Diagnosing FH in Kids and Teens Should Happen Early: In Real Life, It Varies

One of the first global snapshots of familial hypercholesterolemia (FH) in children and adolescents reveals challenges in how young people with this fairly common genetic condition are diagnosed, with implications for prognosis.

Finding FH in childhood would allow physicians to treat these young patients earlier and hopefully prevent future atherosclerotic cardiovascular events, say researchers.

“FH fundamentally is about early identification, diagnosis, and treatment, which means that we need to identify FH in childhood so that we can effectively change the trajectory of the life course of those individuals to match that of the general population,” lead investigator Kanika Dharmayat, BSc, MPH (Imperial College London, England), told TCTMD.

Dharmayat said one of the challenges is that LDL cholesterol levels fluctuate in childhood and there is no agreed upon cutoff to identify those with FH.

“That's where the percentile curves really came in, specifically by gender and age,” she said. “We can see how it varies. Generally, LDL cholesterol levels are higher in girls than in the boys. Also, equally across the genders, the highest [LDL levels] are in the earliest ages, which provides a clear message for healthcare professionals and policymakers. If we do a basic lipid profile panel, we can effectively at least risk-stratify those children for further testing.”

Daniel Soffer, MD (Penn Medicine, Philadelphia, PA), who wasn’t involved in the study, emphasized that FH is a good example of a heritable disease for which an early diagnosis—made at first with lipid screening, and later confirmed with genetic testing, if available—is too rarely made in practice, despite the big payoffs for patients. “We can change their prognosis with early treatment,” said Soffer. “We know that from a lot of different lines of evidence.”

Soffer, the current president of the National Lipid Association, a group that supports lipid screening in all children ages 9 to 11 years, said testing is cheap and is a “great opportunity to help people identify a serious condition at an early age.”

By contrast, cascade screening, which involves measuring lipid levels of all first-degree relatives of a person diagnosed with FH, hasn’t been particularly effective, he said. “The problem is that it’s just hard to do,” said Soffer. “Some families don’t talk to each other, or if they do, they don’t talk about medical problems.”  

Liam Brunham, MD, PhD (University of British Columbia, Vancouver), said the new paper also highlights the limitations of diagnosing FH in children and adolescents using a clinical scoring system like the Dutch Lipid Clinic Network (DLCN) or the Simon Broome criteria.

As such, the paper “highlights the important opportunity for genetic testing to really confirm a diagnosis,” said Brunham. “That’s particularly important in children who may not be old enough yet to have manifested physical [signs or symptoms of FH] and who hopefully don’t yet have a personal history of cardiovascular disease.”

Signs And Symptoms of FH Infrequent in Children

The study, published online in the Lancet, captured nearly 12,000 children and adolescents younger than 18 years with heterozygous FH enrolled in the European Atherosclerosis Society Familial Hypercholesterolemia Studies Collaboration (FHSC). The FHSC is an international effort that has characterized the prevalence, diagnosis, and management of FH patients since 2015.

Of the 63,093 patients in the registry between 2015 and 2021, 18.8% were children or adolescents younger than 18 years. Nearly 93% of the 11,848 children and adolescents were from Europe, with 5,473 from the Netherlands, a country that had a subsidized cascade screening program in place up until 2014. In all, more than 96% of the younger FH patients were from high-income countries and nearly nine out of ten had a final genetically confirmed diagnosis (the remainder had a clinical diagnosis). Just 31.6% of children with FH were index cases, the remainder identified through cascade family screening.

The median age at entry into the FHSC was 9.6 years, and there was an equal representation of males and females. Physical signs of FH, as well as cardiovascular risk factors, including coronary artery disease, were uncommon. Most children or adolescents (72.4%) were not taking any lipid-lowering medication at the time of study entry and the median LDL cholesterol level was 5.00 mmol/L (193.35 mg/dL). For untreated FH cases, the median LDL cholesterol level was highest for both sexes at 2 to 3 years old.

For the cases diagnosed with clinical criteria, particularly the DLCN and MEDPED, patients had a higher median LDL cholesterol level than those confirmed with genetic testing. Interestingly, the 25th and 50th percentiles of children and adolescents with FH diagnosed via the DLCN criteria had LDL levels of 4.34 and 5.22 mmol/L (167.8 and 201.6 mg/dL), respectively. If physicians relied solely on LDL cholesterol levels higher than these cutoffs—ie, higher than the 25th and 50th percentile of LDL levels to diagnose FH—as many as 50% to 75% of confirmed cases would have been missed, say researchers.   

“The guidelines say that the DLCN is not appropriate for children, but we see in the registry that a large proportion are using it,” said Dharmayat. “When we explored that further, it's because the clinicians like the systematic approach that the DLCN offers, but they're still using [FH] cutoffs suitable for adults.”

Children identified with the Simon Broome or Japanese Atherosclerosis Society criteria had LDL cholesterol levels closer to the median of those confirmed with genetic testing. The Simon Broome clinical criteria are adapted for children, said Dharmayat, but even this method of diagnosis misses a large swath of patients with FH.

From Diagnosis to Treatment

The proportion of children or adolescents taking lipid-lowering medication increased with age, with just 10% of children younger than 5 years taking a statin versus 41.0% of those ages 15 to 18 years. The proportion of those taking ezetimibe also increased with age, from 4.3% in those younger than 5 years to 7.8% in those ages 15 to 18 years. The median LDL cholesterol level among those taking medication was 4.35 mmol/L (168.2 mg/dL). For the 1,196 males and 1,235 females taking statins and ezetimibe, 25.6% and 20.2% had an LDL cholesterol less than 3.4 mmol/L (131.5 mg/dL).

Dharmayat said that while only a minority of patients were taking lipid-lowering medication, the present study is a cross-sectional snapshot capturing patients as they are entered into the registry. Future studies will assess changes in treatment once diagnosed with FH, she said.

Brunham, who is an FHSC investigator but wasn’t involved in the present study, pointed out that LDL cholesterol levels might be elevated in children and adolescents with FH, but not to such an extent as to make the diagnosis obvious.

“Lipid levels in children are much lower and the reference ranges are less well established,” he said. “That, and the levels can be quite variable. Whereas in an adult with FH, we would generally expect to see an LDL cholesterol more than 5 mmol/L—or more than 190 mg/dL—but in a child with FH the level might be as low as 3.5 mmol/L (135 mg/dL). One of the things they really showed nicely in this paper is that there's very considerable overlap between the FH and non-FH population in terms of LDL levels. In children, you can't really hang your hat just on the LDL level. You’d only be identifying the most severe cases of FH in children.”

Universal Screening in Children

While it is universally accepted that early diagnosis is critical for FH patients, there is less consensus as to how that should be done, as the current paper makes clear. In 2011, the National Heart, Lung, and Blood Institute first recommended screening for dyslipidemia in children between the ages of 9 and 11 years, and the American Heart Association and the American College of Cardiology, along with other societies, called for universal screening among kids ages 9 to 11 years in the 2018 clinical guidelines for cholesterol management (class IIb recommendation). The American Academy of Pediatrics also makes the same recommendation for lipid screening.

Not everybody is on board, though. The US Preventive Services Task Force, both in 2016 and 2023, concluded that there isn’t enough evidence to assess the balance of benefits and harms of screening for lipid disorders in children and adolescents 20 years or younger.

Soffer said the recommendations for universal screening have received a lot of pushback from general physicians and primary care organizations, with the argument being that screening would result in overmedicalization and unnecessary pharmacotherapy. These groups, he said, misunderstand the rationale for widespread lipid screening in this young patient group. Screening is not intended to diagnose or treat children with early signs of metabolic syndrome or obesity-related conditions, said Soffer.

“It’s to identify people who have monogenic familial hypercholesterolemia, a common disorder,” he said. “It’s one in 250 or one in 300 in the population, somewhere in that ballpark. If you wait until those people show up later in life, their first symptom can be sudden death. You may never get another chance to help them.”

For situations in which physicians identify patients with high LDL cholesterol levels that are the result of early-onset metabolic disorders or obesity, doubling down on lifestyle changes and further monitoring is the course of action, said Soffer. 

Canadian guidelines also recommend universal lipid screening within the first decade of life (after 2 years old), but Brunham said a recent survey of pediatricians showed that very few are doing it. “There's a long way to go to actually implement those guidelines,” said Brunham. “But it's at least the start that we now have those recommendations that we should be testing lipids in children.”