Etiology
Craniosynostosis refers to premature fusion of a cranial suture most often in the cranial vault but occasionally affecting the cranial base. This closure prevents growth of the skull perpendicular to the suture direction (Virchow's law).
Epidemiology
Craniosynostosis of some type affects between 1:2000 and 1:2500 live births. Most cases are isolated, single-suture based and nonsyndromic; only 10%–15% involve 2 sutures and only 6% of cases are associated with a syndrome.
Among isolated, nonsyndromic cases, the most frequent synostosis is sagittal, followed by coronal, metopic, and lamboid.
Among syndromic cases, Crouzon syndrome is the most common, affecting 1:10,000 live births. Saethre-Chotzen syndrome affects 1:25,000, Pfeiffer syndrome 1:100,000, Apert syndrome 1:160,000, and Carpenter syndrome occurs even less frequently.
History
A positive family history of syndromic craniosynostosis condition is common because many syndromes have autosomal dominant (AD) inheritance.
Expressivity is variable.
Characteristic appearance is present at birth, but can be mild, and becomes more pronounced over the first years of life.
Clinical features
Nonsyndromic isolated craniosynostosis results in predictable skull deformities and head abnormalities depending on the involved suture:
- Sagittal > Scaphocephaly ("toaster head")
- Unilateral Coronal > Frontal Plagiocephaly ("oblique head" anterior unilateral flattening and distortion)
- Unilateral Lamboid > Occipital Plagiocephaly (posterior unilateral flattening and distortion)
- Bilateral Coronal > Frontal Brachycephaly (anterior flattening and widening)
- Bilateral Lamboid > Occipital Brachycephaly (posterior flattening and widening)
- Metopic > Trigonocephaly (triangle shaped anterior narrowing)
Various "multiple" suture skull appears exist that occur both syndromically and nonsyndromically
- Acrocephaly/turricephaly (Tower skull) > tall skull height
- Oxycephaly (Pointed head) > retroverted forehead
- Pansynostosis (Cloverleaf skull or Kleeblattschadel anomaly) > Trilobed skull
More than 100 craniosynostosis syndromes have been described. Only the common and relevant ones will be described in order of frequency. Their suture synostosis is variable, but listed below:
Crouzon syndrome (acrocephalosyndactyly type II) (Figure 1)
- AD inheritance
- Associated with multiple mutations in the fibroblast growth factor receptor-2 (FGFR2) gene on chromosome 10
- Usually bicoronal synostosis
- Can be sagittal or lamboid
- Head shape usually brachycephaly or scaphocephaly
- Can have trigonocephaly or oxycephaly
- Other features: midface hypoplasia (mild)
- Ophthalmic findings
- Common:
- Hypertelorism
- Increased inferior scleral show
- Increased ICP
- Strabismus
- Optic nerve compression
- Uncommon: nystagmus

Figure 1. Crouzon syndrome.
Saethre-Chotzen syndrome (acrocephalosyndactyly type III)
- AD inheritance
- Mutations in the TWIST gene on chromosome 7
- Often unilateral, but sometimes bicoronal craniosynostosis
- Other features
- Low-set hairline
- Facial asymmetry
- Brachydactyly/syndactyly
- Ear abnormalities
- Ophthalmic findings: blepharoptosis
Apert syndrome (acrocephalosyndactyly type I)
- AD inheritance
- 2 different mutations on the FGFR2 gene cause the majority of cases,
- Usually bilateral coronal synostosis
- Head shape usually brachycephaly or turricephaly
- Other features
- Syndactyly
- Severe midface hypoplasia
- Mental retardation
- Ophthalmic findings
- Ptosis
- Lateral canthal dystopia
Pfeiffer syndrome (acrocephalosyndactyly type V)
- AD inheritance
- Mutations on the FGFR1 and FGFR2 genes
- Type I
- Bilateral coronal synostosis
- Proptosis
- Type II
- "Cloverleaf" skull
- Proptosis
- Midface hypoplasia
- "Spoon-like" thumbs
- Type III:
- Proptosis
- Midface deficiency
- Neurologic compromise
Carpenter syndrome
- AR inheritance
- Other features: polysyndactyly, short hands, cardiovascular anomalies
- "Tower" shaped skull or "cloverleaf" skull
Although the syndromes have differences in cause and presentation and individual patient deformities are unique, there is considerable overlap in various aspects of presentation that are important for management.
- Fronto-orbital recession, shallow orbits, short anterior cranial fossa cause
- Proptosis with exposure keratopathy and risk of globe luxation
- Strabismus from abnormal extraocular muscle course and the exocyclotorted/shallow orbit
- Cranial vault shape abnormalities with occasional increased intracranial pressure and possible vision loss
- Midface hypoplasia with malocclusion and chronic breathing difficulties
- Other oculoplastic issues
- Unusual refractive errors
- Nasolacrimal duct abnormalities
- Poor blink
- Various adnexal congenital abnormalities:
- Orbital hypertelorism
- Telecanthus
- Lateral canthal dystopia/abnormal canthal tilt
Testing
- Clinical evaluation
- Gene mutation analysis
- History and examination of family members
- CT scan to establish suture synostosis, often best visualized on 3D volumetric rendering
Testing for staging, fundamental impairment
- Ophthalmic exam for strabismus, refractive error, ptosis, amblyopia and optic nerve swelling
- Airway and occlusion exam
Risk factors
- Advanced paternal age is a risk factor for penetration in Crouzon and Apert syndromes.
- Positive family history