Severe triglyceridaemia in PPAR-gamma mutations: uncommon cause often overlooked

Raya Almazrouei, Ben Jones, Sara Haboosh, Jaimini Cegla, Shivani Misra, Imperial College Healthcare NHS Trust, London, UK.

Case: A 28-year-old woman was found to have severe hypertriglyceridemia (63 mmol/l) after presenting with a skin rash consistent with eruptive xanthoma. She had been diagnosed with type 2 diabetes 18 months previously, was managed with metformin and had a history of hypertension, treated with ramipril and amlodipine. Her deceased father had multiple cardiovascular events in his 50ís. She had 13 half siblings (paternal side) of whom three had developed diabetes in their 40s. On examination, her BMI was 24.9 kg/m2. Blood results demonstrated hypercholesteroalemia (total Cholesterol 19.4 mmol/L), sub-optimally controlled diabetes (HbA1c 84 mmol/mol) and normal thyroid function.

Lipid Management: Acutely, variable rate intravenous insulin was commenced and a low-fat diet implemented. She was discharged on basal insulin, metformin, atorvastatin, ezetimibe and fenofibrate along. At follow-up, ApoE genotyping revealed zero copies of ApoE2 and her carotid US was normal.† She was referred to the non-classical diabetes clinic due to lack of clarity around her diabetes diagnosis.


Diabetes assessment: Lipodystrophic features were noted subsequently with central obesity but marked loss of subcutaneous fat in the distal limbs along with calf muscle hypertrophy. Following dramatic changes in lifestyle and weight loss, the patient had stopped insulin and her HbA1c was 35 mmol/mol off all diabetes treatments. Triglycerides were 0.97mmol/L on statin monotherapy. Based on the observed phenotype, genetic testing for familial partial lipodystrophy (FPL) was undertaken and a heterozygous PPAR-gamma mutation (Val318Met) was identified.

Discussion; PPAR-gamma mutations causing FPL type 3, are usually autosomal dominant and typically present in the second decade of life. Unlike lamin A mutations (a more common cause of FPL), mutations in PPAR-gamma present more frequently with lipid abnormalities, hypertension and diabetes may be a late feature. The high doses of insulin associated with severe insulin resistance syndromes are late features of these conditions and practitioners should be alert to the earlier metabolic presentations and clinical features, such that a genetic diagnosis can be made earlier and the high cardiovascular risk can be managed promptly.