Elevated intracranial pressure with craniosynostosis: a multivariate model of age, syndromic status, and number of involved cranial sutures

OBJECTIVE Children with multiple prematurely fused cranial sutures and those undergoing surgical correction later in life appear to experience worse neurocognitive outcomes, but it is unclear whether higher intracranial pressure (ICP) is implicated in this process. The purpose of this study was to elucidate the effect of age at intervention and number of involved cranial sutures on ICP, as well as to assess which cranial suture closure may be more associated with elevated ICP. METHODS The prospective craniofacial database at the authors’ institution was queried for patients undergoing initial corrective surgery for craniosynostosis in whom intraoperative measurement of ICP was obtained prior to craniectomy. Age, involved sutures, and syndromic status were analyzed in the context of measured ICP by using multiple linear regression. RESULTS Fifty patients met the inclusion criteria. Age at procedure (p = 0.028, β = +0.060 mm Hg/month) and multiple-suture involvement (p = 0.010, β = +4.175 mm Hg if multisuture) were both significantly implicated in elevated ICP. The actual number of major sutures involved was significantly correlated to ICP (p = 0.001; β = +1.687 mm Hg/suture). Among patients with single-suture involvement, there was an overall significant difference of median ICP across the suture types (p = 0.008), with metopic having the lowest (12.5 mm Hg) and sagittal having the highest (16.0 mm Hg). Patients with multiple-suture involvement had significantly higher ICP (p = 0.003; 18.5 mm Hg). Patients with craniofacial syndromes were 79.3 times more likely to have multiple-suture involvement (p < 0.001). Corrective surgery for craniosynostosis demonstrated significant intraoperative reduction of elevated ICP (all p < 0.050). CONCLUSIONS Syndromic status, older age at intervention for craniosynostosis, and multiple premature fusion of cranial sutures were associated with significantly higher ICP.

Syndromic craniosynostosis

Syndromic craniosynostoses result from a complex interaction between genetic factors, molecular and cellular events, as well as mechanical and deformational forces. They can all have secondary effects on growth and development. Approximately 180 craniofacial syndromes have been identified and it is thought that about 15% of all craniosynostoses are syndromic. They are due to genetic mutations and among the most common are mutations in the fibroblast growth factor receptor 2 gene (FGFR2). Multidisciplinary care for craniofacial patients is considered the optimal model of care and is based on the concept of management during childhood, the transition into adulthood, and finally support and treatment throughout adulthood.

Familial Pfeiffer Syndrome: Variable Manifestations and Role of Multidisciplinary Team Care

Pfeiffer syndrome is one of the autosomal dominant craniofacial syndromes. Classical clinical manifestations are coronal suture synostosis causing brachycephaly, midface retrusion, airway compromise, broad thumbs, and toes. Pfeiffer syndrome type I (classic type) is associated with FGFR1 mutation. However, wide range of clinical manifestations, with and without craniosynostosis, have been reported. Here, we present a family of Pfeiffer syndrome across 3 generations with identical FGFR1: c.755C>G (p.Pro252Arg) mutation. Where the members of the youngest generation have no cranial involvement. Lastly, we propose a guideline management for familial Pfeiffer syndrome management.

Diabetes, Oxidative Stress, and DNA Damage Modulate Cranial Neural Crest Cell Development and the Phenotype Variability of Craniofacial Disorders

Craniofacial malformations are among the most common birth defects in humans and they often have significant detrimental functional, aesthetic, and social consequences. To date, more than 700 distinct craniofacial disorders have been described. However, the genetic, environmental, and developmental origins of most of these conditions remain to be determined. This gap in our knowledge is hampered in part by the tremendous phenotypic diversity evident in craniofacial syndromes but is also due to our limited understanding of the signals and mechanisms governing normal craniofacial development and variation. The principles of Mendelian inheritance have uncovered the etiology of relatively few complex craniofacial traits and consequently, the variability of craniofacial syndromes and phenotypes both within families and between families is often attributed to variable gene expression and incomplete penetrance. However, it is becoming increasingly apparent that phenotypic variation is often the result of combinatorial genetic and non-genetic factors. Major non-genetic factors include environmental effectors such as pregestational maternal diabetes, which is well-known to increase the risk of craniofacial birth defects. The hyperglycemia characteristic of diabetes causes oxidative stress which in turn can result in genotoxic stress, DNA damage, metabolic alterations, and subsequently perturbed embryogenesis. In this review we explore the importance of gene-environment associations involving diabetes, oxidative stress, and DNA damage during cranial neural crest cell development, which may underpin the phenotypic variability observed in specific craniofacial syndromes.

An Essential Requirement for Fgf10 in Pinna Extension Sheds Light on Auricle Defects in LADD Syndrome

The pinna (or auricle) is part of the external ear, acting to capture and funnel sound toward the middle ear. The pinna is defective in a number of craniofacial syndromes, including Lacrimo-auriculo-dento-digital (LADD) syndrome, which is caused by mutations in FGF10 or its receptor FGFR2b. Here we study pinna defects in the Fgf10 knockout mouse. We show that Fgf10 is expressed in both the muscles and forming cartilage of the developing external ear, with loss of signaling leading to a failure in the normal extension of the pinna over the ear canal. Conditional knockout of Fgf10 in the neural crest fails to recapitulate this phenotype, suggesting that the defect is due to loss of Fgf10 from the muscles, or that this source of Fgf10 can compensate for loss in the forming cartilage. The defect in the Fgf10 null mouse is driven by a reduction in proliferation, rather than an increase in cell death, which can be partially phenocopied by inhibiting cell proliferation in explant culture. Overall, we highlight the mechanisms that could lead to the phenotype observed in LADD syndrome patients and potentially explain the formation of similar low-set and cup shaped ears observed in other syndromes.

Paediatric neuroscience care

Paediatric neurology services care for children aged 0–16 years. Many of these children suffer genetic and complex neurological problems and frequently require life-long support. Hydrocephalus and central nervous system tumours are commonly presenting disorders; however, craniofacial syndromes, spinal disorders, spinal neural tube defects, epilepsy, and trauma including non-accidental injuries are frequently managed. Paediatric nurses specialize in the care of these children and support of their families but as they grow up and transition into adult services, it is the responsibility of general nurses to have a basic understanding of some of their conditions so they can maintain and continue their care.