A teenager with tendon xanthomas: familial hypercholesterolaemia and the LDL receptor
Sanjay, a 12-year-old boy, is referred because his father had a myocardial infarction at 38 years and has yellow, painless swellings over both Achilles tendons. On examination Sanjay has bilateral Achilles tendon thickening and a corneal arcus, but no xanthelasma. His BMI is 18.5 kg/m², blood pressure 104/64 mmHg, and he plays football at school. Fasting lipids show total cholesterol 11.2 mmol/L, LDL cholesterol 9.6 mmol/L, HDL cholesterol 1.0 mmol/L and triglycerides 1.2 mmol/L. Liver function, thyroid function, HbA1c and urine protein are normal. His mother's lipids are normal, but a paternal uncle had a coronary bypass at 42 years. The family eats a typical South Indian diet with frequent fried snacks, and weekends are largely sedentary. The parents ask whether diet alone can bring the LDL down and whether a child can safely take a statin.
1. What is the most likely diagnosis, and what biochemical defect underlies it? Explain why his triglyceride level is normal.
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The most likely diagnosis is heterozygous familial hypercholesterolaemia. The combination of an isolated markedly raised LDL cholesterol, tendon xanthomas, corneal arcus in a child, and a strong paternal history of premature coronary disease is characteristic. The underlying defect is usually a loss-of-function mutation in the LDL receptor gene, although mutations in APOB or PCSK9 can produce a similar phenotype. Reduced LDL receptor activity impairs hepatic uptake and clearance of LDL particles, so LDL remains in circulation longer; hepatic cholesterol synthesis may also increase because intracellular cholesterol is low. Triglycerides are normal because very-low-density lipoprotein production and lipolysis are relatively preserved; the defect is predominantly in LDL clearance. The pattern of isolated hypercholesterolaemia with normal triglycerides and HDL helps distinguish this from combined hyperlipidaemia or metabolic syndrome. Inherited as an autosomal dominant trait, heterozygous familial hypercholesterolaemia affects roughly 1 in 250 people.
2. Explain the mechanism of action of a high-intensity statin in this boy, and why a low-fat diet alone will not normalize his LDL.
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Statins competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis. The fall in hepatic cholesterol activates sterol regulatory element-binding protein 2, which increases transcription of the LDL receptor gene. More LDL receptors on hepatocytes clear LDL from plasma, lowering LDL cholesterol. In heterozygous familial hypercholesterolaemia one LDL receptor allele is defective, so the maximum achievable receptor upregulation is limited; statins still work but often do not bring LDL to target, and additional agents such as ezetimibe, which blocks intestinal cholesterol absorption via NPC1L1, or a PCSK9 inhibitor may be needed. Diet alone typically lowers LDL by only about 10–15%, because most circulating cholesterol is derived from hepatic synthesis and receptor-mediated clearance rather than from dietary cholesterol. Saturated fat intake still matters and should be reduced, but it cannot correct a genetic clearance defect. The family should be counselled that diet and exercise are adjuncts, not substitutes for lipid-lowering drug therapy.
3. What screening and counselling would you offer to the family, and which additional tests would you order to assess his overall cardiovascular risk?
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Cascade screening should be offered to first-degree relatives, starting with the parents and siblings, using a fasting lipid profile; the father is already affected, and the mother should be checked even though her lipids are reported as normal. Genetic testing for LDLR, APOB and PCSK9 can confirm the diagnosis and facilitate cascade testing, but it is not essential to start treatment. Sanjay needs counselling about smoking avoidance, a diet low in saturated fat and refined carbohydrate, regular physical activity, and weight maintenance. Lipoprotein(a) should be measured once because a high level adds risk. Blood pressure, fasting glucose or HbA1c and renal function are reasonable baseline tests. Routine exercise stress testing is not required in an asymptomatic child. Statins are used in children with familial hypercholesterolaemia, usually from around 8–10 years in specialist care, with monitoring of liver enzymes, creatine kinase if symptomatic, growth and pubertal development. The family should understand that treatment is long-term and that adherence is central to reducing premature coronary risk.