Expanding the Spectrum of Vitamin D-Dependent Ricket Type 2: Dominant-Negative VDR Mutation and Postpubertal Calcium Adaptation
https://doi.org/10.15605/jafes.041.S1
- Author:
Mohd Hazriq Awang
1
;
Shireene Ratna Vethakkan
2
;
Ooi Ying Guat
2
;
Tharsini Sarvanandan
2
Author Information
1. Endocrine Unit, University Malaya Medical Centre (UMMC);Medical Faculty, Universiti Teknologi MARA (UiTM)
2. Endocrine Unit, University Malaya Medical Centre (UMMC)
- Publication Type:Journal Article
- MeSH:
Calcium;
Mutation;
Vitamin D;
Rickets
- From:
Journal of the ASEAN Federation of Endocrine Societies
2026;41(S1):70-
- CountryPhilippines
- Language:English
-
Abstract:
Introduction:Vitamin D-dependent rickets type 2 (VDDR2) is traditionally defined by biallelic vitamin D receptor (VDR) mutations
causing resistance to 1,25(OH)₂D. We describe a case of the
classical VDDR2 phenotype with a single VDR mutation
and an interesting physiological adaptation.
Case:A female diagnosed with rickets at age three presented with
a femoral fracture, severe short stature, hypocalcemia (2.1
mmol/L; NR 2.35–2.70), hypophosphatemia (0.8 mmol/L;
NR 1.5–2.10), and evidence of renal phosphate wasting
(TMP/GFR 0.5 mmol/L; NR 1.5–2.4). Biochemistry showed
markedly elevated alkaline phosphatase (1,227 IU/L; NR
50–136) and secondary hyperparathyroidism (20.7 pmol/L;
NR 0.8–7.8). Despite hypocalcemia, 1,25(OH)₂D was
significantly elevated (>450 pmol/L; NR 60–150), consistent
with VDDR2. There was no initial family history; however,
subsequent evaluation of her mother—prompted by the
patient’s diagnosis—revealed a similar biochemical profile,
along with short stature (142 cm) and a history of multiple
fractures. Genetic analysis in both individuals identified a heterozygous missense mutation in exon 10 of the VDR
gene, affecting the ligand-binding domain, supporting a
pattern of dominant inheritance. The patient was treated
with cholecalciferol (1,200 IU daily), calcitriol (5–6 µg
daily), and calcium carbonate (2,000 mg daily). Although
biochemical responsiveness to therapy was evident,
poor adherence resulted in suboptimal metabolic control
throughout childhood and adolescence, including a second
fracture at age 15 and a final adult height of 124 cm. Notably,
calcium and phosphate levels progressively normalized
after puberty, with sustained biochemical stability despite
the patient omitting the treatment.
Conclusion:This case provides two important insights. First, it represents the fourth reported case worldwide demonstrating
a dominant-negative effect of a VDR gene mutation,
whereby a single mutant receptor interferes with wildtype VDR function. Second, it highlights postpubertal
calcium adaptation, in which vitamin D–independent
intestinal absorption may restore mineral homeostasis, and
disease severity can attenuate over time through adaptive
physiological mechanisms.
- Full text:2026080317173978216EP_A092.pdf
