Trichodentoosseous Syndrome

A number sign (#) is used with this entry because of evidence that trichodentoosseous syndrome (TDO) is caused by heterozygous mutation in the DLX3 gene (600525) on chromosome 17q21.

Description

Trichodentoosseous syndrome is an autosomal dominant disorder with complete penetrance characterized by abnormalities involving hair, teeth, and bone (summary by Nguyen et al., 2013).

Clinical Features

Robinson and Miller (1966) described autosomal dominant inheritance of enamel hypoplasia and hypocalcification with associated strikingly curly hair. Lichtenstein et al. (1972) traced the same condition through 6 generations of an Irish-American family. Affected members of this family had a feature not described by Robinson and Miller (1966)--mild increase in bone density, particularly in the skull. The fingernails showed either laminated splitting of the superficial layers or thick cornification. Apparently both keratin and enamel are defective. Crawford (1970) probably reported the same condition. He stated that his case had very curly blond, dry hair (Jorgenson, 1975). The family reported by Winter et al. (1969) probably had TDO syndrome. Taurodontism ('bull teeth') occurs in this condition (see 272700). The family described by Lichtenstein et al. (1972) lived mainly in Washington County, Virginia. Quattromani et al. (1983) described a presumably unrelated family from the Holston River Valley of neighboring Tennessee. The changes in the teeth and brain were similar to those in the original family but the skeletal findings were different: sclerosis and thickening of the calvaria with long bones that showed subtle undertubulation but no sclerosis. The authors suggested that the same gene might be present in the Tennessee family with modification by gene or genes present in one kindred and not in the other.

Shapiro et al. (1983) suggested that more than one fundamentally distinct entity may be subsumed by the designation TDO syndrome. Previously, 2 possibly distinct types had been reported. TDO-I (Lichtenstein et al., 1972) is characterized by kinky or curly hair, dolichocephaly, enamel hypoplasia, increased dental caries, radial dense bones, and occasionally brittle nails. The chondrocranium shows some thickening but calvarial density and thickness are normal. Premature fusion of cranial sutures, especially the sagittal, is responsible for dolichocephaly. Persons with TDO-II (Leisti and Sjoblom, 1978) show sparse as well as curly hair, more striking nail changes, and thickening and sclerosis of the calvaria. Males show narrowing of the ear canal. Dental eruption is delayed in TDO-I and precocious in TDO-II. In TDO-II, dentin is dysplastic whereas it is normal in TDO-I. Shapiro et al. (1983) described a family that differed from both of these. Affected persons showed macrocephaly and obliterated diploe and no long bone sclerosis. Crawford and Aldred (1990) pointed out that the dental changes of amelogenesis imperfecta, hypomaturation-hypoplasia type with taurodontism (AI4; 104510), (Congleton and Burkes, 1979; Crawford et al., 1988) are identical to those in TDO, from which it is distinguished only by the absence of changes in the hair or osteosclerosis. Crawford et al. (1988) observed in the same kindred 2 apparent subtypes of amelogenesis with taurodontism differentiated by the thickness of the enamel and the overall tooth size. Seow (1993) insisted, however, that TDO and amelogenesis imperfecta should not be confused. True taurodontism is indicated, she concluded, by a change in the mandibular first permanent molars and this occurs only in the TDO syndrome.

In western North Carolina, Wright et al. (1997) characterized the phenotypic variation in 3 kindreds with a total of 33 affected members. All TDO individuals with teeth had generalized thin and/or pitted enamel hypoplasia. Taurodontism was present in all affected individuals, but was variably expressed. Unique kinky/curly hair at birth was reported in 85% of affected individuals. The curly hair phenotype was retained past infancy in 46% of affected individuals. Thick cranial bones, lack of visible pneumatization of the mastoid processes, and/or obliteration of the calvarial diploe was seen in 97% of affected persons compared with 30% of the unaffected members of these kindreds. The ABO, Kell, and Gc loci, previously suggested to be linked to TDO, were excluded as candidates in these 3 kindreds. Wright et al. (1997) noted that 1 of the families reported by Congleton and Burkes (1979) was related to their North Carolina kindred and that the other 2 families reported by Congleton and Burkes (1979) lived in close proximity.

Hart et al. (1997, 1997) studied the 3 families previously reported by Wright et al. (1997) and another family with TDO and found that 2 clinical features, taurodontism and enamel hypoplasia, were fully penetrant in all 39 TDO-affected individuals, while bone and hair features were variably expressed.

Nguyen et al. (2013) compared craniofacial variation between 53 TDO-affected individuals and 34 unaffected members of 8 families from 1 kindred and observed marked variation in most of the cranial features measured. The position of the maxilla in relation to the cranial base was more retrusive in TDO-affected individuals compared to unaffected individuals. The authors noted that although patients with TDO are often described as having prognathic mandibles, they found no difference in mandibular projection between patients and controls; however, the relative position of a normal growing mandible would appear more prognathic when aligned next to a retrusive maxilla. TDO-affected individuals also had significantly longer mandibular body length and shorter ramus height, with no difference in gonial angle. Nguyen et al. (2013) stated that a shorter ramus height can mask mandibular projection even when a significant increase in body length is present.

Mapping

Adding another family to the 3 reported by Wright et al. (1997), Hart et al. (1997, 1997) investigated 4 families with a total of 39 TDO-affected members. Using a genomewide search strategy, they found linkage of TDO syndrome to markers on chromosome 17q21; maximum lod = 10.54 at theta = 0.00 for D17S791, with no indication of genetic heterogeneity. Linkage analysis and haplotype reconstruction allowed them to sublocalize the TDO syndrome locus to a 12-cM interval flanked by D17S932 and D17S809.

Molecular Genetics

Price et al. (1998) noted that 2 members of the distal-less homeobox gene family, DLX3 and DLX7 (601911), map to the same region as TDO, namely, chromosome 17q21. They described genomic cloning and sequencing of both the human DLX3 and DLX7 genes and identified a 4-bp deletion in human DLX3 (600525.0001) which correlated with the TDO phenotype in 6 families. The observed mutation was predicted to cause a frameshift and premature termination codon, resulting in a functionally altered DLX3 protein. The finding of a human mutation in a DLX gene was consistent with murine studies indicating their important role in the development of hair, teeth, and bone.

Price et al. (1998) identified the same 4-bp deletion in a Virginia family. A common haplotype for 3 markers surrounding the DLX3 gene was identified in all affected subjects in the 6 original families and the Virginia family. Price et al. (1998) concluded that all affected individuals in these families had inherited the same DLX3 gene deletion from a common ancestor. They also concluded that the variable clinical phenotype observed in these families that share a common mutation suggested clinical variability is not the result of genetic heterogeneity at a major locus, but may reflect genetic heterogeneity at other epigenetic loci or contributing environmental factors or both.

By searching for DLX3 or DLX7 mutations in 3 members (2 affected and 1 unaffected) of a family with amelogenesis imperfecta, Price et al. (1999) approached the question of whether TDO syndrome and AIHHT are allelic disorders. Sequence analyses of the DLX3 and DLX7 genes suggested that that form of amelogenesis is not due to genetic mutations or polymorphisms in the exons of these genes and that it is an entity distinct from TDO.

Dong et al. (2005) studied a family in which affected members had the characteristic dental phenotype but no hair or bone abnormalities, a condition the authors classified as AIHHT, and they identified a 2-bp deletion in the DLX3 gene (560delCT; 600525.0002).

In 7 affected members of a 3-generation family with an attenuated TDO phenotype, Wright et al. (2008) identified heterozygosity for the 560delCT mutation in the DLX3 gene. The authors stated that all affected individuals in this kindred had coarse unmanageable hair with a diminished shaft diameter similar to that seen in individuals with the 4-bp deletion (600525.0001), and that alterations in tooth size and the severity of taurodontism were less severe and bone changes less marked than those seen in individuals with the 4-bp deletion. Wright et al. (2008) concluded that this mutation causes TDO with an attenuated phenotype, not AIHHT, as previously reported.