Physicians' Academy for Cardiovascular Education

Child-parent screening for familial hypercholesterolemia in primary care is feasible and efficient

Wald D.S. et al, NEJM, 2016

Child–Parent Familial Hypercholesterolemia Screening in Primary Care

Wald DS, Bestwick JP, Morris JK, et al.   
N Engl J Med 2016;375:1628-1637


Individuals with FH in the age group of 20-39 years, have a cardiovascular disease (CHD) risk that is 100 times higher compared with individuals without FH [1]. The identification of parents with FH is possible through the systematic screening of children, allowing for the initiation of appropriate therapies in a timely manner [2,3].
FH can be diagnosed based on high cholesterol levels and an FH mutation. A meta-analysis in which only cholesterol levels were examined, revealed that a total cholesterol cut-off value of 1.53 multiples of the median (MoM) and corresponding to the 99.9th percentile, identified 88% of children (age 1-9) with FH [3]. However, not all FH patients have high cholesterol, but on the other hand, also not all FH mutations are known yet.
To overcome these issues, this study aimed to define both factors. The feasibility and efficacy of child–parent FH screening in primary care was assessed by analysing total cholesterol levels and FH mutation data (48 different mutations) in 10,095 children at the age of 1 to 2 years, what took place during routine immunisation visits. Children who did had cholesterol levels above the cut-off of 1.53 MoM (high cholesterol) but no FH mutations, underwent a second cholesterol measurement 3 months later.
Children were considered positive for FH when they had high cholesterol levels and an FH mutation or when they had no FH mutation but also high cholesterol levels in the second measurement.

Main results

  • 92 children had high cholesterol levels and 37 children had an FH mutation. Twenty children had high cholesterol as well as an FH mutation. 17 children had an FH mutation but low cholesterol levels.
  • The prevalence of an FH mutation was 1 in 273 (95% CI: 1 in 198 to 1 in 388), and the prevalence of FH was 1 in 224 (n=45, 95% CI; 1 in 168 to 1 in 308).
  • Among children with an initial high cholesterol level, 28 children were positive for FH (20 with an FH mutation and 8 with a second high cholesterol measurement); this equated to a positive rate of 0.3% from the total cohort (95% CI; 0.2-0.4%).
  • In children with and those without an FH mutation, the cut-off value of 1.53 MoM corresponded to a percentile of 99.2. Of the 30 children who had an FH mutation, 13 (43%; 95% CI, 25-63%) had cholesterol levels at or above this percentile.
  • A total of 14 children (47%, 95% CI: 28-66%) had a cholesterol value at or above the 99th percentile (≥1.50 MoM), 7 children (23%, 95% CI: 10-42%) had a cholesterol value between the 95th and 99th percentiles (1.35-1.50 MoM), and 9 children (30%, 95% CI: 15-49%) had a cholesterol value that was below the 95th percentile.
  • In 27 of the 32 parents with an FH mutation, the parent with the higher cholesterol level had the FH mutation (84%, 95% CI: 67–95%). The result was similar with respect to LDL-c.
  • 90% of the parents who had positive screening results for FH had cholesterol values above the 75th percentile.
  • Among parents who had positive screening results for FH, 25 of 28 (90%) subsequently started treatment with statins.
  • The use of a lower cholesterol cut-off value (≥1.35 MoM) identified 12 more children with FH mutations and 12 more parents who had positive screening results for FH.
  • An estimated 80 persons who had positive screening results for FH (40 children and 40 parents) were identified, which represents a rate of 8 cases per 1,000 children screened.


Child–parent screening for FH is feasible and efficient in primary care during routine child immunisation visits. For every 1000 children screened, 8 persons (4 children and 4 parents) can be identified as having positive screening results for FH. With the proposed screening policy, also FH patients without hypercholesterolemia can be identified.

Editorial comment [4]

McCrindle and Gidding, after summarising the results of the Wald et al study, comment on some important aspects of current FH-screening in their editorial article:
  • The challenges in identifying FH include the incomplete intersection of phenotype with genotype and the fact that not all mutations are known.
  • Lipid screening in children is controversial, given the absence of direct evidence of benefit and the lack of data on the relevant costs.
And they conclude: ‘Linking selective universal screening to early cascade screening, as in the study by Wald et al., identifies additional cases and cases at a younger age, when treatment has greater benefits. Because the cost effectiveness of universal screening, early identification, and treatment is not known, results from the current study will be critical in determining the resources needed and in providing estimates of potential life-years gained on the basis of the number of affected persons identified. The study by Wald et al. provides a critical evaluation of an efficient and effective screening and identification strategy that appropriately targets children. This strategy affords the greatest opportunity for the prevention of atherosclerosis and achievement of a low lifetime risk of cardiovascular disease.’
Find this article online at NEJM


1. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ 1991;303: 893-6.
2. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004; 292: 331-7.
3. Wald DS, Bestwick JP, Wald NJ. Child–parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis. BMJ 2007; 335: 599.
4. McCrindle BW, Gidding SS. What should be the Screening Strategy for Familial Hypercholesterolemia? N Engl J Med 2016;375:1685-1686.