Bone and Radiologic Findings in Congenital Generalized Lipodystrophy: A Systematic Review and Report of 60 Cases

Congenital Generalized Lipodystrophy (CGL), usually caused by pathogenic variants in AGPAT2 (CGL1) and BSCL2 (CGL2), is characterized by near-total loss of subcutaneous adipose tissue, low leptin levels and severe metabolic and systemic comorbidities. Skeletal abnormalities including diffuse sclerosis, lytic-appearing bone lesions, and high bone mineral density have been recognized in CGL, but the prevalence and clinical and radiological features of these bone phenotypes remain ill-defined. The aim of this single-institution case series and systematic review was to evaluate bone manifestations and radiological findings associated with CGL1 and CGL2. Data sources were PubMed, Scopus, Embase, CINAHL Plus, Global Index Medicus, Web of Science: Core, National Institutes of Health medical records. Articles were screened utilizing a dual reviewer process in Covidence. Included publications reported primary bone and radiologic findings in patients with CGL1 or CGL2. Two reviewers extracted data using REDCap and assessed risk of bias. 43 articles were included in the review, presenting 214 cases of CGL (90 CGL1, 81 CGL2, and 43 genetics not reported). Data from NIH patients was extracted by retrospective chart review. The NIH cohort had 60 CGL patients (40 CGL1, 20 CGL2). Skeletal imaging included radiographs, MRI, CT, and NaF PET scans. In the literature and NIH cases, respectively, diffuse osteosclerosis was reported in 37% and 39%, lytic-appearing lesions in 64% and 53%, and high bone mineral density in 68% and 43%. Individuals with CGL1 and CGL2 present with distinct and heterogeneous bone phenotypes including lytic-appearing lesions primarily affecting long bones, diffuse osteosclerosis, and high bone mineral density. These bone manifestations are often overlooked despite high prevalence and clinical relevance. Potential mechanisms include increased differentiation of bone marrow mesenchymal cells into osteocytes and effects of increased insulin or decreased leptin signaling.