Familial partial lipodystrophy type 3 associated with PPARG mutation: diagnostic challenge in an adolescent with severe insulin resistance

Abstract

Familial partial lipodystrophy type 3 (FPLD3) is a rare genetic disorder associated with heterozygous mutations in the PPARG gene, leading to impaired adipogenesis and adipose tissue dysfunction, which result in marked insulin resistance and a severe cardiometabolic phenotype. We report the case of a female patient with a history of precocious puberty and a family history of severe hypertriglyceridemia, who was followed since childhood for metabolic abnormalities. During adolescence, she developed progressive dysglycemia and diabetes mellitus (DM) with significant metabolic decompensation, preserved C-peptide levels, and negative pancreatic autoantibodies, ruling out an autoimmune etiology. The clinical course was characterized by unstable glycemic control, with variable and subsequently high insulin requirements, persistent hypertriglyceridemia, and limited therapeutic response. Genetic testing identified a pathogenic heterozygous variant in PPARG, confirming the diagnosis of FPLD3. Body composition assessment by dual-energy X-ray absorptiometry (DXA) demonstrated abnormal adipose tissue distribution consistent with partial lipodystrophy. This case highlights the importance of considering FPLD3 as a cause of severe insulin resistance and underscores the value of early etiological diagnosis to optimize multidisciplinary follow-up, guide therapeutic strategies, and provide family genetic counseling, aiming to reduce the progression of long-term cardiometabolic complications.