Detecting familial hypercholesterolemia in a 9-year-old girl

A healthy 9-year-old girl presents for a routine well-child visit at her family physician’s clinic. She is undergoing routine blood-work to reassess previously diagnosed mild iron deficiency. During the visit, the physician requests a screening lipid profile, consistent with current universal screening recommendations in the first decade of life and because the patient has a family history of premature cardiovascular disease.^1,2 The child’s mother has hypercholesterolemia and her maternal grandmother had a myocardial infarction at age 48 years. Her physical examination is unremarkable, including a normal body mass index for her age and sex, and she does not have xanthomas or corneal arcus. A nonfasting lipid panel shows a low-density lipoprotein cholesterol (LDL-C) level of 5.3 (reference < 2.8) mmol/L.

Her mother asks why her daughter’s cholesterol levels are high and what should be done about it. She also asks whether her 2 younger children should be screened.

What causes severe dyslipidemia in children, and what further investigations are needed?

Many monogenic processes cause primary dyslipidemia, the most common of which is familial hypercholesterolemia, an autosomal codominant condition. Its heterozygous form has a prevalence of 1 in 250 people, and its homozygous form has a prevalence of 1 in 300 000 people.^1,2 Secondary causes of dyslipidemia include obesity and metabolic syndrome, thyroid and renal disease, and certain medication exposures such as corticosteroids and atypical antipsychotic medications. Therefore, further evaluation should include a thorough history (including medication review), physical examination, and laboratory investigations assessing for diabetes, renal function, thyroid disease, and liver dysfunction.^1,2 Additional online tools may serve as useful to estimate the likelihood of familial hypercholesterolemia, incorporating elements such as clinical signs and symptoms, family history, and the current lipid profile.^1,2

Although a nonfasting test is an appropriate initial lipid screen, children with abnormal results should undergo repeat fasting lipid testing to confirm persistent dyslipidemia before the clinician moves forward with management decisions.^1,2 Normal, borderline, and abnormal lipid levels are defined by the Canadian Pediatric Society’s position statement on dyslipidemia in children.¹ For LDL-C, 3.4 mmol/L or more is abnormal, and 2.8 to 3.4 mmol/L is borderline.

Given this patient’s family history and severely elevated LDL-C (≥ 4.1 mmol/L), her dyslipidemia is most likely caused by heterozygous familial hypercholesterolemia, which is typically the result of pathogenic variants involving the LDL receptor.^1–3 It rarely manifests clinically in childhood and is therefore easily missed in the absence of screening.^1–3 Despite its prevalence, ease of diagnosis, and available treatment options, more than 95% of pediatric cases are estimated to be missed (Table 1).^1,2

Table 1:

Pediatric lipid screening and management¹

Recommendation	Details
Screening	Universal lipid screening is recommended for all children in the first decade of life, after their second birthday. Targeted screening is also recommended for at-risk children, including those with a first-degree relative with premature ASCVD or an LDL-C level of 4.1 mmol/L or higher.
Diagnosis	Although a nonfasting lipid screen is an appropriate initial test, confirmation of diagnosis and subsequent testing should ideally be via fasting lipid profiles. When heterozygous familial hypercholesterolemia is suspected (LDL-C ≥ 4.1 mmol/L in children), genetic testing can facilitate diagnostic confirmation and cascade screening of first-degree relatives but is not absolutely necessary.
Treatment	Therapeutic lifestyle modifications are the first-line therapy. Pharmacotherapy, most typically with statin medications, is recommended if LDL-C levels remain severely elevated (≥ 4.1 mmol/L), typically starting at age 8 to 10 years.
Referral and follow-up	Referral to a pediatric lipid specialist can facilitate diagnosis and treatment; cascade screening of first-degree relatives with lipid screening (with or without genetic testing) should be conducted, if available.

Note: ASCVD = atherosclerotic cardiovascular disease, LDL-C = low-density lipoprotein cholesterol.

What therapeutic lifestyle modifications should be recommended?

Therapeutic lifestyle modifications are the first-line approach for nearly all patients with pediatric dyslipidemia.^2,4,5 Dietary changes should be made, ideally in consultation with a registered dietitian, and include reductions in total and saturated fat intake. Children with hypercholesterolemia should also follow the Canadian physical activity recommendations of 60 minutes of moderate-to-vigorous physical activity per day.^1,2 Although healthy eating and physical activity are important components of cardiovascular risk reduction, most children with heterozygous familial hypercholesterolemia will ultimately require pharmacologic therapy to achieve target LDL-C levels.^1,2,4,5

When should pharmacologic therapy be considered?

Pharmacologic therapy, including statins, should be considered when the LDL-C level remains severely elevated (≥ 4.1 mmol/L) despite a trial of therapeutic lifestyle modifications.^1,2,4,5 Shared decision-making and referral to a pediatric lipid specialist (or a general pediatrician, when access to subspecialty care is limited) should guide this step.^4–7 Statin medications serve as the first-line medication for treatment of severe dyslipidemia secondary to heterozygous familial hypercholesterolemia and are typically started at age 8 to 10 years.^1,2,5 For patients with heterozygous familial hypercholesterolemia, those treated from childhood demonstrate reduced atherosclerotic progression and the potential normalization of risk of premature cardiovascular disease compared with those whose treatment is initiated in adulthood. Systematic reviews and meta-analyses support the safety of statin use in children, with adverse effects comparable to placebo.^1,2,4–7 Adjunctive use of phytosterols or psyllium fibre may provide modest reductions in LDL-C levels; however, evidence supporting a reduction in cardiovascular risk remains limited.^1,2

What follow-up and additional actions are needed?

A pediatric lipid specialist or a pediatrician can support confirmation of the diagnosis of heterozygous familial hypercholesterolemia, including consideration of genetic testing; assist with treatment planning; and guide long-term monitoring.^1,2 Cascade lipid screening in siblings and parents is recommended.^1,2 Genetic testing may complement cascade screening when a pathogenic variant has been identified in the index patient, helping identify additional affected family members who may benefit from early detection and management.^1,2 Repeat lipid testing 4 to 8 weeks after medication initiation and with each dosage change should be arranged to monitor the patient’s response to pharmacotherapy, as recommended by Canadian practice guidance.^1,2

Case revisited

This child’s family physician performs a fasting lipid panel 4 weeks later, confirming a severely elevated LDL-C level. Given the patient’s strong family history and elevated LDL-C, she is referred to a pediatric lipid specialist. Genetic testing identifies a pathogenic heterozygous LDL receptor variant, confirming a diagnosis of heterozygous familial hypercholesterolemia.

After exclusion of secondary causes and a 6-month trial of lifestyle modifications with minimal improvement in LDL-C levels, the patient is started on rosuvastatin (5 mg daily) with more than a 50% reduction and normalization of her LDL-C level at a repeat assessment 6 weeks later. Cascade screening is undertaken for first-degree relatives, and a similar lipid phenotype and causative genotype are identified in 1 of her 2 younger siblings.