Venous hypertension in syndromic and complex craniosynostosis: the abnormal anatomy of the jugular foramen and collaterals.

UNLABELLED: Why craniosynostosis patients develop elevated intracranial pressure (ICP) is still a mystery. Our aim was to investigate jugular foramen size and its relation to venous hypertension and elevated ICP. Secondly, we evaluated whether occipital collateral veins develop as a compensatory mechanism for elevated ICP. We conducted a prospective study in 41 children with craniosynostosis who underwent a 3D-CT-angiography. We evaluated the anatomical course of the jugular vein, the diameter of the jugular foramen and the relation to the presence of papilledema. Additionally, we studied the anatomical variations of the cerebral venous drainage system. The diameter of the jugular foramen was significantly smaller in our patients. Abnormal venous collaterals were most often observed in patients with Apert, Crouzon-Pfeiffer and Saethre-Chotzen syndrome, even in children under two years of age. There was no significant difference in the number of collateral veins in patients with or without papilledema. Collaterals appear to reflect an inborn abnormality of the venous system, rather than a compensating mechanism for elevated ICP. This study confirms the presence of jugular foraminal narrowing in craniosynostosis patients and an abnormal venous system, which may predispose to elevated ICP. LEVEL OF EVIDENCE: Diagnostic II.

Boston type craniosynostosis: report of a second mutation in MSX2.

We describe a family that segregated an autosomal dominant form of craniosynostosis characterized by variable expression and limited extra-cranial features. Linkage analysis and genome sequencing were performed to identify the underlying genetic mutation. A c.443C>T missense mutation in MSX2, which predicts p.Pro148Leu was identified and segregated with the disease in all affected family members. One other family with autosomal dominant craniosynostosis (Boston type) has been reported to have a missense mutation in MSX2. These data confirm that missense mutations altering the proline at codon 148 of MSX2 cause dominantly inherited craniosynostosis.

Complex craniosynostosis is associated with the 2p15p16.1 microdeletion syndrome.

In a screening project of patients with (complex) craniosynostosis using genomic arrays, we identified two patients with craniosynostosis and microcephaly with a deletion in the 2p15p16.1 chromosomal region. This region has been associated with a new microdeletion syndrome, for which patients have various features in common, including microcephaly and intellectual disability. Deletions were identified using Affymetrix 250K SNP array and further characterized by fluorescence in situ hybridization (FISH) analysis and qPCR. The deletions in our two patients overlapped within the 2p15p16.1 microdeletion syndrome area and were 6.8 and 6.9 Mb in size, respectively. FISH and qPCR confirmed the presence of only one copy in this region. Finemapping of the breakpoints indicated precise borders in our patients and were further finemapped in two other previously reported patients. Clinical features of patients with deletions in the 2p15p16.1 region vary. Including data from our patients, now eight out of nine reported patients have microcephaly, one of the major features, and all had intellectual disability. The current reported two patients add different forms of craniosynostosis to the clinical spectrum of this recently recognized microdeletion syndrome.

Sleep apnoea in syndromic craniosynostosis occurs independent of hindbrain herniation.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Assessment of white matter microstructural integrity in children with syndromic craniosynostosis: a diffusion-tensor imaging study.

PURPOSE: To assess whether architectural alterations exist in the white matter of patients with syndromic and complex craniosynostosis. MATERIALS AND METHODS: The medical ethics committee approved this study. Written informed consent was obtained from parents or guardians before imaging. A prospective study was performed in children with syndromic and complex craniosynostosis aged 6-14 years. Forty-five patients were included: four had Apert syndrome, 14 had Crouzon-Pfeiffer syndrome, eight had Muenke syndrome, 11 had Saethre-Chotzen syndrome, and eight had complex craniosynostosis. In addition, seven control subjects were evaluated. For diffusion-tensor imaging, an echo-planar sequence was used with a diffusion gradient (b = 1000 sec/mm(2)) applied in 25 noncollinear directions. Regions of interest (ROIs) were placed in the following white matter structures: pontine crossing tract, corticospinal tracts, medial cerebral peduncles, uncinate fasciculus (measured bilaterally), anterior commissure, frontal and occipital white matter (measured bilaterally), fornix, corpus callosum (measured in the genu and splenium), and corpus cingulum (measured bilaterally). Eigenvalues were measured in all ROIs and fractional anisotropy (FA) was calculated. RESULTS: Across all measured ROIs, FA values were generally lower in all patients combined than in the control subjects (P < .001). There were no significant differences among subgroups of patients. CONCLUSION: Diffusion-tensor imaging measurements of white matter tracts reveal significant white matter integrity differences between children with craniosynostosis and healthy control subjects. This could imply that the developmental delays seen in these patients could be caused by the presence of a primary disorder of the white matter microarchitecture.

Papilledema in isolated single-suture craniosynostosis: prevalence and predictive factors.

The purpose of this retrospective study was to assess the prevalence of papilledema in patients with isolated craniosynostosis. Second, we wanted to assess if the presence of ventricular dilatation on computed tomography (CT) scan is a predictive factor for the occurrence of papilledema. We included 205 consecutive children with an isolated single-suture craniosynostosis, who had at least 1 fundus examination. Preoperative CT scans of the brain were examined for the presence of ventricular dilatation.Papilledema developed in 14 of 205 patients: 10 developed papilledema before surgery and 4 during the follow-up period. Ten of the patients with papilledema had a synostosis of the sagittal suture, and 4 of the metopic suture. Prevalence of papilledema in scaphocephaly was 9.7%, and in trigonocephaly, 5.6%. Based on evaluation of all CT scans, ventricular dilatation seemed not to be a predictive factor for papilledema in children with isolated craniosynostosis.The incidence of papilledema in almost 10% of scaphocephaly patients is remarkably higher than expected. Therefore, we recommend routine preoperative screening, especially for patients with scaphocephaly, but also for patients with trigonocephaly. Postoperative screening is recommended in all patients when there is any uncertainty.