Description and Classification of the Faciocraniosynsotoses

Crouzon’s Syndrome

Described by Dr. Louis Edouard Octave Crouzon in 1912, this syndrome involves only the face and cranium and is not associated with other anomalies elsewhere on the limbs or trunk.¹ The fundamental factor is an underdeveloped midfacial mass that features exorbitism because of the lack of depth of the orbits, inverted occlusion, and receding malar bones. The nose is short (Figs. 183-1 and 183-2). Cranially, brachycephaly is usually present, but sometimes scaphocephaly or a cloverleaf skull may be observed (Fig. 183-3).

FIGURE 183-1 Facial advancement in a patient with Crouzon’s syndrome. A and B, This patient, 9 years of age, had severe facial retrusion with exorbitism. She underwent a frontal advancement procedure in infancy. C and D, The same patient is shown at 16 years of age after a Le Fort III type of facial advancement.

FIGURE 183-2 Frontofacial monobloc. A and B, In this 7-year-old girl with Crouzon’s syndrome, the exorbitism is significant, as well as the dental retrusion, but the relationship between the forehead and nose is good. C and D, The same patient is shown 7 years after monobloc frontonasal advancement.

FIGURE 183-3 Kleeblattschädel. A, This child had a craniofacial abnormality initially detected on prenatal ultrasound; her mother was affected with Crouzon’s syndrome. Photographs (1 and 2) and three-dimensional computed tomography (3 to 6) demonstrate the characteristic cloverleaf pattern associated with multisutural synostosis. B, Stage 1: posterior vault expansion and reconstruction. This child underwent early first-stage surgery to expand and reconstruct the posterior cranial vault from the coronal sutures back to the posterior fossa. Lateral and anterior views (7 and 8) and intraoperative views before (1 and 2) and after (3 and 4) craniotomy and reconstruction are shown. The presence of Lückenschädel with herniation of dura and brain tissue through defects in the calvaria can make elevation of the bone fragments challenging. Dividing the calvarial segments into multiple smaller pieces can make elevation of the required bone easier and safer (5 and 6). C, Stage 2: Fronto-orbital advancement and reconstruction. After stabilization of her cardiac status with repair of a ventricular septal defect and placement of a ventriculoperitoneal shunt, she underwent a second-stage craniofacial procedure for fronto-orbital advancement at 11 months of age. Intraoperative photographs demonstrate the degree of orbital bar advancement and reconstruction of the forehead (1 and 2). Postoperative three-dimensional computed tomography (3 to 5) and a photograph (6) demonstrate the degree of correction achieved, with improvement in exorbitism and rounding of the cranial vault. A midface advancement procedure will be undertaken at a later date.

In almost all cases the coronal and sagittal sutures are involved, as well as the lambdoid sutures in many cases. Frequently, these sutural fusions do not exist at birth. The coronal and sagittal fusions appear at about 1 year of age and the lambdoid later in life. In some cases, the sagittal fusion appears first and is manifested as simple scaphocephaly, with the coronal fusion appearing some months later. Commonly, the diagnosis of Crouzon’s syndrome is difficult to make during the first year of life, even if the brachycephaly is obvious. It is often difficult to know whether the midface will be affected, even on radiologic examination. Midface retrusion and exorbitism appear later in life.

In some cases the diagnosis is evident at birth. In such infants the malformation is usually severe, with marked frontofacial retrusion producing severe exorbitism with a high risk for exposure keratitis or even subluxation of the globes. Retrusion of the maxillae is also severe and produces airway obstruction with obligatory mouth breathing (Fig. 183-4).

FIGURE 183-4 Early monobloc advancement for severe exorbitism. A, This 2-month-old infant with Crouzon’s syndrome has exorbitism threatening his eyes. B, After early monobloc advancement at 3 years of age, the maxilla is still recessed but the exorbitism is corrected.

The relationship of the forehead and face is usually good in patient with Crouzon’s syndrome. There is backward horizontal displacement of all the frontofacial skeleton, as though it were held back by the synostosis.

Apert’s Syndrome (Acrocephalosyndactyly)

First described by Apert in 1906, this syndrome is easy to recognize because of the associated syndactylies (fused digits) of the hands and feet.² These syndactylies are always severe and affect almost all the digits. They can range from nearly complete fusion to fingers well delineated but joined by skin (Fig. 183-5).³

FIGURE 183-5 Apert’s syndrome. A, In this 2-month-old girl with Apert’s syndrome, the brachycephalic appearance is obvious, and the syndactyly is severe. B, An Apert skull from the Musée de l’Homme in Paris shows the wide anterior fontanelles.

(By permission of the Musée de l’Homme.)

The craniofacial involvement is also usually obvious at birth, with brachycephaly, sometimes asymmetric, being associated with facial retrusion of variable degree. Both coronal sutures are always fused, although in some rare cases craniosynostosis is absent (3 cases out of 64 in the senior author’s series). What distinguishes Apert’s from Crouzon’s syndrome faciocranially is the existence of hypertelorism and an open bite, with the anterior part of the maxillary alveolar arch being higher than the posterior part. The face and forehead are also abnormally wide, and the anterior fontanelle is widely open during the first months of life.

Described by Pfeiffer in 1964, this syndrome is an association of faciocraniosynostosis and anomalies of the hands and feet.⁴^–⁶ Although heterogeneous in manifestation, brachycephaly is present as a result of bicoronal synostosis (sometime asymmetric), midface retrusion secondary to maxillary hypoplasia, and hypertelorism. The thumbs and great toes are broad with a varus deviation. Soft tissue syndactyly can be observed. As in Crouzon’s and Apert’s syndromes, some severe forms exist, with precocious marked frontofacial retrusion resulting in ocular and breathing problems. This condition is sometimes associated with a cloverleaf skull.

Saethre-Chotzen Syndrome

Described by Saethre in 1931 ⁷ and Chotzen in 1932,⁸ this syndrome is characterized by the association of bicoronal synostosis, maxillary hypoplasia, ptosis, and ear anomalies.⁵ The craniosynostosis is usually a brachycephaly or, in some cases, a plagiocephaly or even an oxycephaly (acrocephaly). The midface retrusion is most often mild. The ears have prominent antihelical crura. Some patients have soft tissue syndactyly in the hands.

Craniofrontonasal Dysplasia

In the group of patients with craniofacial dysplasia, some have a bicoronal craniosynostosis and form a subgroup with a condition called craniofrontonasal dysplasia, first described by Cohen in 1979.⁹ Brachycephaly, often marked, is associated with the facial anomalies of frontonasal dysplasia, which include hypertelorism, a broad nasal bridge, a bifid nose, and sometimes, soft tissue syndactyly.

Carpenter’s Syndrome

First described by Carpenter in 1901, this syndrome is characterized by craniosynostosis of varying sutures and variable polysyndactyly of the feet, brachydactyly of the fingers, and various soft tissue syndactyly.⁵ Additional abnormalities include congenital cardiac defects, short stature, obesity, and neurocognitive deficiency. Inheritance is autosomal recessive.

Etiology

Although the majority of faciocraniosynostoses are sporadic, there is also evidence for a genetic origin based on observations of familial cases and a growing body of molecular data ¹⁰^–¹⁶ (see also Chapter 181). Crouzon’s syndrome occurs in 1 in 25,000 births, and the frequency of familial cases varies in the literature from 44% to 67%.⁵ Familial cases accounted for 26% in the senior authors’ series. In this series (Table 183-1), the rate of familial cases was lower in the precocious forms of Crouzon’s syndrome than in the common type: 13% versus 29%, respectively. Transmission is autosomal dominant. There is great variability of expression, and both severe and mild forms can be observed in the same family. In fresh mutations (sporadic cases), the paternal age at conception is higher than the mean in the unaffected population. A continually increasing number of mutations for Crouzon’s syndrome have been identified, with most located on the third immunoglobulin-like loop of fibroblast growth factor receptor 2 (FGFR2).⁵

TABLE 183-1 Number of Patients Treated for Isolated Craniosynostosis and Craniofacial Syndromes in Our Series (1976-2004)

TYPE	NO. OF PATIENTS TREATED
Nonsyndromic Craniosynostosis
Oxycephaly	115
Trigonocephaly	350
Scaphocephaly	799
Lambdoids	9
Rare form	93
Positional plagiocephaly	39
Brachycephaly	138
Plagiocephaly	335
Total	1878
Syndromic Craniosynostosis
Apert’s	103
Crouzon’s	120
Saethre-Chotzen	79
Pfeiffer’s	43
Frontonasal dysplasia	30
Other syndromes	38
Total	413

The incidence of Apert’s syndrome is estimated to be between 1 in 100,000 and 1 in 160,000 births.⁵ Most cases are sporadic; few affected patients have children because of the severity of the disease. However, dominant transmission with complete penetrance has been reported in some cases. As in Crouzon’s syndrome, the paternal age at conception is higher than average. Most mutations associated with Apert’s syndrome are present in the linker region between IgII and IgIII on FGFR2.¹⁷

Pfeiffer’s syndrome has autosomal dominant transmission with complete penetrance and variable expression. In our series, 41% of the cases were familial. Mutations causing Pfeiffer’s syndrome are commonly found on FGFR1 and FGFR2.^18,¹⁹

Saethre-Chotzen syndrome also has autosomal dominant transmission. Its penetrance is incomplete with variable expression. In our series, five of the nine cases were familial. In one of the first examples of molecular diagnosis of a craniofacial syndrome, the gene for Saethre-Chotzen syndrome was localized to the short arm of chromosome 7 (7p22) by Brueton and colleagues in 1992,²⁰ and later the TWIST gene was implicated.^21,²²

Females are much more affected by craniofrontonasal dysplasia than males, which is consistent with an X-linked inheritance. In our series, 36% of the cases were familial, and 91% of the patients were female.

Functional Aspects

Intracranial Pressure

More so than with isolated craniosynostoses, a problem of the faciocraniosynostoses is the associated risk for intracranial hypertension and its possible cognitive or visual sequelae. The risk for intracranial hypertension varies according to the type of syndrome.²³^–²⁸ In the senior authors’ series, intracranial pressure was recorded in 68 patients with faciocraniosynostosis. Intracranial hypertension was defined as a baseline pressure of 15 mm Hg or greater. The frequency of intracranial hypertension was 62.5% in Crouzon’s syndrome, 45% in Apert’s syndrome, and 29% in the others.

Without early treatment, intracranial hypertension can lead to optic atrophy and visual loss. This is observed mainly in Crouzon’s syndrome. In the senior authors’ series, papilledema was observed in 35% and optic atrophy in 10% of patients with Crouzon’s syndrome. In the other syndromes, papilledema was present in just 4% to 5%, and no optic atrophy was observed. In addition to the intracranial hypertension, some authors have implicated direct compression of the optic nerve in the optic canal. We have never observed this condition.

In severe cases of multisuture synostosis, such as the Kleeblattschädel (cloverleaf) deformity, calvarial vault expansion may be required early because of problems with cranial constraint and elevated intracranial pressure. In such cases, posterior vault expansion can be performed as an initial first stage in neonates, with a second-stage fronto-orbital reconstruction and advancement being performed at the age of 4 to 9 months (see Fig. 183-3).

Mental Development

There is a great variability in neurocognitive functioning in the different types of faciocraniosynostosis.^26,^28,²⁹ In comparing scores before and after surgery, three main factors appear to be involved as far as mental development is concerned. First, children with Apert’s syndrome have poorer cognitive development, and this is equally true before and after surgical treatment (Table 183-2). Second, early treatment leads to better cognitive outcomes (Table 183-3). Third, cognitive development is only mildly improved after treatment when compared with the patient’s preoperative status. In other words, the main predictive factor is preoperative cognitive status, which is best preserved by early frontal release.

TABLE 183-2 Preoperative and Postoperative Mental Level According to the Type of Faciocraniosynostosis