152 Chapter 9 In general, the expression of Crouzon syndrome with FGFR1 or FGFR2 mutations ranges from a mild to a severe phenotype. In addition to the presence of multiple suture synostosis, exorbitism, and midface hypoplasia, Crouzon is also characterized by a wide spectrum of functional problems, intracranial hypertension (ICH), or conditions that cause ICH such as progressive ventriculomegaly, tonsillar herniation or the presence of Chiari malformation, and obstructive sleep apnea (OSA).5-8 Intellect can vary from above normal to substantial cognitive delay.9 Little is known about the timing and order of interventions in children with this rare disease. The aim of this multicenter study was to examine the clinical signs, required interventions, and treatment course in children with confirmed FGFR3 CAN. METHODS The Research Ethics Review Committees/Internal Review Boards at Erasmus University Medical Centre Rotterdam, the Netherlands, approved this retrospective study, which is a part of ongoing work at the Craniofacial Centre, Erasmus Medical Centre Rotterdam, the Netherlands. John Radcliffe Hospital, Oxford, and Hôpital Necker- Enfants Malades, Paris, France, both full members of the European Reference Network CRANIO, participated in this multicenter retrospective study. Genetic analysis varies by clinic and over time. Whenever the clinical diagnosis Crouzon syndrome was obvious, targeted sequencing of the FGFR2 gene was undertaken, and when the sequencing was negative, additional screening of the FGFR1 and FGFR3 genes or a panel analysis on craniosynostosis genes was performed. From 1975 to 2019, patients with CAN were identified and confirmed by DNA analysis of the c.1172C>A (p.Ala391Glu) mutation in the FGFR3 gene. During this period, Erasmus Medical Centre Rotterdam confirmed the genetic diagnosis of 133 Crouzon cases, 6 of which were genetically CAN. Hôpital Necker-Enfants Malades confirmed 185 Crouzon cases, 5 of which had the CAN genetic mutation. Oxford genetically confirmed 8 CAN cases among a cohort of 77 genetically confirmed Crouzon cases. Data Collection At all three centers, clinical data were retrospectively collected, including sex, age, phenotype, OSA, progressive ventriculomegaly, tonsillar herniation, and interventions. Clinical Measurements Polysomnography was used to screen for the presence of OSA. The obstructive apnea-hypopnea index (OAHI) was used to classify patients into two categories: 1) no/ mild OSA (OAHI ≤ 5) and 2) moderate/severe OSA (OAHI ≥ 5).
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