- Email: [email protected]
Demographic characteristics of craniosynostosis patients in Asia
Accepted Manuscript Demographic characteristics of craniosynostosis patients in Asia Il Hwan Byun, M.D., Jong Won Hong, M.D., Mohammed Hussein, M.D., Yong Oock Kim, M.D., Ph.D. PII:
S1010-5182(18)30050-7
DOI:
10.1016/j.jcms.2018.02.008
Reference:
YJCMS 2910
To appear in:
Journal of Cranio-Maxillo-Facial Surgery
Received Date: 14 October 2017 Revised Date:
27 January 2018
Accepted Date: 13 February 2018
Please cite this article as: Byun IH, Hong JW, Hussein M, Kim YO, Demographic characteristics of craniosynostosis patients in Asia, Journal of Cranio-Maxillofacial Surgery (2018), doi: 10.1016/ j.jcms.2018.02.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Demographic characteristics of craniosynostosis patients in Asia
Kim, M.D., Ph.D. 1
Department of Plastic & Reconstructive Surgery
Institute for Human Tissue Restoration
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Yonsei University College of Medicine, Seoul, Korea
Department of Plastic & Reconstructive Surgery
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2
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Cairo University College of Medicine, Cairo, Egypt
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Il Hwan Byun, M.D.1, Jong Won Hong, M.D.1, Mohammed Hussein, M.D.2, and Yong Oock
ACCEPTED MANUSCRIPT Correspondence: Yong Oock Kim, M.D., Ph.D. Department of Plastic and Reconstructive Surgery
50 Yonsei-ro, Seodaemun-gu, Seoul, Korea Tel: +82-2-2228-2218, Fax: +82-2-577-4914
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E-mail: [email protected]
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Yonsei University College of Medicine
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Institue for Human Tissue Restoration
ACCEPTED MANUSCRIPT Conflict of Interest The authors declare that they have no conflict of interest.
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Ethical Approval
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This study was conducted in accordance with the Declaration of Helsinki.
ACCEPTED MANUSCRIPT Summary Purpose: Craniosynostosis (CRS) is a congenital condition resulting premature fusion of one or more cranial sutures. CRS is classified according to the involved sutures into sagittal,
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metopic, unicoronal, unilambdoid, bicoronal, and multiple-suture CRS, with sagittal suture fusion known to be the most common type. Although multiple studies have presented
demographic characteristics of CRS patients, to date, there is no study representing an Asian
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of Western patients, considering previous reports.
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population. We sought to compare the demographic characteristics of Asian patients to those
Materials and Methods: A total of 266 CRS patients treated in a single institution from 1996 to 2016 were retrospectively reviewed. Data from the patients was collected regardless
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of whether they underwent operation. Patients’ age at the time of presentation, sex, and maternal and paternal age at birth were reviewed. Patients were routinely investigated for abnormal genes (FGFR2 and FGFR3). The Bayley Scales of Infant Development, Second
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Edition (BSID-II), was used to assess the patients’ cognitive and psychomotor development. One-way analysis of variance or the Kruskal-Wallis test was used to compare continuous
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variables. A p value of <0.05 was considered statistically significant.
Results: Our study included 157 males (59.02%) and 109 females (40.98%), with an age ranging from 0.1 to 10.5 years. The mean age at the time of diagnosis was 2.01 ± 2.57 years, and the mean age at operation was 2.16 ± 2.61 years. Of the patients, 27 (10.15%) were bicoronal, 28 patients (10.53%) were metopic, 48 patients (18.04%) were unicoronal, 50 patients (18.80%) were unilamboid, and 67 patients (25.19%) were sagittal. Patients with
ACCEPTED MANUSCRIPT multiple-suture CRS totaled 46 (17.29%). Investigation of abnormal genes revealed six patients (2.20%), including two patients with abnormal FGFR2 and four patients with abnormal FGFR3. Maternal and paternal ages at the patients’ birth were 32.18 ± 4.56 years
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and 34.71 ± 4.72 years, respectively. The mean BSID-II scores were 84.96 ± 22.77 for the Mental Development Index and 84.19 ± 25.62 for the Psychomotor Development Index. To examine the trend of diagnosis of CRS type, we also evaluated the number of new patients
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diagnosed with nonsyndromic CRS per year at our institution. New diagnoses of CRS
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generally increased from the year 2009, although variations continued.
Conclusion: The mean age of our patients is relatively high compared to previous, Western studies. Through this research, we recognized that cultural discrepancies regarding the expectations of Asian parents may lead to prolonged diagnosis of CRS patients, and yet even
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relatively older CRS infants can successfully be treated with surgical intervention. The prevalence of CRS types and BSID-II development scores varied compared to those in previous Western studies. Further investigations at the genetic level are required to compare
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the different populations. To diagnose CRS in an effective and timely manner, a physician
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must be aware of the general characteristics and understand the variations between Western and Eastern populations.
Keywords: craniosynostosis; demographic; Asian
ACCEPTED MANUSCRIPT INTRODUCTION Craniosynostosis (CRS) is a congenital condition resulting premature fusion of one or more cranial sutures, which occurs at an incidence of 3.5 to 4.5 per 10,000 live births
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worldwide (Cohen, 2000). Single-suture CRS is known to have a higher incidence, occurring in approximately 1 per 2,000 live births (Kapp-Simon et al., 2007). CRS may present as an isolated condition or as part of a complex craniofacial syndrome. Although the precise
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pathogenesis of CRS remains unclear, studies have shown that CRS is intimately related to abnormalities of osteoprogenitor cells within the cranial sutures, due to gene mutations in
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fibroblast growth factor receptors (FGFR) and the Msx homeobox (Slater et al., 2008). Craniosynostosis is further classified according to the involved sutures into sagittal, metopic, unicoronal, unilambdoid, bicoronal, and multiple-suture CRS, with sagittal suture fusion known to be the most common type [4]. The skull morphology is closely related to the
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pattern of suture closure; sagittal CRS results in scaphocephaly; unicoronal and unilambdoid CRS result in plagiocephaly; and bicoronal and bilambdoid CRS result in relatively
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symmetric yet brachiocephalic head shapes.
Although multiple studies have presented demographic characteristics of CRS
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patients, to date, there is no study representing Korean or any other Asian population. Thus our work involved examining the demographic characteristics of Korean CRS patients as a selected sample of an Asian population, to provide general guidelines that will aid surgeons in diagnosing and managing Asian CRS patients. Also we sought to compare the demographic characteristics of Asian patients to those of Western patients based on previous reports.
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MATERIALS AND METHODS A total of 266 CRS patients treated at a single institute from 1996 to 2016 were
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retrospectively reviewed. Data from the patients was collected regardless of whether they underwent operation. Patients’ age at the time of presentation, sex, and maternal and paternal age at birth were reviewed. Patients with syndromic CRS as well as those with a history of
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previous CRS operation were excluded. Patients were routinely investigated for abnormal
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genes (FGFR2 and FGFR3) because these are the most commonly involved genetic mutations in CRS (Johnson and Wilkie, 2011).
The Bayley Scales of Infant Development, Second Edition (BSID-II), was used to assess the patients’ cognitive and psychomotor development, as this is a standardized, norm-
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referenced objective test of an infant’s developmental status (Bayley, 1993). The BSID-II provides updated norms, yielding a Mental Development Index (MDI) and Psychomotor Development Index (PDI). The BSID-II scores are often categorized as accelerated, >115;
Starr et al., 2007).
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within normal limits, 85–115; mildly delayed, 70–84; or severely delayed, <70 (Bayley, 1993;
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Means and standard deviations were calculated for all continuous variables, as
appropriate. Categorical variables were expressed as proportions (%). One-way analysis of variance or the Kruskal-Wallis test was used to compare continuous variables. All statistical analyses were assessed with the Statistical Package for Social Sciences (SPSS version 23.0; SPSS Inc., Armonk, NY, USA). A p value of < 0.05 was considered statistically significant.
ACCEPTED MANUSCRIPT RESULTS Between 1996 and 2016, a total 266 CRS patients were included; 157 males (59.02%) and 109 females (40.98%), with an age range of 0.1 to 10.5 years. The mean age at the time
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of diagnosis was 2.01 ± 2.57 years, while the mean age at operation was 2.16 ± 2.61 years. General patient characteristics are presented in Table 1. A total of 220 patients had singlesuture CRS; the sagittal type was the most frequent, while the bicoronal was the least
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frequent. Twenty-seven patients (10.15%) were bicoronal, 28 patients (10.53%) were metopic, 48 patients (18.04%) were unicoronal, 50 patients (18.80%) were unilamboid, and 67 patients
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(25.19%) were sagittal. There were 46 patients (17.29%) with multiple-suture CRS. The CRS type and sex distribution of each group is shown in Table 2 and Figure 1. Interestingly, metopic type CRS showed a sex ratio of a much greater number of males in our study as well as previous studies (Speltz et al., 2007; Zakhary et al., 2014).
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Investigation of abnormal genes revealed six patients (2.20%), two patients with abnormal FGFR2 and four patients with abnormal FGFR3. The two patients with abnormal FGFR2 were multiple types, and four patients with abnormal FGFR3 were metopic, sagittal,
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unicoronal, and multiple types.
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Maternal and paternal ages at the patients’ birth were 32.18 ± 4.56 years and 34.71 ± 4.72 years, respectively. When maternal and paternal ages were analyzed for each group, the mean maternal and paternal ages were the highest for the sagittal type (33.05 ± 4.68 years and 35.59 ± 5.15 years, respectively), whereas the lowest means were noted in the multiplesuture type (30.72 ± 5.75 and 33.78 ± 6.18 years). Yet there was no statistically significant difference between the groups regarding maternal and paternal ages (p = 0.17 and 0.53, respectively). Parental ages by types are summarized in Table 3.
ACCEPTED MANUSCRIPT The mean BSID-II scores were 84.96 ± 22.77 for MDI and 84.19 ± 25.62 for PDI. The mean MDI scores ranged from 77.21 ± 26.73 for the metopic type to 90.45 ± 22.46 for the unilambdoid type, while the mean PDI scores ranged from 71.32 ± 30.65 for the metopic
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type to 86.21 ± 24.56 for the unilambdoid type. The lowest mean scores of both MDI and PDI were noted in the metopic type, and the highest mean scores were noted in the
unilamboid type (Table 4 and Figure 2). As with parental ages, however, there was no
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significant difference between the CRS types associated with BSID-II (p = 0.36 for MDI and 0.33 for PDI).
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To see the trend of diagnosis of CRS type, we also evaluated the number of new patients diagnosed with nonsyndromic CRS per year at our institution (Figure 3 and Table 5).
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New diagnoses of CRS generally increased from year 2009, although variations continued.
DISCUSSION
Despite CRS having been considered as a purely cosmetic problem for long time by
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parents as well as by surgeons, this concept had changed over the past few decades. The ultimate goal of treatment includes normal morphology as well as craniofacial development.
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Studies have shown multiple functional impairments in those patients, including visual impairment, increased intracranial tension, brain growth restriction, and neuropsychiatric disorders (Panchal et al., 2001; Magge et al., 2002; Bristol et al., 2004; Siatkowski et al., 2005; Kordestani et al., 2006). Neurocognitive impairments such as verbal short-term memory and language are reported to be as high as 35% to 50% in school-aged children with CRS (Kapp-Simon et al., 2007). Because the causal implications of this association are partly unclear, many surgeons recommend routine neurodevelopmental tests of CRS patients, to
ACCEPTED MANUSCRIPT help to identify patients at high risk for neurodevelopmental delay; thus earlier intervention could be considered to alleviate future problems (Lekovic et al., 2004; Speltz et al., 2007). As a result, multidisciplinary care guidelines recommended early neurodevelopmental screening
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before the age of 4 months, which should be continued until the age of 8 years (McCarthy et al., 2012).
Craniosynostosis is a condition that is relatively commonly encountered by plastic
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and reconstructive surgeons, and in which the role of surgical treatment is of great importance. The recent concepts in CRS correction are focused on correction of the morphological
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deformity while minimizing neuropsychological dysfunctions (Lekovic et al., 2004). Skull deformity and probable increased intracranial pressure are often considered as potential causes of neurodevelopmental impairment. Surgical intervention varies from the traditional cranial remodeling to the relatively recently proposed distraction osteogenesis, which has
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gained popularity worldwide since its introduction by Sugawara et al in 1998 (Sugawara et al., 1998; Forrest and Hopper, 2013). Since rapid brain volume expansion proceeds until the age of 3 years, and since about 90% of the adult size is reached by the age of 6 years, early
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surgical intervention is critical (Shim et al., 2016). Yet, CRS is an unfamiliar topic in many other fields of medicine, and a physician must understand patient characteristics for timely
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diagnosis and intervention. Thus we analyzed Asian CRS patients to provide general information and to compare characteristics with those of Western patients. In previous studies, Speltz et al. reported CRS patients with mean age of 6.5 ± 3.9
months at diagnosis, and Zakhary et al. presented mean age of 8.9 months (range 5–30 months) at operation.(Speltz et al., 2007; Zakhary et al., 2014). However, these studies excluded patients above 3 and 2 years old, respectively. In our study, the mean age at diagnosis was 2.01 ± 2.57 years. This is quite high compared to the previously mentioned
ACCEPTED MANUSCRIPT studies, but we did not exclude any older patients because we wanted to show the actual raw ages of visiting CRS patients. Even if the visiting plagiocephalic infant is older than 2 or 3 years, a physician must not rule out the possibility of CRS. Parents who visited our
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department with relatively old CRS patients often stated that their elder family members recommended waiting, hoping for recovery of the cranial shape as the infant grew older.
Although the raw age data for CRS patients at diagnosis and operation in previous Western
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studies are not available, some cultural discrepancies may have affected the delay in CRS diagnosis. Despite variations nowadays, many Asians emphasize family discipline and try to
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follow their elders’ teaching and recommendation. Interestingly, the new births in Korea have gradually decreased since 2000, but CRS diagnoses have generally increased, especially from 2010 (Figure 3 and Table 5) (Kosis, 2017). We believe that thorough screening examinations as well as improved knowledge of parents and physicians has led to increased diagnosis,
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which also included relatively old CRS patients as mentioned above. There are some similar and different traits of the CRS type distribution among previous studies and ours. Traditionally, sagittal type is known to be the most common type,
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and our study supports this, showing 25.19% of the patients with this type (Ghali et al., 2002). Studies vary, with the second most common type varying between unicoronal and metopic
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CRS (Bennett et al., 2016). Speltz et al. presented patients of whom 49.60% were sagittal, 21.60% were metopic, 22.40% were unicoronal, and 6.4% were lambdoid (Speltz et al., 2007). Zakhary reported patients of whom 44.00% were sagittal, 31.00% metopic, 13.00% bicoronal, 10.00% unicoronal, and 2.00% multiple-suture CRS (Zakhary et al., 2014). In our study, the most to least common types were sagittal (25.19%), unilamboid (18.80%), unicoronal (18.04%), multiple-suture (17.29%), metopic (10.53%), and bicoronal CRS (10.15%), respectively (Table 2 and Figure 1). Further studies are needed involving larger
ACCEPTED MANUSCRIPT population, but our findings show that the epidemiology of CRS types may differ between Western and Eastern populations. Variations were noted on neurodevelopment indices as well. Starr et al. presented
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mean MDI score of 92.08 and PDI score 84.85 for patients under 30 months, and Speltz et al. gave a mean MDI score of 91.92 ± 9.19 and PDI score of 84.00 ± 12.03 for infants and young children under 24 months (Speltz et al., 2007; Starr et al., 2007). Both studies show MDI
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scores greater than PDI scores, with mild psychomotor development delay. In our study, the mean scores were MDI 84.96 ± 22.77 and PDI 84.19 ± 25.62, showing lower MDI scores and
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similar PDI scores compared to other studies. Such a discrepancy may be due to the wider range of ages of CRS patients in our study. Both mean scores were within normal limits, and physicians must consider the wide variation of neurodevelopment in CRS patients. As mentioned earlier, the brain volume rapidly expands at younger ages, so a doctor must
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thoroughly discuss the risk and benefits of cranioplasty with patients with relatively older CRS children. As with parental ages, there was no significant difference between the CRS types associated with BSID-II. Yet metopic CRS patients showed relatively low mean scores
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compared to other types, and taking such trend as a reference, a physician may expect
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relatively low MDI and PDI scores when treating a metopic CRS patient. Since 2010, the availability of whole exome and genome approaches greatly
accelerated genetic research of genes enriched for mutations in CRS patients (Twigg and Wilkie, 2015). Recent studies advocate a stronger influence of genetic factors in the etiopathogenesis of nonsyndromic CRS. One study proposed that targeted FGFR1, FGFR2, FGFR3, and TWIST1 genetic testing is appropriate as a first-line test for CRS patients, and that analyses of TCF12 and ERF are justified in all patients with coronal synostosis who are negative for FGFR and TWIST1 mutations (Lattanzi et al., 2017). Another study stated that at
ACCEPTED MANUSCRIPT least 57 genetic mutations are associated with CRS, but realistically only a few of these are included in routine laboratory genetic testing (Miller et al., 2017). In our study, 6 patients (2.26%) were reported with abnormal FGFR genes. No specific gene anomaly seemed to be
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associated with a CRS type, but a much greater number of patients is required for a genetic conclusion. Further investigations at the genetic level are required to compare different
populations. Despite extreme genetic heterogeneity of nonsyndromic CRS, genetic analysis
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may aid in early diagnosis of clinically ambiguous cases. Although nonsurgical treatment of CRS remains unavailable so far, advances in genetic research may open a new era in the
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future.
CONCLUSION
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Through our experience, we support that young to even relatively older CRS infants and young children can successfully be treated with surgical intervention. To diagnose CRS in an effective and timely manner, a physician must be aware of the general characteristics
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and understand the variations between Western and Eastern populations. Our data showed relatively late diagnosis of CRS, possibly due to cultural background and misinformation.
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Furthermore, a thorough education of the population is required, targeted to parents as well as physicians. As mentioned earlier, CRS is not only a morphological disorder but also is closely associated with neurodevelopmental impairment. Only through appropriate, timely diagnosis can a CRS patient be treated with better outcomes and minimal complications.
ACCEPTED MANUSCRIPT REFERENCES
Bayley N: The Bayley Scales of Infant Development, 2nd edition. San Antonio, TX: The
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Psychological Corporation, 1993 Bennett KG, Bickham RS, Robinson AB, Buchman SR, Vercler CJ: Metopic craniosynostosis: a demographic analysis outside an urban environment. J Craniofac Surg 27: 544-547, 2016
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Bristol RE, Lekovic GP, Rekate HL: The effects of craniosynostosis on the brain with respect
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to intracranial pressure. Semin Pediatr Neurol 11: 262-267, 2004
Cohen MMM, R. E.: Craniosynostosis. Diagnosis, Evaluation, and Management, 2nd edition. New York: Oxford University Press, 2000
Forrest CR, Hopper RA: Craniofacial syndromes and surgery. Plast Reconstr Surg 131: 86e109e, 2013
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Ghali GE, Sinn DP, Tantipasawasin S: Management of nonsyndromic craniosynostosis. Atlas Oral Maxillofac Surg Clin North Am 10: 1-41, 2002
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Johnson D, Wilkie AO: Craniosynostosis. Eur J Hum Genet 19: 369-376, 2011 Kapp-Simon KA, Speltz ML, Cunningham ML, Patel PK, Tomita T: Neurodevelopment of
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children with single suture craniosynostosis: a review. Childs Nerv Syst 23: 269-281, 2007
Kordestani RK, Patel S, Bard DE, Gurwitch R, Panchal J: Neurodevelopmental delays in children with deformational plagiocephaly. Plast Reconstr Surg 117: 207-218; discussion 219-220, 2006 KOSIS: Korean Statistical Information Service, kosis.kr. , 2017 Lattanzi W, Barba M, Di Pietro L, Boyadjiev SA: Genetic advances in craniosynostosis. Am J Med Genet A 173: 1406-1429, 2017
ACCEPTED MANUSCRIPT Lekovic GP, Bristol RE, Rekate HL: Cognitive impact of craniosynostosis. Semin Pediatr Neurol 11: 305-310, 2004 Magge SN, Westerveld M, Pruzinsky T, Persing JA: Long-term neuropsychological effects of
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sagittal craniosynostosis on child development. J Craniofac Surg 13: 99-104, 2002 McCarthy JG, Warren SM, Bernstein J, Burnett W, Cunningham ML, Edmond JC, et al:
Parameters of care for craniosynostosis. Cleft Palate Craniofac J 49 (Suppl:) 1S-24S,
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2012
Miller KA, Twigg SR, McGowan SJ, Phipps JM, Fenwick AL, Johnson D, et al: Diagnostic
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value of exome and whole genome sequencing in craniosynostosis. J Med Genet 54: 260-268, 2017
Panchal J, Amirsheybani H, Gurwitch R, Cook V, Francel P, Neas B, et al: Neurodevelopment in children with single-suture craniosynostosis and plagiocephaly without synostosis.
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Plast Reconstr Surg 108: 1492-1498; discussion 1499-1500, 2001 Shim KW, Park EK, Kim JS, Kim YO, Kim DS: Neurodevelopmental problems in nonsyndromic craniosynostosis. J Korean Neurosurg Soc 59: 242-246, 2016
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Siatkowski RM, Fortney AC, Nazir SA, Cannon SL, Panchal J, Francel P, et al: Visual field defects in deformational posterior plagiocephaly. J AAPOS 9: 274-278, 2005
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Slater BJ, Lenton KA, Kwan MD, Gupta DM, Wan DC, Longaker MT: Cranial sutures: a brief review. Plast Reconstr Surg 121: 170e-178e, 2008
Speltz ML, Kapp-Simon K, Collett B, Keich Y, Gaither R, Cradock MM, et al: Neurodevelopment of infants with single-suture craniosynostosis: presurgery
comparisons with case-matched controls. Plast Reconstr Surg 119: 1874-1881, 2007 Starr JR, Kapp-Simon KA, Cloonan YK, Collett BR, Cradock MM, Buono L, et al: Presurgical and postsurgical assessment of the neurodevelopment of infants with single-suture craniosynostosis: comparison with controls. J Neurosurg 107: 103-110,
ACCEPTED MANUSCRIPT 2007 Sugawara Y, Hirabayashi S, Sakurai A, Harii K: Gradual cranial vault expansion for the treatment of craniofacial synostosis: a preliminary report. Ann Plast Surg 40: 554-565,
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1998 Twigg SR, Wilkie AO: A genetic-pathophysiological framework for craniosynostosis. Am J Hum Genet 97: 359-377, 2015
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Zakhary GM, Montes DM, Woerner JE, Notarianni C, Ghali GE: Surgical correction of
craniosynostosis. A review of 100 cases. J Craniomaxillofac Surg 42: 1684-1691,
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2014
ACCEPTED MANUSCRIPT Figure 1. Distribution of craniosynostosis type and sex.
Figure 2. Comparison of neurodevelopment scores by craniosynostosis type. BSID-II,
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Bayley Scales of Infant Development, Second Edition; MDI, Mental Developmental Index;
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PDI, Psychomotor Development Index.
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Figure 3. Distribution of craniosynostosis type and year of diagnosis.
ACCEPTED MANUSCRIPT Table 1. Patient characteristics (in comparison to previous studies) Current study
Speltz et al.
Zakhary et al.
Number of patients
266
125
100
Age at diagnosis (y)
2.01 ± 2.57
0.54 ± 0.33
Age at operation (y)
2.16 ± 2.61
Sex Male
157 (59.02%)
76 (60.80%)
Female
109 (40.98%)
49 (39.20%)
32.18 ± 4.56
Paternal age
34.71 ± 4.72
BSID-II MDI
84.96 ± 22.77
91.92 ± 9.19
BSID-II PDI
84.19 ± 25.62
84.00 ± 12.03
Abnormal genes
6 (2.20%) 2 (0.73%)
FGFR3
4 (1.47%)
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FGFR2
73 (73.00%) 23 (23.00%)
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Maternal age
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0.74 (0.42–2.5)
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BSID-II, Bayley Scales of Infant Development, Second Edition; MDI, Mental Developmental Index; PDI, Psychomotor Development Index; FGFR, Fibroblast Growth Factor Receptor.
ACCEPTED MANUSCRIPT Table 2. Patient distribution of craniosynostosis type (in comparison to previous studies) Current study 27 (10.15%: 8 male, 19
13 (13%: 8 male, 5
female)
female)
28 (10.53%: 24 male, 4 27 (21.60%: 18 male, 9 31 (31%: 23 male, 5 female)
Unicoronal
female)
female)
female)
2 (2%: 1 male, 1
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46 (17.29%: 31 male, 15 female)
Sagittal
10 (10%: 5 male, 5
50 (18.80%: 29 male, 21 8 (6.40%: 3 male, 5 female) female)
Multiple
female)
48 (18.04%: 19 male, 29 28 (22.40%: 6 male, 22 female)
Unilambdoid
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Metopic
Zakhary et al.
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Bicoronal
Speltz et al.
female)
67 (25.19%: 46 male, 21 62 (49.60%: 49 male, 13 44 (44%: 36 male, 8 female)
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female)
female)
ACCEPTED MANUSCRIPT Table 3. Maternal and paternal ages at patient birth by craniosynostosis type Paternal age (y)
Bicoronal
32.57 ± 4.29
33.78 ± 4.58
Metopic
32.87 ± 4.22
35.47 ± 5.01
Unicoronal
31.24 ± 4.21
34.54 ± 3.83
Unilambdoid
32.74 ± 3.66
34.82 ± 3.47
Multiple
30.72 ± 5.75
33.78 ± 6.18
Sagittal
33.05 ± 4.68
35.59 ± 5.15
p Value
0.17
0.53
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Maternal age (y)
ACCEPTED MANUSCRIPT Table 4. Neurodevelopment scores by craniosynostosis type BSID-II PDI
Bicoronal
89.30 ± 24.50
88.25 ± 26.43
Metopic
77.21 ± 26.73
71.32 ± 30.65
Unicoronal
85.87 ± 21.67
83.87 ± 23.59
Unilambdoid
90.45 ± 22.46
86.21 ± 24.56
Multiple
82.26 ± 20.06
85.30 ± 26.26
Sagittal
83.35 ± 22.58
85.59 ± 24.58
p Value
0.36
0.33
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BSID-II MDI
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BSID-II, Bayley Scales of Infant Development, Second Edition; MDI, Mental Development Index; PDI, Psychomotor Development Index
ACCEPTED MANUSCRIPT Table 5. Incidence of new births and diagnosis of craniosynostosis per year New birth in Korea
Birth at our institute
CRS at our institute
2000
634,500
1601
1
2001
554,900
1247
4
2002
492,100
1057
5
2003
490,500
944
2004
472,800
990
2005
435,000
920
2006
448,200
758
2007
493,200
1221
2008
465,900
1278
2009
444,800
1193
2010
470,200
2011
471,300
2012
484,600
2013
436,500
2014
435,400
2015 2016
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Year
4 3 7 8
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6
10 18 39
1221
37
1227
22
1158
29
1149
26
438,700
1423
27
406,300
1471
16
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1354
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ACCEPTED MANUSCRIPT
S1010-5182(18)30050-7
DOI:
10.1016/j.jcms.2018.02.008
Reference:
YJCMS 2910
To appear in:
Journal of Cranio-Maxillo-Facial Surgery
Received Date: 14 October 2017 Revised Date:
27 January 2018
Accepted Date: 13 February 2018
Please cite this article as: Byun IH, Hong JW, Hussein M, Kim YO, Demographic characteristics of craniosynostosis patients in Asia, Journal of Cranio-Maxillofacial Surgery (2018), doi: 10.1016/ j.jcms.2018.02.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Demographic characteristics of craniosynostosis patients in Asia
Kim, M.D., Ph.D. 1
Department of Plastic & Reconstructive Surgery
Institute for Human Tissue Restoration
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1
Yonsei University College of Medicine, Seoul, Korea
Department of Plastic & Reconstructive Surgery
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2
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Cairo University College of Medicine, Cairo, Egypt
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Il Hwan Byun, M.D.1, Jong Won Hong, M.D.1, Mohammed Hussein, M.D.2, and Yong Oock
ACCEPTED MANUSCRIPT Correspondence: Yong Oock Kim, M.D., Ph.D. Department of Plastic and Reconstructive Surgery
50 Yonsei-ro, Seodaemun-gu, Seoul, Korea Tel: +82-2-2228-2218, Fax: +82-2-577-4914
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E-mail: [email protected]
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Yonsei University College of Medicine
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Institue for Human Tissue Restoration
ACCEPTED MANUSCRIPT Conflict of Interest The authors declare that they have no conflict of interest.
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Ethical Approval
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This study was conducted in accordance with the Declaration of Helsinki.
ACCEPTED MANUSCRIPT Summary Purpose: Craniosynostosis (CRS) is a congenital condition resulting premature fusion of one or more cranial sutures. CRS is classified according to the involved sutures into sagittal,
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metopic, unicoronal, unilambdoid, bicoronal, and multiple-suture CRS, with sagittal suture fusion known to be the most common type. Although multiple studies have presented
demographic characteristics of CRS patients, to date, there is no study representing an Asian
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of Western patients, considering previous reports.
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population. We sought to compare the demographic characteristics of Asian patients to those
Materials and Methods: A total of 266 CRS patients treated in a single institution from 1996 to 2016 were retrospectively reviewed. Data from the patients was collected regardless
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of whether they underwent operation. Patients’ age at the time of presentation, sex, and maternal and paternal age at birth were reviewed. Patients were routinely investigated for abnormal genes (FGFR2 and FGFR3). The Bayley Scales of Infant Development, Second
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Edition (BSID-II), was used to assess the patients’ cognitive and psychomotor development. One-way analysis of variance or the Kruskal-Wallis test was used to compare continuous
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variables. A p value of <0.05 was considered statistically significant.
Results: Our study included 157 males (59.02%) and 109 females (40.98%), with an age ranging from 0.1 to 10.5 years. The mean age at the time of diagnosis was 2.01 ± 2.57 years, and the mean age at operation was 2.16 ± 2.61 years. Of the patients, 27 (10.15%) were bicoronal, 28 patients (10.53%) were metopic, 48 patients (18.04%) were unicoronal, 50 patients (18.80%) were unilamboid, and 67 patients (25.19%) were sagittal. Patients with
ACCEPTED MANUSCRIPT multiple-suture CRS totaled 46 (17.29%). Investigation of abnormal genes revealed six patients (2.20%), including two patients with abnormal FGFR2 and four patients with abnormal FGFR3. Maternal and paternal ages at the patients’ birth were 32.18 ± 4.56 years
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and 34.71 ± 4.72 years, respectively. The mean BSID-II scores were 84.96 ± 22.77 for the Mental Development Index and 84.19 ± 25.62 for the Psychomotor Development Index. To examine the trend of diagnosis of CRS type, we also evaluated the number of new patients
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diagnosed with nonsyndromic CRS per year at our institution. New diagnoses of CRS
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generally increased from the year 2009, although variations continued.
Conclusion: The mean age of our patients is relatively high compared to previous, Western studies. Through this research, we recognized that cultural discrepancies regarding the expectations of Asian parents may lead to prolonged diagnosis of CRS patients, and yet even
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relatively older CRS infants can successfully be treated with surgical intervention. The prevalence of CRS types and BSID-II development scores varied compared to those in previous Western studies. Further investigations at the genetic level are required to compare
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the different populations. To diagnose CRS in an effective and timely manner, a physician
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must be aware of the general characteristics and understand the variations between Western and Eastern populations.
Keywords: craniosynostosis; demographic; Asian
ACCEPTED MANUSCRIPT INTRODUCTION Craniosynostosis (CRS) is a congenital condition resulting premature fusion of one or more cranial sutures, which occurs at an incidence of 3.5 to 4.5 per 10,000 live births
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worldwide (Cohen, 2000). Single-suture CRS is known to have a higher incidence, occurring in approximately 1 per 2,000 live births (Kapp-Simon et al., 2007). CRS may present as an isolated condition or as part of a complex craniofacial syndrome. Although the precise
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pathogenesis of CRS remains unclear, studies have shown that CRS is intimately related to abnormalities of osteoprogenitor cells within the cranial sutures, due to gene mutations in
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fibroblast growth factor receptors (FGFR) and the Msx homeobox (Slater et al., 2008). Craniosynostosis is further classified according to the involved sutures into sagittal, metopic, unicoronal, unilambdoid, bicoronal, and multiple-suture CRS, with sagittal suture fusion known to be the most common type [4]. The skull morphology is closely related to the
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pattern of suture closure; sagittal CRS results in scaphocephaly; unicoronal and unilambdoid CRS result in plagiocephaly; and bicoronal and bilambdoid CRS result in relatively
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symmetric yet brachiocephalic head shapes.
Although multiple studies have presented demographic characteristics of CRS
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patients, to date, there is no study representing Korean or any other Asian population. Thus our work involved examining the demographic characteristics of Korean CRS patients as a selected sample of an Asian population, to provide general guidelines that will aid surgeons in diagnosing and managing Asian CRS patients. Also we sought to compare the demographic characteristics of Asian patients to those of Western patients based on previous reports.
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MATERIALS AND METHODS A total of 266 CRS patients treated at a single institute from 1996 to 2016 were
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retrospectively reviewed. Data from the patients was collected regardless of whether they underwent operation. Patients’ age at the time of presentation, sex, and maternal and paternal age at birth were reviewed. Patients with syndromic CRS as well as those with a history of
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previous CRS operation were excluded. Patients were routinely investigated for abnormal
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genes (FGFR2 and FGFR3) because these are the most commonly involved genetic mutations in CRS (Johnson and Wilkie, 2011).
The Bayley Scales of Infant Development, Second Edition (BSID-II), was used to assess the patients’ cognitive and psychomotor development, as this is a standardized, norm-
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referenced objective test of an infant’s developmental status (Bayley, 1993). The BSID-II provides updated norms, yielding a Mental Development Index (MDI) and Psychomotor Development Index (PDI). The BSID-II scores are often categorized as accelerated, >115;
Starr et al., 2007).
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within normal limits, 85–115; mildly delayed, 70–84; or severely delayed, <70 (Bayley, 1993;
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Means and standard deviations were calculated for all continuous variables, as
appropriate. Categorical variables were expressed as proportions (%). One-way analysis of variance or the Kruskal-Wallis test was used to compare continuous variables. All statistical analyses were assessed with the Statistical Package for Social Sciences (SPSS version 23.0; SPSS Inc., Armonk, NY, USA). A p value of < 0.05 was considered statistically significant.
ACCEPTED MANUSCRIPT RESULTS Between 1996 and 2016, a total 266 CRS patients were included; 157 males (59.02%) and 109 females (40.98%), with an age range of 0.1 to 10.5 years. The mean age at the time
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of diagnosis was 2.01 ± 2.57 years, while the mean age at operation was 2.16 ± 2.61 years. General patient characteristics are presented in Table 1. A total of 220 patients had singlesuture CRS; the sagittal type was the most frequent, while the bicoronal was the least
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frequent. Twenty-seven patients (10.15%) were bicoronal, 28 patients (10.53%) were metopic, 48 patients (18.04%) were unicoronal, 50 patients (18.80%) were unilamboid, and 67 patients
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(25.19%) were sagittal. There were 46 patients (17.29%) with multiple-suture CRS. The CRS type and sex distribution of each group is shown in Table 2 and Figure 1. Interestingly, metopic type CRS showed a sex ratio of a much greater number of males in our study as well as previous studies (Speltz et al., 2007; Zakhary et al., 2014).
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Investigation of abnormal genes revealed six patients (2.20%), two patients with abnormal FGFR2 and four patients with abnormal FGFR3. The two patients with abnormal FGFR2 were multiple types, and four patients with abnormal FGFR3 were metopic, sagittal,
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unicoronal, and multiple types.
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Maternal and paternal ages at the patients’ birth were 32.18 ± 4.56 years and 34.71 ± 4.72 years, respectively. When maternal and paternal ages were analyzed for each group, the mean maternal and paternal ages were the highest for the sagittal type (33.05 ± 4.68 years and 35.59 ± 5.15 years, respectively), whereas the lowest means were noted in the multiplesuture type (30.72 ± 5.75 and 33.78 ± 6.18 years). Yet there was no statistically significant difference between the groups regarding maternal and paternal ages (p = 0.17 and 0.53, respectively). Parental ages by types are summarized in Table 3.
ACCEPTED MANUSCRIPT The mean BSID-II scores were 84.96 ± 22.77 for MDI and 84.19 ± 25.62 for PDI. The mean MDI scores ranged from 77.21 ± 26.73 for the metopic type to 90.45 ± 22.46 for the unilambdoid type, while the mean PDI scores ranged from 71.32 ± 30.65 for the metopic
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type to 86.21 ± 24.56 for the unilambdoid type. The lowest mean scores of both MDI and PDI were noted in the metopic type, and the highest mean scores were noted in the
unilamboid type (Table 4 and Figure 2). As with parental ages, however, there was no
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significant difference between the CRS types associated with BSID-II (p = 0.36 for MDI and 0.33 for PDI).
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To see the trend of diagnosis of CRS type, we also evaluated the number of new patients diagnosed with nonsyndromic CRS per year at our institution (Figure 3 and Table 5).
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New diagnoses of CRS generally increased from year 2009, although variations continued.
DISCUSSION
Despite CRS having been considered as a purely cosmetic problem for long time by
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parents as well as by surgeons, this concept had changed over the past few decades. The ultimate goal of treatment includes normal morphology as well as craniofacial development.
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Studies have shown multiple functional impairments in those patients, including visual impairment, increased intracranial tension, brain growth restriction, and neuropsychiatric disorders (Panchal et al., 2001; Magge et al., 2002; Bristol et al., 2004; Siatkowski et al., 2005; Kordestani et al., 2006). Neurocognitive impairments such as verbal short-term memory and language are reported to be as high as 35% to 50% in school-aged children with CRS (Kapp-Simon et al., 2007). Because the causal implications of this association are partly unclear, many surgeons recommend routine neurodevelopmental tests of CRS patients, to
ACCEPTED MANUSCRIPT help to identify patients at high risk for neurodevelopmental delay; thus earlier intervention could be considered to alleviate future problems (Lekovic et al., 2004; Speltz et al., 2007). As a result, multidisciplinary care guidelines recommended early neurodevelopmental screening
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before the age of 4 months, which should be continued until the age of 8 years (McCarthy et al., 2012).
Craniosynostosis is a condition that is relatively commonly encountered by plastic
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and reconstructive surgeons, and in which the role of surgical treatment is of great importance. The recent concepts in CRS correction are focused on correction of the morphological
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deformity while minimizing neuropsychological dysfunctions (Lekovic et al., 2004). Skull deformity and probable increased intracranial pressure are often considered as potential causes of neurodevelopmental impairment. Surgical intervention varies from the traditional cranial remodeling to the relatively recently proposed distraction osteogenesis, which has
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gained popularity worldwide since its introduction by Sugawara et al in 1998 (Sugawara et al., 1998; Forrest and Hopper, 2013). Since rapid brain volume expansion proceeds until the age of 3 years, and since about 90% of the adult size is reached by the age of 6 years, early
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surgical intervention is critical (Shim et al., 2016). Yet, CRS is an unfamiliar topic in many other fields of medicine, and a physician must understand patient characteristics for timely
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diagnosis and intervention. Thus we analyzed Asian CRS patients to provide general information and to compare characteristics with those of Western patients. In previous studies, Speltz et al. reported CRS patients with mean age of 6.5 ± 3.9
months at diagnosis, and Zakhary et al. presented mean age of 8.9 months (range 5–30 months) at operation.(Speltz et al., 2007; Zakhary et al., 2014). However, these studies excluded patients above 3 and 2 years old, respectively. In our study, the mean age at diagnosis was 2.01 ± 2.57 years. This is quite high compared to the previously mentioned
ACCEPTED MANUSCRIPT studies, but we did not exclude any older patients because we wanted to show the actual raw ages of visiting CRS patients. Even if the visiting plagiocephalic infant is older than 2 or 3 years, a physician must not rule out the possibility of CRS. Parents who visited our
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department with relatively old CRS patients often stated that their elder family members recommended waiting, hoping for recovery of the cranial shape as the infant grew older.
Although the raw age data for CRS patients at diagnosis and operation in previous Western
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studies are not available, some cultural discrepancies may have affected the delay in CRS diagnosis. Despite variations nowadays, many Asians emphasize family discipline and try to
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follow their elders’ teaching and recommendation. Interestingly, the new births in Korea have gradually decreased since 2000, but CRS diagnoses have generally increased, especially from 2010 (Figure 3 and Table 5) (Kosis, 2017). We believe that thorough screening examinations as well as improved knowledge of parents and physicians has led to increased diagnosis,
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which also included relatively old CRS patients as mentioned above. There are some similar and different traits of the CRS type distribution among previous studies and ours. Traditionally, sagittal type is known to be the most common type,
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and our study supports this, showing 25.19% of the patients with this type (Ghali et al., 2002). Studies vary, with the second most common type varying between unicoronal and metopic
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CRS (Bennett et al., 2016). Speltz et al. presented patients of whom 49.60% were sagittal, 21.60% were metopic, 22.40% were unicoronal, and 6.4% were lambdoid (Speltz et al., 2007). Zakhary reported patients of whom 44.00% were sagittal, 31.00% metopic, 13.00% bicoronal, 10.00% unicoronal, and 2.00% multiple-suture CRS (Zakhary et al., 2014). In our study, the most to least common types were sagittal (25.19%), unilamboid (18.80%), unicoronal (18.04%), multiple-suture (17.29%), metopic (10.53%), and bicoronal CRS (10.15%), respectively (Table 2 and Figure 1). Further studies are needed involving larger
ACCEPTED MANUSCRIPT population, but our findings show that the epidemiology of CRS types may differ between Western and Eastern populations. Variations were noted on neurodevelopment indices as well. Starr et al. presented
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mean MDI score of 92.08 and PDI score 84.85 for patients under 30 months, and Speltz et al. gave a mean MDI score of 91.92 ± 9.19 and PDI score of 84.00 ± 12.03 for infants and young children under 24 months (Speltz et al., 2007; Starr et al., 2007). Both studies show MDI
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scores greater than PDI scores, with mild psychomotor development delay. In our study, the mean scores were MDI 84.96 ± 22.77 and PDI 84.19 ± 25.62, showing lower MDI scores and
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similar PDI scores compared to other studies. Such a discrepancy may be due to the wider range of ages of CRS patients in our study. Both mean scores were within normal limits, and physicians must consider the wide variation of neurodevelopment in CRS patients. As mentioned earlier, the brain volume rapidly expands at younger ages, so a doctor must
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thoroughly discuss the risk and benefits of cranioplasty with patients with relatively older CRS children. As with parental ages, there was no significant difference between the CRS types associated with BSID-II. Yet metopic CRS patients showed relatively low mean scores
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compared to other types, and taking such trend as a reference, a physician may expect
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relatively low MDI and PDI scores when treating a metopic CRS patient. Since 2010, the availability of whole exome and genome approaches greatly
accelerated genetic research of genes enriched for mutations in CRS patients (Twigg and Wilkie, 2015). Recent studies advocate a stronger influence of genetic factors in the etiopathogenesis of nonsyndromic CRS. One study proposed that targeted FGFR1, FGFR2, FGFR3, and TWIST1 genetic testing is appropriate as a first-line test for CRS patients, and that analyses of TCF12 and ERF are justified in all patients with coronal synostosis who are negative for FGFR and TWIST1 mutations (Lattanzi et al., 2017). Another study stated that at
ACCEPTED MANUSCRIPT least 57 genetic mutations are associated with CRS, but realistically only a few of these are included in routine laboratory genetic testing (Miller et al., 2017). In our study, 6 patients (2.26%) were reported with abnormal FGFR genes. No specific gene anomaly seemed to be
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associated with a CRS type, but a much greater number of patients is required for a genetic conclusion. Further investigations at the genetic level are required to compare different
populations. Despite extreme genetic heterogeneity of nonsyndromic CRS, genetic analysis
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may aid in early diagnosis of clinically ambiguous cases. Although nonsurgical treatment of CRS remains unavailable so far, advances in genetic research may open a new era in the
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future.
CONCLUSION
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Through our experience, we support that young to even relatively older CRS infants and young children can successfully be treated with surgical intervention. To diagnose CRS in an effective and timely manner, a physician must be aware of the general characteristics
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and understand the variations between Western and Eastern populations. Our data showed relatively late diagnosis of CRS, possibly due to cultural background and misinformation.
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Furthermore, a thorough education of the population is required, targeted to parents as well as physicians. As mentioned earlier, CRS is not only a morphological disorder but also is closely associated with neurodevelopmental impairment. Only through appropriate, timely diagnosis can a CRS patient be treated with better outcomes and minimal complications.
ACCEPTED MANUSCRIPT REFERENCES
Bayley N: The Bayley Scales of Infant Development, 2nd edition. San Antonio, TX: The
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Psychological Corporation, 1993 Bennett KG, Bickham RS, Robinson AB, Buchman SR, Vercler CJ: Metopic craniosynostosis: a demographic analysis outside an urban environment. J Craniofac Surg 27: 544-547, 2016
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Bristol RE, Lekovic GP, Rekate HL: The effects of craniosynostosis on the brain with respect
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to intracranial pressure. Semin Pediatr Neurol 11: 262-267, 2004
Cohen MMM, R. E.: Craniosynostosis. Diagnosis, Evaluation, and Management, 2nd edition. New York: Oxford University Press, 2000
Forrest CR, Hopper RA: Craniofacial syndromes and surgery. Plast Reconstr Surg 131: 86e109e, 2013
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Ghali GE, Sinn DP, Tantipasawasin S: Management of nonsyndromic craniosynostosis. Atlas Oral Maxillofac Surg Clin North Am 10: 1-41, 2002
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Johnson D, Wilkie AO: Craniosynostosis. Eur J Hum Genet 19: 369-376, 2011 Kapp-Simon KA, Speltz ML, Cunningham ML, Patel PK, Tomita T: Neurodevelopment of
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children with single suture craniosynostosis: a review. Childs Nerv Syst 23: 269-281, 2007
Kordestani RK, Patel S, Bard DE, Gurwitch R, Panchal J: Neurodevelopmental delays in children with deformational plagiocephaly. Plast Reconstr Surg 117: 207-218; discussion 219-220, 2006 KOSIS: Korean Statistical Information Service, kosis.kr. , 2017 Lattanzi W, Barba M, Di Pietro L, Boyadjiev SA: Genetic advances in craniosynostosis. Am J Med Genet A 173: 1406-1429, 2017
ACCEPTED MANUSCRIPT Lekovic GP, Bristol RE, Rekate HL: Cognitive impact of craniosynostosis. Semin Pediatr Neurol 11: 305-310, 2004 Magge SN, Westerveld M, Pruzinsky T, Persing JA: Long-term neuropsychological effects of
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sagittal craniosynostosis on child development. J Craniofac Surg 13: 99-104, 2002 McCarthy JG, Warren SM, Bernstein J, Burnett W, Cunningham ML, Edmond JC, et al:
Parameters of care for craniosynostosis. Cleft Palate Craniofac J 49 (Suppl:) 1S-24S,
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Miller KA, Twigg SR, McGowan SJ, Phipps JM, Fenwick AL, Johnson D, et al: Diagnostic
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value of exome and whole genome sequencing in craniosynostosis. J Med Genet 54: 260-268, 2017
Panchal J, Amirsheybani H, Gurwitch R, Cook V, Francel P, Neas B, et al: Neurodevelopment in children with single-suture craniosynostosis and plagiocephaly without synostosis.
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Plast Reconstr Surg 108: 1492-1498; discussion 1499-1500, 2001 Shim KW, Park EK, Kim JS, Kim YO, Kim DS: Neurodevelopmental problems in nonsyndromic craniosynostosis. J Korean Neurosurg Soc 59: 242-246, 2016
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Siatkowski RM, Fortney AC, Nazir SA, Cannon SL, Panchal J, Francel P, et al: Visual field defects in deformational posterior plagiocephaly. J AAPOS 9: 274-278, 2005
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Slater BJ, Lenton KA, Kwan MD, Gupta DM, Wan DC, Longaker MT: Cranial sutures: a brief review. Plast Reconstr Surg 121: 170e-178e, 2008
Speltz ML, Kapp-Simon K, Collett B, Keich Y, Gaither R, Cradock MM, et al: Neurodevelopment of infants with single-suture craniosynostosis: presurgery
comparisons with case-matched controls. Plast Reconstr Surg 119: 1874-1881, 2007 Starr JR, Kapp-Simon KA, Cloonan YK, Collett BR, Cradock MM, Buono L, et al: Presurgical and postsurgical assessment of the neurodevelopment of infants with single-suture craniosynostosis: comparison with controls. J Neurosurg 107: 103-110,
ACCEPTED MANUSCRIPT 2007 Sugawara Y, Hirabayashi S, Sakurai A, Harii K: Gradual cranial vault expansion for the treatment of craniofacial synostosis: a preliminary report. Ann Plast Surg 40: 554-565,
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1998 Twigg SR, Wilkie AO: A genetic-pathophysiological framework for craniosynostosis. Am J Hum Genet 97: 359-377, 2015
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Zakhary GM, Montes DM, Woerner JE, Notarianni C, Ghali GE: Surgical correction of
craniosynostosis. A review of 100 cases. J Craniomaxillofac Surg 42: 1684-1691,
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2014
ACCEPTED MANUSCRIPT Figure 1. Distribution of craniosynostosis type and sex.
Figure 2. Comparison of neurodevelopment scores by craniosynostosis type. BSID-II,
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Bayley Scales of Infant Development, Second Edition; MDI, Mental Developmental Index;
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PDI, Psychomotor Development Index.
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Figure 3. Distribution of craniosynostosis type and year of diagnosis.
ACCEPTED MANUSCRIPT Table 1. Patient characteristics (in comparison to previous studies) Current study
Speltz et al.
Zakhary et al.
Number of patients
266
125
100
Age at diagnosis (y)
2.01 ± 2.57
0.54 ± 0.33
Age at operation (y)
2.16 ± 2.61
Sex Male
157 (59.02%)
76 (60.80%)
Female
109 (40.98%)
49 (39.20%)
32.18 ± 4.56
Paternal age
34.71 ± 4.72
BSID-II MDI
84.96 ± 22.77
91.92 ± 9.19
BSID-II PDI
84.19 ± 25.62
84.00 ± 12.03
Abnormal genes
6 (2.20%) 2 (0.73%)
FGFR3
4 (1.47%)
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FGFR2
73 (73.00%) 23 (23.00%)
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Maternal age
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0.74 (0.42–2.5)
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BSID-II, Bayley Scales of Infant Development, Second Edition; MDI, Mental Developmental Index; PDI, Psychomotor Development Index; FGFR, Fibroblast Growth Factor Receptor.
ACCEPTED MANUSCRIPT Table 2. Patient distribution of craniosynostosis type (in comparison to previous studies) Current study 27 (10.15%: 8 male, 19
13 (13%: 8 male, 5
female)
female)
28 (10.53%: 24 male, 4 27 (21.60%: 18 male, 9 31 (31%: 23 male, 5 female)
Unicoronal
female)
female)
female)
2 (2%: 1 male, 1
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46 (17.29%: 31 male, 15 female)
Sagittal
10 (10%: 5 male, 5
50 (18.80%: 29 male, 21 8 (6.40%: 3 male, 5 female) female)
Multiple
female)
48 (18.04%: 19 male, 29 28 (22.40%: 6 male, 22 female)
Unilambdoid
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Metopic
Zakhary et al.
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Bicoronal
Speltz et al.
female)
67 (25.19%: 46 male, 21 62 (49.60%: 49 male, 13 44 (44%: 36 male, 8 female)
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female)
female)
ACCEPTED MANUSCRIPT Table 3. Maternal and paternal ages at patient birth by craniosynostosis type Paternal age (y)
Bicoronal
32.57 ± 4.29
33.78 ± 4.58
Metopic
32.87 ± 4.22
35.47 ± 5.01
Unicoronal
31.24 ± 4.21
34.54 ± 3.83
Unilambdoid
32.74 ± 3.66
34.82 ± 3.47
Multiple
30.72 ± 5.75
33.78 ± 6.18
Sagittal
33.05 ± 4.68
35.59 ± 5.15
p Value
0.17
0.53
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Maternal age (y)
ACCEPTED MANUSCRIPT Table 4. Neurodevelopment scores by craniosynostosis type BSID-II PDI
Bicoronal
89.30 ± 24.50
88.25 ± 26.43
Metopic
77.21 ± 26.73
71.32 ± 30.65
Unicoronal
85.87 ± 21.67
83.87 ± 23.59
Unilambdoid
90.45 ± 22.46
86.21 ± 24.56
Multiple
82.26 ± 20.06
85.30 ± 26.26
Sagittal
83.35 ± 22.58
85.59 ± 24.58
p Value
0.36
0.33
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BSID-II MDI
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BSID-II, Bayley Scales of Infant Development, Second Edition; MDI, Mental Development Index; PDI, Psychomotor Development Index
ACCEPTED MANUSCRIPT Table 5. Incidence of new births and diagnosis of craniosynostosis per year New birth in Korea
Birth at our institute
CRS at our institute
2000
634,500
1601
1
2001
554,900
1247
4
2002
492,100
1057
5
2003
490,500
944
2004
472,800
990
2005
435,000
920
2006
448,200
758
2007
493,200
1221
2008
465,900
1278
2009
444,800
1193
2010
470,200
2011
471,300
2012
484,600
2013
436,500
2014
435,400
2015 2016
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Year
4 3 7 8
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6
10 18 39
1221
37
1227
22
1158
29
1149
26
438,700
1423
27
406,300
1471
16
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1354
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