Genetic analysis and effect of triiodothyronine and prednisone trial on bone turnover in a patient with craniotubular hyperostosis

Craniotubular hyperostosis are a group of high bone mass disorders related to mutations in the LRP5 and SOST genes, although other causative genes remain to be identified. Little is known about the bone turnover and the response to T3 or glucocorticoids in these patients. We describe a patient with craniotubular hyperostosis, including mutation analyses of the LRP5, SOST, DKK1 and KRM1 genes. We also studied bone turnover and bone mineral density (BMD), before and after a trial with T3 (75 µg/d for 28 weeks) and T3 and prednisone (T3 100 µg/d for 2 weeks, followed by 10 weeks on prednisone 10 mg/d, and a final 2 weeks period off of medicactions, completing 3 cycles in 42 weeks. Mutation analysis of the complete coding region and flanking highly conserved sequences of SOST, evaluation of the presence of the 52-kb deletion associated with Van Buchem disease in Dutch patients and mutation analysis of exons 2–4 of LRP5, and the coding regions of DKK1 and KRM1 did not reveal any disease-causing mutations. A baseline 5 to 7 fold increase in osteocalcin and in deoxypiridinoline was detected. After 4 weeks on 75 µg/d of T3, osteocalcin decreased 36%, but at week 28, it returned to basal. Deoxypiridinoline did not change. After the first cycle on T3 and prednisone, osteocalcin decreased 72%, and at the end of the third cycle it remained 44% below basal value. Deoxypiridinoline was stable and high during the three cycles; no changes in BMD were observed. As we failed to identify any disease-causing mutations in our patient with craniotubular hyperostosis, we suggest that another gene must be involved in the pathogenesis of his condition. This study provides additional data about the high bone turnover described in craniotubular hyperostosis, and also suggests an abnormal response to T3 excess in this condition.