Riscul invizibil: hipercolesterolemia familială în practica pediatrică

Introduction

Cardiovascular diseases remain the leading causes of morbidity and mortality worldwide⁽¹⁾. Their pathogenesis may begin early in life, even during the first years, particularly in the context of genetic dyslipidemias such as familial hypercholesterolemia (FH)^(2,3). In Romania, FH has not been routinely diagnosed in the pediatric population, with most diagnoses being established in adults within cardiology-focused clinical research settings.

In pediatric practice, however, the need to recognize and diagnose familial hypercholesterolemia has become increasingly apparent, as illustrated by the brief presentation of four clinical cases.

Case 1

A 4-month-old female infant was referred to our clinic (“Alessandrescu-Rusescu” National Institute for Mother and Child Health, Bucharest, Romania) by her family physician, with the following diagnostics: rhinopha­ryngitis, prurigo and anemia.

Her perinatal history was unremarkable, with a birth weight of 3000 g, an Apgar score of 10 and exclusive breastfeeding. Family history was negative for chronic or cardiovascular diseases; however, the father had a reported serum cholesterol level of 250 mg/dL.

On admission, the infant weighed 6100 g. The clinical examination revealed multiple xanthomas on the limbs (Figure 1) and hepatomegaly. Ophthalmologic evaluation identified corneal arcus and retinal vessels with a whitish appearance. The blood sample had a markedly lactescent aspect (Figure 2).

Lipid profile analysis showed extreme abnormalities: total lipemia 22,300 mg/dL (normal: 400-800 mg/dL), total cholesterol 942 mg/dL (normal: 35-160 mg/dL), LDL cholesterol 900 mg/dL (normal: 100-130 mg/dL) and triglycerides 18,260 mg/dL.

At the time of management, the only available therapeutic option for children under 3 years of age was a strictly individualized lipid-lowering diet. In this patient, dietary management included early diversification (replacement of milk feeds with vegetable-based meals), protein sources (blended poultry and beef, casein; carnitine 500 mg/day for three weeks), amino acid supplementation (100 mL every two days for five doses), lipid sources (vegetable oil) and carbohydrates (glucose). Blended carrot soup was used as the main dietary vehicle. At 10 months of age, poultry was replaced with white fish (e.g., pike-perch).

The early clinical course was complicated by two life-threatening episodes of acute pancreatitis during the first month. Subsequently, a progressive reduction in lipid levels was observed, accompanied by the gradual disappearance of xanthomas and slow biochemical improvement. After the age of 10 years old, the patient received intermittent outpatient statin therapy.

Over time, hepatomegaly resolved, somatic growth normalized and both the macroscopic appearance of blood and retinal vessels returned to normal. The last follow-up visit in our clinic occurred at 15 years of age, when the patient showed a favorable evolution, largely attributable to strict adherence to dietary management. She is currently 23 years old.

Of note, sustained family adherence in early childhood, followed by patient cooperation up to 7-8 years old, was essential for successful long-term dietary control.

This case underscores the critical role of early and sustained dietary intervention in achieving significant reductions in lipid levels, with cholesterol decreasing below 300 mg/dL and triglycerides below 1000 mg/dL.

Case 2

A 4-year-old boy at the time of initial evaluation was diagnosed with compound heterozygous familial hypercholesterolemia. He was assessed at the medical center of Prof. Dr. Wiegman in Amsterdam, the Netherlands, where genetic testing performed in the child and his parents confirmed the diagnosis. The patient had inherited one pathogenic variant from each parent (maternal mutation: LDLR c.201X>X, exon 4; paternal mutation: LDLR 571, exon 12), consistent with compound heterozygous FH.

The lipid profile revealed severe dyslipidemia: total cholesterol 942 mg/dL, LDL cholesterol 792 mg/dL, HDL cholesterol 20 mg/dL and total lipids 2286 mg/dL.

Pharmacological treatment with rosuvastatin and ezetimibe was recommended by Prof. Dr. Wiegman. However, at that time, both agents were not approved for use in children under 6 years of age in Europe, nor under 10 years old, according to Centers for Disease Control and Prevention (CDC) recommendations in the United States of America.

The patient was subsequently admitted to the “Alessandrescu-Rusescu” National Institute for Mother and Child Health, Bucharest, Romania, at 5 years of age, in good general condition. Clinical examination identified multiple xanthomas over the elbows, knees and bilateral Achilles tendons (Figures 3 and 4).

Given the age-related therapeutic limitations, statin therapy was initially deferred, and a structured dietary intervention was continued for one year. This approach led to a reduction in total cholesterol to 453 mg/dL and LDL cholesterol to 401 mg/dL, although the values remained significantly above target. After multidisciplinary discussion and parental consent, and once the child reached 6 years old, off-label treatment with rosuvastatin was initiated, starting at 5 mg/day and gradually increased to 10 mg/day over four months.

The most favorable response over a 2.5-year treatment period consisted of a 36.4% reduction in total cholesterol and a 42.3% reduction in LDL cholesterol. Subsequently, lipid levels plateaued and later showed a progressive increase, prompting the addition of ezetimibe to the therapeutic regimen.

The patient was closely monitored, initially monthly, then at four-month and six-month intervals. Clinical evolution revealed the progressive regression and the eventual disappearance of xanthomas.

The treatment was well tolerated, with no reported adverse effects, such as gastrointestinal symptoms, constipation, abdominal pain or myalgia. Transient elevation of liver transaminases was observed, but did not require treatment discontinuation. The patient continues on a lipid-lowering diet, engages in supervised physical activity (sports and dance), and remains under regular clinical and biochemical follow-up.

Case 3

A 1-year-and-11-month-old female patient was referred for evaluation by her family physician due to failure to thrive (body weight at admission: 11.3 kg) and pallor.

Family history revealed elevated lipid levels in the father, with a reported total serum cholesterol of 250 mg/dL. Given this finding, a lipid profile was performed in the child, revealing LDL cholesterol of 341 mg/dL, triglycerides of 199 mg/dL and HDL cholesterol of 40 mg/dL.

A structured lifestyle and dietary intervention were initiated. After three months of a personalized lipid-lowering diet, LDL cholesterol decreased to 207 mg/dL. After one year of dietary management, LDL cholesterol remained relatively stable at 214 mg/dL, while triglycerides decreased to 105 mg/dL.

The patient continues to follow dietary recommendations and remains under regular clinical and biochemical monitoring at six-month to annual intervals.

Case 4

A 6-year-old boy, weighing 27 kg, was evaluated in our clinic. His personal medical history was unremarkable, with no relevant pathological events reported.

Family history was significant for dyslipidemia in both parents: the father had hypercholesterolemia (total serum cholesterol: 250 mg/dL), and the mother had obesity associated with severe hypercholesterolemia (LDL cholesterol: 350 mg/dL). The maternal grandfather had died prematurely at the age of 50 years old, due to cardiac disease, suggestive of early cardiovascular risk in the family.

Biochemical assessment revealed elevated lipid parameters, with total cholesterol of 170 mg/dL and LDL cholesterol of 278 mg/dL. In this context, a diagnosis of suspected familial hypercholesterolemia was considered. A personalized lipid-lowering diet was initiated, together with recommendations for structured and controlled physical activity.

Discussion

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C), leading to accelerated atherosclerosis and premature cardiovascular disease^(3,4). It is most commonly caused by pathogenic variants in genes involved in LDL receptor-mediated clearance, particularly LDLR, but also APOB and PCSK9^(5,6).

The World Health Organization (WHO) has recognized familial hypercholesterolemia as a priority condition for early detection and prevention of cardiovascular disease since 1998⁽²⁾. The estimated prevalence of heterozygous FH is approximately 1 in 200-300 individuals in most populations^(7,8), although it is widely underdiagnosed. Homozygous and compound heterozygous forms are significantly rarer, but associated with markedly severe hypercholesterolemia and early-onset cardiovascular disease⁽³⁾.

In the United States and Europe, familial hypercholesterolemia remains substantially underdiagnosed, with less than 10% of affected individuals identified in many cohorts⁽⁹⁾. This is partly due to the fact that children are usually asymptomatic, and clinical manifestations such as xanthomas or corneal arcus are often absent in early life^(10,11). As a result, the diagnosis is frequently delayed until adolescence or adulthood, when cardiovascular events occur.

Population studies, including EuroAspire-related analyses, highlight significant geographic variability in FH prevalence, and suggest that lipid abnormalities in childhood are more frequent than previously recognized^(3,12,13). However, routine lipid screening in pediatric practice remains inconsistent, and in many countries – including Romania – there is no national program for systematic pediatric FH screening.

Clinical origin and doctoral research

Case 1 and Case 2, characterized by extremely severe lipid abnormalities rarely encountered in pediatrics, represented the starting point for a more comprehensive investigation of dyslipidemias in early childhood. This led to the formulation of a doctoral research project coordinated by Prof. Univ. Dr. Ioan Gherghina at the Doctoral School of “Carol Davila” University of Medicine and Pharmacy, Bucharest, and successfully completed by Dr. Andreea Teodora Constantin, with maximum distinction.

The study aimed to evaluate lipid profile parameters in 3000 children aged 0-9 years old. All analyses were performed exclusively in the laboratory of the “Alessandrescu-Rusescu” National Institute for Mother and Child Health, Bucharest, Romania, a recognized center for clinical and academic research, including PhD-level studies. The results demonstrated that 10.37% of the prospectively evaluated children (with parental and institutional consent) had LDL cholesterol levels above 130 mg/dL (upper limit of normal)⁽¹⁴⁾. Accordingly, more than 300 children were classified as suspected cases of familial hypercholesterolemia. Similar observations have been reported in previous Romanian pediatric studies, which confirmed both the feasibility and clinical utility of early lipid screening and genetic testing in selected cases^(15-17).

These data strongly support the need for earlier identification of at-risk children and integration of lipid screening into routine cardiopediatric practice. The importance of early diagnosis is further emphasized by evidence showing that cumulative LDL exposure from childhood is a major determinant of future cardiovascular risk⁽¹⁸⁾.

Case 3 and Case 4 originate from routine pediatric practice, and were not part of the aforementioned research cohort.

Diagnostic principles of FH

The diagnostic principles of familial hypercholesterolemia include clinical criteria, family history and mandatory clinical examination⁽¹⁹⁾. Clinical evaluation may reveal characteristic findings such as xanthomas and other lipid deposition signs⁽²⁰⁾. Biological evaluation includes lipid profile assessment and genetic testing^(19,20).

Several diagnostic systems exist for FH, including the Simon Broome criteria, the Dutch Lipid Clinic Network criteria and the 2015 American Heart Association recommendations^(19,21,22). All emphasize early identification, ideally within the first one or two years of life.

These systems are largely based on early genetic testing performed in infancy. In the United Kingdom, parental consent was obtained for blood sampling during routine vaccination visits in the first one or two years of life for genetic testing, with an acceptance rate of approximately 84%. In Romania, access to genetic testing remains limited due to high costs and the absence of a national active screening program.

Although genetic testing is considered the gold standard for FH diagnosis, it is not mandatory in routine pediatric practice, when other clinical features and a strong family history are present. However, in the context of the present research, we considered genetic testing mandatory, given that familial hypercholesterolemia is a well-documented monogenic disorder caused by pathogenic variants.

Most authors recommend active population or cascade screening in the first one or two years of life, based on two main advantages: accessible diagnostic criteria and relatively reasonable costs.

Early diagnosis allows the implementation of appropriate lifestyle interventions tailored to the medical condition. Genetic testing remains the gold standard for FH diagnosis.

Genetic study and research implementation

In the doctoral research project mentioned before, genetic analysis was performed at the Regional Center for Medical Genetics in Dolj County, part of the University of Medicine and Pharmacy of Craiova, with institutional approval. This collaboration was facilitated in particular by the late Prof. Univ. Dr. Mihai Ioana, who coordinated the center and supported this research.

Due to financial constraints, genetic testing was approved for 20 patients selected from approximately 300 FH suspected cases. The selection was based on markedly elevated LDL-C levels and evidence of cardiovascular disease or premature deaths among family members.

Pathogenic mutations recognized internationally as causative for FH were identified in five patients, originating from Hungary, Poland, Greece, Argentina and China.

An additional three cases showed variants with possible pathogenic significance.

Overall, 8 of 20 patients (40%) carried mutations associated with familial hypercholesterolemia.

Through this genetic investigation, the study gained national recognition as it included the first pediatric cases in Romania with molecular confirmation of FH. It also achieved international visibility through invitations to scientific meetings and requests for publication in specialized journals.

Differential diagnosis and treatment

The differential diagnosis of familial hypercholesterolemia includes congenital hypothyroidism, nephrotic syndrome, chronic cholestasis, medication-induced dyslipidemia (e.g., corticosteroids) and diabetes mellitus.

The principles of FH management include lifestyle modification, dietary intervention, and individualized lipid-lowering nutrition adapted to the growing child. In children below 3-5 years old, dietary therapy remains the only effective treatment, as demonstrated by Case 1 and Case 3. After 5-6 years of age, structured and continuous physical activity is recommended, adapted to age.

Clinical and biochemical monitoring (lipid profile) is required every 3-6 months and then annually once lipid values stabilize.

Statins are not approved under 6 years of age in Europe and under 10 years old, according to CDC recommendations (Atlanta, USA).

Genetic testing allows early identification of asymptomatic individuals with elevated LDL-C and enables preventive measures that reduce long-term cardiovascular morbidity and mortality.

Conclusions

Familial hypercholesterolemia is a well-documented genetic disorder present from birth, recognized as the most common monogenic inherited disease and, paradoxically, one of the most underdiagnosed conditions worldwide.

Long-term exposure to elevated cholesterol levels leads to progressive damage of the cardiovascular system and other organs, representing the underlying cause of cardiovascular pathology that typically becomes clinically apparent around the age of 18 years. However, at this stage, the diagnosis is established in fewer than 2% of cases.

Familial hypercholesterolemia is now recognized as part of pediatric pathology, with clinical forms that may be initially silent or present with minimal and often nonspecific manifestations, but still pathognomonic, detectable from the first months and years of life (Cases 1, 2, 3 and 4). Severe forms, however, may present early in infancy and can be life-threatening (Cases 1 and 2).

Although several countries worldwide have implemented active universal or cascade screening programs, such initiatives are not currently operational in Romania.

The implementation of active screening in the first one or two years of life, ideally during routine vaccination visits, is strongly recommended. Early identification is essential, as it enables timely therapeutic intervention, primarily through lifestyle modification. In children under 3-5 years of age, dietary intervention remains the only effective treatment strategy.

Genetic testing represents the gold standard for diagnosis, although it is not mandatory in all cases when other diagnostic elements are present, particularly a positive family history and elevated LDL-C levels in multiple family members affected by cardiovascular disease.

Primary care physicians – especially family doctors – have an important role in early detection, particularly during routine vaccination visits, when they have access to both clinical history and basic laboratory testing, including lipid profile assessment.

Autor corespondent:  Ioan Gherghina E-mail: prof_ighe@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.