Physician: Education: Descriptions of Disorders

Crouzon syndrome is estimated to occur in approximately 1 in 25,000 individuals in the general population.

The main feature of Crouzon syndrome is craniosynostosis (premature fusion of two or more skull bones). Crouzon syndrome is distinguished from most other craniosynostosis syndromes by the lack of obvious hand or foot abnormalities. The manifestations of this condition are generally limited to the skull and face. However, cervical spine abnormalities are fairly common, and a smaller percentage of patients may have subtle elbow, hand, musculoskeletal, or internal anomalies. Craniosynostosis, the early closure of skull sutures (meeting place of two bony surfaces) often leads to an abnormal head shape. There is considerable variability in physical appearance between patients. The most common finding is brachycephaly (a shortened distance between the front and back of the head) due to early closure of one or both coronal sutures. Other sutures can be involved as well, and the most dramatic appearance would be that of a cloverleaf (kleeblattschadel) skull deformity when multiple sutures are affected. The most consistent facial feature is prominent eyes. Specifically, the eyes appear to protrude outward (a condition called proptosis) because the bony sockets in which they are held are unusually shallow. Patients may have irritation and dryness of the eyes because the eyelids do not completely cover the eyes during sleep. The eyes may not be perfectly aligned, and may each point slightly outward (exotropia). This may contribute to the visual problems reported by approximately half of Crouzon syndrome patients. Other eye problems include atrophy (wasting) of the optic nerve, and blindness in a small (7-10%) subset of patients. Hearing loss is also common, affecting approximately one half of individuals with Crouzon syndrome. The nose is usually prominent, and is described as beaked or "parrot-like". Dental problems include crowding of teeth, and the appearance of a high, narrow palate. Cleft lip with or without cleft palate occurs in a small percentage of patients. Physical characteristics outside the craniofacial region include abnormalities of the cervical (neck) spine, and acanthosis nigricans. The latter condition, which occurs in a few cases, describes a darkened coloration and velvety feel to patches of skin on the neck, eyelids, and around the mouth.

Crouzon syndrome is an autosomal dominant condition caused by mutation in the FGFR2 (fibroblast growth factor receptor 2) gene on chromosome 10. Multiple mutations in this gene have each been found to cause Crouzon syndrome. Some of the same mutations have also been found in association with other craniosynostosis syndromes. In some patients who have both Crouzon syndrome and acanthosis nigricans, mutations have been found in the FGFR3 gene located on chromosome 4. Crouzon syndrome often arises spontaneously in a family (when an affected child is born to two unaffected parents). This is due to a random or sporadic change (mutation) in the FGFR gene passed down from one parent. Such new mutations are found to occur more frequently with advancing age of the father. Crouzon syndrome may also be inherited from an affected parent. In this instance, there is a 50% chance with each pregnancy for an affected parent to pass the disorder to his/her child. Because of the wide variability in severity of Crouzon syndrome, the child's features may be more or less severe than those of the parent. Pathophysiology: Please refer to the Pathophysiology section under Craniosynostosis.

The TWIST gene which is known to cause Saethre-Chotzen syndrome serves as a transcription factor (protein that regulates the production of other gene products). Specifically, it may produce a transcription factor which works with the fibroblast growth factor receptor (FGFR) gene family, known to cause craniosynostosis in humans. The TWIST gene is known to be active in the development of the head and limbs. If this gene is not working properly, the tissues in these regions may become "disorganized", causing problems in both locations (head/face asymmetry, early closure of the skull bones, "droopy" eyes, and shortened or webbed digits).

The diagnosis of Crouzon syndrome has long been made on a clinical basis. The combination of craniosynostosis (especially of the coronal sutures), typical facial features and lack of hand/foot abnormalities would suggest this as a diagnosis. The lack of hand or foot abnormalities helps to distinguish Crouzon syndrome from other conditions which may have a similar facial appearances (such as Apert, Pfeiffer, and Jackson-Weiss syndromes). Diagnosis can also be confirmed by the finding of a mutation in the FGFR2 or FGFR3 gene. However, several mutations have been found in common in patients with different clinical diagnoses (i.e., Crouzon and Pfeiffer syndromes). The large degree of overlap of physical features between the common craniosynostosis syndromes, as well as the finding of identical mutations in different syndromes will force us to rethink our current diagnostic criteria. In time, we may not be able to distinguish individual syndromes based on molecular information, but consider them all to fall along a spectrum of FGFR-related disorders.

At this time, the gene defect causing Crouzon syndrome cannot be corrected. Treatment is generally geared toward surgical correction of skull deformity, intervention to address significant orthodontic issues, and individual attention to any other complications in that particular patient. The need for correction of skull shape is quite varied. More severely affected individuals may have closure of skull sutures prior to birth, and require early surgical intervention. Indications for early intervention include pansynostosis (closure of all skull sutures leaving no capacity of the skull to expand for brain growth) and an increase in the pressure inside the skull which can lead to blindness, hearing loss, and death if not corrected. Patients with Crouzon syndrome are often best cared for by a team of craniofacial experts in which professionals in plastic surgery, ear/nose/throat surgery, dentistry, orthodontics, genetics, and audiology can address the patient's multiple needs.

Head First, Inc.

National Organization and Support Group for People of Short Stature

Headlines Craniofacial Support
FGFR2 [MIM176943]
OMIM 123500

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