Genetics of Crouzon Syndrome Clinical Presentation

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

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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.

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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]

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