A Col4a5 X-Linked Alport Syndrome Presenting as Steroid-Resistant Focal Segmental Glomerulosclerosis and Progressing to End-Stage Renal Disease

Alport syndrome (AS) is an inherited disorder of type IV collagen affecting the glomerular basement membrane (GBM), classically presenting with progressive nephropathy, sensorineural hearing loss, and ocular abnormalities. We report a 31-year-old woman who first presented in 2023, at approximately 28 years of age, with a one-month history of facial puffiness, pedal oedema, and frothy urine, and was found to have nephrotic-range proteinuria (24-hour urine protein approximately 9 g). A renal biopsy at that time showed focal segmental glomerulosclerosis (FSGS), not otherwise specified (NOS) type, with 10–15% interstitial fibrosis and tubular atrophy (IFTA), and she was treated with corticosteroids, achieving partial remission with a serum creatinine of approximately 1.8 mg/dL. She relapsed in early 2025 with recurrent oedema, proteinuria of 4.2 g/day, new microscopic haematuria, and worsening renal function. A repeat renal biopsy again showed FSGS (three of six glomeruli globally sclerosed) with IFTA that had progressed to 20–25%; immunofluorescence showed no immune deposits, and electron microscopy demonstrated diffuse podocyte foot-process effacement with a glomerular basement membrane thickness ranging from 290.4 to 431.9 nm (mean 361.1 nm), without electron-dense deposits, mesangial interposition, or basement membrane lamellation. Pure tone audiometry demonstrated mild bilateral sensorineural hearing loss, while ophthalmological examination did not identify anterior lenticonus. Clinical whole-exome sequencing identified a heterozygous missense variant in COL4A5, c.4808A>T (p.Tyr1603Phe), classified as a variant of uncertain significance (VUS) and associated with Alport syndrome 1, X-linked (OMIM #301050). A three-generation family history was notable for renal impairment along the maternal line, supporting an X-linked pattern of inheritance. Despite immunosuppressive therapy, her renal function continued to decline, and she progressed to end-stage renal disease (ESRD) requiring renal replacement therapy by January 2026. This case illustrates how X-linked Alport syndrome caused by a missense COL4A5 variant can present with an FSGS-like histological pattern lacking the classical basket-weave lamellation of the GBM, and underscores the value of integrating audiometric, ophthalmological, family history, and genetic evaluation in atypical, familial, or steroid-resistant nephrotic syndrome.