Newborn screening for lipid disorders.

PURPOSE OF REVIEW: Newborn screening is one of the most successful public health programs of the last century and offers unparalleled access to universal screening for a variety of metabolic and other disorders. Interest in development of newborn screening for lipid disorders has intensified in recent years. Screening newborns for lipid disorders has important implications for the health of the newborn as well as their relatives, and in the case of more common lipid disorders like familial hypercholesterolemia, could have important public health implications. RECENT FINDINGS: Recent studies have demonstrated feasibility of measuring biomarkers for heterozygous familial hypercholesterolemia from newborn screening dried blood spot specimens. Another lipid disorder, cerebrotendinous xanthomatosis, is currently amenable to newborn screening utilizing currently available assays. New research in next-generation sequencing as a primary screen in newborns will also identify both common and rare lipid disorders in newborns. SUMMARY: Historically, newborn screening for lipid disorders was not done for many reasons, but new research has developed testing methods that may successfully identify common and rare lipid disorders. This will impact the health of the newborn but could also impact family members and public health.

Preventive Medicine in Pediatric Cardiology Practice.

OBJECTIVES: The objective of the study was to assess contemporary practice patterns of pediatric cardiologists with respect to cholesterol disorders and smoking-related illness. STUDY DESIGN: We sent 2 anonymous surveys to the members of the American Academy of Pediatrics Section on Cardiology and Cardiac Surgery and the Pediheart online community. The surveys addressed training in and management of cholesterol disorders and smoking-related illness. RESULTS: There were 97 responses to the cholesterol disorders survey. A total of 51.6% reported little or no formal training on cholesterol disorders. A total of 56.4% underestimated the prevalence of familial hypercholesterolemia by at least twofold. A total of 54.7% were at least somewhat comfortable prescribing statins. In 5 clinical vignettes, respondents frequently gave clinical recommendations in line with the 2019 American Heart Association guidelines although both undertreatment and overtreatment were recommended. There were 90 responses to the survey on smoking-related illness. Little or no formal training in nicotine addiction (52.3%) or smoking cessation (60.5%) was reported by respondents. Respondents screened for tobacco use in less than a one-third of hospitalizations and less than two-thirds of outpatient clinic visits. Screening for exposure to secondhand smoke was even less common. Twenty-seven percent of respondents never recommend a household smoking ban for their patients. A total of 83.3% were uncomfortable prescribing medications for their patients for smoking cessation, and 65.5% rarely or never refer patients for smoking cessation assistance. CONCLUSION: Although positioned to address the childhood origins of adult heart disease, those cardiologists surveyed placed a limited emphasis on cholesterol disorders and smoking-related disease in their clinical practice.

Familial Hypercholesterolemia Biomarker Distribution in Dried Blood Spots.

OBJECTIVE: To evaluate distribution profiles of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) as candidate markers of familial hypercholesterolemia in newborns, taking into consideration potential confounding factors, such as gestational age, birth weight, sex, and race. STUDY DESIGN: TC, LDL-C, and apoB were measured from 10 000 residual deidentified newborn dried blood spot cards. Concentrations for each biomarker were reported as multiples of the median, with emphasis on describing the 99th percentile values based on birth weight, gestational age, sex, and race. Seasonal variation of biomarkers was also explored. RESULTS: LDL-C and apoB had distribution curves with tails showing extreme elevation, whereas the distribution of TC was less elevated and had the smallest range. Neonates born at early gestational age and low birth weight had significantly greater 99th percentile of multiples of the median values for apoB but not TC or LDL-C. Differences in biomarker concentration based on sex and race were minimal. All biomarkers showed greatest concentrations in the winter as compared with summer months. CONCLUSIONS: LDL-C and apoB had distribution curves supporting candidacy for neonatal familial hypercholesterolemia screening. Future studies are needed to correlate newborn screening results with molecular testing to validate these 2 biomarkers, along with measured cholesterol levels later in childhood.

Evolution of vertebral numbers in primates, with a focus on hominoids and the last common ancestor of hominins and panins.

The primate vertebral column has been extensively studied, with a particular focus on hominoid primates and the last common ancestor of humans and chimpanzees. The number of vertebrae in hominoids-up to and including the last common ancestor of humans and chimpanzees-is subject to considerable debate. However, few formal ancestral state reconstructions exist, and none include a broad sample of primates or account for the correlated evolution of the vertebral column. Here, we conduct an ancestral state reconstruction using a model of evolution that accounts for both homeotic (changes of one type of vertebra to another) and meristic (addition or loss of a vertebra) changes. Our results suggest that ancestral primates were characterized by 29 precaudal vertebrae, with the most common formula being seven cervical, 13 thoracic, six lumbar, and three sacral vertebrae. Extant hominoids evolved tail loss and a reduced lumbar column via sacralization (homeotic transition at the last lumbar vertebra). Our results also indicate that the ancestral hylobatid had seven cervical, 13 thoracic, five lumbar, and four sacral vertebrae, and the ancestral hominid had seven cervical, 13 thoracic, four lumbar, and five sacral vertebrae. The last common ancestor of humans and chimpanzees likely either retained this ancestral hominid formula or was characterized by an additional sacral vertebra, possibly acquired through a homeotic shift at the sacrococcygeal border. Our results support the 'short-back' model of hominin vertebral evolution, which postulates that hominins evolved from an ancestor with an African ape-like numerical composition of the vertebral column.

Parental Attitudes and Ideas Regarding Newborn Screening for Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an inherited disease which causes premature atherosclerotic cardiovascular disease. However, less than 10% of individuals with FH have been identified. OBJECTIVE: To assess parental perspectives for inclusion of FH on routine newborn screening (NBS) and to highlight potential benefits, harms, and ethical concerns. METHODS: Telephone interviews of two groups were conducted: 1) parents of children diagnosed with FH, and 2) parents of children diagnosed with a genetic condition through NBS. Stratified purposive sampling was used to ensure adequate representation. The 11 telephone interviews were conducted in 30-min sessions guided by a semi-structured interview script. At the beginning of the interview, participants were educated on the NBS process and FH. The interviews were transcribed verbatim, and a thematic analysis was performed in multiple steps. RESULTS: All interviewees indicated that they would be interested in having their child be screened for FH on the newborn screen. Reasons supporting screening during the newborn period included knowing their child's diagnosis, the ability to screen family members for FH, incorporation of lifestyle changes, and access to preventive care. Negatives surrounding screening during the newborn period included increased stress or anxiety, knowledge, stigma, and the delay from diagnosis to initiation of pharmacotherapy for FH. CONCLUSION: While these interviewees were in favor of NBS for FH, further education of parents and clinicians is needed to ensure proper implementation. The results of this study may be useful to formulate family notification and care protocols for newborns diagnosed with FH and other diseases.

What is already known on this subject? Familial hypercholesterolemia is a common inherited disorder that predisposes to early cardiovascular disease, but most affected individuals are not diagnosed. Childhood cholesterol screening is an effective but underutilized diagnostic tool. Previous studies report parents find childhood cholesterol screening acceptable, but it is not known if screening newborns would also be acceptable.What does this study add? Interviewees found screening newborns for familial hypercholesterolemia acceptable and would agree to screen their own newborn. The ability to screen other family members and access to early treatment were important factors in their decision to screen. Education of clinicians about familial hypercholesterolemia was an important concern raised by interviewees.

Children with Heterozygous Familial Hypercholesterolemia in the United States: Data from the Cascade Screening for Awareness and Detection-FH Registry.

OBJECTIVE: To describe enrollment characteristics of youth in the Cascade Screening for Awareness and Detection of FH Registry. STUDY DESIGN: This is a cross-sectional analysis of 493 participants aged <18 years with heterozygous familial hypercholesterolemia recruited from US lipid clinics (n = 20) between April 1, 2014, and January 12, 2018. At enrollment, some were new patients and some were already in care. Clinical characteristics are described, including lipid levels and lipid-lowering treatments. RESULTS: Mean age at diagnosis was 9.4 (4.0) years; 47% female, 68% white and 12% Hispanic. Average (SD) highest Low-density lipoprotein cholesterol (LDL-C) was 238 (61) mg/dL before treatment. Lipid-lowering therapy was used by 64% of participants; 56% were treated with statin. LDL-C declined 84 mg/dL (33%) among those treated with lipid-lowering therapy; statins produced the greatest decline, 100 mg/dL (39% reduction). At enrollment, 39% had reached an LDL-C goal, either <130 mg/dL or ≥50% decrease from pre-treatment; 20% of those on lipid-lowering therapy reached both goals. CONCLUSIONS: Among youth enrolled in the Cascade Screening for Awareness and Detection of FH Registry, diagnosis occurred relatively late, only 77% of children eligible for lipid-lowering therapy were receiving treatment, and only 39% of those treated met their LDL-C goal. Opportunities exist for earlier diagnosis, broader use of lipid-lowering therapy, and greater reduction of LDL-C levels.

Prevention of Atherosclerotic Cardiovascular Disease in Children with Familial Hypercholesterolemia.

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH), a common inherited disorder of LDL-C metabolism that predisposes to premature cardiovascular disease, is underdiagnosed. Despite recommendations for screening all children and initiation of lipid-lowering medication beginning at 8-10 years of age, adherence to guidelines is low. Most individuals with FH are inadequately treated, especially women and children. The purpose of this review is to discuss current literature and recommendations for the diagnosis and treatment of heterozygous FH (HeFH) in the pediatric population. RECENT FINDINGS: Twenty-year outcome data demonstrate lower rates of atherosclerotic cardiovascular disease (ASCVD) related events and death in individuals with FH who were treated with statins from childhood, compared to those who initiated statins in adulthood. While diagnosis rates of FH are slowly improving, most clinicians do not adhere to recommendations for cholesterol screening in youth. Identifying youth with FH offers the opportunity for early intervention to prevent ASCVD and identify affected relatives through reverse cascade screening.

Differences in pediatric cholesterol screening rates between family physicians and pediatricians correlate with conflicting guidelines.

Conflicting guidelines regarding universal pediatric cholesterol screening were released between 2011 and 2019, but the impact on screening rates remains understudied. The purpose of this study was to examine trends in pediatric cholesterol screening rates within a single institution in the United States and their association with release of national guidelines, local educational tools, and electronic health record (EHR) modifications. Order placement was defined as ordering a high-density lipoprotein cholesterol level in a patient aged 9-21 years with ≥1 well visit in prior 3 years. Order placement rate (OPR) was calculated per month using 3 months' moving average smoothing and analyzed based on date, patient age, and specialty of ordering clinician. Timing of educational tools, EHR modifications, and national guideline release were analyzed for changes in OPR. Prior to release of 2011 guidelines recommending universal pediatric cholesterol screening, pediatrician OPR was 35% (95% CI: 29-43%) compared to 8% (7-11%) for family physicians. For both specialties, OPR increased after 2011 guidelines, educational initiatives, and EHR changes, but decreased after 2016, with a larger decrease for family physicians (p < 0.001 for all). OPR was consistently higher for pediatricians than for family physicians during the study period, with largest OPR changes correlating with release of guidelines. The findings from the study suggest that conflicting guidelines may contribute to lower overall OPR, and to different screening rates for children cared for by pediatricians compared to family physicians.

Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association.

This scientific statement presents considerations for clinical management regarding the assessment and risk reduction of select pediatric populations at high risk for premature cardiovascular disease, including acquired arteriosclerosis or atherosclerosis. For each topic, the evidence for accelerated acquired coronary artery disease and stroke in childhood and adolescence and the evidence for benefit of interventions in youth will be reviewed. Children and adolescents may be at higher risk for cardiovascular disease because of significant atherosclerotic or arteriosclerotic risk factors, high-risk conditions that promote atherosclerosis, or coronary artery or other cardiac or vascular abnormalities that make the individual more vulnerable to the adverse effects of traditional cardiovascular risk factors. Existing scientific statements and guidelines will be referenced when applicable, and suggestions for risk identification and reduction specific to each setting will be described. This statement is directed toward pediatric cardiologists, primary care providers, and subspecialists who provide clinical care for these young patients. The focus will be on management and justification for management, minimizing information on pathophysiology and epidemiology.

Novel Lipid Thresholds for Screening Predict the Need for Pharmacotherapy.

OBJECTIVE: To identify non-high-density lipoprotein cholesterol (HDL-C) and HDL-C thresholds for pediatric nonfasting lipid screens that are more predictive of the need for lipid-lowering pharmacotherapy and estimate numbers of potentially avoidable fasting lipid panels. STUDY DESIGN: In this retrospective review of children and youths aged 8-21 years presenting for preventive cardiology care, initial lipid results, recommendations for pharmacotherapy, and presence of additional cardiovascular risk factors were noted. Receiver operating characteristic curve analysis calculated threshold lipid values predicting the need for pharmacotherapy and were applied to 2 screening populations. Rates of potentially unnecessary fasting lipid panels were calculated. RESULTS: A non-HDL-C value >156 mg/dL for children with ≥1 cardiovascular risk factors and >199 mg/dL for children without risk factors conferred 95% or greater sensitivity in predicting a recommendation for pharmacotherapy with higher specificity, positive predictive value, and negative predictive value compared with current guidelines. HDL-C was a poor predictor of pharmacotherapy. Application of the current thresholds to screening populations indicated that 38.5%-92.3% of follow-up fasting lipid panels would not result in pharmacotherapy. CONCLUSION: Using higher non-HDL-C and lower HDL-C thresholds could prevent unnecessary follow-up lipid panels and reduce patient anxiety, cost, and time. This could improve compliance with universal pediatric lipid screening for both health care providers and families.

Improving Universal Pediatric Lipid Screening.

OBJECTIVE: To evaluate whether the release of national guidelines, electronic health record (EHR) modifications, and educational initiatives correlated with changes in pediatricians' universal lipid screening practices. STUDY DESIGN: Retrospective review of EHRs in an academic general pediatric practice was performed to measure the prevalence of order placement. A child was "screened" if an order was placed during a well-visit between 9 and 21 years of age. The prevalence of order placement for lipid screens on 22 374 patients from January 2010 to December 2015 was analyzed for date of order and patient age, then compared with timing of guidelines, local educational initiatives, and EHR modifications. Primary study outcome was lipid screening order placement over time. RESULTS: Order placement increased from 8.9% (95% CI 8.3%-9.5%) before any intervention to 50.0% (95% CI 48.8%-51.2%) over the last 12 months of the study period (P < .001). All age groups showed significant increases in order placement. Changes in screening were seen following guideline publications, educational initiatives, and EHR modifications (for all, P < .0001). Order completion was 69.6% (95% CI 68.9%-70.3%). The composite prevalence of screening (order placement multiplied by order completion) was 46.8% over the 6-year study period. CONCLUSIONS: Improved adherence to recommendations for universal lipid screening is possible through educational initiatives and EHR modifications. Inclusion of 12- to 16-year-old adolescents/teenagers as a targeted group for universal screening in addition to recommended age groups improved screening prevalence. Similar efforts could be applicable for implementation of other guidelines.

Referral Patterns and Cascade Screening for Familial Hypercholesterolemia in a Pediatric Lipid Clinic.

Charts of 42 children with familial hypercholesterolemia from a dyslipidemia clinic were reviewed for initial cholesterol screen indication and cascade screening results. Indications were universal screening (8/28 after guideline release, none before), family history (26/42), risk factor (5/42), and other (3/42). Cascade screening identified 63 relatives with unknown familial hypercholesterolemia.

Symptomatic Presentation of an Anamalous Left Coronary Artery from the Pulmonary Artery in an 8-Day-Old.

An 8-day-old presented in extremis and was subsequently diagnosed with an anomalous left coronary artery from the pulmonary artery. Symptomatic presentation at her young age and atypical echocardiogram findings make this case unique and suggest that demonstration of retrograde coronary flow is unnecessary in symptomatic presentation.

Cascade screening for familial hypercholesterolemia from pediatric index cases diagnosed through universal screening.

Heterozygous Familial Hypercholesterolemia (HeFH) is an autosomal dominant disorder causing elevated low density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Universal cholesterol screening in childhood leads to children serving as the index case for their family, but efficacy of cascade screening and genetic counseling in this population is not well understood. The institutional pediatric lipid clinic database was queried from 2011 to 2022 for subjects <18 years who met clinical HeFH diagnostic criteria (N = 256). Median peak LDL-C was 198 mg/dL (IQR 179-238 mg/dL) and 69.5 % of subjects were the index case. The number of new HeFH cases identified per index case was 3.55 ± 1.87. Genetic counseling was offered to 38.7 % of subjects and genetic testing was completed by 10.9 %, 53.6 % of whom had a pathogenic or likely pathogenic genetic variant for HeFH. Our findings highlight the effectiveness of cascade screening from pediatric index cases identified through universal screening. However, genetic counseling and genetic testing may be underutilized in this population.

It is Time to Screen for Homozygous Familial Hypercholesterolemia in the United States.

Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare inherited condition that affects approximately one in 300,000 people. The disorder is characterized by extremely high, life-threatening levels of low-density lipoprotein (LDL) cholesterol from birth, leading to significant premature cardiovascular morbidity and mortality, if left untreated. Homozygous familial hypercholesterolemia is severely underdiagnosed and undertreated in the United States (US), despite guidelines recommendations for universal pediatric lipid screening in children aged 9-11. Early diagnosis and adequate treatment are critical in averting premature cardiovascular disease in individuals affected by HoFH. Yet, an unacceptably high number of people living with HoFH remain undiagnosed, misdiagnosed, and/or receive a late diagnosis, often after a major cardiovascular event. The emergence of novel lipid-lowering therapies, along with the realization that diagnosis is too often delayed, have highlighted an urgency to implement policies that ensure timely detection of HoFH in the US. Evidence from around the world suggests that a combination of universal pediatric screening and cascade screening strategies constitutes an effective approach to identifying heterozygous familial hypercholesterolemia (HeFH). Nevertheless, HoFH and its complications manifest much earlier in life compared to HeFH. To date, little focus has been placed on the detection of HoFH in very young children and/or infants. The 2023 Updated European Atherosclerosis Society Consensus Statement on HoFH has recommended, for the first time, broadening pediatric guidelines to include lipid screening of newborn infants. Some unique aspects of HoFH need to be considered before implementing newborn screening. As such, insights from pilot studies conducted in Europe may provide some preliminary guidance. Our paper proposes a set of actionable measures that states can implement to reduce the burden of HoFH. It also outlines key research and policy gaps that need to be addressed in order to pave the way for universal newborn screening of HoFH in the US.

A Multidisciplinary Approach to Pediatric Obesity Shows Improvement Postintervention.

OBJECTIVE: Outpatient management of pediatric obesity can be difficult, requiring a significant time commitment from both provider and patient. Multidisciplinary clinic-based programs have shown promising effects in reducing BMI during intervention, but whether these changes are sustained over time is not well studied. The purpose of this study was to determine the post-treatment outcomes of children seen in a multidisciplinary pediatric obesity clinic (MPOC). METHODS: A retrospective chart review was performed using the MPOC database, which included all clinic patients from January 2008 to August 2016 who attended a minimum of 2 visits (n = 472). The primary outcome was the absolute change in BMI Z-score (BMIZ) from the final intervention visit compared to 1- and 2-years post-intervention. Multivariate regression analysis was performed to characterize predictors of change in BMIZ. RESULTS: MPOC patients ranged in age from 3 to 18 years. Mean BMIZ decreased significantly during intervention (-0.13 ± 1.47, P < .001) and was maintained at 1- and 2-years post-intervention. In participants ages 3 to 5, BMIZ further decreased at 1 year post intervention (-0.27 ± 0.26, P < .001). Age at time of referral was the only significant predictor of change in BMIZ. CONCLUSIONS: Outpatient, multidisciplinary intervention for pediatric obesity was effective in reducing or stabilizing BMIZ during and beyond the intervention, particularly when patients were referred at an early age. Although primary prevention is the ideal management, multidisciplinary clinic intervention can be effective in the sustained treatment of pediatric obesity.

Toward a Roadmap for Best Practices in Pediatric Preventive Cardiology: A Science Advisory From the American Heart Association.

Cardiovascular disease risk factors are highly prevalent among youth in the United States and Canada. Pediatric preventive cardiology programs have independently developed and proliferated to address cardiovascular risk factors in youth, but there is a general lack of clarity on best practices to optimize and sustain desired outcomes. We conducted surveys of pediatric cardiology division directors and pediatric preventive cardiology clinicians across the United States and Canada to describe the current landscape and perspectives on future directions for the field. We summarize the data and conclude with a call to action for various audiences who seek to improve cardiovascular health in youth, reduce the burden of premature cardiovascular disease, and increase healthy longevity. We call on heart centers, hospitals, payers, and policymakers to invest resources in the important work of pediatric preventive cardiology programs. We urge professional societies to advocate for pediatric preventive cardiology and provide opportunities for training and cross-pollination across programs. We encourage researchers to close evidence gaps. Last, we invite pediatric preventive cardiology clinicians to collaborate and innovate to advance the practice of pediatric preventive cardiology.

A review of guidelines for dyslipidemia in children and adolescents.

The recent publication of new pediatric lipid screening guidelines represents a change in recommendations regarding lipid screening and management for pediatric patients that will affect all health care professionals who care for children and adolescents. The guidelines differ from the selective screening recommended by the 2007 US Preventive Services Task Force, instead recommending routine lipid screening for children and adolescents at ages 9-11 years and again at 17-21 years. Studies have shown that limiting lipid screening to patients with risk factors fails to identify many patients with genetic or acquired dyslipidemias. Without universal screening, many at-risk children will not be identified.

Screening and Management of Dyslipidemia in Children and Adolescents.

This review provides an overview of pediatric dyslipidemia emphasizing screening and treatment recommendations. The presence of risk factors for cardiovascular disease in childhood poses significant risk for the development of atherosclerotic cardiovascular disease and cardiovascular events in adulthood. While atherogenic dyslipidemia is the most common dyslipidemia seen in children and can be suspected based on the presence of risk factors (such as obesity), familial hypercholesterolemia can be found in children with no risk factors. As such, universal cholesterol screening is recommended to identify children with these disorders in order to initiate treatment and reduce the risk of future cardiovascular disease. Treatment of pediatric dyslipidemia begins with lifestyle modifications, but primary genetic dyslipidemias may require medications such as statins. As pediatric lipid disorders often have genetic or familial components, it is important that all physicians are aware that cardiovascular risk begins in childhood, and can both identify these disorders in pediatric patients and counsel their adult patients with dyslipidemia to have their children screened.