A patient presents with xanthomas on the Achilles tendon. Which of the following is the most likely diagnosis?

Explanation

## Correct Answer: A. Familial hypercholesterolemia Achilles tendon xanthomas are a pathognomonic sign of **familial hypercholesterolemia (FH)**, a monogenic disorder of LDL receptor function. The discriminating feature is that xanthomas in FH are firm, nodular deposits of cholesterol esters that form in tendons (especially Achilles) and skin due to chronic, severe hypercholesterolemia (typically LDL >300 mg/dL). These xanthomas develop because macrophages in tendon sheaths become lipid-laden when exposed to persistently elevated LDL cholesterol, forming characteristic nodules. FH affects approximately 1 in 500 Indians (heterozygous form) and presents with premature coronary artery disease, corneal arcus, and xanthelasmas. The Achilles tendon xanthoma is so specific to FH that its presence virtually confirms the diagnosis. Homozygous FH (1 in 1,000,000) presents earlier with xanthomas in childhood and myocardial infarction in the first decade. The pathophysiology involves defective LDL receptors (most common) or apoB-100 mutations, preventing normal LDL clearance and causing accumulation in extrahepatic tissues, particularly tendons where they form visible deposits. ## Why the other options are wrong **B. Tangier disease** — Tangier disease (ABCA1 deficiency) causes severe HDL deficiency and presents with orange-yellow tonsils, hepatosplenomegaly, and neuropathy—not Achilles tendon xanthomas. Patients have very low HDL and normal or low LDL, so cholesterol does not accumulate in tendons. This is an NBE trap because both are lipid disorders, but the clinical phenotype is completely different. **C. Type III hyperlipoproteinemia** — Type III hyperlipoproteinemia (remnant removal disease) causes palmar xanthomas and tuberoeruptive xanthomas, not Achilles tendon xanthomas. It results from apoE2/E2 genotype and presents with elevated cholesterol and triglycerides. The xanthomas are eruptive and palmar, not tendinous—a key clinical distinction that NBE exploits by offering a different xanthoma type. **D. Familial hyperchylomicronemia** — Familial hyperchylomicronemia (Type I hyperlipoproteinemia, lipoprotein lipase deficiency) causes severe hypertriglyceridemia (>1000 mg/dL), eruptive xanthomas, lipemia retinalis, and recurrent pancreatitis—not Achilles tendon xanthomas. LDL cholesterol remains normal, so tendon deposits do not form. The xanthomas are eruptive and widespread, not localized to tendons. ## High-Yield Facts - **Achilles tendon xanthomas** are pathognomonic for familial hypercholesterolemia and indicate LDL >300 mg/dL chronically. - **FH heterozygotes** (1 in 500 Indians) have LDL 300–600 mg/dL and premature CAD; **homozygotes** (1 in 1,000,000) present with xanthomas and MI in childhood. - **LDL receptor mutations** (85% of FH cases) cause defective receptor-mediated endocytosis; **apoB-100 mutations** (10%) prevent LDL binding. - **Corneal arcus** and **xanthelasmas** are other cutaneous signs of FH, but Achilles tendon xanthomas are the most specific. - **Type III hyperlipoproteinemia** causes palmar and tuberoeruptive xanthomas; **Type I** causes eruptive xanthomas—neither affects tendons. ## Mnemonics **FH Xanthoma Sites (TACT)** **T**endon (Achilles—pathognomonic), **A**rcus cornea, **C**utaneous (xanthelasma), **T**uberous (rare). Tendon xanthomas = FH until proven otherwise. **Xanthoma Types by Lipid Disorder** **FH** = Tendinous (Achilles); **Type III** = Palmar + Tuberoeruptive; **Type I** = Eruptive; **Tangier** = Tonsils (orange), not xanthomas. Remember: Achilles = FH always. ## NBE Trap NBE pairs multiple lipid disorders with xanthomas to trap students who confuse xanthoma types. The key discriminator is **Achilles tendon xanthomas**, which are virtually pathognomonic for FH—other disorders cause eruptive, palmar, or tuberoeruptive xanthomas, never tendinous deposits. ## Clinical Pearl In Indian clinical practice, FH is often diagnosed late because Achilles tendon xanthomas are mistaken for tendinitis or ignored. A patient presenting with premature CAD (age <40 in men, <50 in women) and firm nodules on the Achilles tendon should trigger immediate lipid screening and genetic counseling for family members—early statin therapy can prevent MI. _Reference: KD Tripathi Ch. 28 (Lipid Metabolism); Robbins Ch. 5 (Genetic Disorders); Harrison Ch. 375 (Lipid Disorders)_