Neonate With Milky Serum

A 12-day-old male infant presents to our outpatient clinic for a routine follow-up. He is the firstborn infant in a nonconsanguineous marriage. He was born appropriate for gestational age with a birth weight of 3300 gm, normal Apgar scores, and an uneventful postnatal period. He was exclusively breastfed with acceptable weight loss, normal stooling pattern, and urine output. On examination, the patient had stable vitals, was active, alert, and well hydrated with no syndromic features. Newborn screening was normal. Mild clinical icterus was noted; a serum bilirubin sample revealed a grossly milky serum, which necessitated further investigations. No significant family was noted. There were no organomegaly or xanthomas on the physical examination. A liver function test (LFT) and lipid profile were ordered. Total cholesterol 292 mg/dl, low-density lipoprotein (LDL) 144 mg/dl, and triglycerides (TG) 2800 mg/dL were all significantly elevated. High-density lipoprotein (HDL) 12 mg/dl was lower for age, while AST 106 IU/L and ALT 52 IU/L were normal. The remaining LFTs were normal. The parental lipid profile was normal.Congenital hypertriglycidemia, familial hyperchylomicronemia (FH), and familial dysbetalipoprotienemia.Genetic evaluation by Clinical Exome Sequencing (>80–100X on Illumina sequencing platform) revealed a compound heterozygous missense variation in exon 5 of the lipoprotein lipase (LPL) gene (chr8:g.19954258T>C; Depth: 167x), confirming a diagnosis of familial combined hyperlipidemia (FCH).Hypertriglyceridemia is defined as a fasting TG level above the age and gender-adjusted 95th percentile. The etiology of primary hypertriglyceridemia includes genetic defects in triglyceride metabolism. The major classes of dyslipidaemia have been historically classified by Fredrickson.1 Severe hypertriglyceridemia (HTG), defined as TG of greater than 1000 mg/dL is rare in the neonatal period2 and is known to trigger acute pancreatitis in neonates when TG levels exceed more than 2000 mg/dL. Most infants with HTG present asymptomatically, without signs of hypertriglyceridemia, and may be incidentally recognized because of milky serum. In a case report similar to our patient, a 2-month-old infant with poor weight gain was undiagnosed till 2 months of age, when he was noted to have milky serum and eventually diagnosed with lipaemia retinalis and elevated TG levels.3 Severe elevations may require exchange transfusion for hypertriglyceridemia, as discussed in another case of an asymptomatic 24-day-old neonate.4Of the genetic etiologies of neonatal severe hypertriglyceridemia, LPL gene variants contribute to the majority. Notably, genes pertaining to GPIHBP1, APOA5, GPD1, APOC2, and LMF are also implicated but are mainly involved in the catabolic pathway of chylomicrons.5Literature on phenotypic-genotypic correlation in neonates is sparse and beginning to emerge. Existing data in adults suggests that although all affected patients may present with highly elevated TG levels at the onset of illness, the clinical findings and prognosis are worse in the homozygous LPL deficiency.6 This could perhaps explain why our patient, a compound heterozygous, did not develop severe complications despite very high TG levels at presentation. Indian genetic data on FH is rather limited, and there are few genetically confirmed reports, underscoring an urgent need to increase the rates of FH detection.7Following genetic confirmation of the diagnosis of FCH, parents were counseled about lifelong adherence to a low-fat diet, due to increased propensity for accelerated atherosclerosis. Dietary modifications are considered the most effective treatment strategy.8 Restriction of fat and carbohydrates, especially high glycemic and high fructose foods, is key. Dietary fat is not the primary source of liver TG, and a higher-fat diet does not necessarily raise the fasting plasma TG levels. However, changing the type of fat (ie, poly- and monounsaturated fats instead of saturated) is strongly recommended.6 Pharmaco-nutritive interventions (Figure 1) in our patient included dietary modification consisting of restriction of fat intake and initiating Gemfibrozil (20 mg/kg/dose twice daily) therapy along with the addition of medium chain triglycerides oil (MCT), skimmed milk, and multivitamins. Because the infant was exclusively breastfed, the only dietary source of fat to be restricted was breastmilk. However, because of the nutritional and immunological values of breast milk that are important during this phase of growth and development, breastfeeding continued, in a restricted form, for the first 4 months of age. Parents were educated on the nutritional components of different phases of breastmilk, and an individualized breastfeeding plan was conceptualized. Foremilk feeding—the milk secreted at the initial 0 to 10 minutes, containing more water, lactose, proteins, and low in fat—was recommended. Hindmilk feeding—milk produced at the end of feeding that is high in fat, vitamins A, E, and higher calories than foremilk—was withheld. To maintain overall calories, the remaining diet consisted of skimmed milk with added MCT oil and additional supplementation of vitamin A, D, E, and K. By 4 months of age, appropriate complementary feeding was initiated. Parental lipid profile was normal. In case of severe HTG with TG levels greater than 2000 mg/dl and impending acute pancreatitis, therapeutic options include plasmapheresis, exchange transfusion, and intravenous heparin infusions. Plasmapheresis and exchange transfusion lead to direct elimination of lipoprotein particles, thereby decreasing the viscosity of plasma and removing plasma proteases associated with pancreatitis.4 Intravenous Heparin-mediated release of the endothelial LPL into the circulation has been hypothesized as another treatment modality, but its use is disputed and not widely recommended.5 Our patient did not demonstrate any signs of acute pancreatitis and hence did not require these interventions.Gemfibrozil increases very low-density lipoprotein clearance by stimulating vascular endothelial cell LPL activity. Niacin use in hypertriglyceridemia is associated with liver toxicity; hence, its role is not recommended in infancy.7 HMG-CoA reductase inhibitors are known to be effective in controlling triglyceride levels.8 Fibric acid derivatives’ safety and efficacy data in children are sparse. Their use can be considered if TG levels are persistently elevated despite other therapies.Gene therapy for this condition is still in its infancy stages, but its development could herald a new era in cardiovascular health, particularly for more severe cases like familial chylomicronaemia syndrome.9 Our patient responded satisfactorily to timely pharmacological and dietary modifications; hence, genetic therapy may not be required. Gene therapy for FCH is currently unavailable in the Indian subcontinent to the best of our knowledge.The infant continues to be seen in our high-risk follow-up clinic. He has satisfactory weight gain with normal neurodevelopment. No side effects of Gemfibrozil (hepatic enzyme derangements, rash, clinical myopathy) were noted.Lipid profiles were monitored at weekly intervals initially for 2 months and spaced out bimonthly as TG levels stabilized (Figure 2). The most recent TG level was 286 mg/dL. Bimonthly liver function tests were normal. No eruptive xanthomas or hepatosplenomegaly have been noted.Incidentally noted milky serum in an asymptomatic newborn could herald a serious diseasePragmatic dietary modifications in early infancy can have lasting benefits in controlling the diseasePharmacological management appears to be safe; however, there is a need for close follow-up to evaluate for side effects.American Board of Pediatrics Neonatal-Perinatal Content SpecificationUnderstand inborn errors of metabolism and mitochondrial, lysosomal, and peroxisomal disorders.Know the principles and applications of breast milk in the newborn.