Rickets affects an estimated 1 in 200,000 children. The condition is most often caused by a lack of vitamin D in the diet or insufficient sun exposure rather than genetic mutations. Genetic forms of rickets, including vitamin D-dependent rickets, are much less common. The prevalence of the different types of vitamin D-dependent rickets is unknown. VDDR1A is more common in the French Canadian population than in other populations.

Each type of vitamin D-dependent rickets has a different genetic cause: VDDR1A is caused by CYP27B1 gene mutations, VDDR1B is caused by CYP2R1 gene mutations, and VDDR2A is caused by VDR gene mutations. The genetic cause of VDDR2B is unknown. These genes are involved in the body's response to vitamin D, an important vitamin that can be acquired from foods in the diet or made by the body with the help of sunlight exposure. Vitamin D helps maintain the proper balance of several minerals in the body, including calcium and phosphate. These minerals are needed for many functions, including the breakdown of substances (metabolic processes), signaling between cells, and the deposition of minerals in developing bones (bone mineralization). One of vitamin D's major roles is to control the absorption of calcium and phosphate from the intestines into the bloodstream.

The CYP2R1 gene provides instructions for making an enzyme called 25-hydroxylase, and the CYP27B1 gene provides instructions for making an enzyme called 1-alpha-hydroxylase (1α-hydroxylase). These enzymes carry out the reactions that convert vitamin D to its active form, calcitriol. Once converted, calcitriol attaches (binds) to a protein called vitamin D receptor (VDR), which is produced from the VDR gene. The resulting calcitriol-VDR complex then binds to particular regions of DNA and regulates the activity of vitamin D-responsive genes. By turning these genes on or off, the calcitriol-VDR complex helps control the absorption of calcium and phosphate and other processes that regulate calcium levels in the body. The VDR protein is also involved in hair growth through a process that does not require calcitriol binding.

Mutations in any of these genes prevent the body from responding to vitamin D. CYP2R1 and CYP27B1 gene mutations reduce or eliminate the activity of the respective enzyme, which means vitamin D is not converted to its active form. The absence of calcitriol means vitamin D-responsive genes are not turned on (activated). VDR gene mutations alter the vitamin D receptor, often preventing the receptor from interacting with calcitriol or with DNA. As a result VDR cannot regulate gene activity, even with normal amounts of calcitriol in the body.

Without activation of vitamin D-responsive genes, absorption of calcium and phosphate falls, leading to hypocalcemia and hypophosphatemia. The lack of calcium and phosphate slows bone mineralization, which leads to soft, weak bones and other features of vitamin D-dependent rickets. Low levels of calcium stimulate production of PTH, resulting in secondary hyperparathyroidism. Hypocalcemia can also cause muscle weakness and seizures in individuals with vitamin D-dependent rickets. Certain abnormalities in the VDR protein also impair hair growth, causing alopecia in some people with VDDR2A.