Odontochondrodysplasia

A number sign (#) is used with this entry because of evidence that odontochondrodysplasia (ODCD) is caused by compound heterozygous mutation in the TRIP11 gene (604505) on chromosome 14q32.

Description

Odontochondrodysplasia is characterized by mesomelic shortening of tubular bones, ligamentous laxity, and scoliosis, in association with dentinogenesis imperfecta involving both primary and secondary dentition. Affected individuals show variable severity. Radiologic features include trident pelvis, posteriorly flattened vertebrae, and brachydactyly with cone-shaped epiphyses (Maroteaux et al., 1996). Clinical variability and extraskeletal manifestations have been observed (Wehrle et al., 2019).

Mutation in the TRIP11 gene also causes a more severe chondrodysplasia, achondrogenesis type IA (ACG1A; 200600).

Clinical Features

In a 3.5-year-old boy of mixed Australian/Thai parentage, Goldblatt et al. (1991) described a form of spondylometaphyseal dysplasia associated with joint laxity and dentinogenesis imperfecta. The disorder appeared to be different from the spondyloepimetaphyseal dysplasia with joint laxity described by Beighton et al. (1984) (see 271640) as well as from the forms of spondylometaphyseal dysplasia known as the Irapa (271650) and Strudwick (184250) types. The dentinogenesis imperfecta resembled that seen with osteogenesis imperfecta but there were no signs of that disorder. The father's age was not given. X-linked spondylometaphyseal dysplasia (313420) is not associated with dentinogenesis imperfecta.

Bonaventure et al. (1992) presented the cases of 2 additional patients: a brother and sister with short limb dwarfism, joint laxity, and dentinogenesis imperfecta, born to healthy nonconsanguineous parents. Electron microscopic studies revealed large vacuoles of dilated rough endoplasmic reticulum within the cytoplasm of chondrocytes. Gel electrophoresis of pepsin-soluble collagen extracted from cartilage demonstrated type II collagen chains with abnormal mobility. A quantitative decrease in COL1A1 and COL1A2 mRNA was also observed. Overmodification of type II collagen peptides, suggested by the findings, was consistent with the presence of a single base substitution in the COL2A1 gene (120140).

Maroteaux et al. (1996) studied 4 unrelated children with growth retardation, ligamentous laxity, and scoliosis, including the brother and sister previously reported by Bonaventure et al. (1992). Mild facial dysmorphism was present, and 1 patient was referred for evaluation of thoracic deformity, but the most striking feature was shortening of the limbs, especially the hands and feet. Radiographs showed short tubular bones, particularly of the middle segment, with irregular metaphyses, as well as cone-shaped epiphyses of the hands, square iliac wings, horizontal acetabular roofs, and posterior wedging of vertebral bodies. The authors proposed the designation 'odontochondrodysplasia' for the disorder, which they noted was of variable severity.

Unger et al. (2008) reported 6 additional patients with Goldblatt syndrome, including a second sib pair (brother and sister). The main clinical features included short stature, joint laxity, narrow chest, and dentinogenesis imperfecta. Two patients required spinal surgery to correct progressive scoliosis at age 4.5 years and 7 years. Intellectual development was normal but motor delays occurred in some patients. The main radiographic features included congenital platyspondyly with coronal clefts, severe metaphyseal changes (especially hands, wrists, and knees), mesomelic limb shortening, and coxa valga. The occurrence of a second sib pair suggests autosomal recessive inheritance, although none of the reported families (including those with sib recurrence) were consanguineous. One patient was initially suspected of having Torrance type platyspondylic lethal skeletal dysplasia (PLSDT; 151210).

Wehrle et al. (2019) studied 10 patients from 7 families with ODCD, including the 6 patients previously reported by Unger et al. (2008), who were all compound heterozygous for mutations in the TRIP11 gene. The authors observed considerable clinical variability, with early lethality and milder postnatal phenotypes occurring within the same family (family 1), in which a brother died at age 4 months with severe ODCD, whereas his sister was alive at age 16 years with mild disease. In addition, there were extraskeletal disease manifestations, including pulmonary hypoplasia in 3 patients, polycystic kidneys in 1, nephronophthisis in 1, and hydrocephaly in 1.

Inheritance

Maroteaux et al. (1996) noted that the occurrence of odontochondrodysplasia in a brother and sister reported by Bonaventure et al. (1992) suggested autosomal recessive inheritance, although parental mosaicism could not be excluded with certainty.

Wehrle et al. (2019) confirmed autosomal recessive inheritance of OCDC in 7 families.

Molecular Genetics

Wehrle et al. (2019) analyzed the TRIP11 gene in 10 patients from 7 families with ODCD and identified compound heterozygous mutations in all 10 (see, e.g., 604505.0001 and 604505.0005-604505.0012). The unaffected parents were each heterozygous for 1 of the mutations, and unaffected sibs were heterozygous or wildtype. None of the variants were found in public exome databases. Wehrle et al. (2019) noted that all patients carried both a TRIP11 null allele as well as a splice variant that was translated into low-abundance GMAP protein; they concluded that hypomorphic mutations of TRIP11 are the genetic basis for a range of ODCD phenotypes.

Exclusion Studies

Unger et al. (2008) performed complete sequencing of several genes, including the COL2A1 gene, in one or more of the patients they reported with Goldblatt syndrome and identified no pathogenic mutations.