ORIGINAL ARTICLE

Premature Closure of the Spheno-occipital Synchondrosis in Pfeiffer Syndrome: A Link to Midface Hypoplasia James Thomas Paliga, BA,* Jesse A. Goldstein, MD,* Arastoo Vossough, MD, PhD,Þ Scott P. Bartlett, MD,* and Jesse Adam Taylor, MD* Abstract: The spheno-occipital synchondrosis (SOS) is a critical component of midfacial and cranial base growth. Premature closure has been associated with midface hypoplasia in animal models and syndromic craniosynostosis subpopulations with Apert and Muenke syndromes. To link premature SOS closure and midface hypoplasia in patients with Pfeiffer syndrome, a retrospective case-control study was performed in patients treated at a large craniofacial center between 1982 and 2012 diagnosed with Pfeiffer syndrome. At least 1 computed tomography (CT) scan was required to assess SOS patency. Age-/sex-matched control CT scans were also assessed for SOS patency. Three independent reviewers with high interrater reliability (J = 0.88) graded SOS patency as open, partially closed, or completely closed. Wilcoxon rank sum test compared the Pfeiffer patients with control subjects. A total of 63 CT scans in 16 patients with Pfeiffer syndrome, all with midface hypoplasia, and 63 age-/sex-matched control scans, none of whom had midface hypoplasia, met inclusion criteria. Earliest partial SOS closure in patients with Pfeiffer syndrome was seen at 5 days compared with control subjects at 7.07 years. Earliest age at complete fusion was 2.76 years in the Pfeiffer cohort and 12.74 years in control subjects. Average age at partial closure was significantly younger (4.99 T 3.33 years; n = 31 scans) in patients What Is This Box? A QR Code is a matrix barcode readable by QR scanners, mobile phones with cameras, and smartphones. The QR Code links to the online version of the article.

From the *Division of Plastic Surgery, The Perelman School of Medicine at the University of Pennsylvania, and †Department of Radiology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania. Received March 16, 2013. Accepted for publication August 26, 2013. Address correspondence and reprint requests to Jesse Adam Taylor, MD, The Perelman School of Medicine at the University of Pennsylvania, The Children’s Hospital of Philadelphia, Colket Translational Research Bldg, 3501 Civic Center Blvd, 9th Floor, Philadelphia, PA 19104; E-mail: [email protected] This study was funded by the Department of Surgery of The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania. The data included in this article have not been previously presented. The authors report no conflicts of interest. Copyright * 2014 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000000386

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with Pfeiffer syndrome compared with control subjects (10.92 T 3.53 years) (P = 0.0005), whereas average age at complete closure (11.90 T 7.04 years) was not significantly different than that in control subjects (16.07 T 3.39 years). Although definitive causality cannot be concluded, a strong correlation exists between midface hypoplasia and premature SOS closure in Pfeiffer syndrome. Key Words: Spheno-occipital synchondrosis, Pfeiffer syndrome, syndromic craniosynostosis, midface hypoplasia (J Craniofac Surg 2014;25: 202Y205)

P

feiffer syndrome is an autosomal dominant condition affecting roughly 1:70,000 live births and is characterized by various degrees of multisutural synostosis, hand and foot anomalies, and midface hypoplasia.1,2 Like other acrocephalosyndactyly syndromes, Pfeiffer syndrome is attributed to mutations in the fibroblast growth factor receptor gene family, which, through dysregulation of osteoblast and chondrocyte differentiation, is thought to give rise to premature ossification of the cranial sutures and cranial base synchondroses.3Y5 A point of contention in the literature is the contribution of early cranial suture closure versus early cranial base synchondrosis closure in the development of midfacial hypoplasia and retrusion in this patient population. The spheno-occipital synchondrosis (SOS) is located between the posterior border of the body of the sphenoid and the anterior edge of the basiocciput. As the last of the skull base synchondroses to fuse, the SOS is thought to play an important role in the normal development and alignment of the cranial vault and facial skeleton.6Y8 Spheno-occipital synchondrosis fusion begins around age 7 years with completion around age 12 years in females and 14 years in males when evaluated by computed tomography (CT) scan.9Y13 Premature closure of the SOS has been associated with shortening and flattening of the anterior cranial base and midface hypoplasia in animal models.14,15 In addition, our group recently linked premature closure of the SOS with midfacial hypoplasia in patients with Apert syndrome.13 The purpose of this study was to evaluate the timing of SOS closure in Pfeiffer syndrome, all of whom have midfacial hypoplasia, and compare it with age- and sex-matched control subjects, none of whom have midfacial hypoplasia.

METHODS AND MATERIALS This is an institutional review boardYapproved, retrospective, case-control study of patients who presented to the Children’s Hospital of Philadelphia Center for facial reconstruction from 1982 to September 2012. Inclusion criteria required a clinical and genetic (when available) diagnosis of Pfeiffer syndrome and at least 1 finecut head CT scan performed at our institution during the study

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period. An equal number of age- and sex-matched control fine-cut CT scans were identified from an established trauma registry for patients ranging from 0 to 20 years old. Inclusion criteria to the control group required same sex and the age at scan within 3 months of the matched Pfeiffer syndrome scan. Exclusion criteria from the age- and sex-matched control subjects involved an underlying congenital or syndromic diagnosis. All available fine-cut head CT scans were identified and collected, then evaluated independently by 3 reviewersV2 craniofacial surgeons and 1 pediatric neuroradiologist. For each fine-cut CT scan, we recorded the patient’s sex, age of the patient at the time of the scan, and closure status of the SOS. Closure status of the SOS was defined as open, partially closed, or closed. To be considered ‘‘open,’’ no degree of hyperdense bony bridging across the hypodense SOS could be evident (Fig. 1A). 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’’ (Fig. 1B). Only those scans showing a completely fused SOS with complete replacement of the hypodense cartilage with hyperdense bone were labeled as ‘‘closed’’ (Fig. 1C). After each rater independently evaluated the closure status of both the Pfeiffer syndrome and the control groups, the interrater agreement was assessed by Cohen J coefficient. In cases where disagreement with regard to closure status was present, the raters jointly reviewed the imaging and reached a consensus as to the final status.13 Wilcoxon rank sum test was used to compare the average ages in scans showing complete closure, partial closure, or an open SOS between the patients with Pfeiffer syndrome and control groups.

RESULTS During the study period, 19 patients with Pfeiffer syndrome with 89 fine-cut head CT scans were identified. Scans were excluded if there was inadequate or incomplete visualization of the SOS. A total of 16 patients with Pfeiffer syndrome had 63 CT scans that met the inclusion criteria and showed complete visualization of the SOS. The individual CT scans were treated as independent data points with a median of 3 data points per patient. This group consisted of 9 males and 7 females with an age range of 0 to 20 years (Table 1). All patients in the group with Pfeiffer syndrome (n = 16) had a confirmed diagnosis of midface hypoplasia. A total of 63 age- and sex-matched CT scans were identified as meeting inclusion criteria for the control group (Table 1). No patients in the control group had a diagnosis of midface hypoplasia (n = 63). Three independent judges evaluated the CT scans with acceptable interrater reliability (Cohen unweighted J = 0.88). Of the 16 patients in the group with Pfeiffer syndrome, the earliest partial fusion of the SOS was seen at 5 days of life; this is in sharp contrast to the earliest partial closure in the control group at 7.07 years. The earliest age at complete fusion was 2.76 years of age in the Pfeiffer cohort, much earlier than the earliest age at complete

Closure of the SOS in Pfeiffer Syndrome

TABLE 1. Demographic Characteristics of Patients With Pfeiffer Syndrome and Control Subjects

No. patients Sex Male Female Age, y Mean Median Midface hypoplasia No. CT scans CT scans per patient Mean Median

Pfeiffer, n

Control, n

16

63

9 7

35 28

4.4 2 16 63

4.4 2 0 63

3.9 3

1 1

closure in control subjects at 12.74 years. All scans in the group with Pfeiffer syndrome at 1.80 years and older showed either partial or complete closure of the SOS, and this was correlative with the development of midfacial hypoplasia on clinical examination. Accordingly, the latest age at evidenced patency of the SOS was 1.56 years. Complete fusion of the SOS was seen in all scans at 13.45 years or older in the group with Pfeiffer syndrome. Age- and sex-matched control CT scans demonstrated SOS patency until a much later time, with the first recorded partial fusion at 7.07 years, and the range of partial fusion from 7.07 to 15.14 years (Fig. 2). In the CT scans demonstrating a closed SOS, the age at the time of CT ranged from 12.74 to 19.88 years. All CT scans in the 0-to 6.96-year range revealed a patent SOS (Fig. 2). The average age in scans showing an open SOS in the group with Pfeiffer syndrome was significantly younger than the average age at an evidently patent SOS in the control group (0.59 T 0.46 vs 2.33 T 2.30 years; P = 0.0024) (Table 2). The average age of patients in the group with Pfeiffer syndrome who had CT evidence of partial closure was significantly younger than the average age at partial closure in the control group (4.99 T 3.33 vs 10.92 T 3.53 years; P = 0.0005) (Fig. 3). The average age at complete closure was not found to be significantly different between the patients with Pfeiffer syndrome and control groups (P = 0.4654) (Fig. 3).

DISCUSSION The cranial base, initially a cartilaginous structure, forms from the fusion of the parachordal plates around the notochord during embryonic development and plays an important role in craniofacial development.7,8,16,17 Derived from neural crest cells, the anterior cranial base is thought to be a primary driver of midfacial growth.18,19 As the cranial base develops, synchondroses form between prominent ossification centers. Serving a similar function to

FIGURE 1. A, To be considered ‘‘open,’’ no degree of hyperdense bony bridging across the hypodense SOS could be evident. B, 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.’’ C, Only those scans showing a completely fused SOS with complete replacement of the hypodense cartilage with hyperdense bone were labeled as ‘‘closed.’’

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FIGURE 3. Mean age at CT scan by SOS closure status.

FIGURE 2. A, Spheno-occipital synchondrosis status by age at CT scan in the group with Pfeiffer syndrome. B, Spheno-occipital synchondrosis status by age at CT scan in the control group.

the growth plates in long bones, these synchondroses enable rapid bone growth during development and eventually fuse as skeletal maturity is neared.8,20,21 Our group recently linked premature closure of the SOS in Apert syndrome to midfacial hypoplasia.13 In the same case-control study, and using similar methodology, patients with Muenke syndrome were not found to show premature fusion relative to age- and sex-matched control subjects.13 As Apert syndrome typically manifests more severe midface hypoplasia in comparison to Muenke syndrome, the study implicates the age at fusion as being correlated to the degree of midface hypoplasia. With these findings in mind, we felt it would be interesting to characterize the age at fusion of the SOS in patients with Pfeiffer syndrome, a form of syndromic craniosynostosis that manifests midface hypoplasia at a comparable rate and severity as Apert syndrome. In the current study, patients with Pfeiffer syndrome, all of whom had midfacial hypoplasia, were found to undergo significantly TABLE 2. Comparison of SOS Status in Pfeiffer Group Compared With Age/Sex-Matched Controls Pfeiffer

Open Partial fusion Complete fusion

204

Control

No. Scans

Mean Age, y

No. Scans

Mean Age, y

P

23 31 9

0.59 T 0.46 4.99 T 3.33 11.90 T 7.04

51 7 5

2.33 T 2.30 10.92 T 3.53 16.07 T 3.39

0.0024 0.0005 0.4654

earlier fusion of the SOS relative to age- and sex-matched control subjects. These results are consistent with the results of our Apert study and may provide credence to the hypothesis that premature fusion of the cranial base, in general, and the SOS, in particular, is a driving force in the development of midface hypoplasia in these patients. An interesting contrast is provided in the fact that patients with Muenke syndrome, a syndrome with similar rates of craniosynostosis, showed no significant difference in the age at SOS fusion compared with age- and sex-matched control subjects.13 As has been noted, the Muenke phenotype does not typically show the incidence, or the severity, of midface hypoplasia that is commonly present in both Apert and Pfeiffer syndrome populations. And although our data cannot definitively answer the mechanistic question regarding relative importance of cranial vault suture synostosis and cranial base synchondrosis premature closure, it certainly favors the cranial base as the key driver of midfacial hypoplasia. Partial fusion was seen as early as the first few days of life (0.01 years) in our cohort of patients with Pfeiffer syndrome. The average age at the time of scan in patients displaying premature fusion was 4.99 years. Complete closure was noted as early as 2.76 years of age in 1 patient in the group with Pfeiffer syndrome, with an average age at complete closure of 11.90 years. In comparing these values to the group with Apert syndrome previously described, we see a much earlier initiation of fusion in the group with Pfeiffer syndrome compared with the group with Apert syndrome (0.01 years vs 2 years).13 In fact, 5 patients in the group with Pfeiffer syndrome were noted to have partial closure before the age of 2 years, whereas no patients younger than 2 years were shown to have partial closure in the group with Apert syndrome.13 Equally notable, complete fusion was seen in a 2.76-yearold patient with Pfeiffer syndrome, whereas the earliest age at complete fusion in the group with Apert syndrome was 6 years.13 Although definitive conclusions cannot be drawn by comparing the results of the two studies, some interesting questions arise as to the differences in the age at which fusion occurs and may complete in the groups with Apert and Pfeiffer syndromes. In particular, if there are significant differences in the ages at initiation of fusion between the groups, is there also a significant difference between the degrees of midface hypoplasia expressed in each syndrome? Furthermore, does the age at closure and degree of midface hypoplasia correlate to the FGFR mutation that is present? More succinctly, one may question whether significant differences exist between Pfeiffer syndrome with FGFR1 and FGFR2 and how each of these patient populations compares with the Apert population. This study is underpowered to answer these questions, and future work will focus on correlation of molecular diagnosis with cranial base synchondrosis patency. The SOS is not the sole driver of midfacial growth. In the prior study by Rosenberg et al,14 both the cranial vault sutures and cranial base synchondroses were found to contribute to overall craniofacial * 2014 Mutaz B. Habal, MD

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length in a rabbit model. Furthermore, intrinsic mesenchymal growth patterns of the maxilla also contribute to midfacial projection and have been shown to be differentially impacted by FGFR1, FGFR2, and FGFR3 mutations.22 Although not the only driver of growth, the SOS may play a prominent role in the development of midface hypoplasia because of the timeline over which fusion occurs. Normally, the SOS is the last synchondrosis to fuse, and patency is maintained during a crucial period of midfacial growth. Therefore, the premature fusion of the SOS may have a relatively greater impact on the development of midface hypoplasia compared with the other cranial base synchondroses. An important consideration in drawing conclusions from these results is the manner in which SOS closure is evaluated. Comparison across detection methods has proven unreliable, and as such, we aimed to reproduce the methods of the previous study on Apert and Muenke syndromes by utilizing an age- and sex-matched case-control design. This method allows for only a statistical comparison between the affected group and the control group; however, the demographics of each syndromic craniosynostosis group offer valuable comparison. Not only are we limited in comparison across SOS evaluation methodologies, we are also limited by the lack of consensus with regard to average age at initiation of SOS closure and age at completion of closure in the general population. Finally, the study was also limited by an inability to evaluate the control group for midface projection following evidence of fusion due to the use of a trauma registry to obtain normal CT scans. A comparison of midfacial growth to timing of SOS fusion in control subjects would offer additional valuable insight into the role of the synchondrosis. Similarly, the current study was underpowered to correlate the timing of SOS fusion with the degree of midface retrusion. Despite present limitations, the current research has important implications in the pathogenesis, and potentially in treatment, of midface hypoplasia in syndromic craniosynostosis. If premature closure of the SOS is a primary driver of midface growth and development, it may be worthwhile to investigate methods to inhibit or reverse premature fusion in patients with syndromic craniosynostosis and midface hypoplasia.

CONCLUSIONS The SOS begins to fuse prematurely in patients with Pfeiffer syndrome, all of whom have midfacial hypoplasia, relative to ageand sex-matched control subjects, none of whom have midfacial hypoplasia. Complete fusion occurs at similar time points. Although definitive determination of causality cannot be concluded, there exists a strong correlation between midface hypoplasia and premature SOS closure in Pfeiffer syndrome.

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Closure of the SOS in Pfeiffer Syndrome

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Premature closure of the spheno-occipital synchondrosis in Pfeiffer syndrome: a link to midface hypoplasia.

The spheno-occipital synchondrosis (SOS) is a critical component of midfacial and cranial base growth. Premature closure has been associated with midf...
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