Inherited Rickets: The Different Genetic Causes

Rickets is a condition where children’s bones soften and weaken, leading to growth issues and bone deformities. While most rickets cases are due to vitamin D deficiency or poor nutrition, a subset is inherited rickets—caused by genetic changes affecting how the body processes vitamin D, phosphate or bone minerals. This guide explains the main genetic types, their causes, and what families can expect.

How Bones Normally Stay Strong

Bones rely on:

• Calcium and phosphate: Build the mineral matrix.
• Vitamin D (activated form): Helps absorb calcium and phosphate from food.
• Hormones (PTH, FGF23): Regulate mineral balance.

In inherited rickets, one or more steps in this system go awry because of gene mutations.

Main Types of Inherited Rickets

1. Vitamin D–Dependent Rickets Type 1A (VDDR1A)

   • Cause: Mutations in the CYP27B1 gene prevent conversion of vitamin D into its active form (calcitriol).
   • Effect: Low calcitriol means poor calcium absorption, leading to weak bones.
   • Inheritance: Autosomal recessive (both parents carry one altered gene).

2. Vitamin D–Dependent Rickets Type 1B (VDDR1B)

   • Cause: Mutations in CYP2R1, the gene for an enzyme that begins vitamin D activation in the liver.
   • Effect: Reduced 25-hydroxyvitamin D levels and downstream calcitriol shortage.
   • Inheritance: Autosomal recessive.

3. Vitamin D–Dependent Rickets Type 2A (VDDR2A)

   • Cause: Mutations in the vitamin D receptor gene (VDR), so tissues can’t respond to active vitamin D.
   • Effect: Even if vitamin D levels are normal, the body acts as if it’s deficient.
   • Features: Often accompanied by hair loss (alopecia).
   • Inheritance: Autosomal recessive.

4. Vitamin D–Dependent Rickets Type 2B (VDDR2B)

   • Cause: Rare mutations affecting proteins that regulate the vitamin D receptor.
   • Effect: Similar to VDDR2A but without VDR gene changes.
   • Inheritance: Autosomal recessive or dominant, depending on the exact mutation.

5. X-Linked Hypophosphatemic Rickets (XLH)

   • Cause: Mutations in the PHEX gene on the X chromosome increase levels of FGF23, a hormone that wastes phosphate in urine.
   • Effect: Chronic low phosphate leads to weak, bowed bones and dental issues.
   • Inheritance: X-linked dominant (affected mothers or fathers pass the gene to children).

6. Autosomal Dominant Hypophosphatemic Rickets (ADHR)

   • Cause: Mutations in FGF23 make it more resistant to breakdown, raising its levels.
   • Effect: Like XLH, bones lack phosphate and become soft.
   • Inheritance: Autosomal dominant (only one altered gene needed).

7. Autosomal Recessive Hypophosphatemic Rickets (ARHR)

   • Subtypes:
     • ARHR1 (DMP1 gene mutations)
     • ARHR2 (ENPP1 gene mutations)
   • Effect: Both lead to elevated FGF23 or other phosphate-wasting mechanisms.
   • Inheritance: Autosomal recessive.

8. Other Rare Forms

   • For example, Raine syndrome (FAM20C mutations) and hereditary hypophosphatemic rickets with hypercalciuria (SLC34A3 mutations) are very uncommon but important causes.

Symptoms and Signs

Inherited rickets often shows up in early childhood, typically before age 2–3. Common features include:

• Delayed walking or waddling gait
• Bowed legs (genu varum) or knock knees (genu valgum)
• Slow growth and short stature
• Bone pain or tenderness
• Dental problems (delayed tooth eruption, cavities)
• Muscle weakness
• In VDDR2A, patchy hair loss (alopecia)

Severity varies by type and individual. Some children have mild symptoms; others require lifelong treatment.

How Inherited Rickets Is Diagnosed

1. Clinical Examination

   • Check growth charts, bone deformities and muscle tone.

2. Blood Tests

   • Calcium, phosphate, alkaline phosphatase, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and FGF23 levels.

3. Urine Tests

   • Assess phosphate excretion.

4. Genetic Testing

   • Confirms the exact mutation and type of inherited rickets.
   • Helps guide treatment and informs family planning.

5. X-rays

   • Show classic signs: widened growth plates, bowing of long bones and pseudofractures.

If you’re unsure whether your child’s symptoms fit inherited rickets, consider a free, online symptom check, using the doctor approved Ubie Symptom Checker.

Treatment Strategies

Inherited rickets requires tailored therapies based on the underlying cause:

Vitamin D–Dependent Rickets (Types 1 & 2)

• VDDR1A & VDDR1B: High-dose calcitriol (active vitamin D) plus oral calcium.
• VDDR2A & 2B: Often needs very high doses of calcitriol and calcium; some may require intravenous calcium if severe.

Hypophosphatemic Rickets (XLH, ADHR, ARHR)

• Oral phosphate supplements divided throughout the day.
• Active vitamin D analogs (calcitriol or alfacalcidol) to promote bone mineralization.
• For XLH: Burosumab, a monoclonal antibody against FGF23, can help normalize phosphate levels and improve growth.

Other Considerations

• Orthopedic surgery may correct severe bone deformities.
• Physical therapy strengthens muscles and improves mobility.
• Dental care addresses enamel defects and cavities.

Regular monitoring of blood tests and growth is vital. Treatment side effects—like high calcium levels or kidney stones—require ongoing medical supervision.

Living with Inherited Rickets

• Early diagnosis and consistent treatment often lead to good outcomes.
• Many children reach near-normal height and bone strength with modern therapies.
• Psychosocial support: connecting with patient groups reduces isolation.
• Genetic counseling helps families understand inheritance patterns and future risks.

When to Seek Medical Advice

Inherited rickets can range from mild to serious. Always talk to a doctor if your child has:

• Persistent bone pain or muscle weakness
• Noticeable leg bowing or delayed walking
• Growth that falls off established percentiles
• Unexplained dental problems

If you experience symptoms that worry you or could be life threatening, please speak to a doctor right away.

Key Takeaways

• Inherited rickets are genetic disorders disrupting vitamin D, phosphate or bone mineral metabolism.
• Major types include VDDR1A/1B, VDDR2A/2B, XLH, ADHR and ARHR.
• Symptoms appear in early childhood: bowed legs, slow growth, bone pain and dental issues.
• Diagnosis relies on blood tests, genetic testing and X-rays.
• Treatment is lifelong: active vitamin D, phosphate supplements, burosumab (for XLH) and supportive therapies.
• Early intervention improves outcomes; genetic counseling supports families.

Recognizing inherited rickets early and working closely with a pediatric endocrinologist or metabolic bone specialist offers the best chance for normal growth and bone health. Whether you suspect mild or severe symptoms, don’t hesitate to explore a free, online symptom check, using the doctor approved Ubie Symptom Checker, and follow up with your healthcare provider. If you have concerns that could be serious or life threatening, always speak to a doctor.