Key points
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Craniosynostosis syndromes have wide phenotypic variability. Understanding of the underlying genetic causes continues to develop.
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Children with these syndromes are best managed at a multidisciplinary craniofacial center.
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Early management focuses on airway protection, preservation of vision and hearing, and feeding.
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Timing of craniofacial reconstruction is driven by growth and development of the area of interest.
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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 occurs in 1:2000 to 1:2500 live births. Most cases are nonsyndromic. Craniosynostosis syndromes, more than 150 of which have been identified, affect 1:25,000 to 1:100,000 infants. The most common are reviewed in this article.
Craniosynostosis syndromes are diagnosed based on clinical features. Abnormal head shape and midface deficiency with exorbitism are typical craniofacial expressions, and syndromes with these traits may be called craniofacial dysostosis syndromes. Limb and visceral manifestations further delineate each syndrome.
Fibroblast growth factor receptor ( FGFR ) and TWIST mutations are the most commonly associated with craniosynostosis syndromes. Although genotype-phenotype correlations have been characterized, phenotypically similar patients may have genetically distinct syndromes and identical mutations have been found in patients with different clinical diagnoses. Fibroblast growth factors participate in myriad processes including skeletogenesis and limb development. Gain-of-function mutations in FGFR1 , FGFR2 , and FGFR3 cause the FGFR -related craniosynostosis syndromes, which include Crouzon, Apert, Pfeiffer, Beare-Stevenson, Jackson-Weiss, and Muenke syndromes as well as Crouzon syndrome with acanthosis nigricans and FGFR2 -related isolated coronal synostosis. These syndromes account for approximately 17% of craniosynostosis cases.
Crouzon syndrome
Genetics
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FGFR2 mutations
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Autosomal dominant; complete penetrance, variable expressivity
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Occasionally de novo
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1.6:100,000; 4.5% of craniosynostosis cases
Clinical features
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Cardinal features:
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Craniosynostosis
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Midface/orbital hypoplasia
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Clinically normal hands/feet
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Crouzon syndrome, like all craniofacial dysostosis syndromes, is classically characterized by premature fusion of the coronal and frontosphenoidal sutures and the sphenoethmoidal synchondrosis. Fusion results in brachycephaly; midface deficiency; and a short, wide anterior cranial base. The forehead is prominent because of compensatory growth at unaffected sutures. Additional sutures may be involved and rarely there is no sutural involvement ( Fig. 1 ).
Exophthalmos is always present, largely because of orbital hypoplasia with retruded supraorbital, infraorbital, and lateral orbital rims. The widened cranial base can result in hypertelorism. Most patients have exotropia; orbital dystopia and strabismus can be observed. Approximately 20% of patients develop optic atrophy.
Anteroposterior and vertical midface hypoplasia are consistent features. Dental crowding, crossbite, and apertognathia are typical. Cleft lip and palate are rare.
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Other features
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Typically normal intellect
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Hydrocephalus (up to 30%); occasional nonprogressive ventriculomegaly
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Hearing loss common
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Classically normal limbs/axial skeleton (occasional mild anomalies)
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Cardiovascular anomalies rare
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Differential diagnosis
If choanal atresia is present, consider Crouzon syndrome with acanthosis nigricans. Apert, Pfeiffer, Jackson-Weiss, and Saethre-Chotzen syndromes are diagnostic considerations.
Crouzon syndrome
Genetics
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FGFR2 mutations
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Autosomal dominant; complete penetrance, variable expressivity
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Occasionally de novo
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1.6:100,000; 4.5% of craniosynostosis cases
Clinical features
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Cardinal features:
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Craniosynostosis
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Midface/orbital hypoplasia
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Clinically normal hands/feet
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Crouzon syndrome, like all craniofacial dysostosis syndromes, is classically characterized by premature fusion of the coronal and frontosphenoidal sutures and the sphenoethmoidal synchondrosis. Fusion results in brachycephaly; midface deficiency; and a short, wide anterior cranial base. The forehead is prominent because of compensatory growth at unaffected sutures. Additional sutures may be involved and rarely there is no sutural involvement ( Fig. 1 ).
Exophthalmos is always present, largely because of orbital hypoplasia with retruded supraorbital, infraorbital, and lateral orbital rims. The widened cranial base can result in hypertelorism. Most patients have exotropia; orbital dystopia and strabismus can be observed. Approximately 20% of patients develop optic atrophy.
Anteroposterior and vertical midface hypoplasia are consistent features. Dental crowding, crossbite, and apertognathia are typical. Cleft lip and palate are rare.
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Other features
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Typically normal intellect
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Hydrocephalus (up to 30%); occasional nonprogressive ventriculomegaly
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Hearing loss common
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Classically normal limbs/axial skeleton (occasional mild anomalies)
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Cardiovascular anomalies rare
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Differential diagnosis
If choanal atresia is present, consider Crouzon syndrome with acanthosis nigricans. Apert, Pfeiffer, Jackson-Weiss, and Saethre-Chotzen syndromes are diagnostic considerations.
Apert syndrome
Genetics
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FGFR2 mutations
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Specific mutations linked to clinical features (ie, severe craniofacial involvement)
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Most are de novo
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Sometimes autosomal dominant; complete penetrance.
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1:100,000; 4% to 5% of craniosynostosis cases
Clinical features
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Cardinal features:
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Craniosynostosis
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Midface/orbital hypoplasia
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Bilateral syndactyly of hands/feet (minimally second to fourth digits)
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Craniofacial anomalies are generally more severe in Apert than in Crouzon syndrome. Asymmetry frequently affects the cranial base, orbits, and midface. Megalencephaly is common.
Infants with Apert syndrome have bicoronal synostosis with a midline calvarial defect from glabella to the posterior fontanelle that predictably obliterates over time. The anterior cranial base is short. Patients often have a flattened occiput and a wide, steep forehead. The skull is wide with temporal bulging; temporal fat pads are prominent ( Fig. 2 ).
The orbits are hypoplastic; exophthalmos and hypertelorism are always observed. Supraorbital and infraorbital rims are retruded. The lateral orbital wall is ballooned; lateral orbital rim projection is near normal. Palpebral fissures are often downslanting. Exotropia, refractive errors, and strabismus are common; optic atrophy is seen more in Crouzon syndrome. Eyebrows may be interrupted over a bony defect at the lateral supraorbital rim.
The midface is retrusive. The nose is short with a depressed bridge and rounded tip. Ears tend to be large and may be low set.
Lips are hypotonic. Lateral palatal swellings contain mucopolysaccharides and grow with age; the palate is highly arched. The soft palate is often long and thick. Cleft 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 apertognathia ( Fig. 3 ).
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Other manifestations
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Ventriculomegaly common; progressive hydrocephalus rare
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Mental retardation more common than in Crouzon syndrome
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May have normal intellect
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Hearing loss common
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Hard and soft tissue syndactyly (at least second to fourth digits)
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Cardiovascular/genitourinary anomalies ∼10%
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Cervical spine anomalies (C5–C6 fusion) common
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Light skin/hair, hyperhidrosis, acneiform lesions
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Differential diagnosis
Crouzon, Pfeiffer, Saethre-Chotzen, Jackson-Weiss, and Carpenter syndromes are considered, but the pattern of syndactyly usually clinches the diagnosis.
Pfeiffer syndrome
Genetics
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FGFR2 mutations
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Type 1 subset: FGFR1 mutation
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Frequently no identifiable mutation
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Type 1: autosomal dominant; complete penetrance, variable expressivity
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Some type 1, types 2 and 3: de novo
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Combined prevalence 1:100,000
Clinical features
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Cardinal features
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Craniosynostosis
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Midface/orbital hypoplasia
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Broad thumbs/great toes (rarely thumbs normal)
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Variable partial soft tissue syndactyly (second and third digits)
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Three phenotypic types of Pfeiffer syndrome have been delineated.
Patients with type I Pfeiffer syndrome are most likely to have normal intelligence, although mild mental retardation can be seen. The skull is turribrachycephalic. Midface retrusion, exophthalmos, hypertelorism, and nasal bridge depression are variable. Strabismus is common, as is a high arched palate with dental crowding.
Features of type 2 Pfeiffer syndrome include cloverleaf skull, severe exophthalmos, and central nervous system involvement such as hydrocephalus. Elbow ankylosis or synostosis, choanal atresia, and cleft palate may be present. Intellectual disability is common. Patients often die early.
Patients with type 3 Pfeiffer syndrome have a more severe phenotype than those with type 1 with severe exophthalmos and a very short anterior cranial base without cloverleaf skull. Visceral anomalies and elbow ankylosis may be present. Early death is common.
Conductive hearing loss affects more than 80% of patients regardless of subtype. Tracheostomy is often required for patients with types 2 and 3. Hydrocephalus and acquired tonsillar herniation have been reported in most patients with type 1 and all patients with type 3. Cervical fusion (typically C2–C3) is seen more in types 2 and 3 ( Fig. 4 ).
