SAT-088 A Novel Mutation In The Leptin Receptor Associated With Hypertriglyceridemia, Lipodystrophy And Non-alcoholic Fatty Liver

Background  Leptin is an adipocyte-derived peptide hormone that acts in the hypothalamus to stimulate pathways that inhibit feeding and promote energy expenditure. Mutations in the gene encoding leptin or its receptor (LR) are rare and typically lead to extreme obesity. We describe a patient who presented with severe hypertriglyceridemia, non-alcoholic fatty liver (NAFL) and a clinical phenotype of partial lipodystrophy, who upon whole exome sequencing harbored a novel homozygous mutation in the Ig domain of the LR. Clinical case A 45-year-old woman with a past medical history of hypertension presented with abdominal pain and was diagnosed with hypertriglyceridemic pancreatitis. She denied alcohol or recreational drug use. Her BMI was 26 kg/m(2), BP 167/109 mmHg, HR 106, and she had prominent central obesity with a paucity of adipose tissue on the extremities and gluteal region. Triglycerides (Tg) were 2,076 mg/dl, lipase 366 u/l, A1c of 6.0%, ALT 70 u/l, AST 27 u/l. Proteinuria was present, but serum and urine protein electrophoreses were normal. Abdominal CT was suggestive of liver steatosis and pancreatitis. Given her lipodystrophic features, elevated Tg, and fatty liver, we performed whole exome sequencing which revealed a novel homozygous mutation in the leptin receptor (p.S389N) that is predicted to be deleterious. Compared to other reported cases with LR mutations, our patient did not report excessive appetite and denied frequent childhood infections. Further workup showed low fasting leptin, 4.2 ng/ml (8.0-38.9 ng/ml for women with BMI 25-30s), fasting glucose of 114mg/dl and insulin of 21 ulU/ml. IGF-I was 141 ng/ml, FSH 4.6 mIU/mL, LH 3.8 U/ml, estradiol 60 pg/Ml, free testosterone 2.1 pg/ml, TSH 2.67 mlu/l, fT4 1.3ng/dl. Her family history was significant for pancreatitis in mother and maternal grandfather, nonalcoholic steatohepatitis (NASH) in her 14-year-old son and liver problems in her sister, but so far, no other members have been tested for the mutation. She was treated with fenofibrate for hypertriglyceridemia with subsequent decrease of Tg levels to 503 mg/dl. Conclusion Our case is unique in that our patient’s clinical features are less severe in comparison to those reported with other LR mutations. Given that this is a novel homozygous mutation in the Ig region of the LR, and it is predicted to be deleterious, it is still unclear how it relates to her lipodystrophic features and overall clinical presentation. This case highlights the gap in knowledge and the diversity in clinical presentations that may accompany LR mutations and would have been missed if it were not for whole exome sequencing. At the same time, this case raises questions regarding the role of the leptin in hypertriglyceridemia, NASH and NAFL, and to what degree emerging therapies for leptin deficiency can prevent the progression of NASH and NAFL disease, since currently there are no clear therapeutic guidelines.