The Tissues Affected By TDO
Detailed clinical characterization of individuals with TDO (confirmed DLX3 gene mutation) from multiple families show marked variability in the hair, tooth and bone phenotype.

Hair: Hair abnormalities associated with TDO is present in most but not all of the individuals having TDO. Kinky, course and/or curly hair is present at birth in 80% of people with TDO. Only 46% of the individuals with TDO and kinky, course and/or curly hair at birth retain this phenotype after infancy.

Taurodontism: Taurodontism is an enlargement of the pulp chamber in posterior teeth due to the apical displacement of the furcation area that normally begins the separation of the multiple root structures. The degree of taurodontism and the distribution of teeth affected are highly variable. In some individuals there is severe taurodontism of all the posterior teeth with the anterior teeth showing enlarged pulp chambers (Figure 2). Both primary and permanent teeth are typically affected. Mild expression of this trait in a few affected individuals includes having little or no evidence of taurodontism in the first permanent molars with the second permanent molars showing pyramidal root morphology.

Figure2

Bone: Changes in the cranial bones is observed in 93% of individuals with TDO. The majority of affected family members display an increased cranial thickness, obliterated diploë and no visible mastoid pneumatization. The loss of visible mastoid pneumatization is the most common osseous feature seen in affected individuals (82%) and is relatively uncommon in unaffected people (8%). Skeletal manifestations can be seen in affected individuals as young as 3 years of age. There is a trend for skeletal manifestations to become more prevalent in older individuals. Diploë obliteration appears to increase with age. However, 95% of people with TDO that are 16 years of age or younger show some skeletal manifestations. Figure 3 shows a normal cephalometric radiograph (a) with normal bone density and the variably increased bone density in the heads of two middle age females that have TDO.

Gene Defect That Causes TDO
Numerous homeobox genes are known to be expressed during craniofacial development and are considered to be essential for normal morphological development and patterning. The distal-less (DLX) homeobox genes are expressed in both epithelial and mesenchymal craniofacial tissues during embryogenesis.5, 6 The specific role of these genes in controlling the complex growth and development pathways remains to be defined. Analysis of multiple families in North Carolina and one large family in Virginia revealed that the TDO phenotype was associated with a four base pair deletion in the DLX3 homeobox gene.7-9 This deletion results in a frameshift of the 3’ terminal portion of DLX3 and a termination codon at nucleotide 3398. The mutation results in a DLX3 translation product that is 32 amino acids shorter than the normal protein.

DLX3 DNA Sequence:

1 ATGAGCGGCT CCTTCGATCG CAAGCTCAGC AGCATCCTCA CCGACATCTC CAGCTCGCTC
61 AGCTGCCATG CGGGCTCCAA GGACTCGCCC ACCCTGCCCG AATCTACAGT CACTGACCTG
121 GGCTATTACA GCGCTCCTCA GCATGACTAC TACTCGGGCC AGCCCTACGG CCAGACGGTG
181 AACCCCTACA CCTACCACCA CCAGTTCAAT CTCAATGGGC TCGCAGGCAC CGGCGCTTAC
241 TCGCCCAAGT CGGAATATAC CTACGGGGGA TCCTATAGGC AGTACGGAGC GTACCGGGAG
301 CAGCCTTTGC CTGCCCAGGA CCCAGTGTCG GTGAAAGAGG AGCCGGAAGC CGAGGTTCGC
361 ATGGTGAACG GCAAGCCCAA AAAGGTCCGA AAGCCGCGAA CGATCTACTC CAGCTATCAG
421 CTGGCTGCCC TGCAGCGCCG TTTCCAGAAA GCCCAGTATC TGGCCTTGCC TGAGCGCGCC
481 GAGCTAGCTG CACAGCTGGG CCTCACACAA ACACAGGTGA AAATCTGGTT CCAGAACCGC
541 CGCTCCAAGT TCAAAAAGCT CTATAAGAAT GGGGAGGTGC CGCTGGAACA CAGCCCCAAC
601 AACAGTGACT CCATGGCCTG CAACTCACCG CCGTCACCAG CACTCTGGGA CACATCTTCC
661 CATTCCACGC CAGCCCCTGC CCGCAATCCG CTGCCCCCAC CGCTCCCATA CAGTGCCTCC
721 CCCAACTACC TGGACGACCC CACCAACTCC TGGTACCACA CACAGAACCT CAGTGGACCC
781 CACTTACAGC AGCAGCCTCC TCAGCCGGCT ACCCTGCACC ATGCCTCCCC TGGGCCCCCG
841 CCTAACCCTG GGGCTGTGTA CTGAGTACCC ACCTGGCCTG CGCCCCTCCA CGAAGGACCC
901 CCTCCAGGAC CAGGCAGAAG GTGCCCTGTC CTAGCGACAC TCAGGAATCA TTGAGGGGCA
961 CAGGGGGAAA GACTCCCTTC CCTCTCCCTT GTCCCTTCTT CCAGGGGCCC AACAACCTCC
1021 AGATGACAAA TGCATGGACC GAGGATGCCC CCCAATCTCC CTCCCCTTGC TTAGACTGGG
1081 GTGCCCTCCA GACGGCGAGG AGTTCTACCC CAGTGGGGAC AGCACATGCT CTCTGCTCCA
1141 GGAACCCGGA TTGCCTCTAG ATGGCTCATC ACTTTCCAGC TTTTCAAACA CAGTAGAGAC
1201 CTCCAAAATG GGAGCCAGAG TGTTTGCAGG TCCACCTGTG CTGGGGCACC AGGCGCCACG
1261 GATTCCAGCA CAGCCAGACC TAAAGCACCA AGCCG

Fig 1. cDNA sequence of Dlx3 (3). The homeobox sequence is underlined. The four base pair deletion in TDO patients is highlighted. The amplification sequence from RT-PCR should be of 379 base pair segment.

Research
The TDO syndrome was first recognized in 1966 by Robinson and was given its present name by Lichtenstein in 1970. We began our clinical investigation of families with TDO in 1993 through support from the National Institute of Dental and Craniofacial Research. Investigation of large families with TDO led to identification of the trait loci at Chromosome 17q21 and in 1998 identification of the DLX3 gene mutation.8

We are continuing research at both the molecular level to characterize the role of DLX3 in hair, tooth and bone formation and at the clinical level. Clinical studies are currently underway to better define the variability in the hair, tooth and bone manifestations and to identify genes (other than DLX3) that are affecting the TDO phenotype.

TDO Treatment
There are no known pathological problems associated with the hair or bone changes seen in people with TDO caused by the 4 base pair deletion mutation in the DLX3 gene. The dental manifestations can be quite severe resulting in dental abscess formation and in many older patients premature tooth loss. Dental abscess formation appears to result from pulp exposures that occur when the thin enamel covering is worn through allowing the enlarged pulp chambers to be exposed directly to the oral cavity.

Individuals affected with TDO that have very thin enamel can benefit from covering the teeth with a bonded filled composite resin to help prevent exposure of pulp horns through wear. The enamel that is present is typically well mineralized and generally retains bonded materials adequately.

Reshaping of small anterior teeth in the primary or young permanent dentitions can often be accomplished using bonding techniques. In more severe cases the anterior and posterior teeth may require full coverage crowns to protect them and prevent abscess formation. It has been our experience that permanent teeth with