Tricho-dento-osseous syndrome (TDO) is a hereditary disorder primarily affecting hair, teeth, and bone. Additional characteristics may include brittle or peeling fingernails, dolichocephalic head form, long, curly eye lashes, and dental abscess formation. There is considerable variability of these features and it, remains controversial whether this is the result of variable expressivity, of a single gene mutation, allelic mutations or non-allelic mutations.
The specific aim of this investigation is to provide a detailed study of both the phenotype and genotype of TDO in four large families that displays clinical variability of several predominant features. Four large families affected with TDO have been identified for investigation in North Carolina. Four generations of affected and unaffected individuals live nearby making this an ideal population for linkage analysis. Initial studies indicate an autosomal dominant inheritance characterized by male to male transmission. The proposed investigation will include thorough clinical evaluation of all available individuals with a minimum of 30 affected and 30 unaffected people from these four families being used for linkage analysis. Teeth and hair will be evaluated using light microscopy, scanning electron microscopy and/or transmission electron microscopy providing a detailed histological interpretation of the TDO defects-Standardized lateral skull films will be used to characterize and quantify features of the craniofacial complex and evaluate the bony changes described as occurring in TDO patients. Three molecular genetic investigations will be completed beginning with DNA extracts prepared from peripheral venous blood. The reported familial relationships will be confirmed using apolipoprotein B genotyping. Genomic DNA will digested for RFLP characterization using horizontal agarose gel electrophoresis and Southern blotting. The ABO, Kell and Gc loci have been reported as possibly linked to the TDO trait and will be screened . Additional candidate genes potentially involved in abnormal tissue development (e.g.. laminin, keratins) will be screened for linkage with the TDO trait. The immediate goal of this research is to characterize the phenotype and phenotypic variability in large kindred with TDO and a genomic locus linked to the TDO trait.This will allow us to examine the relationship between genotype and phenotype for the TDO syndrome. This study will serve as a preliminary investigation used for obtaining initial genomic characterization and establishing a data base for comparison with as yet unidentified cases of TDO or similar syndromes. Knowledge gained from this research will lead to specific criteria useful in the diagnosis and differentiation of the TDO disorders. The long range goal of this project is to determine the gene responsible for the TDO syndrome and to understand its role in the pathological development of the human dentition and craniofacial complex.
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