VDR – Vitamin D-dependent rickets, type 2

Hereditary vitamin D-dependent rickets type II (HVDRR) is an autosomal recessive disorder caused by biallelic variants in the vitamin D receptor gene. Patients present in infancy with severe rickets, hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, elevated serum 1,25-dihydroxyvitamin D, and often total alopecia. The condition results from end-organ resistance to 1,25(OH)₂D₃ despite normal vitamin D metabolism. Diagnosis relies on genetic testing of VDR and functional assays in skin fibroblasts or lymphocytes. Management includes high-dose oral or intravenous calcium and, in select cases, vitamin D analogs or calcimimetics to bypass receptor defects. Early recognition and molecular confirmation guide therapy and genetic counseling.

Genetic Evidence

VDDR II is inherited in an autosomal recessive pattern with over 100 affected individuals reported from more than 30 unrelated families worldwide. Segregation analyses demonstrate fully penetrant disease in homozygotes or compound heterozygotes and carrier status in parents with elevated 1,25-dihydroxyvitamin D without rickets (PMID:16424674). More than 80 unique VDR variants have been described, including missense substitutions, nonsense and frameshift mutations, splice-site changes, and in-frame deletions (PMID:8796143; PMID:9495519). A recurrent founder allele (c.88C>T (p.Arg30Ter)) truncates the DNA-binding domain and abolishes receptor function (PMID:9495519). Biallelic splice-site mutations (e.g., c.462+1G>C) and exon skipping events further support loss-of-function etiology (PMID:8796143).

Functional Evidence

In vitro studies of patient-derived fibroblasts reveal absent or severely reduced [³H]1,25(OH)₂D₃ binding, defective nuclear localization, and failure to induce CYP24A1 expression (PMID:15308610). Transactivation assays in CV-1 and COS-7 cells show that mutant VDRs (e.g., p.Glu420Lys, p.Ile268Thr) have diminished ligand affinity, impaired RXR heterodimerization, and disrupted coactivator interactions (PMID:12403843; PMID:15308610). Phosphorylation studies identify Ser51 as critical for maximal transactivation, linking PKC signaling to VDR function (PMID:1656468). Structural analyses of H305Q and Y143F/S278A variants confirm altered ligand-binding domain conformation that reduces hormone sensitivity.

Rescue and Therapeutic Insights

Pharmacological enhancement of residual VDR activity has been demonstrated using hexafluoro 1,25(OH)₂D₃ analogs and modulation of phosphorylation pathways. Co-treatment with okadaic acid partially restores transactivation of F251C, I268T, and H305Q mutants by enhancing coactivator recruitment (PMID:16059639). Protease-sensitive assays show improved stability of I268T variants with 20-epi-1,25(OH)₂D₃, suggesting tailored analog therapy. Cinacalcet has emerged as an adjunctive option to control secondary hyperparathyroidism in refractory cases.

Conflicting Evidence and Alternative Mechanisms

A subset of patients displays classical HVDRR without detectable VDR coding mutations. One case exhibited normal VDR sequence but defective nuclear import resulting in 1,25(OH)₂D₃ resistance, implicating noncoding or trafficking defects (PMID:8287584). These findings highlight potential regulatory or post-translational mechanisms contributing to tissue resistance.

Conclusion

The association between VDR loss-of-function variants and vitamin D-dependent rickets type II is definitive, supported by extensive genetic and functional data. Molecular diagnosis enables precision management, informs reproductive risk, and guides emerging therapies targeting residual receptor function. Key take-home: Genetic testing of VDR is essential for accurate diagnosis and therapeutic stratification in HVDRR.

References

• Clinical endocrinology • 1993 • Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene. PMID:8287584
• Clinical endocrinology • 1996 • Identification of a novel mutation in hereditary vitamin D resistant rickets causing exon skipping. PMID:8796143
• Journal of bone and mineral research • 1998 • Hereditary 1,25-dihydroxyvitamin D-resistant rickets due to an opal mutation causing premature termination of the vitamin D receptor. PMID:9495519
• Molecular endocrinology • 2002 • A novel mutation in helix 12 of the vitamin D receptor impairs coactivator interaction and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. PMID:12403843
• Endocrinology • 2004 • Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function. PMID:15308610
• Journal of bone and mineral research • 2005 • Enhanced coactivator binding and transcriptional activation of mutant vitamin D receptors from patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets by phosphorylation and vitamin D analogs. PMID:16059639

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