Diagnosis and Surgical Options for Craniosynostosis

R. Tushar Jha , ... Robert F. Keating , in Principles of Neurological Surgery (Fourth Edition), 2018

Anatomic and Pathologic Considerations

Skull development can be divided into neurocranium and viscerocranium formation, a process starting between 23 and 26 days of gestation. Neurocranium growth leads to cranial vault development via membranous ossification, whereas viscerocranium expansion leads to facial bone formation by ossification. Cranial sutures form by 16 weeks' gestation at the junction of numerous osteogenic fronts and are particularly active areas of bone formation and deposition, directly affected by underlying tension forces of brain growth and dural reflections as well as local growth factors.

The calvarium grows most rapidly during the first 12 months, with the brain doubling in volume in the first 6 months and again by the second birthday. Although calvarial expansion is most pronounced during the first 2 years, growth continues in a linear fashion until the age of 6 to 7 years, at which time the cranium is 90% of the adult size. Most of this cranial growth takes place in the sutures between the bone plates. Within the center of the sutural area, a population of proliferating osteoprogenitor cells is maintained. A portion of these cells enters the pathway of osteogenic differentiation, forming bone-matrix-secreting osteoblasts at the bone edges and contributing to skull expansion. 54 Normal cranial suture closure occurs from front to back and from lateral to medial, with the metopic suture usually closing between 9 and 11 months of age 55 and the remaining sutures fusing in adulthood.

A disturbance in the balance between proliferation, differentiation, and apoptosis causes premature ossification within the suture and its synostosis. 56 Factors disturbing this balance include genetic or acquired changes in growth factor receptor/ligand profiles, loss of direct contact between dural and sutural cells, and increased external mechanical forces. As mentioned previously, many of the syndromic forms of craniosynostosis are attributed to alterations in the FGF/FGFR, TGF-β/TGF-βR, and BMP cascades. Both cerebral hypoplasia and overshunted hydrocephalus have been associated with secondary craniosynostosis, a phenomenon likely attributed to loss of dural contact. 55,57 Both breech positioning and twin pregnancies have been associated with intrauterine constraint-related craniosynostosis, stemming from mechanical force signal transduction. 58

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Antenatal Diagnosis of Congenital Structural Anomalies with Ultrasound

Greggory R. DeVore , John C. Hobbins , in Fetal Physiology and Medicine (Second Edition), 1984

Anencephaly

Anencephaly is a defect of cranial development involving the frontal, parietal, and occipital bones, with subsequent necrosis of the developing cerebral hemispheres. The etiology appears to be multifactorial, having both genetic and environmental components which affect the embryo between the sixteenth and twenty-sixth postconceptual day. The incidence varies from as high as 1 out of 105 births in South Wales to 1 out of 1000 births in other parts of the world (Brock, 1976). Fetuses die either in utero or shortly after birth.

The ultrasound diagnosis can be made as early as the fifteenth week of gestation when a poorly formed cranium is noted. Unfortunately, most cases of anencephaly elude diagnosis until the third trimester, when the clinician requests an ultrasound because of polyhydramnios (Figure. 10). At this time the cranial pole may lie deep within the pelvis, which makes ultrasonic evaluation difficult. In these patients a pelvic examination should be done to lift the cranial pole out of the pelvis, or an x-ray film should be taken for further evaluation.

Figure 10. Sagittal scan showing an anencephalic fetus with polyhydramnios.

 (From Berkowitz and Hobbins, 1982.) Copyright © 1982

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Fibroblast Growth Factor (FGF) and FGF Receptor Families in Bone

Marja M. Hurley , ... Pierre J. Marie , in Principles of Bone Biology (Third Edition), 2008

FGF receptors and human craniosynostosis

The important role of FGFRs during cranial development is supported by genetic evidence that FGFR mutations induce abnormal ossification of the cranial sutures (craniosynostosis) in humans (Lajeunie et al., 1999; Ornitz and Marie, 2002; Wilkie, 2005). Several mutations in FGFR 1 or FGFR2 induce craniofacial abnormalities, causing Apert, Crouzon, Pfeiffer, and Jackson-Weiss syndromes (Wilkie, 2005). Genetic analyses indicated that mutations in the Ig III domain or in the linker between the Ig II and Ig III domain of FGFR-1 and FGFR-2 induce constitutive activation of the receptor (Neilson and Friesel, 1995, 1996; Robertson et al., 1998; Plotnikov et al., 2000). In Crouzon syndrome, the C342Y mutation in FGFR-2 results in the activation of FGFR-2 signaling and decreased binding of FGF-2 to the receptor (Mangasarian et al., 1997). In Apert syndrome, FGFR-2 mutations enhance receptor occupancy by FGF ligands, prolongation of the duration of receptor signaling (Park et al., 1997; Anderson et al., 1998), enhancement of ligand binding (Ibrahami et al., 2001, 2004) or loss of ligand binding specificity to FGFR2 (Yu et al., 2000). A clue to the cellular and molecular mechanisms underlying the phenotype induced by FGFR genetic mutations came from studies in humans with FGFR2 mutations (Marie et al., 2002). FGFR-2 mutations in Apert syndrome accelerate subperiosteal osteogenic differentiation without affecting cell proliferation (Fragale et al., 1999; Lomri et al., 1998; Lemonnier et al.,2000; Tanimoto et al., 2004), a phenotype also found in human nonsyndromic craniosynostosis (DePollack et al 1996; Fragale et al., 1999). Apert mutations of FGFR-2 constitutively increase osteoblast marker genes in calvaria preosteoblasts in part through activation of PKC expression, phosphorylation and activity (Fragale et al., 1999; Lemonnier et al., 2000), resulting in increased N-cadherin–mediated cell-cell adhesion (Lemonnier et al., 2001a). The S252W Apert FGFR2 mutation also downregulates the expression and activity of Src family members Fyn and Lyn in human osteoblasts, which contributes to the premature differentiation phenotype (Kaabeche et al., 2004). This phenotype and underlying signaling mechanisms are consistent with the in vivo phenotype in fused cranial sutures in humans (Marie et al., 2002; Wilkie, 2005).

In mice, activating FGFR mutations induce variable phenotypes. In vitro analyses showed that activating FGFR2 mutations stimulate calvaria bone cell proliferation, but inhibit mineralization (Mansukhani et al., 2000; Ratisoontorn et al., 2003). In vivo, unchanged or increased osteoblast proliferation and differentiation were reported in mice expressing FGFR1 or FGFR2 mutations (Zhou et al., 2000; Chen et al., 2003). Also, activating Apert and Crouzon FGFR2 mutations increase cell proliferation and decrease osteoblast differentiation in mice (Mansukhani et al., 2005). However, conditional inactivation of FGFR2 affects the proliferation of osteoprogenitors, but not the differentiation, of mature osteoblasts in mice (Yu et al., 2003). Moreover, the cell phenotype induced by FGFR2 activation varies with the sutures examined (Wang et al., 2005). Although there are discrepancies in the phenotype induced by point mutations in mice and natural mutations in humans, which may relate to the distinct environmental factors or genetic background, the resulting effect is increased osteogenesis (Marie et al., 2002; Wilkie, 2005).

Several data suggest that the accelerated osteogenesis induced by activation of FGFR signaling may result in part from increased expression of Runx2. Activating FGFR1 and FGFR2 mutations, or a gain-of-function mutation in FGFR2c in the mouse causes premature osteoblast differentiation associated with increased expression of Runx2 (Zhou et al., 2000; Baroni et al., 2004; Eswarakumar et al., 2004). The P253R and S252W FGFR2 mutations were also found to increase Runx2 expression in human calvarial osteoblasts from Apert patients (Tanimoto et al., 2004; Baroni et al., 2005) and increased FGFR2 expression also correlates with Runx2 expression in human cranial osteoblasts (Guenou et al., 2005). Other transcription factors may however be involved downstream of FGFR signaling. For example, FGFR2 activating mutations increase Sox2 expression in murine osteoblasts (Mansukhani et al., 2005). Recent analysis of cell signaling in murine osteoblasts expressing Apert or Crouzon FGFR2 mutations revealed that activation of FGFR downregulates Wnt target genes (Mansukhani et al., 2005) suggesting that Wnt signaling may also be involved in the phenotype induced by FGFR2 activation. Although this may provide a molecular mechanism for the premature osteoblast differentiation and cranial suture ossification induced by FGFR2 signaling, the role of transcription factors or Wnt signaling in human syndromic craniosynostosis is unknown.

Another issue in FGFR signaling is the role of FGFR downregulation in the control of skeletal cells. Constitutive activation of FGFR2 in Apert syndrome accelerates FGFR downregulation in mutant osteoblasts in vitro and in vivo (Lemonnier et al., 2000), which is consistent with the decreased expression of FGFR-2 in Crouzon syndrome (Bresnick et al., 1995). The ubiquitin ligase Cbl was found to control FGFR1 degradation after ligand activation (Wong et al., 2002). Similarly, FGFR2 activation in Apert syndrome induces Cbl-mediated FGFR2 proteasome degradation, as well as Src protein downregulation, which results in increased expression of early markers of osteoblast differentiation (Kaabeche et al., 2004). Activated FGFR2 also shows increased binding to the adaptor protein FRS2 (Hatch et al., 2006), an important molecule involved in the negative feedback mechanism induced following FGFR stimulation (Eswarakumar et al., 2006). Uncoupling between the docking protein FRS2 alpha and activated Crouzon-like FGFR2c mutant results in normal skeletal development in mice (Eswarakumar et al., 2006). These studies emphasize the role of FRS2 alpha and Cbl in the attenuation of signals induced by FGFR activation. In marked contrast, activated FGFR3 in achondroplasia escapes Cbl-mediated ubiquitination and lysosomal degradation, resulting in amplification of the FGFR3 signal in the growth plate (Cho et al., 2004). The kinase activity of mutant FGFR3 affects receptor trafficking, resulting in increased signaling capacity (Lievens et al., 2005).

FGFR2 mutations also promote apoptosis in mature osteoblasts in vitro and in vivo. Constitutive activation of FGFR2 signaling by the C342Y Crouzon and the S252W Apert FGFR-2 mutations promote apoptosis in mouse or human cranial osteoblasts (Chen et al., 2003; Mansukhani et al., 2000; Lemonnier et al., 2001b; Kaabeche et al., 2005). The increased apoptosis in Apert osteoblasts is mediated by increased IL-1 and Fas expression, activation of caspase-8 and increased Bax/Bcl-2 levels (Lemonnier et al., 2001b). FGFR2 activation also results in Cbl-mediated alpha 5 integrin ubiquitination and degradation, which contributes to osteoblast apoptosis (Kaabeche et al., 2005). It is unclear whether the increased apoptosis is a cause or a consequence of the increased osteogenesis. The upregulation of apoptosis by constitutive FGF signaling may be a significant mechanism controlling osteoblast number and osteogenesis. Alternatively, apoptosis in mature osteoblasts may be a necessary event compensating for the accelerated osteoblast differentiation induced by FGFR2 signaling (Lemonnier et al., 2001b). Further studies are required to determine the precise role of apoptosis induced by FGFR signaling during cranial suture formation. Microarray analyses revealed that apoptotic genes are altered by FGFR2 activation in human (Lomri et al., 2001) and murine osteoblasts (Mansukhani et al., 2005), but it is not known whether these genes are involved in the observed phenotype.

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Prenatal Bone Development

BENOIT ST.-JACQUES , JILL A. HELMS , in Pediatric Bone, 2003

Embryonic Origin of Skull Cells

Largely due to technical limitations, studies of skull development are much better established in birds than in mammals. Avian data have therefore been used for extrapolation to mammalian skull origins, including the human skull. It is clear that in both birds and mammals, head mesenchyme originates from two principal sources—the cephalic (or cranial) neural crests and the cephalic paraxial mesoderm [ 48] (Fig. 4A). The neural crest is a transient pluripotent cell population that originates in the folds of the developing neural tube, between the future neural and epidermal ectoderm (Figs. 4B and 4C). As the neural tube develops, neural crest cells delaminate from the prospective dorsal neural tube, undergo an epithelial-to-mesenchymal transition, and migrate in a ventral and lateral direction following a precisely determined pattern both spatially and temporally [49] (Fig. 4D). This migration is rapid and in humans probably takes place between Days 19 and 38 after fertilization, a critical period during which many teratogenic agents can induce craniofacial malformations [47]. The mesenchyme formed by neural crest cells is designated ectomesenchyme to indicate its different embryonic origin (from the ectoderm). Crest cells appear along the entire length of the neural tube and differentiate into a large number of cell types, including neurons and glial cells, melanocytes, smooth muscle, and some endocrine cells. Only cephalic neural crest cells, however, have the additional capability of forming bone, cartilage, and odontoblasts, which are the dentine-secreting cells of the teeth [49]. The contribution of crest cells from different levels of the neural tube has been precisely mapped in cell lineage studies using short-term labeling techniques. Cells originating at the forebrain and midbrain levels will contribute to the frontonasal mass to give rise to all the connective tissue of the face. Cells originating at the level of the rhombomeres (the segmented divisions of the hindbrain) migrate according to their rhombomeric origin to populate the branchial arches and will give rise to all the skeletal elements of the dermal and chondral viscerocranium (Fig. 3C). Crest cells from the posterior midbrain and rhombomeres 1 and 2 populate the first pharyngeal arch (mandibular). Cells from rhombomeres 4 6, and 7 and 8 migrate within arches 2, 3, and 4–6, respectively [49].

FIGURE 4. Origins of skull cells and neural crest cell formation. (A) Dorsal view of the cephalic region of a four-somite chick embryo showing the regions contributing cells to the skull, including the neural folds (nf), in which neural crest cells originate, and the medial head mesoderm (hm, outlined in gray). np, neural plate; nt, neural tube; s, somites. (B) Diagram of tissue interactions leading to specification of the neural ectoderm borders. The neural plate (np) is light gray and the edges of the neural plate are dark gray. Signals emanate from the nonneural ectoderm (n-ne, the prospective epidermis), the node (no), and the paraxial mesoderm (pm). The nature of the ectodermal signal is not known. Signals from the other sources probably include some FGFs and induce Msx1 expression in a restricted domain. (C) Neural crest cell differentiation. Msx1 expression in the prospective neural crest region (nc) induces BMP4 expression and a positive regulatory loop is established to maintain expression of both factors in the nc region and specify the neural crest cell phenotype. n, notochord; ne, neural ectoderm. (D) Neural crest cell migration. Neural crest cells (ncc) delaminate from the edges of the neural ectoderm and migrate away from the closing neural tube (nt) in a ventrolateral pattern. n, notochord; se, surface ectoderm.

Although most of the cephalic mesoderm yields muscles, a detailed analysis of the contribution of cephalic mesoderm in the chick indicates that it also gives rise to the parachordal elements of the skull base. Thus, in the chick, the basipostsphenoid and orbitosphenoid, part of the otic capsule, and the supraoccipital derive from medial cephalic mesoderm [50]. Finally, as indicated previously, the bassioccipital has a different origin altogether, deriving in part from the somitic mesoderm of the occipital somites (paraxial mesoderm).

The origin of the skull vault remains controversial. Despite discrepancies in early experimental results [49], it is likely that the entire cranial vault in the chick is neural crest derived [50,51]. However, extrapolation of the results to mouse and human skull development must be regarded with caution. In rodent embryos, neural crest migration pathways at early stages were elucidated using dye injection techniques, but their contribution to mature structures could not be assessed. Recently, however, a transgenic mouse was engineered that has a permanent neural crest cell marker [52,53]. Analysis of neural crest contribution to different tissues in these animals generally confirmed observations in birds but also indicated that although the frontal and squamosal bones are neural crest derived, the parietal and interparietal bones are probably of mesodermal origin [54]. This interpretation is incorporated in the representation of the embryonic origin of the newborn skull elements depicted in Fig. 5. However, further studies in mammals will be required to confirm this interpretation.

FIGURE 5. Origins of the skull bones. The diagram represents the different bones of a human skull at birth. Embryonic origins of the skeletal elements are depicted by different shadings. Light gray, cephalic neural crest derived; dark gray, possibly medial head mesoderm derived; black, paraxial mesoderm derived (occipital somites).

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Otorhinolaryngology/maxillofacial disorders

Professor Crispian Scully CBE, MD, PhD, MDS, MRCS, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FRCPath, FMedSci, FHEA, FUCL, FBS, DSc, DChD, DMed (HC), Dr (hc) , in Scully's Medical Problems in Dentistry (Seventh Edition), 2014

Craniosynostoses

The premature fusion of certain skull bones (craniosynostosis) prevents normal skull growth, affects the shape of the head and face, and puts pressure on the developing brain. It is seen in Crouzon, Apert, Saethre–Chotzen and Pfeiffer syndromes and in Boston-type craniosynostosis (Ch. 37).

Crouzon syndrome

Crouzon syndrome is a rare genetic disorder characterized by abnormal skull growth with wide-set, bulging eyes (hypertelorism; proptosis) and visual problems caused by shallow eye sockets; eyes that do not point in the same direction (strabismus); a beaked nose; and an underdeveloped maxilla. In addition, there may be cleft lip and palate, dental problems and hearing loss, which is sometimes accompanied by narrow ear canals. People with Crouzon syndrome are usually of normal intelligence.

Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene cause Crouzon syndrome.

Apert craniofacial synostosis

Apert craniofacial synostosis is an autosomal dominant disorder, caused by mutations in the chromosome 10q26 gene encoding FGFR2. CP is associated more significantly with the S252W mutation.

Features include craniosynostosis, facial dysmorphology, hand and feet defects, and learning impairment.

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Craniosynostosis, Genetics of

A.O.M. Wilkie , in Brenner's Encyclopedia of Genetics (Second Edition), 2013

Classification of Craniosynostosis

Craniosynostosis affects about 1 in 2500 individuals and is a significant medical problem. Without surgical treatment, the consequent distortion of skull growth may lead to altered blood flow in the brain, raised intracranial pressure, and cosmetic deformity; in more complex cases, involvement of the facial skeleton may cause additional problems with vision, hearing, nasal breathing, and dental development.

Two methods of classification of craniosynostosis are used: anatomical and etiological (i.e., by cause). The anatomical classification identifies the fused cranial suture. There are six major sutures, comprising single metopic and sagittal sutures and paired coronal and lambdoid sutures ( Figure 1 ). Single suture synostosis most commonly involves the sagittal suture (45% of cases), followed by coronal (22%, including bilateral cases), metopic (22%), and lambdoid (5%). Multiple suture synostosis accounts for the remainder. Alternatively, an etiological classification emphasizes the primary cause of craniosynostosis. The two most common causes of craniosynostosis are restriction of fetal head movement during pregnancy and single gene disorders (syndromes) that predispose to suture fusion. These syndromes may often be recognized by their characteristic clinical features, particularly the combination of facial appearance and limb abnormality. Bilateral coronal and multiple suture synostosis occurs with disproportionate frequency in syndromic cases, whereas sagittal synostosis is underrepresented in this group. The following section summarizes the key diagnostic features of the common craniosynostosis syndromes.

Figure 1. Cranial sutures in the normal skull and in craniosynostosis. Left: Skull viewed from above showing the names and locations of the cranial sutures. Right: Alterations in the skull shape caused by sagittal synostosis (above) and bicoronal synostosis (below). The involved suture(s) is denoted by the thicker line.

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Growth and development of the craniofacial skeleton

Christopher L.B. Lavelle PhD, DSc, DDS, MRCPath, FRCD , in Applied Oral Physiology (Second Edition), 1988

Facial embryology 3, 4

There is a ten-fold increase in head size between the fourth to eighth week of gestation. This illustrates both the rapidity of cranial development at this period and accounts for the catastrophic consequences of maldevelopment that may be apparent at later stages of development.

The process of overt facial differentiation begins during the 3–4th week of gestation with dorsal neural crest tissue migration into the adjacent mesenchyme. The neural crest cells stream around the developing eyes to enter the anterior frontonasal process and posterior branchial arches. This neural crest mesenchymal invasion produces five embryonic facial processes: 5 the frontonasal process; bilateral maxillary processes and bilateral mandibular processes.

The ectodermal furrows between these processes are obliterated as they fill with proliferating mesenchyme and neural crest tissue. Impairment of neural crest cell migration, and/or mesenchymal growth, results in craniofacial anomalies associated with facial clefts. 5 Thus at the completion of neural crest cell migration in the fourth week of embryonic life, the cells contribute to almost all of the loose mesenchymal tissue in the facial region that later differentiates into skeletal and connective tissues, including the jaws and teeth ( Figure 17.1 ). Severe facial asymmetry in some patients may be related to unequal neural crest migration to each side of the face. Certainly diminished neural crest migration has been implicated in Treacher Collins syndrome (mandibulofacial dysostosis), where both maxilla and mandible are underdeveloped due to a generalized lack of mesenchymal tissue. It appears that the neural crest cells with the longest migration path are most susceptible to maldevelopment, whereas those going to the central area tend to complete their migratory movement. At this time, the main divisions of the central nervous system are established: the forebrain; the midbrain; the hindbrain and the spinal cord.

Figure 17.1. The layers of a cranial suture. 1, middle (cellular) zone; 2, capsular zone; 3, cambial zone; 4, edge of cranial bone

Invagination of the nasal placodes surrounded by the elevated medial and lateral nasal swellings dominates the face of the 5-week-old fetus. The eyes appear as elevations on the lateral face and the furrow between the two mandibular processes fills with mesenchyme, unifying the lower jaw and lip. Mandibular symphyseal clefts result from failure of this migratory proliferation. The first branchial groove, below the mandibular processes, also fills centrally with mesenchyme, the most lateral aspect becoming the external auditory meatus. In this regard, malformation or mal-location of the external auditory meatus often serves as a marker for craniofacial anomalies. At this time, the development of the nervous system proceeds with trifurcation of the forebrain into the median diencephalon and the paired hemispheres, as well as hindbrain segmentation into the myelencephalon and metencephalon.

In the sixth week, the oropharynx is opened with the rupture of the stomodeum. The medial nasal swellings merge into a single globular process, which in turn differentiates into the soft tissue nose, central upper lip and premaxilla. These structures comprise the primary palate, with cleft lip and/or palate reflecting their maldevelopment. The maxillary processes continue to enlarge and approach both medial and lateral nasal processes, with the furrow between the maxillary and nasal processes deepening to form the naso-optic groove and subsequent nasolacrimal duct. The relative mesial migration of the eyes and nares results from a reduced growth rate in the frontonasal process coupled with increased lateral head expansion. If these differential growth rates are disturbed, orbital hypertelorism (increased spacing between the eyes) may result. Facial clefting may reflect disordered medial and lateral nasal process fusion, mesencymal proliferation superficial to the nasolacrimal canal and lateral maxillary and mandibular process fusion. At this time, there is rapid expansion of the oral cavity, with the external auditory meatus assuming a posterolateral location.

By the eighth week of gestation, the face assumes more human characteristics. Subsequent changes include relative mesial migration of the eyes, formation of the eyelids, continued reduction of the oral opening, formation of the lips, enlargement of the cheeks and definition of the auricle and external auditory meatus. The eyelids fuse at 9–10 fetal weeks and reopen at 25–26 weeks. The nasal bridge develops at 8–12 weeks. From the end of the first trimester until term there is an absolute increase in the size of all body parts. There is, however, a general reduction in head prominence, with a reduction in the forehead/face ratio and a broadening of the middle and lower portions of the face. Craniofacial development is therefore complex, so that it is a marvel that craniofacial anomalies are not more frequent.

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The Craniofacial Region

Gillian Morriss-Kay , in Kaufman's Atlas of Mouse Development Supplement, 2016

Discussion

The new mouse cell lineage data described above were elucidated at the same time as new insights were achieved into the role of signaling systems in skull development and growth, and these two lines of inquiry have greatly informed each other. This work also coincided with the identification of the genetic defects underlying several human congenital abnormalities affecting craniofacial development and growth. Genetically modified mice have provided important model systems for understanding the developmental pathology involved.

Craniosynostosis is a good example of how these parallel advances have been mutually beneficial. It is a human condition in which one or more skull sutures fuse either prenatally or in infancy, or both, severely compromising the growth of the brain if left untreated. Many genetic defects underlying craniosynostosis have been identified. The genes most commonly involved are those encoding three of the fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3), the BHLH transcription factor TWIST1, and one of the genes involved in Eph–ephrin interactions, EFNB1 (see Johnson and Wilkie, 2011, for a recent review). Studies in the mouse have revealed the importance of all of these genes in sutural growth (Morriss-Kay and Wilkie, 2005 and references therein; Ting et al., 2009). Fgfr2 expression in osteogenic precursor cells is required for maintaining cell proliferation, whereas Fgfr1 is associated with differentiation and the expression of bone-specific proteins. Twist1 acts through Eph–ephrin interactions to regulate development of the boundary that forms the coronal suture.

Studies linking human syndromes with mouse experimental work continue to provide insights into the mechanisms underlying normal and abnormal craniofacial development. In particular, abnormalities in genetically modified mice that are genotypically and phenotypically equivalent to some of the human abnormalities have provided useful insights into the underlying mechanisms, for example, mouse models for Apert and Crouzon syndromes (Pro253Arg and Cys342Tyr mutations of Fgfr2, respectively) (Yin et al., 2008; Eswarakumar et al., 2004). Similarly, the importance of Twist1 has been demonstrated by the finding that loss of function of Tcf12 (TCF12), which encodes a BHLH partner of Twist1, causes coronal synostosis in both humans and mice (Sharma et al., 2013). Knockout and conditional knockout mice, together with reporter genes that allow long-term lineage tracing, continue to be major players in advancing our understanding of the normal and abnormal mechanisms of craniofacial development. The most useful web-based resources linking human phenotypes and experimental mouse studies are the mouse phenotypes and mutant alleles resource maintained by the Jackson laboratory (www.informatics.jax.org/phenotypes.shtml) and the Human Phenotype Ontology (HPO; http://www.human-phenotype-ontology.org/). These enable identification of the molecular links between genetic disorders and abnormal phenotypes, including those of the craniofacial region, in humans and in appropriate transgenic mouse models.

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Neural Crest Cell and Placode Interactions in Cranial PNS Development

Stephen J. Fleenor , Jo Begbie , in Neural Crest Cells, 2014

The cranial peripheral nervous system (PNS), including the cranial nerves and their associated sensory and parasympathetic ganglia, forms from two embryonic cell populations during development: cranial NCC and the ectodermal placodes. While the placodes contribute the paired special sense organs and the majority of the neurons of the cranial sensory ganglia, NCC migrate throughout the head and differentiate into a wide variety of neuroglial and non-neuroglial cell types. In addition to being required to generate the specific derivatives of the cranial PNS, reciprocal interactions between the NCC and placodal cell populations are currently being identified. Here, we describe the interactions between NCC and both placodal ectoderm and placodal derivatives at a molecular and cellular level and discuss their importance for the coordinated development of cranial PNS with both the CNS and the periphery.

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Cranial Remolding Orthoses

Deanna Fish , ... Doug Reber , in Atlas of Orthoses and Assistive Devices (Fifth Edition), 2019

Treatment Recommendations

Early identification of cranial deformities in young infants creates the opportunity for altering external forces acting on the skull that may exacerbate deformation or that may prevent symmetrical and proportional skull growth. Health care professionals such as obstetricians, pediatricians, nurses, therapists, and family practitioners should inspect the infant's head from the front, sides, back, and top during all clinic encounters. When younger infants with asymmetrical or disproportionate cranial development are identified, caregivers should be provided with educational materials and instruction on effective repositioning techniques. 1,70,81,120 These techniques include supervised tummy time and strategic positioning during diapering, feeding, carrying, and handling. Limitations on time spent in car seats, carriers, and swings are recommended, 15,81,86 and care is taken to position nursery furniture relative to bright areas that attract the infant's attention. 91 Purposeful and intentional efforts to alter the infant's position in the first 3 months of life serve to better distribute external forces acting on the developing infant skull. Conservative therapy and repositioning efforts are the first interventions recommended to families before exploring the option of a CRO for a moderately to severely affected infant. 15,120,128

Steinberg et al. 120 studied more than 4000 infants with head shape deformities referred for conservative (physical) therapy as a first intervention. Repositioning therapy included parental counseling and training, discussion of positional preference, repositioning techniques to stretch tightened neck muscles, emphasizing the importance of tummy time for more than 50% of awake time, carrying techniques to promote independent neck and truncal muscle development, and limiting the use of infant supine-positioning devices. Physical therapy involved an initial home program based on age and specific needs determined at the initial visit followed by continued in-office sessions with regimented exercises. In a paper by Cabrera-Martos et al., 16 parents were given exercises, adapted to the infant's motor development level and gross motor skills, to optimize cranial shapes. The exercises had the added benefits of improving infant motor skills and establishing the daily habit of parental involvement in early childhood development. Therapy programs for plagiocephaly designed to address deficiencies in cervical range of motion, antigravity or extensor muscle groups, general weakness, and asymmetry also help in the achievement of motor milestones.

Anthropometric skull measurements establish a baseline for clinical documentation of improvement or progression of the skull deformity. Common clinical measurements include cranial circumference, cranial width, cranial length, and cranial base measurements. Other measurements of cranial vault asymmetry, orbitotragial depth asymmetry, and cranial base asymmetry 67 can be acquired and ratios computed for the CI and CVAI. 91 Table 35.4 lists specific anthropometric measurements, cranial landmarks, and calculations used for documentation, assessment, and comparison of cranial deformities, and Fig. 35.6 shows common anatomical landmarks used for anthropometric measurements.

Understanding normative values relative to cranial development is important in the early identification and intervention of skull deformities. Cranial circumference measurements document cranial growth patterns of the developing brain and skull and have been standardized for both boys and girls. 28 Such cranial growth charts reveal approximately 2 cm of circumferential growth per month in the first 3 months, 1 cm of circumferential growth per month between 4 and 6 months, and approximately 0.5 cm of circumferential growth between 6 and 12 months. After age 12 months, cranial growth slows significantly. 18 This information reinforces the need for early intervention with repositioning and therapy in the early months after birth and consideration of orthotic programs at appropriate times to allow sufficient remaining growth for remodeling efforts. Waiting for spontaneous resolution of skull deformities reduces the window of opportunity for intervention and limits the effectiveness of orthotic intervention. 2,72

Cranial width and length are used to calculate a proportional relationship, specifically the CI. Traditionally, craniofacial specialists have used 78% as the norm for CI, which was based on anthropometric measurements on prone sleeping babies published by Dekaban in 1977. 30 Infants with deformational brachycephaly have a high CI and present with a very wide and short skull. Infants with deformational scaphocephaly have a very low CI because of their narrow skull width in relation to the length. Deformational plagiocephaly tends to present with slightly higher-than-average CI values and significant asymmetry. Studies have documented increases in the CI since the initiation of the Back to Sleep program, 47 and Wilbrand 121 found the following CI means in 2013 on the 401 normal infants measured: 0 to 3 months, CI of 79%; 4 to 6 months, CI of 84%; 7 to 12 months, CI of 82%. These values are considered to be within a normal range as long as they are not accompanied by other deformities such as a high or asymmetrical cranial vault, frontal bossing, or significant parietal bossing.

Cranial vault, orbitotragial depth, and cranial base measurements document differences in symmetry between the right and left sides of the skull and face. A perfectly symmetrical skull and face would reveal no differences between the right and left side measures. Most individuals have slight asymmetry; therefore asymmetry in and of itself is not abnormal or indicative of deformity. Rather, it is the degree of asymmetry (or disproportion) that determines deformation, and standards vary considerably. As reported by Loveday and de Chalain, 91 the CVAI represents a relative value that allows comparison of asymmetry between skulls of different sizes or between the same skull over time as growth occurs. A CVAI of more than 3.5% was reported to represent "significant asymmetry." Although linear measurements may fail to represent the complexity of a three-dimensional deformity, they can be helpful in quantifying and comparing specific aspects of cranial deformation. Hutchison et al. 53,55 used a difference between oblique cranial vault measurements of more than 106% and a CI of 93% as measurements that determined a "case" in their study of 200 infants in New Zealand. Rogers 109 and Graham 46 both consider a cranial vault asymmetry difference of more than 10 mm the point at which a cranial orthosis might be recommended, depending on the infant's age. For infants who are 3 months old or younger, focused repositioning efforts may produce significant changes to the overall symmetry and proportion of the skull and may prevent the need for additional medical treatments. An orthotic evaluation can be performed at any time to establish baseline measurements.

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