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. Author manuscript; available in PMC: 2023 Aug 8.
Published in final edited form as: Bone. 2022 Aug 12;164:116516. doi: 10.1016/j.bone.2022.116516

Craniofacial and Dental Phenotype of Two Girls with Osteogenesis Imperfecta due to Mutations in CRTAP

Juliana Marulanda 1,2, Karissa Ludwig 1,2, Francis Glorieux 1, Brendan Lee 3, V Reid Sutton 3; Members of the BBD Consortium, Jean-Marc Retrouvey 4, Frank Rauch 1,2
PMCID: PMC10408670  NIHMSID: NIHMS1913501  PMID: 35970273

Abstract

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.

Keywords: CRTAP, dentinogenesis imperfecta, osteogenesis imperfecta, platybasia

1. Introduction

Osteogenesis imperfecta (OI) is a heritable condition that affects bone formation, leading to bone fragility, deformity and short stature [1]. OI is also associated with extraskeletal manifestations, such as blue or grey sclera and dentinogenesis imperfecta (DI). In the large majority of cases, OI is caused by genetic variants in one the collagen type I encoding genes, COL1A1 and COL1A2 [2]. The production of collagen type I is a complicated process involving post-translational modifications, folding, secretion, extracellular assembly and crosslinking [1]. Many enzymes, co-factors and transporters participate in this process, and variants in the genes coding for several of these accessory molecules are known to cause OI [1]. Generally, disease-causing variants in genes other than COL1A1 or COL1A2 are found in about 20% of individuals with moderate to severe OI [2].

Cartilage-associated protein (CRTAP) is an endoplasmic reticulum protein that participates in the post-translational modification of the alpha 1 chain of collagen type I [3]. Biallelic loss of function mutations in CRTAP lead to OI. The severity of the phenotype appears to depend on the proportion of residual CRTAP protein. We have previously shown that a CRTAP variant in intron 1 (c.472–1021C>G) that introduces a cryptic splice site, leads to a frameshift and suppresses CRTAP protein production by about 90% causes a moderate OI phenotype with rhizomelia, long-bone fractures, joint laxity and white sclerae [3, 4]. Complete loss of CRTAP function leads to a very severe phenotype and is often lethal in the first year of life [5, 6]. The disorder caused by biallelic CRTAP variants has been named OI type VII according to the gene-based classification [1, 4]. The phenotype-based classification of OI associates biallelic CRTAP variants with OI type II, III or IV, depending on the severity of the manifestations [7].

Mice deficient in Crtap mimic the phenotype of humans with CRTAP loss-of-function mutations and develop rhizomelia, short stature, disorganized proliferating chondrocytes in growth plates and progressive kyphoscoliosis [3]. A recent study described the craniofacial phenotype of Crtap deficient mice as having brachycephalic skulls, fusion of cranial and facial sutures, midface retrusion and class III malocclusion [8]. No detailed information is available on the craniofacial and dental phenotype in humans with biallelic CRTAP mutations. In the present study, we therefore assessed the craniofacial and dental manifestations in two 11-year-old girls with homozygous CRTAP mutations.

2. Patients and Methods

2.1. Subjects

Two individuals with a diagnosis of OI caused by biallelic mutations in CRTAP were recruited through the Brittle Bone Disorders Consortium (BBDC) (https://www.rarediseasesnetwork.org/cms/BBD) and evaluated at the Shriners Hospital for Children in Montreal. The consortium is a Rare Disease Clinical Research Network that is funded by the National Institutes of Health. Their dental exams, panoramic radiographs and intraoral photographs were obtained in the context of the BBDC natural history study that aims to describe the clinical features of OI. CBCT and intraoral scans were performed as part of the BBDC craniofacial ancillary study. The legal guardians provided informed consent; study participants provided assent. The study was approved by the Institutional Review Board of McGill University.

2.2. Cone Beam CT Scan

CBCT scans were acquired with a 3D Accutomo 170 (Morita Inc, Kyoto, Japan) CBCT device in a 170 mm × 120 mm field-of-view and a 250 μm voxel size. The exposure settings for CBCT included a tube voltage of 90 kV and a tube current of 4.5 mA for 17.5 seconds. Image analysis was performed using Anatomage InVivo 6 (Invivo Dental; Anatomage, San Jose, CA) software.

2.3. Craniofacial and dental evaluations

Dental evaluation included clinical examinations, extra-and intraoral photographs and panoramic radiographs that were evaluated by the study dentist. The dental examination included the classification of molar occlusion, overbite, overjet, open bite, crossbite and presence of DI. DI was diagnosed clinically if one tooth appeared opalescent or had gray, brown or yellow color. DI was also assessed radiographically, when partial or complete pulp obliterations and cervical constrictions were observed. On panoramic radiographs, dental agenesis, retained primary teeth, ectopic and impacted permanent teeth, primary or secondary retention and generalized tooth malformations or other radiographic anomalies were recorded.

Extraoral frontal and lateral photographs and soft tissue projection of CBCT scans were used to perform a detailed facial analysis. The facial type was classified as mesoprosopic (normal face), euriprosopic (wide face) or leptoprosopic (long face) according to the facial index (ratio between the bizygomatic width and maximum facial height multiplied by 100) [9]. The facial profile was also evaluated. A facial angle of 168.5 (SD: 6.5) was considered normal [10]. A normal facial proportion (ratio of lower facial height to total facial height) was 55% (SD: 5.05) [11]. The soft tissue profile was assessed in CBCT scans as described [12, 13], by measuring the H and Z angle. The maxillo-mandibular anteroposterior relationship within each other and with the cranial base was measured by the SNA, SNB, ANB, U1-NA, L1-MPA angles. Intraoral photographs in occlusion and intraoral scans were evaluated to assess bilateral molar and canine relationships [14], overjet, overbite, crossbite, open bite and dental crowding [12]. Intraoral scans were acquired using an iTero® scanner and 3D rendering of images and occlusogram were generated using OrthoCAD® (OrthoCAD 5.9 Carlstadt, New Jersey) software. The cranial base morphology was assessed by determining the cranial base angle. Angular values above 129.5 (SD:5.4) were denoted as platybasia [15, 16]. Additionally, skull base anomalies were assessed by basilar impression and basilar invagination as defined by Kovero et al [16]. Anterior cranial base and facial sutures were evaluated for craniosynostosis. Cranial sutures and posterior cranial base were outside of the field of view, thus, not available for cranial suture evaluation.

2.4. Clinical assessment

Height was measured using a Harpenden stadiometer (Holtain Limited, Crymych, UK), and values were converted to age- and sex-specific z-scores according to the reference data published by the Centers for Disease Control and Prevention [17].

2.5. Sequencing and genotyping

Sequence analysis of an OI gene panel was performed as described [2].

3. Results

3.1. Individual 1

Individual 1 is a girl with moderately severe OI caused by a homozygous c.472–1021C>G variant in intron 1 of CRTAP. This variant is known to introduce a cryptic splice site, leading to a frameshift and a 90% reduction in the expression of CRTAP protein [3]. The girl was born at term by spontaneous vaginal delivery with a weight of 3200 g (75th percentile) and a length of 51 cm (50th percentile). No fractures or deformities were noted at birth. The first long-bone fracture (left femur) occurred at the age of 2 months. Intravenous treatment with pamidronate was started following this fracture. She had rodding surgery of the left femur at 7 years of age.

At the age of 11 years, Individual 1 had normal stature (height z-score +0.6) and used a cane for mobility. A postero-anterior spine X-ray showed mild thoracic scoliosis with a Cobb angle of 10.5° and absence of vertebral compression fractures (Figure 1A). The 3D soft tissue reconstruction of the CBCT scan showed a facial index of 80.6 (Z-score −4.1) in the antero-posterior projection and a facial profile of 181° in the lateral projection (Z-score +1.9), indicating a concave facial profile (Figure 1 B and D). Bone and dental 3D reconstruction revealed a right molar and bilateral canine class III relationship. The left molar was class I (Figure 1C). Panoramic X-ray evaluation showed a distal angulation of 15, with no dental agenesis. No other radiological abnormalities were identified (Figure 1E). The frontal intraoral picture in occlusion showed anterior and posterior crossbite, with negative overjet and lower midline deviation (Figure 1F). There was no tooth discoloration, and thus no clinical sign of DI. The occlusogram analysis performed in the intraoral scans showed abnormal incisal and occlusal contacts, caused by the anterior crossbite and retained deciduous teeth due to the present mixed dentition stage (Figure 1G). Cranial base anatomy, as assessed by lateral cephalic CBCT reconstruction, showed a normal position of the Chamberlain line and the tip of the dens axis and a normal cranial base angle of 132° (Figure 1H). Anterior cranial base and facial sutures did not show any sign of abnormal fusion. Cephalometric analysis showed an increased SNB (Sella – Nasion – Point B) angle (Z-score 4.2) indicating mandibular protrusion, a reduced ANB (Point A – Nasion – Point B) angle (Z-score −2.8) and an increased Z angle (Z-score 5.0), confirming a class III malocclusion due to a prognathic mandible (Table 1).

Figure 1:

Figure 1:

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Imaging in Individual 1 A. Antero-posterior spine X-ray showing very mild scoliosis and absence of vertebral compression fractures. B. CBCT 3D reconstruction showing soft tissue - facial proportions. A facial index of 80.6 indicates an euryprosopic facial type (red lines). C. Class III molar and canine relationships (red lines). The left molar relationship is Class I, indicating an asymmetric malocclusion. D. Lateral 3D reconstruction showing a facial angle of 181°, indicating a concave soft tissue profile (red angle). E. Panoramic X-ray showing distal angulation of 15 causing retained first and second deciduous molars, no dental agenesis. F. Intraoral picture in occlusion showing anterior and posterior crossbite, negative overjet and lower midline deviation, and absence of dentinogenesis imperfecta. G. 3D reconstruction of intraoral scan showing abnormal occlusal contacts corresponding to the anterior crossbite. H. Craniometry showing normal cranial base anatomy by the Chamberlain line and tip of dens (red) and a normal cranial base angle of 132° (blue).

Table 1:

Soft tissue and cranial cephalometric measurements of patient 1 and 2. Raw values have been converted to Z-scores.

Cephalometric parameter Mean (SD) Patient 1 Measurement (z-score) Patient 2 Measurement (z-score)
Facial index 87.5 (1.7) 80.6 (−4.10) 99.27 (7.02)
Facial profile (°) 168.5 (6.4) 180 (1.80) 157 (−1.80)
Lower facial height (%) 55.0 (4.9) 57.4 (0.49) 54.6 (−0.08)
Cranial base (°) 129.5 (5.4) 132.4 (0.53) 141.8 (2.28)
SNA (°) 81.0 (3.0) 88.18 (2.39) 76.0 (−1.70)
SNB (°) 78.0 (3.0) 90.8 (4.26) 76.1 (−0.62)
ANB (°) 3.0 (2.0) -2.6 (−2.81) -0.1 (−1.59)
H angle (°) 8.5 (1.2) 11 (2.23) 25.7 (15.36)
Z angle (°) 75.0 (3.2) 91.0 (5.06) 86.3 (3.58)
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Abbreviations: SNA: Sella – Nasion – Point A, SNB (Sella – Nasion – Point B), ANB (Point A – Nasion – Point B).

3.2. Individual 2

Individual 2 is a girl with severe OI who had multiple fractures in utero. She was born by C-section after 36 weeks of gestation and presented with deformities in all four limbs. Sequencing of genomic DNA revealed a homozygous mutation in CRTAP (c.804_809del, p.Glu269_Val270del) which causes protein degradation and a complete inactivation of CRTAP function [18]. Treatment with intravenous pamidronate was started at the age of 15 months. The postero-anterior spine X-ray revealed a severe thoracolumbar right-convex scoliosis with a Cobb angle of 56° at 3 years of age (Figure 2A). Bilateral femur and tibia rodding were delayed until 10 years of age, after scoliosis surgery, to avoid complications during anesthetic procedures. The girl has not achieved independent ambulation and requires a wheelchair for all mobility.

Figure 2:

Figure 2:

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Imaging in Individual 2. A. Anteroposterior spine X-ray showing severe thoracolumbar right convex scoliosis at 3 years of age. B. 3D soft tissue rendering of CBCT showing facial proportions. The facial index is 99 (red lines); cranial bossing in the temporo-parietal region is evident (blue line). C. Asymmetric class III molar and canine relationships (red lines), more severe in the right side. D. Lateral 3D reconstruction with soft tissue projection shows a facial angle of 157°, indicating a convex soft tissue profile (red angle). E. Panoramic X-ray showing no dental abnormality. F. Intraoral picture in occlusion showing an edge-to-edge overjet, lateral open bite and posterior crossbite. Absence of dentinogenesis imperfecta. G. Craniometry showing a normal location of the tip of the dens relative to the Chamberlain line (red line and dot), but an abnormally flat cranial base angle of 141° (blue) indicating platybasia. H. Lateral 3D reconstruction showing wormian bones in skull (arrow). I. 3D intraoral scan reconstruction showing the scarce occlusal contacts located in the anterior-left side of the dental arches.

At the time of the skeletal and craniofacial assessment at 11 years of age, Individual 2 had extreme short stature (height z-score −9.7). The craniofacial analysis of the 3D soft tissue rendering of the CBCT scan showed a facial index of 99 and cranial bossing in the temporo-parietal region (Figure 2B). Lateral bone and dental 3D reconstructions revealed a bilateral molar and canine class III relationships (Figure 2C). Lateral 3D reconstruction with soft tissue projection showed a facial angle of 157°, indicating a convex facial profile, low nasal bridge and anteverted nares (Figure 2D). Panoramic X-ray analysis did not show any abnormality. The frontal intraoral picture in occlusion revealed an edge-to-edge incisor relationship, posterior crossbite and lateral open bite. There was no clinical or radiographic sign of dentinogenesis imperfecta (Figure 2E and F). Craniometry showed a normal cranial base anatomy by the relative position of the Chamberlain line and the tip of the dens axis, but an abnormally flat cranial base angle of 141° indicating platybasia (Figure 2G). Unlike individual 1, lateral 3D cranial reconstruction showed multiple wormian bones in the skull (Figure 2H), however, the anterior cranial base and facial sutures did not show any sign of craniosynostosis. The occlusogram analysis by intraoral scans showed minimal pathological occlusal contacts, predominantly in the anterior left region. No occlusal contacts were detected in the molar area (Figure 2I).

Cephalometric analysis showed a below-average SNA (z-score −1.7) and SNB (z-score −0.62) angle indicating bimaxillary retrusion with a class III dental and skeletal malocclusion (ANB angle z-score −1.59) due to a retrognathic maxilla. However, an increased H angle (z-score 15.36) shows prominent lips that contribute to a convex facial profile (Table 1).

4. Discussion

Here we describe the craniofacial phenotype of two 11-year-old girls with autosomal recessive OI type VII due to mutations in CRTAP. Detailed dental, facial and cephalometric analysis revealed class III malocclusion with an anteroposterior crossbite and lateral open bite, but absence of other abnormalities that are often associated with OI such as dental agenesis, impacted teeth and DI.

Previous studies have reported a high prevalence of class III malocclusion in moderate to severe OI [19, 20]. Bending of the cranial base and a counter-clockwise rotation of the mandibular plane with a decreased lower facial height has been found to be the cause of the relative mandibular prognathism, with a hypoplastic and retrusive maxilla playing an important role in the development of skeletal class III as well [19]. However, these studies were performed in patients with dominant mutations in COL1A1 or COL1A2 [19]. Additionally, it was reported that in OI type V, caused by a mutation in IFITM5, the class III malocclusion is less frequent, whereas a class II malocclusion with bimaxillary retrusion and reduced lower face height is more common [12]. In the present study, the two individuals show a class III malocclusion with normal lower facial height, but with a different skeletal etiology. Individual 1 presents with mandibular prognathism that leads to a skeletal and dental class III, whereas Individual 2 presents with a retrognathic maxilla, pronounced lip protrusion, and a convex facial profile.

A dental study in patients with OI type I, III and IV between 8 to 14 years of age showed a prevalence of antero-posterior crossbite of 38%, and of lateral open bite of 27.5%, traits that were correlated with the severity of the disease [21]. To date, no other reports on dental aspects in OI type VII have been published, but here we show that these occlusal characteristics are present in the two examined individuals, and that the severity of the malocclusion correlates with the skeletal involvement.

Although both individuals have mutations in CRTAP, the phenotypic consequences differ markedly, as Individual 2 has much more severe skeletal and craniofacial involvement. This presumably reflects the fact that the pathogenic variant in Individual 2 leads to a complete loss of CRTAP function, whereas the mutation observed in Individual 1 allows for the production of some normal CRTAP [3, 18].

Genotype-phenotype correlation studies in OI patients with variants affecting the triple-helical domain of collagen type I have found that the majority of patients with glycine substitutions have clinical DI [22], whereas alpha I haploinsufficiency mutations do not lead to DI [23]. Although the mechanism leading to DI has not been completely elucidated, this observation suggests that the type of genetic variant leading to OI is also a determining factor in the development of dental defects [22]. The absence of DI in individuals with biallelic CRTAP mutations suggests that CRTAP is not critical for dentin development in humans. Similarly, individuals with OI due to mutations in IFITM5, SERPINF1 and P3H1 do not have DI [12, 24–26].

An earlier study from our study consortium found that 17% of individuals with pathogenic alleles in COL1A1 or COL1A2 have at least one missing tooth [27]. The prevalence of missing teeth is higher among individuals with more severe OI and when DI is present and even oligodontia (≥6 missing permanent teeth) is observed occasionally [28, 29]. In the present report, none of our two patients presented with dental agenesis, despite the severity of the skeletal phenotype in Individual 2. Nevertheless, missing teeth seem to be also common in patients with non-collagenous types of OI [29]. Indeed, patients with OI type V (caused by a mutation in IFITM5) seem to commonly present missing teeth, especially premolars [12]. Tooth agenesis is a genetically heterogeneous condition, caused by several independent defective genes that act in combination to result in a certain phenotype [30]. Thus, our findings suggest that CRTAP may not be essential for tooth bud formation, dentin matrix secretion and/or mineralization.

This study is limited by the fact that only two individuals with CRTAP variants could be assessed. Individuals with OI due to homozygous CRTAP variants are extremely rare, as variants other than the hypomorphic c.472–1021C>G variant are often lethal in the first year of life. More detailed assessment of the craniofacial phenotype including increased CT resolution and whole cranial vault coverage and the need for dental and malocclusion treatment will hinge on the identification and assessment of more individuals with biallelic CRTAP variants. Additionally, in our two patients, intravenous therapy with bisphosphonates was initiated at the ages of 2 months and at 15 months. It is known that bisphosphonates are effective in increasing bone mineral density and reducing the risk of fractures in pediatric patients with OI and seem to have a positive effect on condyle trabecular bone architecture, [31, 32] but do not seem to influence the prevalence of skull base abnormalities in children with OI [15]. Thus, in order to identify whether early intervention with bisphosphonates could have an effect on the craniofacial complex and more specifically, on the development of craniosynostosis and skeletal class III malocclusion, much larger studies need to be conducted.

In conclusion, in this study on two individuals with biallelic CRTAP variants, the severity of the skeletal phenotype was mirrored in the severity of the craniofacial phenotype. Class III malocclusion and anteroposterior crossbite were common traits between both individuals, while no dental agenesis or DI were detected.

5. Acknowledgments

This study was performed as an activity of the Brittle Bone Disorders Consortium. The Brittle Bone Disorders Consortium (1U54AR068069-08) is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN) and is funded through a collaboration between the National Center for Advancing Translational Sciences (NCATS), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Dental and Craniofacial Research (NIDCR), and the National Institute of Child Health and Human Development (NICHD).The study was also supported by the Shriners of North America.

Disclosures

Juliana Marulanda: None

Karissa Ludwig: None

Francis Glorieux: Novartis, Amgen and Mereo Biopharma: consulting fees and research grants.

Brendan Lee: Sanofi research grant; Biomarin consulting fees

Reid Sutton: Ultragenyx research funding

Jean-Marc Retrouvey: Ultragenyx consulting fees

Frank Rauch: Mereo Biopharma, Ultragenyx, Sanofi, Ibsen: consulting fees; Catabasis: Study grant to institution.

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