Genetics of Crouzon Syndrome 

Updated: Dec 05, 2018
Author: Marie M Tolarova, MD, PhD, DSc; Chief Editor: Maria Descartes, MD 

Overview

Practice Essentials

Severe cases of craniosynostosis syndromes, such as Crouzon syndrome, do not present diagnostic problems. More diagnostically challenging, however, are patients with Crouzon syndrome who demonstrate mild or no dysmorphology in infancy, especially when Crouzon syndrome is absent in parents and other relatives. Therefore, abnormal head shape in infants and even slight facial dysmorphology need to be followed up.

When diagnosed, an infant needs to be referred to a craniofacial center with a track record for treating syndromic craniosynostoses. Multidisciplinary management is critical, especially because surgeries and other procedures are time sensitive. A medical geneticist should be involved through the duration of all treatments.

Crouzon syndrome is named after the French neurologist Louis Edouard Octave Crouzon (1874-1938), who had a deep interest in hereditary neurologic diseases. He described the syndrome as hereditary dysostosis craniofacialis, detailing its presence in a mother and her son, both of whom had a triad of craniofacial deformities, facial anomalies, and exophthalmos.

Crouzon syndrome belongs to a large and heterogeneous group of conditions presenting with craniosynostosis, a common symptom of which is early fusion of one or more cranial sutures. Craniosynostoses have an estimated prevalence of 1 in 2100 to 2500 live births.[1, 2] The major division among craniosynostoses is between the nonsyndromic and syndromic forms. The syndromic forms, which are hereditary, make up 15-30% of all cases.[2] Crouzon syndrome accounts approximately for 4.8% of all cases of craniosynostosis, with the estimated birth prevalence ranging widely, from 1 in 25,000 in early studies[3] to 1 in 60,000 in later studies.[4, 5]

Inheritance of Crouzon syndrome is autosomal dominant, with complete penetrance and variable expressivity.[6] In about 25% of cases, a negative family history of Crouzon syndrome is observed, with the condition in these instances presumably arising from a fresh mutation.

Crouzon syndrome involves premature synostosis of coronal and sagittal sutures, starting in the first postnatal year. Once closed, the sutures have restricted growth potential. Premature fusion of skull base sutures is often seen in cases of multiple sutural synostoses, with the resulting occurrence of midfacial hypoplasia, shallow orbits, a foreshortened nasal dorsum, exophthalmos, maxillary hypoplasia, and occasional upper airway obstruction.[7]

Unlike some other forms of autosomal dominant craniosynostosis, no digital abnormalities are present in Crouzon syndrome. See the image below.

Child with Crouzon syndrome. Note midfacial hypopl Child with Crouzon syndrome. Note midfacial hypoplasia, proptosis secondary to shallow orbits, and ocular hypertelorism.

Pathophysiology

Craniosynostosis is an important cause of childhood morbidity.[8]  Crouzon syndrome arises from mutations in the fibroblast growth factor receptor-2 (FGFR2) gene. Crouzon syndrome with acanthosis nigricans (also called Crouzonodermoskeletal syndrome) has causal mutations in the FGFR3 gene.[9]

Sutures have a number of important functions, including provision of skull flexibility that allows changes in skull volume, thus accommodating brain growth in early life. They also maintain rigid connections between adjacent bones and, once central nervous system (CNS) growth is complete, provide for the alignment and fusion of adjacent bones.[8] Premature closure of cranial sutures results in craniofacial dysmorphology.

In the case of Crouzon syndrome, premature synostosis of the coronal, sagittal, and, occasionally, lambdoidal sutures begins in the first year of life and is completed by the second or third year. The order and rate of suture fusions determine the degree of deformity and disability. Once a suture becomes fused, growth perpendicular to that suture becomes restricted and the fused bones act as a single bony structure. Compensatory growth occurs at the remaining open calvarial sutures (parallel to the closed suture) to allow continued brain growth. Surgical intervention is required to alleviate raised intracranial pressure and to correct calvarial, facial, and dental deformations.[8]

Severe complex pansynostosis of all sutures leads to a so called cloverleaf skull, in which the brain protrudes through the open anterior and parietal fontanelles. As mentioned earlier, premature fusion of skull base sutures is often seen in cases of multiple sutural synostoses, with the resulting occurrence of midfacial hypoplasia, shallow orbits, a foreshortened nasal dorsum, exophthalmos, maxillary hypoplasia, and occasional upper airway obstruction.[7, 10]

Epidemiology

Birth prevalence

Craniosynostosis, in which one or more cranial sutures prematurely fuse, is a common malformation occurring in approximately 1 in 2000 live births. Of those, about 70-85% of cases are nonsyndromic. The rest consist of over 180 syndromes.[11]

Crouzon syndrome is now recognized as one of the most common craniosynostosis syndromes.[12] It accounts for approximately for 4.8% of all cases of craniosynostosis, with a birth prevalence 16.5 per million live births (1 in 60,000).[4] This figure may have been slightly overestimated, however, due to inclusion of cases of Muenke syndrome[12] and possibly also Saethre-Chotzen syndrome. Birth prevalence of 1 in 25,000 live births, from Cohen’s early paper,[3] is still often cited in the literature, but this figure most likely included other craniosynostosis cases and syndromes.

There are two explanations for the inconsistency of reported birth prevalence. First, the phenotypic features may not be present at birth and may instead develop gradually during the first year of life.[13] Second, even if there is a high or complete penetrance of a mutated allele, expressivity ranges widely, from very severe to mild. Very often, the mild forms are underascertained, as they may not lead an individual to seek a treatment. Mild forms may be diagnosed when relatives of patients with typical features of Crouzon syndrome are carefully examined.

Parental age

Glaser demonstrated strong evidence of a paternal age effect in the development of sporadic Crouzon syndrome,[14] although the association between older paternal age and sporadic mutations in Crouzon and Pfeiffer syndromes was described as early as 1975 by Jones and colleagues.[15] It has been suggested that the paternal age/Crouzon syndrome link may result from the accumulation of mutations in the germ line of older men or from the presence of a greater susceptibility to mutations in this age group.[14]

Sex

There is no sex predilection; males and females are equally represented among Crouzon cases.

Ethnicity

Individuals affected with Crouzon syndrome have been described in all ethnicities.

Morbidity

Morbidity in Crouzon syndrome depends on the severity of dysmorphology, symptoms, and treatment procedures, especially surgeries. The premature fusion of cranial sutures leads to facial and cranial dysmorphology, midface hypoplasia, shallow orbits, a foreshortened nasal dorsum, hypertelorism, ocular defects, and, occasionally, upper airway obstruction. Progressive hydrocephalus is common, occurring in about 30% of patients.[16] Crouzon syndrome has been associated with moderate cognitive impairment,[17, 18] but CNS abnormalities and high intracranial pressure are less frequent in Crouzon syndrome than in Apert syndrome.[19] There are no limb malformations involved in Crouzon syndrome.

Prognosis

Early and correct diagnosis of Crouzon syndrome is critical for treatment planning and timing of every procedure. Prognosis depends on the severity of Crouzon syndrome. Care of a multidisciplinary team and case management in a craniofacial center is important. However, even very severe cases of Crouzon syndrome requiring several surgeries and challenging multidisciplinary treatment from infancy to adulthood can, eventually, present with excellent outcomes.

Patient Education

Crouzon Support Network

A program of AmeriFace

PO Box 751112

Las Vegas, NV 89136

24-Hour Toll-free Hotline: (888) 486-1209

Phone:  (702) 769-9264, Fax: (702) 341-5351

http://www.crouzon.org/

info@ameriface.org

National Organization for Rare Disorders, Inc. (NORD)

55 Kenosia Ave

Danbury, CT  06810

Phone: 203-744-0100

Fax: 203-263-9938

https://rarediseases.org/rare-diseases/crouzon-syndrome/

March of Dimes

1550 Crystal Drive, Suite 1300

Arlington, VA  22202

Phone: 888-663-4637

FACES: The National Craniofacial Association

PO Box 11082

Chattanooga, TN 37401

Phone: (423) 266-1632

Toll-free: (800) 332-2373

Email: faces@faces-cranio.org

Cleft Palate Foundation

1504 East Franklin Street, Suite 102

Chapel Hill, NC 27514-2820

Phone: (919) 933-9044

Toll-free: (800) 242-5338

Fax: (919) 933-9604

Email: info@acpa-cpf.org

 

Presentation

History

A detailed family history covering three generations should be taken in each case of Crouzon syndrome that is diagnosed or considered. Take into account that mild and moderate forms of Crouzon syndrome be undiagnosed in families. It is always useful to perform a detailed clinical examination of parents or, if possible, of all first degree relatives of a patient. Attention should be paid to any mild or minimal dysmorphology of the eyes, ears, nose, palate, and teeth in these relatives, but if examination is not possible, it is often helpful to observe photos of these individuals. Parental age at the time of conception of a patient with Crouzon syndrome is also important to note, especially if no Crouzon syndrome is observed in either parent and de novo mutation is being considered. 

The history of pregnancy (antenatal history) is also important, as treatment of pregnant mothers with teratogenic drugs like valproate or fluconazole has been found to be associated with craniosynostosis.[20]

The medical history of patients with craniosynostosis syndromes needs to cover time, types, and complications of surgical interventions; developmental milestones; cognitive development; and any problems related to possibly elevated intracranial pressure and to vision, hearing, and airway. If cleft palate was present, then speech problems need to be described. Development of dentition and occlusion should also be included in the medical history.

Causes

Crouzon syndrome (OMIM: 123500) is caused by mutations in FGFR2, mapped to chromosome locus 10q26.13.[5] Indeed, mutations in the FGFR2 gene have been detected in more than 50% of patients with Crouzon syndrome. (About 50% of cases of Crouzon syndrome are sporadic, with some of them having been shown to be the result of fresh mutations.) FGFR2 mutations also cause Pfeiffer syndrome, Apert syndrome and Jackson-Weiss syndrome.[5, 21, 22, 23]  The majority of mutations have been detected in the third immunoglobulin-like (Ig III) domain and in a linker region between Ig II and Ig III of the FGFR2 gene. Most of these mutations are missense. Several mutations leading to changed alternative splicing were recognized in exon IIIb and exon IIIc.[9, 11]

The majority of mutations (over 76) causing Crouzon syndrome have been found in the Ig III domain, although some have occurred in the tyrosine kinase domain of the FGFR2 gene.[24, 9, 11, 25, 8, 26, 14] They are generally gain-of-function mutations leading to constitutive activation of the FGFR2 receptor without a need for ligand binding. Increased functioning of the FGFR2 receptor leads to a premature closure of the cranial sutures.[27] A characteristic midface retrusion may be due to additional gene-to-gene interactions during development.[28]

Note that in addition to the fact that FGFR2 mutations are observed in Apert syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome, those syndromes are caused by similar Pro(250, 252, 253)Arg mutations in the Ig II-III linker region of different FGFR genes; Pro252Arg in FGFR1 is one of the genetic factors causing Pfeiffer syndrome, while Pro253Arg and Ser252Trp in FGFR2 are detected in 98% of Apert syndrome cases. These syndromes have a similar skull phenotype (turribrachycephaly) that is distinct from the phenotype of the Crouzon syndrome skull. The mutations in the Ig II-III linker region lead to an increased ligand sensitivity or altered ligand specificity of the FGFR2 receptor, resulting also in its increased functioning.[29]

Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome, OMIM: 612247) represents a clinically and genetically distinct entity from "classic" Crouzon syndrome. Indeed, craniosynostosis is associated with abnormalities in skin and skeleton. Mutation Ala391Glu in the transmembrane domain of the FGFR3 gene leads to ligand-independent constitutive activation of FGFR3.[30]

The phenotypic spectrum of the Pro250Arg mutation in the linker region of the FGFR3 gene, called Muenke craniosynostosis or FGFR3-associated coronal synostosis,[31]  is so widely variable that patients with this mutation have been diagnosed with Crouzon syndrome, Pfeiffer syndrome, Saethre-Chotzen syndrome, Jackson-Weiss syndrome, and even nonsyndromic craniosynostosis.

Physical Examination

Dysmorphology in fully developed Crouzon syndrome is characteristic, which means that a physical examination, including a broad clinical evaluation, is often the first step in diagnosis. Characteristic phenotypic features include craniosynostosis, maxillary hypoplasia, shallow orbits, and ocular proptosis. Such evidence may in some cases be present at birth, but in most cases it develops gradually during the first year of life.[32]

Craniofacial abnormalities

The order, rate, and progression of sutural synostoses are the key factors in cranial malformation. Craniosynostosis commonly begins during the first year of life and usually is completed by 2-3 years of age. The most common result is brachycephaly, but scaphocephaly and trigonocephaly are also seen.[24, 33] Cloverleaf skull is most severe but rare, developing in about 7% of Crouzon syndrome patients.[34]

Involvement of multiple sutures is eventually found in most patients: coronal and sagittal in 20%; coronal, sagittal, and lambdoidal in 75%; and sagittal and lambdoidal in 4%.[32]

In all cases of Crouzon syndrome, ocular proptosis of variable severity (owing to shallow orbits), with or without divergent strabismus, is observed. Conjunctivitis or keratitis results from a high frequency of exophthalmos-associated eye exposure. Hypertelorism and frontal bossing may be observed in some cases.

Midface hypoplasia in Crouzon syndrome may cause upper airway problems. Nasal septum deviation may also be present. 

In addition to performance of a clinical observational exam, objective measurements should be taken, including head circumference; interpupillary, inner canthal, and outer canthal measurements; palpebral fissure length; and ear and philtrum lengths.[11]

Eyes

Exotropia is very common, and luxation of the eyeballs has been observed in some cases. Approximately 46% of patients experience poor vision, with optic nerve atrophy found in 22% of patients, and blindness in 7%.[32]  Not-so-common findings include nystagmus, coloboma of the iris, aniridia, anisocoria, microcornea, macrocornea, cataract, and glaucoma.[32]

Visual acuity, ocular motility, anterior segment structures, and the retina, as well as the optic disc (for signs of papilledema), should be assessed, with ophthalmologic examination carried out via a standard protocol and cycloplegic retinoscopy.[11]

Ears

Conductive hearing deficit is found in approximately half of patients with Crouzon syndrome. In addition, some patients exhibit atresia of the external auditory canal.

Oral cavity and dental anomalies

Lateral palatal swelling is observed in about a half of patients with Crouzon syndrome, but in the majority of such cases, it does not present as a median pseudocleft, which is more typical in Apert syndrome. Cleft lip and palate and cleft palate are rare. The maxilla is hypoplastic, and the anteroposterior dimension of the maxillary dental arch is shortened. In addition, the dental arch width is reduced. Malocclusions include mandibular prognathism, unilateral or bilateral crossbite (in about 60% of patients with Crouzon syndrome), crowding, ectopic eruption of maxillary first molars, and anterior open bite.[32, 35]

Central nervous system

Progressive hydrocephalus, chronic herniation of cerebellar tonsils, and jugular foramen stenosis on the skull base with venous obstruction, headaches, and seizures may occur. An age-appropriate clinical neurologic assessment should be performed for diagnosis of seizures, evidence of intracranial pressure alterations, facial palsies, sensory impairment, and other neurologic signs and symptoms. Chiari I malformation may be asymptomatic in the first year of life or may be present with signs of increased intracranial pressure (headache, vomiting), ataxia, spasticity, and abnormalities of breathing, swallowing, or sleep. If craniosynostosis involves multiple sutures, the incidence of increased intracranial pressure can reach 62%. If only one suture is involved, there is still a risk of about 7%.[36]

Detailed neurobehavioral assessment may be warranted for patients experiencing difficulties in a regular classroom, as learning disabilities have been reported in patients with sagittal craniosynostosis.[37, 38]

 

DDx

Diagnostic Considerations

A thorough clinical examination forms a basis for diagnostic considerations. The clinical examination should include medical history and pregnancy history of the mother; family history of parents, first-degree relatives, and other available relatives; and clinical examination of these relatives. It is very useful to construct a pedigree showing affected individuals. Objective measurements of the head, a thorough examination of the eyes and extremities, and a general examination of all organ systems to reveal even subtle malformations should be performed. Neurologic assessment, ophthalmologic and audiologic examinations, and a thorough radiologic examination of the head and extremities are necessary.

It is necessary to establish the diagnosis of a proband. Findings on the initial evaluation (complete medical history, physical examination, review of systems, family history) should help to direct a selection of the most appropriate molecular genetic study (see Table 1).

 Table 1. Skeletal features that help to distinguish craniosynostosis syndromes* (Open Table in a new window)

Disorder

Thumbs

Hands

Great Toes

Feet

Targets for genetic testing

Crouzon syndrome

Normal

Normal

Normal

Normal

FGFR2

Crouzon syndrome with acanthosis nigricans

Normal

Normal

Normal

Normal

FGFR3

Apert syndrome

Fusion of thumb to fingers is occasionally seen

Soft tissue with or without  bone syndactyly

Fusion of great toe to other toes is occasionally seen

Soft tissue with or without bone syndactyly

FGFR2

Pfeiffer syndrome

Broad, medially deviated

Variable brachydactyly

Broad, medially deviated

Variable

brachydactyly

FGFR1, FGFR2

Muenke

syndrome

 

Normal

With or without carpal fusion

May or may not be broad

Tarsal fusion may or may not be present

FGFR3

Jackson-Weiss syndrome

Normal

Variable

Broad, medially deviated

Abnormal tarsals

FGFR2

Beare-Stevenson syndrome

Normal

Normal

Normal

Normal

FGFR2

*Adapted from Robin et al (2011).[39]

Differential Diagnoses

  • Apert syndrome (OMIM: 101200)

    Craniosynostosis, midface hypoplasia, and hand and foot syndactyly, with bony structures tending to fuse. Inheritance is autosomal dominant, resulting from mutations in the Ig II-III linker region of the FGFR2 gene.

  • Beare-Stevenson cutis gyrata syndrome (OMIM 123790)

    Craniosynostosis is associated with cutaneous disorders (cutis gyrata, acanthosis nigricans). Inheritance is autosomal dominant, resulting from mutations of the FGFR2 gene.

  • Carpenter syndrome (OMIM 201000)

    Craniosynostosis (acrocephaly), brachydactyly of the hands with syndactyly, preaxial polydactyly and syndactyly of the feet, congenital heart defects, growth retardation,

    mental retardation, hypogenitalism. Inheritance is autosomal recessive.

  • Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome; OMIM: 612247)

    Craniofacial features are similar to those observed in patients with classic Crouzon syndrome (craniosynostosis with Crouzonoid facies), in addition to acanthosis

    nigricans and other severe physical manifestations, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanae. Unlike classic Crouzon syndrome, which lacks any specific cutaneous features, the presence of acanthosis nigricans is essential for the clinical diagnosis of Crouzon syndrome with acanthosis nigricans. Affected individuals develop early onset, severe, and widespread rugose thickening and hyperpigmentation of the skin.

    In addition to the most common locations on the neck and in axillae, patients with Crouzon syndrome with acanthosis nigricans are affected periorally and periorbitally,

    on the chest, around the umbilicus, and on the breasts.

    Notably, the endocrine abnormality typical of patients with acanthosis nigricans is lacking. Genetically, the diagnosis is confirmed by detection of the specific missense

    Ala391Glu mutation in the transmembrane domain of the FGFR3 gene. Inheritance is autosomal dominant.

  • Jackson-Weiss syndrome (OMIM 123150)

    Craniosynostosis, midfacial hypoplasia, and foot anomalies in an Amish kindred. Broad great toes with varus deviation and tarsal/metatarsal fusions, lack of

    thumb abnormalities, craniofacial features suggestive of Pfeiffer syndrome. Inheritance is autosomal dominant, caused by mutations in the Ig III domain of the FGFR2 gene.

  • Muenke syndrome (OMIM: 602849)

    Unicoronal or bicoronal synostosis, macrocephaly, midfacial hypoplasia, and developmental delay. Thimble-shaped middle phalanges, brachydactyly, carpal and tarsal fusions, and deafness are more variable characteristics of the disease. Exhibiting a variable phenotype, Muenke syndrome arises via autosomal dominant inheritance, resulting from a Pro250Arg mutation in the Ig II-III linker region of the FGFR3 gene.

  • Pfeiffer syndrome (OMIM 101600)

    Craniosynostosis, hand and foot abnormalities characterized by broad thumbs and halluces with occasional cutaneous syndactyly, mild cranial deformities,

    lack of osseous fusion of the phalanges. Inheritance is autosomal dominant, caused by mutation in the Ig II-III linker region of the FGFR1 gene or in the

    Ig III domain or tyrosine kinase domain of the FGFR2 gene.

  • Saethre-Chotzen syndrome (OMIM 101400)

    Craniosynostosis, characteristic facies, relatively mild cranial deformity, normal thumbs, and lack of osseous fusion of the hand bones are the main features. Inheritance is autosomal dominant, caused by TWIST1 loss-of-function mutation in 46-80% of patients. TWIST1 is a transcriptional regulator that inhibits expression of the RUNX2 gene, which is a master gene for ossification. TWIST1 decreased function leads to increased functioning of RUNX2 and accelerated ossification of cranial sutures. (Cunningham et al, 2007)

  • Solitary cases of Crouzon syndrome are caused by fresh mutations.

 

Workup

Laboratory Studies

Molecular genetic analysis

Identification of a mutation in the proband should be followed by genetic testing of the parents. It has been suggested to start with testing for FGFR3 mutations, followed by testing for FGFR2, FGFR1, and TWIST1 mutations.[11]  The detection rate of known mutations varies in different craniosynostosis syndromes (see Table 2).

Table 2.  Efficiency (mutation detection rate) of molecular testing* (Open Table in a new window)

Syndrome

Gene

Mutation Detection Rate

Pfeiffer

FGFR1,FGFR2

  67%

Apert

FGFR2

>98%

Crouzon

FGFR2

>50%

Crouzonodermoskeletal  

FGFR3

 100%

Muenke

FGFR3

 100%

Saethre-Chotzen

TWIST1

   46-80%

*Adapted from Kimonis et al (2007).[11]

The presence of parental mosaicism can be checked by DNA sequencing technology. Findings may be helpful in genetic counseling with regard to recurrence risk of paternal age–effect syndromes in a family with a single affected child.[40]

All Crouzon-like patients with associated acanthosis nigricans have the FGFR3 Ala391Glu mutation. If testing is performed on a child with features of Crouzon syndrome during the first year of life (before the usual onset of acanthosis nigricans), concurrent testing for FGFR2 and FGFR3 mutations is recommended.

Prenatal diagnosis may be carried out by chorionic villus sampling in the 10th to 14th week of gestation. Preimplantation genetic diagnosis is possible for parents who have been identified as heterozygotes for the mutation.

Imaging Studies

Imaging studies are a necessary part of the diagnosis of Crouzon syndrome and of treatment planning, management, and monitoring.

In the initial diagnosis of craniosynostosis, brain computed tomography (CT) scanning or magnetic resonance imaging (MRI) are used to evaluate the patient for hydrocephalus and structural anomalies. Three-dimensional (3D) CT scanning to assess the endocranial and ectocranial surfaces of the skull is considered the gold standard for determining the presence of craniosynostosis.[11]

Midface hypoplasia and orthodontic and surgical treatment of malocclusions require lateral cephalograms, panoramic radiographs, and cone-beam CT scanning. Additional imaging studies are needed for assessment of upper airway obstruction.

Skull radiography

Radiographic findings demonstrate synostosis, craniofacial deformities, digital markings of the skull, basilar kyphosis, widening of hypophyseal fossa, small paranasal sinuses, and maxillary hypoplasia with shallow orbits. The coronal, sagittal, lambdoidal, and metopic sutures may be involved

Cervical radiography

Radiologic abnormalities include butterfly vertebrae and fusions of the bodies and the posterior elements. Cervical fusions are present in approximately 18% of patients. C2-C3 and C5-C6 are affected with equal frequency. Block fusions involving multiple vertebrae are also observed.

Limb radiography

Hand abnormalities are radiographically detectable by metacarpophalangeal analysis, although the hands could be considered normal clinically. Subluxation of the radial head occurs.

CT scanning

Comparative 3D reconstruction analysis of the calvaria and cranial base precisely defines the pathologic anatomy and permits specific operative planning.

MRI

MRI is used to demonstrate occasional corpus callosum agenesis and optic atrophy.

 

Treatment

Medical Care

Treatment of patients with Crouzon syndrome requires interdisciplinary and multidisciplinary care and management and should be performed and coordinated in craniofacial centers that have ample experience with syndromic craniosynostoses. The correct and timely diagnosis of each symptom, as well as the timing of each procedure, is critical for preventing further problems, sequelae, and complications. The experienced craniofacial team will develop a treatment plan that will be adjusted as needed during the course of treatment.

Treatment considerations include the following:

  • A high prevalence of visual impairment in patients with craniosynostotic syndromes, such as Crouzon syndrome, has been reported; almost a half of the cases had potentially correctable causes, including amblyopia and ametropia [41]  
  • Early detection of eye problems to reduce amblyopia by correction of refractory errors and timely treatment of strabismus and patching are indicated; optic atrophy remains an important cause of visual impairment before cranial decompression [42]
  • To relieve airway obstruction, a nasal continuous positive airway pressure device may be needed
  • Close otologic and audiologic follow-up is indicated to detect sensorineural hearing loss
  • Management of speech may be necessary

Surgical Care

The goal of surgery is to stage reconstruction to coincide with facial growth patterns, visceral function, and psychosocial development.

Surgical treatment varies according to the variable expressivity of the disease. It usually begins during a child’s first year with fronto-orbital advancement with cranial decompression. Subsequent development of midfacial hypoplasia needs correction. Procedures for this purpose include the Le Fort III osteotomy or its segmental variants, monobloc frontofacial advancement, or bipartition osteotomy.[43]

Early decompressive craniectomy with frontal bone advancement is most often indicated to prevent or treat increased intracranial pressure because newborns with Crouzon syndrome develop multiple suture synostoses and fused synchondroses.

Fronto-orbital and midfacial advancements help in the cosmetic reconstruction of facial dysmorphic features.

The craniofacial disjunction procedure, followed by gradual bone distraction (Ilizarov procedure), has been reported to produce complete correction of exophthalmos and improvement in the functional and aesthetic aspects of the middle third of the face without the need for bone graft, in patients aged 6-11 years.

Adult Crouzon syndrome, often presenting with marked midface hypoplasia and exorbitism, can be corrected by orbital decompression and zygomaticomaxillary advancement.[43]

The following treatments may be necessary:

  • Shunting procedures for hydrocephalus
  • Tracheostomy for airway compromise
  • Myringotomy to drain middle ear secretions secondary to distorted nasopharynx
  • Orthodontic management

Consultations

A multidisciplinary team of specialists, including the following, is needed to coordinate the care of patients affected by Crouzon syndrome:

  • Neonatologist
  • Pediatrician
  • Neurosurgeon
  • Neurologist
  • Neuroradiologist
  • Plastic surgeon
  • Oromaxillofacial surgeon
  • Craniofacial anesthesiologist
  • Orthodontist
  • Dentist
  • Ophthalmologist
  • Clinical geneticist
  • Speech, physical, and occupational therapists
  • Psychosocial team

Diet

Appropriate diet is required after oromaxillofacial surgeries and during orthodontic treatment.

Activity

Appropriate restriction of activities is required only after cranial and oromaxillofacial surgeries.

 

 

Medication

Medication Summary

See the list below:

  • Drug therapy currently is not a component of the standard of care for Crouzon syndrome. See Treatment.

 

Follow-up

Further Outpatient Care

Carefully monitor postoperative complications.

Further Inpatient Care

Admit the patient with Crouzon syndrome for surgical intervention. Tracheostomy may be needed for airway management.

Transfer

Transfer may be indicated for further diagnostic evaluation and surgical intervention.

Complications

Complications can include the following:

  • Wound infections, frontal bone osteomyelitis, epidural abscess, and periorbital abscess
  • Increased intracranial pressure and postoperative hydrocephalus
  • Cerebrospinal fluid (CSF) leak
  • Respiratory distress and obstructive sleep apnea
  • Facial nerve palsy, blindness, diplopia, and velopharyngeal incompetence
  • Optic atrophy - Remains an important cause of visual impairment before decompressive craniectomy