Kathleen Romero
Alex V. Levin

BASICS

DESCRIPTION

• Craniofacial syndromes are divided into craniosynostoses and clefting syndromes.

• Craniosynostosis describes premature sutural fusion. Craniostenosis is the result.

• Simple craniosynostosis refers to premature closure of a single suture. Compound craniosynostosis involves 2 or more sutures.

• In primary synostosis, the most common type, cranial sutures are fused prematurely because of genetic factors. In secondary craniosynostosis, premature sutural fusion is secondary to another known disorder/process (1).

EPIDEMIOLOGY

Prevalence

• Crouzon syndrome: 16.5 per million live births and accounts for 4.8% of all craniosynostosis, making it the most common craniosynostosis syndrome.

• Apert syndrome: Estimated of 1 per 160,000 live births, approximately 4.5% of all craniosynostosis.

• Other craniofacial disorders are less common.

RISK FACTORS

No known risk factors other than genetic.

Genetics

• Crouzon syndrome: Autosomal dominant, variable expression. 25% are spontaneous mutations (no family history), although affected parents may be missed if mild. Mutations in fibroblast growth factor receptor genes: FGFR2 (10q26) or FGFR3 (4p16) gene. Associated with advanced paternal age (2).

• Apert syndrome: Autosomal dominant, FGFR2 gene. Most patients have 1 of 2 specific mutations in exon IIIa. Associated with advanced paternal age. (3)

• Pfeiffer syndrome: Autosomal dominant, complete penetrance and variable expression, FGFR2 and FGFR1 (8p11.2) (4).

• Saethre-Chotzen: Autosomal dominant, high penetrance and variable expression, basic helix—loop–helix transcription factor called TWIST1 (7p21–22) or FGFR3. Advanced maternal age is a risk factor for new mutations (5).

• Treacher Collins syndrome (mandibulofacial dysotosis): Autosomal dominant, variable expression. Positive family history in approximately 40% of patients, TCOF1 gene (5q32–33.1). Advanced paternal age is a risk factor for new spontaneous mutations.

• Goldenhar syndrome (oculo-auricular-vertebral spectrum): Most cases sporadic, autosomal recessive and autosomal dominant, estimated recurrence in first-degree relatives approximately 2%. Several loci described including 5p15.33-pter (dominant), 8q11 (dominant), 11q12–13 (dominant), 14q22 (dominant or recessive) and 22q11.2 (dominant). The SALL1 gene (16q12.1) has been mutated in some sporadic cases.

PATHOPHYSIOLOGY

Virchow first described how premature closure of one cranial suture promotes growth parallel to that suture and inhibits growth perpendicular to it (1).

ETIOLOGY

There are 3 classic theories: Primary dysgenesis with secondary cranial base abnormalities, primary cranial base malformation with secondary obliteration of the cranial sutures, primary defect in the mesenchymal blastema producing both an abnormal cranial base and craniosynostosis.

DIAGNOSIS

HISTORY

• Family history and examination of parents and siblings may be helpful.

• History of associated syndromic abnormalities may help direct diagnosis (e.g., hearing loss, developmental delay, acanthosis nigricans, upper airway obstruction, hydrocephalus, syndactyly).

PHYSICAL EXAM

• Visual function 90% of vision loss is secondary to amblyopia, and 10% is secondary to structural abnormalities of the globe or visual pathways.

• Position/shape/integrity of the lids, palpebral fissures, and canthi. Examine for trichiasis, entropion, ectropion, colobomas, distichiasis, ptosis, epicanthal folds, symblepharon, and ankyloblepharon. Vertical and horizontal fissure length, upper and lower lid crease position, and marginal reflex distance are important points of information, when obtainable. Ptosis (especially Saethre-Chotzen).

• Characteristic downslanting lower lid coloboma with sharp upswing medially in Treacher-Collins. Horizontal lid shortening on forced closure (e.g., crying).

• Evaluate for exorbitism and corneal exposure.

• Evaluation of the optic nerves papilledema.

• Telecanthus is measured by the intercanthal distance. In infants, generally <20 mm; in older children <24 mm; in adults, <30 mm.

• Hypertelorism is technically measured by the distance between the bony medial orbital walls. Mustarde Index: ratio of the intercanthal distance to the interpupillary distance. Normal≤0.50. Values greater than this represent telecanthus and a possible underlying hypertelorism.

• Assess for caruncle abnormalities in Goldenhar

• Strabismus and refractive error common. Amblyopia common. Most common strabismus is exotropia slightly more than esotropia. Vertical deviations and A- or V-patterns can occur alone or in combination with the horizontal deviation. Dissociated vertical deviation, pseudo-overacting inferior oblique muscles.

• May have nasolacrimal duct anomalies/obstruction/dysfunction

• Rare associated anterior segment or retinal abnormalities other than optic nerve malformations (frontonasal dysplasia)

• Systemic malformations: Syndactyly (Apert), large great toe and thumb (Pfeiffer), hearing loss, external ear malformations, midfacial hypoplasia, protruding tongue, acanthosis nigricans (Apert), dental malocclusion, and palatal abnormalities

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Molecular genetic testing

Imaging

Initial approach

• The use of ancillary testing is on a case-by-case basis

• Skeletal survey if skeletal dysplasia also suspected

• Magnetic resonance imaging (MRI) of the brain

• Computerized tomography (CT) with 3-dimensional reconstruction of the skull and face

• Dental Panorex radiography

Follow-up & special considerations

• Follow up is largely dictated by the severity of ophthalmic findings.

• Requires multidisciplinary team, which may include genetics, plastic surgery, neurosurgery, oral surgery, orthodontics, ophthalmology, otolaryngology, pediatrics, psychiatry, nutrition, speech therapy, and social work.

• Ongoing concern of corneal exposure, may be worse with older age, especially if exorbitism or lower lid coloboma.

• Risk in first decade of amblyopia. Monitor visual function.

• Ophthalmology may be asked to attend craniofacial surgical interventions for prophylactic probing of nasolacrimal system, monitoring of eye pressure, or optic nerve concerns.

• Monitor for papilledema or optic nerve compression.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis can often be easily limited to a few syndromes and further delineated by a genetic workup.

TREATMENT

ADDITIONAL TREATMENT

General Measures

Immediate ophthalmic consultation is usually obtained to evaluate for corneal exposure, orbital dystopia, extraocular muscle dysfunction lid abnormalities, and papilledema.

SURGERY/OTHER PROCEDURES

• Maximize multidisciplinary procedures under anesthesia

• Initial craniofacial surgery usually aimed at relieving increased intracranial pressure and allowing for brain growth (e.g., strip craniectomy). Later surgery to reposition orbits (orbital advancement) often requires periosteal elevation and dissection of orbital contents from the orbital walls. Orbital walls fractured approximately 15 mm anterior to the orbital apex as needed for particular syndrome repairs, allowing the orbit to be shifted in any desired direction. Later surgery designed for further reconstruction to improve appearance.

• Ophthalmology may be needed during or after craniofacial surgery. Postoperative concerns include chemosis, exposure, optic nerve impingement, papilledema, extraocular muscle dysfunction, and lid malposition.

• The variety and types of surgical repairs for the ophthalmic surgical problems generally follow the basic tenets that govern their use in patients who do not have craniofacial problems. Tarsorrhaphy or lid reconstruction may be needed for corneal exposure.

• If nasolacrimal probing/intubation indicated, pathway may be very anomalous and intranasal anatomy crowded, nasal endoscopy may be helpful. Preoperative evaluation to ensure no anterior encephalocele with brain in nasopharynx (frontonasal dysplasia).

• Strabismus surgery complicated by absent/anomalous extraocular muscles. Preoperative plan may be assisted by ultrasound, CT, and MRI. Intraoperative exploration using limbal incision recommended. Preoperative assessment often cannot predict muscle patterns. Reoperation frequent. May not be able to normalize alignment in all fields of gaze.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

• The initial ophthalmic evaluation should be accomplished as soon as possible after the diagnosis of any craniofacial abnormality is made, preferably before any surgical intervention.

• The most common initial concern, especially in the multiple craniosynostoses (e.g., Apert, Crouzon, clover-leaf deformity) is maintenance of an adequate airway.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Ongoing monitoring is essential to evaluate for corneal exposure (which may increase with age), vision abnormalities, papilledema, and ocular misalignment.

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