Insulin-Resistant Diabetes Associated With a Novel POLD1 Variant of Uncertain Significance in a Pediatric Patient.

Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by pathogenic variants in the POLD1 gene and characterized by progressive lipodystrophy and severe metabolic complications. We report an eight-year-old Saudi male presenting with atypical, insulin-resistant diabetes, acanthosis nigricans, and preserved C-peptide levels, raising suspicion for a syndromic form of diabetes. Genetic testing revealed a heterozygous variant of uncertain significance (VUS) in POLD1. Notably, the patient lacked classical features of MDPL, including overt lipodystrophy, mandibular hypoplasia, and hearing loss, posing a diagnostic challenge. Although the patient's phenotype showed partial overlap with reported POLD1-related disorders, the available evidence was insufficient to establish a definitive molecular diagnosis. Early recognition of atypical presentations of severe insulin resistance is crucial for appropriate evaluation, surveillance, and genetic counseling. Further functional studies and long-term follow-up are required to clarify the pathogenicity of the identified variant and its clinical implications.