[Four cases of nephrotic syndrome with TRPC6 gene variations and literature review]

Objective: To investigate the clinical characteristics, treatment and prognosis of TRPC6 variation induced children with steroid-resistant nephrotic syndrome (SRNS). Methods: Clinical data of four patients with nephrotic syndrome carrying TRPC6 variations, who were admitted to the Department of Nephrology and Rheumatology, Children's Hospital of Shanghai from Jan. 2017 to Dec. 2019, was retrospectively analyzed. The literature search was conducted with "nephrotic syndrome" "child" and "TRPC6 variation" as keywords in China National Knowledge Infrastructure (CNKI), Wanfang, Weipu and Pubmed databases until August 2020. Results: One of the four cases was male, and the others were female. Onset age ranged from 4-year-1-month to 12-year-2-month. They presented severe proteinuria, hypoalbuminemia or edema as a first symptom. Four patients had anemia, and two patients had secondary hyperparathyroidism, and one patient had renal atrophy. Renal pathology showed that one case was immune complex associated with glomerulonephritis, and the rest were focal segmental glomerular sclerosis (FSGS). They had been initially treated with corticosteroids for more than four weeks, but they had inadequate responses. They were then treated with corticosteroids combined with immunosuppressants (for example, cyclophosphamide, a calcineurin inhibitor, or mycophenolate mofetil). However, the symptoms did not improve. Additionally, four children progressed to end-stage renal disease within 2 to 6 months.Their whole exon gene testing suggested that the variation types of TRPC6 gene were respectively c.2684G>T, c.523C>T, c.2678G>A, c.2683C>T, and all patients had de novo variations in TRPC6. One article in Chinese and 9 articles in English were found, which made up 27 patients. The data of 31 cases (including this group) were analyzed. There were 18 missense variations, one frameshift variation, one synonymous variation and one splicing variation. The onset age was from 4 months age to 14 years old. Among all patients, 18 cases had massive proteinuria and hypoproteinemia, 6 cases only showed proteinuria. The pathological type of 19 cases were FSGS, 2 cases were IgA nephropathy, 2 cases were minimal change disease, 1 case was collapse glomerulopathy, 1 case was C1q nephropathy, and 1 case was immune complex associated glomerulonephritis. Glucocorticoid therapy was ineffective in 18 cases, and calcineurin inhibitor was ineffective in 11 cases. The prognosis of the disease was poor. Renal failure occurred in 12 cases, and the time to end stage renal disease was from 4 months to 13.8 years. Conclusions: TRPC6 variation can cause SRNS at a young age. FSGS is the primary pathological type of SRNS causing by TRPC6 variation. Glucocorticoid and immunosuppressive therapy are mostly ineffective. The disease progressed rapidly and the prognosis is poor.