A patient with multiple tendon xanthomas is found to have a serum cholesterol level of 398 mg/dL and an LDL level of 220 mg/dL. What is the most likely defect?

Correct Answer: C. LDL receptor defect

The clinical presentation of tendon xanthomas with markedly elevated LDL cholesterol (220 mg/dL) and total cholesterol (398 mg/dL) is pathognomonic for familial hypercholesterolaemia (FH) due to LDL receptor deficiency. Tendon xanthomas—firm, nodular deposits in the Achilles tendon and extensor tendons of the hand—are virtually diagnostic of FH and result from chronic LDL accumulation in connective tissue. The LDL receptor is the primary mechanism for clearing LDL particles from circulation; its deficiency (either homozygous or heterozygous) causes severe elevation of LDL-C. In heterozygous FH (1 in 500 Indians), LDL-C typically ranges 200–400 mg/dL; in homozygous FH (1 in 1,000,000), it exceeds 600 mg/dL. The defect impairs hepatic uptake of LDL via the apoB-100/E receptor pathway, leading to prolonged LDL circulation time and increased tissue deposition. This contrasts with other dyslipidemias where LDL elevation is less severe or xanthomas are absent. Indian guidelines (ICMR, CSIR) recognize FH as a major cardiovascular risk factor requiring aggressive statin therapy and, in severe cases, PCSK9 inhibitors or apheresis.

Why the other options are wrong

A. Lipoprotein lipase deficiency — Lipoprotein lipase (LPL) deficiency causes Type I hyperlipoproteinaemia (familial chylomicronaemia), characterized by massive hypertriglyceridaemia (often >1000 mg/dL) with normal or near-normal LDL-C. Patients present with eruptive xanthomas (small, yellow papules on buttocks and elbows), lipemic plasma, and recurrent pancreatitis—NOT tendon xanthomas. LDL levels remain low because chylomicrons bypass the LDL receptor pathway. B. PCSK9 gain-of-function mutation — PCSK9 gain-of-function mutations cause autosomal dominant hypercholesterolaemia (ADH), a form of FH with LDL-C elevation similar to LDL receptor defects. However, PCSK9 mutations account for only _{3–5% of FH cases in India, whereas LDL receptor mutations account for} 80%. The clinical presentation (tendon xanthomas, LDL 220 mg/dL) is more consistent with the commoner LDL receptor defect. PCSK9 inhibitors are therapeutic agents, not primary genetic causes in most FH patients. D. Defective Apo B-100 — Defective apoB-100 (familial defective apoB-100, FDB) causes Type IIb hyperlipoproteinaemia with elevated LDL-C and triglycerides, but LDL levels are typically lower (150–250 mg/dL) than in LDL receptor deficiency. FDB accounts for <5% of FH cases and rarely presents with prominent tendon xanthomas. The mutation impairs LDL receptor binding, but the mechanism is distinct from receptor deficiency and produces a milder phenotype.

High-Yield Facts

Mnemonics

FH Xanthoma Types TENT = Tendon xanthomas → LDL receptor defect (FH); Eruptive xanthomas → Type I (LPL deficiency); Nodular → Cholestasis; Tuberous → LCAT deficiency. Use this to differentiate xanthoma types by underlying lipid disorder. FH Genetic Causes (80-5-5 Rule) 80% LDL receptor mutations, 5% PCSK9, 5% apoB-100 defects, 10% other. When you see tendon xanthomas + high LDL, default to LDL receptor deficiency.

NBE Trap

NBE may pair PCSK9 mutations with FH to test whether students confuse genetic causes of FH; PCSK9 is a newer, therapeutically relevant gene but accounts for only 3–5% of FH, whereas LDL receptor deficiency is the dominant cause. The clinical presentation (tendon xanthomas, LDL 220 mg/dL) strongly favours the commoner defect.

Clinical Pearl

In Indian clinical practice, FH is often diagnosed late because xanthomas are mistaken for benign nodules; early recognition via lipid screening in first-degree relatives of premature MI patients (<45 years in men, <55 in women) enables cascade screening and prevents cardiovascular events. Statins are first-line, but many Indian FH patients require combination therapy (statin + ezetimibe ± PCSK9 inhibitor) to reach LDL-C <70 mg/dL.

_Reference: Robbins Ch. 5 (Genetic Disorders); Harrison Ch. 397 (Lipid Disorders); KD Tripathi Ch. 32 (Lipid-Lowering Drugs)_