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Multicentre approach to epidemiological aspects of craniosynostosis in Germany
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Multicentre approach to epidemiological aspects of craniosynostosis in Germany C. Neusel a , D. Class b , A.W. Eckert c , R. Firsching b , P. Göbel d , D. Götz a , R. Haase e , G. Jorch f , A. Köhn a , S. Kropf g , L. Patzer h , I. Schanze i , C. Zahl j , A. Rissmann a,∗ a
Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke University Magdeburg, Leipziger Str. 44, Haus 39, 39120 Magdeburg, Germany b Universitaetsklinik fuer Neurochirurgie, Leipziger Str. 44, 39120 Magdeburg, Germany c Department of Oral and Maxillofacial Surgery, University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany d Department of Paediatric Surgery and Paediatric Urology, Hospital St. Elisabeth and St. Barbara Halle (Saale), Mauerstraße 5, 06110 Halle (Saale), Germany e Department of Neonatology and Paediatric Intensive Care, University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany f Department of Paediatrics, University Hospital Magdeburg, Leipziger Str. 44, Haus 10, 39120 Magdeburg, Germany g Institute of Biometry and Medical Informatics, Medical Faculty Otto-von-Guericke University Magdeburg, Leipziger Str. 44, Haus 2, 39120 Magdeburg, Germany h Department of Paediatrics, Hospital St. Elisabeth and St. Barbara Halle (Saale), Mauerstraße 5, 06110 Halle (Saale), Germany i Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, Haus 1, Haus 39, Magdeburg, 39120 Germany j Department of Oral and Maxillofacial Surgery, University Hospital Magdeburg, Leipziger Str. 44, Haus 19, 39120 Magdeburg, Germany Accepted 3 October 2018
Abstract We know of no current published data on the prevalence of craniosynostosis in Germany, so our objective in this study was to contribute to the limited knowledge of its epidemiology by assessing time trends, the frequency of prenatal diagnosis, and the timing of diagnosis and treatment. Data were collected in Saxony-Anhalt during the period 2000–17, and we designed a retrospective multicentre cohort study. The prevalence was 4.8 cases of craniosynostosis/10 000 births, and did not increase during that time. We compared the data of 91 patients with those of 273 controls. There were 75 boys and 16 girls (ratio 4.7:1). Fifty-one children had isolated craniosynostosis, consisting of 46 with a single-suture, and five with a multisuture, synostosis. Twenty-nine were associated with other congenital malformations, and 11 were syndromic. Three cases had been diagnosed prenatally, and 34 had skull deformities diagnosed immediately after birth at a mean (SD) age of 3.4 (4.7) months. The mean (SD) age at the time of first admission to hospital in one of the three surgical centres of Saxony-Anhalt was 5.9 (5.5) months, and 65 patients were operated on at a mean age of 9.1 (6.3) months. In contrast to published reports we found a prevalence of 4.8 cases of craniosynostosis/10 000 births that did not increase during the period 2000–16. Although we found a low prenatal detection rate, the diagnosis and treatment in this cohort study seemed timely. © 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Craniosynostosis; Children; Epidemiology; Diagnosis; Prenatal
∗
Corresponding author. E-mail addresses: [email protected] (C. Neusel), [email protected] (D. Class), [email protected] (A.W. Eckert), [email protected] (R. Firsching), [email protected] (P. Göbel), [email protected] (D. Götz), [email protected] (R. Haase), [email protected] (G. Jorch), [email protected] (A. Köhn), [email protected] (S. Kropf), [email protected] (L. Patzer), [email protected] (I. Schanze), [email protected] (C. Zahl), [email protected], [email protected] (A. Rissmann). https://doi.org/10.1016/j.bjoms.2018.10.003 0266-4356/© 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Neusel C, et al. Multicentre approach to epidemiological aspects of craniosynostosis in Germany. Br J Oral Maxillofac Surg (2018), https://doi.org/10.1016/j.bjoms.2018.10.003
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Introduction Craniosynostosis is the premature closure of one or more of the sutures of the skull, which can result in a range of deformities. The sutures are open at the time of birth to ensure flexibility of the skull at the time of passage through the birth canal and allow for craniofacial growth, particularly during the first two years of life. The metopic (medial frontal) suture begins to close during the eighth month of life, whereas the other main sutures (sagittal, lambdoid, and coronal) remain open until adulthood.1 An overview of the prevalence of craniosynostosis is shown in Table 1. German data published in 1997 recorded craniosynostosis in 10/10 000 births but the reference is from a French study published in 1987.2,3 Kweldam et al reported a prevalence of 6.4 cases/10 000 births in 2007 from The Netherlands.4 EUROCAT (European Surveillance of Congenital Anomalies) shows a prevalence of 2.89 (95% CI 2.71 to 3.08) cases/10 000 births between 2011 and 2015.5 The Statistische Bundesamt in Wiesbaden reported 8.14 cases/10 000 births (766 999 live births, 624 cases) for the year 2000 in Germany. For the year 2016, 8.35 cases/10 000 births were reported (792 495 live births, 662 cases) in Germany.6 As these figures reflect the number of hospital admissions with the diagnosis “craniosynostosis”, it is still not clear how many patients had been admitted more than once with the same diagnosis.7–10 Premature fusion of the sutures causes a range of craniofacial deformities because one part of the skull cannot grow while others increase in size by a compensatory reaction.11 The resulting shapes of the skull can give rise to complications such as visual disorders, hearing deficiencies, developmental delays in speech and language, as well as raised intracranial pressure and cognitive impairment.12 Craniosynostosis is a heterogeneous condition that may be classified clinically according to aetiology (such as primary or secondary origin), the number of closed sutures, and the appearance of the skull.13 The key distinction is between isolated craniosynostosis on the one hand, and craniosynostosis with coexisting congenital anomalies (which indicates a syndrome) on the other. It can therefore also be divided into syndromic (as a part of a syndrome) or non-syndromic (isolated).12,14 A number of genetic mutations that encode regulatory proteins, tyrosine kinase receptors, ligand receptors, and transmembrane proteins have been associated with the development of craniosynostosis.15 As well as genetic abnormalities being a major risk factor, other external fac-
tors (such as maternal drug use in pregnancy) may have a bearing on its development.16 Diagnosis requires a clinical examination combined with ultrasound, plain radiographs, and magnetic resonance imaging or computed tomography.17 From previous publications we know that it can be detected by prenatal ultrasound in most cases.18,19 Depending on the aetiology of the deformity the disease may be treated conservatively, surgically, or both, but any treatment is the subject of debate.3,20 Surgical repair is indicated primarily to prevent increased intracranial pressure with neurological complications, and secondarily to correct the individual deformity and associated functional disorders.21,22 Lee et al showed that there had been an increase in the prevalence of craniosynostosis in data from hospitals in Europe and the United States,23 but we know of no epidemiological studies that have focussed on its prevalence and its prenatal diagnosis in Germany. The aim of this study, therefore, was to find out the prevalence of craniosynostosis over the years in a defined population in one German state, Saxony-Anhalt, and to analyse the proportions of prenatal diagnosis, timing of diagnosis, and treatment in these cases.
Patients and methods Collection of data We organised a retrospective multicentre cohort study that comprised a review of clinical records from 2000 –2017. Ninety-one patients were identified with the diagnosis craniosynostosis at the University Hospital Magdeburg, University Hospital Halle (Saale), and Hospital St. Elisabeth and St. Barbara Halle (Saale). The study included all the relevant departments eligible to carry out this type of operation or diagnosis within the State of Saxony-Anhalt. Data were obtained from maternity and paediatric records, and the hospital documentary programme (Medico, Medizinische Dokumentation, Cerner Deutschland). We also included data from the Malformation Monitoring Centre of SaxonyAnhalt, and collected information on pregnancy, perinatal period, diagnosis, treatment, and general health. Patients with craniosynostosis that had been verified by clinical examination and diagnostic imaging, and followed by indication for surgical intervention between 1 January 2000 and 31 December 2017, were included. Data from the Malformation Monitoring Centre SaxonyAnhalt (a population-based congenital anomalies registry
Table 1 Summary of published data on the prevalence of craniosynostosis. Country
Time span
Prevalence/10 000 births
First author, year, and reference no.
USA Western Australia The Netherlands The Netherlands The Netherlands
1976–1985 1980–1994 1997 2007 2008–2013
3.1 5.06 2.6 6.4 7.2
French 19908 Singer 19999 Kweldam 20114 Kweldam 20114 Cornelissen 201610
Please cite this article in press as: Neusel C, et al. Multicentre approach to epidemiological aspects of craniosynostosis in Germany. Br J Oral Maxillofac Surg (2018), https://doi.org/10.1016/j.bjoms.2018.10.003
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Fig. 1. Prevalence of craniosynostosis 2000–2016.
programme) were obtained for those born between 1 January 2000 and 31 December 2016 to find out the prevalence of craniosynostosis (a total of 142 cases). Cases recorded from the three hospitals do overlap with the cases recruited from the Malformation Monitoring Centre, which include all pregnancies (live births, still births, and termination of pregnancy after prenatal diagnosis). Details of this database and the methods of recruitment of cases have been described elsewhere.24 Controls Birth by year, by month, and single or multiple birth-matched cases without any congenital anomalies from the data from the Malformation Monitoring Centre, Saxony-Anhalt, were reviewed as controls (273 matched children so that one case was compared with three controls). Statistical analysis The data are given as mean (SD) for continuous variables or number (%) for discrete variables. The significance of differences in baseline characteristics was compared using the Mann–Whitney U test. The chi squared test was used for differences between categorical variables. The trend over time was also investigated with the chi squared test for linear trend, and estimated with 95% CI. We used the software package IBM SPSS Statistics for Windows (version 24, IBM Corp). Probabilities of less than 0.05 were accepted as significant.
The study was approved by the local Medical Faculty Research Ethics Committee of the University of Magdeburg.
Results Between 1 January 2000 and 31 December 2016 a total of 298 141 births was registered, of which 295 354 were live births. There was a total prevalence of 4.8 cases of craniosynostosis/10 000 births (95% CI 4.1 to 5.6; n = 142) in all births (live births, still births, and terminations of pregnancy after prenatal diagnosis) and a prevalence of 4.2 cases/10 000 live births (95% CI 3.5 to 4.9; n = 123). During the whole study period there was no significant trend in time either for outcomes of all pregnancies (p = 0.303, chi squared 20.034, df 16) or for live births (p = 0.328, chi squared 17.005, df 16) (Fig. 1). A total of 91 patients with craniosynostosis were identified at the three hospitals between 1 January 2000 to 31 December 2017. There were two cases of twins of whom three developed craniosynostosis. One mother had had fertility treatment (in vitro fertilization by intracytoplasmic sperm injection). The rest of the personal and clinical details of patients and controls are shown in Table 2, and the focus on the time of diagnosis in Table 3. The types of craniosynostosis and the appearance of the skull are shown in Table 4. Seventy-nine patients had a single-suture, and 12 had a multi-suture, synostosis. None was of secondary origin. A
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Table 2 Baseline characteristics of the study group. Data are number (%) of subjects except where otherwise stated.
Sex: Male Female Type of delivery: Spontaneous delivery Primary caesarean section Secondary caesarean section: Vacuum extraction Forceps Cephalic presentation: Regular vertex presentation Irregular vertex presentation Breech presentation Transverse lie s Mean (SD): Weight (g) Length (cm) Head circumference (cm) Gestational age (weeks) Maternal age (years) Paternal age (years) Follow-up (years)
Patients (n = 91)
Controls (n = 273) (%)
75 16
150 (54.9) 123 (45.1)
28 16 13 1 1
189 (69.2) 36 (13.2) 30 (11.0) 17 (6.2) 1 (0.4)
36 3 3 3
248 (90.9) 12 (4.4) 11 (4.0) 2 (0.7)
3206 (620) (n = 90) 50.6 (4.2) (n = 60) 34.8 (1.8) (n = 41) 38.6 (2.3) n = 90) 28.6 (5.3) (n = 83) 32.2 (6.2) (n = 53) 7.5 (4.4) (n = 53)
3403 (521) 51.1 (2.6) 34.7 (1.6) 39.1 (1.7) 28.6 (5.7) 32.1 (7.0)
<0.001 (21.823; 1)
0.002 (17.360; 4)
0.017 (10.193; 3)
Table 3 Focus on time of diagnosis. Data are number of subjects unless otherwise stated. No. Prenatal noticed by ultrasound (n = 91): Yes No Unknown Being noticed at birth (n = 91): Yes No Unknown Procedure after being noticed at birth (n = 91): Special diagnostics Observation None/unknown Detected by (n = 41): Parents Midwife Paediatrician Surgery centre Treated by operation (n = 91): Yes No/unknown Mean (SD) age (months): At detection (n = 88) At time of special diagnostics (n = 88) First contact at surgical centre (n = 88) At operation (n = 62)
p value (chi squared; df)
3 25 63 34 18 39 23 4 64 12 5 28 7
(z for the Mann-Whitney test) 0.013 (−2.495) 0.248 (−1.157) 0.631 (−0.482) 0.222 (−1.224) 0.868 (−0.167) 0.839 (-0.204)
Table 4 Types of craniosynostosis. Type
No.
Scaphocephaly Complex Turricephaly/brachycephaly Plagiocephaly: Posterior Anterior Trigonocephaly
43 2 5 1 7 33
Table 5 Classification of subgroups. Subgroup
No.
Multiple congenital anomalies Syndromic/other syndrome Isolated single-suture Isolated multisuture
29 11 46 5
65 26 3.4 (4.7) 5.6 (5.5) 5.9 (5.5) 9.1 (6.3)
genetic cause was confirmed in five patients typically associated with a syndrome of craniosynostosis. We identified one of each of the following syndromes: Muenke, craniofrontonasal, Proteus, Jacobsen, and Monosomy 6q25 syndrome, respectively. Six had a pathological genetic alteration, which may be either a secondary origin of the associated cran-
iosynostosis or a new association with craniosynostosis but without clear pathogenic mutations in several other genes. It may therefore have secondary causes. We have found one of each case: Feingold syndrome; deletion of chromosome 12 (GRIN2B-Gen, 46,XY,del(12)(p13.1p13.31).ish del(12)(pter+,ETV6-,qter + )); mosaic 45 × 0/46XY combined with microduplication 22q11.21; Kabuki syndrome; and twins with sonic hedgehog (SHH) mutation. Having considered the number of affected sutures, genetic aspects, and other malformations, we formed four subgroups (Table 5).
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Discussion
Conclusions
Of 298 141 births (live births, still births, or terminations of pregnancy after prenatal diagnosis) during the last 17 years, we identified 142 children with craniosynostosis, of whom there were 123 among the 295 354 live births. The total prevalence was 4.8 cases/10 000 births. Similar results have been reported from The Netherlands by Kweldam et al and from Western Australia by Singer et al.4,9 Our study does not confirm an increase of prevalence over the years, though in contrast, Lee et al showed an increase in the prevalence in hospital data in a review of earlier population-based studies.23 We could not identify a significant trend over time for craniosynostoses in Central Germany, but this may be the effect of the small number studied, because of the rarity of the disease. We also found no significant difference in prevalence for live births and for all outcomes of pregnancy, which can be explained by the low rate of prenatally-detected craniosynostosis. We hope that these population-based data on prevalence will highlight the current burden of the condition in children, and pave the way for further research, and work on prevention, as well as improved diagnosis and treatment. Our baseline data showed significant differences between patients and controls in the dominance of male sex, lower birth weight, fewer spontaneous deliveries, and more abnormal cephalic presentations. These differences have also been published elsewhere.4,16 Unlike Agrawal et al, who claimed that craniosynostosis can be detected by prenatal ultrasound in most cases,18 we found that prenatal ultrasound was not a particularly useful instrument for diagnosis. Clinical symptoms such as ophthalmic or speech disorders and raised intracranial pressure can be associated with verified craniosynostosis. The timing of the start of treatment is also important to ensure the physiological development of the bones of the skull and prevent neurological symptoms. It is therefore advised to classify the deformity of the skull early, based on clinical findings and imaging.13,18 Ultrasound was not a routine procedure in clinical practice in our group, the reason for which might be the large number of cases with multiple congenital anomalies and in which other malformations were more common. Another aspect is the lack of guidelines for the diagnosis of craniosynostosis in Germany, unlike other countries such as The Netherlands.25 Nevertheless, we confirmed a large proportion of conspicuous deformities of the skull that were diagnosed immediately after delivery. An early diagnosis and follow up ensures timely treatment. The validity of the current results may be limited by incomplete data in clinical records as a result of the retrospective and multicentre design of the study. One reason for inaccurate data may be that some patients seek treatment in centres outside the region with a bigger caseload and more experience. However it is not a big group, as diagnostic flow is organised by the general practitioner within the region. In the overlap of the data registries we saw only 11 cases diagnosed in the region who sought treatment elsewhere.
This study presents for the first time to our knowledge population-based data on the prevalence of craniosynostosis in Germany. The data showed no clear increase in prevalence in the last 17 years in Central Germany. Although the prenatal detection rate was low, analysis confirmed that diagnosis and treatment were timely. Conflict of interest This paper was Chantal Neusel’s doctoral thesis, and she obtained financial support from the Otto-von-Guericke University Medical Faculty Magdeburg, Germany, as a doctoral scholarship. Ethics statement/confirmation of patients’ permission The study was approved by the local Medical Faculty Research Ethics Committee of the University of Magdeburg (189/14).
Acknowledgements We thank all the children and parents who took part in the study, and our colleagues who were involved in the diagnosis and treatment for their interdisciplinary cooperation and documentation of data. References 1. Weinzweig J, Kirschner RE, Farley A, et al. Metopic synostosis: defining the temporal sequence of normal suture fusion and differentiating it from synostosis on the basis of computed tomography images. Plast Reconstr Surg 2003;112:1211–8. 2. Marchac D, Renier D. Treatment of craniosynostosis in infancy. Clin Plast Surg 1987;14:61–72. 3. Berg K, Grundmann U, Wilhelm W, et al. Craniosyinostosis operations in childhood. Anästhesiol Intensivmed Notfallmed Schmerzther 1997;32:138–50 (paper in German). 4. Kweldam CF, van der Vlugt JJ, van der Meulen JJ. The incidence of craniosynostosis in the Netherlands, 1997–2007. J Plast Reconstr Aesthet Surg 2011;64:583–8. 5. EUROCAT- European Surveillance of Congenital Anomalies. Data on prevalence rates of congenital anomalies. Available from URL:http://www.eurocat-network.eu/. Last accessed 29 September 2018. 6. Statistisches Bundesamt Gesundheitsberichterstattung (GBE) der Länder. Available from URL: http://www.gbe-bund.de Last accessed 29 September 2018. 7. Bremer S, Kiess W, Thome U, et al. Prevalence of gastroschisis, omphalocele, spina bifida, and orofacial clefts in neonates from January 2000–December 2010 in Leipzig, Saxony, Saxony-Anhalt, and Germany. Gesundheitswesen 2018;80:122–8. Erratum: Gesundheitswesen 2018; 80:e11 (papers in German). 8. French LR, Jackson IT, Melton III LJ. A population-based study of craniosynostosis. J Clin Epidemiol 1990;43:69–73.
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9. Singer S, Bower C, Southall P, et al. Craniosynostosis in Western Australia, 1980–1994: a population-based study. Am J Med Genet 1999;83:382–7. 10. Cornelissen M, Ottelander Bd, Rizopoulos D, et al. Increase of prevalence of craniosynostosis. J Craniomaxillofac Surg 2016;44:1273–9. 11. Müke R. Viewpoint on the pathogenesis and therapy of craniosynostosis. Acta Neurochirurg Wien 1972;26:191–250 (paper in German). 12. Garza RM, Khosla RK. Nonsyndromic craniosynostosis. Semin Plast Surg 2012;26:53–63. 13. Badve CA, Mallikarjunappa MK, Iyer RS, et al. Craniosynostosis: imaging review and primer on computed tomography. Pediatr Radiol 2013;43:728–43. 14. Derderian C, Seaward J. Syndromic craniosynostosis. Semin Plast Surg 2012;26:64–75. 15. Wilkie AO, Byren JC, Hurst JA, et al. Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 2010;126:e391–400. 16. Singh RP, Dhariwal D, Bhujel N, et al. Role of parental risk factors in the aetiology of isolated non-syndromic metopic craniosynostosis. Br J Oral Maxillofac Surg 2010;48:438–42. 17. Agrawal D, Steinbok P, Cochrane DD. Diagnosis of isolated sagittal synostosis: are radiographic studies necessary? Childs Nerv Syst 2006;22:375–8.
18. Delahaye S, Bernard JP, Rénier D, et al. Prenatal ultrasound diagnosis of fetal craniosynostosis. Ultrasound Obstet Gynecol 2003;21:347–53. 19. Simanovsky N, Hiller N, Koplewitz B, et al. Effectiveness of ultrasonographic evaluation of the cranial sutures in children with suspected craniosynostosis. Eur Radiol 2009;19:687–92. 20. Goyal K, Chaturvedi A, Prabhakar H. Factors affecting the outcome of patients undergoing corrective surgery for craniosynostosis: a retrospective analysis of 95 cases. Neurol India 2011;59:823–8. 21. Massimi L, Caldarelli M, Tamburrini G, et al. Isolated sagittal craniosynostosis: definition, classification, and surgical indications. Childs Nerv Syst 2012;28:1311–7. 22. Al-Namnam NM, Hariri F, Rahman ZA. Distraction osteogenesis in the surgical management of syndromic craniosynostosis: a comprehensive review of published papers. Br J Oral Maxillofac Surg 2018;56:353–66. 23. Lee HQ, Hutson JM, Wray AC, et al. Changing epidemiology of nonsyndromic craniosynostosis and revisiting the risk factors. J Craniofac Surg 2012;23:1245–51. 24. Greenlees R, Neville A, Addor M, et al. Paper 6: EUROCAT member registries: organization and activities. Birth Defects Res A Clin Mol Teratol 2011;91(Suppl 1):S51–100. 25. Mathijssen IM. Guideline for care of patients with the diagnoses of craniosynostosis: working group on cradiosynostosis. J Craniofac Surg 2015;26:1735–807.
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Multicentre approach to epidemiological aspects of craniosynostosis in Germany C. Neusel a , D. Class b , A.W. Eckert c , R. Firsching b , P. Göbel d , D. Götz a , R. Haase e , G. Jorch f , A. Köhn a , S. Kropf g , L. Patzer h , I. Schanze i , C. Zahl j , A. Rissmann a,∗ a
Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke University Magdeburg, Leipziger Str. 44, Haus 39, 39120 Magdeburg, Germany b Universitaetsklinik fuer Neurochirurgie, Leipziger Str. 44, 39120 Magdeburg, Germany c Department of Oral and Maxillofacial Surgery, University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany d Department of Paediatric Surgery and Paediatric Urology, Hospital St. Elisabeth and St. Barbara Halle (Saale), Mauerstraße 5, 06110 Halle (Saale), Germany e Department of Neonatology and Paediatric Intensive Care, University Hospital Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany f Department of Paediatrics, University Hospital Magdeburg, Leipziger Str. 44, Haus 10, 39120 Magdeburg, Germany g Institute of Biometry and Medical Informatics, Medical Faculty Otto-von-Guericke University Magdeburg, Leipziger Str. 44, Haus 2, 39120 Magdeburg, Germany h Department of Paediatrics, Hospital St. Elisabeth and St. Barbara Halle (Saale), Mauerstraße 5, 06110 Halle (Saale), Germany i Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, Haus 1, Haus 39, Magdeburg, 39120 Germany j Department of Oral and Maxillofacial Surgery, University Hospital Magdeburg, Leipziger Str. 44, Haus 19, 39120 Magdeburg, Germany Accepted 3 October 2018
Abstract We know of no current published data on the prevalence of craniosynostosis in Germany, so our objective in this study was to contribute to the limited knowledge of its epidemiology by assessing time trends, the frequency of prenatal diagnosis, and the timing of diagnosis and treatment. Data were collected in Saxony-Anhalt during the period 2000–17, and we designed a retrospective multicentre cohort study. The prevalence was 4.8 cases of craniosynostosis/10 000 births, and did not increase during that time. We compared the data of 91 patients with those of 273 controls. There were 75 boys and 16 girls (ratio 4.7:1). Fifty-one children had isolated craniosynostosis, consisting of 46 with a single-suture, and five with a multisuture, synostosis. Twenty-nine were associated with other congenital malformations, and 11 were syndromic. Three cases had been diagnosed prenatally, and 34 had skull deformities diagnosed immediately after birth at a mean (SD) age of 3.4 (4.7) months. The mean (SD) age at the time of first admission to hospital in one of the three surgical centres of Saxony-Anhalt was 5.9 (5.5) months, and 65 patients were operated on at a mean age of 9.1 (6.3) months. In contrast to published reports we found a prevalence of 4.8 cases of craniosynostosis/10 000 births that did not increase during the period 2000–16. Although we found a low prenatal detection rate, the diagnosis and treatment in this cohort study seemed timely. © 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Craniosynostosis; Children; Epidemiology; Diagnosis; Prenatal
∗
Corresponding author. E-mail addresses: [email protected] (C. Neusel), [email protected] (D. Class), [email protected] (A.W. Eckert), [email protected] (R. Firsching), [email protected] (P. Göbel), [email protected] (D. Götz), [email protected] (R. Haase), [email protected] (G. Jorch), [email protected] (A. Köhn), [email protected] (S. Kropf), [email protected] (L. Patzer), [email protected] (I. Schanze), [email protected] (C. Zahl), [email protected], [email protected] (A. Rissmann). https://doi.org/10.1016/j.bjoms.2018.10.003 0266-4356/© 2018 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
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Introduction Craniosynostosis is the premature closure of one or more of the sutures of the skull, which can result in a range of deformities. The sutures are open at the time of birth to ensure flexibility of the skull at the time of passage through the birth canal and allow for craniofacial growth, particularly during the first two years of life. The metopic (medial frontal) suture begins to close during the eighth month of life, whereas the other main sutures (sagittal, lambdoid, and coronal) remain open until adulthood.1 An overview of the prevalence of craniosynostosis is shown in Table 1. German data published in 1997 recorded craniosynostosis in 10/10 000 births but the reference is from a French study published in 1987.2,3 Kweldam et al reported a prevalence of 6.4 cases/10 000 births in 2007 from The Netherlands.4 EUROCAT (European Surveillance of Congenital Anomalies) shows a prevalence of 2.89 (95% CI 2.71 to 3.08) cases/10 000 births between 2011 and 2015.5 The Statistische Bundesamt in Wiesbaden reported 8.14 cases/10 000 births (766 999 live births, 624 cases) for the year 2000 in Germany. For the year 2016, 8.35 cases/10 000 births were reported (792 495 live births, 662 cases) in Germany.6 As these figures reflect the number of hospital admissions with the diagnosis “craniosynostosis”, it is still not clear how many patients had been admitted more than once with the same diagnosis.7–10 Premature fusion of the sutures causes a range of craniofacial deformities because one part of the skull cannot grow while others increase in size by a compensatory reaction.11 The resulting shapes of the skull can give rise to complications such as visual disorders, hearing deficiencies, developmental delays in speech and language, as well as raised intracranial pressure and cognitive impairment.12 Craniosynostosis is a heterogeneous condition that may be classified clinically according to aetiology (such as primary or secondary origin), the number of closed sutures, and the appearance of the skull.13 The key distinction is between isolated craniosynostosis on the one hand, and craniosynostosis with coexisting congenital anomalies (which indicates a syndrome) on the other. It can therefore also be divided into syndromic (as a part of a syndrome) or non-syndromic (isolated).12,14 A number of genetic mutations that encode regulatory proteins, tyrosine kinase receptors, ligand receptors, and transmembrane proteins have been associated with the development of craniosynostosis.15 As well as genetic abnormalities being a major risk factor, other external fac-
tors (such as maternal drug use in pregnancy) may have a bearing on its development.16 Diagnosis requires a clinical examination combined with ultrasound, plain radiographs, and magnetic resonance imaging or computed tomography.17 From previous publications we know that it can be detected by prenatal ultrasound in most cases.18,19 Depending on the aetiology of the deformity the disease may be treated conservatively, surgically, or both, but any treatment is the subject of debate.3,20 Surgical repair is indicated primarily to prevent increased intracranial pressure with neurological complications, and secondarily to correct the individual deformity and associated functional disorders.21,22 Lee et al showed that there had been an increase in the prevalence of craniosynostosis in data from hospitals in Europe and the United States,23 but we know of no epidemiological studies that have focussed on its prevalence and its prenatal diagnosis in Germany. The aim of this study, therefore, was to find out the prevalence of craniosynostosis over the years in a defined population in one German state, Saxony-Anhalt, and to analyse the proportions of prenatal diagnosis, timing of diagnosis, and treatment in these cases.
Patients and methods Collection of data We organised a retrospective multicentre cohort study that comprised a review of clinical records from 2000 –2017. Ninety-one patients were identified with the diagnosis craniosynostosis at the University Hospital Magdeburg, University Hospital Halle (Saale), and Hospital St. Elisabeth and St. Barbara Halle (Saale). The study included all the relevant departments eligible to carry out this type of operation or diagnosis within the State of Saxony-Anhalt. Data were obtained from maternity and paediatric records, and the hospital documentary programme (Medico, Medizinische Dokumentation, Cerner Deutschland). We also included data from the Malformation Monitoring Centre of SaxonyAnhalt, and collected information on pregnancy, perinatal period, diagnosis, treatment, and general health. Patients with craniosynostosis that had been verified by clinical examination and diagnostic imaging, and followed by indication for surgical intervention between 1 January 2000 and 31 December 2017, were included. Data from the Malformation Monitoring Centre SaxonyAnhalt (a population-based congenital anomalies registry
Table 1 Summary of published data on the prevalence of craniosynostosis. Country
Time span
Prevalence/10 000 births
First author, year, and reference no.
USA Western Australia The Netherlands The Netherlands The Netherlands
1976–1985 1980–1994 1997 2007 2008–2013
3.1 5.06 2.6 6.4 7.2
French 19908 Singer 19999 Kweldam 20114 Kweldam 20114 Cornelissen 201610
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Fig. 1. Prevalence of craniosynostosis 2000–2016.
programme) were obtained for those born between 1 January 2000 and 31 December 2016 to find out the prevalence of craniosynostosis (a total of 142 cases). Cases recorded from the three hospitals do overlap with the cases recruited from the Malformation Monitoring Centre, which include all pregnancies (live births, still births, and termination of pregnancy after prenatal diagnosis). Details of this database and the methods of recruitment of cases have been described elsewhere.24 Controls Birth by year, by month, and single or multiple birth-matched cases without any congenital anomalies from the data from the Malformation Monitoring Centre, Saxony-Anhalt, were reviewed as controls (273 matched children so that one case was compared with three controls). Statistical analysis The data are given as mean (SD) for continuous variables or number (%) for discrete variables. The significance of differences in baseline characteristics was compared using the Mann–Whitney U test. The chi squared test was used for differences between categorical variables. The trend over time was also investigated with the chi squared test for linear trend, and estimated with 95% CI. We used the software package IBM SPSS Statistics for Windows (version 24, IBM Corp). Probabilities of less than 0.05 were accepted as significant.
The study was approved by the local Medical Faculty Research Ethics Committee of the University of Magdeburg.
Results Between 1 January 2000 and 31 December 2016 a total of 298 141 births was registered, of which 295 354 were live births. There was a total prevalence of 4.8 cases of craniosynostosis/10 000 births (95% CI 4.1 to 5.6; n = 142) in all births (live births, still births, and terminations of pregnancy after prenatal diagnosis) and a prevalence of 4.2 cases/10 000 live births (95% CI 3.5 to 4.9; n = 123). During the whole study period there was no significant trend in time either for outcomes of all pregnancies (p = 0.303, chi squared 20.034, df 16) or for live births (p = 0.328, chi squared 17.005, df 16) (Fig. 1). A total of 91 patients with craniosynostosis were identified at the three hospitals between 1 January 2000 to 31 December 2017. There were two cases of twins of whom three developed craniosynostosis. One mother had had fertility treatment (in vitro fertilization by intracytoplasmic sperm injection). The rest of the personal and clinical details of patients and controls are shown in Table 2, and the focus on the time of diagnosis in Table 3. The types of craniosynostosis and the appearance of the skull are shown in Table 4. Seventy-nine patients had a single-suture, and 12 had a multi-suture, synostosis. None was of secondary origin. A
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Table 2 Baseline characteristics of the study group. Data are number (%) of subjects except where otherwise stated.
Sex: Male Female Type of delivery: Spontaneous delivery Primary caesarean section Secondary caesarean section: Vacuum extraction Forceps Cephalic presentation: Regular vertex presentation Irregular vertex presentation Breech presentation Transverse lie s Mean (SD): Weight (g) Length (cm) Head circumference (cm) Gestational age (weeks) Maternal age (years) Paternal age (years) Follow-up (years)
Patients (n = 91)
Controls (n = 273) (%)
75 16
150 (54.9) 123 (45.1)
28 16 13 1 1
189 (69.2) 36 (13.2) 30 (11.0) 17 (6.2) 1 (0.4)
36 3 3 3
248 (90.9) 12 (4.4) 11 (4.0) 2 (0.7)
3206 (620) (n = 90) 50.6 (4.2) (n = 60) 34.8 (1.8) (n = 41) 38.6 (2.3) n = 90) 28.6 (5.3) (n = 83) 32.2 (6.2) (n = 53) 7.5 (4.4) (n = 53)
3403 (521) 51.1 (2.6) 34.7 (1.6) 39.1 (1.7) 28.6 (5.7) 32.1 (7.0)
<0.001 (21.823; 1)
0.002 (17.360; 4)
0.017 (10.193; 3)
Table 3 Focus on time of diagnosis. Data are number of subjects unless otherwise stated. No. Prenatal noticed by ultrasound (n = 91): Yes No Unknown Being noticed at birth (n = 91): Yes No Unknown Procedure after being noticed at birth (n = 91): Special diagnostics Observation None/unknown Detected by (n = 41): Parents Midwife Paediatrician Surgery centre Treated by operation (n = 91): Yes No/unknown Mean (SD) age (months): At detection (n = 88) At time of special diagnostics (n = 88) First contact at surgical centre (n = 88) At operation (n = 62)
p value (chi squared; df)
3 25 63 34 18 39 23 4 64 12 5 28 7
(z for the Mann-Whitney test) 0.013 (−2.495) 0.248 (−1.157) 0.631 (−0.482) 0.222 (−1.224) 0.868 (−0.167) 0.839 (-0.204)
Table 4 Types of craniosynostosis. Type
No.
Scaphocephaly Complex Turricephaly/brachycephaly Plagiocephaly: Posterior Anterior Trigonocephaly
43 2 5 1 7 33
Table 5 Classification of subgroups. Subgroup
No.
Multiple congenital anomalies Syndromic/other syndrome Isolated single-suture Isolated multisuture
29 11 46 5
65 26 3.4 (4.7) 5.6 (5.5) 5.9 (5.5) 9.1 (6.3)
genetic cause was confirmed in five patients typically associated with a syndrome of craniosynostosis. We identified one of each of the following syndromes: Muenke, craniofrontonasal, Proteus, Jacobsen, and Monosomy 6q25 syndrome, respectively. Six had a pathological genetic alteration, which may be either a secondary origin of the associated cran-
iosynostosis or a new association with craniosynostosis but without clear pathogenic mutations in several other genes. It may therefore have secondary causes. We have found one of each case: Feingold syndrome; deletion of chromosome 12 (GRIN2B-Gen, 46,XY,del(12)(p13.1p13.31).ish del(12)(pter+,ETV6-,qter + )); mosaic 45 × 0/46XY combined with microduplication 22q11.21; Kabuki syndrome; and twins with sonic hedgehog (SHH) mutation. Having considered the number of affected sutures, genetic aspects, and other malformations, we formed four subgroups (Table 5).
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Discussion
Conclusions
Of 298 141 births (live births, still births, or terminations of pregnancy after prenatal diagnosis) during the last 17 years, we identified 142 children with craniosynostosis, of whom there were 123 among the 295 354 live births. The total prevalence was 4.8 cases/10 000 births. Similar results have been reported from The Netherlands by Kweldam et al and from Western Australia by Singer et al.4,9 Our study does not confirm an increase of prevalence over the years, though in contrast, Lee et al showed an increase in the prevalence in hospital data in a review of earlier population-based studies.23 We could not identify a significant trend over time for craniosynostoses in Central Germany, but this may be the effect of the small number studied, because of the rarity of the disease. We also found no significant difference in prevalence for live births and for all outcomes of pregnancy, which can be explained by the low rate of prenatally-detected craniosynostosis. We hope that these population-based data on prevalence will highlight the current burden of the condition in children, and pave the way for further research, and work on prevention, as well as improved diagnosis and treatment. Our baseline data showed significant differences between patients and controls in the dominance of male sex, lower birth weight, fewer spontaneous deliveries, and more abnormal cephalic presentations. These differences have also been published elsewhere.4,16 Unlike Agrawal et al, who claimed that craniosynostosis can be detected by prenatal ultrasound in most cases,18 we found that prenatal ultrasound was not a particularly useful instrument for diagnosis. Clinical symptoms such as ophthalmic or speech disorders and raised intracranial pressure can be associated with verified craniosynostosis. The timing of the start of treatment is also important to ensure the physiological development of the bones of the skull and prevent neurological symptoms. It is therefore advised to classify the deformity of the skull early, based on clinical findings and imaging.13,18 Ultrasound was not a routine procedure in clinical practice in our group, the reason for which might be the large number of cases with multiple congenital anomalies and in which other malformations were more common. Another aspect is the lack of guidelines for the diagnosis of craniosynostosis in Germany, unlike other countries such as The Netherlands.25 Nevertheless, we confirmed a large proportion of conspicuous deformities of the skull that were diagnosed immediately after delivery. An early diagnosis and follow up ensures timely treatment. The validity of the current results may be limited by incomplete data in clinical records as a result of the retrospective and multicentre design of the study. One reason for inaccurate data may be that some patients seek treatment in centres outside the region with a bigger caseload and more experience. However it is not a big group, as diagnostic flow is organised by the general practitioner within the region. In the overlap of the data registries we saw only 11 cases diagnosed in the region who sought treatment elsewhere.
This study presents for the first time to our knowledge population-based data on the prevalence of craniosynostosis in Germany. The data showed no clear increase in prevalence in the last 17 years in Central Germany. Although the prenatal detection rate was low, analysis confirmed that diagnosis and treatment were timely. Conflict of interest This paper was Chantal Neusel’s doctoral thesis, and she obtained financial support from the Otto-von-Guericke University Medical Faculty Magdeburg, Germany, as a doctoral scholarship. Ethics statement/confirmation of patients’ permission The study was approved by the local Medical Faculty Research Ethics Committee of the University of Magdeburg (189/14).
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Please cite this article in press as: Neusel C, et al. Multicentre approach to epidemiological aspects of craniosynostosis in Germany. Br J Oral Maxillofac Surg (2018), https://doi.org/10.1016/j.bjoms.2018.10.003