Pathophysiology of Different Types of Rickets.

Rickets is characterized by defective mineralization of the growth plates due to impaired calcium or phosphate metabolism. The underlying pathophysiology varies depending on the etiology

1. Nutritional Rickets
   Cause: Deficiency of vitamin D, calcium, or phosphorus due to inadequate intake or sun exposure.
   Pathophysiology:
   • Vitamin D Deficiency → Decreased intestinal calcium absorption.
   • Low Serum Calcium → Secondary hyperparathyroidism (↑PTH).
   • Increased PTH → Renal phosphate wasting (hypophosphatemia).
   • Hypophosphatemia & Low Calcium → Poor bone mineralization → Rickets.
2. Vitamin D-Dependent Rickets Type 1 (VDDR1, Pseudovitamin D Deficiency Rickets)
   Cause: Autosomal recessive defect in CYP27B1 gene (1α-hydroxylase deficiency).
   Pathophysiology:
   • Deficient 1α-hydroxylase → Impaired conversion of 25(OH)D to 1,25(OH)₂D.
   • Low 1,25(OH)₂D → Poor intestinal calcium absorption → Hypocalcemia.
   • Hypocalcemia → Secondary hyperparathyroidism → Renal phosphate loss → Hypophosphatemia.
   • Low Calcium & Phosphorus → Defective bone mineralization → Rickets.
3. Vitamin D-Dependent Rickets Type 2 (VDDR2, Hereditary Vitamin D-Resistant Rickets, HVDRR)
   Cause: Mutation in vitamin D receptor (VDR), leading to end-organ resistance to 1,25(OH)₂D.
   Pathophysiology:
   • Defective VDR → Impaired response to 1,25(OH)₂D, even with high levels.
   • Poor Calcium Absorption → Hypocalcemia → Secondary hyperparathyroidism.
   • Renal Phosphate Wasting → Hypophosphatemia.
   • Severe Bone Mineralization Defects → Alopecia (in severe cases).
4. X-Linked Hypophosphatemic Rickets (XLH)
   Cause: Mutation in PHEX gene, leading to increased fibroblast growth factor 23 (FGF23) activity.
   Pathophysiology:
   • Increased FGF23 → Renal phosphate wasting → Hypophosphatemia.
   • Suppression of 1α-hydroxylase → Low 1,25(OH)₂D levels.
   • Poor Phosphate Availability → Defective mineralization → Rickets.
   • Normal PTH & Calcium (Unlike vitamin D-related rickets).
5. Autosomal Dominant Hypophosphatemic Rickets (ADHR)
   Cause: Gain-of-function mutation in FGF23, leading to excessive phosphate loss.
   Pathophysiology:
   • FGF23 Overactivity → Renal phosphate wasting → Hypophosphatemia.
   • Decreased 1,25(OH)₂D → Impaired calcium absorption.
   • Poor Bone Mineralization → Rickets.
6. Hereditary Hypophosphatasia (HPP)
   Cause: Mutation in ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP).
   Pathophysiology:
   • Deficient TNSALP → Impaired breakdown of pyrophosphate.
   • Increased Pyrophosphate → Inhibition of hydroxyapatite formation.
   • Defective Bone & Teeth Mineralization → Rickets, fractures, and premature tooth loss.
7. Renal Tubular Acidosis (RTA) & Rickets
   Cause: Defective renal acid handling leading to chronic acidosis.
   Pathophysiology:
   • Chronic Acidosis → Bone buffering (release of calcium & phosphate).
   • Hypophosphatemia & Hypocalcemia → Defective mineralization.
   • Type 1 (Distal) & Type 2 (Proximal) RTA → Renal phosphate wasting.
   • Metabolic Acidosis → Direct inhibition of bone mineralization → Rickets.
8. Chronic Kidney Disease (CKD)-Associated Rickets (Renal Osteodystrophy)
   Cause: Reduced renal function leading to abnormal calcium-phosphorus metabolism.
   Pathophysiology:
   • Reduced 1,25(OH)₂D Synthesis → Poor calcium absorption → Hypocalcemia.
   • Secondary Hyperparathyroidism → Renal phosphate wasting.
   • Hypophosphatemia & Low Calcium → Bone demineralization → Rickets