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 lowdensity 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 (
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=protein&doptcmdl=genbank&term=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.
