Severe hypertriglyceridemia (fasting triglycerides >500 mg/dL) is an uncommon and heterogeneous condition in children. The aim of this work was to assess the etiology of severe hypertriglyceridemia seen in 8 pediatric patients. Eight pediatric cases with severe hypertriglyceridemia underwent clinical, biochemical, and genetic evaluations. The laboratory tests performed included lipoprotein separation by ultracentrifugation and measurement of their lipid content, measurement of apolipoproteins, analyses of post-heparin plasma lipoprotein lipase (LPL) activity and mass, detection of autoantibodies against GPIHBP1, and targeted next-generation sequencing. All children (3-16 years) had recorded fasting serum triglyceride levels >800 mg/dL (9 mmol/L) at least once. Five cases with pathogenic or likely pathogenic biallelic variants in GPIHBP1 (2 cases), APOA5 (1 case), APOC2 (1 case), and LPL (1 case) were diagnosed with familial chylomicronemia syndrome based on their clinical, biochemical, and genetic features. Additionally, 1 child had autoimmune chylomicronemia due to the presence of autoantibodies against GPIHBP1. Finally, 2 patients had severe hypertriglyceridemia due to secondary causes: 1 girl with the onset of type 1 diabetes in the context of diabetic ketoacidosis, and the other patient due to total parenteral nutrition and low-molecular-weight heparin. The etiology of severe hypertriglyceridemia in children is heterogeneous. A multidisciplinary approach helps to reach a definitive diagnosis and, therefore, to recommend specific therapy.

Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations. The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.

Familial chylomicronemia syndrome (FCS) is a rare monogenic disorder characterized by severe hypertriglyceridemia caused by pathogenic variants in genes involved in triglyceride metabolism. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) plays a critical role in the lipolytic processing of triglyceride-rich lipoproteins. We present 3 unrelated cases of FCS with a newly identified homozygous complex insertion-deletion variant in GPIHBP1, namely c.460_461delinsAAA, p.Ala154Lysfs*153. All 3 cases presented with severe hypertriglyceridemia, a high FCS clinical score, and significantly reduced lipoprotein lipase (LPL) activity (being 6.6 mUI the value corresponding to 20% of normal activity). These observations expand the spectrum of pathogenic GPIHBP1 variants in FCS. The identification of GPIHBP1 variant reinforces the causal link between GPIHBP1 mutations and LPL deficiency, as evidenced by diminished LPL activity, and further expands the genetic landscape of FCS.

Familial chylomicronemia syndrome (FCS) is a rare disorder of triglyceride (TG) metabolism caused by loss of function variants in one of five known canonical genes involved in chylomicron lipolysis and clearance-LPL, APOC2, APOA5, LMF1, and GPIHBP1. Pathogenic variants in LPL, which encodes the hydrolytic enzyme lipoprotein lipase, account for over 80%-90% of cases. FCS may present in infancy with hypertriglyceridemia-induced acute pancreatitis and is challenging to manage both acutely and in the long-term. Here, we report our experience managing two unrelated infants consecutively diagnosed with hypertriglyceridemia-induced acute pancreatitis caused by LPL deficiency. Both had elevated TGs at presentation (205 and 30 mmol/L, respectively) and molecular genetic testing confirmed each infant carried a different homozygous pathogenic variant in the LPL gene, specifically, c.987C>A (p.Tyr329Ter) and c.632C>A (p.Thr211Lys). The more severely affected infant had cutaneous xanthomata, lipemia retinalis and lipemic plasma at presentation, and required management in an intensive care setting. Acute stabilisation was achieved using insulin and heparin infusions together with the iterative implementation of a fat-restricted diet, low in long chain triglycerides (LCT) and supplemented with medium chain triglycerides (MCT). In both cases, provision of adequate caloric intake (~110-120 kcal/kg/day) was also found to be important for a sustained TG reduction during the acute phase of management. In summary, a high index of suspicion is required to diagnose FCS in infants with hypertriglyceridemia-induced acute pancreatitis, management of which can be challenging, highlighting the need for more evidence-based recommendations.

Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia (MCM), characterized by highly variable triglyceride levels with acute episodes of severe hypertriglyceridemia (HTG), are caused by rare variants in genes associated with the catabolism of circulating lipoprotein triglycerides, mainly including LPL, APOC2, APOA5, GPIHBP1, and LMF1. Among them, the LMF1 gene only accounts for 1%. This study described a Chinese patient with severe HTG carrying compound heterozygous variants of a rare nonsense variant p.W168X in exon 3 and a missense variant p.R416Q in exon 9 in the LMF1 gene. These heterozygous variants account for his family's decreased lipase activity and mass, which caused the FCS phenotype.