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NPHP4 Nephronophthisis Corticomedullary Cysts — ESENeph MCQ

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HardTubular DisordersNPHP4 Nephronophthisis Corticomedullary CystsESENeph

A 40-year-old man presents with recurrent episodes of gross haematuria, flank pain, and low-grade fever. CT shows bilateral multiple small cysts at the corticomedullary junction with normal-sized kidneys. He has a urinary concentrating defect (polyuria, low urine osmolality after water deprivation). eGFR is 42 mL/min/1.73m2 and declining. There is no proteinuria. Genetic testing reveals a homozygous NPHP4 mutation. What is the diagnosis?

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Correct answer: C — Nephronophthisis (NPHP4-related)

NPHP4 mutations cause nephronophthisis type 4 — a ciliopathy characterised by corticomedullary cysts, tubular basement membrane disruption, and progressive tubulointerstitial fibrosis. Key distinguishing features from ADPKD: normal-sized kidneys (not enlarged), small cysts at the corticomedullary junction (not large cortical cysts), minimal proteinuria (tubulointerstitial rather than glomerular disease), and early urinary concentrating defect (polyuria/polydipsia from medullary damage). NPHP4 encodes nephroretinin, a ciliary/centrosomal protein. There is no specific treatment — management is supportive CKD care. Transplantation is definitive and NPHP does not recur in the graft. Extra-renal features (retinal dystrophy, cerebellar, hepatic) depend on the specific NPHP gene involved.

Reference: Hildebrandt et al 2009 – Nephronophthisis; JRCPTB 2022 – Nephrology Curriculum