Crouzon Syndrome 

Updated: Jul 23, 2019
Author: Amarateedha Prak LeCourt, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Crouzon syndrome represents the most common syndromic craniosynostosis and was described in 1912 as one of the varieties of craniofacial dysostosis caused by premature obliteration and ossification of two or more sutures, most often coronal and sagittal.[1, 2, 3, 4, 5] Virchow introduced the term craniostenosis.[6] The type of obliterated sutures determines the type of craniostenosis. Oxycephaly, scaphocephaly, wedge skull, and oblique head are differentiated.[1, 3, 4, 6] Crouzon syndrome with oxycephaly and Apert syndrome with oxycephaly and syndactylia (acrocephalosyndactyly) are the most common types of dysostosis. Some authors connect those syndromes as one, calling it Crouzon-Apert syndrome, but symptomatologic differentiation makes classification difficult. Acanthosis nigricans (shown in the image below) is the main dermatologic manifestation of Crouzon syndrome (see Acanthosis Nigricans).[3, 4, 7, 8]

Acanthosis nigricans of the axillary fossa in Crou Acanthosis nigricans of the axillary fossa in Crouzon syndrome.

Pathophysiology

Dysplasias of the skeleton (including craniofacial dysostosis) are caused by the malformations of the mesenchyme and ectoderm. The unknown teratogenic factors are taken into account. Dysplasias are inherited in an autosomal dominant pattern. Inheritance may come from an affected parent(s), although cases exist in which mutations arise de novo. Mutation of the gene (locus 10q26) for fibroblast growth factor receptor 2 (FGFR2) has been identified as a causative factor for Crouzon syndrome. Typically, the mutations occur on exons 8 or 10. Moreover, the mutation in the transmembrane region of FGFR3 (locus 4p16.3) was detected in this syndrome and was observed in cases with acanthosis nigricans coexistence.[2, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]

Etiology

This syndrome is inherited in an autosomal dominant pattern.[3, 18]

Mutation of FGFR2C342Y/+ is a marked cause of Crouzon syndrome that is characterized by craniosynostosis and midfacial hypoplasia. Beyond skeletal effects, the FGFR2C342Y/+ mutation is now implicated in affecting tooth development.[18, 20, 21]

Epidemiology

Frequency

The prevalence is very low; Crouzon syndrome is currently estimated to occur in 1 in 25,000 people in the general population.[4] Crouzon syndrome is rare worldwide.[3, 4]

Race

Race is not noted as a predisposing factor.[3]

Sex

Sex factor does not play any role.[3]

Age

Deformation of bony face is visible just after the birth. Other syndrome factors reveal themselves with time.[3, 6]

Prognosis

High intracranial pressure caused by disproportion between craniostenosis and the brain growing may lead to death.[1, 3, 6]

Patient Education

Found to be of high priority among craniofacial microsomia adult patients’ and caregivers’ concerns are etiological understanding, depth and availability of information, and ensuring an accurate diagnosis. Regarding etiology, frequently patients were unsure about the underlying cause. From this misunderstanding, patients were found to self-attribute incorrect origins for the disorder.[22]

In terms of treatment, patients and caregiver expectations may need to be mitigated. Data and some adult patients having undergone surgical repairs as youths support the idea that parent caregivers may best serve their children by postponing operative intervention until children are older and are able to actively make decisions on their healthcare. Some adult patients also make the case that parents should not project their own apprehensions about the disorder on the children, which may produce negative psychological effects on the afflicted. Medical practitioners should make their best attempts to keep both patients and caregivers involved and informed of treatment plans, risks, alternative approaches where applicable, and follow-up methods of coping should surgery be elected.[19, 22, 23, 24]

Furthermore, providers must exercise caution and precision in their diagnosis of associated breathing disorders. Equivocal usage of choanal atresia and choanal stenosis could add further confusion about not only etiology, but also patient and caregiver beliefs about the success of surgical procedures. Where choanal atresia is responsive to early surgery and may lessen the likelihood of later tracheostomy or continuing management, other obstructions might not be as amenable.[25]

 

Presentation

History

History findings are described below.[1, 3, 6]

Bony face deformity is observed at birth, followed with time by other factors of the syndrome.

Patients report headache.

Convulsions often occur; mental retardation is frequently observed.

Visual acuity is reduced.

Physical Examination

Physical examination findings are described below.[1, 3, 4, 6, 25, 26, 27, 28]

Coronal and sagittal sutures are obliterated; fontanels remain not obliterated and pulsating for a long time.

Lateral and anteroposterior flattening of the acrocranium is observed, growing only at the vertical axis.

Anteroposterior diameter is smaller than transverse diameter.

The forehead is high and wide.

Wide face and hypoplastic maxilla producing pseudoprognathism are observed. See an example shown below.

Deviation of the nasal septum, narrowed or obliterated anterior nares, and wide beaked nose are present.

Hypertelorism, divergent squint, eyelid scheme antimongoloid, shallow orbits, and upper eyelid falling "frog face" are observed. See the image shown below.

Acrocephaly, beaked nose, "frog face," and pseudop Acrocephaly, beaked nose, "frog face," and pseudoprognathism of Crouzon syndrome.

Proptosis has been observed.

The upper lip is shortened and sometimes cleaved.

Malocclusion, malposed teeth, hypsistaphylia (narrow/high-arched palate), rhinolalia, and dysphasia are noted (as depicted below).

Malposed teeth and acanthosis nigricans around the Malposed teeth and acanthosis nigricans around the mouth in Crouzon syndrome.

Hypodontia may occur.

Characteropathy is often observed.

Short stature and no physiologic spinal curvature are observed. Children are straight as a reed. Refer to the following images.

No physiological spinal curvature is observed in C No physiological spinal curvature is observed in Crouzon syndrome.
Short stature and dark skin of Crouzon syndrome. Short stature and dark skin of Crouzon syndrome.

Koilosternia rarely occurs.

Skin usually is dark.

Syndromic acanthosis nigricans appears in the axillary fossa, mouth angular, and on the lips in childhood.

In a rare case study, deep linear creases on the lips, ear lobes, palms, and soles of the feet were observed, along with redundant skin on the scalp.[29]

In lieu of an in-person physical examination, some phenotypic assessment tools based on standardized photographs can be used to evaluate patients with general craniofacial microsomia.[30]

Complications

Several complications can arise from Crouzon syndrome as result of its characteristic external and internal malformations.

Papilledema may occur due to intracranial hypertension.[5]

There is a high prevalence of cerebrospinal fluid rhinorrhea.[31]

Progressing optic nerve atrophy leads to vision impairment because of the intracranial hypertension.

One case study of a younger patient found that spontaneous prolapse of the eyeball due to rubbing occurred when shallow orbit and proptosis were present.[32]

Impairment of hearing indicates disorders of the middle ear or, according to one case study, atresia of the external auditory canals.[33]

Psychological and sociobehavioral issues have resulted from social stigmas associated with visible manifestations of craniosynostosis.[19, 22, 23, 24]

Developmental and cognitive disabilities have been correlated with intracranial pressure from untreated craniofacial malformations (eg, cranial vault abnormalities).[33, 34]

The incidence of chronic tonsillar herniation (eg, Chiari malformation type I) is correlated highly with Crouzon syndrome.[35, 36]

Neurolinguistic abilities may be affected as a result of craniosynostosis.[37]

 

DDx

Diagnostic Considerations

Crouzon syndrome can present with acanthosis nigricans. During genetic testing, if no mutations are identified for FGFR2, a review of mutations on FGFR3 should be conducted. Crouzon syndrome comorbid with acanthosis nigricans typically yields positive results for the latter, while Crouzon syndrome without acanthosis nigricans is associated with the former.[14, 19, 38]

In the course of genetic testing—should either mutations of FGFR2 or FGFR3 be absent—a screening for the interleukin 11 receptor alpha gene (IL11RA) on band 9p21 may prove fruitful. A case study conducted on members of a consanguineous family found evidence that Crouzon-like symptoms could manifest based on mutations in IL11RA.[39]

Differential Diagnoses

 

Workup

Laboratory Studies

Histopathologic examination of skin changes can reveal acanthosis nigricans.

Imaging Studies

Imaging studies are described below.[1, 3, 4, 6, 38]

Skull, spine, and hand radiography is usually necessary to confirm the diagnosis.

Skull radiography reveals the following:

  • Oxycephaly - Acrocranium (most characteristic), obliterated sutures (mostly coronal, sagittal)
  • Deep digitate impression, shallow eye sockets (exophthalmos)
  • Turkish saddle deepened with osseous sternum connecting anterior and posterior clinoid processes
  • Shortened anterior cranial fossa
  • Cranial base deformity; develops sequentially from anterior to posterior [40]
  • Underdeveloped lateral nasal sinuses
  • Tympanic membranes fixed oblique, narrowed external auditory canals, absence of mastoid processes pneumatization, and small pyramids with symptoms of sclerosis

On spine radiography, lumbarization and the presence of bifid spinous process are possible, and slight symptoms of achondroplasia may be visible.

Radiographic examination of the metacarpal bones and fingers reveals slight achondroplasia.

Two- and three-dimensional ultrasonography have been used to screen for symptoms associated with the disorder prenatally, but genetic testing would be required to confirm the results.

Other Tests

Other tests may include the following:

  • Ophthalmologic examination with ophthalmoscopy
  • Laryngologic examinations with audiography
  • General physical examination with ECG
  • Psychiatric examinations and psychological testing
  • Stomatologic examination
  • EEG - Low-voltage, increased convulsive excitability
  • Genetic testing

Histologic Findings

Histologic features of acanthosis nigricans include hyperkeratosis, acanthosis, and papillomatosis. In the basal layer, the amount of pigment cells is also increased in the upper dermis. No difference exists in histologic features of acanthosis nigricans among symptomatic, benign, and malignant forms.

 

Treatment

Approach Considerations

Patient care necessitates multifaceted specialization and management. High among the approaches is the implementation of plastic reconstructive surgery, which has been found to have immediate benefits. Despite the reparative effects of surgeries, continued follow up is still generally required for patients (dependent upon the severity of the malformations).[23]

On the horizon for drug therapies, an US Food and Drug Administration–approved trial for compounds (leflunomide, cyclosporin A, and their functional analogs) that influence craniosynostosis is at animal testing level and has shown some effect.[41]

Medical Care

Nonsurgical treatment of Crouzon syndrome has been performed using orthopedic and orthodontic devices, as well as prosthetics.[42, 43]

Patients with sleep-disordered breathing as a consequence of syndromic craniosynostosis have been treated with Tübingen palatal plate appliances as well as continuous positive airway pressure machines.[34]

Speech and language therapy is common, and hearing aids may benefit patients affected by hearing impairment.[22]

Surgical Care

Neurosurgical procedures such as decompressive craniectomy are recommended in cases of intracranial hypertension, which can cause papilledema and optic atrophy. This surgery is difficult, and the procedure must be considered and undertaken in stages. Papilledema may persist despite craniectomy.[5] For intracranial hypertension derived from hydrocephalus, ventriculoperitoneal shunts have also been found to be effective.[19, 31]

Facial plastic surgery can be of great benefit.[44] It is usually based on various craniofacial osteogenesis distraction methods and systems; patients usually wear a custom-fitted helmet (or cranial band) for several months after surgery.[6, 45, 46, 47, 48, 49, 50, 51, 52] Additionally, ocular surgeries (eg,. lateral canthoplasty) have been used to repair the antimongoloid slants found in patients afflicted by craniosynostosis.[53] It is one of the few syndromes for which the cosmetic results of the surgery can be strikingly effective. The surgery minimizes the risk linked to the neurological complications, but it also has an impact on stigmatization feelings and the psychological and social implications.[23] Respiratory difficulties may be alleviated by tracheostomy or nasal stents.[19, 34]

Minimally invasive endoscopic surgery can be used to repair cerebrospinal fluid leaks.[31]

Asymptomatic patients could have malocclusions repaired with orthodontic treatment using orthognathic surgery (but may also forgo it).[19]

Consultations

Consultations with audiologists, ophthalmologists, otorhinolaryngologists, neurologists, neurosurgeons, pediatricians, psychiatrists, reconstructive surgeons, speech pathologists, and stomatologists are usually required.

Complications

Complications that may occur from surgical procedures are described below.[23, 31, 52, 54, 55]

Osteotomies (namely Le Fort II and III) can lead to infraorbital nerve damage, orbital/globe injury, strabismus, excess blood loss, and infection. In one case study, cerebrospinal fluid rhinorrhea and sinus pain persisted despite no initial complications post surgery.

Distraction osteogenesis can have complications such as surgical site infections (superficial and deep), abscess formation, correction device failures (eg, distractors), and asymmetric advancement.

For reconstructive surgeries of craniofacial malformations in general, psychological issues may arise from the consequences of multiple surgeries and recuperation periods. For younger patients, postoperative hospitalizations can affect school attendance, which can produce stigmatization by peers (eg, intrusive questions about physical changes or absences) or being held back from progressing in their education.

Owing to the respiratory issues associated with Crouzon syndrome, anesthesiologists may encounter difficulties with airway management and intubation when the patient is placed under general anesthesia.

Long-Term Monitoring

Children with syndromic craniosynostosis have been found to be at increased risk of sleep-disordered breathing such as obstructive sleep apnea syndrome. In one study, children with Crouzon were subsequently also affected by a higher likelihood of daytime sleepiness.[34, 56]