Circummaxillary Sutures in Patients With Apert,Crouzon,and Pfeiffer Syndromes Compared to Nonsyndromic Children: Growth,Orthodontic,and Surgical Implications

Abstract

Objective:

To evaluate patency of circummaxillary sutures in children with Apert, Crouzon, and Pfeiffer Syndromes and to compare it to a nonsyndromic matched control group.

Design:

Case–control study.

Setting:

Tertiary care public hospital.

Materials and Methods:

Thirty-eight computed tomography (CT) scans of patients affected by syndromic craniofacial synostosis (13 patients with Apert syndrome, 20 patients with Crouzon syndrome, and 5 patients with Pfeiffer syndrome), average age 5 ± 2.8 years, range 1.9 to 12 years, were compared to age- and sex-matched control CTs of 38 nonsyndromic children. Computed tomography scans of the study group had to be performed prior to any midfacial surgery.

Main Outcome Measures:

Midpalatal suture, zygomaticomaxillary sutures, and pterigomaxillary sutures were evaluated and scored.

Results:

The syndromic group showed a significant earlier ossification of all sutures compared to the nonsyndromic group. Significant differences were already present in early childhood and continued through adolescence.

Conclusions:

Based on the differences in terms of maxillary sutural ossification identified, midfacial hypoplasia does not seem to be only secondary to premature cranial base ossification, but also to primary synostosis of facial sutures, thus providing new insights into the pathogenesis of midface deficiency in children with craniofacial-synostosis. Care should be taken when planning any maxillary orthopedics, such as expansion or maxillary protraction, given the high frequency of early fusion of circummaxillary sutures.

Keywords

Apert syndrome craniofacial growth craniofacial morphology facial growth maxilla midfacial growth orthodontics orthognathic surgery orthopedic treatment palatal development synostosis

Introduction

Syndromic craniosynostoses are characterized by the premature fusion of one or more of the calvarial sutures in association with extracranial anomalies that define a distinct syndrome. More than 180 genetic syndromes involve craniosynostosis (Kimonis et al., 2007), many of which demonstrate an autosomal dominant pattern of inheritance. Mutations in fibroblast growth factor receptors (FGFRs) are the most common cause of syndromic craniosynostosis (Eswarakumar et al., 2005). The mutation leads to the formation of a fibroblast growth factor receptor 2 (FGFR2) which causes the premature closure of the cranial sutures and sutures of the orbits (Bachler & Neubüser, 2001).

Crouzon, Apert, and Pfeiffer syndromes are the most frequent syndromic craniosynostoses. These syndromes present skull shape anomalies, exorbitism, hypertelorism, and midface hypoplasia (Cohen & Kreiborg, 1996). The prevalence of Apert syndrome is 6 to 15 in 1 000 000 births; Pfeiffer syndrome has a prevalence of 1 in 100 000 births, while Crouzon syndrome is more frequent, 16 in 100 000 000 births (Ko, 2016).

Midface deficiency in all 3 planes of space is a characteristic feature, for which these syndromes are commonly defined as craniofacial-synostosis (CFS) (Cohen & Kreiborg, 1996; Kreiborg et al., 1999; Meazzini et al., 2005). The most common clinical problems related to midfacial hypoplasia are ocular and respiratory problems.

It is generally believed that growth of the maxillary complex is reduced because of early fusion of the cranial base sutures, while circummaxillary sutures are often believed to be still patent. Therefore, many orthodontists attempt midfacial orthopedics, as they would in nonsyndromic children, such as palatal expansion or even maxillary protraction with a face mask. Unfortunately, expansion in patients where sutures are not patent is generally ineffective and may lead to severe pain and dental and periodontal damage (Graber & Vanarsdall, 1994, Digregorio et al., 2019), as palatal expansion requires the mechanical opening of maxillary and palatal sutures (Haas, 1965).

The purpose of this study was, thus, to evaluate the patency of circummaxillary sutures in children with Crouzon, Apert, and Pfeiffer syndromes and compare it to a nonsyndromic control group, in order to have a better understanding of maxillary growth impairment in CFS. In addition, we propose a simplified method for a computed tomography (CT)-based radiological classification of the maturational stage of circummaxillary sutures. The study was conducted according to the criteria set by the declaration of Helsinki and the protocol was approved by the local ethics committee.

Materials and Methods

A retrospective analysis on CT scans of syndromic patients and healthy controls was carried out. A total of 38 syndromic young patients were retrospectively collected. Inclusion criteria were diagnosis of CFS, no previous midfacial surgery, and good quality CT of all maxillary structures. The sample comprised 13 patients affected by Apert syndrome, 20 by Crouzon syndrome, and 5 by Pfeiffer syndrome; 20 were males, 18 were females, aged from 1 year and 11 months to 12 years (mean age 5 years ± 2.8). The control sample was extrapolated from the archives of our Hospital and from SIRIO radiological diagnostics and comprised 38 patients; 20 males, 18 females, aged from 2 years and 5 months to 12 years and 9 months (mean age 8 years ± 3.3). In the control group the main indications for CT were trauma or orthodontic treatment.

Computed tomography scans were carried out in different hospitals and scanning parameters were not uniform, being a retrospective study, but only high-quality cone beam CT (CBCT) or traditional CT scans (width of each section ≤ 2 mm) were included. For each study axial, coronal, and sagittal sections were available. Multiplanar reformations were performed with softwares for surgical navigation and planning when not previously present. Studies were visualized with softwares provided by the producer or with Xero software (Agfa HealthCare Corporation).

For each patient, 5 circummaxillary sutures were considered: zygomaticomaxillary suture (ZMS) bilaterally, pterigomaxillary suture (PMS) bilaterally, and midpalatal suture (MS). Each suture was evaluated on 2 different planes. In particular, the ZMS and the MS were analyzed on the axial and the coronal plane; the PMS was evaluated on the axial and the sagittal plane.

Classification Method

The radiological classification of maturational stages of the ZMS and the MS was based on an adaptation of previous studies (Angelieri et al., 2013; Angelieri et al., 2017).

- Stage 1: the suture appears like a continuous low-density line in the middle, between 2 uniform high-density lateral lines corresponding to the cortical bone. In this stage, the suture may be considered open (Figure 1A and B).

- Stage 2: the suture appears like a single uniform high-density line with no or little interdigitation. In this stage the suture may be considered still open (Figure 1C and D).

- Stage 3: the suture appears like a single scalloped high-density line with interdigitation or like 2 thin scalloped high-density lines with little low-density spaces in the middle. In this stage, the suture is starting to close (Figure 1E and F).

- Stage 4: the suture is no longer visible in many areas of its original location and the parasutural bone appears as completely reworked with increased bone density. In this stage, the suture may be considered closed (Figure 1G and H).

For the evaluation of the PMS, we needed to simplify this classification, because of its complex anatomy. Therefore, only stage 1 (Figure 2A), stage 2 (Figure 2B), and stage 4 (Figure 2C) were identified. Finally, we gave each suture a score according to the maturational stage from 1 to 4.

Statistical Analysis

An interobserver analysis was carried out in order to assess the reproducibility of our classification method. Three observers (an expert maxillofacial surgeon, an expert orthodontist, and a maxillofacial surgery resident) did individually a single-blinded evaluation on 5 CT scans of syndromic patients and 5 CT scans of healthy controls and weighted κ coefficient was calculated. The agreement was defined according to the scale of Landis and Koch.

In addition, an intraexaminer analysis was performed. The second examination was made after 6 months and an intraclass correlation coefficient was chosen for the statistical correlation.

As concerns the statistical analysis both syndromic and control patients were divided into 4 age groups (1-3, 4-6, 7-9, and 10-12 years) and for each suture the highest stage was considered. Mean maturational stage with standard deviation was calculated for each group and data were organized in histograms and line graphs. Maturational stages between syndromic and nonsyndromic patients were compared with an independent Student t test. The percent of open sutures (stage 1 and 2) in syndromic patients was calculated for each type of suture analyzed, in all groups of age.

Given the presence of multiple comparisons and the increased risk of type I error, a Benjamini-Hochberg correction was carried out and the adjusted P value was set at .029. Statistical analysis was carried out with Stata version 10 software (StataCorp 2007; Stata Statistical Software: Release 10: StataCorp LP).

Results

The weighted κ values, for interexaminer reproducibility of the identification of the maturational stages of the ZMS, demonstrated good agreement with average weighted κ coefficient of 0.86 (95% CI: 0.74-1.00), almost perfect agreement with average weighted κ coefficient of 0.91 (95% CI: 0.84-1.00) for the MS and relatively good agreement with average weighted κ coefficients of 0.71 (95% CI: 0.64-1.00) for the PMS.

A sensitivity power analysis (used when the sample size is predetermined by study constraints) was run for the independent sample t tests, determining the size effect found with the sample we had (Cohen d). Observed power was calculated, given the sample size reached, setting α (type I error) at 0.029 and calculating the population size effect for each test (Cohen, 1988). The observed power of each test was between 0.93 and 0.99 (Table 1).

Table 1.

Mean and Standard Deviation (SD) of Maturational Stages of the ZMS, MS, and PMS in Syndromic Patients and in the Control Group.^a

	N =38	Sutures	Control patients (mean ± SD)	Syndromic patients (mean ± SD)	P value	Cohen d (Effect size)	Observed power
1-3 Years	10	ZMS	1.6 ± 0.55	2.3 ± 0.48	.031	1.35	0.96
		MS	1.4 ± 0.55	3.1 ± 0.88	.001	2.32	0.99
		PMS	1.8 ± 0.45	3.3 ± 1.16	.016	1.70	0.94
4-6 Years	11	ZMS	1.7 ± 0.48	2.36 ± 0.67	.018	1.13	0.91
		MS	1.6 ± 0.52	3.55 ± 0.82	.000	2.83	0.99
		PMS	1.9 ± 0.32	3.64 ± 0.81	.000	2.82	0.99
7-9 Years	9	ZMS	1.67 ± 0.65	2.71 ± 0.95	.030	1.28	0.92
		MS	2.17 ± 0.83	3.86 ± 0.38	.000	2.60	0.99
		PMS	1.92 ± 0.29	3.43 ± 0.98	.000	2.10	0.97
10-12 Years	8	ZMS	2.71 ± 0.76	3.57 ± 0.53	.010	1.30	0.93
		MS	2.71 ± 0.76	3.86 ± 0.38	.003	1.91	0.94
		PMS	2.57 ± 0.78	3.71 ± 0.76	.018	1.30	0.93

Abbreviations: MS, midpalatal suture; PMS, pterigomaxillary suture; SD, standard deviation; ZMS, zygomatico maxillary suture.

^a P values of the independent samples t test was set at 0.028 after Benjamini-Hochberg correction. Given the small size of the samples; Cohen d effect size coefficient was calculated and relative observed powers were listed.

Syndromic patients aged 1 to 3 years (n = 10) had a mean maturational stage of the ZMS of 2.3 ± 0.48, while in the control group the mean was 1.6 ± 0.55 (ns). The mean stage of MS was 3.1 ± 0.88, while in the control it was 1.4 ± 0.55 (value = .001). Pterigomaxillary suture was 3.3 ± 1.16, while the control group was 1.8 ± 0.45 (P = .016). Syndromic patients aged 4 to 6 years (n = 11) had a mean maturational stage of the ZMS of 2.36 ± 0.67, while in the control group the mean was 1.7 ± 0.48 (P = .018). Midpalatal suture was 3.55 ± 0.82, while the control group was 1.6 ± 0.52 (P = .000). Pterigomaxillary suture was 3.8 ± 0.6, while the control group was 1.9 ± 0.32 (P = .000).

Syndromic patients aged 7 to 9 years (n = 9) had a mean maturational stage of the ZMS of 2.7 ± 0.95, while in the control group the mean was 1.67 ± 0.65 (ns). Midpalatal suture was 3.86 ± 0.38, while the control group was 2.17 ± 0.83 (P = .000). Pterigomaxillary suture was 3.43 ± 0.98, while the control group was 1.92 ± 0.29 (P = .000).

Syndromic patients aged 10 to 12 years (n = 8) old had a mean maturational stage of the ZMS of 3.57 ± 0.53, while in the control group the mean was 2.71 ± 0.76 (P = .010). Midpalatal suture was 3.86 ± 0.38, while in the control group the mean was 2.71 ± 0.76 (P = .003). Pterigomaxillary suture was 3.71 ± 0.76, while the control group was 2.57 ± 0.78 (P = .018).

Taking into consideration the whole sample of syndromic (n = 38) and nonsyndromic patients, the difference between the groups, without age separation, was significant for all sutures ( P = .000). A visual representation of the progressive ossification of each suture in every age-group is given in Figure 3A-D.

In every age-group, the mean maturational stage of each suture was compared. In syndromic patients aged 1 to 3 years, the ZMS were open (stage 1 and 2) in 70% of cases, MS and PMS in 30%. In syndromic patients aged 4 to 6 years, the ZMS were open (stage 1 and 2) in 64% of cases, the MS in 18%, and the PMS in 9%. In syndromic patients aged 7 to 9 years the ZMS were open (stage 1 and 2) in 40% of cases, the MS and the PMS were fused in all patients. In syndromic patients aged 10 to 12 years all sutures were fused.

Discussion

To the best of our knowledge this is the first study describing the patency of the circummaxillary sutures with CTs in growing patients affected by Crouzon, Apert, and Pfeiffer syndromes.

The results of this study show that, not only calvarial and cranial base sutures are prematurely closed but also circummaxillary sutures. Samples are not large, given the prevalence of CFS and the need for high-quality CT scans, nevertheless, power of the study was high.

There are several theories on the etiology of midface hypoplasia in craniosynostosis. Until recently, the most held theory was that premature ossification of the cranial base secondarily induced midfacial hypoplasia (Rosenberg et al., 1997; Eswarakumar et al., 2005). But is maxillary retrusion truly only due to cranial base synostosis? Kreiborg et al. (1999) suggested that, maybe, also early lack of sutural growth of the maxilla and an abnormal remodeling pattern result in a maxilla that is small in 3 planes of space. No actual study was ever carried out; therefore, no evidence was given for these statements. Meazzini et al. (2005), in nonoperated patients, reported no horizontal growth of the maxilla after age 7, therefore, after the age in which in nonsyndromic patients the cranial base component of maxillary growth is significantly reduced, suggesting that cranial base might not be the only cause of maxillary growth impairment, though again, no imaging of the sutures was provided.

Interestingly, in mouse models (Purushothaman et al., 2011), premature synostosis of the premaxillary-maxillary, nasal-frontal, and maxillary-palatine sutures were shown. These were detected in the absence of premature ossification of the cranial base. Therefore, midfacial hypoplasia does not seem to be secondary to premature cranial base ossification, but rather primary synostosis of facial sutures, thus providing new insights into the pathogenesis of midface deficiency in humans with CFS.

Other studies demonstrated high levels of FGFR1-2 expression during midfacial membranous ossification in human and mouse embryonic tissue, also suggesting that FGFR1-2 mutations directly affect midfacial embryonic tissue outgrowth (Bachler & Neubüser, 2001; Britto et al, 2001), indicating that abnormalities of intramembranous bone ossification, such as decreased bone formation or increased apoptosis, not only affect the calvarial bones, as has been previously described, but also involve the facial skeleton.

Growth modification of the maxilla is highly dependent on the level of maturation of the circummaxillary sutures. Histological examination of nonsyndromic human autopsy material demonstrated similar maturational stages of the transverse palatine and pterygopalatine sutures during the infantile, juvenile, and adolescent growth stages (Melsen & Melsen, 1982). These sutures show an increasing interdigitation and complexity from the infantile through the adolescent stages, with complete fusion of the sutures in the adult. Recently, Angelieri et al. (2017) described a method of classification of the MS and ZMS maturational stages on CBCT images that can be useful for late adolescent and young adult patients in whom the efficacy of orthodontic rapid maxillary expansion (RME) is unpredictable.

In our study, according to clinical implications, we considered appropriate to simplify Angelieri’s classification method by reducing the number of scores. Specifically, Angelieri’s classification identifies 2 different stages (stages B and C) to describe the phase during which sutures are closing. Therefore, given that Angelieri’s stages B and C are often detectable in the same suture and at the same time, we chose to unify these 2 stages under the name of stage 3. Stages D and E were unified into stage 4, because, clinically, even if the suture is only partially closed (stage D of Angelieri’s classification corresponds to the closure of the palatine part of the MS or of the inferior part of the ZMS, while stage E describes the final phase, when the suture is no longer visible) and surgically assisted palatal expansion would be required. We needed to add stage 1, an earlier stage, not present in Angelieri’s classification, given the much younger age of our samples. Stage 1 was characterized by a wider suture. For the PMS, considering it’s anatomical and histological complexity, only 3 stages were identified. Nevertheless, PMS assessment reliability was the lowest (κ coefficient = 0.71).

Before starting with CT evaluation, observers were trained using sample images of each radiological stage of sutural maturation. Common mistakes in which a nontrained operator might incur, are, as an example, not distinguishing the vomer insertion, which looks like a single high-density line as a suture in stage 2, from the suture itself.

As can be clearly seen from the histograms (Figure 3A-D), at the same age, the 3 circummaxillary sutures were at a more advanced stage in syndromic patients, in comparison with the control group. In every age-group, in syndromic patients, the MS and the PMS were at a more advanced stage of maturation in comparison with the ZMS and more so, before 9 years of age.

Rapid maxillary expansion is often unsuccessful in the general population after 15 years (Angelieri et al., 2013). Angelieri et al found closed MS in girls older than 11 years and in boys older than 14 years. On dry human skulls, the pterygomaxillary sutural area at 6.5 years of age was found to be linear with evidence of a gap between the pterygoid process of the sphenoid bone and the maxillary tuberosity. In contrast, the anatomy of this region changes dramatically by 12 years of age, when the 2 bony surfaces are more interdigitated (Melsen, 1972; Melsen & Melsen, 1982).

According to our study, in healthy children, stage 3 was already found at 9 years of age. In syndromic patients, the closure of the circummaxillary sutures starts earlier. Midpalatal suture and PMS were found in stage 4 already at 4 years of age (only 18% and 9% of the sutures, respectively, were found radiologically open between 4 and 6 years, none after 7 years). The ZMS was found open in 64% of cases between 4 and 6 years, in 40% between 7 and 9 years, no sutures were found to be radiologically open between 10 and 12 years of age.

Clinically at stage 3 an attempt at orthopedic expansion of the maxilla seems to be still advisable in some syndromic patients, although, an exact clinical correlation with each maturational stage as seen on a CT is not available at this time and clinical–radiological correlation will probably become easier with the gradual improvement of CT quality.

Rapid maxillary expansion was first introduced by Angell in 1860. It was then popularized in the mid-1960s (Haas, 1965). Rapid maxillary expansion appears to involve an ample portion of the craniofacial complex, as the maxilla is associated with 10 bones in the face and head (Melsen, 1972). The introduction of 3-dimensional CT imaging allowed to evaluate quantitatively the extent of disarticulation of these sutures in young orthodontic patients following treatment with RME (Garrett et al., 2008; Leonardi et al., 2011). Many investigators have pointed out that RME results in complex changes in the craniofacial structures. Timms (1980) showed that the maxilla and the palatine bones moved apart, along with the pterygoid processes of the sphenoid bone. Jafari et al. (2003) in a 3D study on a finite element model of a human skull showed an expansive force at the intermaxillary suture, but also high forces on various structures on the craniofacial complex, particularly the sphenoid and zygomatic bones.

Separation of the palatal bone from the pterygoid process is relatively easy to obtain only in infantile and early mixed dentition skulls. Attempted disarticulation in the late juvenile and adolescent periods was always accompanied by fracture of the greatly interdigitated osseous surfaces and if performed in adults it induced periodontal damage (Melsen & Melsen, 1982).

In general, in nonsyndromic children, orthodontic expansion of the maxilla is almost always carried out between 6 and 12 years of age, when sutures are still completely patent. Although there is a lack of validated correlation between clinical response and CT imaging, nevertheless, in syndromic patients, we recommend CT evaluation of the maturational stage of circummaxillary sutures. Already at age 4 to 6 years only seldom in CFS patients, sutures were found to be radiologically open. Therefore, treatment through orthodontic expansion should be evaluated with extreme care. RPE in a patient with fused sutures may be a risk for the teeth and for the periodontal support (Digregorio et al., 2019). Furthermore, syndromic children have extremely severe dental crowding, which ideally would need early expansion or maxillary protraction with anchorage on the deciduous dentition. In the presence of closed sutures, the strain on the deciduous teeth may cause either early loss, with resulting mesial movement of permanent molars and worsening of dental crowding, or ankylosis and subsequent impaction of the permanent premolars (Meazzini et al., 2011). Therefore, an orthodontic treatment carried out on a child affected by CFS needs to be complemented by a profound knowledge of the biological mechanisms which lead to the facial defect and extreme clinical circumspection.

Conclusion

This study proposes a classification method for the assessment of maturational stages of circummaxillary sutures, which seems reproducible and based on easily accessible CT examinations.

In consideration of the early radiological apparent fusion of circummaxillary sutures in syndromic patients, in most of these patients, orthopedic treatment on the maxilla should be carried out with great prudence. Computed tomography scans might help the clinical decision between exclusive orthodontic treatment or surgically assisted expansion in syndromic children, although further development in CT accuracy will improve our ability to correlate clinical prognosis with CT imaging.

Footnotes

Acknowledgments

The authors thank Dr Dario Lanzani, SIRIO Radiology, for the help in collecting control CT scans. Part of the data in this article were used as the MD thesis of Dr Margherita Lisciandrano.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Maria Costanza Meazzini, DMD, MMSc

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