Clinical heterogeneity and disease progression during adolescence in AGPAT2-associated congenital generalized lipodystrophy: a case series of four patients.

Abstract

Objectives: This case series describes the clinical presentation and longitudinal course of four adolescents with genetically confirmed AGPAT2-associated congenital generalized lipodystrophy (CGL) followed at a pediatric lipodystrophy center.

Case presentation: Despite shared phenotypic features - including generalized lipoatrophy, muscular hypertrophy, acromegaloid features, and hyperphagia - metabolic severity varied markedly, even between siblings carrying the same homozygous AGPAT2 variant. All three female patients experienced rapid metabolic deterioration during puberty, developing insulin resistance, diabetes, and severe hypertriglyceridemia, while the male patient remained relatively metabolically stable. Three patients developed progressive albuminuria during adolescence, and two required ACE inhibitor therapy for hypertension, highlighting early renal involvement independent of diabetes. Metreleptin therapy led to substantial metabolic improvement in all treated patients, with normalization of glycemic control, triglyceride levels, and liver enzymes, as well as reduced hyperphagia and, in one case, spontaneous menarche. However, metabolic decompensation occurred during acute illness in one patient, necessitating treatment escalation, indicating that metreleptin does not fully protect against metabolic stress. Notably, pronounced daytime fatigue persisted in three patients despite metabolic stabilization, suggesting an underrecognized, potentially central component of the disease.

Conclusions: These findings underscore the phenotypic variability of AGPAT2-associated CGL, the critical impact of puberty - especially in females - the frequent early onset of nephropathy, and the partial but incomplete response to leptin replacement. Close monitoring during adolescence and individualized management are essential.