Craniosynostosis Syndromes

Carolyn Dicus Brookes, DMD, MD, Brent A. Golden, DDS, MD,

Timothy A. Turvey, DDS*

KEYWORDS
 Craniofacial dysostosis  Craniosynostosis syndromes  Crouzon  Apert  Pfeiffer  Muenke

KEY POINTS
 Craniosynostosis syndromes have wide phenotypic variability. Understanding of the underlying genetic causes continues to
develop.
 Children with these syndromes are best managed at a multidisciplinary craniofacial center.
 Early management focuses on airway protection, preservation of vision and hearing, and feeding.
 Timing of craniofacial reconstruction is driven by growth and development of the area of interest.
 In the past, intellectual disability was assumed. However, many patients with craniofacial dysostosis syndromes live rich
lives and have normal or even exceptional intellect provided they are raised in a nurturing, stimulating environment.

Craniosynostosis is premature fusion of cranial sutures, and it Crouzon syndrome

occurs in 1:2000 to 1:2500 live births.1,2 Most cases are non-
syndromic. Craniosynostosis syndromes, more than 150 of Genetics
which have been identified, affect 1:25,000 to 1:100,000 in-
fants.2,3 The most common are reviewed in this article.
 FGFR2 mutations
Craniosynostosis syndromes are diagnosed based on clinical
 Autosomal dominant; complete penetrance, variable
features. Abnormal head shape and midface deficiency with
expressivity
exorbitism are typical craniofacial expressions,1,2,4e6 and
 Occasionally de novo
syndromes with these traits may be called craniofacial dysos-
 1.6:100,000; 4.5% of craniosynostosis cases2,10
tosis syndromes. Limb and visceral manifestations further
delineate each syndrome.
Fibroblast growth factor receptor (FGFR) and TWIST muta- Clinical features
tions are the most commonly associated with craniosynostosis
syndromes. Although genotype-phenotype correlations have
Cardinal features:
been characterized, phenotypically similar patients may have
 Craniosynostosis
genetically distinct syndromes and identical mutations have
 Midface/orbital hypoplasia
been found in patients with different clinical diagnoses.2,7,8
 Clinically normal hands/feet
Fibroblast growth factors participate in myriad processes
including skeletogenesis and limb development. Gain-of-func-
tion mutations in FGFR1, FGFR2, and FGFR3 cause the FGFR- Crouzon syndrome, like all craniofacial dysostosis syndromes,
related craniosynostosis syndromes, which include Crouzon, is classically characterized by premature fusion of the coronal
Apert, Pfeiffer, Beare-Stevenson, Jackson-Weiss, and Muenke and frontosphenoidal sutures and the sphenoethmoidal syn-
syndromes as well as Crouzon syndrome with acanthosis nig- chondrosis.11 Fusion results in brachycephaly; midface defi-
ricans and FGFR2-related isolated coronal synostosis. These ciency; and a short, wide anterior cranial base. The forehead is
syndromes account for approximately 17% of craniosynostosis prominent because of compensatory growth at unaffected su-
cases.9 tures. Additional sutures may be involved and rarely there is no
sutural involvement (Fig. 1).6,12,13
Exophthalmos is always present, largely because of orbital
hypoplasia with retruded supraorbital, infraorbital, and lateral
orbital rims. The widened cranial base can result in hyper-
telorism. Most patients have exotropia;14 orbital dystopia and
The authors have nothing to disclose.
strabismus can be observed.15 Approximately 20% of patients
Department of Oral & Maxillofacial Surgery, University of North
Carolina-Chapel Hill, 149 Brauer Hall, CB #7450, Chapel Hill, NC 27599- develop optic atrophy.14
7450, USA Anteroposterior and vertical midface hypoplasia are
* Corresponding author. consistent features. Dental crowding, crossbite, and apertog-
E-mail address: Tim_Turvey@unc.edu nathia are typical. Cleft lip and palate are rare.15

Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 103–110

1061-3315/14/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.04.001 oralmaxsurgeryatlas.theclinics.com
104 Dicus Brookes et al.

Fig. 1 Crouzon syndrome. Frontal views of a child with Crouzon syndrome. The only prior procedures performed were placement of PET
and VP shunt. PET, pressure equalization tubes; VP, ventriculoperitoneal.

Other features
 Typically normal intellect Craniofacial anomalies are generally more severe in Apert
 Hydrocephalus (up to 30%); occasional nonprogressive than in Crouzon syndrome.13 Asymmetry frequently affects
ventriculomegaly16,17 the cranial base, orbits, and midface.15 Megalencephaly is
 Hearing loss common18 common.27
 Classically normal limbs/axial skeleton (occasional mild Infants with Apert syndrome have bicoronal synostosis
anomalies)19e23 with a midline calvarial defect from glabella to the posterior
 Cardiovascular anomalies rare fontanelle that predictably obliterates over time.12,13
The anterior cranial base is short. Patients often have a
Differential diagnosis flattened occiput and a wide, steep forehead. The skull is
wide with temporal bulging; temporal fat pads are prominent
If choanal atresia is present, consider Crouzon syndrome with (Fig. 2).15,28
acanthosis nigricans. Apert, Pfeiffer, Jackson-Weiss, and The orbits are hypoplastic; exophthalmos and hypertelorism
Saethre-Chotzen syndromes are diagnostic considerations.6 are always observed.14 Supraorbital and infraorbital rims are
retruded. The lateral orbital wall is ballooned; lateral orbital
rim projection is near normal. Palpebral fissures are often
Apert syndrome downslanting.15 Exotropia, refractive errors, and strabismus
are common;14 optic atrophy is seen more in Crouzon syn-
Genetics drome.29,30 Eyebrows may be interrupted over a bony defect at
the lateral supraorbital rim.15
 FGFR2 mutations The midface is retrusive. The nose is short with a depressed
 Specific mutations linked to clinical features (ie, severe bridge and rounded tip.15 Ears tend to be large and may be low
craniofacial involvement)24 set.15,31
 Most are de novo Lips are hypotonic.15 Lateral palatal swellings contain mu-
 Sometimes autosomal dominant; complete copolysaccharides and grow with age; the palate is highly
penetrance.2 arched.32,33 The soft palate is often long and thick.33 Cleft
 1:100,000; 4% to 5% of craniosynostosis cases2,25,26 palate is seen more than in Crouzon syndrome or the general
population. Delayed and ectopic dental eruption are common.
Most patients have dental crowding, crossbite, and apertog-
Clinical features nathia (Fig. 3).15,34,35

Cardinal features: Other manifestations

 Craniosynostosis  Ventriculomegaly common; progressive hydrocephalus
 Midface/orbital hypoplasia rare16,36
 Bilateral syndactyly of hands/feet (minimally second to  Mental retardation more common than in Crouzon
fourth digits) syndrome
Craniosynostosis Syndromes 105

Fig. 2 Apert syndrome. (AeC) Frontal, lateral and superior views of a 3-D CT reconstruction of an infant with Apert syndrome. Note the
wide midline calavarial defect and turribrachycephaly.

Fig. 3 Apert syndrome. (A) Frontal and profile views of another infant with Apert syndrome. (B) Hands and feet of the same child
demonstrating polysyndactyly. (C) Palatal view of the same patient as a teenager. Note the significant crowding, lateral palatal swellings,
and highly arched palate.
106 Dicus Brookes et al.

 May have normal intellect

 Hearing loss common37,38
 Hard and soft tissue syndactyly (at least second to fourth
digits)39
 Cardiovascular/genitourinary anomalies w10%40
 Cervical spine anomalies (C5eC6 fusion) common20
 Light skin/hair, hyperhidrosis, acneiform lesions41,42

Differential diagnosis

Crouzon, Pfeiffer, Saethre-Chotzen, Jackson-Weiss, and Car-

penter syndromes are considered, but the pattern of syndac-
tyly usually clinches the diagnosis.6

Pfeiffer syndrome

Genetics43e45
Fig. 4 Lateral cephalometric radiograph of a patient with
 FGFR2 mutations Pfeiffer syndrome. Note the severe midface deficiency and the
 Type 1 subset: FGFR1 mutation cervical spine fusion.
 Frequently no identifiable mutation
 Type 1: autosomal dominant; complete penetrance, var-
iable expressivity Differential diagnosis
 Some type 1, types 2 and 3: de novo
 Combined prevalence 1:100,0002,44 Differential diagnosis includes Saethre-Chotzen and Jackson-
Weiss syndromes, although in the latter thumbs are
unaffected.43
Clinical features

Cardinal features Muenke syndrome

 Craniosynostosis
 Midface/orbital hypoplasia Genetics
 Broad thumbs/great toes (rarely thumbs normal)4,46
 Variable partial soft tissue syndactyly (second and third  FGFR3 mutation
digits)44  Autosomal dominant; incomplete penetrance, variable
expressivity
 Sometimes de novo51
Three phenotypic types of Pfeiffer syndrome have been
 1:30,00052; 8% of craniosynostosis cases9
delineated.43
Patients with type I Pfeiffer syndrome are most likely to
have normal intelligence, although mild mental retardation Clinical features
can be seen.43 The skull is turribrachycephalic. Midface ret-
rusion, exophthalmos, hypertelorism, and nasal bridge Coronal synostosis (usually bilateral) and various minor anom-
depression are variable. Strabismus is common, as is a high alies characterize Muenke syndrome.
arched palate with dental crowding.45,47 Phenotypic variation is considerable: additional sutures may
Features of type 2 Pfeiffer syndrome include cloverleaf skull, be involved or patients may be simply macrocephalic or even
severe exophthalmos, and central nervous system involvement normocephalic (Figs. 5 and 6).51e53 Females are affected more
such as hydrocephalus. Elbow ankylosis or synostosis, choanal severely.52e54 Mild midface hypoplasia, downslanting palpebral
atresia, and cleft palate may be present. Intellectual disability fissures, mild ptosis, and high arched palate may be seen.
is common. Patients often die early.2,6,43 Strabismus is common.52 Ventriculomegaly, hydrocephalus,
Patients with type 3 Pfeiffer syndrome have a more severe and cervical spine anomalies are rare.16,55
phenotype than those with type 1 with severe exophthalmos Minor clinical anomalies of the hands and feet (brachy-
and a very short anterior cranial base without cloverleaf skull. dactyly, clinodactyly) affect some. Soft tissue syndactyly is
Visceral anomalies and elbow ankylosis may be present. Early rare. Radiographic hand and foot abnormalities may be noted
death is common.43 despite an unremarkable clinical examination.51,55
Conductive hearing loss affects more than 80% of patients Almost all patients have sensorineural hearing loss.53
regardless of subtype. Tracheostomy is often required for pa- Normal intellect is typical, although developmental delay af-
tients with types 2 and 3. Hydrocephalus and acquired tonsillar fects roughly one-third of patients.51,52
herniation have been reported in most patients with type 1 and
all patients with type 3.48 Cervical fusion (typically C2eC3) is Differential diagnosis
seen more in types 2 and 3 (Fig. 4).49,50
Classical prognosis is poor for patients with types 2 and 3 Muenke syndrome may be confused with other craniofacial
Pfeiffer syndrome; however, some of these patients show dysostosis syndromes or nonsyndromic craniosynostosis; ge-
normal or only mildly delayed neurodevelopment.2 netic testing for all patients with coronal synostosis is thus
Craniosynostosis Syndromes 107

Fig. 5 Muenke syndrome. (A) Frontal and profile views of an infant with Muenke syndrome. (B) Frontal and lateral views of a 3-D CT
reconstruction of the same patient.

Fig. 6 Muenke syndrome. Frontal, lateral, and superior views of a 3-D CT reconstruction of another patient with Muenke syndrome. Note
the dramatic phenotypic variation.
108 Dicus Brookes et al.

advocated.51,52 If Muenke syndrome is diagnosed, genetic Signs and symptoms of increased ICP include a bulging
counseling and early assessment for and management of fontanelle, papilledema, radiographic beaten copper skull
hearing loss and developmental delay are indicated.53 Further, appearance (Fig. 7), headaches, nausea or vomiting, and irri-
patients with Muenke syndrome seem to require reoperation tability; diagnosis can be challenging, especially in the very
more often than do their nonsyndromic counterparts.54 young.16
Increased ICP may require a ventriculoperitoneal shunt,
endoscopic third ventriculostomy, or early/repeat cranial
Treatment considerations in craniosynostosis decompression.
syndromes
Other systems
Patients with craniosynostosis syndromes are best managed by
a multidisciplinary craniofacial team. Treatment is individually A comprehensive medical evaluation is performed early in life.
tailored; protocol details vary from center to center. Core Exophthalmos increases risk for corneal abrasion, exposure
considerations relevant to patients with syndromic craniosy- keratitis, and globe trauma. Unaddressed strabismus can lead
nostosis are reviewed here. to amblyopia. Early assessment by a pediatric ophthalmologist
is indicated, for these reasons and to monitor for papilledema.
Airway and feeding Ocular lubrication, tarsorrhaphy, or early fronto-orbital
advancement are strategies to protect the globes.
Obstructive sleep apnea is common.56e58 Midface deficiency, Patients require regular evaluation for middle ear disorders
choanal stenosis or atresia, a long thick velum, laryngotracheal and hearing loss, which are common.
anomalies, and central apneas all contribute to airway Timing of cleft palate repair depends on speech acquisition;
compromise. If a specific level of obstruction is identified it it may be delayed relative to routine cleft management.
may be addressed. As lymphoid tissue reaches its peak size, Dental development should be monitored by a pediatric
tonsillectomy or adenoidectomy may be indicated. Midfacial dentist and an orthodontist.
advancement may prove helpful for children and adolescents. Limb anomalies are managed by pediatric orthopedists.
Nasopharyngeal tubes, continuous positive airway pressure, or Visceral anomalies are managed by the appropriate specialists.
tracheostomy are sometimes required. Genetic evaluation and counseling are crucial.
Assessment for airway obstruction and central apnea begins The potential psychosocial and educational impact of these
in infancy; reassessment frequency is determined by diagnosis conditions necessitates ongoing monitoring by a trained psy-
and individual features. chiatrist or psychologist.
Although infants are obligate nasal breathers, those with
craniosynostosis syndromes may be forced to breathe through Craniofacial treatment sequence
their mouths; this can impede feeding. Nasogastric or gastro-
stomy tubes may be required to supplement intake. Timing of intervention is based on growth of the affected re-
gion; adjustments to timing are prompted by functional or
Central nervous system psychosocial concerns.
Brain growth drives rapid increase in cranial vault size
Increased intracranial pressure (ICP) is a concern whenever during the first year of life. Cranial vault decompression and
sutures fuse prematurely; it is seen more frequently in syn- reconstruction is undertaken during this period to prevent
dromic than nonsyndromic craniosynostosis. Venous conges- increased ICP and its untoward effects. A staged approach
tion, hydrocephalus, and upper airway obstruction likely all to cranial dysmorphology is often required. Fronto-orbital
contribute to intracranial hypertension.16,59 advancement, involving fused suture release, anterior vault

Fig. 7 Beaten copper skull appearance on a child with Crouzon syndrome prior to surgical intervention.
Craniosynostosis Syndromes 109

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