CT imaging of craniofacial malformations

Neuroimag Clin N Am 13 (2003) 541 – 572

CT imaging of craniofacial malformations Paul A. Caruso, MDa,*, Gordon J. Harris, PhDb, Bonnie L. Padwa, DMD, MDc a

Department of Radiology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA b 3D Imaging Service, Department of Radiology, Harvard Medical School, Boston, MA, USA c Division of Plastic and Oral Surgery, Harvard School of Dental Medicine, Children’s Hospital, Boston, MA, USA

Cross-sectional medical imaging techniques, including CT and MR imaging, frequently are employed in the evaluation of patients with craniofacial (CF) malformations. Because of its superior visualization of bone, CT is an important tool in the preoperative assessment and postoperative follow-up of patients with CF deformities. This article explores the role of CT in the diagnosis and presurgical evaluation of CF malformations.

Technical considerations In this article, the authors highlight two applications that aid in the evaluation of CF pathology: twodimensional (2D) techniques, such as multiplanar reformats recently facilitated by multidetector scanners, and volumetric techniques, such as three-dimensional (3D) reconstructions and maximum intensity projections (MIP). Protocol Specific protocol parameters, including the use of contrast and sedation, depend on the deformity, indication for the study, and condition and age of the patient [1,2]. A general approach to the imaging of these patients is reviewed in this article. A concise patient or parent interview and clinical examination guide the study protocol. A history of

* Corresponding author. Department of Radiology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114. E-mail address: [email protected] (P.A. Caruso).

hearing loss, cranial neuropathy, or neurologic disorder may influence the choice of scan excursion, reformats to be performed, and indication for complementary studies such as MR imaging. If there are findings consistent with bilateral coronal synostosis or known syndromic craniosynostosis, consideration should be made for intravenous contrast administration to assess the craniocervical venous drainage. Several reports show abnormal venous drainage from jugular foramen stenosis in these patients [3 – 6]. Patients are scanned in the supine position in the axial plane. The scan excursion depends on the indication for the study and the patient’s diagnosis. Those with isolated craniosynostosis may be scanned from the cranial vertex through the foramen magnum. In patients with syndromic craniosynostosis, the scan excursion should be carried through the hyoid bone to include the maxilla and mandible, as many patients have associated maxillary and mandibular deformities. For CF malformations without synostosis, the scan may be carried from the frontal sinuses through the hyoid bone. The authors’ protocol includes the following parameters: helical mode, kV 120 – 140, mAs 120 – 140, and collimation 1 to 2.5 mm. The images are reconstructed in bone and soft tissue algorithms at 1.25-mm slices with 0.6-mm overlap. The reconstructed set in soft tissue algorithm is then sent to a workstation where volume- or surfaceshaded renderings and MIP are performed to generate a 3D model. These reconstructed data sets then are used for 3-mm bone and soft tissue reformats in the axial and coronal planes. If there is a history of hearing loss, the original data set may be reviewed at 1-mm intervals in bone algorithm, and windows in the axial and coronal planes and magnified for imaging of the temporal bones.

1052-5149/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1052-5149(03)00061-3

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Two-dimensional techniques CT provides the ability to re-image an axially acquired data set in other 2D planes through the postprocessing tool of mutliplanar reformats. Reformats do not alter the individual CT voxels but simply change the display of the original data in different orientations. The acquisition parameters that most affect the quality of reformats are slice section thickness and slice interval. Pitch has a less significant effect, but higher pitches may degrade reformats secondary to artifacts such as zebra-type striping [7]. In general, the thinner the slices and the closer to isotropic voxel dimensions, the better the resolution of the reformatted images. For example, on conventional single-detector helical scanners, protocols using slice thickness greater than 3 mm may produce blurred reconstructions out of plane with a stepping artifact. With this relation in mind, multidetector CT scanners represent a further technical advance. Studies show that multidetector scanners offer shorter acquisition times, decrease in tube current load, and improved spatial resolution [8]. The rapidity of multidetector scanners may be useful in CF imaging, when often faced with the imaging of children, many of whom require sedation or are imaged postprandially without pharmacologic sedation. Although the increased radiation dose with multidetector scanners, compared with single-detector scanners, in highquality mode remains a concern, the improvement in reformats essentially obviates rescanning the pa-

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tient in a second coronal plane [8]. Several reports highlight the general usefulness of 2D reformats in neuro- and body imaging [7,9,10]. The usefulness of reformats in CF imaging depends on the specific indication for the scan and type of CF abnormality; however, in certain instances, such as CF malformations involving the temporal bones or skull base, the addition of high-quality reformats provides distinct advantages. For example, coronal and oblique reformats are essential for evaluation of congenital aural dysplasias, which may be components of many CF malformations, such as hemifacial microsomia (HFM). Sagittal reformats may be helpful in craniometric evaluation of the skull base in patients with syndromic craniosynostosis. Three-dimensional techniques Volumetric visualization techniques include 3D surface- or volume-rendered reconstructions and MIP. 3D reconstruction is a well-established technique that provides volumetric views of the anatomy that quickly summarize the relationship among structures. There are two methods of volume reconstruction in routine clinical use: volume rendering and surface rendering. In volume rendering, the entire data set is maintained; however, the various voxels are assigned levels of transparency or color according to the organ system and indication. A spherical, orthogonal, or arbitrary user-defined ‘‘clipping volume’’ may be employed, in which voxels outside the

Fig. 1. Craniofacial development. (A) Scanning electron micrograph (SEM) of a 10-day-old mouse embryo (human age 29 days). The neural tube (white outline), somites (ovals), pharyngeal arches, and neural crest cell migration are depicted schematically. After closure of the anterior neuropore at 24 days’ gestation, the cranial neural tube undergoes segmentation: the three most cranial segments are termed neuromeres: N1 corresponds to the prosencephalon; N2 and N3, to the mesencephalon. The eight following segments are termed rhombomeres, R1 – 8, and comprise the rhombencephalon. At 19 to 21 days’ gestation, the paraxial mesoderm condenses around the neural tube into cuboidal bodies, termed somites. The seven most rostral somites are less well defined and are termed somitomeres (dashed ovals). By 29 days’ gestation, the four pharyngeal arches have appeared as surface elevations along the primitive oral cavity and pharynx. MxP, the maxillary prominence and MnP, the mandibular prominence, comprise the first pharyngeal arch. The second (II), third (III), and fourth (IV) pharyngeal arches may be seen at this age. Neural crest cells form from surface ectoderm at the dorsal crests of the neural tube. There is an anatomic registration between the segments of the neural tube and neural crest cell migration giving rise to the craniofacial primordia, depicted here as migrational streams (arrows). Neural crest cell migration from N1, N2, and N3 (dashed white converging arrows) gives rise to the cranial vault and calvaria (membranous neurocranium). Neural crest cell migration from the rhombomeres (black arrows) heralds the formation of the pharyngeal arches and gives rise to formation of the viscerocranium (face, jaws, middle ears). The cranial base (cartilaginous neurocranium) originates from the paraxial mesoderm (converging gray arrows). (B) SEM of human embryo at 5 weeks’ gestation shows the midfacial primordia: frontonasal prominence (FNP), medial nasal prominence (m), lateral nasal prominence (l), maxillary (MxP), and mandibular (MnP) prominences of the first pharyngeal arch. The second pharyngeal arch (PA2) is seen. (C) SEM of developing face of human embryo at 6 weeks’ gestation shows fusion of the medial prominence of the nasal placode with the maxillary prominence of the first pharyngeal arch to form the upper lip. (D) SEM of the developing palate in 12-day mouse embryo (human age 7 weeks) shows derivation of the primary palate (P1) from the medial nasal prominence and growth of the secondary palate (P2) from the maxillary prominence. (Courtesy of K. Sulik, Chapel Hill, NC.)

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region of interest are rendered invisible [7]. In surface rendering, a threshold houndsfield attenuation is applied above or below which data are discarded, leaving only a surface model defined by voxels at the selected threshold. These data may be filtered or augmented. Thresholding, however, may be problematic and portions of the object of interest may be unwittingly discarded secondary to partial volume effects [7]. 3D reconstructions are employed routinely in the evaluation of patients with CF malformations and trauma [2]. Many reports highlight the usefulness of 3D CT, suggesting improvements in diagnosis and presurgical planning, including decreased operative time and costs and decreased risk of operative complications for the patient [2,11 – 13]. Recent studies have focused on the cost effectiveness of 3D CT. Medina et al suggest that 3D CT is cost-effective in terms of quality-adjusted life years (QALY) in evaluating children with a family history or clinical findings of craniosynostosis. For healthy children with isolated head deformities, radiography was found to be a more cost-effective method [14]. Cerovac et al reported minimal usefulness of 3D CT in the diagnosis of and presurgical planning for patients with nonsyndromic craniosynostosis [15]. MIP reconstruction is a volumetric technique in which a viewing line or ray is first established by the operator from a selected perspective. Only voxels of maximum value are retained and displayed along this ray by the computer [7]. This postprocessing technique usually results in the display of high-attenuation values, such as bone- or contrast-enhanced vessels. In CF imaging, MIP may be useful in the evaluation of craniosynostosis: it may clarify equivocal findings on plain film radiography and may display more anatomic detail within the sutures compared with other postprocessing techniques, such as volume- or surface-rendered 3D reconstructions [16].

Embryology and genetics A basic understanding of CF development is essential to a discussion of the imaging of CF malformations. This understanding may be couched

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in traditional morphologic descriptions of the embryology of the neurocranium and pharyngeal (branchial) arches. Gastrulation, the formation of the trilaminar embryo, composed of ectoderm, mesoderm, and endoderm, marks the beginning of morphogenesis at 15 to 16 days’ gestation [17]. The notochord develops at 18 days and induces the development of the neural tube and neural crest at 19 to 21 days [18]. Neural crest migration is believed to induce pharyngeal arch formation (Fig. 1). By 28 days, four well-defined pairs of pharyngeal arches are present in the human embryo [17,19]. Development of the face derives from the maxillary and mandibular prominences of the first pharyngeal arch and the frontonasal prominence that develops along the ventrolateral forebrain. The nasal placode appears within the frontonasal prominence at approximately 28 days’ gestation and gives rise to the medial and lateral nasal prominences (or processes) [17]. The paired medial nasal prominences enlarge and, during the sixth week, fuse in the midline to form the premaxilla (the philtrum of the lip, columella, tip, and cartilaginous septum of the nose and the bone around the four maxillary incisors). The maxillary processes enlarge and migrate medially and ventrally to form the lateral aspects of the upper lip and the maxillae and zygomae [17,20]. Development of the palate occurs from the sixth to twelfth gestational weeks, during which time the primary palate (from the medial nasal prominences) and the secondary palate (palatine processes of the maxillary prominences) fuse (Fig. 1D) [17]. Advances in molecular genetics have led to a deeper understanding of the complex molecular events underlying the embryologic steps in CF development. This vast literature may be highlighted by a brief description of the muscle segment homeobox (MS) and paired box (PAX) gene families that exemplify the role of patterning genes involved in CF morphogenesis. These gene families were identified in vertebrates, based on homology with the Drosophila melanogaster genome. The three genes in the MSX gene family (MSX 1 – 3) each contain a common DNA sequence called the homeobox that encodes a 60 amino acid DNA-binding domain, the homeodomain. The nine genes in the PAX gene family (PAX 1 – 9) each

Fig. 2. Nonsyndromic sagittal synostosis in 12-month-old boy. (A) Axial CT shows fused sagittal suture posteriorly (long white arrow), fused metopic suture anteriorly (white arrowhead), and patent coronal sutures (short white arrows). (B) 2D sagittal reformat shows dolicocephalic configuration of the cranium and approximate plane of axial slice in A (white line). (C) 3D volume rendered and (D) 3D MIP reconstructions of the cranial vertex demonstrate complete fusion of the mid and posterior aspect of the sagittal suture (black arrows). (Courtesy of P. Ellen Grant, MD, Boston, MA.)

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contain a common DNA sequence called the paired box that encodes a 128 amino acid DNA-binding domain, the paired domain. These gene families encode transcription factors that regulate the expression of downstream target genes, which in turn guide

normal development of the face and cranium [21]. Studies have shown that certain MSX gene mutations in mice result in phenotypic CF malformations, such as cleft palate, brachycephaly, and abnormal dentition [21,22].

Fig. 3. Complex bilateral coronal and sagittal synostosis in 4-month-old boy. (A) Shows usefulness of 2D CT sagittal reformat for craniometric evaluation. The Welcher basal angle is enlarged (155
) consistent with platybasia. The clivus-canal angle is abnormally acute (110
). The frontal contour is flattened and there are several lacunar impressions along the calvaria (black arrows in A, B). (B) Axial CT shows patency of coronal sutures (arrowheads) at this level. The sagittal suture (s) is closed. (C) Oblique maximum intensity projection (MIP) demonstrates the coronal suture (short black arrows), which appears patent inferiorly and the patent lambdoid suture (small long arrows). Multiple large calvarial lacunes are noted where protruded dura was found surgically. (D) Apicoposterior volume rendered view. The superior aspect of the lamboid sutures is not well defined. (E) 3D MIP with removal of the skull base data. This technique clarifies the findings of synostosis of the mid and posterior aspects of the sagittal suture (s), fusion of the superior aspects of the coronal sutures (black arrows) and patent lambdoid sutures (L). (F) Postoperative 3D volume rendered image of the cranial vertex shows improvement in the frontal contour and calvarial closure. (Courtesy of W. Butler, MD, and P. Ellen Grant, MD, Boston, MA.)

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Craniofacial malformations

Craniosynostosis

Classification

Nonsyndromic craniosynostosis The incidence of nonsyndromic craniosynostosis is estimated at between 1 per 1700 and 1 per 2500 live births [25,26]. The majority of craniosynostoses are nonsyndromic (85%) and the remainder is associated with other anomalies and are syndromic (15%) [27]. The most common type is nonsyndromic sagittal synostosis, which accounts for 40% to 60% of craniosynostoses (Fig. 2) [28,29]. Coronal synostosis (15% – 30% of cases [25,30,31]) is the second most common type: 47% are unilateral nonsyndromic, 9% bilateral nonsyndromic, and 34% bilateral syndromic [32]. Up to 75% of cases of bilateral coronal synostoses may be syndromic [6]. Metopic synostosis occurs less frequently, with a reported incidence of 1 per 2500 to 1 per 15,000 births [33,34]; 8% to 15% of patients have associated anomalies [33,34]. CT plays several roles in the diagnosis and treatment of patients with craniosynostosis. CT is a well-accepted modality for determining the extent of synostosis and the effect on the underlying brain (eg, frontal lobes in metopic synostosis) and for postoperative follow-up (Fig. 3) [34,35]. In patients with nonsyndromic sagittal or coronal synostosis, however, plain film radiography may be sufficient for

Developments in the genetics of CF development have prompted reassessment of traditional classification schemes and the relationship between phenotypically defined CF malformations [23]. There are many classification systems for CF deformities that are either predominantly morphologic, based on clinical descriptions of patterns of dysmorphism, or etiologic, based on the known or suspected causes of CF malformations, whether teratogenic, chromosomal, or genetic. The desideratum of a comprehensive classification scheme accounting for the new genetic nomenclature yet preserving clinical and phenotypic distinctions may be problematic. In certain cases, for example, the same mutation may result in two phenotypically distinct syndromes: Crouzon’s syndrome and Pfeiffer’s syndrome both may result from an FGFR2, Cys278Phe mutation [23]. Separate mutations, conversely, may result in the same phenotype: Pfeiffer’s syndrome may be caused by a Pro252Arg mutation of FGFR1 or a Thr341Pro substitution on FGFR2; there are several mutations also for Crouzon’s syndrome on FGFR2 [23]. In this article, the classification system from Gorlin et al [24] is employed.

Fig. 3 (continued).

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diagnosis, and debate continues as to the specific indications for CT and 3D CT in these patients. Gellad et al reviewed 103 cranial sutures with pathologic or surgical correlation in 36 patients and found that CT was more accurate (94%) than skull radio-

graphs (89%) in the evaluation of sutural synostosis [36]. More recently, Medina et al shown that MIP reconstructions may have a lower false-positive rate than shaded surface rendering displays [16]. If the clinical or plain film radiographic assessment is

Fig. 4. Deformational plagiocephaly in a 3-month-old boy. (A) Axial CT image shows left occipital plagiocephaly. The lambdoid sutures (black arrows) appear anatomically patent. The auricle (a) is anteriorly displaced and the cranium roughly describes the shape of a parallelogram. These findings suggest positional molding rather than unilambdoid synostosis. (B) In the volume rendered image, however, patency of the left lambdoid suture (black arrows) is difficult to confirm. (C, D) Posterior and oblique MIP images clearly demonstrate sutural patency (black arrows). (Courtesy of P. Ellen Grant, MD, Boston, MA.)

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indeterminate with regard to diagnosis, CT imaging with 3D reconstructions is indicated. This situation can occur in posterior plagiocephaly where it may be difficult to distinguish deformational (nonsynostotic) plagiocephaly from unilambdoid synostosis (Fig. 4) [37]. CT also may be used for presurgical planning, establishment of a presurgical baseline, and postoperative follow-up. Syndromic craniosynostosis More than 90 craniosynostotic syndromes have been described, including Crouzon’s, Apert’s, Pfeiffer’s, FGFR3-associated Pro250Arg (Muenke) type, Saethre-Chotzen’s, and Carpenter’s [24,38]. Since the identification of the MSX2 gene in a family with Boston-type craniosynostosis in 1993, many mutations in six different genes involving more than a dozen craniosynostotic syndromes have been identified [39 – 51]. The fibroblast growth factor receptor genes (FGFR1, FGFR2, and FGFR 3) and TWIST gene mutations account for the majority of cases identified to date, and among these, mutations of FGFR 2 gene on 10q26 are the most frequent [52]. The FGFR genes (FGFR 1 – 4) are a family of genes that encode the major signal transduction-binding proteins for the fibroblast growth factors (FGFs 1 – 23) [52 – 54]. Recent work suggests a role for FGFR2 in promoting osteoblast stem-cell proliferation and a role for FGFR1 in osteogenic differentiation in the cranial sutures [55,56]. Mutations leading to an imbalance in expression of the FGFR genes may result in accelerated differentiation of the ostoblast precursors at the expense of proliferation along the sutures (ie, premature closure of the sutures) [55,56]. Apert’s syndrome Apert’s syndrome is a rare condition with an estimated incidence of 1 to 15 per 1,000,000 live births characterized by bicoronal craniosynostosis, midface hypoplasia, and syndactyly of the fingers and toes [57 – 59]. Ser252Trp and Pro253Arg mutations on the FGFR2 gene account for the majority of cases, and, although most cases are sporadic, autosomal dominant, transmission is reported [27,38,47,58,60]. The CF abnormalities include a gaping midline calvarial defect that runs from the glabela to the posterior fontanelle along the widened metopic and sagittal sutures [38,59,61] and may contain islands of bone. There is bilateral coronal synostosis with flattening of the forehead and turribrachycephaly (Fig. 5) [38,59,61]. The cranial base is malformed with a shortened clivus and diminutive anterior cranial fossa [38,59,61]. Central nervous system abnormalities, including Chiari I malformations, malformations of

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the corpus callosum and of cortical development, and ventriculomegaly, are reported [62]. Ocular deformities include hypertelorism with prolapsed ethmoids, downward-slanting palpebrae, and shallow orbits with exorbitism [63]. The midface is retruded with thickened maxillary alveolar processes, a V-shaped palate with dental crowding, and class III malocclusion with anterior open bite [63,64]. Cleft palate (30%) and choanal stenosis may be present [38,63]. Otitis media is common because of eustachian tube dysfunction related to cleft palate; the ears may be low set; and stapes fixation has been reported [38,63]. Syndactyly of the hands and feet is a characteristic feature, and, although a range of abnormalities is described, a digital hand mass involving fusion of the second, third, and fourth fingers is a nearly constant feature [65].

Crouzon’s syndrome Crouzon’s syndrome occurs in 15 to 16 per 1,000,000 live births [66] and is characterized by coronal synostosis, midface hypoplasia, and ocular proptosis [66,67]. Although most cases of Crouzon’s syndrome are sporadic, autosomal dominant transmission is reported [68,69]. More than 30 mutations for Crouzon’s syndrome have been identified involving the IgIII region of the FGFR 2 gene [46]. This same region contains many mutations that cause Pfeiffer’s syndrome and certain mutations, such as Cys278Phe, may cause either phenotype [23]. The overlap of the mutational spectra for these two syndromes reflects a gradation in phenotype and underlies the nosologic conundrum of assigning eponyms to certain patients (Fig. 6) [52]. Brachycephaly (bilateral coronal synostosis) is seen most often in patients with Crouzon’s syndrome, but various sutures or combinations of sutures may close prematurely and lead to turribrachycephaly, scaphocephaly, trigonocephaly, or Kleeblattschadel [24,67,70]. Ocular proptosis resulting from shallow bony orbits and hypertelorism is characteristic [67]. There may be optic atrophy, exotropia, visual loss, and blindness [24,70]. Cleft palate is seen less frequently in Crouzon’s syndrome than in Apert’s syndrome [67]. The midface is hypoplastic with constriction of the maxilla, a high-arched palate, and dental crowding [67]. Conductive hearing loss, external auditory canal atresia, and cervical vertebral fusions may occur. Syndactyly is not seen, another distinguishing feature from Apert’s syndrome [67,71]. Hydrocephalus, Chiari I malformations, and jugular foramen stenosis with venous obstruction may occur [3 – 5,72].

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Fig. 5. Apert’s syndrome. (A) 3D surface rendering shows turribrachycephaly, steep, flat forehead, harlequin configuration of the orbit from coronal synostosis, gaping anterior fontanelle and widened metopic suture. (B) Axial CT demonstrates hypertelorism and exorbitism with frontalization of the sphenoid wings and mild ballooning of the ethmoids. (C) 2D sagittal reformat demonstrates diminutive crowded posterior fossa and ventriculomegaly. (D – F) are from another patient. (D) 3D surface rendering shows midfacial retrusion, class III malocclusion (the lower arch is anterior to the upper arch), and pseudoprognathism. (E) 2D coronal reformat shows the V-shaped high-arched palate (p), bulging alveolar ridge, and dental crowding. (F) Radiographs of the feet show syndactyly.

Anomalies of the first and second pharyngeal arch CT is helpful in the evaluation and presurgical planning for patients with first and second pharyngeal arch disorders [73,74]. 2D CT is useful for

cephalometric assessment, and 3D CT can be used to summarize the major structural abnormalities of the CF skeleton, including the temporal bone anomalies responsible for hearing loss in these patients [75 – 78].

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Fig. 5 (continued).

Hemifacial microsomia HFM is the second most common facial birth defect after cleft lip and palate, with an incidence of 1 per 5600 live births [79]. The many terms used for this disorder—oculo-auricular-vertebral spectrum, facio-auriculo-vertebral dysplasia, first arch syndrome, lateral facial dysplasia, and otomandibular dysostosis—highlight its phenotypic complexity and heterogeneity and the lack of consensus regarding the minimum diagnostic criteria. Some investigators describe the principal clinical manifestations as facial asymmetry with deviation of the chin toward the affected side and ear anomalies [80 – 82]. The OMENS (orbit, mandible, ear, cranial nerve, and soft tissues) classification system, proposed by Vento et al, grades the severity of each of the five major CF manifestations of HFM [83]. Goldenhar’s syndrome is considered a variant within the HFM spectrum and is characterized by the additional findings of vertebral anomalies and epibulbar dermoids [79,84]. Facial asymmetry is a constant finding and 10% to 33% of patients have bilateral (asymmetric) involvement [24]. Clinical and radiographic features include hypoplasia of the mandible, maxilla, temporal bones, and soft tissues; orbital hypoplasia and/or distopia; ear anomalies ranging from anotia to mild deformities; cranial nerve paresis/paralysis; skeletal (vertebral), cardiac, and renal anomalies [24,81,83].

Several theories regarding the pathogenesis of HFM have been advanced, including vascular disruption of the stapedial artery in the developing embryo and abnormalities in neural crest cell migration in the first and second pharyngeal arches [85,86]. CT plays a role in the diagnosis and management of patients with HFM, because it reliably depicts the degree of CF skeletal and soft-tissue hypoplasia (Figs. 7, 8). Rahbar et al found CT useful in the characterization middle ear deformities in patients with HFM [78]. In a series of 155 patients with HFM, Padwa et al found 15 (9.7%) displaying features of frontal plagiocephaly, although 93% of these patients were determined on clinical grounds to have deformational plagiocephaly, CT may aid in confirming the clinical impression or clarifying the rare case of true craniosynostosis [87].

Treacher Collins syndrome (mandibulofacial dysostosis) Treacher Collins syndrome (TCS) is an autosomal dominant CF malformation with a reported incidence between 1 per 10,000 to 1 per 50,000 live births [88,89]. The gene for TCS, TCOF1, has been mapped to 5q32-33.1 and found to encode a putative nucleolar phosphoprotein [90 – 95]. Genetic studies reveal at least 52 different mutations in the coding region of the gene, but clear genotype-phenotype correlations

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Fig. 6. (A, B) Anteroposterior (AP) and lateral photographs of a patient with FGFR2 (Ser354Cys[exon9]) point mutation (Pfeiffer’s Syndrome, Pfeiffer – Crouzon’s Spectrum) that demonstrates midface retrusion, relative mandibular prognathism, and mild exorbitism. (C, D) AP and lateral surface renderings show maxillary hypoplasia and downward-slanting shallow orbits. A ventricular shunt catheter (s) is present. (D – F) Axial CT images, demonstrate the maxillary hypoplasia (black arrowheads) and characteristic shallow orbits.

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Fig. 6 (continued).

have not been published [96 – 99]. Various explanations are offered regarding the pathogenesis of TCS, including abnormal differentiation of pharyngeal arch mesoderm, derangement in ossification of the viscerocranium, ischemia from hypoplasia of the stapedial artery, or defect of ectomesenchymal cells within the developing trigeminal ganglia [24,74, 100 – 102]. Hypoplasia, or deficiency of the zygoma, is considered by some investigators to be the central event of TCS [24,74,103]. Patients with TCS have mandibular retrognathia, microgenia, steep occlusal and mandibular planes with an anterior to posterior face height discrepancy, an obtuse mandibular angle, and a characteristic concave antigonial notch [24,74,104 – 106]. The maxilla is deficient in width and posterior height but the dentoalveolus actually is protrusive and overprojected [74]. Cleft palate is seen in 35% of patients [107]. The palpebral fissures are downward slanting (89%), and coloboma (69%) and absence of the eyelashes in the medial two thirds of the lower lid are common findings [104 – 106]. The nose may appear large against the background of hypoplastic malar bones and supraorbital ridges [24]. Anomalies of the temporal bone and ossicles of the inner ear [75,77, 108] and external ear (77%) are frequent (Fig. 9) [104 – 106]. Nager syndrome (acrofacial dysostosis) Nager syndrome is a rare disorder [24] characterized by CF anomalies similar to those of TCS but with additional acral skeletal deformities that involve the radial aspect of the upper limb and the tibial

aspect of the lower limb [24]. Both autosomal dominant and autosomal recessive inheritance have been suggested [84,104] and cases reported with abnormalities of chromosomes 1 and 9 [109 – 111]; ZFP-37 has been proposed as a candidate gene [112]. On imaging, the CF abnormalities are similar to those of TCS [24]. The mandible, maxilla, and zygoma are hypoplastic and there is associated cleft palate (more than 60%), missing teeth, and downward-slanting palpebral fissures [24,113,114]. Temporal bone abnormalities are common, including auricular dysplasia (80%), external auditory canal atresia, and ossicular dysplasia (Fig.10) [114,115]. Radial anomalies include thumb hypoplasia or aplasia and radioulnar synostosis. Abnormalities of the lower limb occasionally may be seen, including talipes, duplication of proximal hallucal phalanx, and, more rarely, absence of tibia and fibula [24]. 3D volume renderings summarize the axial data set in several concise projections that may be more familiar to the surgeon. 3D data sets may be useful for preoperative surgical simulations [116]. The volume CT data set may, moreover, be converted into an actual hand-held physical model. Serial section CT (or MR imaging) data may be converted by several processes, such as stereolithography or fused deposition modeling, to produce a plastic model of the volume image data set (Fig.10G – I). Orofacial clefts Orofacial clefts involve osseous and soft tissues of the CF region; there is wide variability in location and

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Fig. 7. Two patients with hemifacial microsomia. (A, B) AP and oblique surface renderings show left mandibular hypoplasia, deviation of the chin to the affected side, maxillary hypoplasia with deformity of the left alveolar arch, and zygomatic hypoplasia with incomplete arch. (C, D) Axial CT images show cleft of the left dentoalveolus and palate and right occipital plagiocephaly. (E) Surface rendering and (F) axial CT from another patient show right mandibular and maxillary hypoplasia with right aural dysplasia.

severity of clefts. They may be unilateral or bilateral, associated with other anomalies (syndromic) or isolated (nonsyndromic). They may be paramedian, median, or lateral. Epidemiology Orofacial clefts are among the most common congenital facial anomalies. Cleft lip with or without cleft palate [CL(P)] represents the majority of orofa-

cial clefts, accounting for 98.8% of all clefts in a series of 3988 patients reviewed by Fogh-Andersen [117]. Estimates of incidence vary by race and cleft type. Within the white population, the incidence of CL(P) is 1 per 1000, with a higher incidence in Native Americans (3.6/1000) and a lower incidence in African Americans (0.3/1000) [24,118,119]. CP, considered a separate entity from CL(P), has an estimated incidence of 0.4 per 1000 live births [117,120]. Approx-

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Fig. 7 (continued).

imately 60% of all cases of CL(P) are nonsyndromic; however, over 300 syndromes have orofacial clefts as a feature [121]. Developmental models There are two models for the development of facial clefts. The classic model suggests that facial clefts result from a disturbance in the normal fusion of the facial primordia [eg, failure of fusion of the medial nasal processes with the maxillary prominence results in CL(P)] [20]. The mesodermal migration model proposes that a disturbance in neural crest migration is the principal cause [20,122]. Neural crest cells migrate from along the dorsolateral neural tube ventrally to supplement the mesoderm of the frontonasal prominence and the pharyngeal arches. Disturbance in this migration depletes the mesenchyme of the facial primordia and may lead to clefting. More recent work on the molecular events underlying facial morphogenesis has identified several key factors that guide forebrain and CF development. The forebrain and media nasal prominences arise from a continuous cell sheet, which undergoes partitioning but retains similar molecular signaling pathways [123]. Sonic hedgehog (SHH) is a gene first expressed in the mesendoderm during gastrulation [124 – 126]. It plays a role in ventral forebrain patterning. Mutations in SHH cause holoprosencephaly (HPE), a

disorder associated with midline facial deformities [125,126]. Some SHH mutants develop cyclopia, believed to result from failure of SHH to regulate the PAX6 gene, a gene expressed in eye development [124]. Mutations in SHH truncate development of the forebrain and the facial primordia resulting in HPE, midline clefts, and hypotelorism [127]. Overexpression of SHH conversely leads to an expansion of the frontonasal prominence resulting in hypertelorism [127]. SHH thus highlights the intimate relationship between forebrain and facial development. Retinoic acid, transforming growth factor (TGF)-a, transforming growth factor-b, and epidermal growth factor receptor (EGFR) are other genes implicated in CF morphogenesis [128,129]. Several genes have been identified in patients with nonsyndromic CL(P): OFC1 on chromosome 6p23, OFC2 on chromosome 2p13, and OFC3 on chromosome 19q13.2. The gene product for OFC2 is TGF-a, a ligand for EGFR, which participates in fusion of the palate [130]. Classification Many classification systems for orofacial clefts have been proposed, including Tessier, HarkinsAmerican Association of Cleft Palate Rehabilitation, Karfik, Van der Meulen, DeMyer, and Sedano [131 – 138]. The Tessier system is anatomic, descrip-

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Fig. 8. Patient with mild form of hemifacial microsomia. (A) Surface rendering of the facies demonstrates subtle left facial hypoplasia. (B) Axial CT and (C) coronal 2D reformat show mild left maxillary hypoplasia. The AP dimension of the left zygomatic arch is diminished. The left temporomandibular joint is more anterior in position. There is mild left maxillary hypoplasia with a cant of the palate on the affected side. (D) Axial CT demonstrates the left mandibular hypoplasia. (E) 2D coronal reformat shows hypoplasia of the left temporalis and masseter (*) muscles. (F, G) Surface renderings summarize the osseous findings.

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Fig. 8 (continued).

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tive, avoids etiologic assignments, and relates the superficial soft tissue clefts to underlying osseous abnormalities. Clefts are numbered from 0 to 14 in a counterclockwise fashion from the labia to the frontal region. The Tessier system is followed here (Fig. 11). Common cleft lip and palate If treated by an interdisciplinary team, patients with CL(P) should have few residua of their initial deformity. Patients with labial clefts can develop midfacial hypoplasia in the vertical, transverse, and sagittal planes with a resulting class III malocclusion, overclosed mandible (pseudoprognathism), and crossbite. Occasionally, patients have hypernasal speech as a result of a short or scarred soft palate and hearing loss secondary to eustachian tube dysfunction. The nasal ala is hypoplastic and displaced off the upper lateral cartilage and the nasal septum is deflected toward the cleft side [139]. Tessier clefts Each Tessier type cleft has distinct soft tissue and osseous features and imaging must be tailored to the type of cleft and specific request of the referring clinician. No. 0 and No. 14 Tessier clefts The No. 0 Tessier cleft represents a median CF dysraphia, characterized by midline deficiency as in the HPE spectrum or by midline widening as in frontonasal dysplasia (FND). No. 14 Tessier cleft is the cranial prolongation of the No. 0 cleft. In such cases, consideration should be given to imaging of the brain, possibly by MR imaging, in addition to CT of the CF region. Frontonasal dysplasia Failure of fusion of the two paired medial nasofrontal processes is believed to underlie the midline facial cleft syndrome or FND, characterized by midline cleft lip and palate, hypertelorism, cranium bifidum occultum (large midline cranial dehiscence), and basal cephaloceles (Fig.12) [117, 139] Several investigators report the association between FND and central nervous system and ocular

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anomalies [140 – 143]. The Sedano and DeMyer classification systems have been developed for this group of CF malformations [131,133]. The Sedano system divides FND into four types, A through D. In a review of 11 children with Sedano facies types A, B, and D, Naidich et al find intracranial calcifications (55%) and lipoma (45%) in types B and D patients and suggests that these Sedano types should be imaged for intracranial abnormalities [140]. The Type B group may be further divided into a low group with the cleft involving the upper lip and palate and a high group with the cleft involving the nose and frontal bones. Holoprosencephaly spectrum Deficiency of the frontonasal and medial nasal prominences may occur in the setting of a field defect in ventral forebrain patterning and result in the HPE CF phenotype. A spectrum of midline abnormalities may be seen, including hypoplasia or absence of the nose, premaxilla and secondary palate, maxillary incisor teeth, defect in the mid portion of the upper lip, and hypotelorism (Fig.13) [126,127, 129,139,144]. DeMyer et al [132,145] and Elias et al [134] describe the range of CF deformities in the HPE spectrum. No. 3 and No. 4 Tessier clefts (oblique clefts) The No. 3 and No. 4 Tessier clefts exemplify the oblique facial clefts. The No. 3 cleft involves the philtrum and floor of the nose and results in a vertical defect between the nasal ala and inferior palpebra (Fig.14). The No. 4 Tessier cleft courses from the upper lip to the inferior orbital rim, but spares the nose. The vertical distance between the inferior orbital rim and the mouth is decreased and there is associated orbital dystopia (Fig.15) [20] No. 7 Tessier cleft (macrostomia, lateral or transverse facial clefts) Macrostomia, is the most common of the rare CF clefts [117,146,147]. No. 7 Tessier clefts can occur in isolation or in association with HFM [24]. The incidence of isolated lateral facial cleft (macrosotomia) is

Fig. 9. Treacher Collins syndrome. (A, B) AP and lateral photographs of a patient with TCS demonstrate downward-sloping palpebral fissures, absence of the eyelashes on the medial two-thirds of the lower eyelid and mandibular retrograthia. (C) Oblique surface rendering shows hypoplasia of the zygoma (*), egg-shaped orbit with defective floor and lateral orbital wall, and incomplete zygomatic arch (arrow). (D) AP surface rendering shows maxillary hypoplasia. (E) Axial CT. The sphenoid wings constitute the entire lateral wall of the right orbit secondary to zygomatic hypoplasia. Note the underdeveloped mastoids and thick lateral walls of the hypoplastic tympanic cavities. ( F) Axial CT shows the protruded maxilla.

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Fig. 10. Nager syndrome. (A) AP photograph shows downward-slanting palpebral fissures, midfacial hypoplasia, retromicrognathia, and aural dysplasia. A tracheostomy tube is present. (B) AP and (C) oblique surface renderings demonstrate the deficiency of the lateral wall of the right orbit secondary to zygomatic hypoplasia. Note the maxillary hypoplasia, micrognathia with dysplastic ramus, and widened gonial angle (g). (D) 2D coronal reformat and (E) axial CT show gaping defect (*) of the inferolateral right orbit. The orbital process of the right zygoma is aplastic. The left side is more mildly involved. Note the palatal cleft (arrow). (F) Axial CT shows bilateral aural dysplasias. (G) Lateral photograph, (H) lateral surface rendering, and (I) lateral view of plastic model generated from the 3D CT data. This progression from patient to handheld physical model highlights this application of 3D CT to presurgical planning.

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Fig. 11. Tessier classification system of facial clefts. (A) Soft tissue and (B) bony clefts. (From Tessier P. Anatomic classification of facial, craniofacial and laterofacial clefts. J Max Fac Surg 1976:4:69; with permission.)

estimated at between 1 per 50,000 to 1 per 175,000 live births [117,146,147]. It is a soft tissue cleft coursing laterally from the oral commissure to the preauricular region [20]. As part of the HFM spectrum, it can be associated with an abnormally positioned temporomandibular joint; hypoplasia of the mandibular ramus, maxilla, and zygomatic arch; auricular malformations; absent parotid gland and duct; and paresis/hypoplasia of cranial nerves V and VII and their associated musculature [20].

Summary Because of its superior depiction of bone detail, CT is a useful tool in the characterization of CF

deformities and presurgical planning. Modern CT scanners and workstations provide 2D techniques such as multiplanar reformats and 3D techniques, such as MIP and volume renderings, which may be used effectively in the diagnosis and management of patients with CF malformations.

Acknowledgments The authors acknowledge Caroline Robson, MB, ChB, Department of Radiology, Children’s Hospital, Boston, for her support of the chapter, and Mr. Richard Cortese, Massachusettes Eye and Ear Infirmary, for his assistance in preparation of the images.

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Fig. 12. Frontonasal dysplasia. Surface rendering (A) and axial CT (B) show wide midline cranial defect involving the nasal and frontal bones (cranium bifidum occultum), hypertelorism, harlequin configuration of the left orbit, and wide nasal bridge. (C) Sagittal T1-weighted and (D) axial T2-weighted MR images demonstrate callosal hypoplasia and hypertelorism.

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Fig. 13. Midline facial cleft, holoprosencephaly spectrum. (A) Intraoral photograph; shows midline cleft of the dentoalveolus and missing central incisors. Axial CT images (B, C) show the mid alveolar osseous cleft. The secondary palate (derivative from the maxillary prominence of the first pharyngeal arch) is intact. (D) 3D surface rendering summarizes the osseous findings.

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Fig. 14. No. 3 Tessier cleft. (A) Photograph shows an oblique cleft involving the philtrum and inferior palpebra. There is dystopia of the medial canthus and a superior palpebral coloboma. The left alar base is drawn up superiorly. Series of axial CT images (B – E) demonstrates the oblique left paramedian cleft involving the dentoalveolus and palate extending into the nasal floor. Note the mandibular hypoplasia and external auditory canal atresia in this patient with associated hemifacial microsomia. (F) Surface rendering summarizes the osseous findings and clarifies the configuration of the cleft (small and large arrows).

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Fig. 14 (continued).

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Fig. 15. No. 4 Tessier cleft. (A) Photograph shows an oblique oro-ocular cleft involving the right lip, cheek, and lower eyelid. There is a decrease in the vertical distance between the lip and the inferior orbital rim. (B) Axial CT shows the cleft of the lip and maxillary alveolus. (C, D) AP and oblique surface renderings demonstrate the course and width of the osseous cleft (c).

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