Lipid disorders and familial hypercholesterolaemia — formative SAQs

SAQ 1 — The school-age child with a high LDL-C (20 marks, ~15 minutes)

A well 9-year-old boy is found on a school-entry lipid panel to have an LDL-C of 6.2 mmol per litre, a normal triglyceride and a normal HDL. His father had a myocardial infarction at 48. The boy is asymptomatic, his examination is normal, and there are no xanthomas. [5]

Questions

1. Give the most likely diagnosis, the single most important confirmatory test, and the alternative you must exclude before committing to it. (5 marks) [2]
2. Outline the investigation bundle and interpret the paediatric LDL-C thresholds that support the diagnosis. (5 marks) [2]
3. Describe the definitive management, naming the first-line drug, the age at which it is started, and the evidence for its safety in children. (6 marks) [4]
4. Explain how you will use this child to identify other cases in the family, and the inheritance pattern that underpins that strategy. (4 marks) [1]

Model answer (must-hit)

1. The most likely diagnosis is heterozygous familial hypercholesterolaemia: an untreated LDL-C well above 5.0 mmol per litre, with a normal triglyceride and a first-degree family history of premature cardiovascular disease, crosses the FH threshold. The confirmatory test is genetic testing of LDLR, APOB and PCSK9. Before committing to the diagnosis, exclude a secondary cause — hypothyroidism, nephrotic syndrome, cholestasis or a drug — with a thyroid-stimulating hormone, renal function and urinalysis, and liver function. [2]
2. Send a repeat lipid profile with lipoprotein(a), a secondary-cause screen, and the genetic test. The thresholds that flag likely FH are an untreated LDL-C at or above 5.0 mmol per litre (190 mg per decilitre) regardless of family history, or at or above 4.0 mmol per litre (160 mg per decilitre) with a family history — this child meets both. A borderline result is repeated, and a markedly raised LDL-C above 10 mmol per litre would place homozygous FH at the top of the differential. [2]
3. The foundation is a heart-healthy diet low in saturated fat, regular activity, and avoidance of smoking. The first-line drug is a statin, started at the lowest licensed dose from age 8 to 10 years and titrated to an LDL-C target ideally below 3.1 mmol per litre. The safety evidence is strong: a statin started in childhood normalised carotid intima-media thickness, and the twenty-year follow-up showed no penalty to growth, puberty or hepatic safety. [4] [6]
4. Familial hypercholesterolaemia is autosomal dominant, so each first-degree relative has a one in two chance of carrying the variant. Cascade testing of both parents and all siblings is arranged once the index variant is confirmed; a parent with the variant is treated, and siblings are offered pre-symptomatic genetic testing. One index case, worked up properly, identifies and treats a whole family. [1]

SAQ 2 — The adolescent with xanthomas (20 marks, ~15 minutes)

A 14-year-old girl is referred for bilateral Achilles-tendon xanthomas and an LDL-C of 14 mmol per litre. She has had intermittent exertional chest discomfort. Her parents are first cousins. [3]

Questions

1. Give the most likely diagnosis and the clinical features that mark it as the severe form. (4 marks) [3]
2. Outline the urgent assessment of her exertional chest discomfort and the investigations that gauge the disease burden. (5 marks) [3]
3. Describe the intensive management, naming the therapies specific to this severe form beyond the standard drug ladder. (7 marks) [3]
4. Explain the inheritance, the implication for her siblings, and the psychosocial and transition issues for this adolescent. (4 marks) [1]

Model answer (must-hit)

1. The most likely diagnosis is homozygous familial hypercholesterolaemia. The untreated LDL-C above 10 mmol per litre, childhood tendon xanthomas, parental consanguinity and exertional cardiac symptoms together mark the severe homozygous form rather than heterozygous disease. [3]
2. Her exertional chest discomfort may be premature coronary ischaemia, so the assessment is a paediatric cardiology emergency: an electrocardiogram, troponin and echocardiography to look for coronary and aortic-valve involvement, and cardiology review. Genetic testing should include LDLR, APOB, PCSK9 and LDLRAP1 (given the consanguinity), and carotid intima-media thickness or cardiac imaging gauges the disease burden in this severe form. [3]
3. Beyond lifestyle and an oral statin-plus-ezetimibe combination, the therapies specific to homozygous FH are LDL apheresis from early childhood, a PCSK9 inhibitor such as evolocumab, and consideration of lomitapide, the ANGPTL3 inhibitor evinacumab, or liver transplant. The newer agents and apheresis have extended survival, but homozygous FH remains a severe, life-shortening disease that needs intensive, multidisciplinary care. [3]
4. Homozygous FH usually follows autosomal recessive or bilallelic inheritance when both parents are carriers, so each sibling should be offered testing. For this adolescent the psychosocial issues are substantial — a severe chronic disease, intensive treatment with apheresis, and the prospect of early cardiovascular disease — and the transition to adult care must address adherence, fertility and contraception counselling, and an honest, non-stigmatising account of the diagnosis and prognosis. [1]