BACKGROUND AND AIMS: For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8-10 years for those with a low density lipoprotein cholesterol (LDL-C) >3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. METHODS: Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. RESULTS: Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3-11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those >10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. CONCLUSIONS: The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those >10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations.

1st Department of Pediatrics National and Kapodistrian University of Athens and Department of Inborn Errors of Metabolism and Inherited Dyslipidemias MITERA Children's Hospital Athens Greece

3rd Department of Internal Medicine General University Hospital and 1st Faculty of Medicine Charles University U Nemocnice 1 128 08 Prague 2 Czech Republic

Cardiovascular Research Group Research and Development Unit Department of Health Promotion and Chronic Diseases National Institute of Health Doutor Ricardo Jorge Lisbon Portugal and University of Lisboa Faculty of Sciences BioISI Biosystems and Integrative Sciences Institute Lisboa Portugal

Centre for Cardiovascular Genetics Institute for Cardiovascular Science University College London London UK

Centre for Cardiovascular Surgery and Transplantation Pekarska 53 656 91 Brno Czech Republic; Medical Faculty Masaryk University Brno Czech Republic

Centre for Heart Muscle Disease Institute for Cardiovascular Science University College London London UK

Centres Hospitaliers Jolimont Lipid Clinic Haine Saint Paul Belgium

Department of Cardiology and Internal Medicine Erasmus Medical Center Rotterdam the Netherlands

Department of Pediatrics and Academic Medical Center Amsterdam the Netherlands

Division of Pediatric Pulmonology Allergology and Endocrinology Department of Pediatrics and Adolescent Medicine Medical University Vienna Austria

FH Registry of the Austrian Atherosclerosis Society Vienna Austria

Institute of Genetic Epidemiology Department of Genetics and Pharmacology Medical University of Innsbruck Schöpfstraße 41 6020 Innsbruck Austria

Lysosomal Disorders Unit Royal Free Hospital London UK

National Advisory Unit on Familial Hypercholesterolemia Department of Endocrinology Morbid Obesity and Preventive Medicine Oslo University Hospital Oslo Norway; Department of Nutrition University of Oslo Oslo Norway

National Advisory Unit on Familial Hypercholesterolemia Department of Endocrinology Morbid Obesity and Preventive Medicine Oslo University Hospital Oslo Norway; Unit for Cardiac and Cardiovascular Genetics Department of Medical Genetics Oslo University Hospital Oslo Norway

See more in PubMed

Nordestgaard B.G., Chapman M.J., Humphries S.E., Ginsberg H.N., Masana L., Descamps O.S. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur. Heart J. 2013;34(45) 3478-90a. PubMed PMC

Marks D., Thorogood M., Neil H.A., Humphries S.E. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168(1):1–14. PubMed

Wald D.S., Bestwick J.P., Wald N.J. Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis. BMJ. 2007;335(7620):599. PubMed PMC

Benn M., Watts G.F., Tybjaerg-Hansen A., Nordestgaard B.G. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur. Heart J. 2016;37(17):1384–1394. PubMed

Akioyamen L.E., Genest J., Shan S.D., Reel R.L., Albaum J.M., Chu A. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open. 2017;7(9) PubMed PMC

Humphries S.E., Whittall R.A., Hubbart C.S., Maplebeck S., Cooper J.A., Soutar A.K. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J. Med. Genet. 2006;43(12):943–949. PubMed PMC

Talmud P.J., Shah S., Whittall R., Futema M., Howard P., Cooper J.A. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013;381(9874):1293–1301. PubMed

Futema M., Shah S., Cooper J.A., Li K., Whittall R.A., Sharifi M. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clin. Chem. 2015;61(1):231–238. PubMed PMC

Harada-Shiba M., Ohta T., Ohtake A., Ogura M., Dobashi K., Nohara A. Guidance for pediatric familial hypercholesterolemia 2017. J. Atheroscler. Thromb. 2018;25(6):539–553. PubMed PMC

Watts G.F., Sullivan D.R., Poplawski N., van Bockxmeer F., Hamilton-Craig I., Clifton P.M. Familial hypercholesterolaemia: a model of care for Australasia. Atheroscler Suppl. 2011;12(2):221–263. PubMed

Wiegman A., Gidding S.S., Watts G.F., Chapman M.J., Ginsberg H.N., Cuchel M. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur. Heart J. 2015;36(36):2425–2437. PubMed PMC

Descamps O.S., Tenoutasse S., Stephenne X., Gies I., Beauloye V., Lebrethon M.C. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218(2):272–280. PubMed

Goldberg A.C., Hopkins P.N., Toth P.P., Ballantyne C.M., Rader D.J., Robinson J.G. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S1–S8. PubMed

Harada-Shiba M., Arai H., Oikawa S., Ohta T., Okada T., Okamura T. Guidelines for the management of familial hypercholesterolemia. J. Atheroscler. Thromb. 2012;19(12):1043–1060. PubMed

NICE. Familial hypercholesterolaemia . 2017. Identification and Management. PubMed

Dale P., Shortland G., Datta D., Cole D. 2015. Hyperlipidaemia in Paediatric Practice.

Luirink I.K., Wiegman A., Kusters D.M., Hof M.H., Groothoff J.W., de Groot E. 20-Year follow-up of statins in children with familial hypercholesterolemia. N. Engl. J. Med. 2019;381(16):1547–1556. PubMed

Kusters D.M., Avis H.J., de Groot E., Wijburg F.A., Kastelein J.J., Wiegman A. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. Jama. 2014;312(10):1055–1057. PubMed

Braamskamp M., Kastelein J.J.P., Kusters D.M., Hutten B.A., Wiegman A. Statin initiation during childhood in patients with familial hypercholesterolemia: consequences for cardiovascular risk. J. Am. Coll. Cardiol. 2016;67(4):455–456. PubMed

Vuorio A., Docherty K.F., Humphries S.E., Kuoppala J., Kovanen P.T. Statin treatment of children with familial hypercholesterolemia--trying to balance incomplete evidence of long-term safety and clinical accountability: are we approaching a consensus? Atherosclerosis. 2013;226(2):315–320. PubMed

Vuorio A., Kuoppala J., Kovanen P.T., Humphries S.E., Tonstad S., Wiegman A. Statins for children with familial hypercholesterolemia. Cochrane Database Syst. Rev. 2017;7 CD006401. PubMed PMC

Ramaswami U., Cooper J., Humphries S.E., Group FHPRS The UK paediatric familial hypercholesterolaemia register: preliminary data. Arch. Dis. Child. 2017;102(3):255–260. PubMed PMC

Humphries S.E., Cooper J., Dale P., Ramaswami U., Group FHPRS The UK paediatric familial hypercholesterolaemia register: statin-related safety and 1-year growth data. J Clin Lipidol. 2018;12(1):25–32. PubMed PMC

Medeiros A.M., Alves A.C., Bourbon M. Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement. Genet. Med. : official journal of the American College of Medical Genetics. 2016;18(4):316–324. PubMed

Galema-Boers J.M., Versmissen J., Roeters van Lennep H.W., Dusault-Wijkstra J.E., Williams M., Roeters van Lennep J.E. Cascade screening of familial hypercholesterolemia must go on. Atherosclerosis. 2015;242(2):415–417. PubMed

Bogsrud M.P., Langslet G., Wium C., Johansen D., Svilaas A., Holven K.B. Treatment goal attainment in children with familial hypercholesterolemia: a cohort study of 302 children in Norway. J Clin Lipidol. 2018;12(2):375–382. PubMed

Narverud I., van Lennep J.R., Christensen J.J., Versmissen J., Gran J.M., Iversen P.O. Maternal inheritance does not predict cholesterol levels in children with familial hypercholesterolemia. Atherosclerosis. 2015;243(1):155–160. PubMed

Kreissl A., Walleczek N., Espina P.R., Hallwirth U., Greber-Platzer S. Selective screening for familial hypercholesterolemia in Austrian children - first year results. BMC Pediatr. 2019;19(1):208. PubMed PMC

Mollaki V., Drogari E. Genetic causes of monogenic familial hypercholesterolemia in the Greek population: lessons, mistakes, and the way forward. J Clin Lipidol. 2016;10(4):748–756. PubMed

Ruel I., Aljenedil S., Sadri I., de Varennes E., Hegele R.A., Couture P. Imputation of baseline LDL cholesterol concentration in patients with familial hypercholesterolemia on statins or ezetimibe. Clin. Chem. 2018;64(2):355–362. PubMed

Mollaki V., Progias P., Drogari E. Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum. Atherosclerosis. 2014;237(2):798–804. PubMed

van der Graaf A., Cuffie-Jackson C., Vissers M.N., Trip M.D., Gagne C., Shi G. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J. Am. Coll. Cardiol. 2008;52(17):1421–1429. PubMed

Langslet G., Bogsrud M.P., Wium C., Johansen D., Svilaas A., Holven K.B. Some children with a familial hypercholesterolemia mutation may exhibit persistent low LDL levels. J Clin Lipidol. 2018;12(5):1327–1328. PubMed

Wiegman A., de Groot E., Hutten B.A., Rodenburg J., Gort J., Bakker H.D. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 2004;363(9406):369–370. PubMed

Kusters D.M., Wiegman A., Kastelein J.J., Hutten B.A. Carotid intima-media thickness in children with familial hypercholesterolemia. Circ. Res. 2014;114(2):307–310. PubMed

Narverud I., Retterstol K., Iversen P.O., Halvorsen B., Ueland T., Ulven S.M. Markers of atherosclerotic development in children with familial hypercholesterolemia: a literature review. Atherosclerosis. 2014;235(2):299–309. PubMed

Wiegman A., Hutten B.A., de Groot E., Rodenburg J., Bakker H.D., Buller H.R. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. Jama. 2004;292(3):331–337. PubMed

Sivapalaratnam S., van Loendersloot L.L., Hutten B.A., Kastelein J.J., Trip M.D., de Groot E. Long-term LDL-c lowering in heterozygous familial hypercholesterolemia normalizes carotid intima-media thickness. Atherosclerosis. 2010;212(2):571–574. PubMed