Tooth development associated with mutations in hereditary vitamin D–resistant rickets

Hereditary vitamin D–resistant rickets (HVDRR) is a rare genetic disorder caused by mutations at the level of the vitamin D receptor (VDR) gene. The disease is characterized by refractory hypocalcemia, elevated serum levels of 1,25-dihydroxy-vitamin D, retarded growth, sparse body hair (sometimes alopecia), premature tooth loss, enlarged pulp chambers, thin dentine, and hypoplastic enamel. The aims of this study were 1) to document the dental development of children with HVDRR in association with the mutation type within the VDR and 2) to evaluate the association between dental development and the timing of and response to HVDRR treatment. Genome analysis was performed for 4 affected children (2 y 2 mo to 6 y 8 mo) under treatment with high doses of vitamin D and calcium. Longitudinal records of clinical and radiographic data on their dental development were assessed in relation to genetic profile and response to treatment. Treatment success depended on the position of the mutation within the VDR protein: children with the p.R391S mutation had a favorable outcome but maintained alopecia totalis, while 1 child with the p.H397P mutation and normal hair had no response to very high doses of vitamin D. The primary incisors, formed prenatally and first to emerge, were missing in 3 children and mobile in 1 child; parents reported loss within months posteruption. Posterior teeth were present, having erupted after treatment initiation. Hypoplastic enamel in emerging teeth was associated with late treatment onset. Mutation type in the VDR gene appears to be related to differences in the disease phenotype and response to treatment. Dental development represents an indicator of the disease process, initially protected by maternal blood levels of calcium and later restored by therapeutic supplies that normalize these levels. Knowledge Transfer Statement: Two novel mutations were associated with different HVDRR phenotypes, one of which responded positively to treatment. Early detection of the mutation should help pediatricians forecast treatment protocol and response. The results also highlight the direct relationship between dental development and blood calcium levels, underscoring the importance of early diagnosis and treatment of HVDRR to minimize the loss of primary teeth and reduce structural abnormalities of permanent teeth.