Clinical scores fail to sufficiently identify children with familial hypercholesterolaemia

Area of Science:

• Pediatrics
• Genetics
• Cardiology

Background:

• Familial hypercholesterolemia (FH) is an inherited condition leading to high LDL-C levels and increased cardiovascular risk.
• Early diagnosis and intervention are crucial for preventing premature cardiovascular events in children with FH.
• Current clinical diagnostic criteria (Simon Broome, MEDPED, guideline-derived) are used to identify potential FH cases.

Purpose of the Study:

• To evaluate the diagnostic accuracy of three clinical criteria for identifying familial hypercholesterolemia in children.
• To compare the sensitivity and specificity of Simon Broome, MEDPED, and guideline-derived criteria against genetic testing results.
• To determine the effectiveness of these clinical scores in detecting genetically confirmed FH in pediatric populations.

Main Methods:

• A cohort of 1337 children with elevated LDL-C levels was assessed.
• Clinical data were collected via a self-reporting questionnaire.
• Genetic testing was performed to identify pathogenic variants confirming heterozygous FH (HeFH).

Main Results:

• Genetic analysis identified 211 children with a pathogenic FH mutation out of 1337 participants.
• Clinical criteria identified varying numbers of children with FH: Simon Broome (210/1337), MEDPED (125/1337), and guideline-derived (112/835).
• Clinical scores demonstrated high specificity (0.91-0.97) but low sensitivity (0.44-0.54), with similar performance across subgroups.

Conclusions:

• Clinical FH diagnostic scores in children exhibit high specificity but low sensitivity, potentially leading to missed diagnoses.
• Approximately half of mutation-positive children were missed by these clinical criteria, delaying essential preventive treatment.
• The study advocates for a lower threshold for genetic testing in children with suspected FH due to the limitations of current clinical scores.