Robert D. Evans

from Genotype to Phenotype: The Differential Expression of Fgf, Fgfr, and Tgfβ Genes Characterizes Human Cranioskeletal Development and Reflects Clinical Presentation in Fgfr Syndromes

Mutations in the fibroblast growth factor receptor (FGFR) genes 1, 2, and 3 are causal in a number of craniofacial dysostosis syndromes featuring craniosynostosis with basicranial and midfacial deformity. Great clinical variability is displayed in the pathologic phenotypes encountered. To investigate the influence of developmental genetics on clinical diversity in these syndromes, the expression of several genes implicated in their pathology was studied at sequential stages of normal human embryo-fetal cranial base and facial ossification (n = 6). At 8 weeks of gestation, FGFR1, FGFR2, and FGFR3 are equally expressed throughout the predifferentiated mesenchyme of the cranium, the endochondral skull base, and midfacial mesenchyme. Both clinically significant isoforms of FGFR2, IgIIIa/c and IgIIIa/b, are coexpressed in maxillary and basicranial ossification. By 10 to 13 weeks, FGFR1 and FGFR2 are broadly expressed in epithelia, osteogenic, and chondrogenic cell lineages. FGFR3, however, is maximally expressed in dental epithelia and proliferating chondrocytes of the skull base, but poorly expressed in the osteogenic tissues of the midface. FGF2 and FGF4, but not FGF7, and TGFbeta1 and TGFbeta3 are expressed throughout both osteogenic and chondrogenic tissues in early human craniofacial skeletogenesis. Maximal FGFR expression in the skull base proposes a pivotal role for syndromic growth dysplasia at this site. Paucity of FGFR3 expression in human midfacial development correlates with the relatively benign human mutant FGFR3 midfacial phenotypes. The regulation of FGFR expression in human craniofacial skeletogenesis against background excess ligand and selected cofactors may therefore play a profound role in the pathologic craniofacial development of children bearing FGFR mutations.

Toward Pathogenesis of Apert Cleft Palate: FGF, FGFR, and TGFβ Genes Are Differentially Expressed in Sequential Stages of Human Palatal Shelf Fusion

OBJECTIVE Critical cellular events at the palatal medial edge epithelium (MEE) occur in unperturbed mammalian palatogenesis, the molecular control of which involves a number of growth factors including transforming growth factor beta 3 (TGF beta 3). Apert syndrome is a monogenic human disorder in which cleft palate has been significantly correlated to the fibroblast growth factor receptor (FGFR) 2-Ser252Trp mutation. We report the relative expression of these genes in human palatogenesis. METHODS The expression of the IgIIIa/b and IgIIIa/c transcript isoforms of FGFR2 and the proteins FGFR1, FGFR2, and FGFR3 was studied in situ throughout the temporospatial sequence of human palatal shelf fusion and correlated with the expression of TGF beta 3. In addition, the immunolocalization of the ligand FGFs 2, 4, and 7 was undertaken together with the intracellular transcription factor STAT1, which is activated by FGFR signaling. RESULTS FGFRs are differentially expressed in the mesenchyme and epithelia of fusing palatal shelves, in domains overlapping those of their ligands FGF4 and FGF2 but not FGF7. Coexpression is seen with TGF beta 3, which is implicated in MEE dynamics and FGF and FGFR upregulation, and STAT1, an intracellular transcription factor that mediates apoptosis. CONCLUSIONS The coregulation of molecules of the FGFR signaling pathway with TGF beta 3 throughout the stages of human palatal fusion suggests their controlling influence on apoptosis and epitheliomesenchymal transdifferentiation at the MEE. Experimental evidence links FGFR2-IgIIIa/b loss of function with palatal clefting, and these correlated data suggest a unique pathological mechanism for Apert cleft palate.

Functional outcomes in monobloc advancement by distraction using the rigid external distractor device.

Background: Craniofacial dysostosis syndromes produce multisutural synostoses combined with severe midfacial retrusion. This may cause serious functional problems, including airway obstruction, exposure of the eyes, visual pathway dysfunction, and raised intracranial pressure. Early midface advancement may be necessary to address these issues. Distraction osteogenesis has provided the facility to achieve significant advances safely and is often in excess of that which is achievable by conventional means. Methods: A retrospective study of 20 patients with craniofacial dysostosis and severe midface hypoplasia who underwent monobloc advancement osteotomies using the rigid external distractor system principally for functional reasons was undertaken. The multidisciplinary management and outcome measures of these patients were recorded. Results: The midface was distracted an average of 16.4 mm, with a range of 12 to 22 mm. Ocular protection was achieved in all patients with preoperative exposure keratopathy and/or globe subluxation. Improvements in optic disc swelling and pattern visually evoked potentials were seen in those patients with threatened visual impairment. Improvement in airway obstruction was seen in those patients with abnormal polysomnography. Decannulation was achieved in five of the seven patients with tracheostomies. Fifty percent had a reduction in hyponasality, and the visual appearance of speech was improved. Complications included persistent cerebrospinal fluid leakage, acquired hypernasality in 25 percent, cranial bone loss, and sinus formation requiring surgical revision. Conclusions: Monobloc distraction osteogenesis results in good aesthetic and functional outcomes. The relatively high rate of complications remains a concern, and further adaptations of technique are needed to reduce the risks of this procedure.

Cervical spine in Pfeiffer's syndrome.

Studies of cervical spine anomalies in patients with Crouzons and Aperts syndromes have shown an increased incidence of fusions in comparison with that in the normal population. Currently, only small series of patients with Pfeiffers syndrome who exhibit abnormalities have been published. The objective was to assess the incidence and pattern of radiological cervical spine abnormalities in patients with Pfeiffers syndrome. All cervical spine radiographs of 22 patients with a confirmed diagnosis of Pfeiffers syndrome treated at Great Ormond Street Hospital during the last 10 years were studied. All of the radiographs were reviewed by the craniofacial team along with a pediatric radiologist with experience in the assessment of skeletal dysplasias. Radiological abnormalities included hypoplasia of the neural arches, hemivertebrae, and a “butterfly” vertebra as well as vertebral fusion. Evidence of vertebral fusion was present in 16 (73%) of cases. Fusion of both the vertebral bodies and the posterior elements were noted. C2-C3 was the level most commonly involved, although fusion was noted at all levels within the cervical spine. Block fusions involving multiple vertebrae were noted. Analysis of sequential radiographs in 11 patients revealed evidence of progression in eight patients. These results reveal an incidence of anomalies that is higher than previously reported. The older age of the patients in our study demonstrates the progressive nature of the cervical fusions in Pfeiffers syndrome.

Three-dimensional image analysis of facial skeletal changes after monobloc and bipartition distraction.

Background: Both monobloc and facial bipartition distraction are important tools for correcting functional and aesthetic problems in patients with syndromic craniosynostosis. Three-dimensional computed tomographic reconstructions have become increasingly useful in planning and analyzing surgical results. This study measured the differential deformation of the facial skeleton following distraction osteogenesis with the rigid external distractor frame, looking especially at correction of the midface concavity. Correction of the midface concavity aims to not only improve the appearance but also increase the upper airway volume. Methods: Ten children with syndromic craniosynostoses were studied. Seven children with Crouzon syndrome underwent monobloc distraction and three with Apert syndrome underwent facial bipartition distraction using the rigid external distractor frame. The patients’ ages ranged from 4 months to 15 years. The medial advancement and the lateral advancement of the facial skeleton were compared by landmarking three-dimensional computed tomographic reconstructions using the sella turcica as the fixed point. To compare the shape of the monobloc segment from the preoperative to postoperative scans, a color map was generated. Results: Of the seven patients who underwent monobloc distraction, the mean medial advancement of the face was 4.9 mm greater than the lateral advancement. With the bipartition distraction, the mean central area advancement was 11.4 mm farther than the lateral aspect of the facial skeleton. Conclusions: Both monobloc and in particular the facial bipartition distraction differentially advance the central part of the face more than the lateral areas. This bending of the face appears to have both cosmetic and functional advantages.

Prevalence of abnormal pattern reversal visual evoked potentials in craniosynostosis.

Background: The purpose of this study was to examine the prevalence and type of changes observed in the pattern reversal visual evoked potentials recorded at the first assessment of children with craniosynostosis. Methods: Visual evoked potentials were recorded from 114 patients with craniosynostosis. Eighty-one patients were syndromic and 33 were nonsyndromic. No patient had received any craniofacial surgical intervention. At the time of the test, 22 of 40 patients were aged 6 months and younger, and 18 patients were between 6 months and 1 year of age. Pattern reversal visual evoked potentials were recorded from a midoccipital electrode positioned 3 cm above the inion. The pattern reversal visual evoked potentials elicited to 50′ checks with three reversals per second viewed with both eyes were analyzed for n80-p100 amplitude, p100 latency, and breadth of waveform. Results: Sixty percent of patients had abnormal pattern reversal visual evoked potentials to 50′ checks. This did not show a significant association with age, or classification of craniosynostosis. Conclusions: The high prevalence of abnormal pattern reversal visual evoked potentials to a robust stimulus suggests that visual pathway dysfunction, as measured electrophysiologically, can affect a majority of patients with craniosynostosis. This study indicates that a baseline evaluation of all children with craniosynostosis at their first presentation is essential if subsequent electrophysiologic visual pathway monitoring is to take place.

The Cervical Spine in Saethre-Chotzen Syndrome

Twenty patients with a diagnosis of Saethre-Chotzen syndrome had their cervical spine radiographs reviewed. Radiologic abnormalities including vertebral fusion were present in 9 of the 20 patients. Fusion of both the vertebral bodies and the posterior elements was noted, although the latter site was more common. C2-3 was the level most commonly involved, although other levels were recorded. Analysis of sequential radiographs in nine patients revealed evidence of progression in seven patients. In those studies in children aged under 2 years, only 1 of 18 films showed evidence of fusion, while in those over 2 years of age, 10 of 12 showed evidence of fusion. These results reveal that the incidence of cervical anomalies in Saethre-Chotzen syndrome is greater than that in the general population. There is both direct and indirect evidence that the vertebral fusions are progressive during childhood.

Hand anomalies in Crouzon syndrome

Abstract Objective. To review the hand radiographs of patients with Crouzon syndrome, to look for extracranial manifestations of the condition at this site. Design. The hand radiographs of those with Crouzon syndrome attending the Craniofacial Service at Great Ormond Street between 1985 and 1996 were reviewed. Results. Thirty-three patients underwent a total of 34 radiographs, one patient having had a serial study. This revealed a range of minor anomalies. Most striking was the presence of carpal fusions in four cases, a feature which has not previously been reported. Conclusion. The hands of Crouzon syndrome may have anomalies including carpal fusions, and these results are evidence that the condition may produce subtle effects on the hands.

Occipital plagiocephaly: an epidemic of craniosynostosis?

“A bizarre epidemic … 400% increase since 1992.” “Unkind cut: some physicians do unnecessary surgery on heads of infants.”1 These terms were used last year by the Wall Street Journal , in company with the British media, to report that the incidence of posterior skull asymmetry, or occipital plagiocephaly, and its surgical management, had increased to epidemic proportions. Such headlines have resulted in anxiety among parents, general practitioners, and paediatricians, and it is therefore important to be clear about the causes of the asymmetry. One cause of plagiocephaly is craniosynostosis, which is premature fusion of the cranial sutures—the adaptive fibrous joints between the bones of the skull. The resulting abnormal skull shape is usually an isolated anomaly but it may be associated with a craniofacial syndrome such as that of Crouzon or Apert. The skull shape is predictable from the suture or sutures involved. Premature fusion of the lambdoid sutures, …

Midface osteotomy versus distraction: The effect on speech, nasality, and velopharyngeal function in craniofacial dysostosis

Objective: To assess speech outcomes following midface advancement and to explore whether the type of advancement surgery affects speech differently in patients with craniofacial dysostosis. Design: Prospective, before-after group design. Subjects: Fifteen consecutive patients were included in the study. Eight underwent advancement by osteotomy and seven by distraction. All patients were seen preoperatively and at least once postoperatively. Main Outcome Measures: Percentage of consonants correct, nature and type of articulation errors, nasalance score, severity ratings of resonance and of velopharyngeal function using nasendoscopy and lateral videofluoroscopy, and amount of forward advancement. Results: No statistically significant differences were found between groups for pre- and postoperative changes of percentage of consonants correct (p  =  .755, median difference 3.0, 95% confidence interval for median difference [−14.22, 20.22]) and nasalance (p  =  .171, median difference  =  −12.00, 95% confidence interval for median differences [−30.46, 6.46]). There was no statistically significant correlation between amount of forward advancement and nasalance (r  =  .87, p  =  .799) and percentage of consonants correct (r  =  −.550, p  =  .064). Findings from lateral videofluoroscopy and nasendoscopy are described. Individual changes of speech outcomes are reported. Conclusions: In view of the small sample size, results need to be interpreted with caution. However, the study adds to current limited knowledge with this clinical group. Further research with bigger sample sizes and randomization of patients into the different surgical groups is warranted.