25-Hydroxylase Deficiency Clinical Features
I cannot provide a definitive answer about the clinical features of 25-hydroxylase deficiency because this specific enzyme deficiency is not adequately described in the provided evidence, which focuses primarily on 1α-hydroxylase deficiency (vitamin D-dependent rickets type 1) and general vitamin D metabolism disorders.
What the Evidence Actually Addresses
The provided guidelines and research discuss:
- 1α-hydroxylase deficiency (VDDR-I): A well-characterized disorder caused by mutations in CYP27B1, preventing conversion of 25(OH)D to active 1,25(OH)₂D 1, 2, 3
- General vitamin D deficiency: From inadequate sun exposure, malabsorption, or dietary insufficiency 4, 5
- X-linked hypophosphatemia (XLH): A distinct phosphate-wasting disorder with rickets 6
Theoretical Clinical Presentation of 25-Hydroxylase Deficiency
If 25-hydroxylase (hepatic enzyme converting vitamin D to 25(OH)D) were deficient, the expected biochemical pattern would include:
- Low serum 25(OH)D levels despite adequate vitamin D intake or sun exposure
- Low or low-normal 1,25(OH)₂D levels (due to lack of substrate)
- Hypocalcemia and hypophosphatemia
- Secondary hyperparathyroidism 6
Expected Skeletal Manifestations
Based on vitamin D deficiency rickets patterns 6:
- In infants and children: Delayed walking, waddling gait, progressive lower limb deformities (varus or valgus deformity), widening of distal metaphyses at wrists and ankles, rachitic rosary (prominent costochondral junctions), Harrison's groove (horizontal thoracic indentation), dolichocephaly with frontal bossing 6
- Radiographic findings: Cupped and flared metaphyses, widened irregular growth plates, preferentially affecting sites of rapid growth (distal femora, tibiae, radii) 6
- In adults: Short stature, osteomalacia, bone pain, pseudofractures, muscle weakness, increased fracture risk 6
Distinguishing Feature
The key diagnostic distinction would be failure to respond to standard vitamin D₂ or D₃ supplementation (since the conversion step is blocked), but dramatic response to 25(OH)D (calcifediol) supplementation 6, 7. One case report describes a patient with apparent 25-hydroxylase deficiency who had low-normal 25(OH)D despite massive vitamin D₂ doses (17.5 mg/day) but responded to 25(OH)D₃ at 20-50 mcg/day 7.
Critical Caveat
True isolated 25-hydroxylase deficiency is extremely rare or possibly non-existent as a recognized clinical entity in the medical literature. The case described 7 suggested dual abnormalities including both impaired 25-hydroxylation and end-organ resistance. Most rickets/osteomalacia cases result from nutritional deficiency, malabsorption, 1α-hydroxylase deficiency, or vitamin D receptor mutations 1, 2.