BASICS

DESCRIPTION

• Crouzon syndrome, a craniosynostosis disorder, is characterized by premature closure of calvarial and cranial base sutures, as well as those of the orbit and maxillary complex.

• Distinctive malformations of the skull and facial region are its hallmark.

EPIDEMIOLOGY

Incidence

1 case per 60,000 live births.

Prevalence

1 case per 25,000 population.

RISK FACTORS

Genetics

• It may be transmitted as an autosomal dominant disorder with complete penetrance and variable expressivity, or appear as a new mutation. Crouzon syndrome has no race or sex predilection.

• Caused by mutations in the fibroblast growth factor receptor-2 (FGFR2) gene, which is mapped to chromosome locus 10q25–10q26.

• 50% of incidents are not inherited and are the result of new mutations.

GENERAL PREVENTION

Genetic counseling.

PATHOPHYSIOLOGY

Premature closure of cranial sutures, most commonly the coronal and sagittal sutures, results in abnormal skull growth of the orbits and maxillary complex. The degree of deformity is dictated by the order and rate of suture fusion. Growth perpendicular to a fused suture is restricted promoting compensatory growth at the remaining open sutures (1).

ETIOLOGY

See “Genetics.”

COMMONLY ASSOCIATED CONDITIONS

• Acanthosis nigricans is the main dermatologic manifestation of Crouzon syndrome.

– Characterized by thickened, velvety, light-brown to black markings on the neck, under the arms, or in the groin

– Detectable after infancy

DIAGNOSIS

HISTORY

• Craniofacial abnormalities are often present at birth and may progress with time.

• Headaches and loss of vision secondary to elevated intracranial pressure

• Decreased mental function

• Visual disturbance secondary to excessive exposure of cornea or conjunctiva leading to ocular redness and irritation or burning sensation

• Unexplained loss of visual acuity or double vision

• Hearing loss secondary to ear canal stenosis or atresia

PHYSICAL EXAM

• Common ophthalmic features

– Proptosis secondary to shallow orbits

– Divergent strabismus or exotropia

– Ocular hypertelorism

– Exposure keratitis or conjunctivitis

• Common facial features

– Midfacial hypoplasia secondary to small, underdeveloped maxilla

– Beaked nose

– Short upper lip

– Relative mandibular prognathism secondary to protrusion of the lower jaw

• Other manifestations

– Upper airway obstruction

– Obstructive sleep apnea which can often present in infancy

– Papilledema or optic atrophy secondary to elevated intracranial pressure

– Progressive hydrocephalus

– Chronic tonsillar herniation

– Hearing loss secondary to recurrent ear infections

– Crowding of the upper teeth

– V-shaped maxillary dental arch

– Narrow, high, or cleft palate

– Bifid uvula

– Cervical vertebral body fusions

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Molecular analysis for FGFR2 mutation

– Although the mutation is present in more than 50% of patients with Crouzon syndrome, it may also be present in Apert syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome.

– All patients with associated acanthosis nigricans have an Ala391Glu mutation within the transmembrane region of the FGFR3 gene.

Imaging

Initial approach

• Skull radiography – to show synostosis, craniofacial deformities, digital markings on skull, widening of hypophyseal fossa, small paranasal sinuses, maxillary hypoplasia, and shallow orbits

• Spine radiography – to show fusion of the vertebral bodies and posterior elements

• Limb radiography – to demonstrate subluxation of the radial head

• CT head/orbits with 3-dimensional reconstruction – to define pathologic anatomy

• MRI brain – to show corpus callosum agenesis and optic atrophy

Follow-up & special considerations

Genetics evaluation.

Diagnostic Procedures/Other

• Laryngologic examination with audiography

• Sleep study to evaluate for obstructive apnea

• Ophthalmologic examination

• General physical examination with ECG

• Psychiatric examination and psychological testing

• EEG – low-voltage, increased convulsive excitability

Pathological Findings

• Immunohistochemical analysis of cranial sutures, performed with labeled anti-FGFR2 antibodies, demonstrates that sutures obtain lower levels of FGFR2 activity in both stenosed and nonstenosed sutures.

• Histological features of acanthosis nigricans demonstrate hyperkeratosis, acanthosis, and papillomatosis. There are increased pigment cells in the upper dermis of the basal layer.

DIFFERENTIAL DIAGNOSIS

• Apert syndrome

– Craniosynostosis combined with syndactyly of the hands and feet involving second, third, and fourth digits

• Pfeiffer syndrome

– Craniosynostosis combined with broad thumbs and great toes, complex cardiovascular malformations and variable partial soft tissue syndactyly of the hands and feet.

• Carpenter syndrome

– Craniosynostosis combined with craniofacial dysmorphism, finger and toe abnormalities, heart defects, growth and mental retardation.

• Saethre-Chotzen syndrome

– Craniosynostosis combined with low-set frontal hair line, deviated nasal septum, variable facial asymmetry and partial cutaneous syndactyly

TREATMENT

ADDITIONAL TREATMENT

General Measures

• Early detection and management of amblyopia and refractive error

• Nasal continuous positive airway pressure device to relieve obstructive sleep apnea

• Nasopharyngeal airway as a better tolerated treatment modality in the management for obstructive sleep apnea (2)[B]

• Speech management

Issues for Referral

• Neurosurgeon

• Neuroradiologist

• Neurologist

• Ophthalmologist

• Oromaxillofacial surgeon

• Genetic specialist

• Psychiatrist

• Stomatologist

• Laryngologist

SURGERY/OTHER PROCEDURES

• Craniofacial and neurosurgical intervention with the goal to stage reconstruction to correlate with facial growth patterns, visceral function, and psychosocial development (1).

– In the first year of life, it is preferable to release the synostotic sutures of the skull to allow adequate cranial volume to promote brain growth and expansion. This can be performed with fronto-orbital advancement with cranial decompression.

– Subsequent development of midfacial hypoplasia may be repaired with the Le Fort III osteotomy, monobloc frontofacial advancement or bipartition osteotomy.

– Endoscopy before midface advancement is recommended to identify airway obstruction that may interfere with respiratory improvement after midface advancement (3).

– Early craniectomy with frontal bone advancement may be needed to prevent or treat increased intracranial pressure secondary to multiple suture synostoses and fused synchondroses.

– Skull reshaping may be repeated as the child grows.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

• Admit for surgical intervention

– Shunting procedures for hydrocephalus

– Tracheostomy for airway compromise

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Ophthalmology and neurology for long-term monitoring.

Patient Monitoring

Monitor postoperative complications.

DIET

No special diet is required.

PROGNOSIS

• Depends on the severity of the malformation

• Patients usually have a normal lifespan

COMPLICATIONS

• Brain compression and mental retardation may result in severely affected individuals unless relieved by early craniectomy.

• Upper airway obstruction can lead to acute respiratory distress.

• Increased intracranial pressure and optic atrophy may occur secondary to a disproportion between craniostenosis and growing brain matter.

• Postoperative complications

– Postoperative hydrocephalus and elevated intracranial pressure

– Cerebrospinal fluid leak

– Respiratory distress

– Wound infections, extradural abscess, frontal bone osteomyelitis, periorbital abscess

– Blindness, diplopia, facial nerve palsy

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