Craniosynostosis Syndromes

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

• Nonsyndromic single suture craniosynostosis, syndromic craniosynostosis and multiple suture craniosynotosis share much overlap and can be differentiated as above.
• Craniofacial malformation
• Hemifacial microsomia
• Treacher-Collins syndrome (mandibulofacial dysotosis)
• Goldenhaar syndrome (oculoauriculovertebral syndrome)
• Velocardiofacial syndrome
• Fetal alcohol syndrome
• Pierre-Robin sequence

Natural history

In nonsyndromic unilateral coronal craniosynostosis, ophthalmic and periocular complications have been reported in 68% of patients in childhood in the following descending order of frequency:

• Strabismus 32%
• Ptosis 21%
• Lateral canthal dystopia 14%
• Nasolacrimal obstruction 12%
• Cranial nerve palsy 9%

Corneal exposure risk is lifelong and increases with age because of impaired orbital bone growth and age-related diminished tear film health.

Complex strabismus presents in infancy and childhood characterized by inferior oblique overaction and V-pattern exotropia.

• This is a result of the posteriorized trochlea and associated altered direction of the superior oblique tendon as well as the excyclotorsion of the orbit, resulting in superior insertion of the medial rectus and lateral insertion of the superior rectus.

In infancy, 40% of patients have intracranial pressure above 15 mm Hg that can be from crowding or aqueductal stenosis.

• True optic nerve atrophy from foramina synostosis is rare.

Maxillary hypoplasia progresses throughout childhood and results in chronic respiratory problems and is associated with elevated pulmonary pressure and pneumonia with rare right heart failure.

Medical therapy

• Address refractive error.
• Consider patching for amblyopia.
• Topical lubricants for corneal exposure

Surgery

Usually in coordination with a multidisciplinary team, en bloc cranial bone repositioning is the most definitive and complex repair.

A neurosurgeon and craniofacial plastic surgeon are most often involved, and oral surgeons and oculoplastic surgeons have important contributions.

When appropriate, these surgeries are performed first as appropriate:

• Fronto-orbital advancement to advance the superior rim and roof and reduce proptosis
• Le Fort III osteotomy and advancement to the maxilla and midface forward
• Le Fort I advancement for Angle class III malocclusion
• Orbital hypertelorism repair
• Cranial vault remodeling with rigid fixation and bone grafts

An occasionally useful tool being used more frequently is distraction osteogenesis, wherein external devices provide calibrated slow movement of bone segments.

Ptosis surgery, lateral canthoplasty, and medial canthopexy are occasionally needed and are often performed subsequently.

Strabismus surgery is performed after craniofacial bone surgery.

• Binocularity is rarely achieved and therefore early surgical intervention is not recommended.

Tarsorrhaphy is a temporizing measure useful for cases of severe corneal exposure or globe luxation, but the risk of amblyopia should be considered.

Other management considerations

Shunting is occasionally needed and is preferable to optic nerve sheath fenestration in cases of increased ICP.

Common treatment responses, follow-up strategies

Multiple surgeries are standard.

These cases are complex and unique, so management is somewhat individualized.

Patient outcomes are best when care is administered through a coordinated multidisciplinary team.

Unilateral orbital advancement for nonsyndromic craniosynostosis has been reported to be complicated by postoperative ptosis in 29% of patients.

Strabismus and amblyopia occur with less frequency, although overall the rates of both are decreased after surgery.

Disease-related complications

• Amblyopia (from refractive error, ptosis, strabismus) in at least one eye in the majority of patients
• Optic atrophy (Crouzon and Apert)
• Globe luxation (Crouzon and Apert)
• Anesthetic complications secondary to respiratory obstruction
• Exophthalmos, proptosis causing ocular exposure
• Strabismus
• Absence of extraocular muscles (Crouzon and Apert)
• Secondary intracranial hypertension can be a complication

It is possible that Hippocrates described cranial suture fusion–related skull abnormalities in 100 BC.

The term craniosynostosis was coined by Otto in 1830.

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