Shriners Hospital for Children - Canada, Montreal, QC, Canada; Department of Pediatrics, McGill University, Montreal, QC, Canada.
Shriners Hospital for Children - Canada, Montreal, QC, Canada.
Bone. 2022 Nov;164:116516. doi: 10.1016/j.bone.2022.116516. Epub 2022 Aug 12.
Mutations in CRTAP lead to an extremely rare form of recessive osteogenesis imperfecta (OI). CRTAP deficient mice have a brachycephalic skull, fusion of facial bones, midface retrusion and class III dental malocclusion, but in humans, the craniofacial and dental phenotype has not been reported in detail. Here, we describe craniofacial and dental findings in two 11-year-old girls with biallelic CRTAP mutations. Patient 1 has a homozygous c.472-1021C>G variant in CRTAP intron 1 and a moderately severe OI phenotype. The variant is known to create a cryptic splice site, leading to a frameshift and nonsense-mediated RNA decay. Patient 1 started intravenous bisphosphonate treatment at 2 years of age. At age 11 years, height Z-score was +0.6. She had a short and wide face, concave profile and class III malocclusion, with a prognathic mandible and an antero-posterior crossbite. A panoramic radiograph showed a poor angulation of the second upper right premolar, and no dentinogenesis imperfecta or dental agenesis. Cone-beam computed tomography confirmed these findings and did not reveal any other abnormalities. Patient 2 has a homozygous CRTAP deletion of two amino acids (c.804_809del, p.Glu269_Val270del) and a severe OI phenotype. As previously established, the variant leads to instability of CRTAP protein. Intravenous bisphosphonate treatment was started at the age of 15 months. At 11 years of age her height Z-score was -9.7. She had a long and narrow face and convex profile, maxillary retrusion leading to a class III malocclusion, an edge-to-edge overjet and lateral open bite. Panoramic radiographs showed no dental abnormalities. Cone-beam computed tomography showed occipital bossing, platybasia and wormian bones. In these two girls with CRTAP mutations, the severity of the skeletal phenotype was mirrored in the severity of the craniofacial phenotype. Class III malocclusion and antero-posterior crossbite were a common trait, while dental agenesis or dentinogenesis imperfecta were not detected.
CRTAP 基因突变导致一种极为罕见的隐性成骨不全症（OI）。CRTAP 缺陷型小鼠具有短头颅、面骨融合、中面部后缩和 III 类牙颌畸形，但在人类中，尚未详细报道颅面和牙列的表型。在这里，我们描述了两名 11 岁 CRTAP 双等位基因突变女孩的颅面和牙列发现。患者 1 携带 CRTAP 内含子 1 中的纯合 c.472-1021C>G 变异，表现为中度严重的 OI 表型。该变异会导致一个新的剪接位点，从而导致移码和无意义介导的 RNA 衰变。患者 1 在 2 岁时开始接受静脉内双膦酸盐治疗。11 岁时，身高 Z 评分+0.6。她具有短宽的面部、凹面型和 III 类错颌，下颌前突，存在前牙反颌。全景片显示右上第二前磨牙角度不良，无牙本质生成不全或牙缺失。锥形束 CT 证实了这些发现，并未发现其他异常。患者 2 携带 CRTAP 两个氨基酸（c.804_809del，p.Glu269_Val270del）的纯合缺失，表现为严重的 OI 表型。如前所述，该变异导致 CRTAP 蛋白不稳定。15 个月大时开始接受静脉内双膦酸盐治疗。11 岁时，身高 Z 评分-9.7。她具有长而窄的面部和凸面型，上颌后缩导致 III 类错颌，前牙深覆盖伴侧方开颌。全景片未见牙列异常。锥形束 CT 显示枕骨隆突、扁平颅底和脑回骨。在这两名 CRTAP 基因突变的女孩中，骨骼表型的严重程度反映在颅面表型的严重程度上。III 类错颌和前牙反颌是共同特征，而未发现牙缺失或牙本质生成不全。
