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Original article
How does obstructive sleep apnoea evolve in syndromic craniosynostosis? A prospective cohort study
  1. Caroline Driessen1,
  2. Koen F M Joosten2,
  3. Natalja Bannink2,
  4. Hansje H Bredero-Boelhouwer1,
  5. Hans L J Hoeve3,
  6. Eppo B Wolvius4,
  7. Dimitris Rizopoulos5,
  8. Irene M J Mathijssen1
  1. 1Department of Plastic, Reconstructive and Hand Surgery, Dutch Craniofacial Centre, Erasmus Medical Centre—Sophia Children's Hospital, Rotterdam, The Netherlands
  2. 2Department of Pediatrics, Dutch Craniofacial Centre, Erasmus Medical Centre—Sophia Children's Hospital, Rotterdam, The Netherlands
  3. 3Department of Otolaryngology, Dutch Craniofacial Centre, Erasmus Medical Centre—Sophia Children's Hospital, Rotterdam, The Netherlands
  4. 4Department of Oral and Maxillofacial Surgery, Dutch Craniofacial Centre, Erasmus Medical Centre—Sophia Children's Hospital, Rotterdam, The Netherlands
  5. 5Department of Biostatistics, Dutch Craniofacial Centre, Erasmus Medical Centre—Sophia Children's Hospital, Rotterdam, The Netherlands
  1. Correspondence to Caroline Driessen, Department of Plastic and Reconstructive Surgery, Dutch Craniofacial Centre, Erasmus Medical Centre—Sophia Children's Hospital, Post office box 2060, SK 1202, Rotterdam 3000 CB, The Netherlands; c.driessen{at}erasmusmc.nl

Abstract

Objective To describe the course of obstructive sleep apnoea syndrome (OSAS) in children with syndromic craniosynostosis.

Design Prospective cohort study.

Setting Dutch Craniofacial Centre from January 2007 to January 2012.

Patients A total of 97 children with syndromic craniosynostosis underwent level III sleep study. Patients generally undergo cranial vault remodelling during their first year of life, but OSAS treatment only on indication.

Main outcome measures Obstructive apnoea-hypopnoea index, the central apnoea index and haemoglobin oxygenation-desaturation index derived from consecutive sleep studies.

Results The overall prevalence of OSAS in syndromic craniosynostosis was 68% as defined by level III sleep study. Twenty-three patients were treated for OSAS. Longitudinal profiles were computed for 80 untreated patients using 241 sleep studies. A mixed effects model showed higher values for the patients with midface hypoplasia as compared to those without midface hypoplasia (Omnibus likelihood ratio test=7.9). In paired measurements, the obstructive apnoea-hypopnoea index (Z=−3.4) significantly decreased over time, especially in the first years of life (Z=−3.3), but not in patients with midface hypoplasia (Z=−1.5). No patient developed severe OSAS during follow-up if it was not yet diagnosed during the first sleep study.

Conclusions OSAS is highly prevalent in syndromic craniosynostosis. There is some natural improvement, mainly during the first 3 years of life and least in children with Apert or Crouzon/Pfeiffer syndrome. In the absence of other co-morbid risk factors, it is highly unlikely that if severe OSAS is not present early in life it will develop during childhood. Ongoing clinical surveillance is of great importance and continuous monitoring for the development of other co-morbid risk factors for OSAS should be warranted.

  • Clin Neurophysiology
  • Congenital Abnorm
  • Plastic Surgery
  • Sleep

https://doi.org/10.1136/archdischild-2012-302745

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    What is already known on this topic

    • 40% of the patients with syndromic craniosynostosis develop obstructive sleep apnoea syndrome (OSAS).

    • OSAS in syndromic craniosynostosis is mainly due to midface hypoplasia.

    • OSAS may be related to increased intracranial pressure in children with syndromic craniosynostosis.

    What this study adds

    • The prevalence of OSAS in children with syndromic and complex craniosynostosis using level III sleep studies is 68%, which is higher than previously reported.

    • Sleep disordered breathing in craniosynostosis can be successfully managed longitudinally using level III sleep studies.

    • The sleep study outcomes are worst during the first 3 years of life.

    • It is highly unlikely that severe OSAS develops if it is not diagnosed early in life provided that other co-morbid factors for OSAS remain unchanged.

    Introduction

    Craniosynostosis is a congenital disorder which is characterised by premature fusion of the calvarian sutures, which restricts the normal growth of the skull, brain and face.1 ,2 Consequently, 40% of the patients with syndromic or complex craniosynostosis develop obstructive sleep apnoea syndrome (OSAS).3 ,4 This is mainly due to midface hypoplasia, which is one of the features of Apert, Crouzon and Pfeiffer syndrome.3–5 Mandibular hypoplasia, pharyngeal collapse and airway anomalies may also be present in syndromic craniosynostosis.6 ,7 A disturbed sleeping pattern results in major physical and functional impairment, such as failure to thrive, recurrent infections, disturbed cognitive functions, delayed development, cor pulmonale or even sudden death.8 Moreover, OSAS may be related to increased intracranial pressure (ICP) due to carbon dioxide retention and cerebral blood flow changes.9–11 It will then further contribute to the neurological, cognitive and ophthalmological morbidity.12 Regular screening for OSAS in patients with syndromic craniosynostosis is required.3 ,7 ,13 The gold standard to diagnose OSAS is polysomnography,14 ,15 but ambulatory cardiorespiratory monitoring (level III) is also a feasible way to detect sleep disordered breathing.13

    There is a lack of prospective, longitudinal data on the prevalence and course of OSAS in children with syndromic craniosynostosis. Therefore, we conducted a prospective cohort study aimed at describing how OSAS evolves in a population of syndromic craniosynostosis patients.

    Materials and methods

    Study group

    A prospective cohort study was conducted from January 2007 to January 2012 at the Dutch Craniofacial Centre, which is the only referral centre for syndromic cases of craniosynostosis in the Netherlands. The study was approved by the local ethics committee (Erasmus MC 2005-273).

    Inclusion criteria included the diagnosis of syndromic and complex craniosynostosis and age <18 years old. All subjects’ parents were invited to participate by means of written informed consent. Diagnosis was based on genetic analysis.16 If no genetic mutation was found in a patient with multi-suture synostoses he or she was classified as having complex craniosynostosis. Patients with Apert and Crouzon/Pfeiffer syndrome were combined as one subgroup since midface hypoplasia is one of the shared characteristics of their phenotype. Patients with Muenke and Saethre-Chotzen syndrome and complex craniosynostosis were combined as a second subgroup. All patients generally undergo cranial vault remodelling during their first year of life, but obstructive sleep apnea (OSA) treatment only on indication.

    For study purpose, a sleep study was performed in all children regardless of clinical complaints annually up to the age of 6 years (so at age 1, 2, 3, 4, 5 and 6 years old) and once every 3 years thereafter (so at 9, 12, 15 and 18 years old). If the findings were abnormal it was repeated within 3–6 months. Patients were considered eligible for the study (1) if multiple sleep studies were performed or (2) if OSAS was diagnosed and treated before the minimum of two sleep studies could be captured. The patients in whom successful multiple sleep studies were available before OSAS intervention were included in the longitudinal analyses up to treatment. Patients were excluded if multiple sleep studies were not available due to technical failure. Moreover, sleep studies after OSAS treatment were excluded from the longitudinal analyses.

    Sleep study

    Overnight ambulant (level III) sleep study data were recorded using the Embletta Portable Diagnostic system and measurements were analysed using Somnologica for Embletta software V.3.3 ENU (Medcare Flage, Reykjavik, Iceland). Circumferential elastic trace belts (X act) were used to compute a respiratory inductance plethysmography of the thorax and abdomen. X-flow was calculated using thoracic and abdominal results with Embletta software V.3.3 ENU. Nasal flow was measured with a pressure transducer attached to a nasal cannula (Salter Labs, Arvin, USA). Haemoglobin-oxygen saturation (SpO2) and heart rate were assessed using an infant or paediatric oxygen sensor (averaging time 6–7 s; OxiMax; Nellcor, Pleasanton, USA). Caregivers were instructed to start the recording at bedtime and end it the next morning.

    Although we acknowledge the manual for scoring of sleep events by the American Academy of Sleep Medicine (AASM),17 we used the scoring that was previously reported by Guilleminault et al and Ward et al. Analyses of the sleep study data included the following: firstly, we quantified the duration of total sleep time. This period was defined as the first moment of regular breathing after the start of the recording up to the last moment of regular breathing before the recording was ended by the parents including the whole period in between. Secondly, we then determined the baseline breathing rate. Thirdly, we assessed the presence of apnoeas (≥80% flow reduction) and hypopnoeas (50–80% flow reduction).18 ,19 To account for age-related variability in the respiratory rate, the minimum length of an event in seconds was equivalent to two breaths. Events associated with ≥4% reduction in SpO2 from baseline were all included regardless of length. Hypopnoeas were only included in summary statistics if a subsequent reduction in SpO2 of ≥4% from baseline occurred. Obstructive events were recognised by the distinct pattern of paradox thoracic and abdominal movements. Isolated central apnoeas were scored if both thoracic and abdominal movements were absent. They were reported to be of minor significance previously20 but will indeed be presented for completeness.

    Due to a lack of electroencephalography, arousals could not be scored reliably and were therefore not used as a criterion. As a primary outcome, we indexed the total number of obstructive and mixed apnoeas and desaturation-associated hypopnoeas (oAHI) to the duration of sleep (ie, episodes per hour of sleep). As secondary outcomes, we calculated the central apnoea index (CAI) from the number of central apnoeas per hour, haemoglobin oxygenation-desaturation index (ODI) from the number of desaturations (≥4% from baseline) per hour of sleep, as well as the mean oxygenation-saturation and the lowest measured oxygenation-saturation level.17

    Box 1

    Definitions for the purpose of study18,19

    Apnoea: ≥80% flow reduction

    ▸ equivalent to two breaths or/and

    ▸ any length if associated with desaturation

    Hypopnoea: 50–80% flow reduction

    ▸ if associated with desaturation

    Desaturation: ≥4% reduction in SpO2 from baseline

    oAHI: total number of obstructive and mixed apnoeas and desaturation-associated hypopnoeas/TST in hours

    CAI: total number of central apnoeas/TST in hours

    ODI: total number of haemoglobin oxygenation-desaturations/TST in hours

    In which TST=total sleep time

    Based on type III study

    OSAS was defined as an oAHI ≥1 per hour,19 ,21 and the severity is characterised as mild: <5 per hour (severity grade 1); moderate: 5–24 per hour (severity grade 2) and severe: ≥25 per hour (severity grade 3).18 ,19 ,21 ,22 ,23

    Statistical analysis

    A repeated measurement analysis was performed for longitudinal assessment of patients with midface hypoplasia (Apert and Crouzon/Pfeiffer syndrome) and without midface hypoplasia (Muenke and Saethre-Chotzen syndrome and complex craniosynostosis). oAHI and ODI were analysed using a linear mixed effects model to account for the correlation between multiple measurements in the same child. We relaxed the common linearity assumption for the effect of age on the sleep study parameters using natural cubic splines (ie, age is allowed to possibly have a nonlinear association with the ODI or oAHI). We also included an interaction term to allow for different evolutions in time for each of the two diagnostic groups. Residual plots were used to validate the model's assumptions and the omnibus likelihood ratio test was performed to compare longitudinal evolutions. For intra-patient comparisons, a non-parametric Wilcoxon signed rank test was performed on the whole cohort and on different strata to compare two subsequent sleep study outcomes. Paired comparisons were performed between two subsequent studies, meaning that a second sleep study of one pair can also be the first sleep study in the subsequent age strata. Pearson χ2 testing was used to test the distribution of diagnoses among the patients who deteriorated and those that were stable or improved.

    Data are presented as median (range). In all tests the significance level was set to 5%.

    Results

    Patients’ characteristics

    A total of 157 children with syndromic or complex craniosynostosis were considered for inclusion (figure 1). A flowchart of inclusion is presented in figure 1. The study cohort consisted of 97 patients. All patients underwent cranial vault remodelling before the age of 1 by protocol, except for three (two late presentation of craniosynostosis, one patient with Pfeiffer syndrome without craniosynostosis).

    Figure 1
    Figure 1

    Flowchart inclusion. Patients were included only after informed consent was obtained and if multiple sleep studies were available. In 17 patients the end point (obstructive sleep apnoea syndrome treatment) was reached before multiple sleep studies could be captured. Eighty patients could be included in the analysis of the natural course. They underwent the presented research protocol, which resulted in the given number of repeated measurements per patient.

    The overall prevalence of OSAS using level III sleep studies was 68%. Moderate or severe OSAS was prevalent in 25 patients (26%), of which 16 had midface hypoplasia. Baseline characteristics are presented in table 1.

    View this table:
    Table 1

    Baseline characteristics

    Twenty-three patients (23.7%) were treated for OSAS based on symptoms of snoring, difficulty in breathing, restless sleep and/or nightly sweating. In all patients a sleep study was performed, which revealed mild OSAS in the majority of patients. Five of 23 had moderate or severe OSAS. The median age at treatment was 4.5 years with a range of 4 months to 18 years old. In patients who did not need OSAS treatment in the first year of life, adenotonsillectomy (ATE) was considered as the first option. These were all patients who suffered from symptoms of OSAS in combination with an abnormal sleep study. It was performed in 20 patients, resulting in an overall ATE prevalence of 20%. In one child tonsillectomy needed to be repeated. Other treatments included transverse widening of the hypoplastic maxilla with a hyrax expander (n=1), midface advancement (n=6), tracheostomy (n=3) or ventilation (n=2). In two cases with Crouzon/Pfeiffer syndrome, OSAS contributed to the increased ICP as measured during the simultaneous sleep study and invasive ICP monitoring. In both cases ATE was performed, which could not prevent the need for secondary cranial vault reconstruction.

    In 17 of 23 patients, the study end point was reached before multiple sleep studies could be captured. In the remaining six patients, multiple sleep studies were available before OSAS treatment and these patients are included in longitudinal profiles.

    Eighty patients in whom 241 sleep studies were captured were included in the prospective analysis. The average number of measurement per child was three (four patients had six sleep studies (=4×6); 10×5; 24×4; 43×3; 80×2). In 32 sleep studies only the saturation profile was available due to artefacts in the abdominal or thoracic trace or nasal flow. The saturation signal (partially) failed in four patients in whom no apnoeas were observed.

    A summary of the sleep study outcomes is presented in table 2. Data are presented as median (range). With regard to central sleep apnoea, we found a significant correlation between the oAHI and CAI (R=0.43, p<0.001). Also, there was a significant correlation between the oAHI and the ODI (R=0.43, p<0.001) and the oAHI with the lowest saturation (R=−0.28, p<0.001), but not of the oAHI with the mean saturation (R=0.003, p=0.96).

    View this table:
    Table 2

    Summary of the sleep study outcomes

    Longitudinal OSAS profile

    A linear mixed effects model was generated, which combines all results of available sleep studies. For both the oAHI and ODI, we observed that the severity decreases with increasing age in a nonlinear way. The patients with midface hypoplasia have higher obstructive apnoea and hypopnoea indices compared to the patients without midface hypoplasia, although the overall course was not statistically significant (LRT=7.9, d.f.=4, p=0.095) (figure 2). The longitudinal course in ODI is comparable for patients with and without midface hypoplasia (LRT=1.5, d.f.=4, p=0.82) (figure 3).

    Figure 2
    Figure 2

    Natural course obstructive apnoea hypopnoea index. Fitted profiles for obstructive apnoea-hypopnoea index (oAHI) with 95% point-wise CI for patients with and without midface hypoplasia. Omnibus likelihood ratio test for differences in the average longitudinal evolution between the two groups = 7.9, d.f.=4, p=0.095. 32 of 241 indices are missing due to technical failure; the profile was calculated using 209 indices. The black line presents an oAHI of 1, representing the cut-off point for having obstructive sleep apnoea syndrome.

    Figure 3
    Figure 3

    Natural course oxygenation-desaturation index (ODI). Fitted profiles for ODI with 95% point-wise CI for patients with and without midface hypoplasia. Omnibus likelihood ratio test for differences in the average longitudinal evolutions between the two groups = 1.5, d.f.=4, p=0.82. The profile was calculated using 241 indices. The black line presents an ODI of 1. Average reference values of the ODI from previous research reports vary from 0.8(23) to 1.4(2).

    Intra-patient comparison

    Paired sleep studies (n=161 pairs) were analysed. The median time between two sleep studies was 1.1 year (2 months–3.7 years).

    Overall, the oAHI decreased from 0.8 (0.0–17.2) to 0.4 (0.0–8.1) (p=0.001), the CAI decreased from 2.0 (0.0–14.7) to 1.5 (0.0–9.7) (p=0.035) and the ODI improved from 0.9 (0–22.0) to 0.4 (0–22.0) (p=0.001), indicating a minor but statistically significant improvement in breathing (table 3). The mean saturation (p=0.64) was stable at 97.6% and the lowest measured saturation slightly increased from 90% (71–96%) to 91% (71–98%) (p=0.012).

    View this table:
    Table 3

    Paired sleep study outcomes

    The patients were stratified according to diagnosis and age at the first sleep study to trace back the significant differences in oAHI and ODI (table 3). Median oAHI and ODI values were abnormal with a maximum value of 1.0 and 1.5 respectively in the patients aged 0–3 years old. In all strata the oAHI and ODI decrease. Improvement mainly takes place during the first 3 years of life and occurs in all syndrome diagnoses. In patients with Apert and Crouzon/Pfeiffer syndrome, saturation improves but airway obstruction as represented by the oAHI does not significantly get better over time.

    Thirteen of 80 patients (16%) had a subsequent sleep study, the outcome of which was worse than the previous one. In these patients, the second sleep study was captured at a median age of 2 years old (3 months–4.3 years). They had different syndromic diagnoses (3 Apert syndrome, 3 Crouzon/Pfeiffer syndrome, 3 Muenke syndrome, 4 complex craniosynostosis), which were not distributed differently compared to the 67 patients who were stable or improved (Pearson χ2 2.6, 4 d.f., p=0.62). Ten patients had no OSAS originally and developed mild OSAS during follow-up. Of them, only the three patients with complaints of airway resistance were treated by ATE (two Crouzon syndrome, one complex craniosynostosis). Three patients deteriorated from mild OSAS to moderate OSAS. One of them (Crouzon syndrome) improved naturally; the other two were treated by ATE (Apert syndrome; Crouzon syndrome). None of the patients developed severe OSAS during follow-up.

    Discussion

    This study confirms the high prevalence of OSAS (68%) in children with syndromic craniosynostosis. The high prevalence is in line with the high prevalence of OSAS reported by Al-Saleh and coauthors in a recent study.24 In former studies, it was found to be around 40%.3 ,4 We are the first to report that OSAS is highly prevalent also in the patients without midface hypoplasia. The longitudinal profiles of untreated patients show that OSAS is stable or improves over time in the majority of children with syndromic craniosynostosis. The best natural improvement is achieved in the first years of life and it is worst in patients with midface hypoplasia.

    Our results should be interpreted keeping two important things in mind. First of all, upper airway resistance syndrome (UARS) can easily be missed since this abnormality is associated with respiratory effort-related arousals (RERAs) and snoring but not necessarily abnormal apnoea or desaturation indices.25 ,26 Second, the longitudinal profiles do not include the most severe OSAS patients who require early treatment. In the 80 patients who do not require instant treatment, OSAS is stable or improves over time in the majority of patients. Both the median oAHI and ODI are under 1 in untreated patients. The only abnormal median values are an ODI of 1.5 and oAHI of 1 in patients younger than 3 years old. This may be due to the brisk autonomic control of respiration in young children which is unrelated to craniosynostosis and improves during the first years of life.20 ,27 It is not surprising that this stratum has the most significant improvement. Also, patients without midface hypoplasia show some significant improvement in contrast to patients without midface hypoplasia in whom maxillary growth in the sagittal plane is lacking.28 ,29

    Thirteen patients with mild or no OSAS initially deteriorated, but none of the patients developed severe OSAS. Even if a patient deteriorates, treatment for OSAS was required only in 5/13. It appears that most patients were not so badly affected (meaning either the presence of symptoms of OSAS or sleep study indices that fit moderate or severe OSAS) that intervention was needed. Rates of ventilation are low but 20% of the total study population needed ATE, which is much higher compared to community samples (0.5–1.6% in children aged 0–9 in the Netherlands).30 It has been previously shown that it successfully treats OSAS31 ,32 in up to 60% of children with craniosynostosis and OSAS, as compared to 75–100% of otherwise healthy children.14 Treatment of OSAS is nowadays at least recommended if morbidity is present.33 It is not yet clear whether UARS or mild OSAS without accompanying symptoms or signs should also be treated, but the effect of sleep on neurodevelopment and cardiorespiratory and endocrine co-morbidity has been acknowledged in this journal previously.34

    Treatment of OSAS should at least be considered if a child presents with increased ICP.34 In craniosynostosis, a second peak of increased ICP often occurs around the age of 3.5 years35 and mainly in patients with midface hypoplasia (Apert syndrome 35%; Crouzon/Pfeiffer syndrome 62.5%), who also have the highest risk of developing OSAS.35 ,36 Increased ICP has been causally related to OSAS and it might be managed by correcting for airway obstruction.34

    With regard to central sleep apnoea, we found a significant correlation between the oAHI and CAI. It must be noted however that this correlation was not present20 when excluding patients aged <1 year old and when using the more strict definition of the central apnoeas needing to last >20 s or to be associated with a desaturation as suggested by the AASM.17 The presented CAI is probably an overestimation of severity of central sleep apnoea. As reported previously,20 the CAI decreases with increasing age, which underlines the important role of growing up. Although central sleep apnoea and obstructive sleep apnoea may be two distinct entities, it is important to consider and combine both when evaluating sleep disordered breathing in syndromic craniosynostosis.

    This study is limited by the lack of studying sleep efficacy and sleep quality since the data are derived from level III sleep studies.14 Also, OSAS is highly dependent on upper airway infections, adenotonsillar hypertrophia and body position, making the sleep study's outcome a variable parameter.

    We are the first to use longitudinal data to study OSAS in syndromic craniosynostosis. The strengths of the study lie in the big population. Our accompanying evidence shows that severe cases of OSAS are recognised early. If significant OSAS is not present during the first years of life, the data from our study suggest that it is highly unlikely to develop. We therefore recommend a single, sleep study around the age of 1 year. If this one is normal, a wait-and-see policy can be used and the sleep study should only be repeated if a clinical setback in breathing occurs or if suspicion for increased ICP arises. Ongoing clinical surveillance is of great importance and continuous monitoring for the development of other co-morbid risk factors for OSAS should be warranted.

    In conclusion, OSAS has a high prevalence in syndromic craniosynostosis. Patients younger than 3 years old have the highest oAHI and ODI, which improve over time. Patients with Apert, Crouzon or Pfeiffer syndrome have the highest indices, the smallest improvement over time and the highest number of OSAS treatments. It is highly unlikely in syndromic craniosynostosis that if severe OSAS is not present early in life it will develop during childhood.

    Acknowledgments

    The authors thank the Carolien Bijl Foundation for funding of research on syndromic craniosynostosis.

    References

    1. ↵
      1. Panchal J,
      2. Uttchin V
      . Management of craniosynostosis. Plast Reconstr Surg 2003;111:2032–48; quiz 49.
      OpenUrlCrossRefPubMed
    2. ↵
      1. Hayward R
      . Craniosynostosis and the paediatrician. Arch Dis Child 1990;65:568.
      OpenUrlFREE Full Text
    3. ↵
      1. Pijpers M,
      2. Poels PJ,
      3. Vaandrager JM,
      4. et al
      . Undiagnosed obstructive sleep apnea syndrome in children with syndromal craniofacial synostosis. J Craniofac Surg 2004;15:670–4.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Mixter RC,
      2. David DJ,
      3. Perloff WH,
      4. et al
      . Obstructive sleep apnea in Apert's and Pfeiffer's syndromes: more than a craniofacial abnormality. Plast Reconstr Surg 1990;86:457–63.
      OpenUrlCrossRefPubMed
    5. ↵
      1. Sculerati N,
      2. Gottlieb MD,
      3. Zimbler MS,
      4. et al
      . Airway management in children with major craniofacial anomalies. Laryngoscope 1998;108:1806–12.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Hoeve HL,
      2. Joosten KF,
      3. van den Berg S
      . Management of obstructive sleep apnea syndrome in children with craniofacial malformation. Int J Pediatr Otorhinolaryngol 1999;49(Suppl 1):S59–61.
      OpenUrlCrossRefPubMed
    7. ↵
      1. Lo LJ,
      2. Chen YR
      . Airway obstruction in severe syndromic craniosynostosis. Ann Plast Surg 1999;43:258–64.
      OpenUrlCrossRefPubMed
    8. ↵
      1. Nixon GM,
      2. Brouillette RT
      . Sleep. 8: paediatric obstructive sleep apnoea. Thorax 2005;60:511–16.
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Gonsalez S,
      2. Hayward R,
      3. Jones B,
      4. et al
      . Upper airway obstruction and raised intracranial pressure in children with craniosynostosis. Eur Respir J 1997;10: 367–75.
      OpenUrlAbstract
      1. Taylor WJ,
      2. Hayward RD,
      3. Lasjaunias P,
      4. et al
      . Enigma of raised intracranial pressure in patients with complex craniosynostosis: the role of abnormal intracranial venous drainage. J Neurosurg 2001;94:377–85.
      OpenUrlCrossRefPubMed
    11. ↵
      1. Thompson DN,
      2. Harkness W,
      3. Jones BM,
      4. et al
      . Aetiology of herniation of the hindbrain in craniosynostosis. An investigation incorporating intracranial pressure monitoring and magnetic resonance imaging. Pediatr Neurosurg 1997;26:288–95.
      OpenUrlPubMed
    12. ↵
      1. Hayward R,
      2. Gonsalez S
      . How low can you go? Intracranial pressure, cerebral perfusion pressure, and respiratory obstruction in children with complex craniosynostosis. J Neurosurg 2005;102:16–22.
      OpenUrlPubMed
    13. ↵
      1. Bannink N,
      2. Mathijssen IM,
      3. Joosten KF
      . Use of ambulatory polysomnography in children with syndromic craniosynostosis. J Craniofac Surg 2010;21:1365–8.
      OpenUrlCrossRefPubMed
    14. ↵
      1. Schechter MS
      ; Section on Pediatric Pulmonology SoOSAS. Technical report: diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics 2002;109:e69.
      OpenUrlAbstract/FREE Full Text
    15. ↵
      1. Primhak R,
      2. Kingshott R
      . Sleep physiology and sleep-disordered breathing: the essentials. Arch Dis Child 2012;97:54–8.
      OpenUrlAbstract/FREE Full Text
    16. ↵
      1. Wilkie AO,
      2. Byren JC,
      3. Hurst JA,
      4. et al
      . Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 2010;126:e391–400.
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Iber C,
      2. Ancoli-Israel S,
      3. Chesson AL,
      4. et al
      . The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications. West Chester, IL: American Academy of Sleep Medicine, 2007.
    18. ↵
      1. Guilleminault C,
      2. Lee JH,
      3. Chan A
      . Pediatric obstructive sleep apnea syndrome. Arch Pediatr Adolesc Med 2005;159:775–85.
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Ward SL,
      2. Marcus CL
      . Obstructive sleep apnea in infants and young children. J Clin Neurophysiol 1996;13:198–207.
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Driessen C,
      2. Mathijssen IM,
      3. De Groot MR,
      4. et al
      . Does central sleep apnea occur in children with syndromic craniosynostosis? Respir Physiol Neurobiol 2012;181:321–5.
      OpenUrlCrossRefPubMed
    21. ↵
      1. Goroza E,
      2. Sagy M,
      3. Sagy N,
      4. et al
      . Severity assessment of obstructive sleep apnea syndrome (OSAS) in pediatric patients. Clin Pediatr (Phila) 2009;48:528–33.
      OpenUrlAbstract/FREE Full Text
    22. ↵
      1. Sheldon SH
      . Evaluating, diagnosing, and treating sleep disorders. Pediatr Ann 2008;37:449–51.
      OpenUrlCrossRefPubMed
    23. ↵
      1. Verhulst SL,
      2. Schrauwen N,
      3. Haentjens D,
      4. et al
      . Reference values for sleep-related respiratory variables in asymptomatic European children and adolescents. Pediatr Pulmonol 2007;42:159–67.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Al-Saleh S,
      2. Riekstins A,
      3. Forrest CR,
      4. et al
      . Sleep-related disordered breathing in children with syndromic craniosynostosis. J Craniomaxillofac Surg 2011;39:153–7.
      OpenUrlCrossRefPubMed
    25. ↵
      1. Guilleminault C,
      2. Los Reyes VD
      . Upper-airway resistance syndrome. Handb Clin Neurol 2011;98:401–9.
      OpenUrlCrossRefPubMed
    26. ↵
      1. Pepin JL,
      2. Guillot M,
      3. Tamisier R,
      4. et al
      . The Upper Airway Resistance Syndrome. Respiration 2012;83:559–6.
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      1. Susarla SM,
      2. Thomas RJ,
      3. Abramson ZR,
      4. et al
      . Biomechanics of the upper airway: Changing concepts in the pathogenesis of obstructive sleep apnea. Int J Oral Maxillofac Surg 2010;39:1149–59.
      OpenUrlCrossRefPubMed
    28. ↵
      1. Bachmayer DI,
      2. Ross RB
      . Stability of Le Fort III advancement surgery in children with Crouzon's, Apert's, and Pfeiffer's syndromes. Cleft Palate J 1986;23(Suppl 1):69–74.
      OpenUrlPubMed
    29. ↵
      1. Meazzini MC,
      2. Mazzoleni F,
      3. Caronni E,
      4. et al
      . Le Fort III advancement osteotomy in the growing child affected by Crouzon's and Apert's syndromes: presurgical and postsurgical growth. J Craniofac Surg 2005;16:369–77.
      OpenUrlCrossRefPubMed
    30. ↵
      1. Statline C
      . 2011. http://statline.cbs.nl/statweb (accessed 1 Mar 2012).
    31. ↵
      1. Amonoo-Kuofi K,
      2. Phillips SP,
      3. Randhawa PS,
      4. et al
      . Adenotonsillectomy for sleep-disordered breathing in children with syndromic craniosynostosis. J Craniofac Surg 2009;20:1978–80.
      OpenUrlCrossRefPubMed
    32. ↵
      1. Edwards TJ,
      2. David DJ,
      3. Martin J
      . Aggressive surgical management of sleep apnea syndrome in the syndromal craniosynostoses. J Craniofac Surg 1992;3:8–10; discussion 1.
      OpenUrlCrossRefPubMed
    33. ↵
      1. Kaditis A,
      2. Kheirandish-Gozal L,
      3. Gozal D
      . Algorithm for the diagnosis and treatment of pediatric OSA: a proposal of two pediatric sleep centers. Sleep Med 2012;13:217–27.
      OpenUrlCrossRefPubMed
    34. ↵
      1. Marucci DD,
      2. Dunaway DJ,
      3. Jones BM,
      4. et al
      . Raised intracranial pressure in Apert syndrome. Plast Reconstr Surg 2008;122:1162–8; discussion 9–70.
      OpenUrlCrossRefPubMed
    35. ↵
      1. de Jong T,
      2. Bannink N,
      3. Bredero-Boelhouwer HH,
      4. et al
      . Long-term functional outcome in 167 patients with syndromic craniosynostosis; defining a syndrome-specific risk profile. J Plast Reconstr Aesthet Surg 2010;63:1635–41.
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      1. Renier D,
      2. Lajeunie E,
      3. Arnaud E,
      4. et al
      . Management of craniosynostoses. Childs Nerv Syst 2000;16:645–58.
      OpenUrlCrossRefPubMedWeb of Science
    View Abstract

    Footnotes

    • Presented at the International Society of Craniofacial Surgery (ISCFS, Livingstone, Zambia, 27 August–2 September 2011)

      European Society of Pediatric Otorhinolaryngology (ESPO, Amsterdam, The Netherlands, 20–23 May 2012)

    • Contributors CD selected and designed the study; she included the patients, assessed sleep studies, performed the statistical analyses and drafted the manuscript. KFMJ was involved in conceptualising and designing the study; he was also involved in interpretation of sleep studies. He supervised data collection, co-wrote the manuscript and performed multiple reviews as well as a final critical review. NB conceptualised the longitudinal design of the study; she included patients, assessed sleep studies, performed a critical review with great input and finally approved the paper. HHB-B was involved in study design, in the assessment of sleep studies, in reviewing the paper and approving the final draft. HLJH conceptualised the study, and was involved in interpretation of data. He assessed and treated patients, brainstormed on the topics of discussion and critically reviewed and approved the final version. EBW conceptualised the study, and was involved in interpretation of data. He assessed and treated patients, brainstormed on the topics of discussion and critically reviewed and approved the final version. DR conceptualised the study set-up, designed the methodology, performed and reviewed statistical analyses, gave intellectual input to the paper's methods and results section, reviewed and approved the manuscript. IMJM conceptualised and designed the study. She supervised data collection and was involved in interpretation of data; she assessed and treated patients, gave major input to the focus of the study and discussion, and performed multiple thorough reviews before finally approving the manuscript.

    • Funding The research project was funded by the Carolien Bijl Foundation.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval Erasmus MC MEC-2005-273.

    • Provenance and peer review Not commissioned; externally peer reviewed.