.

Background and Objectives: Congenital nephrotic syndrome (CNS), a genetic disease caused by mutations in genes on autosomes, usually occurs in the first three months after birth. A number of genetic mutations in genes, which encode for the components of the glomerular filtration barrier have been identified. We investigated mutations in NPHS1, NPHS2, PLCE1 (NPHS3), and WT1 genes that relate to the disease in Vietnamese patients. Materials and Methods: We performed genetic analysis of two unrelated patients, who were diagnosed with CNS in the Vietnam National Children’s Hospital with different disease status. The entire coding region and adjacent splice sites of these genes were amplified and sequenced using the Sanger method. The sequencing data were analyzed and compared with the NPHS1, NPHS2, PLCE1, and WT1 gene sequences published in Ensembl (ENSG00000161270, ENSG00000116218, ENSG00000138193, and ENSG00000184937, respectively) using BioEdit software to detect mutations. Results: We detected a new variant p.Ser607Arg and two other (p.Glu117Lys and p.Ser1105Ser) in the NPHS1 gene, as well as two variants (p.Arg548Leu, p.Pro1575Arg) in the PLCE1 gene. No mutations were detected in the NPHS2 and WT1 genes. Patient 1, who presented a heterozygous genotype of p.Ser1105Ser and p.Arg548Leu had a mild disease status but patient 2, who presented a homozygous genotype of these alleles, had a severe phenotype. Conclusions: These results suggest that variants p.Ser1105Ser (in NPHS1 gene) and p.Arg548Leu (in PLCE1 gene) in the homozygous form might play a role in the development of the disease in patients.

A female, term neonate presented with generalized edema, heavy proteinuria, hypoalbuminemia and hyperlipidemia in the second week of life. The clinical and laboratory features were compatible with the diagnosis of congenital nephrotic syndrome. Treatment included albumin infusion, empirical penicillin, steroid and continuous arterio-venous hemofiltration. Intestinal perforation developed at the 19th day of age and led to a fatal outcome. At autopsy, thrombosis of the superior mesenteric artery and its branches was noted, and histology of the kidney was compatible with congenital nephrotic syndrome of the Finnish type. The risk of thromboembolism, arterial or venous, should be considered in patients with nephrotic syndrome, even in the neonatal period. Preventive measures, including avoiding volume depletion and femoral arterial/venous puncture, are essential in managing these patients. Prophylactic anticoagulation and infusion of fresh frozen plasma may be warranted to avoid such potentially lethal complications of thromboembolism.

Congenital nephrotic syndrome (CNS), a genetic disease caused by the mutations in genes on autosomes,is usually occurs in the first three months after birth. The mutations in genes that encode for the structural andfunctional proteins of podocytes lead to loss of the function of glomerular filtration. So far, a number of genesrelated to the disease have been identified such as: NPHS1, NPHS2, PLCE1 (NPHS3), ACTN4, CD2AP, INF2and WT1. In this article, we amplified all of exons in NPHS1 and PLCE1 genes of two Vietnamese patientswith CNS and members of patients’ family. PCR products were purified and sequenced directly on automaticsequencer ABI 3500 Bio System (USA). The sequencing results were compared with the sequences of NPHS1and PLCE1 genes published in the Ensembl database (ENSG00000161270 and ENSG00000138193,respectively) by using BioEdit software to detect mutations. We identified two mutations: c.2398C>T(p.Arg800Cys, exon 18), c.3315A>G (p.Ser1105Ser, exon 26) in NPHS1 gene and two mutations: c.5330 C>T(p.Thr1777Ile, exon 23), c.5780A>G (p.His1927Arg, exon 25) in PLCE1 gene in study patients. These twopatients carried simultaneously the mutations in the NPHS1 and PLCE1 genes with serious phenotype. Theresults of our study might be evidences for the role of mutations in NPHS1 and PLCE1 genes in thedevelopment of disease in patients. These are useful information in identifying the cause of disease and providethe genetic counseling to the patients’ family.

Congenital and infantle nephrotic syndrome

Molecular Basis of Proteinuria

Congenital nephrotic syndrome of Finnish type is a rare disease in Taiwan characterized by intrauterine onset of massive urinary loss of protein. We describe a typical baby of congenital nephrotic syndrome with generalized edema occurring at 3 months of age. Renal biopsy at 4 months of age showed a tubular microcystic change in histology. He had a partial response to corticosteroid. We tried persantin, indomethacin, and captopril since 10 months of age without significant improvement. The baby suffered from recurrent infections and respiratory difficulties due to having upper airway edema since 3 months of age. The baby passed away at 1 year and 2 months of age with severe psychomotor retardation. The first try of the combination of persantin, indomethacin, and captopril for congenital nephrotic syndrome is described.

Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome

Syndromes néphrotiques congénitaux et infantiles

Information on etiology of congenital nephrotic syndrome in non-Caucasian populations is limited. This study aimed to determine the genetic basis of congenital nephrotic syndrome in Indian patients. In this observational, cross-sectional study, whole exome sequencing was performed on samples from all children diagnosed with congenital nephrotic syndrome, presenting at centers collaborating in a nationwide registry and biorepository. Analysis was targeted to focus on reported or novel, pathogenic or likely pathogenic variants in 89 genes implicated in etiology of nephrotic syndrome. Sanger sequencing was used to confirm disease-causing variants in patients and allelic segregation of compound heterozygous variants in samples from parents. Inheritance of a shared haplotype was analyzed among ten individuals carrying the most common variant. During 2017-2019, 34 patients with congenital nephrotic syndrome were screened. Consanguinity and similar illness in siblings were reported in eleven patients each. Homozygous or compound heterozygous, pathogenic or likely pathogenic variants were found in NPHS1 in 24 cases, including two novel variants. One patient each had homozygous pathogenic or likely pathogenic known or novel variant in NPHS2, PLCE1, OSGEP and LAMB2 genes. Patients with OSGEP and LAMB2 mutations had phenotype typical of Galloway Mowat and Pierson syndromes, respectively. Three variants in NPHS1 were common to 16 individuals. One reported variant in exon 19 (c.2600G>A; p.Gly867Asp) appears to share a common founder. A genetic cause was determined for 82.4% patients with congenital nephrotic syndrome. Variants in NPHS1 are most common in Indian patients and founder mutations might be present.

Syndromes néphrotiques congénitaux et infantiles

In the literature review are presented the etiology, clinical and genetic features of congenital and infantile nephrotic syndrome (NS) in children, as of isolated and with extra-renal manifestations. Congenital NS is diagnosed in children from birth to 3 months, infantile NS – from 4 to 12 months. Clinical and genetic features of hereditary variants of congenital and infantile NS in children caused by mutations of genes encoding the main components of slit diaphragm, glomerular basement membrane and the cytoskeleton of the podocyte feet are described. R. Preston et al (2019) believe that clinical phenotyping combined with targeted genetic analysis is effective in diagnosing steroid-resistant congenital and infantile NS in children. Currently, genetic testing is recommended before initiating immunosuppressive therapy and performing a biopsy of the kidney. Mutational screening of genes is shown in hereditary variants of congenital (NPHS1, NPHS2, WT1, LAMB2, PLCE1, LMX1B) and infantile (NPHS2, NPHS1, WT1, PLCE1, TRPC6, ACTN4, ADCK4, COQ2, COQ6) NS in children. The NPHS1 mutation detection rate remains high amongst non–Finnis cases of congenital NS. In international practice, with the aim of early diagnosis and treatment of steroid-resistant congenital and infantile NS in children, modern methods of mutational screening are used. Renal biopsy fades into the background. The literature review presents a modern strategy of drug and early renal replacement therapy. Recommendations for the management of Finnish-type congenital NS in children followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis, and transplantation. The 5-years survival of patients with congenital and infantile nephrotic syndrome after kidney transplantation is more than 90 %, the survival rate of the renal allograft is more than 80 %.

Congenital nephrotic syndrome (CNS) is a rare disease defined as heavy proteinuria, hypoalbuminemia, hyperlipidemia, and edema presenting in the first three months of life. It is most commonly caused by mutations in the NPHS1 gene associated with nephrotic syndrome type 1, also known as Finnish-type CNS, which is inherited in an autosomal recessive manner. Symptomatic treatment with intravenous albumins, vitamins, minerals, nutritional, and hormonal supplementation and treatment of complications are mandatory. Children refractory to the symptomatic treatment are recommended to undergo nephrectomy and renal replacement therapy, preferably renal transplantation. We report on a child with Finnish type CNS with a NPHS1 mutation, which is the first case confirmed by genetic study in Slovenia. We showed for the first time that homozygous mutation c.2928-3del in the NPHS1 gene caused exon 22 skipping, leading to a truncated protein and Fin-minor phenotype.

Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations. We performed direct exon sequencing of NPHS1, NPHS2, and the relevant exons 8 and 9 of WT1, whereas the LAMB2 gene was screened by enzymatic mismatches cleavage. We detected disease-causing mutations in 66.3% (53 of 80) families (NPHS1, NPHS2, WT1, and LAMB2: 22.5%, 37.5%, 3.8%, and 2.5%, respectively). As many as 84.8% of families with congenital onset (0-3 months) and 44.1% with infantile onset (4-12 months) of nephrotic syndrome were explained by mutations. NPHS2 mutations were the most frequent cause of nephrotic syndrome among both families with congenital nephrotic syndrome (39.1%) and infantile nephrotic syndrome (35.3%), whereas NPHS1 mutations were solely found in patients with congenital onset. Of 45 children in whom steroid treatment was attempted, only 1 patient achieved a lasting response. Of these 45 treated children, 28 had causative mutations, and none of the 28 responded to treatment. First, two thirds of nephrotic syndrome manifesting in the first year of life can be explained by mutations in 4 genes only (NPHS1, NPHS2, WT1, or LAMB2). Second, NPHS1 mutations occur in congenital nephrotic syndrome only. Third, infants with causative mutations in any of the 4 genes do not respond to steroid treatment; therefore, unnecessary treatment attempts can be avoided. Fourth, there are most likely additional unknown genes mutated in early-onset nephrotic syndrome.

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