Steroid-resistant nephrotic syndrome type 2 is an autosomal recessive disorder characterized clinically by childhood onset of proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial ... Steroid-resistant nephrotic syndrome type 2 is an autosomal recessive disorder characterized clinically by childhood onset of proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. The disorder is resistant to steroid treatment and progresses to end-stage renal failure in the first or second decades (summary by Fuchshuber et al., 1996). Some patients show later onset of the disorder (Tsukaguchi et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome and FSGS, see NPHS1 (256300).
Naruse et al. (1980) reported 2 sons, of first-cousin parents, who developed the nephrotic syndrome at ages 14 and 15 years. The disorder was resistant to treatment with corticosteroid. Both had progressive renal failure, and renal biopsy in ... Naruse et al. (1980) reported 2 sons, of first-cousin parents, who developed the nephrotic syndrome at ages 14 and 15 years. The disorder was resistant to treatment with corticosteroid. Both had progressive renal failure, and renal biopsy in one showed focal glomerulosclerosis. Schwarz et al. (1976) reported 3 sibs with nephrotic syndrome and focal glomerular sclerosis. Fuchshuber et al. (1995) reported 8 families with childhood-onset steroid-resistant nephrotic syndrome. The age at onset ranged from 3 months to 5 years, and there was rapid progression to end-stage renal failure before age 10. These patients had no disease recurrence after transplantation. Renal biopsy showed focal segmental glomerulosclerosis in 18 cases and minimal-change disease in 2 cases. Fuchshuber et al. (1996) reported a consanguineous Libyan family with steroid-resistant nephrotic syndrome. The disorder was diagnosed in 4 sibs at the ages of 15, 13, 8, and 9 years; renal biopsy taken in 3 of the 4 showed mesangial proliferation with focal and segmental glomerulosclerosis. A fifth sib, who was apparently healthy at 18 months of age, was found to have haplotypes identical to the 4 affected sibs; reexamination revealed mild proteinuria and mild mesangial hypercellularity with IgM deposits on renal biopsy. Caridi et al. (2003) identified homozygous or compound heterozygous mutations in the NPHS2 gene in 14 (12%) of 120 patients with steroid-resistant nephrotic syndrome. The age at onset of proteinuria ranged from 1 to 100 months, and all showed progressive renal failure. Histologic findings were consistent with focal segmental glomerulosclerosis in most patients, although minimal-change disease and mesangial proliferation with IgM deposits were rarely observed. Most required renal transplantation; 2 had recurrence of disease after transplantation. Becker-Cohen et al. (2007) reported an Arab girl, born of distantly related parents, with NPHS2 confirmed by genetic analysis (R138X; 604766.0002). Prenatal ultrasound suggested hyperechoic kidneys, but amniotic fluid was normal. She was found to have nephrotic syndrome at age 2 months. Initial kidney biopsy was normal, but a repeat biopsy performed at 1 year of age showed diffuse mesangial proliferation with segmental sclerosis in 7 glomeruli. Electron microscopy showed diffuse effacement of podocyte foot processes. She later developed edema and her renal function gradually deteriorated, leading to chronic hemodialysis at age 2.5 years. Six months later she received a deceased donor renal transplant, which was complicated by recurrence of nephrotic syndrome 4 years after transplant. - Clinical Variability Tsukaguchi et al. (2000) reported a 3-generation Brazilian family in which 7 of 10 sibs had late-onset marked proteinuria (all patients), focal segmental glomerulosclerosis (2 patients), or end-stage renal failure requiring kidney transplant (2 patients). The average age of disease onset was 26 years, and the pedigree pattern was consistent with autosomal recessive inheritance. Linkage analysis showed linkage to chromosome 1q25-q31. The phenotype could be distinguished from that described by Fuchshuber et al. (1995) by the later age at onset and the fact that not all patients developed frank nephrotic syndrome. Tsukaguchi et al. (2000) identified affected individuals from 5 additional families with a similar phenotype: the mean age of onset was 21 (range 9 to 31) and 70% of affected individuals progressed to end-stage renal disease. Pathology showed FSGS. Caridi et al. (2003) identified a heterozygous mutation in the NPHS2 gene in 8 children with proteinuria, including 5 who had a partially steroid-responsive form of the disorder and a slightly milder phenotype. However, the authors could not exclude a second pathogenic mutation in these patients.
In 14 of 16 families with steroid-resistant nephrotic syndrome mapping to chromosome 1, 10 of which were previously reported (Fuchshuber et al., 1995; Fuchshuber et al., 1996), Boute et al. (2000) identified 10 different NPHS2 mutations (604766.0001-604766.0010), comprising ... In 14 of 16 families with steroid-resistant nephrotic syndrome mapping to chromosome 1, 10 of which were previously reported (Fuchshuber et al., 1995; Fuchshuber et al., 1996), Boute et al. (2000) identified 10 different NPHS2 mutations (604766.0001-604766.0010), comprising nonsense, frameshift, and missense mutations, segregating with the disease. One mutation (R138Q; 604766.0001) was found in approximately one-third of the patients. Caridi et al. (2001) identified homozygous or compound heterozygous mutations in the NPHS2 gene (see, e.g., 604766.0001 and 604766.0004) in 9 of 44 Italian patients with sporadic occurrence of early-onset nephrotic syndrome with focal segmental glomerulosclerosis. All had early onset of proteinuria in childhood and progressed to renal failure necessitating renal transplant. They were not responsive to steroid treatment. - Susceptibility to NPHS2 Tsukaguchi et al. (2002) identified a polymorphism in the NPHS2 gene (R229Q; 604766.0011) that contributed to the development of late-onset renal disease characterized by proteinuria and focal segmental glomerulosclerosis in 6 families. In vitro functional expression assays indicated that the R229Q mutant protein had decreased binding to nephrin (NPHS1; 602716) (41.5% compared to wildtype), suggesting mild functional impairment. Tsukaguchi et al. (2002) concluded that the R229Q variant itself may not cause disease, but appeared to increase susceptibility to renal disease when combined with another pathogenic NPHS2 mutation.
NPHS2 is the most common known form of inherited steroid-resistant nephrotic syndrome, accounting for 45 to 55% of familial forms and 8 to 20% of sporadic disease (Caridi et al., 2010).