2024 Volume 31 Issue 7 Pages 1048-1057
Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of premature coronary artery disease. Early detection and treatment are vital, especially in children. To improve FH diagnosis in children, the Japan Atherosclerosis Society (JAS) released new guidelines in July 2022. This study assessed and compared the sensitivity and specificity of the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022.
Methods: From September 2020 to March 2023, 69 children with elevated plasma LDL-C levels (≥ 140 mg/dL) were included in a pediatric FH screening project in Kagawa. The children were evaluated using genetic testing alongside the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022.
Results: Using the JAS pediatric FH 2017 criteria, eight children were diagnosed as FH-positive and 61 children as FH-negative. The JAS pediatric FH 2022 criteria identified 15 children with definite FH, 31 with probable FH, and 23 with possible FH. Genetic testing detected FH pathogenic variants in 24 children. The sensitivity and specificity for the JAS pediatric FH 2017 criteria were 0.292 and 0.978, respectively. For the JAS pediatric FH 2022 criteria, the sensitivity was 0.542 for definite FH with a specificity of 0.956, and 0.917 for probable FH with a specificity of 0.467.
Conclusion: The clinical diagnostic criteria of the JAS pediatric FH 2022 guidelines demonstrated improved diagnostic efficiency compared with those of 2017, as evidenced by the increased sensitivity while preserving specificity.
See editorial vol. 31: 1026-1028
Familial hypercholesterolemia (FH) is a genetic disorder that affects approximately 1 in 300 individuals1). Those with FH experience elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) from birth and face a significantly increased risk of developing coronary artery disease (CAD) at a young age2). Therefore, early diagnosis and preventive treatment are crucial in children with FH3).
Pediatric FH can be diagnosed on the basis of clinical diagnostic criteria and genetic testing. Clinical diagnostic criteria include elevated plasma LDL-C levels, a family history of FH, or premature CAD (pCAD). Genetic testing offers a means of diagnosing individuals who do not meet the clinical criteria, identifying asymptomatic family members, and initiating early treatment to mitigate the onset of pCAD. It is worth noting that in certain cases of FH, individuals may not exhibit pathogenic variants4). In Japan, the 2017 pediatric FH guidelines by the Japan Atherosclerosis Society (JAS) primarily emphasized elevated LDL-C levels (≥ 140 mg/dL) and a family history of FH or pCAD found in blood relatives --closer than the two parents5). This guideline aimed to maintain high specificity using a concise set of criteria. However, recent evidence has demonstrated that only 32% of children with pathogenic variants of FH were identified under the 2017 pediatric FH guidelines, revealing its limited sensitivity6). To enhance the detection of pediatric FH and facilitate early surveillance of at-risk individuals, the JAS revised its guidelines in July 2022. Compared with the 2017 version, the updated guidelines have incorporated notable modifications. The new JAS pediatric FH guidelines introduced categories for “probable FH” and “possible FH.” In addition, they distinguished the presence of pCAD in family history from the history of FH and included “Parental LDL-C ≥ 180 mg/dL” as a separate criterion. Moreover, they redefined the family history of FH from “among blood relatives closer than parents” to “including parents or siblings”7).
Since its inception in 2012, the Kagawa Prefecture has implemented the “Kagawa health checkups for the prevention of lifestyle-related diseases in children,” incorporating LDL-C blood testing6). Annually, over 7,000 children aged 9 or 10 undergo these health checkups in primary schools. Those presenting with LDL-C levels of ≥ 140 mg/dL are advised to consult their primary care physicians and undergo additional examination at their local medical institutions to rule out the possibility of primary dyslipidemia7-10). For cases in which a diagnosis cannot be made based on current guidelines, the children are then referred to one of four designated hospitals for a comprehensive reevaluation and to undergo genetic testing following an in-depth consultation6). This study employed genetic testing results from children redirected from local medical institutions to assess and compare the sensitivity and specificity of the clinical diagnostic criteria outlined in the JAS pediatric FH guidelines of 2017 and 2022.
The 2022 JAS pediatric FH guidelines introduced several updates from its 2017 predecessor. The new categories of “probable FH” and “possible FH” were added. “Probable FH” is determined when LDL-C levels fall between 140 and 179 mg/dL, coupled with a family history of pCAD or parental LDL-C levels exceeding 180 mg/dL. This category is also applicable for LDL-C levels of 180–249 mg/dL in the absence of a family history. Conversely, “possible FH” is identified when LDL-C levels are 100–139 mg/dL with a family history of FH, pCAD, or when parental LDL-C levels exceed 180 mg/dL, and when LDL-C is within 140–179 mg/dL without such a history. The 2022 guideline redefined the parameters of family history in FH from “among blood relatives closer than parents” to “parents or siblings.” Furthermore, the new guideline delineates the role of pCAD in the family history from the FH categorization, placing it on the same level as the criterion “Parental LDL-C ≥ 180 mg/dL.”
Study PopulationChildren aged 9 or 10 who exhibited LDL-C levels of 140 mg/dL or higher during primary school health checkups were advised to consult with primary care physicians and local medical institutions6). According to the protocol outlined in the “Manual of Kagawa Health Checkups for Preventing Lifestyle-Related Diseases in Children (2020)” provided by the Kagawa Pediatric Association, children with LDL-C levels ranging from 140 to 199 mg/dL underwent further assessment to identify potential secondary lipid abnormalities, including obesity, diabetes, thyroid dysfunction, nephrotic syndrome, and cholestatic liver disease. Additionally, family histories of FH and pCAD were reviewed. If the children were suspected of having FH or their LDL-C levels reached 200 mg/dL or higher, they were referred to one of the four designated medical hospitals: Kagawa University Hospital, Shikoku Medical Center for Children and Adults, Mitoyo General Hospital, and Kagawa Prefectural Central Hospital. From September 2020 to March 2023, 69 children suspected of having FH, including eight siblings from four different family lines, were referred from local medical institutions to these designated hospitals.
Clinical Characteristics of the ChildrenChildren referred from local medical institutions underwent genetic testing after informed consent was obtained. Subsequently, we reassessed their lipoprotein profiles, including measurements of LDL-C, high-density lipoprotein cholesterol, triglycerides, and total cholesterol (TC) levels. We also gathered various clinical data, including height, weight, heart rate, and blood pressure. To calculate the percentage of overweight individuals, we used the formula [(actual weight-standard weight)/standard weight]×100%, where standard weight was determined using school health statistics, adjusted for the child’s sex, age, and height. In addition, we collected family medical histories, including familial occurrences of FH and pCAD, alongside the LDL-C levels of the parents. pCAD was defined as CAD with onset before 55 years of age in men and before 65 years of age in women. Parental LDL-C levels and Achilles tendon examinations were typically not conducted at the local medical institutions or the four designated hospitals. This information was sourced from interviews or health examination records when parents accompanied their children to the hospitals.
Genetic TestingIn this study, 69 children with suspected FH underwent genetic analysis at Kanazawa University11). The process involved using a next-generation sequencing platform to evaluate genotypes. Specifically, the coding regions of apolipoprotein B, LDL receptor (LDLR), LDL receptor adaptor protein 1, and proprotein convertase subtilisin/kexin type 9 (PCSK9) were sequenced as previously described11). In addition, copy number variations at the LDLR locus were assessed using the eXome Hidden Markov Model12). The pathogenicity of the identified variants was determined through multidisciplinary sessions involving genetic specialists, according to the guidelines of the American College of Medical Genetics and Genomics.
Statistical AnalysisThe clinical characteristics of the children were presented as median (interquartile range) and analyzed using Student’s t-test or one-way analysis of variance, followed by Tukey’s post hoc test for multiple comparisons to evaluate these characteristics across two or three distinct groups. Statistical analysis was conducted using SPSS version 28 (SPSS Inc., Chicago, IL), and a p-value of <0.05 was considered statistically significant. Sensitivity and specificity rates were calculated on the basis of the results of genetic testing.
Ethical ConsiderationsThe protocol was approved by the Ethics and Human Genome Committees of Kagawa University (Heisei 30-187, Heisei 30-059), Shikoku Medical Center for Children and Adults, Mitoyo General Hospital, and Kagawa Prefectural Central Hospital. All procedures adhered to the ethical standards set forth by the responsible committee for human experimentation and complied with the most recent version of the Declaration of Helsinki. Written informed consent for the genetic testing of the children was obtained from at least one parent.
Between April 2020 and March 2023, 22,371 children in Kagawa Prefecture underwent preventive health checkups for lifestyle-related diseases, achieving a participation rate of 90.3%. Of these, 916 children (4.1%) were referred to their local medical institutions for further consultation with their primary care physicians because their LDL-C levels were 140 mg/dL or higher. Although the precise number of children visiting local medical institutions is unknown, 69 children were suspected of having FH based on the “Manual of Kagawa Health Checkups for Preventing Lifestyle-Related Diseases in Children.” They were included from September 2020 to March 2023 for genetic testing to identify pathogenic variants of FH. The clinical characteristics of the children are presented in Table 1. Using the JAS pediatric FH 2017 criteria, eight children received a positive FH diagnosis and 61 a negative FH diagnosis. Conversely, using the 2022 JAS pediatric FH criteria, 15 children were categorized as having definite FH, 31 as having probable FH, and 23 as having possible FH. The definite FH group exhibited notably elevated LDL-C and TC levels compared with the probable and possible FH groups. Furthermore, the LDL-C values were higher in the probable FH group than in the possible FH group.
Characteristics | ALL | JAS pediatric FH 2017 | JAS pediatric FH 2022 | |||
---|---|---|---|---|---|---|
(n = 69) | positive (n = 8) | negative (n = 61) | definite (n = 15) | probable (n = 31) | possible (n = 23) | |
Age (IQR), y | 10 (10-11) | 10 (10-11) | 10 (10-11) | 10 (10-11) | 10 (10-11) | 11 (10-12) |
Male sex, n (%) | 33 (48) | 4 (50) | 29 (48) | 9 (60) | 14 (45) | 10 (43) |
Height (IQR), (cm) | 139.4 (135.0-148.6) | 142.6 (137.3-146.1) | 139.3 (135.0-148.6) | 138.0 (135.6-146.9) | 137.5 (132.1-144.3) | 141.4 (136.4-153.5) |
BW (IQR), (kg) | 36.8 (30.2-43.5) | 36.6 (33.7-40.6) | 36.8 (29.7-43.5) | 34.6 (30.8-44.7) | 34.0 (29.5-40.7) | 38.3 (32.0-45.1) |
POW (IQR), % in child | 4.73 (-7.10-13.60) | 0.54 (-9.67-4.70) | 5.60 (-6.17-14.07) | -3.32 (-10.02-9.68) | 5.52 (-3.57-11.69) | 6.36 (-10.85-17.12) |
HR (IQR), RPM | 83 (75-92) | 70 (66-75) | 83 (76-93) | 71 (66-83) | 79 (75-92) | 90 (82-93) |
SBP (IQR), mmHg | 100 (90-110) | 96 (94-103) | 101 (90-111) | 103 (92-107) | 100 (93-112) | 101 (90-108) |
DBP (IQR), mmHg | 58 (54-64) | 60 (54-65) | 58 (53-64) | 57 (54-65) | 60 (54-63) | 59 (54-69) |
Serum lipids (IQR), mg/dL | ||||||
LDL-C | 168 (144-190) | 181 (169-200) | 164 (142-189) | 200 (183-246)*† | 180 (151-190)* | 152 (134-161) |
HDL-C | 64 (53-72) | 61 (55-76) | 64 (53-71) | 70 (55-77) | 64 (56-72) | 64 (50-69) |
TG | 78 (57-111) | 70 (58-82) | 81 (57-111) | 75 (61-96) | 76 (55-109) | 84 (62-155) |
TC | 252 (227-272) | 262 (252-279) | 252 (221-270) | 291 (262-352)*† | 252 (230-272) | 228 (214-241) |
JAS, Japan Atherosclerosis Society; FH, Familial hypercholesterolemia; n: number; IQR, interquartile range; POW, percentage of overweight; LDL- C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; TC, total cholesterol; Data were presented as median (IQR); *: p<0.05 vs. possible FH; †: p<0.05 vs. probable FH.
In this cohort of 69 children, 24 were found to carry pathogenic variants, whereas the remaining 45 did not (Fig.1). The variants identified were all heterozygous. Classification based on the 2017 JAS pediatric FH criteria resulted in eight children being assigned to the positive FH group and 61 to the negative. Within these groups, seven children with pathogenic variants were found in the positive FH group and 17 in the negative FH group (Fig.1). Alternatively, using the 2022 JAS pediatric FH criteria, children were divided into definite FH (15 children), probable FH (31 children), and possible FH (23 children). Of these, 13 children with pathogenic variants were in the definite FH group, nine in the probable FH group, and two in the possible FH group (Fig.1). Furthermore, we compared the LDL-C and TC levels between individuals with and without pathogenic variants of FH within the definite, probable, and possible FH groups (Supplemental Fig.1). The analysis revealed no significant differences in the LDL-C and TC levels between the definite and possible FH groups. A similar absence of significant differences was observed in LDL-C and TC levels among the probable FH group, regardless of the presence of pathogenic variants (Supplemental Fig.1).
Fig. 1. A total of 69 children suspected to have FH were categorized into positive and negative FH groups based on the criteria outlined in the 2017 JAS pediatric FH guideline. Additionally, using the criteria outlined in the 2022 JAS pediatric FH guideline, they were further classified as having definite, probable, and possible FH. The number of children with FH pathogenic variants was calculated. FH, Familial hypercholesterolemia; G (+/-), positive or negative for genetic testing.
A: LDL-C levels of patients with or without FH pathogenic variants from definite, probable and possible FH groups. B: TC levels of patients with or without FH pathogenic variants from definite, probable and possible FH groups. The data was presented as the average value (-) and individual measurement values (●). FH, Familial hypercholesterolemia; LDL-C, low-density cholesterol; TC, total cholesterol; G (+/-), positive or negative for genetic testing.
In this study, 12 types of pathogenic variants were identified in the LDLR gene and one in the PCSK9 gene (Table 2). Within the definite FH group, 10 pathogenic variants were identified, whereas the probable and possible FH groups exhibited six and two pathogenic variants, respectively. Specifically, we found two splice-site variants in the definite FH group and one splice-site variant in the probable FH group. Among the children with pathogenic variants of FH, one child had variants in both the LDLR and PCSK9 genes. Nonetheless, the LDL-C level was 203 mg/dL, which did not exceed the 250 mg/dL threshold. In addition, this child had no family history of FH or pCAD, but the parental LDL-C level was 204 mg/dL. Therefore, this child was diagnosed with definite FH. Furthermore, two children with pathogenic variants of FH were classified as possible FH cases. This categorization was based on LDL-C levels of 174 and 177 mg/dL, which did not exceed the 180 mg/dL threshold, coupled with the absence of any familial history of FH or pCAD and parental LDL-C levels below 180 mg/dL.
Gene | Nucleotide Change | Variant type | Number of Children | ACMG | Judgement |
---|---|---|---|---|---|
Definite FH | |||||
LDLR | c.301G>A | Missense | 1 |
PM1/PP2/PP3/PP4/PP5 likely pathogenic |
pathogenic |
c.682G>C | Missense | 1 |
PM1/PM2/PP1/PP3/PP5 likely pathogenic |
pathogenic | |
c.1187-10G>A | Splice-site | 1 |
PP3/PP4/PS3 likely pathogenic |
pathogenic | |
c.1195G>A | Missense | 1* |
PM1/PM2/PP3/PP5 likely pathogenic |
likely pathogenic | |
c.1207T>C | Missense | 3 |
PM1/PM2/PM5/PP3 likely pathogenic |
pathoenic | |
c.1702C>G | Missense | 2 |
PM2/PP1/PP3/PP5 likely pathogenic |
pathogenic | |
c.1705+1G>C | Splice-site | 1 |
PVS1/PM2/PM4/PP4 pathogenic |
pathogenic | |
c.1783C>T | Missense | 1 |
PM1/PM2/PP3/PP4 likely pathogenic |
pathogenic | |
c.2579C>T | Missense | 1 |
PVS1/PM2/PM4/PP4 pathogenic |
pathogenic | |
PCSK9 | c.94G>A | Missense | 2* |
PS1/PS3/PP4/PP5 pathogenic |
pathogenic |
Probable FH | |||||
LDLR | c.361T>C | Missense | 1 |
PM1/PM2/PM5/PP3 likely pathogenic |
likely pathogenic |
c.401G>A | Missense | 1 |
PM1/PM2/PM5/PP3 likely pathogenic |
likyly pathogenic | |
c.1207T>C | Missense | 3 |
PM1/PM2/PP3/PP5 likely pathogenic |
pathogenic | |
c.1702C>G | Missense | 1 |
PM2/PP1/PP3/PP5 likely pathogenic |
pathogenic | |
c.1705+1G>C | Splice-site | 1 |
PVS1/PM2/PM4/PP4 pathogenic |
pathogenic | |
PCSK9 | c.94G>A | Missense | 2 |
PS1/PS3/PP4/PP5 pathogenic |
pathogenic |
Possible FH | |||||
LDLR | c.547C>T | Missense | 1 |
PM2/PP3/PP5/PM1 likely pathogenic |
likely pathogenic |
c.2579C>T | Missense | 1 |
PVS1/PM2/PM4/PP4 pathogenic |
pathogenic |
FH, Familial hypercholesterolemia; LDLR: low density lipoprotein receptor; PCSK9: Proprotein convertase subtilisin/kexin type 9; ACMG American College of Medical Genetics and Genomics; *: one child had pathogenic variants in both the LDLR and PCSK9 genes.
The LDL-C levels of several children with suspected FH were measured at 130–139 mg/dL in the designated hospitals. Therefore, in the stratification of the children by LDL-C levels, the distribution was as follows: 8, 26, 31, and 4 children in the LDL-C groups of 130–139, 140–179, 180–249, and over 250 mg/dL, respectively (Table 3). Of the eight children in the 130–139 mg/dL LDL-C range, all eight were diagnosed with possible FH, which was attributed to a parental history of LDL-C levels exceeding 180 mg/dL. Among the 26 children with LDL-C levels between 140 and 179 mg/dL, two were diagnosed with definite FH because of a family history of FH, nine were diagnosed with probable FH on the basis of a family history of pCAD or parental LDL-C levels over 180 mg/dL, and the remaining 15 were diagnosed with possible FH in the absence of a family history. Among the 31 children with LDL-C levels ranging from 180 to 249 mg/dL, diagnoses of definite FH were given to two children with a family history of FH, two with a family history of pCAD, and five with a family history of parental LDL-C levels exceeding 180 mg/dL. An additional 22 children without any family history of FH or pCAD were diagnosed with probable FH. Finally, in the group of four children with LDL-C levels exceeding 250 mg/dL, definite FH was diagnosed. Within this subgroup, one child had a family history of pCAD, two had a family history of parental LDL-C levels exceeding 180 mg/dL, and one had no family history (Table 3).
LDL-C (mg/dL) | ||||
---|---|---|---|---|
130-139 | 140-179 | 180-249 | 250- | |
Number of children | 8 | 26 | 31 | 4 |
With family history of FH | possible (0) | definite (2) | definite (2) | definite (0) |
With family history of pCAD | possible (0) | probable (1)* | definite (2) | definite (1) |
Parental LDL-C ≥ 180 mg/dL | possible (8) | probable (9) * | definite (5) | definite (2) |
No family history of FH or pCAD | NE | possible (15) | probable (22) | definite (1) |
LDL-C, low-density cholesterol; FH, Familial hypercholesterolemia; pCAD, premature coronary artery disease; NE, not examined. *: one child had both family histories of pCAD and parental LDL-C ≥ 180 mg/dL.
To assess the efficiency of the diagnostic criteria outlined in the JAS pediatric FH guidelines of 2017 and 2022, we evaluated the number of children classified as positive and definite FH cases under each set of criteria. Table 4 shows that, of the eight children positive for FH using the 2017 JAS criteria, half had a family history of FH and the other half had a family history of pCAD. Subsequent genetic testing revealed that four of the children with a family history of FH and three with a family history of pCAD carried pathogenic FH variants. In contrast, the 2022 JAS criteria identified children with definite FH, in which four children had a family history of FH, three had a family history of pCAD, seven had a parental LDL-C level of ≥ 180 mg/dL, and one had an LDL-C level of ≥ 250 mg/dL. Genetic testing results revealed that all four children with a family history of FH exhibited these genetic variations. In addition, three children with a familial pCAD history were found to carry pathogenic variants. Of the children with a parental LDL-C level of 180 mg/dL or higher, five had genetic variants. Furthermore, the sole child with an LDL‑C level exceeding 250 mg/dL also had a pathogenic variation.
Items of criteria in JAS pediatric FH 2017 and 2022 | ||||
---|---|---|---|---|
JAS pediatric FH 2017 | Family history of FH | Family history of pCAD | ||
Positive FH, n | 4 | 4 | ||
G (+) in Positive FH, n (%) | 4 (100) | 3 (75) | ||
JAS pediatric FH 2022 | Family history of FH | Family history of pCAD |
Parental LDL-C ≥ 180 mg/dL |
Child’s LDL-C ≥ 250 mg/dL |
Definite FH, n | 4 | 3 | 7 | 1 |
G (+) in Definite FH, n (%) | 4 (100) | 3 (100) | 5 (71) | 1 (100) |
JAS, Japan Atherosclerosis Society; FH, Familial hypercholesterolemia; G (+), positive for genetic testing; pCAD, premature coronary artery disease; LDL-C, low-density cholesterol; n: number.
The analysis revealed that the 2017 JAS pediatric criteria for FH had a sensitivity of 0.292 and a specificity of 0.978 for detecting pathogenic variants associated with FH. Conversely, applying the 2022 JAS pediatric criteria resulted in a sensitivity of 0.542 and a specificity of 0.933 for definitive FH diagnosis. When combining cases classified as definite and probable FH, the sensitivity and specificity were found to be 0.917 and 0.467, respectively (Table 5).
Criteria | Sensitivity | Specificity |
---|---|---|
JAS pediatric FH 2017 | ||
Positive FH | 0.292 | 0.978 |
JAS pediatric FH 2022 | ||
Definite FH | 0.542 | 0.956 |
Definite + Probable FH | 0.917 | 0.467 |
JAS, Japan Atherosclerosis Society; FH, Familial hypercholesterolemia.
This study revealed that the updated diagnostic criteria introduced in the JAS pediatric FH guidelines of 2022 have doubled the sensitivity for detecting FH cases compared with the 2017 version while maintaining the same specificity. Including definite and probable criteria for FH has also been shown to allow for more effective monitoring of FH cases with a high level of sensitivity.
In children with FH, the manifestation of physical signs such as tendon xanthomas is uncommon. As a result, the 2017 JAS pediatric FH guidelines heavily depended on detecting elevated levels of LDL-C and a familial history of FH or pCAD13). However, the recognition of a family history of FH or pCAD is often challenging14). Therefore, the lower sensitivity of the 2017 guidelines has been associated with delays in initiating treatment for pediatric FH6, 15). The 2022 JAS pediatric FH guidelines have incorporated an additional parameter that considers a parental LDL-C level of ≥ 180 mg/dL and a family history of FH and pCAD7). Our previous study demonstrated that over 50% of children with FH have a family history of a parental LDL-C level of ≥ 180 mg/dL6). This study further identified that a majority of the children presenting with LDL-C levels of ≥ 180 mg/dL and having a parent with similar LDL-C levels were carriers of pathogenic variants of FH. Consequently, the inclusion of a parental LDL-C level of ≥ 180 mg/dL increases the diagnostic rate of pediatric FH.
In the 2022 JAS pediatric FH guidelines, a distinction was made between a family history of pCAD and a family history of FH, recognizing that pCAD may arise from etiologies other than FH. Notably, a study found that only 1 in 15 individuals with pCAD have FH16). Additionally, evidence shows that the use of statins is associated with a lower incidence of CAD and decreased overall mortality17). According to real-world data from the Explore J Study, children with FH were found to develop CAD at an average age of approximately 59.5 years18). In our study, which had a limited sample size, we observed that four children with a family history of FH had pathogenic variants of FH. Interestingly, among the four children with a family history of pCAD, three had pathogenic variants of FH. This finding underscores the need for further research to verify the distinction between a family history of pCAD and a family history of FH.
The JAS pediatric FH guidelines of 2022 introduced the probable and possible categories of FH. By combining probable with definite FH, the guidelines successfully identified more than 90% of children with FH pathogenic variants. Early diagnosis and treatment of FH are crucial for preventing atherosclerosis and pCAD3, 19). Consequently, the implementation of the 2022 JAS pediatric FH guidelines can greatly facilitate the management and monitoring of a broader population of children with confirmed or suspected FH.
Conversely, the enhanced sensitivity was accompanied by a decrease in specificity upon incorporating probable FH into the criteria. However, this inclusion mitigates the risk of overlooking FH cases. Moreover, the accuracy of family histories tends to improve over time, which may result in the reclassification of some instances initially identified as probable FH to definite FH in the absence of FH-specific pathogenic variants. Therefore, continual monitoring is essential.
As of 2023, Kagawa Prefecture is the only region in Japan to conduct universal FH screening at the prefectural level. It is crucial to recognize the potential for continuing regional disparities. Evaluating the effectiveness of this approach and encouraging similar programs elsewhere are vital steps toward the widespread establishment of universal FH screening.
In this study, a three-tiered screening approach was employed, yielding insights not only into the identification of individuals with elevated LDL-C levels but also into a subgroup with a high probability of FH. It is pertinent to underscore that the possible FH cases in this study solely comprise individuals with LDL-C levels between 130 and 139 mg/dL combined with parental LDL-C levels exceeding 180 mg/dL, or individuals with LDL-C levels between 140 and 179 mg/dL in the absence of family history. This does not encompass the entire possible category as described in the clinical guidelines. Therefore, the conclusions drawn from this investigation pertain specifically to this subset of children and may not be generalizable to all individuals classified as having possible FH under the broader guideline criteria. This nuance is important for the accurate understanding and clinical integration of our study findings. Therefore, further validation within a general pediatric cohort is essential.
Furthermore, it is necessary to corroborate the 2022 JAS pediatric FH guidelines using data from other regions since these guidelines were developed on the basis of our previously reported data.
The clinical criteria outlined in the JAS pediatric FH guidelines of 2022 exhibit enhanced sensitivity while preserving specificity compared with the 2017 criteria. By combining definite and probable FH cases, there is an improvement in sensitivity that facilitates more thorough surveillance and follow-up of individuals suspected of having FH. This proactive approach significantly reduces the likelihood of undetected cases of pediatric FH.
This study received support from various sources, including a research grant from the Japan Agency for Medical Research and Development (AMED) under grant number 22gk0110065h0001, grants from the Ministry of Health, Labor, and Welfare for Research on Rare and Intractable Diseases and Research on Primary Dyslipidemia, a grant from the Ministry of Education, Culture, Sports, Science and Technology for Research on the Significance of LDL Cholesterol Screening in Elementary School Children, and a grant from the Japanese Circulation Society (Project for Genome Analysis in Cardiovascular Diseases). We would like to express our gratitude to the officials in Kagawa Prefecture and the 17 municipalities (Takamatsu City, Marugame City, Sakaide City, Zentsuji City, Kanonji City, Sanuki City, Higashikagawa City, Mitoyo City, Tonosho Town, Shodoshima Town, Miki Town, Naoshima Town, Utazu Town, Ayagawa Town, Kotohira Town, Tadotsu Town, Manno Town) for their cooperation in this research. We also extend our appreciation to the members of the Review Committee of Kagawa health checkups for childhood lifestyle-related diseases prevention, Kagawa Medical Association, and Kagawa Pediatric Association for their support in this study.
We thank Phoebe Chi, MD, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.
The authors declare that there is no conflict of interest.