Neonatal hyperlipidemia with pancreatitis: Novel gene mutation of lipoprotein lipaseMH Shah1, R Roshan2, R Desai1, SS Kadam1
1 Division of Neonatology, Department of Pediatrics, King Edward Memorial Hospital, Pune, Maharashtra, India
2 Department of Clinical Hematology, Sahyadri Specialty Hospital, Pune, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_731_17
Source of Support: None, Conflict of Interest: None
Keywords: Gemfibrozil, hypertriglyceridemia, lipemia retinalis, lipoprotein lipase, pancreatitis
Genetic deficiency of lipoprotein lipase (LPL) causes a rare autosomal recessive type I hyperlipoproteinemia, with estimated prevalence of one in million.LPL gene is located on chromosome 8p22 and mutation in this gene causes LPL deficiency. The disorder is usually seen in children and manifests as recurrent abdominal pain, eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and pancreatitis. LPL deficiency associated with pancreatitis is very rare in neonates. We report this rare association of pancreatitis with novel mutation of LPL gene in a neonate.
A 23-day-old male infant, born to a primigravida mother from a third degree consanguineous marriage, was admitted with complaints of fever, vomiting, and lethargy. He was delivered at 39 weeks of gestational age with a birth weight of 3.55 kg and was fed mother's milk soon after birth. History was not suggestive of dyslipidemia, recurrent pancreatitis, premature cardiovascular disease, or sudden death in either of the maternal or paternal family members.
Physical examination revealed an afebrile active baby without any dysmorphic features. Vital parameters including respiratory rate (46 breaths/min), blood pressure (62/40 mm of Hg), temperature (98.8°F), capillary refill time (<3 s), and oxygen saturation (97%) were normal except for tachycardia (168/min). At admission, baby's weight, length, and head circumference were 3.21 kg (<3rd percentile), 50 cm (3rd percentile), and 34.5 cm (3rd percentile), respectively. Respiratory, cardiac, and neurological examinations were normal. No abdominal distension, hepatosplenomegaly, rigidity, or guarding was noted. Neonatal sepsis was suspected and antibiotics were started after sepsis work up. During routine sampling, the resident observed the lipaemic nature of the blood sample [Figure 1]. In addition to sepsis screen, triglyceride (TG) level was also requested. Laboratory parameters for sepsis including CRP and blood culture were negative. Kidney function (urea – 34 mg/dL, creatinine –0.60 mg/dL, sodium – 139 meq/dL, potassium – 4.7 meq/dL), liver function (total bilirubin – 1.6 mg/dL, SGPT – 26, SGOT –34, total protein – 5.7 mg/dL, albumin – 3.8 mg/dL), blood sugar (99 mg/dL), and thyroid function (FT4-1.25 ng/dL, TSH – 1.97 μU/mL) tests were normal. Investigations show high-serum triglycerides (10,300 mg/dL) and elevated serum lipase (517 IU/L, Normal <8 IU/L). Hemogram showed hemoglobin of 26 g%; WBC of 6,570/μL with 45% neutrophils, 46% lymphocytes, and 2% monocytes; and platelet count of 457,000/μl. Lipemia retinalis was noted on funduscopy [Figure 2]. Abdominal ultrasonography was normal. In view of high-serum triglycerides and lipase levels, LPL deficiency with acute pancreatitis was suspected. Lipid profile of father showed high LDL level (cholesterol – 164 mg/dL, high density lipoprotein (HDL) cholesterol – 32 mg/dL, triglycerides – 144 mg/dL, very low density lipoprotein (VLDL) – 29 mg/dL, low density lipoprotein (LDL) –103 mg/dL), whereas mother's cholesterol as well as LDL levels were high (cholesterol – 200 mg/dL, HDL cholesterol – 35 mg/dL, triglycerides – 145 mg/dL, VLDL – 29 mg/dL, LDL – 136 mg/dL).
To confirm the diagnosis, DNA genome sequencing revealed a novel homozygous missense variation at nucleotide position 478 (c. 478C>T) in exon 4 of the LPL gene (chr8:19810869; C>T; depth: 96×) that resulted in amino acid substitution of phenylalanine for leucine at codon 160 (p. Leu160Phe; ENST00000311322). The Leu160Phe variant was present in lipase domain of the protein and has not been reported in both the 1,000 genomes and ExAC databases.
Treatment in our patient included dietary modification consisting restriction of fat intake and pharmacological intervention with Gemfibrozil (20 mg/kg twice daily) along with addition of medium chain triglyceride (MCT) oil and multivitamins. Expressed breast milk was centrifuged at 3,000 rpm for 15 min at room temperature and supernatant, which mainly contains fat, was removed. Lipid profile on day 3 of admission showed triglycerides of 4,760 mg/dL, cholesterol of 433 mg/dL, HDL cholesterol of 88 mg/dL, and VLDL of 952 mg/dL. triglycerides (TGs) further reduced to 1,782 mg/dL on day 9 of treatment. Hemoglobin and serum lipase level also normalized. After discussion and counseling, the baby was started on a skimmed milk powder besides MCT oil (1 mL, every 6 hourly mixed with feeds) and multivitamins and discharged home. In last follow-up at 2 months of age, the infant was growing between 3rd and 15th percentile (weight, length, and head circumference) as per World Health Organization's growth chart. No eruptive xanthomas or hepatosplenomegaly was noted on clinical examination. The recent TG level was 872 mg/dL. The infant is followed up in high-risk clinic every month for growth and development assessment besides monitoring for any side effects of the drug therapy.
LPL deficiency (MIM 238600) is a rare autosomal recessive disorder of lipoprotein metabolism characterized by elevated TG levels and an increased risk of recurrent pancreatitis. LPL deficiency commonly manifests during childhood with 25% of cases occurring during infancy, where neonatal presentation is rare.
Lipemic blood points to chylomicronemia syndrome, of which LPL deficiency is just one possible diagnosis. High clinical suspicion is necessary to diagnose neonatal pancreatitis as typical symptoms like abdominal pain, vomiting, ileus, dehydration seen in older children are not common. Although LPL deficiency is an important primary cause of chylomicronemia, ApoC-II deficiency and circulating LPL inhibitor result in a clinical and biochemical phenotype similar to LPL deficiency. Acquired chylomicronemia may be caused by hypothyroidism, renal failure, or diabetes mellitus.
Upto 40% of children with acute pancreatitis may have normal amylase levels. Studies have observed elevated lipase in 100% infants, whereas raised amylase was seen in only 60% infants with acute pancreatitis, attributing it to developmental differences in the expression of the pancreatic enzymes during the first few months of life. Also, lipase estimation has less interference than amylase in a lipemic blood sample.,
Our patient also has high hemoglobin value at admission that can be because of the interference of markedly elevated TGs in automated Coulter results, thus necessitating special precautions while interpreting such results.
Other commonly used diagnostic investigations in adults include ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance cholangio-pancreatography (MRCP). The distribution of echogenicity on US in pancreatitis and size of pancreas is age dependent, thus not useful in infants. CT, MRI, or MRCP is not preferred in neonates because of radiation exposure, technical feasibility, and sedation.
Definitive diagnosis of LPL deficiency requires either a post-heparin plasma LPL assay or DNA analysis of the LPL or APOC2 genes. The available enzyme assays have limitations for the determination of LPL activity as far as the sensitivity and substrate stability are concerned. Molecular analysis is becoming the most applied diagnostic method and nearly 100 disease-causing LPL mutations have been reported. Most LPL deficiency-causing mutations are missense, although nonsense, deletion, insertion, splicing, and other mutations have been reported.
Although functional studies or enzyme activity estimation could not be done because of limited availability and cost factor, the variant identified in our patient (Leu160Phe) is a novel variant and was present in lipase domain of LPL protein. Missense mutations in this domain are associated with loss of catalytic activity of LPL enzyme. In our case, since we have identified the gene defect, prenatal diagnosis in subsequent pregnancy is possible as each sibling has 25% chance of being affected.
There are no clinical guidelines available for the treatment of LPL deficiency-induced neonatal hyperlipidemia with acute pancreatitis; hence, appropriate treatment was a challenge. The most effective treatment is dietary modification by restricting fat intake to 10–15% of recommended dietary allowance, aiming at providing 110–120 kcal/kg of energy by adjusting carbohydrate and protein content. Pharmacological agents are required to maintain TG level <2,000 mg/dL to prevent risk of pancreatitis, if dietary measures fail to control hypertriglyceridemia. Lipid-lowering medications, such as statins, fibrates, and niacin, are generally ineffective in patients with LPL deficiency. Gemfibrozil has been used for the treatment and also has a potential to prevent episodes of acute pancreatitis.,
Hyperchylomicronemia-induced recurrent pancreatitis occurs when triglyceride level exceeds 2,000 mg/dL leading to pancreatic insufficiency, which is the major complication of this disease. We started dietary and gemfibrozil therapy simultaneously as TG levels were very high (>10,000 mg/dL). Baby is on regular follow-up for growth and development assessment and is closely monitored for any adverse effects due to gemfibrozil.
Neonates may not manifest with typical symptoms and signs of pancreatitis as in this case. We recommend biomarkers especially lipase for diagnosing pancreatitis in at risk neonates as radiological investigations may be either normal or not feasible. Gemfibrozil can be safely used in neonates with severe hypertriglyceridemia due to LPL deficiency.
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[Figure 1], [Figure 2]