Steroid-resistant nephrotic syndrome associated with certain SGPL1 variants in a family: Case report and literature review

Abstract

Objectives: Steroid-resistant nephrotic syndrome (SRNS) is a clinical syndrome characterized by the lack of response to standard steroid therapy, usually progressing to end-stage renal disease. We reported two cases of female identical twins with SRNS caused by SGPL1 variants in one family, reviewed the relevant literature, and summarized their clinical phenotypes, pathological types, and genotypic characteristics.

Methods: Two cases of nephrotic syndrome caused by SGPL1 variants were admitted to Tongji Hospital, affiliated with Tongji Medical College of Huazhong University of Science and Technology. Their clinical data were retrospectively collected, and the peripheral blood genomic DNA was captured and sequenced by whole exome sequencing. Related literature published in PubMed, CNKI, and Wan fang databases was reviewed.

Results: We described two Chinese identical twin girls with isolated SRNS due to compound heterozygous variants in the SGPL1 (intron4 c.261 + 1G > A and intron12 c.1298 + 6T > C). The patients were followed up for 60.0 months and 53.0 months, respectively, having no extra-renal manifestations. They all died due to renal failure. A total of 31 children with SGPL1 variants causing nephrotic syndrome (including the reported two cases) were identified through a literature review.

Conclusions: These two female identical twins were the first reported cases of isolated SRNS caused by SGPL1 variants. Almost all homozygous and compound heterozygous variants of SGPL1 had extra-renal manifestations, but compound heterozygous variants in the intron of SGPL1 may have no obvious extra-renal manifestations. Additionally, a negative genetic testing result does not completely rule out genetic SRNS because the Human Gene Mutation Database or ClinVar is constantly being updated.

Keywords: SGPL1 gene mutation; clinical phenotype; genotype; proteinuria; steroid-resistant nephrotic syndrome.

Figure 1

Representative images of renal pathology in case 1. Light microscopy: Most glomerular segmental mesangial cells were mildly hyperplasia, and the mesangial stroma was hyperplasia. There was no obvious lesion in the glomerular basement membrane, and no dense deposits were seen under the endothelial and epithelium. Renal tubular epithelial cells showed degeneration. Atrophy was seen in some segments of renal tubules, and the basement membrane of renal tubules was thickened in some segments. The renal interstitium was widened, and flaky fibrosis was seen. (A, PAS, magnification × 400; B, PASM, magnification × 400; C, Masson, magnification × 400). Immunofluorescence microscopy: IgM (+++) was deposited in the glomerular mesangial region and capillary wall as a mass of immunofluorescence. (D, magnification × 200). Transmission electron microscopy: Most segments of the capillary basement membrane had no obvious lesions, and a few segments showed mesangial insertion. The rough endoplasmic reticulum in podocytes expanded, mitochondria swelled, small lipid droplets and lysosomes increased slightly, and foot processes fused widely. The mesangial matrix was mild to moderate hyperplasia, and a small amount of the dense deposits was seen in the mesangial area (E,F).

Figure 2

Blood albumin, UACR and eGFR at the follow-up of case 1. After 60.0 months of follow-up, the eGFR of case 1 was 14.8 ml/(min × 1.73 m²). UACR, urinary albumin to creatinine ratio; eGFR, estimated glomerular filtration rate.

Figure 3

Blood albumin, UACR and eGFR at the follow-up of case 2. After 53.0 months of follow-up, the eGFR of case 2 was 12.2 ml/(min × 1.73 m²). UACR, urinary albumin to creatinine ratio; eGFR, estimated glomerular filtration rate.

Figure 4

The distribution of extra-renal symptoms at the location of SGPL1 variants. While intron12 did not show extra-renal symptoms, introns and exons at other sites did, to varying degrees.