CRANIOMAXILLOFACIAL DEFORMITIES/COSMETIC SURGERY
The Spheno-Occipital Synchondrosis Fuses Prematurely in Patients With Crouzon Syndrome and Midface Hypoplasia Compared With Age- and Gender-Matched Controls Youssef Tahiri, MD, CM, MSc, FRCSC,* J. Thomas Paliga, BA,y Arastoo Vossough, MD,z Scott P. Bartlett, MD,x and Jesse A. Taylor, MDk Purpose:
Premature closure of the spheno-occipital synchondrosis (SOS) has been associated with midface hypoplasia in animal models and patients with specific forms of syndromic craniosynostosis. The present study aimed to characterize SOS fusion in patients with Crouzon syndrome.
Patients and Methods:
A case-control study was performed in patients with Crouzon syndrome treated at the Children’s Hospital of Philadelphia from 1984 to 2012. The cases included patients with Crouzon syndrome and at least 1 high-quality computed tomography (CT) scan in which SOS patency could be assessed. Age- and gender-matched control CT scans were identified for comparison. The patient age at the CT scan was evaluated as the predictor, with SOS patency identified as the outcome variable. Three independent reviewers with high inter-rater reliability graded the SOS patency as open, partially fused, or completely fused. The Wilcoxon rank sum test was used to compare the Crouzon group and the controls.
Results:
During the study period, 30 patients were identified with Crouzon syndrome. A total of 24 patients, all with midface hypoplasia and with 112 cranial CT scans, met the inclusion criteria. Accordingly, 112 age- and gender-matched control CT scans were assessed. No patient in the control group had midface hypoplasia. Within the Crouzon group, the average age at complete closure (14.0 3.4 years) evident on the CT scan was significantly younger than that in the control group (16.6 2.2 years; P = .0152). The average age when the scans showed complete patency of the SOS in the Crouzon group (1.3 1.1 years) was significantly younger than that in the control group (3.2 2.3 years; P = .0001).
Conclusions: The SOS closes significantly earlier in patients with Crouzon syndrome compared with age- and gender-matched controls. The strong statistical correlation supports premature closure of the SOS as a possible mechanistic contributor to midface hypoplasia. Ó 2014 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 72:1173-1179, 2014
Crouzon syndrome was initially reported in 1912 by the French neurosurgeon Dr Octave Crouzon.1 The incidence has been estimated at 1 in 65,000 live births, and the inheritance is autosomal dominant, with an
occurrence that is both sporadic and familial.2 Premature fusion of the cranial sutures and cranial base synchondroses in patients with Crouzon syndrome has been attributed to mutations in the fibroblast growth
Received from Perelman School of Medicine at the University of
Address correspondence and reprint requests to Dr Taylor: Division
Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA.
of Plastic Surgery, Perelman School of Medicine at the University of
*Craniofacial Fellow, Division of Plastic Surgery.
Pennsylvania, Children’s Hospital of Philadelphia, Colket Translational
yClinical Research Fellow, Division of Plastic Surgery.
Research Bldg, 3501 Civic Center Blvd, 9th Fl, Philadelphia, PA 19104;
zAssociate Professor of Radiology, Department of Radiology.
e-mail: [email protected]
xProfessor of Surgery, Division of Plastic Surgery.
Received October 2 2013
kAssistant Professor of Surgery, Division of Plastic Surgery.
Accepted November 11 2013
The present study was funded by the Department of Surgery of the Children’s Hospital of Philadelphia and the Perelman School of
Ó 2014 American Association of Oral and Maxillofacial Surgeons
Medicine at the University of Pennsylvania.
http://dx.doi.org/10.1016/j.joms.2013.11.015
0278-2391/13/01426-2$36.00/0
The data included in our report have been presented at the International Society of Craniofacial Surgery in September 2013.
1173
1174 factor receptor (FGFR) 2 gene and, in rare instances, the FGFR 3 gene.3-5 Classic phenotypical features of Crouzon syndrome include bicoronal synostosis, exorbitism, and maxillary hypoplasia with relative mandibular prognathism.6 The spheno-occipital synchondrosis (SOS) is a site of endochondral ossification in the cranial base. It is located between the posterior border of the body of the sphenoid and the anterior edge of the basiocciput. Fusion of this synchondrosis starts at around age 7, with completion at around 12 and 14 years old in girls and boys, respectively.7-11 It has been thought to play an important role in the normal development and growth of the cranial vault and facial skeleton, because it is the last of the synchondroses of the skull base to fuse.12-14 Moreover, premature closure of the SOS has been associated with shortening and flattening of the anterior cranial base and midface hypoplasia in animal models and patients with Apert and Pfeiffer syndrome.11,15-17 It is possible that the SOS plays a mechanistic role in the development of midface hypoplasia in FGFR-mediated, syndromic craniosynostosis.15-17 To date, no study has examined the timing of closure of the SOS in patients with Crouzon syndrome, the most common of the acrocephalosyndactyly syndromes. The present study aimed to characterize the timing of SOS fusion in patients with Crouzon syndrome, a population with high rates of midface hypoplasia, relative to nonaffected controls without midface hypoplasia. We hypothesized that the SOS would close significantly earlier in patients with Crouzon syndrome than in age- and gender-matched controls.
Patients and Methods STUDY DESIGN AND PATIENT POPULATION
The institutional review board of the Children’s Hospital of Philadelphia reviewed and approved the present study. We performed a retrospective, case-control study of patients who had presented to the Children’s Hospital of Philadelphia Center for Facial Reconstruction from 1982 to September 2012. Patients with a clinical and genetic (when available) diagnosis of Crouzon syndrome and at least 1 fine-cut head computed tomography (CT) scan were included as cases. The scans were excluded if the visualization of the SOS was inadequate or incomplete. Using an established trauma registry for patients ranging from 0 to 20 years old, we identified an equal number of age- and gender-matched control finecut CT scans. The inclusion criteria for the control group were same gender and age at scanning within 3 months of the matched Crouzon syndrome scan. Age- and gender-matched controls with any underlying congenital or syndromic diagnosis were excluded.
CLOSURE OF THE SOS IN CROUZON SYNDROME VARIABLES AND DATA COLLECTION METHODS
The patient demographics, including age, gender, presence of midface hypoplasia, number of CT scans, and fusion status of the SOS (ie, open, partially closed, or closed) were recorded. The SOS was defined as open when no degree of hyperdense bony bridging across the hypodense SOS was evident (Fig 1A). It was considered partially closed when complete fusion was not evident, but some degree of hyperdense bony bridging was found across the hypodense cartilaginous SOS (Fig 1B). Finally, it was defined as closed when the CT scan showed a completely fused SOS, with complete replacement of the hypodense cartilage with hyperdense bone (Fig 1C). Using fine-cut head CT scans, the closure status of the SOS in the Crouzon syndrome and control groups were evaluated independently by 3 reviewers—2 craniofacial surgeons and 1 pediatric neuroradiologist. STATISTICAL ANALYSIS
The inter-rater agreement was evaluated using Cohen’s k coefficient, and the judges jointly reviewed the imaging studies and reached a consensus when a disagreement with regards to fusion status was present.11 The average age for the scans showing complete closure, partial closure, or an open SOS between the Crouzon and control groups was compared using the Wilcoxon rank sum test.
Results During the study period, 30 patients were identified with Crouzon syndrome. A total of 24 patients with 112 head CT scans met the inclusion criteria and had complete visualization of the SOS. The Crouzon group consisted of 12 boys and 12 girls, with a mean age of 6.6 years (Table 1). No significant differences were found in the demographics within the Crouzon group. The individual CT scans were treated as independent data points. The median number of CT scans for each patient with Crouzon syndrome was 4. All 24 patients in this group had a confirmed diagnosis of midface hypoplasia (Fig 2). A total of 112 age- and gender-matched CT scans were identified as meeting the inclusion criteria for the control group (Table 1). No patients in the control group had a diagnosis of midface hypoplasia (n = 112). Three independent reviewers evaluated the CT scans, with 97.3% inter-rater reliability (Cohen unweighted k = 0.96). Of the 24 patients in the Crouzon group, the earliest partial fusion of the SOS was seen at 1.0 year. This was in sharp contrast to the earliest partial closure in the control group at 6.3 years. The earliest age at complete closure was 7.0 years in the Crouzon cohort, much
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TAHIRI ET AL
FIGURE 1. Fusion status of the spheno-occipital synchondrosis (SOS). A, The SOS was defined as open when no degree of hyperdense bony bridging across the hypodense SOS was evident. B, The SOS was considered partially closed when complete fusion was not evident, but some degree of hyperdense bony bridging across the hypodense cartilaginous SOS was present. C, The SOS was defined as closed when the computed tomography scan showed a completely fused SOS with complete replacement of the hypodense cartilage with hyperdense bone. Tahiri et al. Closure of the SOS in Crouzon Syndrome. J Oral Maxillofac Surg 2014.
earlier than the earliest age at complete closure in the controls at 14.4 years. All scans in the Crouzon group at 4.9 years and older showed either partial or complete closure of the SOS. This correlated with the presence of midfacial hypoplasia on clinical examination. Accordingly, the latest age that evidenced patency of the SOS was 4.9 years. Complete fusion of the SOS was seen in all scans by 10.9 years of age and older in the Crouzon group (Fig 3A). However, the age- and gender-matched control CT scans showed SOS patency until a much later time, with the first recorded partial fusion at 6.3 years (range 6.3 to 14.0). On the CT scans showing a closed SOS,
the age at CT scanning ranged from 14.4 to 20.2 years. All CT scans in the 0.2- to 6.2-year range revealed a patent SOS (Fig 3B). Within the Crouzon group, the average age at complete SOS fusion evident on the CT scan was 14.0 3.4 years (n = 31) and was significantly lower than the average age at complete SOS fusion in the control group (16.6 2.2 years; n = 18; P = .0152). The average age at partial closure was significantly younger (5.3 2.2 years; n = 46) within the Crouzon group than the age in the control group (10.7 2.4 years; n = 18; P = .0001). Finally, the average age of the patients with CT scans showing complete patency of the SOS
1176
CLOSURE OF THE SOS IN CROUZON SYNDROME
Table 1. DEMOGRAPHIC CHARACTERISTICS OF CROUZON AND CONTROL GROUPS
Characteristic Patients (n) Gender (n) Male Female Age (yr) Mean Median Midface hypoplasia (n) CT scans (n) CT scans per patient (n) Mean Median
Crouzon Group Control Group 24
112
12 12
55 57
6.6 5.3 24 112
6.6 5.3 0 112
4.67 4
1 1
Abbreviation: CT, computed tomography. Tahiri et al. Closure of the SOS in Crouzon Syndrome. J Oral Maxillofac Surg 2014.
in the Crouzon group (1.3 1.1 years; n = 35) was significantly lower than that in the control group (3.2 2.3 years; n = 76; P = .0001; Table 2, Fig 4). To provide a graphic representation of the initiation of SOS fusion, a Kaplan-Meier survival curve is shown in Figure 5 showing a leftward shift in the SOS patency curve relative to the controls.
Discussion The present study aimed to characterize the timing of SOS fusion in patients with Crouzon syndrome, a population with a high rate of midface hypoplasia rela-
tive to nonaffected controls without midface hypoplasia. The present results have shown that the SOS in patients with Crouzon syndrome, all of whom had midfacial hypoplasia, fuses significantly earlier than the SOS of age- and gender-matched controls, none of whom had midface hypoplasia. Although we could not show causality, the association between premature SOS fusion and midface hypoplasia was statistically significant, lending additional evidence to the mechanistic role of early SOS fusion in the development of midface hypoplasia in patients with Crouzon syndrome. Premature closure of the SOS in patients with Apert syndrome has been linked to midfacial hypoplasia in a study from our group.11 Moreover, in the same study, patients with Muenke syndrome were not found to have premature fusion relative to their age- and gender-matched controls.11 Because midface hypoplasia is typically more marked in patients with Crouzon and Apert syndrome than in those with Muenke syndrome, the results of our study and those of previous studies11,15-17 suggest a direct correlation between the age of fusion and the degree of midface hypoplasia in these patient populations. The cranial base plays an important role in craniofacial development,13,14,18,19 with the anterior cranial base considered a primary driver of midfacial growth.20,21 Synchondroses form between prominent ossification centers during cranial base development. They are involved in bone growth during development and eventually fuse at skeletal maturity.14,22,23 The SOS is a site of endochondral ossification in the cranial base and is located between the posterior border of the body of the sphenoid and the anterior edge of the
FIGURE 2. A, Example of a patient with Crouzon syndrome with midface hypoplasia (anteroposterior view). B, Lateral view of the same patient. Tahiri et al. Closure of the SOS in Crouzon Syndrome. J Oral Maxillofac Surg 2014.
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TAHIRI ET AL
A
B
FIGURE 3. A, Spheno-occipital synchondrosis (SOS) status by age at computed tomography (CT) scan in Crouzon group. B, SOS status by age at CT scan in control group. Tahiri et al. Closure of the SOS in Crouzon Syndrome. J Oral Maxillofac Surg 2014.
basiocciput. The SOS is thought to play an important role in the normal development of the cranial vault and facial skeleton, because it is the last synchondrosis of the skull base to fuse and its patency parallels midfacial growth.10,11,16 Although it has generally been thought to be gender dependent and to start at around age 7, with completion at about 12 and 14 years of age in girls and boys, respectively,7-11 the time of fusion of this synchondrosis is still a matter of debate in published studies. To overcome this limitation and not use published norms as our comparison group, we compiled and reviewed our own age- and gender-matched controls using an established trauma registry for patients ranging from 0 to 20 years old. Midfacial growth is not only driven by the patency of the SOS. In addition to the cranial base synchondrosis, other structures, such as the cranial vault sutures, subcranium, facial sutures, and central nervous system,
Table 2. COMPARISON OF SOS STATUS BETWEEN CROUZON GROUP AND AGE- AND GENDER-MATCHED CONTROL GROUP
Crouzon Group
SOS Status Open Partial fusion Complete fusion
could also play a role in craniofacial growth.11,16 Britto et al24 found that the intrinsic mesenchymal growth patterns of the maxilla, differentially affected by mutations of the FGFR1, FGFR2, and FGFR3 genes, played a role in midfacial growth. Moreover, Rosenberg et al16 suggested that many dysmorphic features seen in craniosynostosis might have resulted solely from cranial base fusion. This important role of the cranial base in craniomaxillofacial growth has also been shown in other studies.25-34 Complete fusion of the SOS in our Crouzon cohort was seen as early as 7.0 years of age, and the average age of patients with CT scans showing complete patency of the SOS in the Crouzon group was 14.0 years. Previous work by our group has shown that complete fusion of the SOS was noted as early as 2.8 years, with an average age of 11.9 years in the Pfeiffer group; as early as 3.1 years, with an average age of 6 years in the Apert group; and as early as 10.6 years, with an average age of 13.8 years in the Muenke group. Moreover, partial fusion was seen as
Control Group
Scans Mean Age Scans Mean Age (n) (yr) (n) (yr)
P Value
35 46
1.3 1.1 5.3 2.2
76 18
3.2 2.3
The Spheno-Occipital Synchondrosis Fuses Prematurely in Patients With Crouzon Syndrome and Midface Hypoplasia Compared With Age- and Gender-Matched Controls Youssef Tahiri, MD, CM, MSc, FRCSC,* J. Thomas Paliga, BA,y Arastoo Vossough, MD,z Scott P. Bartlett, MD,x and Jesse A. Taylor, MDk Purpose:
Premature closure of the spheno-occipital synchondrosis (SOS) has been associated with midface hypoplasia in animal models and patients with specific forms of syndromic craniosynostosis. The present study aimed to characterize SOS fusion in patients with Crouzon syndrome.
Patients and Methods:
A case-control study was performed in patients with Crouzon syndrome treated at the Children’s Hospital of Philadelphia from 1984 to 2012. The cases included patients with Crouzon syndrome and at least 1 high-quality computed tomography (CT) scan in which SOS patency could be assessed. Age- and gender-matched control CT scans were identified for comparison. The patient age at the CT scan was evaluated as the predictor, with SOS patency identified as the outcome variable. Three independent reviewers with high inter-rater reliability graded the SOS patency as open, partially fused, or completely fused. The Wilcoxon rank sum test was used to compare the Crouzon group and the controls.
Results:
During the study period, 30 patients were identified with Crouzon syndrome. A total of 24 patients, all with midface hypoplasia and with 112 cranial CT scans, met the inclusion criteria. Accordingly, 112 age- and gender-matched control CT scans were assessed. No patient in the control group had midface hypoplasia. Within the Crouzon group, the average age at complete closure (14.0 3.4 years) evident on the CT scan was significantly younger than that in the control group (16.6 2.2 years; P = .0152). The average age when the scans showed complete patency of the SOS in the Crouzon group (1.3 1.1 years) was significantly younger than that in the control group (3.2 2.3 years; P = .0001).
Conclusions: The SOS closes significantly earlier in patients with Crouzon syndrome compared with age- and gender-matched controls. The strong statistical correlation supports premature closure of the SOS as a possible mechanistic contributor to midface hypoplasia. Ó 2014 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 72:1173-1179, 2014
Crouzon syndrome was initially reported in 1912 by the French neurosurgeon Dr Octave Crouzon.1 The incidence has been estimated at 1 in 65,000 live births, and the inheritance is autosomal dominant, with an
occurrence that is both sporadic and familial.2 Premature fusion of the cranial sutures and cranial base synchondroses in patients with Crouzon syndrome has been attributed to mutations in the fibroblast growth
Received from Perelman School of Medicine at the University of
Address correspondence and reprint requests to Dr Taylor: Division
Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA.
of Plastic Surgery, Perelman School of Medicine at the University of
*Craniofacial Fellow, Division of Plastic Surgery.
Pennsylvania, Children’s Hospital of Philadelphia, Colket Translational
yClinical Research Fellow, Division of Plastic Surgery.
Research Bldg, 3501 Civic Center Blvd, 9th Fl, Philadelphia, PA 19104;
zAssociate Professor of Radiology, Department of Radiology.
e-mail: [email protected]
xProfessor of Surgery, Division of Plastic Surgery.
Received October 2 2013
kAssistant Professor of Surgery, Division of Plastic Surgery.
Accepted November 11 2013
The present study was funded by the Department of Surgery of the Children’s Hospital of Philadelphia and the Perelman School of
Ó 2014 American Association of Oral and Maxillofacial Surgeons
Medicine at the University of Pennsylvania.
http://dx.doi.org/10.1016/j.joms.2013.11.015
0278-2391/13/01426-2$36.00/0
The data included in our report have been presented at the International Society of Craniofacial Surgery in September 2013.
1173
1174 factor receptor (FGFR) 2 gene and, in rare instances, the FGFR 3 gene.3-5 Classic phenotypical features of Crouzon syndrome include bicoronal synostosis, exorbitism, and maxillary hypoplasia with relative mandibular prognathism.6 The spheno-occipital synchondrosis (SOS) is a site of endochondral ossification in the cranial base. It is located between the posterior border of the body of the sphenoid and the anterior edge of the basiocciput. Fusion of this synchondrosis starts at around age 7, with completion at around 12 and 14 years old in girls and boys, respectively.7-11 It has been thought to play an important role in the normal development and growth of the cranial vault and facial skeleton, because it is the last of the synchondroses of the skull base to fuse.12-14 Moreover, premature closure of the SOS has been associated with shortening and flattening of the anterior cranial base and midface hypoplasia in animal models and patients with Apert and Pfeiffer syndrome.11,15-17 It is possible that the SOS plays a mechanistic role in the development of midface hypoplasia in FGFR-mediated, syndromic craniosynostosis.15-17 To date, no study has examined the timing of closure of the SOS in patients with Crouzon syndrome, the most common of the acrocephalosyndactyly syndromes. The present study aimed to characterize the timing of SOS fusion in patients with Crouzon syndrome, a population with high rates of midface hypoplasia, relative to nonaffected controls without midface hypoplasia. We hypothesized that the SOS would close significantly earlier in patients with Crouzon syndrome than in age- and gender-matched controls.
Patients and Methods STUDY DESIGN AND PATIENT POPULATION
The institutional review board of the Children’s Hospital of Philadelphia reviewed and approved the present study. We performed a retrospective, case-control study of patients who had presented to the Children’s Hospital of Philadelphia Center for Facial Reconstruction from 1982 to September 2012. Patients with a clinical and genetic (when available) diagnosis of Crouzon syndrome and at least 1 fine-cut head computed tomography (CT) scan were included as cases. The scans were excluded if the visualization of the SOS was inadequate or incomplete. Using an established trauma registry for patients ranging from 0 to 20 years old, we identified an equal number of age- and gender-matched control finecut CT scans. The inclusion criteria for the control group were same gender and age at scanning within 3 months of the matched Crouzon syndrome scan. Age- and gender-matched controls with any underlying congenital or syndromic diagnosis were excluded.
CLOSURE OF THE SOS IN CROUZON SYNDROME VARIABLES AND DATA COLLECTION METHODS
The patient demographics, including age, gender, presence of midface hypoplasia, number of CT scans, and fusion status of the SOS (ie, open, partially closed, or closed) were recorded. The SOS was defined as open when no degree of hyperdense bony bridging across the hypodense SOS was evident (Fig 1A). It was considered partially closed when complete fusion was not evident, but some degree of hyperdense bony bridging was found across the hypodense cartilaginous SOS (Fig 1B). Finally, it was defined as closed when the CT scan showed a completely fused SOS, with complete replacement of the hypodense cartilage with hyperdense bone (Fig 1C). Using fine-cut head CT scans, the closure status of the SOS in the Crouzon syndrome and control groups were evaluated independently by 3 reviewers—2 craniofacial surgeons and 1 pediatric neuroradiologist. STATISTICAL ANALYSIS
The inter-rater agreement was evaluated using Cohen’s k coefficient, and the judges jointly reviewed the imaging studies and reached a consensus when a disagreement with regards to fusion status was present.11 The average age for the scans showing complete closure, partial closure, or an open SOS between the Crouzon and control groups was compared using the Wilcoxon rank sum test.
Results During the study period, 30 patients were identified with Crouzon syndrome. A total of 24 patients with 112 head CT scans met the inclusion criteria and had complete visualization of the SOS. The Crouzon group consisted of 12 boys and 12 girls, with a mean age of 6.6 years (Table 1). No significant differences were found in the demographics within the Crouzon group. The individual CT scans were treated as independent data points. The median number of CT scans for each patient with Crouzon syndrome was 4. All 24 patients in this group had a confirmed diagnosis of midface hypoplasia (Fig 2). A total of 112 age- and gender-matched CT scans were identified as meeting the inclusion criteria for the control group (Table 1). No patients in the control group had a diagnosis of midface hypoplasia (n = 112). Three independent reviewers evaluated the CT scans, with 97.3% inter-rater reliability (Cohen unweighted k = 0.96). Of the 24 patients in the Crouzon group, the earliest partial fusion of the SOS was seen at 1.0 year. This was in sharp contrast to the earliest partial closure in the control group at 6.3 years. The earliest age at complete closure was 7.0 years in the Crouzon cohort, much
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TAHIRI ET AL
FIGURE 1. Fusion status of the spheno-occipital synchondrosis (SOS). A, The SOS was defined as open when no degree of hyperdense bony bridging across the hypodense SOS was evident. B, The SOS was considered partially closed when complete fusion was not evident, but some degree of hyperdense bony bridging across the hypodense cartilaginous SOS was present. C, The SOS was defined as closed when the computed tomography scan showed a completely fused SOS with complete replacement of the hypodense cartilage with hyperdense bone. Tahiri et al. Closure of the SOS in Crouzon Syndrome. J Oral Maxillofac Surg 2014.
earlier than the earliest age at complete closure in the controls at 14.4 years. All scans in the Crouzon group at 4.9 years and older showed either partial or complete closure of the SOS. This correlated with the presence of midfacial hypoplasia on clinical examination. Accordingly, the latest age that evidenced patency of the SOS was 4.9 years. Complete fusion of the SOS was seen in all scans by 10.9 years of age and older in the Crouzon group (Fig 3A). However, the age- and gender-matched control CT scans showed SOS patency until a much later time, with the first recorded partial fusion at 6.3 years (range 6.3 to 14.0). On the CT scans showing a closed SOS,
the age at CT scanning ranged from 14.4 to 20.2 years. All CT scans in the 0.2- to 6.2-year range revealed a patent SOS (Fig 3B). Within the Crouzon group, the average age at complete SOS fusion evident on the CT scan was 14.0 3.4 years (n = 31) and was significantly lower than the average age at complete SOS fusion in the control group (16.6 2.2 years; n = 18; P = .0152). The average age at partial closure was significantly younger (5.3 2.2 years; n = 46) within the Crouzon group than the age in the control group (10.7 2.4 years; n = 18; P = .0001). Finally, the average age of the patients with CT scans showing complete patency of the SOS
1176
CLOSURE OF THE SOS IN CROUZON SYNDROME
Table 1. DEMOGRAPHIC CHARACTERISTICS OF CROUZON AND CONTROL GROUPS
Characteristic Patients (n) Gender (n) Male Female Age (yr) Mean Median Midface hypoplasia (n) CT scans (n) CT scans per patient (n) Mean Median
Crouzon Group Control Group 24
112
12 12
55 57
6.6 5.3 24 112
6.6 5.3 0 112
4.67 4
1 1
Abbreviation: CT, computed tomography. Tahiri et al. Closure of the SOS in Crouzon Syndrome. J Oral Maxillofac Surg 2014.
in the Crouzon group (1.3 1.1 years; n = 35) was significantly lower than that in the control group (3.2 2.3 years; n = 76; P = .0001; Table 2, Fig 4). To provide a graphic representation of the initiation of SOS fusion, a Kaplan-Meier survival curve is shown in Figure 5 showing a leftward shift in the SOS patency curve relative to the controls.
Discussion The present study aimed to characterize the timing of SOS fusion in patients with Crouzon syndrome, a population with a high rate of midface hypoplasia rela-
tive to nonaffected controls without midface hypoplasia. The present results have shown that the SOS in patients with Crouzon syndrome, all of whom had midfacial hypoplasia, fuses significantly earlier than the SOS of age- and gender-matched controls, none of whom had midface hypoplasia. Although we could not show causality, the association between premature SOS fusion and midface hypoplasia was statistically significant, lending additional evidence to the mechanistic role of early SOS fusion in the development of midface hypoplasia in patients with Crouzon syndrome. Premature closure of the SOS in patients with Apert syndrome has been linked to midfacial hypoplasia in a study from our group.11 Moreover, in the same study, patients with Muenke syndrome were not found to have premature fusion relative to their age- and gender-matched controls.11 Because midface hypoplasia is typically more marked in patients with Crouzon and Apert syndrome than in those with Muenke syndrome, the results of our study and those of previous studies11,15-17 suggest a direct correlation between the age of fusion and the degree of midface hypoplasia in these patient populations. The cranial base plays an important role in craniofacial development,13,14,18,19 with the anterior cranial base considered a primary driver of midfacial growth.20,21 Synchondroses form between prominent ossification centers during cranial base development. They are involved in bone growth during development and eventually fuse at skeletal maturity.14,22,23 The SOS is a site of endochondral ossification in the cranial base and is located between the posterior border of the body of the sphenoid and the anterior edge of the
FIGURE 2. A, Example of a patient with Crouzon syndrome with midface hypoplasia (anteroposterior view). B, Lateral view of the same patient. Tahiri et al. Closure of the SOS in Crouzon Syndrome. J Oral Maxillofac Surg 2014.
1177
TAHIRI ET AL
A
B
FIGURE 3. A, Spheno-occipital synchondrosis (SOS) status by age at computed tomography (CT) scan in Crouzon group. B, SOS status by age at CT scan in control group. Tahiri et al. Closure of the SOS in Crouzon Syndrome. J Oral Maxillofac Surg 2014.
basiocciput. The SOS is thought to play an important role in the normal development of the cranial vault and facial skeleton, because it is the last synchondrosis of the skull base to fuse and its patency parallels midfacial growth.10,11,16 Although it has generally been thought to be gender dependent and to start at around age 7, with completion at about 12 and 14 years of age in girls and boys, respectively,7-11 the time of fusion of this synchondrosis is still a matter of debate in published studies. To overcome this limitation and not use published norms as our comparison group, we compiled and reviewed our own age- and gender-matched controls using an established trauma registry for patients ranging from 0 to 20 years old. Midfacial growth is not only driven by the patency of the SOS. In addition to the cranial base synchondrosis, other structures, such as the cranial vault sutures, subcranium, facial sutures, and central nervous system,
Table 2. COMPARISON OF SOS STATUS BETWEEN CROUZON GROUP AND AGE- AND GENDER-MATCHED CONTROL GROUP
Crouzon Group
SOS Status Open Partial fusion Complete fusion
could also play a role in craniofacial growth.11,16 Britto et al24 found that the intrinsic mesenchymal growth patterns of the maxilla, differentially affected by mutations of the FGFR1, FGFR2, and FGFR3 genes, played a role in midfacial growth. Moreover, Rosenberg et al16 suggested that many dysmorphic features seen in craniosynostosis might have resulted solely from cranial base fusion. This important role of the cranial base in craniomaxillofacial growth has also been shown in other studies.25-34 Complete fusion of the SOS in our Crouzon cohort was seen as early as 7.0 years of age, and the average age of patients with CT scans showing complete patency of the SOS in the Crouzon group was 14.0 years. Previous work by our group has shown that complete fusion of the SOS was noted as early as 2.8 years, with an average age of 11.9 years in the Pfeiffer group; as early as 3.1 years, with an average age of 6 years in the Apert group; and as early as 10.6 years, with an average age of 13.8 years in the Muenke group. Moreover, partial fusion was seen as
Control Group
Scans Mean Age Scans Mean Age (n) (yr) (n) (yr)
P Value
35 46
1.3 1.1 5.3 2.2
76 18
3.2 2.3
