Ever since its discovery by Windhaus, the importance of the active metabolite of vitamin D (1,25-dihydroxyvitamin D₃; 1,25-(OH)2D₃) has been ever expanding. In this review, the attention is shifted towards the importance of the extra-skeletal effects of vitamin D, with special emphasis on the immune system. The first hint of the significant role of vitamin D on the immune system was made by the discovery of the presence of the vitamin D receptor on almost all cells of the immune system. In vitro, the overwhelming effect of supra-physiological doses of vitamin D on the individual components of the immune system is very clear. Despite these promising pre-clinical results, the translation of the in vitro observations to solid clinical effects has mostly failed. Nevertheless, the evidence of a link between vitamin D deficiency and adverse outcomes is overwhelming and clearly points towards avoidance of vitamin D deficiency especially in early life.

Congenital generalized lipodystrophy (CGL) is a rare disorder marked by near-total loss of adipose tissue and severe metabolic disturbances due to leptin deficiency and the inability to store nutrients in adipose tissue effectively. Metreleptin is the only approved leptin replacement therapy for this condition. Here we present the >20-year follow-up of two sisters with CGL type 1 (AGPAT2 deficiency, OMIM# 608594), enrolled in early metreleptin trials. Clinical outcomes, adherence, immunogenicity, and pregnancies were assessed. Both cases showed rapid and sustained metabolic improvement after metreleptin initiation, allowing insulin discontinuation and triglyceride normalization. Menstrual cycles resumed within six months; allowing both to carry successful pregnancies while continuing metreleptin. Both cases experienced reduced treatment adherence over time, linked to psychological distress. One case developed both anti-drug antibodies and neutralizing activity through immune based assay after 14 years, but without significant clinical impact. In conclusion, these cases highlight both the sustained metabolic benefits of therapy and the complex challenges that may arise over time, such as antibody formation and difficulties in maintaining long-term adherence. Documentation of unmet medical needs can provide guidance and impetus for improved therapeutic approaches to achieve optimum quality of life.