Novel Association of FCGR2A Mutation with Steroid-Resistant Nephrotic Syndrome - A Case Report

Introduction

Steroid-resistant nephrotic syndrome (SRNS) is defined as the lack of remission despite a 6-week daily oral prednisolone course at 60 mg/m²/day or 2 mg/kg/day. Calcineurin inhibitors (CNI) are the first-line therapy for initial or late steroid resistance.¹ National and international guidelines recommend a panel of genes for screening of children with SRNS to identify monogenic forms for which standard immunosuppressive treatment may be ineffective.^1,2 We report the first association of FCGR2A gene mutation with this condition that adds to reported genetic associations.

Case Report

A 6-year-old boy was diagnosed with idiopathic nephrotic syndrome (INS) 1 year before his presentation to our hospital. He was on a tapering prednisolone dosage due to persistent proteinuria when he first reported to us. Initial examination revealed generalized anasarca with 100/min pulse rate, 24/min respiratory rate, and 142/86 blood pressure (stage 2 hypertension); urine protein was 4+ by dipstick. His weight was 19 kg (with severe edema), and his height was 107 cm (between the 3^rd and 10^th centile as per the Indian academy of pediatrics (IAP) growth chart for age and sex).³ His laboratory reports mentioned Hb-9.5 g/dL, total leukocyte count-14000, platelet count-5.5 lacs/mm³, urea-208 mg/dL, creatinine-0.6 mg/dL, serum albumin-1.6 g/dL, and cholesterol-461 mg/dL.

During the ongoing treatment, he experienced multiple hospitalizations for cellulitis, pneumonia, hypertensive emergency, AKI, oliguria, and edema control. Renal ultrasound showed bilateral mildly raised echogenicity with a normal renal artery Doppler study. He was diagnosed with SRNS, and a kidney biopsy followed. Light microscopy revealed focal segmental glomerulosclerosis, not otherwise specified variant with superimposed acute tubular necrosis. Immunofluorescence showed non-specific trappings of IgG, IgM, IgA, and C3 components along the sclerosed glomerular segments. After AKI resolution, he was initiated on cyclosporine and low-dose alternate-day steroids. However, the treatment was discontinued within 3 months due to decline in renal function and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m². His proteinuria remained in the nephrotic range. Rituximab rescue therapy was deferred due to young age and recurrent infections. Cyclosporine drug levels were unavailable and parents refused a repeat kidney biopsy.

Whole-exome sequencing revealed an FCGR2A missense mutation (Exon 6; variant c.752C>T, pThr251Ile; heterozygous, autosomal dominant/recessive), classified as a “variant of uncertain significance” for susceptibility to nephrotic syndrome.^4,5

The child developed recurrent pericardial effusions with impending tamponade 6 months ago, unexplained by the underlying nephrotic syndrome, necessitating pigtail insertion and drainage. Pericardial fluid cytology and cultures were sterile and biochemistry suggested transudative effusion. Workup for tuberculosis (TB), including a CECT chest, was inconclusive. However, due to strong clinical suspicion of TB, he was started on antitubercular drugs with steroids for TB pericardial effusion. After 4 months of medication, the effusion regressed.

The child was on regular follow-up for over 1 year and progressed to kidney failure, for which he was initiated on maintenance hemodialysis. He required four antihypertensives for blood pressure control. He was worked up for kidney transplantation with his mother being the potential donor. Unfortunately, he succumbed to an episode of diarrhea and sepsis within 1 month of hemodialysis.

Discussion

FCGR2A encodes CD32A, a low-affinity Fcγ receptor on neutrophils, macrophages, Langerhans cells, and platelets. It mediates the uptake of bound immune complexes. In eosinophils, CD32A plays a role in triggering granule release; mutations in the gene have been implicated in diseases such as lupus nephritis, ulcerative colitis, lymphomas, and an increased risk of pneumococcal infections.⁴

In a case-control study of 103 children with INS, Rossi et al. identified the first association between FCGR2A polymorphisms and INS, excluding SRNS patients.⁴ The Indian Society of Pediatric Nephrology and International Pediatric Nephrology Association guidelines recommend 79 genes for screening children with SRNS to detect monogenic forms in which standard immunosuppressive treatment may be ineffective, and FCGR2A is notably absent from this list.^1,2 In our patient, the FCGR2A mutation manifested as late-onset SRNS and FSGS with a rapid progression to CKD within 2 years of the first episode.

In conclusion, FCGR2A polymorphisms may be implicated in SRNS non-responsiveness to immunosuppressive therapy, leading to rapid progression to kidney failure.