20.500.12556/DiRROS-28434 Early mortality in children with homozygous familial hypercholesterolemia case reports of deaths at ages five and seven and a systematic review of global evidence Background: Homozygous familial hypercholesterolemia (HoFH) is a leading cause of premature atherosclerotic cardiovascular disease (ASCVD) and early mortality if left untreated or inadequately treated. Objective: This study presents 2 pediatric cases of early death from Pakistan due to familial hypercholesterolemia (FH) and provides a systematic review of similar cases reported globally. Methods: Genetic analysis was conducted using next-generation sequencing to confirm pathogenic variants. For the systematic review, published reports of individuals with FH who died before the age of 18 years were identified. Data were extracted on demographic features, personal and family history, genetic variants, treatment given, and cause of death. Results: Both patients, born to consanguineous families, presented with markedly elevated low-density lipoprotein cholesterol (LDL-C) levels (792 mg/dL [20.48 mmol/L] and 896 mg/dL [23 mmol/L], respectively), multiple xanthomas, and early-onset myocardial infarction, and died at the ages of 5 and 7 years, respectively. Their genetic analysis revealed a pathogenic frameshift variant in the LDLR gene: NM_000527.5: c.2416dupG (p.Val806GlyfsTer11). The systematic review included 12 studies reporting pediatric FH-related mortality. Common clinical features included tendon xanthomas, elevated LDL-C levels, family history, and early-onset ASCVD. Genetic testing was performed in a few cases, which revealed pathogenic variations in the LDLR gene. Most of the patients received inadequate lipid-lowering therapy. The most common causes of death were severe coronary artery disease, myocardial infarction, and sudden cardiac arrest. Conclusion: Our 2 cases and the accompanying systematic review identified additional cases of premature mortality. Collectively, these findings highlight diagnostic delays and inadequate treatment as common factors among patients who died prematurely. familial hypercholesterolemia homozygous FH mortality atherosclerosis LDLR true false true Angleški jezik Ni določen Neznano 2026-03-19 09:22:18 2026-03-19 09:22:18 2026-03-26 03:43:02 0000-00-00 00:00:00 2026 0 0 str. 402-410 issue 2 Vol. 20 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-053.2 1933-2874 10.1016/j.jacl.2025.12.010 263378691 RAZ_Khan_Madeeha_2026.pdf RAZ_Khan_Madeeha_2026.pdf 1 4908F28A62BC73CBA6E7ABBB4ADE269B 2276b11665e8ec6e632c6a02e2a2592307d0cd2366a442486cc26265716a3e77 da937f16-236c-11f1-8070-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=42090 https://www.lipidjournal.com/article/S1933-2874(25)00541-0/fulltext 0 e57c62fd-236c-11f1-8070-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=42091 Univerzitetni klinični center Ljubljana 0 0 0