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Recent advances in the mapping and isolation of genes responsible for birth defects are reviewed. Groups of disorders where rapid progress has been made include bone dysplasias, craniosynostoses and craniofacial syndromes.
Although the need to prevent the secondary effects of craniosynostosis on the central nervous system is fundamental to the practice of craniofacial surgery, the detailed structural anatomy of the central nervous system in the syndromal craniosynostoses has become the subject of recent interest. A clinical and radiographic review of a population of 59 patients with Crouzon's syndrome determined the frequency of central nervous system deformities. Twelve percent of patients had evidence of decreased mental function. Ventriculomegaly on computed tomographic scan was present in 51% and found to be of three grades: mild, moderate, and severe (hydrocephalus). This was nonprogressive in 7 of the 11 patients with follow-up computed tomographic scans. Ten patients underwent surgical release to increase intracranial space; however, 6 of these patients showed no progression in ventricular size. Nonventricular anomalies were found less frequently (14%). Central nervous system findings show fewer nonventricular anomalies than in Apert's syndrome patients, with a corresponding higher mental function. The principal anomaly of ventriculomegaly is not directly related to suture defect and may represent a primary brain abnormality. Recommendations are made for the assessment and management of patients with Crouzon's syndrome with reference to these areas.
Distraction osteogenesis has provided a powerful technique for the treatment of severe midfacial hypoplasia. Skeletal fixation is a critical component of successful distraction osteogenesis. This is a report on the development of a new approach to bone fixation for distraction osteogenesis of the midface, based on circumferential suspension of the entire midfacial skeleton using surgical wires placed through the soft palate. This technique offers the advantages of (1) complete control of the attitude of the midface in terms of a precise dispersion of forces that can determine the desired pitch, yaw, and roll of this skeletal complex during the active phase of distraction, (2) being compatible with young children in the deciduous dentition stage because it obviates the need for rigid fixation devices on the maxillary lateral walls in the proximity of numerous dental follicles of the unerupted adult dentition, (3) actually serving as the instrument for posterior maxillary "lift" in cases of skeletal open bite malocclusions (frequently seen in the craniosynostoses), thereby allowing the clinician to determine the final occlusal and palatal planes and simultaneously close the open bite. An illustrative case of a 5(1/2)-year-old girl with Apert syndrome is presented wherein her ventilatory obstruction and ocular proptosis were significantly improved.
Although the incidence of elevated intracranial pressure is increased in patients with the craniosynostosis syndromes, the significance of these findings and their impact on clinical practice remain unclear. The morbidity related to elevated intracranial pressure in patients with Apert and Pfeiffer syndromes was reviewed. Sixty-seven patients with Apert syndrome and 39 patients with Pfeiffer syndrome were identified. The morbidity in 5 of the 106 patients (4.7 percent) was felt to be directly related to persistently elevated intracranial pressure. These included 2 deaths, 1 due to brainstem herniation after an elective subcranial Le Fort III advancement and 1 following removal of a lumboperitoneal shunt during the surgical release of syndactyly. The remaining 3 complications included bilateral papilledema detected 3.5 years after cranial vault remodeling in 1 patient and venous hypertension with excessive bleeding detected during elevation of the bicoronal flap in 2 patients, resulting in delay of a planned Le Fort III advancement. Patients with the syndromal craniosynostoses are at risk for complications resulting from elevated intracranial pressure from infancy through adulthood despite surgical attempts to increase cranial capacity in infancy. Clinical guidelines are proposed by which these patients should be evaluated beyond infancy in a regular fashion so as to reduce morbidity from unrecognized elevations in intracranial pressure.
Accumulating clinical genetic data support the hypothesis that alterations in osteoblast differentiation are closely associated with craniosynostoses. Gain-of-function mutations in FGFR1, FGFR2, FGFR3, and Msx2 and loss-of-function mutations in Twist are examples of such alterations. Several studies have examined how these mutations alter the expression patterns for transcription factors such as Runx2 and noncollagenous extracellular matrix molecules such as osteopontin and osteocalcin. One limitation of such studies is that they examine samples derived from craniosynostotic patients with sutures that have already fused, thus missing the dynamic osteogenic process of suture fusion. In this study, in situ hybridization was used to localize Runx2, osteopontin, and osteocalcin expression in the sagittal and posterior frontal sutures in mice (n = 20), before (day 13), during (days 23, 33, and 43), and after (day 53) the period of physiological posterior frontal suture fusion. The data demonstrated similar patterns of expression in fusing (posterior frontal) and nonfusing (sagittal) sutures. The expression of all three genes was primarily concentrated in the osteogenic fronts of both sutures and decreased with time. Notably, none of the three genes was expressed in the mesenchyme of either fusing or nonfusing sutures. The data suggest that the molecular signals leading to bone formation along the osteogenic fronts in fusing and nonfusing sutures are similar, raising the possibility that other factors, such as antagonists of osteogenesis, might have a role in maintaining suture patency.
We describe a 4-year-old boy with Crouzon syndrome, with associated acanthosis nigricans and Chiari-I malformation, who developed increased intracranial pressure necessitating posterior cranial expansion. Postoperatively, an arteriovenous fistula appeared over the mastoid region. Cerebral angiography demonstrated bilateral atresia of the jugular veins and occlusion of the left sigmoid and right transverse sinuses. We propose that increased intracranial venous pressure, secondary to bilateral jugular foraminal stenosis, caused hydrocephaly and venous dilation in the scalp vasculature. The latter set the stage for a traumatic arteriovenous fistula of the scalp, probably resulting from laceration of an adjacent artery and vein. Jugular atresia is a basilar malformation common to achondroplasia and certain eponymous syndromic craniosynostoses. Our patient has a mutation in fibroblast growth factor receptor 3, a different locus in the same gene mutated in achondroplasia.
The objective of this study was to review the characteristics of congenital nasal pyriform aperture stenosis (CNPAS) in a series of 20 children seen between 1993 and 1996. The diagnosis was made by physical examination and computed tomography scan. A single central maxillary incisor was detected in 12 cases (60%). Three children had morphological abnormalities of the pituitary gland shown on magnetic resonance imaging. One child had an antidiuretic hormone deficiency, and another child had a growth hormone deficiency. Two children had craniosynostoses, 1 of which was Apert's syndrome. All patients underwent operation by a sublabial approach, and 1 was referred for a columellar necrosis after nasal stenting. After surgery, all patients showed improvement, and the nasal stenting was usually removed 1 week after surgery. Follow-up revealed normal breathing. In conclusion, CNPAS was previously considered to be an unusual cause of nasal obstruction in neonates and infants. The number of cases treated recently in our department suggests that this newly recognized entity is more common than expected.
BACKGROUND: Apert syndrome is one of the craniosynostosis syndromes, with a birth prevalence estimated to be between 9.9 and 15.5/million, and accounts for 4.5 per cent of craniosynostoses. Although conductive hearing loss is common in Apert syndrome there are contradicting reports regarding the cause of this hearing loss. There is also no detailed information available on the management of hearing loss in Apert syndrome. MATERIALS AND METHODS: A retrospective analysis of case notes of Apert syndrome patients seen between 1970 and 2003 at Great Ormond Street Children's Hospital, London, was undertaken. RESULTS: Seventy case notes were obtained. The incidence of congenital hearing impairment was between 3 and 6 per cent. Almost all patients had otitis media with effusion (glue ear), which tended to persist into adult life. More than 56 per cent of cases developed permanent conductive hearing loss by 10-20 years. Repeated grommet insertion was common; even though 35 per cent had trouble with ear discharge and persistent conductive hearing loss. Statistically, grommets made no difference to the risk of developing permanent hearing loss. CONCLUSION: This study, of the largest number of Apert syndrome cases assembled to date, showed that early optimization of hearing with possible hearing aids needs to be considered. Repeated grommet insertion does not help in optimizing hearing, especially if ear discharge complicates the picture.
A number of congenital and acquired conditions can affect the skull, face and jaws resulting in a wide range of craniofacial abnormalites that commonly present at birth or in early infancy. This article aims to outline the aetiology, pathogenesis, diagnosis and principles of management of those conditions that commonly present to a craniofacial unit namely the craniosynostoses.
The formation of cranial bone requires the differentiation of osteoblasts from undifferentiated mesenchymal cells. The balance between osteoblast recruitment, proliferation, differentiation and apoptosis in sutures between cranial bones is essential for calvarial bone formation. The mechanisms that control human osteoblasts during normal calvarial bone formation and premature suture ossification (craniosynostosis) begin to be understood. Our studies of the human calvaria osteoblast phenotype and calvarial bone formation showed that premature fusion of the sutures in non-syndromic and syndromic (Apert syndrome) craniosynostoses results from precocious osteoblast differentiation. We showed that Fibroblast Growth Factor-2 (FGF-2), FGF receptor-2 (FGFR-2) and Bone Morphogenetic Protein-2 (BMP-2), three essential factors involved in skeletal development, regulate the proliferation, differentiation and apoptosis in human calvaria osteoblasts. Mechanisms that induce the differentiated osteoblast phenotype have also been identified in human calvaria osteoblasts. We demonstrated the implication of molecules (N-cadherin, Il-1) and signaling pathways (src, PKC) by which these local factors modulate human calvaria osteoblast differentiation and apoptosis. The identification of these essential signaling molecules provides new insights into the pathways controlling the differentiated osteoblast phenotype, and leads to a more comprehensive view in the mechanisms that control normal and premature cranial ossification in humans.
Although great diversity marks the craniosynostoses, our experience related to that from other centers allows us to draw certain conclusions for their management. For the asymmetric synostoses, operative intervention should be carried out in infancy or early childhood. Although the unilateral approach is our preferred method, the bilateral approach can yield equally satisfactory results. Surgeons should, therefore, familiarize themselves with both methods and individualize for the given deformity. Mild symmetric (upper face) synostoses are best managed in infancy or early childhood, utilizing bilateral orbital advancement with the expectation that the need for additional major surgery will be at worst 50 per cent and likely significantly less. For moderate to severe synostoses, delaying major intervention to later childhood or adolescence maximizes the chance of obtaining a satisfactory result by a single procedure, either an extended LeFort III or monoblock advancement. Individualization of each case is essential, and the need for brain and eye protection or the psychologic needs of the patient may dictate a modification of the treatment guidelines. Patients and parents must be aware that growth and development subsequent to surgery is not entirely predictable, and there may be a need for a second major intervention at a subsequent time, despite these established guidelines.
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