PEDIATRIC/CRANIOFACIAL Earlier Evidence of Spheno-Occipital Synchondrosis Fusion Correlates with Severity of Midface Hypoplasia in Patients with Syndromic Craniosynostosis Jesse A. Goldstein, M.D. J. Thomas Paliga, B.A. Jason D. Wink, B.A. Scott P. Bartlett, M.D. Hyun-Duc Nah, Ph.D., D.D.S. Jesse A. Taylor, M.D. Philadelphia, Pa.
Background: The spheno-occipital synchondrosis is an important driver of facial and cranial base growth. The current study characterizes its fusion in patients with Apert, Crouzon, and Pfeiffer syndromes and correlates early fusion with the presence, and degree, of midface hypoplasia. Methods: A retrospective case-control study was performed of all syndromic patients treated between 1996 and 2012. Case computed tomographic scans and age- and sex-matched control scans were analyzed as demonstrating either open, partially fused, or completely fused synchondroses, and patient age at each scan was recorded. Midface hypoplasia as determined by sella-nasion–A point angle measurement at the time of midface surgery was correlated to fusion status. Results: Fifty-four patients with 206 computed tomographic scans met inclusion criteria. Two hundred six age- and sex-matched control scans were also identified. Average age at computed tomographic scanning was 6.1 years. The earliest ages of partial and complete fusion were 1.1 and 7.0 years, respectively, among cases; and 6.2 and 12.7 years, respectively, among controls. The odds of synchondrosis fusion in case computed tomographic scans was 66.0 times that of controls (95 percent CI, 9.2 to 475.5 times that of controls; p < 0.000001). Average age of synchondrosis fusion was 3.5 years (range, 0.5 to 6.0 years). Average sella-nasion–A point angle at the time of midface surgery was 67.5 degrees (range, 58 to 76 degrees), with a positive correlation between earlier age of fusion and more severe midface hypoplasia (p = 0.028). Conclusions: The spheno-occipital synchondrosis fuses earlier in syndromic patients compared with age-matched controls. Moreover, there is a positive correlation between earlier fusion and degree of midface hypoplasia, although definitive causality cannot be concluded. This is the first study to demonstrate such a correlation in human subjects. (Plast. Reconstr. Surg. 134: 504, 2014.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.
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atients with syndromic forms of craniosynostosis such as Apert, Crouzon, and Pfeiffer syndromes present with complex congenital anomalies including multiple affected cranial sutures, hand and feet abnormalities, and varying degrees of midface hypoplasia. These patients represent a therapeutic challenge for craniofacial surgeons, often requiring many complicated From the Division of Plastic Surgery, Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia. Received for publication June 5, 2013; accepted January 23, 2014. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000419
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surgical interventions over the course of their lifetimes. Although the genetic basis of many of these features has been established, the cause and the type and timing of treatment of midface hypoplasia in this population remain controversial.1–6 The spheno-occipital synchondrosis has garnered recent attention as an important site of cranial base and midface growth that may be disturbed in patients with syndromic craniosynostosis.7 A major site of endochondral cranial base growth, the spheno-occipital synchondrosis is located in the midline at the junction of the Disclosure: The authors have no financial disclosures to report.
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Volume 134, Number 3 • Spheno-Occipital Synchondrosis Closure posterior border of the body of the sphenoid and the anterior edge of the basiocciput and may be an important contributor to anteroposterior growth of the cranial base well into adolescence. The spheno-occipital synchondrosis is the last of the synchondroses of the cranial base to fuse, and closure time is also sex-dependent, with fusion occurring in girls slightly earlier at approximately age 12 years and in boys slightly later at approximately age 14 years.8,9 An important component of cranial base and consequently facial growth, its premature fusion has been shown in animal models10 (and with increasing evidence in humans7,11) to be associated with both cranial base and midface hypoplasia. The purpose of this study was to explore the relationship between timing of spheno-occipital synchondrosis fusion in patients with Apert, Crouzon, and Pfeiffer syndromes and midface development. To evaluate the role the spheno-occipital synchondrosis plays in midface hypoplasia, we developed two hypotheses: first, the spheno-occipital synchondrosis fuses significantly earlier in patients with syndromic craniosynostosis compared with age- and sex-matched controls; and second, the timing of spheno-occipital synchondrosis fusion correlates with the degree of midface hypoplasia in patients with syndromic craniosynostosis.
PATIENTS AND METHODS After approval of The Children’s Hospital of Philadelphia Institutional Review Board, a retrospective case control study was performed to characterize the timing of spheno-occipital synchondrosis fusion in patients with syndromic craniosynostosis. Fine-cut computed tomographic scanning served as the unit for comparison in this study, with each study group patient contributing multiple computed tomographic scans. Case
computed tomographic scans were identified from an ongoing database of patients with craniofacial anomalies who presented to The Children’s Hospital of Philadelphia between 1996 and 2012. Those patients with diagnoses of Apert, Crouzon, or Pfeiffer syndrome served as the study group. A prospective and independently maintained trauma registry served as the source of control computed tomographic scans that were age- and sex-matched to each study group computed tomographic scan. The spheno-occipital synchondrosis status of both study group and control computed tomographic scans was assessed based on a previously published three-tier scale.7 Three independent and blinded reviewers consisting of two craniofacial surgeons and one neuroradiologist evaluated the spheno-occipital synchondrosis in each computed tomographic scan. The spheno-occipital synchondrosis was determined to be open, partially fused, or completely fused (Fig. 1). Open synchondroses were defined as those without any evidence of apposition along the entire width of the synchondrosis. Partial fusion was defined as the existence of any area in which the anterior and posterior bony edges had bridged the cartilaginous hypodense synchondrosis. Complete fusion was assigned to synchondroses that demonstrated complete obliteration of the hypodense synchondrosis with replacement by hyperdense bone. Each rater independently evaluated the status of the synchondrosis, and interrater agreement was assessed by the Cohen kappa coefficient. In cases with disagreement, the computed tomographic scan was reviewed jointly and a consensus was reached among reviewers. From our cohort of study patients with multiple computed tomographic scans, a subgroup of patients who underwent midface advancement
Fig. 1. (Left) To be considered open, no degree of hyperdense bony bridging across the hypodense spheno-occipital synchondrosis could be evident. (Center) If any degree of hyperdense bony bridging across the hypodense cartilaginous synchondrosis was present but complete fusion was not evident, the closure status was considered partially closed. Note the bony bridging. (Right) Only those scans showing a completely fused spheno-occipital synchondrosis with complete replacement of the hypodense cartilage with hyperdense bone were labeled as closed.
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Plastic and Reconstructive Surgery • September 2014 surgery and who also had at least two computed tomographic scans demonstrating progression in spheno-occipital synchondrosis fusion were identified. These patients required at least one computed tomographic scan with an open spheno-occipital synchondrosis and a subsequent computed tomographic scan demonstrating either partial or compete spheno-occipital synchondrosis fusion. The age of first evidence of this computed tomography–demonstrated progression of spheno-occipital synchondrosis fusion was recorded for each patient and compared with a cephalometric analysis of midface projection (sella-nasion–A point angle) immediately preceding midface advancement surgery. Statistical Analysis Statistical analysis used the McNemar matchedpairs test to evaluate the odds of spheno-occipital synchondrosis fusion in each pair of case-control computed tomographic scans. Kaplan-Meier survival analysis was performed to characterize and compare the timing of spheno-occipital synchondrosis fusion in case and control computed tomographic scans. Finally, to assess the relationship between timing of first evidence of computed tomography–demonstrated spheno-occipital synchondrosis fusion and severity of midface hypoplasia, linear regression analysis was performed.
RESULTS Two hundred six case computed tomographic scans in 54 patients with syndromic craniosynostosis met inclusion criteria and were compared to 206 age- and sex-matched control computed tomographic scans from 206 trauma patients. The average age at computed tomographic scanning was 6.6 years (range, 0.0 to 20.2 years). The diagnoses and spheno-occipital synchondrosis status of both case and control computed tomographic scans are listed in Table 1. Sixty-five case computed tomographic scans (32 percent) compared with 132 control computed tomographic scans (65 percent) demonstrated an open synchondrosis. In contrast, 85 case computed tomographic scans (42 percent)
and 42 control computed tomographic scans (20 percent) demonstrated partial spheno-occipital synchondrosis fusion, whereas 56 cases (27 percent) and 32 controls (16 percent) demonstrated complete spheno-occipital synchondrosis fusion. The earliest age of computed tomography–demonstrated partial fusion was 1.1 years in syndromic computed tomographic scans and 6.2 years in control computed tomographic scans, and the earliest age of computed tomography–demonstrated complete fusion was 7 years in syndromic computed tomographic scans and 12.7 years in control computed tomographic scans (Fig. 2). To take advantage of the case-control design, the McNemar matched-pairs test was used to evaluate the odds of spheno-occipital synchondrosis fusion in each case-control matched pair. Odds of spheno-occipital synchondrosis fusion were significantly higher in Apert (OR, 8.0; 95 percent CI, 1.0 to 63.9; p = 0.04), Crouzon (OR, 37.0; 95 percent CI, 5.1 to 269.7; p < 0.0001), and Pfeif fer computed tomographic scans (OR, 19.0; 95 percent CI, 2.5 to 141.9; p < 0.0004) than in ageand sex-matched control computed tomographic scans. Combined, the odds of computed tomography–demonstrated spheno-occipital synchondrosis fusion were 66-fold greater in all syndromic patients than in controls (OR, 66.0; 95 percent CI, 9.2 to 475.5; p < 0.00001). Kaplan-Meier survival analysis was used to compare the timing of spheno-occipital synchondrosis fusion between case and control computed tomographic scans (Fig. 3). At time zero, there is no evidence of spheno-occipital synchondrosis fusion in either case or control computed tomographic scans. In addition, at time 20 years, there is nearly 100 percent spheno-occipital synchondrosis fusion in both case and control scans. Leftward shift of the case (syndromic) curve demonstrates a significantly earlier timing of sphenooccipital synchondrosis fusion in case computed tomographic scans than in control computed tomographic scans (p < 0.00001). Twenty-five patients were identified in our cohort who underwent midface advancement surgery who also had computed tomography–demonstrated
Table 1. Diagnoses and Spheno-Occipital Synchondrosis Status Apert Crouzon Pfeiffer Total Controls
No. of Patients
Total CT Scans
Open SOS (%)
Partially Fused SOS (%)
Fused SOS (%)
15 24 15 54 206
38 112 56 206 206
0 38 (34) 27 (48) 65 (32) 132 (64)
19 (50) 43 (38) 23 (41) 85 (42) 42 (20)
19 (50) 31 (28) 6 (11) 56 (27) 32 (16)
CT, computed tomographic; SOS, spheno-occipital synchondrosis.
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Volume 134, Number 3 • Spheno-Occipital Synchondrosis Closure DISCUSSION
Fig. 2. Age at first evidence of spheno-occipital synchondrosis fusion.
progression in spheno-occipital synchondrosis fusion. Average age of first evidence of progression of spheno-occipital synchondrosis fusion was 3.7 years (range, 0.4 to 7.4 years), whereas average age of midface surgery was 5.9 years (range, 4.0 to 9.3 years). Sella-nasion–A point angle measurements immediately before midface surgery averaged 67.4 degrees (range 58 to 76 degrees), demonstrating significant anteroposterior midface hypoplasia in all patients. Linear regression analysis demonstrated a relationship between spheno-occipital synchondrosis fusion progression, age, and sellanasion–A point angle (p = 0.02), indicating an association between earlier age of spheno-occipital synchondrosis fusion and more severe midface hypoplasia (Fig. 4).
The role of the cranial base in the development of the human midface has yet to be fully elucidated. This study’s findings provide the strongest evidence to date that insufficient midface growth in patients with syndromic craniosynostosis is associated with premature fusion of the spheno-occipital synchondrosis. We establish in a matched-pairs analysis that patients with Apert, Crouzon, and Pfeiffer syndromes are at increased odds of spheno-occipital synchondrosis fusion compared with age- and sex-matched controls when examined by computed tomographic analysis. In addition, we show that this spheno-occipital synchondrosis fusion occurs significantly earlier in syndromic patients that in control patients. Finally, we demonstrate a significant association between earlier age of computed tomography– demonstrated spheno-occipital synchondrosis fusion and more severe midface hypoplasia at the time of midface advancement surgery. Our center has recently characterized differential closure of the spheno-occipital synchondrosis in patients with Apert and Muenke syndromes and in patients with Pfeiffer syndrome. McGrath and colleagues demonstrated through similar methodology a difference in spheno-occipital synchondrosis fusion timing in patients with Apert syndrome who have a nearly 100 percent incidence of midface hypoplasia and patients with Muenke syndrome who have significantly lower rates of midface hypoplasia.7 Paliga et al. found similar closure timing in their cohort of Pfeiffer
Fig. 3. Kaplan-Meier survival analysis. Orange line, syndromic craniosynostosis; blue line, controls. Likelihood ratio test, 22.8 (p < 0.00001). SOS, spheno-occipital synchondrosis.
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Fig. 4. Sella-nasion–A point angle (normal sella-nasion–A point angle, 81 ± 3 degrees). Linear regression demonstrates a positive relationship between earlier age of spheno-occipital synchondrosis closure (years) and more severe midface hypoplasia (sella-nasion–A point angle in degrees) (p = 0.02). SNA, sella-nasion–A point angle; SOS, spheno-occipital synchondrosis.
syndrome patients.12 However, neither study rigorously evaluated the difference in closure timing with control scans or was powered to assess the relationship between the timing of spheno-occipital synchondrosis closure and degree of hypoplasia of the midface. Other publications have cited the sphenooccipital synchondrosis as important in midface growth. These include several case reports of early spheno-occipital synchondrosis fusion in patients with syndromic craniosynostosis,13,14 various animal studies,10,15,16 and limited retrospective reviews.2,7,11 Rosenberg and colleagues provide the most compelling laboratory evidence for the relationship between synchondrosis growth and midface projection. In their rabbit synostosis model, they compared cephalometric growth in 60 animals after cranial vault, cranial base, or combined sutural immobilization. They conclude that cranial base fusion may play an equal if not more important role compared with cranial vault fusion in craniofacial length restriction and midface hypoplasia. These results highlight the role of arrested cranial base growth in the development of dysmorphic features seen in syndromic craniosynostosis. This finding is consistent with other investigators, confirming both a primary directive and translational role of the cranial base in craniofacial growth.10 However, there are important differences between human and animal model cranial bases that may lessen the inferences that can be drawn from such work.
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As the above study implies, cranial base synchondroses differ considerably from cranial vault sutures in terms of both form and function. Forming from the fusion of the parachordal plates around the notochord during embryonic development, the cranial base plays an important active role in craniofacial development.1,17–19 As the cranial base develops, synchondroses form between prominent ossification centers, which serve a function similar to long bone growth plates by enabling rapid bone growth during development before fusion as skeletal maturity is neared.19–21 All of the cranial base synchondroses except for the spheno-occipital synchondrosis fuse in infancy, whereas the spheno-occipital synchondrosis remains open until adolescence, prompting investigations into its role in cranial base and midfacial development.8,9,13,17 In contrast, cranial vault formation occurs through intramembranous ossification and may rely more on a passive development from surrounding functional matrix than in the endochondral basicranium.22 Premature spheno-occipital synchondrosis fusion is likely not the only driver of midface hypoplasia—intrinsic midface growth across open facial sutures and cranial vault morphology may also play roles. Indeed, developmental genetic analysis by Britto and colleagues has shown a differential expression of fibroblast growth factor receptors (FGFR) in human embryos with high activity of FGFR1 and FGFR2 in facial osteogenic fronts in 8- to 13-week human embryos but minimal FGFR3 activity.23 Although these findings are
Volume 134, Number 3 • Spheno-Occipital Synchondrosis Closure also found in the cranial base, differential FGFR expression in midface bony mesenchyme may partly explain why Apert, Crouzon, and Pfeiffer syndromes, which are associated with gain-of-function mutations in FGFR1 and FGFR2, demonstrate higher rates of midface hypoplasia than in patients with Muenke syndrome (FGFR3 mutations). It is difficult to explain why FGFR mutations may affect development at the spheno-occipital synchondrosis preferentially, and, indeed, this may not be the case. However, as the last of the cranial base synchondroses to fuse, the effect of early closure at the spheno-occipital synchondrosis may simply be magnified because of the lengthy period over which the premature fusion acts. In other words, other cranial base synchondroses and facial sutures that are programmed to close by age 2, and not by age 12 or 14 years as is the case with the spheno-occipital synchondrosis, may not demonstrate the profundity of phenotypic dysmorphology. It is also notable that even in controls the spheno-occipital synchondrosis begins to fuse by age 7 to 9 years. Large, population-based computed tomographic studies of the spheno-occipital synchondrosis have demonstrated continued growth at the spheno-occipital synchondrosis until approximately 50 percent of the surface area of the synchondrosis is fused.24,25 An important consideration in drawing conclusions from these results is the manner in which spheno-occipital synchondrosis closure is evaluated. Comparison across detection methods has proven unreliable and, as such, we aimed to reproduce the methods previously established at our center by evaluating computed tomographic scans in an age- and sex-matched case-control design. Although more rigorous than standard retrospective methodologies, this design prohibits any conclusions of causality. In addition, we rely on computed tomographic scans obtained as part of normal clinical care, often at irregular intervals, which, though the best modality available, significantly diminishes the power of the current study to accurately reflect spheno-occipital synchondrosis closure timing. Finally, as many authors have previously done, we use the sella-nasion–A point angle as a proxy measure for the degree of midface hypoplasia. The sella-nasion–A point angle, however, only assesses the degree of midface projection, and the presence of hypoplasia is inferred. Because of these limitations, we are careful to conclude a strong correlation and not causality. Despite present limitations, these data have important implications in the pathogenesis and, potentially, treatment of midface hypoplasia in
syndromic craniosynostosis. If premature closure of the spheno-occipital synchondrosis is a primary driver of midface growth and development, it may prove to be an important target for intervention either to reverse midface hypoplasia before complete fusion, or to prevent it altogether with earlier intervention.
CONCLUSIONS The spheno-occipital synchondrosis fuses earlier in patients with Apert, Crouzon, and Pfeiffer syndromes and midface hypoplasia than in ageand sex-matched control patients without midface hypoplasia. In addition, earlier spheno-occipital synchondrosis fusion is correlated with more severe midface hypoplasia in syndromic patients. Although definitive determination of causality cannot be concluded, these data bolster the argument that the spheno-occipital synchondrosis is an important component of midface growth and may be an important target for intervention. Jesse A. Taylor, M.D. Perelman School of Medicine at the University of Pennsylvania The Children’s Hospital of Philadelphia Colket Translational Research Building 3501 Civic Center Boulevard, Ninth Floor Philadelphia, Pa. 19104 [email protected]
acknowledgment
This work was funded by the Division of Plastic Surgery of The Children’s Hospital of Philadelphia. references 1. Nie X. Cranial base in craniofacial development: Developmental features, influence on facial growth, anomaly, and molecular basis. Acta Odontol Scand. 2005;63:127–135. 2. Hoyte DA. The cranial base in normal and abnormal skull growth. Neurosurg Clin N Am. 1991;2:515–537. 3. Marchac A, Arnaud E. Cranium and midface distraction osteogenesis: Current practices, controversies, and future applications. J Craniofac Surg. 2012;23:235–238. 4. Shetye PR, Davidson EH, Sorkin M, Grayson BH, McCarthy JG. Evaluation of three surgical techniques for advancement of the midface in growing children with syndromic craniosynostosis. Plast Reconstr Surg. 2010;126:982–994. 5. Graewe FR, Morkel JA, Hartzenberg HB, Ross RJ, Zuehlke AE. Midface distraction without osteotomies in an infant with upper respiratory obstruction. J Craniofac Surg. 2008;19:1603–1607. 6. Katzen JT, McCarthy JG. Syndromes involving craniosynostosis and midface hypoplasia. Otolaryngol Clin North Am. 2000;33:1257–1284, vi. 7. McGrath J, Gerety PA, Derderian CA, et al. Differential closure of the spheno-occipital synchondrosis in syndromic craniosynostosis. Plast Reconstr Surg. 2012;130:681e–689e.
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Plastic and Reconstructive Surgery • September 2014 8. Powell TV, Brodie AG. Closure of the spheno-occipital synchondrosis. Anat Rec. 1963;147:15–23. 9. Ingervall B, Thilander B. The human spheno-occipital synchondrosis: I. The time of closure appraised macroscopically. Acta Odontol Scand. 1972;30:349–356. 10. Rosenberg P, Arlis HR, Haworth RD, Heier L, Hoffman L, LaTrenta G. The role of the cranial base in facial growth: Experimental craniofacial synostosis in the rabbit. Plast Reconstr Surg. 1997;99:1396–1407. 11. Coben SE. The spheno-occipital synchondrosis: The missing link between the profession’s concept of craniofacial growth and orthodontic treatment. Am J Orthod Dentofacial Orthop. 1998;114:709–712; discussion 713. 12. Paliga JT, Goldstein JA, Vossough A, Bartlett SP, Nah HD, Taylor JA. Premature closure of the spheno-occipital synchondrosis in patients with Pfeiffer syndrome: A link to midface hypoplasia. J Craniofac Surg. 2014;25:202–205. 13. Kreiborg S, Prydsoe U, Dahl E, Fogh-Anderson P. Clinical conference I. Calvarium and cranial base in Apert’s syndrome: An autopsy report. Cleft Palate J. 1976;13:296–303. 14. Ousterhout DK, Melsen B. Cranial base deformity in Apert’s syndrome. Plast Reconstr Surg. 1982;69:254–263. 15. Ma W, Lozanoff S. Spatial and temporal distribution of cellular proliferation in the cranial base of normal and midfacially retrusive mice. Clin Anat. 1999;12:315–325. 16. Bütow KW. Craniofacial growth disturbance after skull base and associated suture synostoses in the newborn chacma baboon: A preliminary report. Cleft Palate J. 1990;27:241–251; discussion 251.
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17. Friede H. Normal development and growth of the human neurocranium and cranial base. Scand J Plast Reconstr Surg. 1981;15:163–169. 18. Couly GF, Coltey PM, Le Douarin NM. The triple origin of skull in higher vertebrates: A study in quail-chick chimeras. Development 1993;117:409–429. 19. Shum L, Wang X, Kane AA, Nuckolls GH. BMP4 promotes chondrocyte proliferation and hypertrophy in the endochondral cranial base. Int J Dev Biol. 2003;47:423–431. 20. Reddi AH. Interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: Noggin, chordin and DAN. Arthritis Res. 2001;3:1–5. 21. Pizette S, Niswander L. Early steps in limb patterning and chondrogenesis. Novartis Found Symp. 2001;232:23–36; discussion 36. 22. Levi B, Wan DC, Wong VW, Nelson E, Hyun J, Longaker MT. Cranial suture biology: From pathways to patient care. J Craniofac Surg. 2012;23:13–19. 23. Britto JA, Evans RD, Hayward RD, Jones BM. From genotype to phenotype: The differential expression of FGF, FGFR, and TGFbeta genes characterizes human cranioskeletal development and reflects clinical presentation in FGFR syndromes. Plast Reconstr Surg. 2001;108:2026–2039; discussion 2040. 24. Madeline LA, Elster AD. Suture closure in the human chondrocranium: CT assessment. Radiology 1995;196:747–756. 25. Bassed RB, Briggs C, Drummer OH. Analysis of time of closure of the spheno-occipital synchondrosis using computed tomography. Forensic Sci Int. 2010;200:161–164.
Background: The spheno-occipital synchondrosis is an important driver of facial and cranial base growth. The current study characterizes its fusion in patients with Apert, Crouzon, and Pfeiffer syndromes and correlates early fusion with the presence, and degree, of midface hypoplasia. Methods: A retrospective case-control study was performed of all syndromic patients treated between 1996 and 2012. Case computed tomographic scans and age- and sex-matched control scans were analyzed as demonstrating either open, partially fused, or completely fused synchondroses, and patient age at each scan was recorded. Midface hypoplasia as determined by sella-nasion–A point angle measurement at the time of midface surgery was correlated to fusion status. Results: Fifty-four patients with 206 computed tomographic scans met inclusion criteria. Two hundred six age- and sex-matched control scans were also identified. Average age at computed tomographic scanning was 6.1 years. The earliest ages of partial and complete fusion were 1.1 and 7.0 years, respectively, among cases; and 6.2 and 12.7 years, respectively, among controls. The odds of synchondrosis fusion in case computed tomographic scans was 66.0 times that of controls (95 percent CI, 9.2 to 475.5 times that of controls; p < 0.000001). Average age of synchondrosis fusion was 3.5 years (range, 0.5 to 6.0 years). Average sella-nasion–A point angle at the time of midface surgery was 67.5 degrees (range, 58 to 76 degrees), with a positive correlation between earlier age of fusion and more severe midface hypoplasia (p = 0.028). Conclusions: The spheno-occipital synchondrosis fuses earlier in syndromic patients compared with age-matched controls. Moreover, there is a positive correlation between earlier fusion and degree of midface hypoplasia, although definitive causality cannot be concluded. This is the first study to demonstrate such a correlation in human subjects. (Plast. Reconstr. Surg. 134: 504, 2014.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.
P
atients with syndromic forms of craniosynostosis such as Apert, Crouzon, and Pfeiffer syndromes present with complex congenital anomalies including multiple affected cranial sutures, hand and feet abnormalities, and varying degrees of midface hypoplasia. These patients represent a therapeutic challenge for craniofacial surgeons, often requiring many complicated From the Division of Plastic Surgery, Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia. Received for publication June 5, 2013; accepted January 23, 2014. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000419
504
surgical interventions over the course of their lifetimes. Although the genetic basis of many of these features has been established, the cause and the type and timing of treatment of midface hypoplasia in this population remain controversial.1–6 The spheno-occipital synchondrosis has garnered recent attention as an important site of cranial base and midface growth that may be disturbed in patients with syndromic craniosynostosis.7 A major site of endochondral cranial base growth, the spheno-occipital synchondrosis is located in the midline at the junction of the Disclosure: The authors have no financial disclosures to report.
www.PRSJournal.com
Volume 134, Number 3 • Spheno-Occipital Synchondrosis Closure posterior border of the body of the sphenoid and the anterior edge of the basiocciput and may be an important contributor to anteroposterior growth of the cranial base well into adolescence. The spheno-occipital synchondrosis is the last of the synchondroses of the cranial base to fuse, and closure time is also sex-dependent, with fusion occurring in girls slightly earlier at approximately age 12 years and in boys slightly later at approximately age 14 years.8,9 An important component of cranial base and consequently facial growth, its premature fusion has been shown in animal models10 (and with increasing evidence in humans7,11) to be associated with both cranial base and midface hypoplasia. The purpose of this study was to explore the relationship between timing of spheno-occipital synchondrosis fusion in patients with Apert, Crouzon, and Pfeiffer syndromes and midface development. To evaluate the role the spheno-occipital synchondrosis plays in midface hypoplasia, we developed two hypotheses: first, the spheno-occipital synchondrosis fuses significantly earlier in patients with syndromic craniosynostosis compared with age- and sex-matched controls; and second, the timing of spheno-occipital synchondrosis fusion correlates with the degree of midface hypoplasia in patients with syndromic craniosynostosis.
PATIENTS AND METHODS After approval of The Children’s Hospital of Philadelphia Institutional Review Board, a retrospective case control study was performed to characterize the timing of spheno-occipital synchondrosis fusion in patients with syndromic craniosynostosis. Fine-cut computed tomographic scanning served as the unit for comparison in this study, with each study group patient contributing multiple computed tomographic scans. Case
computed tomographic scans were identified from an ongoing database of patients with craniofacial anomalies who presented to The Children’s Hospital of Philadelphia between 1996 and 2012. Those patients with diagnoses of Apert, Crouzon, or Pfeiffer syndrome served as the study group. A prospective and independently maintained trauma registry served as the source of control computed tomographic scans that were age- and sex-matched to each study group computed tomographic scan. The spheno-occipital synchondrosis status of both study group and control computed tomographic scans was assessed based on a previously published three-tier scale.7 Three independent and blinded reviewers consisting of two craniofacial surgeons and one neuroradiologist evaluated the spheno-occipital synchondrosis in each computed tomographic scan. The spheno-occipital synchondrosis was determined to be open, partially fused, or completely fused (Fig. 1). Open synchondroses were defined as those without any evidence of apposition along the entire width of the synchondrosis. Partial fusion was defined as the existence of any area in which the anterior and posterior bony edges had bridged the cartilaginous hypodense synchondrosis. Complete fusion was assigned to synchondroses that demonstrated complete obliteration of the hypodense synchondrosis with replacement by hyperdense bone. Each rater independently evaluated the status of the synchondrosis, and interrater agreement was assessed by the Cohen kappa coefficient. In cases with disagreement, the computed tomographic scan was reviewed jointly and a consensus was reached among reviewers. From our cohort of study patients with multiple computed tomographic scans, a subgroup of patients who underwent midface advancement
Fig. 1. (Left) To be considered open, no degree of hyperdense bony bridging across the hypodense spheno-occipital synchondrosis could be evident. (Center) If any degree of hyperdense bony bridging across the hypodense cartilaginous synchondrosis was present but complete fusion was not evident, the closure status was considered partially closed. Note the bony bridging. (Right) Only those scans showing a completely fused spheno-occipital synchondrosis with complete replacement of the hypodense cartilage with hyperdense bone were labeled as closed.
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Plastic and Reconstructive Surgery • September 2014 surgery and who also had at least two computed tomographic scans demonstrating progression in spheno-occipital synchondrosis fusion were identified. These patients required at least one computed tomographic scan with an open spheno-occipital synchondrosis and a subsequent computed tomographic scan demonstrating either partial or compete spheno-occipital synchondrosis fusion. The age of first evidence of this computed tomography–demonstrated progression of spheno-occipital synchondrosis fusion was recorded for each patient and compared with a cephalometric analysis of midface projection (sella-nasion–A point angle) immediately preceding midface advancement surgery. Statistical Analysis Statistical analysis used the McNemar matchedpairs test to evaluate the odds of spheno-occipital synchondrosis fusion in each pair of case-control computed tomographic scans. Kaplan-Meier survival analysis was performed to characterize and compare the timing of spheno-occipital synchondrosis fusion in case and control computed tomographic scans. Finally, to assess the relationship between timing of first evidence of computed tomography–demonstrated spheno-occipital synchondrosis fusion and severity of midface hypoplasia, linear regression analysis was performed.
RESULTS Two hundred six case computed tomographic scans in 54 patients with syndromic craniosynostosis met inclusion criteria and were compared to 206 age- and sex-matched control computed tomographic scans from 206 trauma patients. The average age at computed tomographic scanning was 6.6 years (range, 0.0 to 20.2 years). The diagnoses and spheno-occipital synchondrosis status of both case and control computed tomographic scans are listed in Table 1. Sixty-five case computed tomographic scans (32 percent) compared with 132 control computed tomographic scans (65 percent) demonstrated an open synchondrosis. In contrast, 85 case computed tomographic scans (42 percent)
and 42 control computed tomographic scans (20 percent) demonstrated partial spheno-occipital synchondrosis fusion, whereas 56 cases (27 percent) and 32 controls (16 percent) demonstrated complete spheno-occipital synchondrosis fusion. The earliest age of computed tomography–demonstrated partial fusion was 1.1 years in syndromic computed tomographic scans and 6.2 years in control computed tomographic scans, and the earliest age of computed tomography–demonstrated complete fusion was 7 years in syndromic computed tomographic scans and 12.7 years in control computed tomographic scans (Fig. 2). To take advantage of the case-control design, the McNemar matched-pairs test was used to evaluate the odds of spheno-occipital synchondrosis fusion in each case-control matched pair. Odds of spheno-occipital synchondrosis fusion were significantly higher in Apert (OR, 8.0; 95 percent CI, 1.0 to 63.9; p = 0.04), Crouzon (OR, 37.0; 95 percent CI, 5.1 to 269.7; p < 0.0001), and Pfeif fer computed tomographic scans (OR, 19.0; 95 percent CI, 2.5 to 141.9; p < 0.0004) than in ageand sex-matched control computed tomographic scans. Combined, the odds of computed tomography–demonstrated spheno-occipital synchondrosis fusion were 66-fold greater in all syndromic patients than in controls (OR, 66.0; 95 percent CI, 9.2 to 475.5; p < 0.00001). Kaplan-Meier survival analysis was used to compare the timing of spheno-occipital synchondrosis fusion between case and control computed tomographic scans (Fig. 3). At time zero, there is no evidence of spheno-occipital synchondrosis fusion in either case or control computed tomographic scans. In addition, at time 20 years, there is nearly 100 percent spheno-occipital synchondrosis fusion in both case and control scans. Leftward shift of the case (syndromic) curve demonstrates a significantly earlier timing of sphenooccipital synchondrosis fusion in case computed tomographic scans than in control computed tomographic scans (p < 0.00001). Twenty-five patients were identified in our cohort who underwent midface advancement surgery who also had computed tomography–demonstrated
Table 1. Diagnoses and Spheno-Occipital Synchondrosis Status Apert Crouzon Pfeiffer Total Controls
No. of Patients
Total CT Scans
Open SOS (%)
Partially Fused SOS (%)
Fused SOS (%)
15 24 15 54 206
38 112 56 206 206
0 38 (34) 27 (48) 65 (32) 132 (64)
19 (50) 43 (38) 23 (41) 85 (42) 42 (20)
19 (50) 31 (28) 6 (11) 56 (27) 32 (16)
CT, computed tomographic; SOS, spheno-occipital synchondrosis.
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Volume 134, Number 3 • Spheno-Occipital Synchondrosis Closure DISCUSSION
Fig. 2. Age at first evidence of spheno-occipital synchondrosis fusion.
progression in spheno-occipital synchondrosis fusion. Average age of first evidence of progression of spheno-occipital synchondrosis fusion was 3.7 years (range, 0.4 to 7.4 years), whereas average age of midface surgery was 5.9 years (range, 4.0 to 9.3 years). Sella-nasion–A point angle measurements immediately before midface surgery averaged 67.4 degrees (range 58 to 76 degrees), demonstrating significant anteroposterior midface hypoplasia in all patients. Linear regression analysis demonstrated a relationship between spheno-occipital synchondrosis fusion progression, age, and sellanasion–A point angle (p = 0.02), indicating an association between earlier age of spheno-occipital synchondrosis fusion and more severe midface hypoplasia (Fig. 4).
The role of the cranial base in the development of the human midface has yet to be fully elucidated. This study’s findings provide the strongest evidence to date that insufficient midface growth in patients with syndromic craniosynostosis is associated with premature fusion of the spheno-occipital synchondrosis. We establish in a matched-pairs analysis that patients with Apert, Crouzon, and Pfeiffer syndromes are at increased odds of spheno-occipital synchondrosis fusion compared with age- and sex-matched controls when examined by computed tomographic analysis. In addition, we show that this spheno-occipital synchondrosis fusion occurs significantly earlier in syndromic patients that in control patients. Finally, we demonstrate a significant association between earlier age of computed tomography– demonstrated spheno-occipital synchondrosis fusion and more severe midface hypoplasia at the time of midface advancement surgery. Our center has recently characterized differential closure of the spheno-occipital synchondrosis in patients with Apert and Muenke syndromes and in patients with Pfeiffer syndrome. McGrath and colleagues demonstrated through similar methodology a difference in spheno-occipital synchondrosis fusion timing in patients with Apert syndrome who have a nearly 100 percent incidence of midface hypoplasia and patients with Muenke syndrome who have significantly lower rates of midface hypoplasia.7 Paliga et al. found similar closure timing in their cohort of Pfeiffer
Fig. 3. Kaplan-Meier survival analysis. Orange line, syndromic craniosynostosis; blue line, controls. Likelihood ratio test, 22.8 (p < 0.00001). SOS, spheno-occipital synchondrosis.
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Fig. 4. Sella-nasion–A point angle (normal sella-nasion–A point angle, 81 ± 3 degrees). Linear regression demonstrates a positive relationship between earlier age of spheno-occipital synchondrosis closure (years) and more severe midface hypoplasia (sella-nasion–A point angle in degrees) (p = 0.02). SNA, sella-nasion–A point angle; SOS, spheno-occipital synchondrosis.
syndrome patients.12 However, neither study rigorously evaluated the difference in closure timing with control scans or was powered to assess the relationship between the timing of spheno-occipital synchondrosis closure and degree of hypoplasia of the midface. Other publications have cited the sphenooccipital synchondrosis as important in midface growth. These include several case reports of early spheno-occipital synchondrosis fusion in patients with syndromic craniosynostosis,13,14 various animal studies,10,15,16 and limited retrospective reviews.2,7,11 Rosenberg and colleagues provide the most compelling laboratory evidence for the relationship between synchondrosis growth and midface projection. In their rabbit synostosis model, they compared cephalometric growth in 60 animals after cranial vault, cranial base, or combined sutural immobilization. They conclude that cranial base fusion may play an equal if not more important role compared with cranial vault fusion in craniofacial length restriction and midface hypoplasia. These results highlight the role of arrested cranial base growth in the development of dysmorphic features seen in syndromic craniosynostosis. This finding is consistent with other investigators, confirming both a primary directive and translational role of the cranial base in craniofacial growth.10 However, there are important differences between human and animal model cranial bases that may lessen the inferences that can be drawn from such work.
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As the above study implies, cranial base synchondroses differ considerably from cranial vault sutures in terms of both form and function. Forming from the fusion of the parachordal plates around the notochord during embryonic development, the cranial base plays an important active role in craniofacial development.1,17–19 As the cranial base develops, synchondroses form between prominent ossification centers, which serve a function similar to long bone growth plates by enabling rapid bone growth during development before fusion as skeletal maturity is neared.19–21 All of the cranial base synchondroses except for the spheno-occipital synchondrosis fuse in infancy, whereas the spheno-occipital synchondrosis remains open until adolescence, prompting investigations into its role in cranial base and midfacial development.8,9,13,17 In contrast, cranial vault formation occurs through intramembranous ossification and may rely more on a passive development from surrounding functional matrix than in the endochondral basicranium.22 Premature spheno-occipital synchondrosis fusion is likely not the only driver of midface hypoplasia—intrinsic midface growth across open facial sutures and cranial vault morphology may also play roles. Indeed, developmental genetic analysis by Britto and colleagues has shown a differential expression of fibroblast growth factor receptors (FGFR) in human embryos with high activity of FGFR1 and FGFR2 in facial osteogenic fronts in 8- to 13-week human embryos but minimal FGFR3 activity.23 Although these findings are
Volume 134, Number 3 • Spheno-Occipital Synchondrosis Closure also found in the cranial base, differential FGFR expression in midface bony mesenchyme may partly explain why Apert, Crouzon, and Pfeiffer syndromes, which are associated with gain-of-function mutations in FGFR1 and FGFR2, demonstrate higher rates of midface hypoplasia than in patients with Muenke syndrome (FGFR3 mutations). It is difficult to explain why FGFR mutations may affect development at the spheno-occipital synchondrosis preferentially, and, indeed, this may not be the case. However, as the last of the cranial base synchondroses to fuse, the effect of early closure at the spheno-occipital synchondrosis may simply be magnified because of the lengthy period over which the premature fusion acts. In other words, other cranial base synchondroses and facial sutures that are programmed to close by age 2, and not by age 12 or 14 years as is the case with the spheno-occipital synchondrosis, may not demonstrate the profundity of phenotypic dysmorphology. It is also notable that even in controls the spheno-occipital synchondrosis begins to fuse by age 7 to 9 years. Large, population-based computed tomographic studies of the spheno-occipital synchondrosis have demonstrated continued growth at the spheno-occipital synchondrosis until approximately 50 percent of the surface area of the synchondrosis is fused.24,25 An important consideration in drawing conclusions from these results is the manner in which spheno-occipital synchondrosis closure is evaluated. Comparison across detection methods has proven unreliable and, as such, we aimed to reproduce the methods previously established at our center by evaluating computed tomographic scans in an age- and sex-matched case-control design. Although more rigorous than standard retrospective methodologies, this design prohibits any conclusions of causality. In addition, we rely on computed tomographic scans obtained as part of normal clinical care, often at irregular intervals, which, though the best modality available, significantly diminishes the power of the current study to accurately reflect spheno-occipital synchondrosis closure timing. Finally, as many authors have previously done, we use the sella-nasion–A point angle as a proxy measure for the degree of midface hypoplasia. The sella-nasion–A point angle, however, only assesses the degree of midface projection, and the presence of hypoplasia is inferred. Because of these limitations, we are careful to conclude a strong correlation and not causality. Despite present limitations, these data have important implications in the pathogenesis and, potentially, treatment of midface hypoplasia in
syndromic craniosynostosis. If premature closure of the spheno-occipital synchondrosis is a primary driver of midface growth and development, it may prove to be an important target for intervention either to reverse midface hypoplasia before complete fusion, or to prevent it altogether with earlier intervention.
CONCLUSIONS The spheno-occipital synchondrosis fuses earlier in patients with Apert, Crouzon, and Pfeiffer syndromes and midface hypoplasia than in ageand sex-matched control patients without midface hypoplasia. In addition, earlier spheno-occipital synchondrosis fusion is correlated with more severe midface hypoplasia in syndromic patients. Although definitive determination of causality cannot be concluded, these data bolster the argument that the spheno-occipital synchondrosis is an important component of midface growth and may be an important target for intervention. Jesse A. Taylor, M.D. Perelman School of Medicine at the University of Pennsylvania The Children’s Hospital of Philadelphia Colket Translational Research Building 3501 Civic Center Boulevard, Ninth Floor Philadelphia, Pa. 19104 [email protected]
acknowledgment
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