ESPE Abstracts

Background: Hereditary vitamin D resistant rickets (HVDRR) or vitamin-D dependent rickets type II is an autosomal recessive disorder caused by mutations in the vitamin D receptor (VDR) gene, causing end-organ resistance to the action of 1,25-dihydroxyvitamin D (calcitriol), thus resulting in the distinct characteristics of early-onset rickets, hypocalcemia, and secondary hyperparathyroidism. The currently accepted treatment modality is bypassing the affected receptor with high dose intravenous calcium, however, the calcimimetic cinacalcet has been used as an adjunctive therapy in a few limited case reports.

Methods: This case series describes the clinical presentation (phenotype), biochemical profiles, genetic mutations, and management of eight Saudi patients with HVDRR. Retrospective chart reviews were conducted to collect clinical and biochemical data prior to and after treatment, and genetic analysis to identify the disease-causing mutation was carried out.

Results: Eight patients, including two sets of siblings (three patients were brothers and two were sisters), were reviewed. Universal among the group were the findings of alopecia, hypocalcemia, elevated alkaline phosphatase, and secondary hyperparathyroidism. There was heterogeneity in the presence of skeletal signs of rickets at diagnosis, a finding which varied with age at diagnosis. Genetic analysis revealed three distinct mutations: first, a mutation in the ligand binding domain at exon 8:c.886C>A:p.Y295X in two unrelated patients; this resulted in a slightly milder phenotype as one patient was able to maintain normocalcemia on oral calcium alone, second, a truncating ligand binding mutation at exon 6:c.1035T>Cp.Y>X in two sisters, and third, a homozygous missense mutation of the DNA binding domain at exon 1:c.88C>T in three brothers. This DNA binding domain mutation resulted in a more severe phenotype than the two ligand binding domain mutations. All patients responded well to the current standard therapy of intermittent high dose intravenous calcium, as shown by the normalization of hypocalcemia, improvement in PTH levels, and, clinically, the ability to achieve independent mobilization. Additionally, four patients received adjunctive cinacalcet, the use of which, in our series, was safe (no episodes of hypocalcemia) and showed some initial promise in improving secondary hyperparathyroidism.