Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta - A retrospective cohort study

Abstract

Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, caused mainly by mutations in the collagen I genes (COL1A1 and COL1A2). Dentinogenesis imperfecta (DGI) and other dental aberrations are common features of OI. We investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. The clinical examination included radiographic evaluations. Teeth from 81 individuals were available for histopathological evaluation. COL1A1/2 mutations were found in 104 individuals by nucleotide sequencing. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p.Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p = 0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C terminal of p.Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p = 0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Seventeen had missense mutations where glycine to serine was the most prevalent substitution (53%). Taurodontism occurred in 18% and retention of permanent second molars in 31% of the adolescents. Dental aberrations are strongly associated with qualitatively changed collagen I. The varying expressivity of DGI is related to the location of the collagen I mutation. Genotype information may be helpful in identifying individuals with OI who have an increased risk of dental aberrations.

Fig 1. Clinical appearance of dentinogenesis imperfecta (DGI) and retention of permanent second molars.

A 15-year-old girl with OI type I and DGI and a splice mutation in COLIA2, c.1197+5G>A. A. Clinical picture of DGI with characteristic grey-blue discoloration, and a Class III malocclusion with an anterior open bite. B. Typical signs of DGI with calcified pulp chambers and bulbous crowns with constriction at cervix. Retention of both upper permanent second molars with a vertical inclination can be noted (arrows).

Fig 2. Skeletal reference points, lines and angles.

Reference points: S: The center of sella turcica, N: Nasion, Sp: Spina, the apex of the anterior nasal spine, Pm: Pterygomaxillare, A: The most concave point of anterior maxilla, B: The most concave point on mandibular symphysis, Gn: Gnathion, the lowest point in the lower border of the mandible in the median plane, Go: Gonion, the most posterior inferior point on angle of mandible. Reference lines: SN, SpPm (NL), ML: The mandibular line. Reference angles: SNA, SNB, SN/SpPm, SN/ML.

Fig 3. Location of mutations in COL1A1 and COL1A2 in individuals with clear signs of dentinogenesis imperfecta (DGI) in the deciduous dentition with no or subtle signs in the permanent dentition.

Distribution of missense mutations, from N- to C-terminal, resulting in glycine substitutions in COL1A1 and presence of DGI in the deciduous dentition with only subtle signs in the permanent dentition (n = 9). Affected residues are numbered from translation initiation. In one child, a splice mutation was found in intron 47 (c.3424-6C>G) and in one child with no signs of DGI in the permanent dentition, a nonsense mutation, p.(Ala327*), (c.972_978dup) was detected. Distribution of missense mutations, from N- to C-terminal, resulting in glycine substitutions in COL1A2 and presence of DGI in the deciduous dentition with only subtle signs in the permanent dentition (n = 7) and no signs in the permanent dentition (n = 1). Affected residues are numbered from translation initiation.

Fig 4. Varying expressivity of dentinogenesis imperfecta (DGI) in deciduous and permanent dentitions.

A boy with OI type IV due to a missense mutation in COLIA1, p.(Gly821Ser), c.2461G>A, and differences in expressivity of DGI between the dentitions. A. At seven years of age. Discoloration and attrition in the deciduous teeth can be seen while the erupting permanent first lower incisors show no signs of DGI. B and C. At 16 years of age. B. No clinical signs of DGI are seen. C. Panoramic radiograph showing retention with a mesioangular inclination of the right upper permanent second molar (arrow). Only discreet signs of DGI are seen.

Fig 5. Location of mutations in COL1A1 and COL1A2 in individuals with dentinogenesis imperfecta (DGI) in both dentitions.

Distribution of missense mutations, from N- to C-terminal, resulting in glycine substitutions in COL1A1 and presence of DGI in the deciduous and permanent dentition (n = 7). In two children mutations were found in intron 32 (c.2235+1G>A); and in one in intron 21 (c.1197+5G>A). Distribution of missense mutations, from N- to C-terminal, resulting in glycine substitutions in COL1A2 and presence of DGI in the deciduous and permanent dentition (n = 8). In one individual a mutation was found in intron 43 (c.2835+1G>A). Affected residues are numbered from translation initiation.

Fig 6. Histological findings in individuals with varying expressivity of dentinogenesis imperfecta (DGI).

A. Ground section illustrating normal dentin. B. Ground section of a lower deciduous molar from an individual with OI type I and clinical DGI only in the deciduous dentition. Variation in width and branching of some dentin tubuli (arrows). No cell lacunae in the body of the dentin or layering of dentin are seen. C. Ground section of a lower permanent molar from an individual with OI type III and DGI. Cell lacunae* and branching of dentin tubuli** (arrows). The extent of hyaline dentin void of dentin tubuli is extensive compared to A and B.

Fig 7. Radiographic appearance of taurodontism.

Two eight-year-old boys with OI type I, quantitative defects caused by a mutation in COL1A1 and no DGI. A. In this individual, apically extended pulp chamber, taurodontism, in the right first permanent lower molar is seen. B. Normal morphology of the corresponding tooth in the other boy.

Fig 8. Distribution of taurodontism and retained permanent second molars in different types of OI.

Taurodontism could be evaluated in 87 individuals and retention of permanent second molars in 93.