A 45-year-old man with a family history of early renal failure presents with hypertension (BP 160/95 mmHg) and bilateral flank pain. On examination, both kidneys are palpable and markedly enlarged. Imaging confirms autosomal dominant polycystic kidney disease (ADPKD). The structure marked **B** in the diagram shows markedly enlarged kidneys (1 kg each). Which of the following genetic mutations is most likely responsible for this degree of renal enlargement and the patient's early presentation with hypertension?

Question

A 45-year-old man with a family history of early renal failure presents with hypertension (BP 160/95 mmHg) and bilateral flank pain. On examination, both kidneys are palpable and markedly enlarged. Imaging confirms autosomal dominant polycystic kidney disease (ADPKD). The structure marked **B** in the diagram shows markedly enlarged kidneys (>1 kg each). Which of the following genetic mutations is most likely responsible for this degree of renal enlargement and the patient's early presentation with hypertension?

Accepted Answer

A. PKD1 gene mutation on chromosome 16 — accounts for ~85% of ADPKD cases and typically leads to ESRD by the 5th–6th decade. ## Why PKD1 gene mutation on chromosome 16 is correct

The marked bilateral renal enlargement (>1 kg each) and early presentation with hypertension in this 45-year-old patient is most consistent with PKD1 mutation. PKD1 accounts for ~85% of ADPKD cases and is associated with more severe disease, including larger kidneys and earlier progression to ESRD (typically by age 50–60 years). The hypertension is often the first clinical manifestation, driven by RAAS activation from cyst-compressed nephrons. This patient's clinical picture — marked enlargement, hypertension, and family history of early renal failure — fits the PKD1 phenotype precisely.

## Why each distractor is wrong

- **PKD2 gene mutation on chromosome 4**: While this accounts for ~15% of ADPKD cases, PKD2 is associated with milder disease, smaller kidneys, and later progression to ESRD (7th decade or beyond). This patient's early presentation and marked renal enlargement are inconsistent with PKD2.
- **PKHD1 gene mutation**: This causes autosomal *recessive* PKD (ARPKD), a distinct disease with neonatal presentation, massive bilateral kidneys, oligohydramnios, Potter sequence, and congenital hepatic fibrosis. ARPKD is not inherited in an autosomal dominant pattern and presents in infants, not adults.
- **COL4A3 gene mutation**: This causes Alport syndrome, characterized by progressive hereditary nephritis with hematuria, sensorineural hearing loss, and ocular abnormalities. Alport syndrome does not cause the bilateral cystic kidney enlargement seen in ADPKD.

**High-Yield:** PKD1 (chromosome 16, ~85%) = severe, early ESRD (50s–60s); PKD2 (chromosome 4, ~15%) = mild, late ESRD (70s+). Hypertension is often the *first* sign of ADPKD.

[cite: Robbins 10e Ch 20]

Answer

B. PKHD1 gene mutation — causes autosomal recessive PKD with neonatal presentation and congenital hepatic fibrosis

Answer

C. PKD2 gene mutation on chromosome 4 — accounts for ~15% of ADPKD cases and typically leads to ESRD by the 7th decade or later

Answer

D. COL4A3 gene mutation — causes Alport syndrome with progressive renal failure and sensorineural hearing loss

Explanation

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