Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Familial hypercholesterolaemia in children and adolescents from 48 countries : a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life.peer-reviewe

Implementing a Clinical Research Department to Support Pediatric Studies: A SWOT Analysis

The safety, tolerability, pharmacokinetics and efficacy of most drugs used in pediatrics have not been studied in different age groups and are administered “off-label use”. Clinical pediatric drug trials require specific and stringent compliance with laws, regulations, guidelines, and patient/parent/public involvement, which in turn increases resource use and makes support useful from a medical, qualitative, economic, and system perspective. We examined the strengths, weaknesses, opportunities and threats of implementing a Research Department for the Support of Pediatric Studies (RDPS) in Vienna. We used the SWOT (“strengths”, “weaknesses”, “opportunities”, and “threats”) analysis to collect comprehensive data and facts on the internal strengths, weaknesses (company analysis), and external opportunities and threats (environmental analysis). The company analysis revealed a productivity gain, due to a highly specialized team and standardized processes. The environmental analysis outlined a considerable 360-degree potential for a qualitative and quantitative medical- and social-scientific expansion of the service portfolio. The establishment of a RDPS leads to the centralization of pediatric studies by bundling tasks and concentration of specialist knowledge, which enables the exploitation of synergies, the standardization of processes, the promotion of professionalism, flexibility, innovations and the reduction of inefficiencies in the form of duplication of tasks. RDPS offers tailored advice and support for different types of pediatric studies

Comparison of Bioelectrical Impedance-Based Methods on Body Composition in Young Patients with Obesity

(1) Background: The determination of body composition is an important method to investigate patients with obesity and to evaluate the efficacy of individualized medical interventions. Bioelectrical impedance-based methods are non-invasive and widely applied but need to be validated for their use in young patients with obesity. (2) Methods: We compiled data from three independent studies on children and adolescents with obesity, measuring body composition with two bioelectrical impedance-based devices (TANITA and BIACORPUS). For a small patient group, additional data were collected with air displacement plethysmography (BOD POD) and dual-energy X-ray absorptiometry (DXA). (3) Results: Our combined data on 123 patients (age: 6–18 years, body mass index (BMI): 21–59 kg/m²) and the individual studies showed that TANITA and BIACORPUS yield significantly different results on body composition, TANITA overestimating body fat percentage and fat mass relative to BIACORPUS and underestimating fat-free mass (p < 0.001 for all three parameters). A Bland–Altman plot indicated little agreement between methods, which produce clinically relevant differences for all three parameters. We detected gender-specific differences with both methods, with body fat percentage being lower (p < 0.01) and fat-free mass higher (p < 0.001) in males than females. (4) Conclusions: Both bioelectrical impedance-based methods provide significantly different results on body composition in young patients with obesity and thus cannot be used interchangeably, requiring adherence to a specific device for repetitive measurements to ascertain comparability of data

The Effect of a Fat-Restricted Diet in Four Patients with Familial Chylomicronemia Syndrome: A Long-Term Follow-Up Study

(1) Background: Familial chylomicronemia syndrome (FCS) is a very rare autosomal recessive disorder characterized by severely elevated triglycerides and clinical symptoms in early childhood mainly presenting with abdominal pain, acute pancreatitis and hepatosplenomegaly. Primary treatment is a lifelong very strict low-fat diet, which might be challenging in pediatric patients. So far, data about children with FCS are rare. The aim of this study was to show the familial chylomicronemia syndrome traffic light table for pediatric patients and to assess the dietary fat intake and impact on triglycerides in children with FCS. (2) Methods: We performed a retrospective analysis in four children (50% male) affected by FCS from the Department of Pediatrics and Adolescent Medicine, Medical University of Vienna between January 2002 and September 2020. (3) Results: The four patients presented with classical FCS symptoms and showed baseline triglycerides (TG) exceeding 30,000 mg/dL in two patients, 10,000 mg/dL and 2400 mg/dL in one patient each. After diagnosis, fat percentage of total daily caloric intake was decreased and resulted immediately in triglyceride reduction. In all patients, FCS was genetically confirmed by mutations in genes encoding lipoprotein lipase. Acute pancreatitis and hepatosplenomegaly disappeared under the fat-restricted diet. A FCS traffic light table was developed as a dietary tool for affected families. (4) Conclusions: A restriction of dietary fat between 10% to 26% of the total daily caloric intake was feasible and effective in the long-term treatment of genetically confirmed FCS in children and could reduce the risk for acute pancreatitis. The dietary tool, the pediatric FCS traffic light table and the age-appropriate portion sizes for patients between 1 to 18 years, supports children and their parents to achieve and adhere to the lifelong strict low-fat diet

Human Milk Processing and Its Effect on Protein and Leptin Concentrations

(1) Background: For the storage of human milk (HM), freezing, thawing, and/or pasteurization are routinely used in neonatal intensive care units. We aimed to analyze the effects of different HM processing types on the nutritional contents in HM, adipose tissue, and the neuroprotection markers leptin and adiponectin. (2) Methods: HM samples from 136 mothers of preterm and term infants (gestational age 23 + 0 to 41 + 6) were collected and divided into four groups: (i) fresh HM, (ii) fresh pasteurized HM, (iii) thawed HM, and (iv) thawed pasteurized HM. The macronutrients were analyzed by mid-infrared transmission spectroscopy and the adiponectin and leptin were analyzed by high-sensitivity adiponectin and leptin enzyme-linked immunosorbent assay (ELISA). (3) Results: No significant differences were observed in the protein, carbohydrate, or fat concentrations between the HM processing types. The leptin levels were significantly lower after pasteurization in comparison to HM without pasteurization (p p < 0.05). (4) Conclusions: HM processing had an impact on leptin concentrations but no effect on the protein level. These data support the use of unpasteurized human milk for preterm infants’ nutrition and normal brain development. The protein levels of the milk of mothers from preterm compared to full-term infants differed, underlining the importance of individualized target fortification

A Selective Screening Strategy Performed in Pre-School Children and Siblings to Detect Familial Hypercholesterolemia

(1) Background: Familial hypercholesterolemia (FH), a most common genetic disorder, is underdiagnosed and untreated, especially in children. Individuals with heterozygous familial hypercholesterolemia mostly present without clinical symptoms and are not informed about their high risk for myocardial infarction. Early diagnosis and treatment can prevent premature atherosclerosis and cardiovascular events in patients with FH. The aim was to evaluate the detection rate of pre-school children with FH at school doctor visits in Vienna and, moreover, to examine the frequency of FH identified in the children&rsquo;s siblings by this type of screening. (2) Methods: The selective FH- screening was implemented at the school enrolment examinations in the public primary schools of Vienna. The study period included the school years starting in 2017 to 2020. FH was suspected if a questionnaire on hypercholesterolemia, or cardiovascular events in the family history or on the presence of xanthomas or xanthelasma, was positive. Subsequently, lipid testing was performed on pre-school children and their siblings and elevated lipid screening was defined as either positive by LDL-C &ge; 160 mg/dL and/or non-HDL-C &ge; 190 mg/dL or as borderline by LDL-C &ge; 130 mg/dL and/or non-HDL-C &ge; 160 mg/dL. (3) Results: 66,108 pre-school children participated in the school enrolment examination in 868 public elementary schools in Vienna. In 512 (4%) children, the questionnaire caused suspicion of FH. 344 families agreed their participation in the study. Out of 344 (52% male) tested pre-school children, 20 individuals (40% male) had elevated blood lipid levels with a mean LDL-C of 155 &plusmn; 29 mg/dL and a non-HDL-C of 180 &plusmn; 24 mg/dL. Out of 291 (44% male) tested siblings, 17 individuals (41% male) showed elevated lipids with a mean LDL-C of 144 &plusmn; 19 mg/dL, and a non-HDL-C of 174 &plusmn; 19 mg/dL. (4) Conclusions: Screening is the key for early diagnosis and treatment of FH. We have implemented a pre-school screening strategy in cooperation with school physicians. We could identify 20 pre-school children and 17 siblings with an elevated lipid screening test. Full implementation of FH-screening in the pre-school examination visits in Vienna would help to detect high-risk children

Maternal Diet Influences Human Milk Protein Concentration and Adipose Tissue Marker

(1) Background: Adequate protein intake plays an essential role in growth and neurodevelopment, especially in preterm infants. We investigated the effects of maternal diet and body mass index (BMI) on human milk (HM) composition. (2) Methods: HM samples were obtained from 136 lactating mothers (BMI: 18.0–36.7 kg/m2), of which 93% gave birth to preterm infants. Macronutrient content in HM was measured by mid-infrared transmission spectroscopy. Leptin and adiponectin were analyzed using appropriate ELISAs. Maternal diet was determined by 24-h recall. (3) Results: Significant positive associations were found between protein, fat, carbohydrate and energy intake, and levels of corresponding macronutrients in HM, especially in protein concentrations (p p p = 0.035) in HM. Maternal BMI was positively associated with a higher protein level in HM (p p < 0.05). (4) Conclusions: Knowledge of maternal diet and BMI impacting HM composition is essential to optimize the feeding of newborn infants. This is especially relevant in the nutritional management of preterm infants; it can be utilized in approaches to improve growth rates and the appropriate development of infants and to prevent obesity

Longitudinal Assessment of Serum 25-Hydroxyvitamin D Levels during Pregnancy and Postpartum—Are the Current Recommendations for Supplementation Sufficient?

(1) Background: Pregnant women are at risk of vitamin D deficiency. Data on pregnancy outcomes in women with vitamin D deficiency during pregnancy are controversial, and prospective longitudinal data on vitamin D deficiency with consistent definitions in pregnant women are scarce. (2) Methods: The aim of this prospective longitudinal cohort study was to investigate 25-hydroxyvitamin D levels over the course of pregnancy and postpartum in singleton and twin pregnancies with regard to dietary and supplemental vitamin D intake and environmental factors influencing vitamin D levels, evaluated by a standardized food frequency questionnaire. (3) Results: We included 198 healthy singleton and 51 twin pregnancies for analysis. A total of 967 study visits were performed over a 3-year period. Overall, 59.5% of pregnant women were classified as vitamin D deficient in the first trimester, 54.8% in the second trimester, 58.5% in the third trimester, 66.9% at birth, and 60% 12 weeks postpartum, even though 66.4% of the study population reported daily pregnancy vitamin intake containing vitamin D. Dietary vitamin D intake did not affect vitamin D levels significantly. (4) Conclusions: The majority of pregnant women evaluated in this study were vitamin D deficient, despite administration of pregnancy vitamins containing vitamin D. Individualized vitamin D assessment during pregnancy should be considered to ensure adequate supplementation and prevention of hypovitaminosis D

The Impacts of Single Preterm Human Donor Milk Compared to Mother’s Own Milk on Growth and Body Composition

(1) If mother´s own milk (MOM) is not available, pooled term human donor milk (HDM) is commonly used. Compared to MOM, term HDM contains less protein and fat and is associated with impaired growth. HDM from mothers of preterm infants is an alternative source and contains higher protein levels compared to term HDM, but the impacts on growth and body composition are unclear. (2) Methods: Infants born below 32 weeks of gestation and below 1500 g between 2017–2022, who underwent air displacement plethysmography (Pea Pod®) to determine body composition (FFM: fat-free mass; FM: fat mass) at term-equivalent age, were included. A comparison between infants fed with MOM > 50% (MOM-group) and single preterm HDM > 50% (HDM-group) was conducted. (3) Results: In total, 351 infants (MOM-group: n = 206; HDM-group: n = 145) were included for the analysis. The median FFM-Z-score (MOM-group: −1.09; IQR: −2.02, 1.11; HDM-group: −1.13; IQR: −2.03, 1.12; p = 0.96), FM-Z-score (MOM-group: 1.06; IQR: −0.08, 2.22; HDM-group: 1.19; IQR: −0.14, 2.20; p = 0.09), and median growth velocity (MOM-group: 23.1 g/kg/d; IQR: 20.7, 26.0; HDM: 22.5 g/kg/d; IQR: 19.7, 25.8; p = 0.15) values were not significantly different between the groups. (4) Conclusion: Single preterm HDM is a good alternative to support normal growth and body composition