Analysis of Children and Adolescents with Familial Hypercholesterolemia.
To evaluate the effectiveness of criteria based on child-parent assessment in predicting familial hypercholesterolemia (FH)-causative mutations in unselected children with hypercholesterolemia.



LDLR, APOB, and PCSK9 genes were sequenced in 78 children and adolescents (mean age 8.4 ± 3.7 years) with clinically diagnosed FH. The presence of polygenic hypercholesterolemia was further evaluated by genotyping 6 low-density lipoprotein cholesterol (LDL-C)-raising single-nucleotide polymorphisms.



Thirty-nine children (50.0%) were found to carry LDLR mutant alleles but none with APOB or PCSK9 mutant alleles. Overall, 27 different LDLR mutations were identified, and 2 were novel. Children carrying mutations showed higher LDL-C (215.2 ± 52.7 mg/dL vs 181.0 ± 44.6 mg/dL, P <.001) and apolipoprotein B levels (131.6 ± 38.3 mg/dL vs 100.3 ± 30.0 mg/dL, P <.004), compared with noncarriers. A LDL-C of ~190 mg/dL was the optimal value to discriminate children with and without LDLR mutations. When different diagnostic criteria were compared, those proposed by the European Atherosclerosis Society showed a reasonable balance between sensitivity and specificity in the identification of LDLR mutations. In children without mutation, the FH phenotype was not caused by the aggregation of LDL-C raising single-nucleotide polymorphisms.



In unselected children with hypercholesterolemia, LDL-C levels >190 mg/dL and a positive family history of hypercholesterolemia appeared to be the most reliable criteria for detecting FH. As 50% of children with suspected FH did not carry FH-causing mutations, genetic testing should be considered.
Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy.
Ilenia
I
Minicocci
Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy.
Simone
S
Pozzessere
Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy.
Cristina
C
Prisco
Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy.
Anna
A
Montali
Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy.
Alessia
A
di Costanzo
Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
Eliana
E
Martino
Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
Francesco
F
Martino
Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy. Electronic address: marcello.arca@uniroma1.it.
Marcello
M
Arca
D000293:Adolescent; D017677:Age Distribution; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D008078:Cholesterol, LDL / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005820:Genetic Testing; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology / Q000235:genetics*; D015994:Incidence; D008297:Male; D011446:Prospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
D008078:Cholesterol, LDL
Genetics; LDL receptor gene; children; familial hypercholesterolemia; screening