SUN-748 - Unmasking Vitamin D-Dependent Rickets Type 1A in Adulthood after Decades of Misclassified Disease

Vitamin D-dependent rickets type 1A (VDDR1A) is an exceptionally rare autosomal-recessive disorder caused by pathogenic CYP27B1 mutations that impair renal 1α-hydroxylase activity and disrupt 1,25-dihydroxyvitamin D synthesis. Although its biochemical profile is distinctive, clinical overlap with more common rickets forms often leads to diagnostic delays, particularly when patients initially appear to respond only partially or transiently to conventional therapy. We report a striking case of a woman diagnosed throughout childhood with “vitamin D-resistant rickets” who, despite classical clinical features, only achieved definitive molecular confirmation of VDDR1A in adulthood after years of fragmented and inconclusive evaluation. She presented in infancy with motor delay, hypotonia, wrist widening, short stature, and progressive genu varum requiring eight corrective orthopedic surgeries, reflecting the extensive skeletal morbidity that accumulated during untreated enzymatic deficiency. Adult evaluation revealed persistent short stature and a biochemical pattern highly suggestive of hereditary rickets, with markedly elevated alkaline phosphatase and parathyroid hormone levels, hypocalcemia, hypophosphatemia, low urinary calcium and phosphorus, and normal 25-hydroxyvitamin D concentrations. Genetic testing finally identified a homozygous CYP27B1 p.Thr325Met missense mutation, a pathogenic variant known to result in absent enzymatic activity and described as extremely rare in large genomic datasets, emphasizing the exceptional nature of this presentation. This long-delayed molecular clarification enabled targeted treatment with calcitriol combined with calcium and phosphate supplementation, yielding clinical stability, biochemical improvement, and prevention of additional deformities, although irreversible skeletal sequelae persisted after decades of misclassified disease. This case is notable not only for its severe phenotype and diagnostic delay but also for the exceptional rarity of the p.Thr325Met mutation, underscoring the critical need for heightened clinical suspicion and early genetic testing in atypical, refractory, or discordant presentations of rickets. Disseminating such cases is essential to improve recognition of rare CYP27B1 variants, reduce diagnostic latency, prevent avoidable morbidity, and refine clinician awareness of hereditary rickets worldwide.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*