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0 min readIntroduction
Vitamin D resistant rickets, now more accurately termed hypophosphatemic rickets, refers to a group of rare genetic disorders characterized by impaired phosphate reabsorption in the kidneys, leading to low serum phosphate levels and subsequent skeletal abnormalities despite adequate vitamin D status. Unlike nutritional rickets caused by vitamin D deficiency, these conditions involve defects in phosphate homeostasis. The condition manifests in infancy or early childhood with features of rickets, including growth retardation, bone pain, and skeletal deformities. Understanding the underlying genetic basis is crucial for accurate diagnosis and management.
Types of Vitamin D Resistant Rickets
There are several genetic forms of hypophosphatemic rickets, each with a distinct underlying cause:
1. X-linked Hypophosphatemia (XLH)
- Genetics: Caused by mutations in the PHEX gene located on the X chromosome. This gene encodes for phosphate-regulating endopeptidase homolog X-linked, which regulates fibroblast growth factor 23 (FGF23).
- Pathophysiology: Mutations in PHEX lead to increased FGF23 levels. FGF23 inhibits phosphate reabsorption in the proximal renal tubules and reduces intestinal calcium absorption, resulting in hypophosphatemia.
- Clinical Features: Typically presents in infancy with bowed legs, growth retardation, and dental abnormalities.
- Inheritance: X-linked dominant, affecting males more severely than females.
2. Autosomal Recessive Hypophosphatemia (ARHR)
- Genetics: Caused by mutations in genes encoding sodium-phosphate cotransporters (NaPi-IIa or NaPi-IIc) in the proximal renal tubules. SLC34A1 (NaPi-IIa) and SLC34A3 (NaPi-IIc) are the most commonly affected genes.
- Pathophysiology: Mutations disrupt phosphate reabsorption in the kidneys, leading to hypophosphatemia.
- Clinical Features: Similar to XLH, but often presents later in childhood.
- Inheritance: Autosomal recessive, requiring both parents to be carriers.
3. Vitamin D Receptor (VDR) Abnormalities (Hereditary Vitamin D-Resistant Rickets - VDDR Type I)
- Genetics: Mutations in the VDR gene, which encodes the vitamin D receptor.
- Pathophysiology: Impaired ability of target tissues to respond to vitamin D, leading to decreased calcium absorption and secondary hyperparathyroidism.
- Clinical Features: Presents with rickets despite normal or elevated vitamin D levels.
- Inheritance: Autosomal recessive.
4. Other rarer forms
- Hypophosphatasia: Deficiency of tissue-nonspecific alkaline phosphatase (TNSALP)
- Autosomal dominant hypophosphatemic rickets (ADHR): Mutations in FGF23
Diagnosis
Diagnosis involves a combination of clinical evaluation, biochemical tests, and genetic testing:
- Biochemical Tests: Low serum phosphate, normal or elevated serum calcium, elevated alkaline phosphatase, and normal 25-hydroxyvitamin D levels.
- Urine Phosphate Excretion: Increased tubular reabsorption of phosphate (TRP) in XLH and ARHR.
- Genetic Testing: Confirms the specific genetic defect.
- Radiological Findings: Characteristic radiographic features of rickets, including widening of the growth plates and bone demineralization.
Management
The primary goal of treatment is to increase serum phosphate levels and improve skeletal mineralization:
- Phosphate Supplementation: Oral phosphate supplements are the mainstay of treatment.
- Active Vitamin D Analogues: Calcitriol (1,25-dihydroxyvitamin D3) or alfacalcidol are used to enhance intestinal calcium absorption.
- FGF23 Inhibitors: Monoclonal antibodies against FGF23 (burosumab) are a newer treatment option for XLH, approved by the FDA in 2018.
- Orthopedic Management: Surgical correction of skeletal deformities may be necessary in severe cases.
| Feature | XLH | ARHR | VDDR Type I |
|---|---|---|---|
| Gene | PHEX | SLC34A1/SLC34A3 | VDR |
| Inheritance | X-linked dominant | Autosomal recessive | Autosomal recessive |
| FGF23 Levels | Elevated | Normal | Normal |
| Vitamin D Levels | Normal | Normal | Normal/Elevated |
Conclusion
Vitamin D resistant rickets encompasses a spectrum of rare genetic disorders characterized by impaired phosphate homeostasis. Accurate diagnosis, based on clinical features, biochemical tests, and genetic analysis, is crucial for initiating appropriate treatment. While phosphate supplementation and active vitamin D analogues remain the cornerstone of management, newer therapies like burosumab offer promising alternatives, particularly for XLH. Early intervention and multidisciplinary care are essential to optimize growth and prevent long-term skeletal complications.
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