Caroline Driessen

Introduction: Apert syndrome is a rare type of syndromic craniosynostosis. Patients have an explicit phenotype with craniofacial dysmorphologies and severe symmetrical syndactyly of the hands and feet. This review includes background information about the syndrome and several aspects of the treatment. Areas covered: The cause of Apert syndrome is found in unique mutations in the Fibroblast Growth Factors Receptor (FGFR) 2 gene in 99%. It results in cranial suture fusion, craniofacial dysmorphologies and severe symmetrical syndactyly of the hands and feet. Patients with Apert syndrome are at risk for mental retardation, mobility impairment and intracranial hypertension (ICHT). This is the result of a complex interaction between (1) abnormal skull growth, (2) ventriculomegaly, (3) venous outflow obstruction and (4) obstructive sleep apnea (OSA). Mental retardation is mainly determined by the FGFR2 mutation and treatment is directed at protecting the intrinsic potential of neurocognition. Expert Opinion: To prevent ICHT, we prefer an occipital expansion in the first year of life. Screening on ICHT and its underlying causes is necessary at least until the age of ten by means of skull circumference measurements, fundoscopy, optical coherence tomography, MRI and polysomnography. Multicentre studies on long-term outcome are required to validate the rationale of different clinical protocols.

Our aim was to evaluate if optical coherence tomography (OCT) can be used as an alternative for fundoscopy to screen for increased intracranial pressure (ICP) in children with craniosynostosis We performed a prospective cohort study at the Dutch Craniofacial Centre. We included 38 patients with nonsyndromic scaphocephaly and Crouzon’s syndrome aged 3–8 years old, in whom we scored complaints suggestive of increased ICP and performed fundoscopy and OCT. Main outcome measures total retinal thickness (TRT) which was measured on 58 OCT scans. Forty-three percent of fundoscopies revealed pathologic changes of the papil in at least one eye. Retinal thickness was increased in patients with an abnormal fundoscopy as compared to patients with a normal papil (TRT p < 0.001). Patients with Crouzon’s syndrome had a significantly increased retinal thickness as compared to patients with scaphocephaly (TRT p < 0.001). The current study demonstrates that OCT in children with craniosynostosis is feasible. It confirms that retinal thickness increases in case of papilledema. Given the quantitative character, OCT has a high potential as an alternative tool to screen for papilledema in craniosynostosis and other pediatric populations.

The aim of this study was to test the hypothesis that obstructive sleep apnea syndrome (OSAS) exhibits oxidative stress and inflammation in patients who have a congenital, craniofacial anomaly. This prospective, cross-sectional cohort study included ambulant sleep study data to asses OSAS in patients with syndromic craniosynostosis and Treacher Collins syndrome. Laboratory analyses were performed including malondialdehyde, tumor necrosis factor α (TNF-α), interleukin 6, and high-sensitivity C-reactive protein. Forty-eight patients were included; 11 were adults; 37 were children. The patients’ body mass indexes were normal, with a median (SD) of 0.7 (−1.82 to 2.48) in children and 20.5 (15.2–29.4) in adults. Obstructive sleep apnea syndrome was diagnosed in 23 of 48 patients. It was mild (median obstructive apnea–hypopnea index [oAHI], 2.3; oxygenation-desaturation index [ODI], 0.9) in 16 patients and moderate/severe in 7 patients (median oAHI, 10.8; ODI, 5.0). Neither oxidative stress nor inflammation had a correlation with the oAHI and ODI. Only TNF-α was found significantly higher in both the OSAS and non-OSAS groups compared with the reference values (median, 15.1 pg/mL and 12.3 pg/mL versus 4.05 [0.0–8.1 pg/mL], P < 0.001 and P < 0.001, respectively). Based on our findings we conclude that (mainly mild) OSAS, oxidative stress, as well as high-sensitivity C-reactive protein and interleukin 6 levels are not abnormal in the day time in a population of nonobese patients with a craniofacial anomaly. The increased level of TNF-α cannot be explained by OSAS. Future research should focus on mapping chronobiologic changes for further interpretation of the results.

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.

Hindbrain herniation (HH) is frequently found in syndromic craniosynostosis. It may cause impairment of the respiratory centres and manifest as sleep-disordered breathing. Our aim was to quantify sleep apnoea caused by HH in children with syndromic craniosynostosis. Seventy-one children with syndromic and complex craniosynostosis (aged 0–18 years) underwent prospective magnetic resonance imaging and a sleep study. The position of the cerebellar tonsils and respiratory parameters were evaluated and analysed. None of the included patients had undergone previous foramen magnum decompression. HH was present in 35 % of the patients and was more frequent in children with Crouzon syndrome (63 %) than in other types of craniosynostosis (p = .018). There was a positive association between the position of the cerebellar tonsils and papilledema (p = .002). Sleep studies of children with craniosynostosis and HH were not different from those without HH. Obstructive sleep apnoea syndrome was not more prevalent in children with HH compared to those without HH (p = .12). A cluster analysis using indices of apnoea revealed that three new clusters between which age was significantly different (p = .025). Sleep apnoea in syndromic craniosynostosis is not caused by HH. Rather, our evidence suggests that sleep-disordered breathing in craniosynostosis may be caused by brain stem immaturity in young children or upper airway obstruction. Therefore, as long as the child remains asymptomatic, our preferred management of HH is to be conservative and provide regular neurosurgical follow-up.

Children with craniosynostosis are at risk for increased intracranial pressure, and additional possibilities to screen for increased intracranial pressure are required. The authors' aim was to use ultrasound measurements of the optic nerve sheath to understand and express the variability of intracranial pressure in syndromic craniosynostosis. Therefore, five pediatric patients with craniosynostosis underwent invasive 24-hour intracranial pressure monitoring and simultaneous optic nerve sheath measurements. In three patients, the intracranial pressure was abnormal, and during the second half of the night, the optic nerve sheath was increased in all three patients. The optic nerve sheath diameter changes during the night and is as dynamic as the intracranial pressure. To the best of their knowledge, the authors are the first to describe a real-time relationship of the optic nerve sheath with increased intracranial pressure in children.

Object: Children with syndromic or complex craniosynostosis are evaluated for increased intracranial pressure (ICP) using funduscopy to detect papilledema. However, papilledema is a late sign of increased ICP. Because papilledema might be preceded by an increase in optic nerve sheath (ONS) diameter, the authors conducted a prospective study to establish the validity and applicability of measuring the ONS using ultrasonography. Methods: From January 2007 to December 2009, 175 bilateral ultrasonography ONS measurements were performed in 128 patients with syndromic or complex craniosynostosis during the daytime. The measurements were correlated with ONS diameter assessed on CT and simultaneous funduscopy, when available. Furthermore, results were compared by using thresholds for ONS diameters on ultrasonography that are available in the literature. Results: The mean ONS diameter on ultrasonography was 3.1 ± 0.5 mm. The CT measurement was significantly correlated with the ultrasonography measurement (r = 0.41, p < 0.001). The mean ONS diameter in 38 eyes with papilledema was 3.3 ± 0.5 mm, compared with 3.1 ± 0.5 mm in the eyes of patients without papilledema (p = 0.039). Relative to the age-related thresholds, the ONS diameter was too large in 11 eyes (3%), particularly in patients with Crouzon syndrome. Compared with funduscopy, ultrasonography sensitivity was 11%, specificity was 97%, and positive and negative predictive values were 40% and 86%, respectively. Conclusions: Ultrasonography is a valid and easy way of quantifying the ONS. Although the ONS diameter is larger in children with papilledema, it cannot be used as a daytime screening tool instead of funduscopy. The ONS diameter is possibly a more real-time indicator of ICP.