Peter G. Richards

Prevalence and complications of single gene and chromosomal disorders in craniosynostosis

OBJECTIVES: We describe the first cohort-based analysis of the impact of genetic disorders in craniosynostosis. We aimed to refine the understanding of prognoses and pathogenesis and to provide rational criteria for clinical genetic testing. METHODS: We undertook targeted molecular genetic and cytogenetic testing for 326 children who required surgery because of craniosynostosis, were born in 1993–2002, presented to a single craniofacial unit, and were monitored until the end of 2007. RESULTS: Eighty-four children (and 64 relatives) had pathologic genetic alterations (86% single-gene mutations and 14% chromosomal abnormalities). The FGFR3 P250R mutation was the single largest contributor (24%) to the genetic group. Genetic diagnoses accounted for 21% of all craniosynostosis cases and were associated with increased rates of many complications. Children with an initial clinical diagnosis of nonsyndromic craniosynostosis were more likely to have a causative mutation if the synostoses were unicoronal or bicoronal (10 of 48 cases) than if they were sagittal or metopic (0 of 55 cases; P = .0003). Repeat craniofacial surgery was required for 58% of children with single-gene mutations but only 17% of those with chromosomal abnormalities (P = .01). CONCLUSIONS: Clinical genetic assessment is critical for the treatment of children with craniosynostosis. Genetic testing of nonsyndromic cases (at least for FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses. Single-gene disorders that disrupt physiologic signaling in the cranial sutures often require reoperation, whereas chromosomal abnormalities follow a more-indolent course, which suggests a different, secondary origin of the associated craniosynostosis.

Fgfr3 P250r Mutation Increases the Risk of Reoperation in Apparent ‘nonsyndromic’ Coronal Craniosynostosis

Many patients with a clinical diagnosis of “nonsyndromic” coronal craniosynostosis have been found to be heterozygous for the fibroblast growth factor receptor 3 (FGFR3) mutation Pro250Arg. The phenotype associated with this mutation is variable and lacks highly distinctive features, so it is difficult to diagnose on clinical examination alone. The authors present a retrospective study of 76 patients with isolated coronal synostosis who were operated on in a single dedicated craniofacial unit over 25 years. The authors investigated whether any single factor, including the presence of a FGFR3 Pro250Arg mutation, predisposed to an increased transcranial reoperation rate. Eight patients had repeat transcranial surgery for a functional indication. Heterozygosity for the FGFR3 Pro250Arg mutation, present in 29 patients in the cohort, was the only factor found to have a significant association (P = 0.048) with the transcranial reoperation rate. Six patients (20.7%) with the mutation underwent reoperation on the basis of raised intracranial pressure, as compared with two patients (4.3%) without the mutation. This highlights the need for genetic analysis and long-term clinical follow-up in apparently “isolated” coronal synostosis.

The preoperative incidence of raised intracranial pressure in nonsyndromic sagittal craniosynostosis is underestimated in the literature

OBJECT The presence of raised intracranial pressure (ICP) in untreated nonsyndromic, isolated sagittal craniosynostosis (SC) is an important functional indication for surgery. METHODS A retrospective review was performed of all 284 patients presenting with SC to the Oxford Craniofacial Unit between 1995 and 2010. RESULTS Intraparenchymal ICP monitoring was performed in 39 children following a standard unit protocol. Monitoring of ICP was offered for all patients in whom nonoperative management was considered on the basis of minimal deformity or in cases in which parents were reluctant to agree to corrective surgery. These patients presented at an older age than the rest of the cohort (mean age 56 months), with marked scaphocephaly (16/39, 41%), mild scaphocephaly (11, 28%), or no scaphocephalic deformity (12, 31%). Raised ICP was found in 17 (44%) patients, with no significant difference in its incidence among the 3 different deformity types. Raised ICP was not predicted by the presence of symptoms of ICP or developmental delay or by ophthalmological or radiological findings. CONCLUSIONS The incidence of raised ICP in SC reported here is greater than that previously published in the literature. The lack of a reliable noninvasive method to identify individuals with elevated ICP in SC mandates consideration of intraparenchymal ICP monitoring in all patients for whom nonoperative management is contemplated.

REOPERATION FOR INTRACRANIAL HYPERTENSION IN TWIST1 CONFIRMED SAETHRE-CHOTZEN SYNDROME: A 15 YEAR REVIEW

Background: Saethre-Chotzen syndrome is a syndromic craniosynostosis defined by a genetic mutation affecting the TWIST1 gene on chromosome 7p21. It is typically associated with unicoronal or bicoronal synostosis, eyelid ptosis, dysmorphic external ears, and other variable facial and limb abnormalities. Surgical management of the craniosynostosis addresses the calvarial deformity and may relieve or reduce the risk of intracranial hypertension. The aim of this study was to assess surgical intervention, with particular consideration of the reoperation rate for intracranial hypertension, in Saethre-Chotzen syndrome patients. Methods: A retrospective case note analysis was performed on all patients with a confirmed TWIST1 gene abnormality who attended the Oxford Craniofacial Unit over a 15-year period. Each patients mutation and clinical features were recorded. Surgical intervention and sequelae were examined in greater detail. Results: Thirty-four patients with genetically confirmed Saethre-Chotzen syndrome were identified. All had craniosynostosis (bicoronal, 76 percent; unicoronal, 18 percent; bicoronal and sagittal, 6 percent), and the majority had eyelid ptosis, low frontal hairline, and external ear anomalies. Thirty-one patients had received surgical intervention. Nine of 26 patients (35 percent) with at least 12 months of follow-up after primary intervention and eight of 19 patients (42 percent) with at least 5 years of follow-up developed intracranial hypertension necessitating secondary calvarial surgery. Conclusions: Despite standard surgical intervention, patients with Saethre-Chotzen syndrome have a high rate (35 to 42 percent) of recurrent intracranial hypertension necessitating further surgical expansion. All patients with either bicoronal synostosis or unicoronal synostosis with syndromic features should be screened for TWIST1 mutations, as this confers a greater risk than nonsyndromic synostosis of the same sutures. Regular follow-up throughout the childhood years is essential.

The incidence of raised intracranial pressure in nonsyndromic sagittal craniosynostosis following primary surgery.

OBJECT Raised intracranial pressure (ICP) is recognized to occur in patients with nonsyndromic isolated sagittal craniosynostosis (SC) prior to surgery. However, the incidence of raised ICP following primary surgery is rarely reported and there appears to be a widely held assumption that corrective surgery for SC prevents the later development of intracranial hypertension. This study reports the incidence of postoperative raised ICP in a large cohort of patients with SC treated by 1 of 2 surgical procedures in a single craniofacial unit. METHODS A retrospective review was performed of all patients with SC who underwent either a modified strip craniectomy (MSC) or calvarial remodeling (CR) procedure under the care of the Oxford Craniofacial Unit between 1995 and 2010 and who were followed up for more than 2 years. The influence of patient age at surgery, year of surgery, sex, procedure type, and the presence of raised ICP preoperatively were analyzed. RESULTS Two hundred seventeen children had primary surgery for SC and were followed up for a mean of 86 months. The overall rate of raised ICP following surgery was 6.9%, occurring at a mean of 51 months after the primary surgical procedure. Raised ICP was significantly more common in those patients treated by MSC (13 of 89 patients, 14.6%) than CR (2 of 128 patients, 1.6%). Also, raised ICP was more common in patients under 1 year of age, the majority of whom were treated by MCS. No other factor was found to have a significant effect. CONCLUSIONS Postoperative raised ICP was found in more than 1 in 20 children treated for nonsyndromic SC in this series. It was significantly influenced by the primary surgical procedure and age at primary surgery. Careful long-term follow-up is essential if children who develop raised ICP following surgery are not to be overlooked.

Implications of a vertex bulge following modified strip craniectomy for sagittal synostosis.

Background: Modified strip craniectomy is a common treatment for early isolated sagittal synostosis. The authors assessed the significance of the development of a progressive vertex bulge following strip craniectomy as a predictor of raised intracranial pressure or multiple suture synostosis. Methods: All cases of sagittal synostosis treated by modified strip craniectomy (removal of the sagittal suture with lateral barrel staving) at the authors’ institution were reviewed. Eighty-nine patients with isolated sagittal synostosis were treated by modified strip craniectomy, usually before 6 months of age, between 1995 and 2005. Seven patients were noted to have developed a progressive vertex bulge. The vertex bulge was noted an average of 8 months postoperatively (range, 2 to 25 months). The clinical records of these seven patients were evaluated with regard to their clinical course, radiologic investigations, genetics testing, intracranial pressure monitoring, and the need for further surgery. Results: Computed tomographic scanning demonstrated new synostosis involving other calvarial sutures in five patients. Five patients underwent intracranial pressure monitoring, and this was elevated in four patients. One patient required a ventriculoperitoneal shunt for hydrocephalus. All patients underwent genetic screening, and two were found to have fibroblast growth factor receptor (FGFR) mutations (one FGFR2 and one FGFR3 mutation). All patients required reoperation (calvarial remodeling) for either raised intracranial pressure, deteriorating head shape, or both. Conclusions: A progressive vertex bulge after modified strip craniectomy is a sign of possible raised intracranial pressure, the development of progressive multiple suture synostosis, or both. It is an indication for genetic testing for FGFR mutations.

Posterior calvarial distraction in craniosynostosis - an evolving technique.

BACKGROUND Posterior advancement of the occiput is an established surgical option for the treatment of raised intracranial pressure (ICP) secondary to craniocerebral disproportion in syndromic craniosynostoses. Distraction osteogenesis has gained popularity in a variety of craniofacial procedures to achieve greater advancement in the anterior craniofacial skeleton, but has only relatively recently been used in the posterior calvarium. We report the Oxford Craniofacial Units experience of using distraction techniques to expand the occiput. METHODS We preformed a retrospective casenote review of all patients with syndromic craniosynostoses who underwent posterior distraction at our centre from 2007 to 2010, as identified by the Oxford Craniofacial Database. RESULTS Ten syndromic patients underwent posterior distraction (mean age of 18.1 months). Successful calvarial expansion (mean advancement of 19.7 mm) was achieved in all patients clinically and radiologically. There were 6 minor and 1 major complications. CONCLUSIONS Posterior distraction was successfully performed in 10 patients including babies as young as 3 months of age. It achieved a reduction in turricephaly, an improvement in the cephalic index, and a resolution of raised ICP. We have customised our surgical technique to address individual patient needs. The use of distraction techniques in the occiput appears to increase the reliability of expansion in this region.

Aneurysmal bone cyst as a rare cause of spinal cord compression in a young child.

Study Design. Case report. Objectives. To report: 1) one of the youngest cases of aneurysmal bone cysts presenting with cord compression at the cervicothoracic junction with 7-year follow-up; and 2) the technique we used to stabilize such a small spine. Summary of Background Data. Aneurysmal bone cyst is an uncommon but well-recognized tumor affecting the spine of children. The mean age of presentation is 16 years. It has hardly been reported below the age of 4 years. All data are in the form of case reports or series. Surgical or nonoperative management can be used. Spinal implant systems are not designed for use in very small children. Methods. Clinical data analysis. Results. A girl presented at age 2 years and 3 months with cord compression at the cervicothoracic junction. After an inconclusive biopsy, a formal excision and reconstruction of the C7 and T1 were performed anteriorly and posteriorly. We used a fibular graft, internal fixation with crossed plates from the maxillofacial implant tray and a Cervifix® rod contoured into a rectangle with sublaminar titanium cables. Postsurgery, she had a left Horner syndrome that has never recovered and motor weakness of the right arm that improved but did not fully recover. She developed a staphylococcal infection 6 months postsurgery that was managed by removal of the rectangle. She developed a posterior recurrence 10 months postsurgery, which was managed surgically. Follow-up has been for 7 years without further evidence of recurrence. Conclusions. Both surgical and nonsurgical management has been advocated for these tumors. The cord compression at presentation forced us toward surgical management. It is likely that observational data are the only evidence available for clinical decision-making. In this case, we were able to obtain good access to the front of the upper thoracic spine by a supraclavicular approach. Tiny plates are available to maxillofacial surgeons that can be adapted for use in the spines of small children.

Raised intracranial pressure is frequent in untreated nonsyndromic unicoronal synostosis and does not correlate with severity of phenotypic features.

Background: In a small number of children with unicoronal synostosis, the phenotype is mild and the aesthetic benefit of surgical correction is potentially outweighed by surgical risk. Raised intracranial pressure, however, would necessitate intervention. The authors documented the incidence of raised intracranial pressure in children with mild features and/or parental reluctance to proceed directly to surgery. Methods: A retrospective review of all children with (1) a clinical diagnosis of nonsyndromic unicoronal synostosis; (2) unicoronal synostosis confirmed on computed tomographic scanning; (3) negative family history for unicoronal synostosis; and (4) negative genetic screening (including P250R encoded by FGFR3, exons IIIa and IIIc in FGFR2 and TWIST1) was completed. Results: Of the 80 children studied, seven (9 percent) underwent formal intracranial pressure monitoring because of a combination of mild clinical features (n = 4) and/or parental reluctance to proceed with surgery (n = 3). Intracranial pressure monitoring was reported as high in three (42 percent), borderline in two (29 percent), and normal in two patients (29 percent). The findings did not correlate with the degree of clinical deformation or age at presentation. There was little correlation with clinical and radiographic features of raised intracranial pressure in this genetically screened nonsyndromic group. Conclusions: High or borderline raised intracranial pressure was present in five of seven cases. The risk did not correlate with degree of deformity or age at presentation. Formal intracranial pressure monitoring should be considered in all children with unicoronal synostosis not proceeding directly to surgical intervention, in combination with routine long-term follow-up and repeated intracranial pressure monitoring where indicated. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V.

The changing face of paediatric hydrocephalus: A decade’s experience

All 253 children receiving neurosurgical intervention for hydrocephalus (HCP) at a single British Neurosurgical Unit over a decade were investigated by retrospective case note review. Referral rates and mean age at presentation remained stable throughout, as did proportions of children presenting due to myelomeningocoele or meningitis. Comparing the first and second halves of the decade, the predominant aetiologies (intraventricular haemorrhage [IVH] at <1 year and brain tumour at 1-16 years) reduced from comprising half (70/129) of all cases to just over one-third (43/124). Other significant changes included a 45% reduction in neonatal IVH and a 179% increase in rare miscellaneous disorders. Outcome after 4 years of follow-up for all patients showed 44.4% without deficit, 11.9% with non-cognitive neurological deficits only, 11.5% with cognitive impairment only, 13.5% with both cognitive and neurological impairments, and 15.5% mortality.