Diagnosis Scoring for Clinical Identification of Children With Heterozygous Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is a frequent monogenic condition characterized by progressive atherosclerosis requiring preventive therapy from childhood. In a pediatric setting, heterozygous FH (hFH) in children may not be identified from common forms of hypercholesterolemia (HC). Objective: To elaborate a clinical scoring system for the diagnosis of hFH, defined by the presence of a disease-causing mutation of the gene for the low-density lipoprotein receptor (LDLR). Patients and Methods: A total of 100 unrelated children (6 +/- 3 years old, 43 boys, 57 girls) with type IIa HC (LDLC > 130 mg/dL) and complete genetic testing (at loci for genes for LDLR, apolipoprotein B, proprotein convertase subtilisin-like kesin type 9, and apolipoprotein E) were selected for score elaboration. Of 60 criteria from clinical records and family questionnaires, predictors of having hFH were estimated by logistic regression analysis. Scores were validated in 38 other unrelated children with HC. Results: Three independent predictors of hFH were identified according to the LDLR genotype (50Mut+/50Mut-): low-density lipoprotein cholesterol before (262 vs 178 mg/dL, P < 0.001) and after (225 vs 142 mg/dL, P < 0.001) 3 months or more of a lipid-lowering diet, combined with parental statin usage (odds ratio 6.2; 95% confidence interval 1.4-28.3; P = 0.018). High precision and accuracy of the scoring system (area under the receiver operating characteristic curve = 0.94; 95% confidence interval 0.91-0.98) were translated into 4 probability classes (definite/probable/possible/improbable hFH) with a false-negative rate of 12%. Conclusions: A score distinguishing hFH from common HC provides a simple tool for appropriate clinical decision and care in high-risk children. JPGN 48:456-463, 2009.