What causes vitamin D dependent rickets?

January 6, 2026 •

4 min read

Affecting fewer than 1 in 200,000 children, vitamin D dependent rickets (VDDR) is a rare genetic disorder of bone development. Unlike nutritional rickets, it is not caused by a simple lack of vitamin D in the diet but rather by inherited defects that disrupt the body's ability to properly use the vitamin.

Quick Summary

This rare genetic condition is caused by inherited mutations affecting the body's ability to activate or properly respond to vitamin D. This disruption leads to impaired calcium absorption and the resulting bone weakening characteristic of rickets.

Key Points

Genetic Mutations: The core cause of vitamin D dependent rickets (VDDR) is inherited mutations in genes that control vitamin D metabolism or function.
VDDR Type 1: This type results from mutations (CYP27B1 or CYP2R1) that impair the enzymes needed to convert inactive vitamin D into its active form, calcitriol.
VDDR Type 2: Caused by mutations in the VDR gene, this type involves a defective vitamin D receptor, leading to resistance to calcitriol, even when levels are high.
Resistance vs. Deficiency: VDDR is a resistance or processing problem, not a simple dietary lack of vitamin D, and does not respond to standard vitamin D supplementation alone.
Alopecia and VDR: Hair loss (alopecia) is often a distinguishing feature in VDDR Type 2A, reflecting the importance of the vitamin D receptor in hair follicle development.
Importance of Diagnosis: Correctly identifying the genetic cause through specialized testing is critical for effective management, as treatments differ significantly from those for nutritional rickets.

Vitamin D is an essential nutrient for the body, primarily known for its role in helping the body absorb calcium and phosphorus, which are critical for building and maintaining strong bones. In healthy individuals, vitamin D is synthesized in the skin from sunlight exposure and can also be obtained from certain foods. This vitamin undergoes a two-step activation process in the liver and kidneys to become its potent, biologically active form, calcitriol. This molecule then binds to a vitamin D receptor (VDR) to regulate gene activity for proper calcium and phosphate levels. However, in individuals with vitamin D dependent rickets (VDDR), this complex process is interrupted by specific genetic mutations.

The Genetic Causes of Vitamin D Dependent Rickets

VDDR is classified into different types based on the specific genetic mutation that causes the impairment in the vitamin D pathway. The disease is typically inherited in an autosomal recessive pattern, meaning an individual must inherit a mutated gene from both parents to be affected.

VDDR Type 1A: A Defect in Activation

This form, also known as pseudo-vitamin D deficiency rickets, results from mutations in the CYP27B1 gene. This gene provides the instructions for producing the enzyme 1-alpha-hydroxylase, which is primarily active in the kidneys.

Enzyme Deficiency: The mutation impairs the activity of the 1-alpha-hydroxylase enzyme, preventing the conversion of 25-hydroxyvitamin D (the inactive form) into the active form, calcitriol.
Biochemical Profile: Affected individuals typically have normal or high levels of the inactive 25-hydroxyvitamin D but abnormally low levels of the active calcitriol.

VDDR Type 1B: A Problem with 25-Hydroxylation

This is a rarer form caused by mutations in the CYP2R1 gene, which instructs the body to make the enzyme 25-hydroxylase.

Initial Step Failure: The mutated enzyme prevents the initial conversion of vitamin D into 25-hydroxyvitamin D, the precursor to the active form.
Metabolite Levels: Patients with VDDR Type 1B show very low levels of 25-hydroxyvitamin D.

VDDR Type 2A: Resistance to Vitamin D

Also called hereditary vitamin D-resistant rickets, this type is caused by mutations in the VDR gene.

Receptor Resistance: The mutation alters the vitamin D receptor (VDR), making target organs resistant to the active form of vitamin D, even when calcitriol levels are high. The VDR cannot properly interact with calcitriol or the DNA it is meant to regulate.
Associated Alopecia: A significant portion of individuals with VDDR Type 2A experience partial or total hair loss (alopecia).

Emerging Causes: VDDR Type 3

A recently identified, extremely rare form of VDDR (sometimes referred to as VDDR Type 3) is caused by a gain-of-function mutation in the CYP3A4 gene.

Accelerated Inactivation: This specific mutation results in an enzyme with enhanced activity that leads to the accelerated breakdown and inactivation of vitamin D metabolites.
Clinical Presentation: This leads to functional vitamin D deficiency due to a different mechanism than the other VDDR types.

Comparison of VDDR Types


Feature	VDDR Type 1A	VDDR Type 1B	VDDR Type 2A	VDDR Type 3
Cause	Mutation in CYP27B1 gene	Mutation in CYP2R1 gene	Mutation in VDR gene	Gain-of-function mutation in CYP3A4
Mechanism	Impaired 1-alpha-hydroxylase enzyme; cannot activate vitamin D fully	Impaired 25-hydroxylase enzyme; cannot perform initial activation step	Defective vitamin D receptor (VDR); target organs are resistant to calcitriol	Accelerated inactivation of vitamin D metabolites
Calcitriol Levels	Abnormally low	Low to normal levels	Abnormally high	Abnormally low
25(OH)D Levels	Normal to high	Abnormally low or undetectable	Normal	Abnormally low
Alopecia	Not typically present	Not typically present	Often present	Not a reported feature
Inheritance	Autosomal recessive	Autosomal recessive	Autosomal recessive (or rarely dominant)	Autosomal dominant (de novo)

Clinical Manifestations and Treatment

The signs of VDDR typically appear within the first year of life and are often indistinguishable from severe nutritional rickets. These include poor growth, muscle weakness (hypotonia), bone pain, and skeletal deformities such as bowed legs, widened wrists, and enlarged costochondral junctions (rachitic rosary). In severe cases, low blood calcium (hypocalcemia) can cause muscle cramps and seizures.

Diagnosis involves a combination of clinical evaluation, biochemical tests, and genetic analysis to pinpoint the underlying mutation. It's crucial to differentiate VDDR from nutritional rickets because the treatment strategies are significantly different. A genetic diagnosis provides important information for guiding treatment and genetic counseling for the family.

Treatment aims to restore normal mineral homeostasis and can be complex, often requiring management by a pediatric endocrinologist.

VDDR Type 1: Since the body cannot produce sufficient active vitamin D, treatment involves lifelong supplementation with calcitriol (the active form). In some cases, high doses of calcium may also be necessary.
VDDR Type 2: Because the body is resistant to calcitriol, very high doses of oral calcitriol and calcium are often required. In severe, non-responsive cases, high-dose intravenous calcium infusions may be necessary to correct hypocalcemia and promote bone mineralization.

For more in-depth medical information on VDDR, you can consult sources such as the National Institutes of Health.

Conclusion

Vitamin D dependent rickets is a rare but serious genetic disorder that undermines the body's ability to maintain bone health by interfering with the activation or reception of vitamin D. Instead of a simple nutritional deficiency, the root cause lies in specific genetic mutations affecting enzymes like 1-alpha-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), or the vitamin D receptor (VDR), or in rare cases, accelerated inactivation via CYP3A4. Early and accurate genetic diagnosis is paramount to distinguish VDDR from nutritional rickets and implement the correct, specialized treatment plan. Without proper management, the condition can lead to severe and progressive skeletal deformities. Continued research into these genetic pathways offers promise for improving diagnostic tools and developing more effective, targeted therapies for affected individuals.

Frequently Asked Questions

No. While both conditions lead to softened bones and can look similar, nutritional rickets is caused by a lack of vitamin D from diet or sunlight. Vitamin D dependent rickets (VDDR) is caused by rare genetic mutations that prevent the body from properly processing or responding to vitamin D.

The main difference is the point of failure in the vitamin D pathway. Type 1 is a deficiency of active vitamin D caused by faulty activating enzymes. Type 2 is a resistance to active vitamin D caused by a defective vitamin D receptor, leading to high levels of active vitamin D that the body cannot use.

As VDDR is a genetic disorder, it cannot be cured. However, it can be effectively managed with lifelong specialized treatments, such as high-dose calcitriol and/or calcium supplementation, to promote normal growth and prevent bone deformities.

Hair loss, or alopecia, is a characteristic feature of VDDR Type 2A, which involves mutations in the VDR gene. This occurs because the vitamin D receptor is also involved in the normal hair growth cycle, a process that is disrupted by the genetic mutation.

Genetic testing is often necessary to confirm the specific type of VDDR and rule out other forms of rickets. This is especially important for cases that do not respond to standard vitamin D therapy, as the correct diagnosis guides the specialized treatment plan.

Symptoms typically appear in infancy and include skeletal deformities such as bowed legs, bone pain, delayed growth, muscle weakness, and in severe cases, seizures caused by low blood calcium.

Yes, research has identified a very rare VDDR Type 3, caused by a gain-of-function mutation in the CYP3A4 gene. This mutation leads to an accelerated breakdown of vitamin D metabolites, creating a functional deficiency.