Abstract
Purpose
This study assesses the success of the recently terminated Dutch nationwide cascade screening by examining whether children with familial hypercholesterolemia (FH) were identified through family screening or due to cardiovascular (CVD) events in the FH parent.
Methods
We collected clinical information of all children (0–18 years) with FH with a pathogenic variant at our outpatient lipid clinic between 1992 and 2014 and their FH parents and FH grandparents.
Results
We analysed 292 FH children from 205 parents with FH. A history of premature CVD was present in 20% of the parents (29% of the fathers, 9% of the mothers) and 49% of the FH grandparents.
Conclusion
The fact that CVD is still a presenting event of FH in especially fathers shows that nationwide screening might have been terminated too early. Therefore we recommend to proceed the cascade screening.
Keywords
1. Introduction
Familial hypercholesterolemia (FH) is a disorder of lipid metabolism associated with a severe risk of cardiovascular disease (CVD) [
1
, 2
]. Effective CVD prevention is available, consisting of lifestyle changes and lifelong statin treatment [3
, 4
]. Recent data showed that FH is more prevalent in the Netherlands than previously assumed: these data suggest that the prevalence might be as high as 1:244 [[5]
]. In The Netherlands a well-known nationwide cascade screening in families with a pathogenic variant causing FH has been carried out over the last 15 years. This programme, supported by the Dutch Ministry of Public Health, Welfare and Sport, involved genetic fieldworkers who visited relatives at home, and collected medical information and blood samples. Due to end of funding, this national cascade screening programme has terminated at the end of 2013. At that moment >28.000 people with FH were identified, 42% of the expected number of FH patients in The Netherlands [[6]
]. The aim of the programme is that FH patients are identified through cascade family screening rather than as a consequence of CVD bringing them into clinical attention. A method to assess the success of our cascade screening programme is to study whether children with FH have been identified through cascade screening or due to CVD in the parents. The aim of this study was to identify how many of the children treated at our clinic were referred because of a parent with CVD.2. Patients and methods
2.1 Participants
All consecutive children with FH who visited the outpatient lipid clinics of the Erasmus MC or Sophia Children Hospital The Netherlands for the first time with an age ≤18 years, between April 1993 and November 2014 were considered eligible for inclusion in this study. The diagnosis FH was based on identification of a FH pathogenic variant in the LDL-receptor (LDLR) gene or the Apolipoprotein B (APOB) gene. The variants in patients were reviewed by a specialist of the laboratory that identified and characterized these variants (dr. ir. J. Defesche). All variants presented in this study were pathogenic variants, either because they have been published as pathogenic by in vitro activity assays or by co-segregation in families. Children diagnosed with FH based on clinical grounds were excluded.
The Medical Ethical Review Committee of the Erasmus MC, The Netherlands, considered the protocol non-Medical Research Involving Human Subjects Act (WMO) therefore review of the protocol was waved. (Table 1, Table 2).
Table 1General characteristics of children with FH.
| Children with FH (n = 292) | Parent with CVD (n = 41) | Parent without CVD (n = 164) | p-value | |
|---|---|---|---|---|
| Girls, n (%) | 154 (53) | |||
| Maternal inheritance, n (%) | 125 (43) | |||
| Paternal inheritance, n (%) | 167 (57) | |||
| Dutch Ethnicity, n (%) | 273 (94) | |||
| Age (yrs) first visit (mean ± SD) | 10.6 ± 4.3 | 12.1 ± 3.9 | 11.1 ± 4.3 | 0.39 |
| Age (yrs) started statin (mean ± SD) | 13.6 ± 3.1 | 13.9 ± 2.6 | 14.2 ± 3.2 | 0.23 |
| DNA pathogenic variants, n (%) | 59 (100) | |||
| LDL receptor pathogenic variant | 269 (92) | |||
| p.Trp44* | 32 (11) | |||
| c.313+1G > A | 27 (9.2) | |||
| c.191-2A > G | 24 (8.2) | |||
| Apo B gene pathogenic variant | 23 (7.9) | |||
| Untreated lipid values 1evisit, mean ± SD | ||||
| Total cholesterol (mmol/l) | 7.1 ± 1.5 | |||
| LDL-C (mmol/l) | 5.4 ± 1.4 | |||
| HDL-C (mmol/l) | 1.3 ± 0.3 | |||
| Triglyceride (mmol/l) | 1.0 ± 0.5 | |||
| Cholesterol lowering Medication | ||||
| Medication at 1e visit | 2 (1) | |||
| Started medication after 1e visit | 180 (63) | |||
| No medication at all | 90 (31) | |||
FH = familial hypercholesterolemia, LDL-C = low density lipoprotein cholesterol, HDL-C = high density lipoprotein cholesterol, CVD = cardiovascular disease.
Table 2General characteristics of FH parents and FH grandparents.
| Parents with FH (n = 205) | Paternal (n = 114) | Maternal (n = 91) | P-value | |
|---|---|---|---|---|
| Inheritance (%) | 100 | 56 | 44 | |
| Caucasian Ethnicity, n (%) | 194 (95) | 111 (97) | 84 (92) | 0.18 |
| History of CVD, n (%) | 41 (20) | 33 (29) | 8 (9) | 0.002 |
| Mortality parent, n (%) | 5 (2.4) | 5 (4.4) | 0 (0) | |
| Age (yrs) 1e CVD event (mean ± SD) | 41 ± 8.4 | 42 ± 8.6 | 40 ± 8.3 | 0.54 |
| Untreated total cholesterol (mmol/l) | 9.3 ± 1.9 | 9.4 ± 1.7 | 9.3 ± 2.1 | 0.043 |
| Index parent | 39 (82) | 40 (46) | 37 (34) | 0.88 |
| Grandparents with FH | ||||
| History of CVD grandparents | 49 (102) | |||
| Age (yrs) 1e CVD event (mean ± SD) | 51 ± 11.1 | |||
Oldest child per parent selected, CVD = cardiovascular disease, FH = familial hypercholesterolemia.
2.2 Study design
FH patients are treated by the Cardiovascular Genetics (CVG) team consisting of a lipidologist, a nurse practitioner and a research nurse specialized in collecting pedigree data. Parents are advised to bring their children from the age of 10 years for follow-up. Children and parents with FH receive regular tailored education about their disease, lifestyle advices, benefits of using statins and the effect of treatment on lipid profiles.
Clinical data such as medication, LDLR or APOB gene pathogenic variant, plasma lipid values triglycerides, total, LDL -cholesterol (LDL-C) and HDL-cholesterol (HDL-C), family history of cardiovascular disease and general characteristics such as age, sex and date of first visit were collected from the childrens' files. Genetic testing of FH pathogenic variants of all the children was performed by the laboratory of cardiovascular genetics in the Academic Medical Centre, Amsterdam [
[7]
].Pedigree data and clinical data of the FH parents and grandparents of all children were collected. Premature CVD was defined as one of the following: myocardial infarction, proven angina, Coronary Artery Bypass Grafting (CABG) or Percutaneous Coronary Intervention, stroke and peripheral arterial disease in men < 55 years and women < 60 years [
[8]
]. These events were assessed from the patients' medical records and adjudicated by the study team.2.3 Statistics
All data were analysed anonymously using SPSS (version 21.0). Chi-square tests to assess differences in proportions, and the student t-test (since the data were normally distributed) to assess differences in means were used. The values are presented as mean ± Standard Deviation (S.D.), unless otherwise specified. Dichotomous variables are presented as numbers and percentages. Statistical significance was defined as P≤0.05. For the analysis per parent we selected the oldest child.
3. Results
A total of 292 of 308 consecutive FH children were included in this study. Sixteen subjects were excluded because of FH on clinical grounds. Of the 292 children of 205 parents with FH, 154 were girls. Most children (57%) inherited FH from their father. The majority was Caucasian (94%). Fifty-nine different pathogenic variants were identified. The p.Trp44* pathogenic variant of the LDLR gene was the most prevalent (11%). An APOB pathogenic variant was detected in 8% of the subjects. The average age at first visit to the lipid clinic was 10.6 ± 4.3 years (range: 0.2–18.0 years). Untreated lipid levels were known of the majority of the children (92%). They had an untreated total cholesterol level of 7.1 ± 1.5 mmol/l and an LDL-C level of 5.4 ± 1.4 mmol/l. Sixty-three percent of the FH children started with a statin after their first visit; 95% of the FH children used a statin at a certain point during follow-up. The mean age of starting statin treatment was 13.6 ± 3.1 years.
3.1 CVD in parents of FH children
A history of CVD was present in 20% (n = 41) of the FH parents; 29% (n = 33) of the fathers and 9% (n = 8) of the mothers. With one exception, all suffered from premature CVD. The mean age of the first event was of 41 ± 8.5 years. In five of these parents (all men), CVD was fatal. Of the grandparents with FH, 49% had a history of CVD, the mean age of their first event was 51 ± 11.1 years. It was not possible to analyse differences in percentage of FH parents with CVD between the first decade (1993–2003) and the second (2004–2014) because of the low number of children visiting the out-patient clinic in the first decade.
Children with a parent without CVD tended to visit the lipid clinic at a younger age than children with a parent with CVD (11.1 vs 12.1 years; p = 0.392), but they started statin treatment a bit older (14.2 vs 13.9 years, p = 0.231), both not significant.
4. Discussion
Even in the setting of active cascade screening, 1:5 children with FH are identified because their parent experienced CVD, mostly at a premature age. An earlier study from The Netherlands revealed a higher percentage of CVD (31%) in first-degree relatives of genetically confirmed FH children with a similar age and lipid profile compared to our study [
[9]
]. This difference might be the result of the effect of nationwide cascade screening. Another explanation could be a referral bias towards a more severe phenotype as the inclusion of this study took place earlier, 1989–2001 when treating FH children was not common practice.Compared to other countries, our data are in line with findings from FH children in Norway which also show 21% premature CVD in their parents with FH [
[10]
]. In this study children were identified through screening of families with a known mutation or referred to the lipid clinic.Although not significant, children with a parent without CVD visit the lipid clinic at a younger age than children with parents with CVD (11.1 vs 12.1 years). This finding highlights the result of the active screening programme, bringing these children into attention at an early age.
Children with a parent with CVD started with a statin a few months earlier (13.9 vs 14.2 years), suggesting a more proactive treatment in these children. The mean age of starting treatment at 13.6 years is in line with another large cohort of FH children in The Netherlands [
[11]
]. Our results show that we don't fulfil the current guideline for screening and starting statin treatment in FH children. Several studies demonstrate atherosclerosis starts already in young children with FH [[12]
], only since 2013 panels and guidelines, recommended that children with suspected FH should be screened between the ages of 5 and 10 years and start with a statin and lifestyle advices about smoking, healthy diet and physical activity when LDL levels are > 4.0 mmol/l between the age of 8 and 10 years [[13]
][[14]
].On the one hand one might argue that the prevalence of 1:5 parents with CVD is high; children ≤18 years should not have a parent with premature CVD. On the other hand a lot of progress has been achieved in the last two decades since grandparents experienced more CVD. Although the grandparents are older, the expectation based on current data is that the percentage CVD in the parents will remain lower. This can mainly be explained due to the efficacy of statin treatment available since 1990 but also through the systematic approach by the cascade screening [
3
, 15
]. Patient tailored education and annual follow up by the physician and nurse practitioner of our CVG team working together with the national FH foundation, brings children with FH timely into clinical attention.This study has a number of limitations. Our data are from a single tertiary referral centre. The majority of our study population is Caucasian, while 21% of Dutch population are non-Caucasian. Therefore we cannot extrapolate our results to other ethnicities. The strength of this study is the complete data collection in a relatively large group of children with FH and their FH parent and FH grandparent.
5. Conclusions and recommendations
The fact that CVD is still a presenting event of FH in especially fathers, shows that nationwide screening might have been terminated too early. Therefore we recommend to proceed the cascade screening by genetic fieldworkers in The Netherlands as well as in other countries. It ensures that the next generation will be in clinical attention to start statin treatment in time, to prevent CVD.
6. Contribution of authors
JMHGB, JERVL, HWORVL and JV initiated the conception and design of the study. JMHGB performed data analysis, JMHGB, JERVL and JV wrote the manuscript. HWORVL, JEDW and MW carefully reviewed the manuscript. All authors approved the final version of the submitted manuscript.
We kindly acknowledge dr. ir. J.C. Defesche AMC Amsterdam, the Netherlands for helping with the evaluation of the pathogenicity of the variants.
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Article info
Publication history
Published online: July 10, 2015
Accepted:
July 8,
2015
Received in revised form:
June 17,
2015
Received:
March 8,
2015
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
