Clinical and genetic findings in a Chinese family with VDR-associated hereditary vitamin D-resistant rickets

Abstract

Hereditary vitamin D-resistant rickets (HVDRR) is a rare autosomal recessive disorder characterized by severe rickets, hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated alkaline phosphatase. This disorder is caused by homogeneous or heterogeneous mutations affecting the function of the vitamin D receptor (VDR), which lead to complete or partial target organ resistance to the action of 1,25-dihydroxy vitamin D. A non-consanguineous family of Chinese Han origin with one affected individual demonstrating HVDRR was recruited, with the proband evaluated clinically, biochemically and radiographically. To identify the presence of mutations in the VDR gene, all the exons and exon–intron junctions of the VDR gene from all family members were amplified using PCR and sequenced. The proband showed rickets, progressive alopecia, hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated alkaline phosphatase. She also suffered from epilepsy, which is rarely seen in patients with HVDRR. Direct sequencing analysis revealed a homozygous missense mutation c.122G>A (p.C41Y) in the VDR gene of the proband, which is located in the first zinc finger of the DNA-binding domain. Both parents had a normal phenotype and were found to be heterozygous for this mutation. We report a Chinese Han family with one individual affected with HVDRR. A homozygous missense mutation c.122G>A (p.C41Y) in the VDR gene was found to be responsible for the patient’s syndrome. In contrast to the results of treatment of HVDRR in other patients, our patient responded well to a supplement of oral calcium and a low dose of calcitriol.

Hereditary diseases: Vitamin D and bone formation

Hereditary vitamin D-resistant rickets (HVDRR) has been diagnosed in a patient with weak bone formation, near-total hair loss, and epilepsy. Although 45 different causative mutations have been identified globally, this is only the second case reported in a patient of Han Chinese descent. HVDRR is a rare hereditary disorder caused by mutation of the vitamin D receptor gene (VDR); patients’ cells cannot respond to vitamin D, which is essential for incorporating calcium into healthy bones. Weibo Xia at the Peking Union Medical College Hospital and colleagues in China identified a mutation in the DNA-binding region of VDR responsible for the patient’s symptoms. Remarkably, the patient’s condition improved following low doses of oral vitamin D and calcium. The authors hypothesize that this response is estrogen-dependent, and that this treatment may help other female adolescents with HVDRR.

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