Clinical and genetic characterization of a patient with vitamin D-dependent rickets type 1A: results from long-term follow-up

Abstract Background Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by mutations in CYP27B1 , leading to disrupted calcium – phosphate homeostasis, with consequent skeletal deformities and growth retardation. Evidence regarding long-term disease outcomes and optimal monitoring strategies remains limited. This study aimed to characterize the longitudinal clinical course and biochemical dynamics in VDDR1A and evaluate their potential relevance for disease monitoring. Methods A 2-year-2-month-old girl presenting with growth retardation, skeletal deformities, and hypocalcemia underwent comprehensive clinical, biochemical, and radiological evaluation. Whole-exome sequencing with Sanger validation was performed. Individualized treatment with calcitriol and calcium supplementation was administered, with 28 months of longitudinal follow-up. Results A compound heterozygous variant combination in CYP27B1 (c.580G>T and c.1442delA) was identified. Early treatment led to rapid symptom resolution, restoration of independent walking, correction of skeletal deformities, and catch-up growth (height from − 4 SD to -2.3 SD). Biochemical abnormalities normalized within one year, with radiographic improvement by Month 10. Hypercalcemia first emerged at Month 19 and progressed despite stepwise reduction of calcium supplementation and calcitriol. At Month 23, nephrocalcinosis and hypercalciuria were identified, prompting temporary calcitriol withdrawal and treatment of hypercalcemia. Five months after calcitriol withdrawal, recurrent bone pain developed. Notably, biochemical alterations preceded symptom recurrence, with ALP and PTH increasing earlier and more prominently than calcium or phosphate. As early as two months after withdrawal, ALP and PTH had increased (185.1% and 297.2%, respectively) despite normal calcium or phosphate levels. By five months, these increases were more pronounced (274% and 1885%), while calcium and phosphate showed only modest declines (35.0% and 23.2%). Conclusions This study reports a previously unreported compound heterozygous CYP27B1 genotype and provides detailed 28-month longitudinal treatment data. Long-term follow-up highlights both therapeutic benefit and the need for careful monitoring of treatment-related complications in VDDR1A. ALP and PTH increased before recurrent bone pain while serum calcium and phosphate remained within their reference ranges, suggesting their potential value as complementary biochemical indicators during longitudinal monitoring.