Increased bone density associated with DLX3 mutation in the tricho-dento-osseous syndrome

Tricho-dento-osseous syndrome (TDO) (OMIM #190320) is an autosomal dominant disorder characterized and named for the three most commonly affected tissues hair, teeth, and bones. Common to all individuals with TDO studied to date is a four base-pair deletion in the DLX3 gene on chromosome 17q21. This mutation is associated with a variable bone phenotype that includes alteration in intramembranous bone formation in the skull. The purpose of this study was to characterize and compare endochondral bone phenotypes and variability at central and peripheral locations of the skeleton by evaluating bone density in individuals having the same DLX3, 4 bp DEL,NT3198 mutation (OMIM 600525) and non-affected family members using dual-energy x-ray absorptiometry (DEXA). Thirty-four individuals (20 TDO-affected and 14 non-affected) participated in this prospective study. All participants were evaluated for the DLX3 mutation associated with TDO. All subjects received DEXA scans at common, literature-supported osteoporotic test regions including: (1) non-dominant distal radius/ulna, (2) femoral neck, and (3) lumbar spine L2–4. There was a significant increase (P< 0.05) in bone mineral density in TDO-affected individuals compared with control individuals at each test region. The markedly increased bone density in individuals having the DLX3, 4 bp DEL,NT3198 mutation shows that this alteration affects both endochondral and intramembranous bone formation and suggests that the DLX3 gene is important in bone formation and/or homeostasis of the appendicular skeleton.