Fig. 38.1
Five main facial prominences. F frontal, Mx maxillary, Mn mandibular
During the fifth week of gestation, the two mandibular processes may begin to fuse centrally, the furrow between them filling with migrating neural crest cells (Fig. 38.2). The first branchial groove, below the mandibular processes, also fills with mesenchyme centrally; the patent lateral portion will form the external auditory meatus. Six swellings arise, three cephalad and three caudal to the lateral aspect of the first branchial groove and will eventually give rise to the external ear. Ear anomalies can arise from this time forward. The maxillary processes continue to enlarge, flanking the recently perforated stomodeum to form the primitive oral cavity. The most prominent event in the fifth week is the enlargement of the medial and lateral nasal swellings, accompanied by the invagination of the intervening nasal placodes into olfactory grooves. The eyes appear as elevations on the lateral face as the optic vesicle reaches the overlying ectoderm, forming a two-layered optic cup.
Fig. 38.2
Derivatives from neural crest cells in the adult face
In the sixth week, fusion of the medial nasal processes produces a central mass of tissue, which will ultimately give rise to the soft tissue of the nose, the central upper lip, and the premaxilla. The lateral nasal processes will become the nasal alae. The mandibular processes have completed fusion by the end of week 6. The maxillary processes continue to enlarge and approach the nasal processes. The furrow between the maxillary and nasal processes deepens, forming the naso-optic groove (Fig. 38.3). This groove will incorporate neuroectodermal cells, forming the canal that will become the nasolacrimal duct. Persistence of the naso-optic groove produces oculo-oral clefts.
Fig. 38.3
The developing face: sixth week. Frontal view of the sixth-week embryo shows fusion of the maxillary processes to the lateral nasal groove forming the nasolacrimal furrow. The rudimentary eyes are seen laterally positioned (Adapted from Converse et al. [134])
Relative growth of tissues including decreased rate of growth of the frontonasal process accompanied by increased expansion of the lateral head gives the appearance of medial migration of the eyes during the seventh week of gestation (Fig. 38.4). Abnormalities in this differential growth rate may result in hypertelorism. Lower facial fissures and furrows have nearly all closed by this time, and the maxillary processes have fused at the midline. The frontonasal process lengthens vertically as it collapses horizontally, forming a transverse furrow at the bridge of the nose. The eyelids appear as ridge-like elevations and begin the enlargement process that leads to fusion.
Fig. 38.4
The developing face: seventh week. Maxillary and mandibular fusions are complete. Frontal rotation of the orbits continues. Note the prominent nasofrontal overhang (Adapted from Converse et al. [134])
By the eighth week of gestation, the face has taken on a human appearance. The nares are oriented anteriorly. The eyes are still relatively widely spaced and will continue their medial migration until approximately 4 months gestation. The angle of exorbitism will slowly decrease during gestation and will continue to narrow even after birth and into adulthood (Fig. 38.5). The eyelids fuse at weeks 9–10 and reopen at weeks 25–26. The nasal bridge develops between 8 and 12 weeks, with reorientation of the nares from anterior to caudal. Elongation and growth will proceed from this point forward, but the major architecture of the face is in place by the end of this early fetal period.
Fig. 38.5
Separation of the globes at different stages of gestation. (Modified from Fries and Katowitz [48], with permission)
An appreciation of the development of the bony skull is also critical to understanding congenital craniofacial deformities. The developing skull has two major components: the cranial base and calvarium. The calvarium arises from neural crest mesoectodermal cells, which condense on the cartilaginous precursors of the crista galli, lesser wings of the sphenoid, and petrous ridges. Beginning in weeks 5–6, these sites give rise to the dura mater which rapidly grows to surround the enlarging brain [1] (Fig. 38.6). These dural sheets meet and determine the sites of the cranial sutures, which are kept open to allow for intracranial expansion (Fig. 38.7). The bone of the cranium arises from osteoblastic centers at dural sutural condensations. Premature fusion, or synostosis, occurs when this process of intentional patency fails, resulting in the head deformities characteristic of the craniosynostoses (Figs. 38.8 and 38.9).
Fig. 38.6
Cranial base cartilage . Schematic representation of the cranial base cartilage at 5 and 8 weeks of gestation. The complete adult cranial base is shown at right (Adapted from Friede [135])
Fig. 38.7
Normal sutures and fontanelles of the fetal skull
Fig. 38.8
Scaphoid skull . An example of Virchow’s law, closure of the sagittal suture produces a boat-like (scaphoid) skull shape. Normal skull appears as shaded area of drawing
Fig. 38.9
Common calvarial abnormalities resulting from craniosynostosis: (a) oxycephaly, (b) trigonocephaly, (c) plagiocephaly, (d) acrocephaly, (e) brachycephaly, (f) scaphocephaly
The second major component of the developing cranium is the cranial base. Neural crest mesoectoderm gives rise to basal cartilages that flank and eventually surround the notochord. The alisphenoid, orbitosphenoid, and prechordal cartilages develop into the sphenoid, zygomatic, temporal, and ethmoid bones (Fig. 38.6). Premature fusion of the cranial base sutures can result in reduced midfacial growth and shallow orbits, particularly with sphenozygomatic and sphenoethmoidal synostosis. The prechordal cartilage also gives rise to the nasal septum . Growth of the nasal septum and ethmoid sinuses allows for the collapse of the wide interorbital distance of the embryonic face.
Craniosynostoses
The craniosynostoses are an etiologically and pathogenetically heterogeneous group of disorders that share the common feature of premature closure of one or more of the cranial sutures (Fig. 38.7). This premature closure results in inhibition of growth in a direction perpendicular to the involved suture, with growth proceeding normally parallel to the involved suture (Virchow’s law) [2] (Fig. 38.8).
Specific terms have been coined to describe the typical skull deformities associated with various synostoses (Fig. 38.9). The term oxycephaly was originally used as a synonym for any craniosynostosis and was thus applied to all deformities of the skull [3]. However, this term is now used to refer to multiple synostoses, usually including at least coronal and sagittal sutures. This produces compensatory upward growth of the cranium, resulting in a “tower” skull. Brachycephaly refers to the cranial deformity arising from bilateral coronal synostosis. This produces a shortened calvarium from front to back, with exaggerated upward growth, allowed by a patent sagittal suture. When delayed closure of the anterior fontanelle causes a pointing of the top of the skull, the term acrobrachycephaly is applied. Plagiocephaly is a term coined by Virchow to describe the bony abnormality resulting from the unilateral premature closure of the coronal suture, producing a variety of asymmetric deformities, depending on the location and extent of synostosis. Table 38.1 outlines specific cranial deformations and their respective synostotic sutures (see also Chap. 40).
Table 38.1
Skull deformities arising from craniosynostosis
Deformity | Suture | Characteristics |
|---|---|---|
Oxycephaly | Multiple synostoses including coronal and sagittal | “Tower skull” (turricephaly alternative term) Compensatory upward movement of the cranium |
Brachycephaly | Bilateral coronal suture | Shortened calvarium front to back Upward growth allowed by patent sagittal suture |
Acrobrachycephaly | Bilateral coronal with patient anterior fontanelle | Pointed top of the skull Delayed closure of the anterior fontanelle |
Plagiocephaly | Unilateral coronal | Asymmetric deformity Variable depending on extent and location |
Scaphocephaly | Interparietal sagittal | Elongated, narrow skull resembling the hull of a ship |
Trigonocephaly | Metopic | Triangular frontal area Keel-shaped forehead |
Triphyllocephaly | Lambdoidal and coronal | “Cloverleaf skull” (Kleeblattschadel) Trilobar skull with cerebral eventration through open sagittal suture and anterior fontanelle |
Approximately 15% of patients with craniosynostosis are diagnosed with an identifiable craniosynostosis syndrome. The craniosynostosis syndromes are genetic disorders with specific inheritance patterns. For many of the dysmorphic syndromes, it is possible to find families that display a particular phenotype in either an autosomal-dominant, autosomal-recessive, or X-linked manner [4]. Non-syndromic craniosynostosis may also display a familial component, with similar suture involvement in several members of the same family [5]. With the advancement of gene mapping and cloning techniques, investigation of both the simple and complex human craniofacial dysmorphologies has expanded rapidly. Progress in molecular biology has localized the genetic defect in many families with craniosynostosis syndromes. Crouzon, Apert, and Pfeiffer syndromes have been genetically linked by mutations of the fibroblast growth factor receptor 2 gene (FGFR2) on the long arm of chromosome 10, specifically 10q25–q26 [6–12]. Even non-syndromic forms of craniosynostosis have been linked to mutations in the FGFR gene [13]. Fibroblast growth factor receptor 8, which plays an important role in outgrowth and patterning of the face, central nervous system, and extremities also maps to human chromosome 10q25–26, suggesting that some forms of acrocephalosyndactyly may involve mutations in this gene, as well [6].
Crouzon Syndrome
Crouzon syndrome accounts for approximately 4.8% of all cases of craniosynostosis, making it the most common of the craniosynostosis syndromes. The birth prevalence has been calculated to be 16.5 per l,000,000 [14, 15]. Crouzon syndrome is inherited in an autosomal-dominant fashion. As mentioned, the defect has been mapped to several mutations of the FGFR2 gene and has thus far displayed significant genetic homogeneity [11, 16]. FGFR2 is a member of the tyrosine kinase receptor family and has a high affinity for peptides that signal the transduction pathways for embryogenesis, cellular differentiation and polarity, and mitogenesis of the developing face and skull [9, 17, 18]. In Crouzon syndrome, the FGFR2-mediated effect on the ERK-MAPK regulatory pathway may play an important role in the development of the craniosynostosis phenotype [19].
Suture involvement in Crouzon syndrome is variable; coronal and sagittal synostosis are most common, followed by lambdoidal synostosis [20]. This pattern leads to the typical features of a shortened calvarium, steep forehead, and flattened occiput. Acrobrachycephaly and oxycephaly are characteristic, though triphyllocephaly, or cloverleaf skull, may also occur. Midface retrusion and shallow, widespread orbits are caused by hypoplasia of the frontal, ethmoid, sphenoid, and maxillary bones. This results in the classic Crouzon phenotype of hypertelorism and exophthalmos (Fig. 38.10) [21, 22].
Fig. 38.10
Patient with Crouzon syndrome . Characteristic features include brachycephaly, exorbitism, hypoplastic maxilla, low-set ears, and strabismus
Of the non-craniofacial manifestations of Crouzon disease, stylohyoid ligament calcification (50%), cervical spine abnormalities (40%), and elbow abnormalities (18%) are most common. Though not associated with syndactyly, minor hand deformities are present in 10%. Other musculoskeletal and visceral anomalies are also seen [23].
Vision loss can occur for a range of reasons in Crouzon syndrome. As mentioned previously, the most common ocular findings are hypertelorism and proptosis, which, if severe, can lead to exposure keratopathy and even globe subluxation [24–26]. Other reported anterior segment findings in Crouzon patients are numerous and have included megalocornea, microcornea, keratoconus, aniridia, anisocoria, blue sclera, cataract, corectopia, ectopia lentis, glaucoma, iris coloboma, nystagmus, and optic nerve hypoplasia [27].
Optic nerve involvement, either optic atrophy or papilledema , is also a common finding, present in up to 80% of patients in a 1958 study by Bertelson [28] though more recent reports have shown a lower percentage of optic nerve involvement [22]. The etiology of optic nerve disease is not well understood. Crouzon patients with optic atrophy often have near-normal optic canal dimensions [22]. As with all the craniosynostoses, optic nerve swelling must raise suspicion for elevated intracranial pressure and headache, which may occur in up to 60% of Crouzon patients [29].
Strabismus is commonly found in Crouzon syndrome, occurring in up to 92% of those affected and can lead to amblyopia, which is the most common cause of visual impairment in these patients [15, 25, 26, 30]. Various alignment patterns have been described, including esotropia, exotropia, and hypertropia. Absent or abnormally inserting extraocular muscles, common in the craniofacial syndromes, contribute to specific strabismus patterns [31]. Absent or abnormal superior oblique muscles and excyclorotation of the orbits can result in relative overaction of the inferior oblique muscles or pseudo inferior oblique overaction, causing the common V-pattern exotropia [32]. Recently, with the use of computed topography or magnetic resonance imaging, the rectus extraocular muscles have been found to insert on the globe more laterally in Crouzon patients, which contributes to the common V-pattern exotropia. For example, if the superior rectus inserts more laterally, when it is engaged, it pulls the eye upward and outward instead of just upward [33]. Refractive errors , including significant compound astigmatism and anisometropia, are very common in this group of patients [15, 25].
While other behavioral issues related to social perceptions may develop in children with Crouzon syndrome, mental retardation is uncommon. A recent study found most children to have IQ measurements similar to a normative database [34]. Cases of impaired mental functioning may be related to damage from prior episodes of raised intracranial pressure. Seizures and structural abnormalities of the brain, such as agenesis of the corpus callosum, hypoplasia of the septum pellucidum, ventriculomegaly, and encephalomalacia, are also reported and may contribute [12].
Apert Syndrome
Apert syndrome (acrocephalosyndactyly) comprises approximately 4.5% of all cases of craniosynostosis. It has a distinct phenotype, characterized by craniosynostosis, exorbitism, midface hypoplasia, and severe, symmetric syndactyly of the hands and feet [35]. Birth prevalence, fairly uniform over different populations, has been estimated to be between 1 per 65,000 births, with an increased incidence in advanced paternal age [36–38]. Though the syndrome is inherited in an autosomal-dominant fashion, most cases present as de novo mutations (likely related to the decreased reproductive behavior in this group of patients), with the mutation rate calculated to be 7.8 × 10−6 per gene per generation [36]. In 1995, two adjacent mutations were identified in the FGFR2 gene on the long arm of chromosome 10 [10, 39]. More recently, two additional de novo mutations have been identified on the same gene [40]. As in some of the other craniosynostoses, a paternal age effect has been seen with Apert syndrome. The term “selfish spermatogonial selection ” has been used to describe this association. This is characterized by the dysregulation of spermatogonial cell behavior through RAS-mediated pathways allowing for clonal expansion of mutant sperm in the older male population [41].
Typical features of Apert syndrome include oxycephaly, a flattened occiput, a severely hypoplastic midface, a prominent “parrot-beak” nose, hypertelorism, proptosis, strabismus, and low-set ears (Fig. 38.11). The Apert calvaria at birth is characterized by coronal synostosis and a widely gaping midline defect. The midfrontal region of the brain may not be covered with bone during early infancy, which often produces a prominent frontal pseudoencephalocele [42]. As the child matures, coalescence of bony islands closes this midline defect. The temporal bones are obliquely situated in all patients with Apert syndrome, and triphyllocephaly or cloverleaf skull is found in approximately 4% of patients [42].
Fig. 38.11
Patient with Apert syndrome . Characteristic features include brachycephaly with frontal overhang, “parrot-beak” nose, ptosis, strabismus, and midface retrusion. Note the high, arched palate
Another defining feature of Apert syndrome is true megalocephaly with postmortem brain weights dramatically above the 95th percentile regardless of age [42]. Central nervous system abnormalities , including defects of the corpus callosum and limbic structures, misshapen brain, and gyral anomalies, can occur in up to 12% of patients [43, 44]. Ventriculomegaly is reported to occur in about 60% of patients, though frank increased intracranial pressure is less common. Compared to Crouzon syndrome, intelligence is more likely to be subnormal [34, 43].
The ophthalmic manifestations of Apert syndrome closely parallel those of Crouzon syndrome, although hypertelorism and proptosis are often less prominent. Elevated intracranial pressure can occur in up to 83% of patients, with secondary papilledema and/or optic nerve pallor [45]. Extraocular muscle anomalies have been described, which contribute to strabismus and amblyopia [32, 46]. Refractive error , including astigmatism, is also common [47]. Less common ophthalmic findings include keratoconus, ectopia lentis, congenital glaucoma, and oculocutaneous albinism [47–49].
The associated orthopedic findings make Apert syndrome unique among the craniosynostoses. Syndactyly of the hands typically presents as a mid-digital mass involving the second, third, and fourth digits with variable proximal interdigital syndactyly (Fig. 38.12). The first and fifth digits are variably involved. A foot deformity in Apert syndrome is very characteristic and predictable, with progressive synostosis on what is presumably an unsegmented cartilaginous mass. Medial deviation of the great toe, fusion of the two phalanx digits, and progressive fusion of the midfoot and hindfoot in a supinated position are all characteristic [50]. Other orthopedic manifestations can be present and contribute to progressive loss of joint motion [51–53].
Fig. 38.12
Syndactyly in Apert syndrome . Hand of a child with Apert syndrome showing proximal syndactyly of digits 2 and 3, 4 and 5, and near-total fusion of digits 3 and 4
A range of other problems can occur in Apert syndrome. Oropharyngeal manifestations are frequently severe and can include a characteristic trapezoidal-shaped mouth with a Byzantine-arch-shaped palate (Fig. 38.11). Cleft soft palate and bifid uvula have been reported in 30–75% [54, 55]. Midface hypoplasia is also common and can lead to difficulty with intubation during general anesthesia, as well as generalized breathing issues and obstructive sleep apnea [56]. Dental anomalies include delayed tooth eruption, ectopic tooth eruption, severe bite malocclusion, and crowding of teeth. Cardiovascular and genitourinary anomalies occur in around 10% of those affected [57]. Apert patients also often develop severe acne in adolescence, which is thought to occur from abnormally sensitive androgen receptors [58] (Fig. 38.13).
Fig. 38.13
Patient with Saethre–Chotzen syndrome . Characteristic features include low-set hairline, ptosis, strabismus, mild facial asymmetry, and low-set ears
Pfeiffer Syndrome
Pfeiffer syndrome is generally inherited in an autosomal-dominant fashion, although it can less commonly occur sporadically . It is thought to occur in about 1 in 70,000 live births [59]. Similar to other acrocephalosyndactyly syndromes, Pfeiffer syndrome is caused by mutations in the FGFR gene family, specifically FGFR2 gene on chromosome 10 and FGFR1 gene on chromosome 8 [60]. These mutations are thought to cause premature ossification of the cranial sutures secondary to dysregulation of osteoblast and chondrocyte differentiation [61–63]. Interestingly, identical genotypic mutations of FGFR 2 have been identified in Crouzon syndrome, which is quite phenotypically distinct from Pfeiffer syndrome, suggesting that there may be other factors involved in phenotypic presentation of these conditions [63]. Alternatively, Pfeiffer and Apert syndromes are clinically similar, but genetically very distinct. There is also some phenotypic overlap with Muenke syndrome, although Muenke is caused by FGFR3 mutations.
Patients with Pfeiffer syndrome have premature fusion of the coronal and lambdoid sutures and occasionally the sagittal sutures. In more severe phenotypes, a cloverleaf skull can develop. Hydrocephaly, seizures, and, less commonly, mental retardation/developmental delay may accompany synostosis. The characteristic facial appearance is a very wide head with flat occiput, high forehead, small nose with a low nasal bridge, and hypertelorism [64]. Midface hypoplasia is common with associated maxillary hypoplasia, highly arched palate, malocclusion, and crowded teeth. These features may contribute to breathing difficulties and increase risks with general anesthesia. Patients have broad and deviated thumbs and first toes, often with partial syndactyly on the hands and feet (Fig. 38.14).
Fig. 38.14
Patient with Pfeiffer syndrome . (a) Clinical photograph demonstrating exophthalmos, hypertelorism, small mandible, “parrot-beaked” nose, recessed supraorbital ridges, and increased forehead height. (b) Enlarged thumb of same patient. (c) Broad, long great toe
Ocular findings in Pfeiffer syndrome can be similar to Crouzon syndrome, with moderate-severe proptosis, hypertelorism, and lateral canthal dystopia. Papilledema can occur with raised intracranial pressure. More recently, it has become apparent that FGFR mutations in Pfeiffer syndrome may also play a role in anterior segment development, with one patient recently found to have microcornea, limbal scleratization, corectopia, and glaucoma. Thus, close anterior segment examinations are also important with regular intraocular pressure monitoring [65].
Based on phenotype severity, Pfeiffer syndrome has been divided into three clinical subtypes. Type 1 or “classic” Pfeiffer syndrome is characterized by individuals with relatively mild manifestations including brachycephaly, midface hypoplasia, and finger and toe abnormalities. It is usually associated with normal neurologic development and with either FGFR1 or 2 mutations. Type 2 consists of a “cloverleaf skull ,” extreme proptosis, skeletal abnormalities, and developmental delay. Type 3 is similar to type 2, but without the cloverleaf skull. Both types 2 and 3 have an increased risk of death due to severe neurological and respiratory impairment. These types are more often associated with FGFR2 mutations. There can be significant clinical overlap between clinical subtypes, making characterization difficult [64].
Saethre–Chotzen Syndrome
Saethre–Chotzen syndrome (acrocephalosyndactyly, type III) is a heterogeneous, autosomal-dominant disorder characterized by craniosynostosis, facial dysmorphism, and mild limb abnormalities (Fig. 38.13) [66]. In 1997, it was found to be associated with mutations in the TWIST1 gene on chromosome 7p21–22 [67]. The TWIST1 gene functions in mesenchymal signaling during embryogenesis. Mutations in the TWIST1 gene are thought to lead to genomic haploinsufficiency, which causes uncontrolled receptor signaling and changes cranial skeletal development, ultimately leading to premature cranial suture closure [68, 69]. With the ability of genotypic diagnosis, many patients previously diagnosed with Saethre–Chotzen have actually been re-characterized as having a Muenke craniosynostosis from an FGFR3 mutation (see next section for a more detailed discussion of Muenke syndrome) [70, 71]. Since its discovery, over 100 TWIST1 mutations have been identified. Not surprisingly, as a result of the variety of TWIST1 mutations, there is significant variability in the Saethre–Chotzen phenotype [72].
Because of its heterogenous phenotype, Saethre–Chotzen is particularly challenging to diagnose clinically. As illustrated above, genetic testing is an important tool for definitive diagnosis. Classic features include a low frontal hairline, prominent crus helicis (ear anomaly), and syndactyly of the index and middle fingers. Brachydactyly and clinodactyly can also occur. While bilateral coronal craniosynostosis is the most common suture anomaly, not all patients with Saethre–Chotzen have craniosynostosis [66, 73, 74]. Recently, a unique pattern of craniosynostosis has been described in these patients involving fusion of the metopic, bicoronal, and anterior sagittal sutures, which has been termed “peace sign synostosis” [75]. Unlike in Apert, Crouzon, and Pfeiffer syndromes, midface hypoplasia is rare in Saethre–Chotzen [74, 75].
Similar to Apert syndrome, a highly arched palate, cleft palate, and dental anomalies can occur. A depressed nasal bridge can be found. Intelligence is frequently normal, although some degree of cognitive limitation, schizophrenia, and/or seizure disorder have been described [76]. The ears are small and low set, and hearing may be diminished [74, 77, 78].
Ophthalmic features in Saethre–Chotzen syndrome differ from the other craniosynostoses. Upper eyelid ptosis is much more common, occurring in up to 90% of patients. There may also be downward slanting of the palpebral fissures [74]. Proptosis and hypertelorism are not prominent features. Lacrimal duct stenosis and tearing can occur [79]. Strabismus is common and present in over half of patients. Other variable features include refractive error (usually myopia and/or astigmatism) and optic atrophy [74].
Muenke Syndrome
Muenke syndrome was first described in 1996. Since then , many patients who were thought to have Saethre–Chotzen syndrome have been re-characterized as having Muenke syndrome by genetic testing [80]. It is inherited in an autosomal-dominant fashion and is characterized by a mutation in the FGFR3 gene [81]. Of all patients with genetically confirmed craniosynostosis, 25–30% are thought to have Muenke syndrome [82]. With an incidence of 1 in 30,000 live births, it now constitutes the most common craniosynostosis syndrome.
The Muenke phenotype is heterogenous, with some patients having no clinical features, some having only craniosynostosis, and others having presentations that overlap with other craniosynostosis syndromes (i.e., Crouzon, Saethre–Chotzen, or Pfeiffer). It is characterized by uni- or bilateral coronal synostosis, broad toes, and carpal and calcaneal fusions [83]. The characteristic facial features include a flat forehead, elevated or depressed eyebrows, anterior displacement of the ears, and deviation of the nasal root. Bilateral coronal synostosis usually results in brachycephaly, but turribrachycephaly (“tower shaped” skull) or a cloverleaf skull can also be observed. Macrocephaly without craniosynostosis can occur. Again, there may be no synostosis at all.
Other variable features, similar to those seen in the craniosynostoses that also evolve from FGFR mutations include intracranial anomalies, midface hypoplasia, a highly arched palate, cleft lip/palate, sensorineural hearing loss, skeletal abnormalities, brachydactyly (short fingers/toes), broad thumbs/toes, and syndactyly. Patients may be developmentally normal or may have mental retardation, developmental delay, or epilepsy. Up to 30% of affected individuals may have some degree of developmental delay [71, 81].
Ophthalmic manifestations are highly variable. Affected individuals can have hypertelorism, telecanthus, lateral canthal dystopia, and ptosis. Proptosis, unlike in Crouzon and Pfeiffer syndromes, is rare. Strabismus is the most common ocular finding in Muenke syndrome. Anisometropia can also occur. As such, amblyopia is not uncommon. Similar to the other craniosynostoses, optic nerve damage can occur from occult-raised intracranial pressure [84].
Carpenter Syndrome
Carpenter syndrome is a rare, autosomal-recessive condition with an incidence of 1 per 1 million live births [85]. It is characterized by brachycephaly and a classic cloverleaf-shaped skull, but distinguishable from some of the other craniosynostosis syndromes based on the presence of syndactyly, polydactyly, and an autosomal-recessive inheritance pattern. It has been mapped to a mutation in the Ras-like in rat brain 23 (RAB23) gene on chromosome six. This gene plays an important role in sonic hedgehog signaling pathways during embryogenesis [86].
Craniofacial abnormalities in Carpenter syndrome include shallow supraorbital ridges, micrognathia, midface hypoplasia, external ear malformations, depressed nasal bridge, and an upturned nose. In order of decreasing frequency, the sagittal, metopic, coronal, and lambdoid sutures are most commonly affected [87]. Most patients have some degree of intellectual disability [86]. Furthermore, over half of those affected will have some form of central nervous system abnormality. Increased intracranial pressure can occur with secondary hydrocephalus. Congenital heart disease, hypogenitalism, obesity, and umbilical hernia are associated [88].
The ocular findings of Carpenter syndrome are less well defined due to the rarity of the disease, though hypertelorism with relative telecanthus and epicanthal folds have been described in most cases [89].
Clefting Syndromes
The second major group of craniofacial abnormalities falls under the umbrella of clefting syndromes. The clefting syndromes encompass a wide variety of disorders from complex malformations involving the whole head to more subtle defects in apposition of junctional facial structures. Clefts may arise as part of a recognizable syndrome (e.g., Treacher–Collins) or in non-syndromic forms. The origin of facial clefting is not well understood, and there may be different factors involved depending on the cleft type. Two major mechanisms have been proposed. The first is that a failure of fusion occurs between the embryologic facial processes, resulting in true or primary clefts. This type of clefting is restricted to the following borders: lateronasomaxillary clefting (naso-ocular clefts), medionasomaxillary clefting (cleft lip), intermaxillary clefting (cleft palate), and maxillomandibular clefting (macrostomia) [3] (Fig. 38.15). The failure of fusion is thought to arise from deficient epithelial cell degeneration with inappropriate persistence of epithelium between the borders of the facial processes. The second major proposed mechanism relates to a failure of mesodermal migration to fill the facial processes, resulting in structural collapse and epithelial dehiscence. Other theories of cleft formation have included failure of neural crest cell migration, failure of neural crest cell degeneration, and/or failure of ossification (producing “pseudo-clefts” not associated with true facial sutures) [90–93].
Fig. 38.15
Facial clefting . Patient illustrating a midline facial cleft affecting the lip and nostril, possibly due to failure of the maxillary process to fuse
Facial clefting may arise as the result of a single gene defect, either as part of a syndrome (e.g., Treacher–Collins, velo-cardio-facial syndrome) or as an isolated phenotypic effect (X-linked cleft palate with ankyloglossia, autosomal-dominant orofacial clefting) [94]. Both trisomy 13 and 18 are associated with clefting [95]. Cleft lip, cleft palate, and atypical facial clefting have been reported to be associated with maternal use of cocaine [96], antiepileptic drugs [97], and benzodiazepines [98]. Clefting has been induced in animal models with administration Dilantin, corticosteroids, 6-aminonicotinamide, and retinoids, which cause a first and second branchial arch syndrome in rats [99].
Regional Classification of Clefts Affecting the Orbital Adnexa
Paul Tessier’s classification of the craniofacial clefts, introduced in 1976, remains the most widely accepted and universally recognized means of describing the location of facial clefting. It is a topographic, not a pathogenetic, classification scheme. As seen in Fig. 38.16, Tessier’s system divides the face vertically through the midline, assigning the number 0 to the lower facial midline and the number 14 to the upper facial midline. Each major cleft is assigned a number, progressing in a clockwise manner about the orbit on the right side of the face and in a counterclockwise manner on the left [100]. Each cleft may involve both soft tissue and underlying bony skeleton.
Fig. 38.16
Tessier’s clockface system . Numbers progress clockwise for the left eye and counterclockwise for the right eye. (a) Soft-tissue clefts. (b) Bony clefts (Adapted from Tessier [100])
To better clarify the ophthalmic consequences of the clefting syndromes, Fries and Katowitz grouped the orbital clefts into four regional categories progressing from medial to lateral, as outlined in Table 38.2 and Fig. 38.17 [48].
Table 38.2
Regional classification of orbital adnexa in the clefting disorders
Region | Presentation | Tessier clefts |
|---|---|---|
Area 1 | ||
Median facial clefts | Hypertelorism | 0, 1, 13, 14 |
Area 2 | ||
Medial canthal and nasolacrimal clefts | Median canthal dystopia | 2, 3,4 |
Nasolacrimal disorders | 11, 12, 13 | |
Area 3 | ||
Central eyelid clefts | Colobomatous defects | 4, 5, 6, 9, 10, 11 |
Area 4 | ||
Lateral canthal clefts | Lateral canthal dystopia | 6, 7,8 |
Fig. 38.17
Regional classification of the facial clefts. (a) Area I: median cleft positions. (b) Area II: medial canthal and nasolacrimal cleft positions. Note relation to punctum and infraorbital foramen for cleft number 4. (c) Area III: eyelid cleft positions. (d) Area IV: lateral canthal and facial cleft positions (Adapted from Fries and Katowitz [48])
Area I: Median Facial Clefts
Midline facial clefts vary in severity (Fig. 38.18). The primary manifestation of this group of clefts (0, 1, 13, 14) is orbital hypertelorism. Hypertelorism associated with midline clefts, labeled by Tessier as the 0–14 clefting syndrome, is more commonly known as median craniofacial dysraphia or the median facial cleft syndrome [101]. Features of this syndrome include hypertelorism ; midline facial cleft involving the nose, lip, and sometimes the palate; broadened nasal root; lack of formation of the nasal tip; bifid anterior cranium; and widow’s peak. Fourteen clefts involving the upper midface but sparing the lower face can sometimes produce the syndrome of frontal encephalocele or giant pneumatization of the frontal sinus. This cleft allows herniation of the frontal lobes through the area of the frontal sinus and is characterized by a widened forehead, hypertelorism, and widely spaced eyebrows. Paramedian clefts (numbers 1 and 13) generally occur unilaterally and produce asymmetric hypertelorism through lateral displacement of the orbit on the affected side.
Fig. 38.18
Regional classification : Area l. Midline facial Tessier numbers 0–14 demonstrating cleft hypertelorism, frontal encephalocele, and bifid nose
Area II: Medial Canthal and Nasolacrimal Clefts
The naso-ocular clefts (Tessier numbers 2, 3, 11, and 12) may produce varying degrees of hypertelorism, generally of lesser severity than the midline clefts (Fig. 38.19). Telecanthus, medial canthal dystopia, and nasolacrimal abnormalities are characteristic. The lower face clefts (Tessier cleft numbers 2, 3, and 4) are more common than the upper face clefts (numbers 10, 11, and 12), which generally only occur paired with their lower face counterparts (e.g., the 4–10, 3–11, or 2–12 cleft pairs).
