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The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.

Familial hypercholesterolemia (FH) is a prevalent (1:500 individuals) inherited disorder that strongly predisposes to premature atherosclerosis and subsequent cardiovascular disease. 1 In children with FH, atherosclerosis progression is observed before puberty. 2 Consequently, guidelines for FH treatment advocate initiation of statins in children as young as 8 years. 3 However, longterm efficacy and safety data for statin therapy initiated during childhood do not exist. We followed up a cohort of children with FH receiving statin therapy until adulthood.Methods | We conducted a cohort study of 214 children heterozygous for FH, living in the Netherlands, aged 8 to 18 years, who were randomized between 1997 and 1999 into a singlecenter, 2-year, double-blind, placebo-controlled trial of pravastatin. 4 Results showed a significant regression of carotid intima-media thickness (IMT) after statin treatment compared with placebo.After the trial, all children received pravastatin (20-40 mg/d) and were followed up until March 2011 along with 95 unaffected siblings. Patients were instructed to adhere to the Step 2 diet. During follow-up, several patients switched to other statins. After 10 years, all participants underwent a physical examination, fasted blood sample, assessment of family and medical history, including the occurrence of adverse events,The low-density lipoprotein levels of patients with FH at follow-up did not meet current treatment standards and carotid IMT was thicker than in unaffected siblings. More robust lipid-lowering therapy or earlier initiation of statins may be required to completely restore arterial wall morphology and avert cardiovascular events later in life in this high-risk population.

Rationale: Familial hypercholesterolemia (FH) predisposes patients to premature cardiovascular disease, with the process of atherosclerosis initiated in early childhood.Objective: As part of an ongoing trial to assess the efficacy and safety of rosuvastatin in children with FH aged 6 to 17 years, we report the differences in carotid intima-media thickness (cIMT) at baseline between children with FH and their unaffected siblings. Methods and Results: B-mode ultrasound measurements of the carotid artery were made in 196 children with FHand 64 of their siblings. Mean (±SE) cIMT in children with FH was significantly greater than that of unaffected siblings (0.398±0.052 versus 0.377±0.045 mm; P<0.001). A significantly greater cIMT value was observed before the age of 8 years. Multivariable analyses showed that age, male sex, and presence of FH were independent predictors of cIMT. Conclusions:The difference in mean cIMT between children with FH and their unaffected siblings may be significant as early as age 8 years. This study confirms the need for early cholesterol lowering in this high-risk population. These patients participating in a carefully monitored study will help assess the long-term efficacy on cIMT and safety of statin therapy in young children. measured with CDC standardized assays. Ultrasound measurements on all participants were made using the Acuson Sequoia 512 instrument (Siemens AG, Malvern, PA; Erlangen, Germany) equipped with an 85-Mhz linear array transducer. All sonographers were trained and certified before their participation in the study. B-mode scans of the right and left common carotid artery, carotid bulbs, and internal carotid artery were obtained according to strict protocol specifications. Image readings were randomly assigned to image analysts for qualitative and quantitative evaluation. Image analysts were blinded to subjects. Mean cIMT was defined as the mean IMT of the right and left common carotid arteries, the carotid bulb, and the internal carotid far wall segments. For subjects in whom the scan of 1 of the segments had failed, mean IMT was calculated as the mean of the other 2 segments. We assessed differences in demographic and cIMT between FH subjects and siblings by logistic or linear regression analysis with generalized estimating equations in the SAS procedure GENMOD to account for correlations within families. The same procedure was used to explore the association univariately between mean cIMT (response variable) and demographic and clinical characteristics (explanatory variables). Multivariable analysis was used to identify independent predictors after stepwise backward selection. An equation for difference in cIMT (ΔIMT) was derived by subtracting the equation for children with FH (if GROUP=1), that is, IMT FH =β1AGE+β2GROUP+β3AGE ×GROUP=β1AGE+β2+β3AGE, from the equation for their siblings (if GROUP=0), that is, IMT SIB =β1AGE, as described previously.2 This calculation resulted in ΔIMT=β2+β3AGE. β's and SE were derived from the output of a linear regression analysis fo...

Statins enjoy widespread acceptance as effective drugs to reduce morbidity and mortality in patients with and without cardiovascular disease, and are considered safe for long-term use. However, these compounds are contraindicated during pregnancy based on their potential teratogenic effects. Owing to the increasing number of young women eligible for statin therapy and the concern that the discontinuation of statin therapy might be harmful for both mother and child with hypercholesterolemia, gestational exposure to statins has increasingly become an issue of significant clinical importance. In this systematic review of both human and animal studies on the teratogenic effects of statins during pregnancy, we found that most of the available data in fact suggests that statins are unlikely to be teratogenic. In humans, the observed congenital anomalies were isolated and no consistent pattern has emerged to suggest that a common mechanism could underlie these observations. Animal studies show conflicting results, but in the reports in which an excess of congenital anomalies was reported in the statin-treated rodents, excessive doses were used compared with the regimens we commonly prescribe to human subjects.

Different screening strategies are currently recommended to identify children with (familial) hypercholesterolaemia in order to initiate early lipid management. However, these strategies are characterised to date by low adherence by the medical community and limited compliance by parents and children. In a literature review, the authors assess which children should undergo screening and which children are in effect identified through the currently recommended strategies. Furthermore, the authors discuss the different screening tools and strategies currently used in Europe and what is known about the negative aspects of screening. The authors conclude that currently recommended selective screening strategies, which are mainly based on family history, lack precision and that a large percentage of affected children who are at increased risk of future coronary artery disease are not being identified. The authors propose universal screening of children between 1 and 9 years of age, a strategy likely to be most effective in terms of sensitivity and specificity for the identification of children with familial hypercholesterolaemia. However, this concept has yet to be proven in clinical practice.

BackgroundStatins are currently the preferred pharmacological therapy in individuals with familial hypercholesterolemia (FH) with the aim to prevent premature atherosclerosis. In adults, these agents have been proven to be safe and well tolerated; however, non-adherence is a significant clinical issue.ObjectivesIn this study, we evaluated tolerability and adherence to statin therapy in young adult FH patients 10 years after this was initiated in their childhood.MethodsA questionnaire including items on medical history, adherence and reasons for discontinuation was sent to 214 young adult FH patients that initiated statin therapy at least 10 years ago. Tolerability was defined as 100 % minus the percentage of patients that discontinued statin therapy due to side effects. Adherence was defined as the extent to which patients took their medication as prescribed by their physician. We labelled patients adherent if they took 80 % or more of their pills in the month preceding our assessment.ResultsFollow-up was successful in 205 (95.8 %) subjects (age 18–30 years). A history of side effects was reported by 40 (19.5 %) of the patients, and mainly consisted of muscle complaints and gastrointestinal symptoms. Three patients (1.5 %) discontinued statin therapy because of side effects. Rhadbomyolysis or other serious adverse events were not reported. In fact, 169 (82.4 %) of 205 patients remained on statin treatment and 78.7 % (148 out of 188) were adherent. None of the patient characteristics were significantly associated with adherence.ConclusionsIndividuals with FH who started statin therapy in childhood demonstrated good adherence during ten years of treatment. Furthermore, statin therapy was well tolerated; only a small minority discontinued therapy because of side effects and the side effects that were reported were mild in nature.

Background-Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. Mutations in the genes encoding for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) underlie ADH. Nevertheless, a proportion of individuals who exhibit the ADH phenotype do not carry mutations in any of these 3 genes.Estimates of the percentage of such cases among the ADH phenotype vary widely. We therefore investigated a large pediatric population with an unequivocal ADH phenotype to assess the molecular basis of hereditary hypercholesterolemia and to define the percentage of individuals with unexplained dyslipidemia. Methods and Results-We enrolled individuals with low-density lipoprotein cholesterol levels above the 95th percentile for age and gender and an autosomal dominant inheritance pattern of hypercholesterolemia from a large referred pediatric cohort of 1430 children. We excluded children with thyroid dysfunction, nephrotic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, and obesity (body mass index Ͼ75th percentile for age and gender), as well as children referred via a cascade screening program and those from families with a known molecular diagnosis. Of the 269 children who remained after the exclusion criteria were applied, 255 (95%) carried a functional mutation (LDLR, 95%; APOB, 5%). Conclusion-In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date.