Question

A 2-year-old with bowed legs did not improve after vitamin D supplementation. Investigations reveal: phosphate low, calcium normal, ALP elevated. What is the most likely diagnosis?

• A. Nutritional rickets
• B. Hypophosphatemic rickets
• C. Vitamin D-dependent rickets
• D. Renal tubular acidosis

Hint:

Biochemical Patterns in Rickets:
$\bullet$ Nutritional Rickets: Calcium $\downarrow$ or Normal, Phosphate $\downarrow$, ALP $\uparrow\uparrow$, PTH $\uparrow\uparrow$, $25(\text{OH})\text{D} \downarrow$.
$\bullet$ Hypophosphatemic Rickets: Calcium Normal, Phosphate $\downarrow\downarrow$, ALP $\uparrow\uparrow$, PTH Normal, $1,25(\text{OH})_2\text{D}$ Inappropriately Normal/Low (Gene: PHEX $\rightarrow \uparrow$ FGF-23).

Answer 1

The Correct Option is B

Concept:
Rickets is a disorder of defective mineralization of the growth plate cartilage and newly formed osteoid matrix in growing children.
Refractoriness to standard nutritional doses of Vitamin D (ergocalciferol/cholecalciferol) defines Vitamin D-resistant rickets, the most common form of which is X-Linked Hypophosphatemic Rickets (XLHR).
Explanation:
• X-Linked Hypophosphatemic Rickets (XLHR): Caused by inactivating mutations in the PHEX gene (Phosphate-regulating endopeptidase homolog, X-linked) on chromosome Xp22.1.

• Loss of PHEX function causes pathological overexpression and elevated circulating levels of Fibroblast Growth Factor 23 (FGF-23), a potent phosphaturic hormone secreted by osteocytes.

• Elevated FGF-23 exerts two distinct actions in the renal proximal tubule:
1. Downregulates sodium-phosphate cotransporters (NaPi-IIa and NaPi-IIc), leading to severe renal phosphate wasting and profound hypophosphatemia.
2. Inhibits renal $1\alpha$-hydroxylase (CYP27B1), suppressing the conversion of $25(\text{OH})\text{D}$ to $1,25(\text{OH})_2\text{D}$, resulting in inappropriately low/normal calcitriol levels.

• Classic biochemical profile: Normal serum Calcium, Low serum Phosphate, Markedly Elevated Alkaline Phosphatase (ALP), and normal or mildly elevated PTH.

• Clinically, children present in the second year of life as weight-bearing begins with progressive lower-limb deformities (severe genu varum bowing), waddling gait, and disproportionate short stature that fails to respond to native vitamin D.

• Treatment involves oral phosphate solutions combined with active vitamin D (calcitriol), or the monoclonal anti-FGF23 antibody Burosumab.
Final Answer:
The failure to respond to vitamin D along with the biochemical combination of low phosphate, normal calcium, and elevated alkaline phosphatase confirms Hypophosphatemic Rickets.