Quantification of TDO associated phenotypes and DLX3 c.571-574delGGGG mutation

Objectives: Tricho-dento-osseous syndrome (TDO), a rare syndrome caused by mutations in the DLX3 homeobox gene, is characterized by enamel hypoplasia, taurodontism, curly hair, and increased bone density. Here we study these variably expressed phenotypic features in a sample of families from North Carolina, Virginia, and Tennessee segregating for the TDO trait. Methods: Data was collected from 105 individuals (61 affected, 44 unaffected) on (i) Bone density t-scores standardized by gender and age for the total body, forearm, wrist, hip, and spine; (ii) tooth morphology: crown body (CB)/ root (R), length, and enamel (E)/ width (W) for first and second permanent molars; and (iii) levels of bone alkaline phosphatase (BAP), osteocalcin (OC), and n-telopeptide (standardized by creatinine; NTx/Cre), as indicators of bone formation and reabsorption. Welch two sample t-tests for equality of means were conducted after grouping individuals by TDO status (+, -). Results: Difference in means for TDO+/-, for the total body, wrist, hip, and spine bone density t-scores, is highly significant (p-values <<0.00001). Mean CB/R for teeth 19 and 30 is significantly larger for TDO+ (<0.005), confirming taurodontism in that group. Further, these two teeth show significantly smaller mean length (<=.006). Thin enamel in TDO+ is supported by significantly low E/W for teeth 18 and 19 (0.048, 0.038). While difference in mean BAP, OC, and NTx/Cre in TDO+/- is not significant, it approaches significance for OC (0.078). Conclusion: Results of this study provide quantitative evidence of taurodontism, decreased enamel thickness, and increased bone density in TDO affected individuals. Although multiple bone marker levels are not significantly different, the role of age and/or gender as potential confounders remains to be explored. Quantification of the TDO associated phenotypes will allow further characterization of individuals having the DLX3 4G delete or other DLX3 mutations. NIH grant # R01-DE015196.