What is the workup for a pediatric patient with a concern for familial hypercholesterolemia (FH)?

Workup for Pediatric Patient with Suspected Familial Hypercholesterolemia (FH)

The diagnostic workup for pediatric FH should include detailed family history, lipid profile measurements, exclusion of secondary causes, and genetic testing when available to ensure early identification and treatment of this condition.

Initial Diagnostic Evaluation

• Obtain a detailed family history focusing on premature cardiovascular disease, elevated cholesterol levels, and known FH diagnoses in family members 1
• Measure fasting lipid profile on at least two separate occasions (>2 weeks but <3 months apart) to establish baseline LDL-cholesterol levels 1
• Exclude secondary causes of hypercholesterolemia including hypothyroidism, renal failure, and other metabolic disorders 1
• Consider FH highly probable in children with:
  • Untreated LDL-cholesterol >4.9 mmol/l (>190 mg/dl) with parental history of high LDL-cholesterol, premature ASCVD, or positive genetic test for FH 1
  • Untreated LDL-cholesterol >4.0 mmol/l (>160 mg/dl) with parental history of high LDL-cholesterol or premature ASCVD 1
  • Untreated LDL-cholesterol >3.5 mmol/l (>135 mg/dl) with a parent having a pathogenic gene variant for FH 1

Genetic Testing

• Genetic testing should be performed in the index case (proband) when cascade testing in the family is recommended 1
• Test for pathogenic variants in LDLR, APOB, and PCSK9 genes 1
• Note that standard adult phenotypic criteria (e.g., Dutch Lipid Clinic Network criteria) should not be used in children or during cascade testing 1
• A negative genetic test does not exclude FH if clinical features are strongly suggestive 1

Physical Examination

• Evaluate for physical stigmata of FH, particularly in children with very high LDL-cholesterol levels:
  • Tendon xanthomas (especially Achilles tendons)
  • Cutaneous xanthomas
  • Arcus cornealis (particularly concerning if present before age 10) 1, 2
• Assess for signs of premature atherosclerosis 2

Additional Testing

• Consider non-invasive imaging techniques to evaluate for subclinical atherosclerosis in children with confirmed FH 3
• For suspected homozygous FH (HoFH), which is more severe:
  • Diagnose if untreated LDL-cholesterol >10 mmol/l (>400 mg/dl) with physical stigmata before age 10 and/or both parents with FH 1
  • Rule out sitosterolaemia and cerebrotendinous xanthomatosis which can present similarly 1
  • Consider earlier and more aggressive evaluation and management 1, 3

Cascade Testing

• Once a pediatric index case is identified, cascade testing should be offered to all first-degree relatives 1
• Use age-specific, sex-specific, and country-specific LDL-cholesterol thresholds for phenotypic cascade testing 1
• Genetic cascade testing is preferred when a pathogenic variant has been identified in the index case 1

Common Pitfalls to Avoid

• Delaying diagnosis and treatment - early identification is crucial to reduce lifetime LDL-cholesterol burden 1, 4
• Using adult diagnostic criteria in children - specific pediatric criteria should be used 1
• Failing to screen family members after identifying an index case 1, 4
• Missing homozygous FH cases which require more urgent intervention 3
• Inadequate follow-up - regular monitoring is essential to ensure treatment goals are met 5

Early identification of FH in childhood is essential as atherosclerotic changes begin early in life, and prompt treatment can significantly reduce the risk of premature cardiovascular disease 3, 2, 4.