Crouzon syndrome

Definition

Crouzon syndrome is a genetic condition that causes early closure of the bones in the skull. This event is called craniosynostosis and causes the skull to be formed differently in affected individuals. Because of the craniosynostosis, individuals affected with Crouzon syndrome will have the characteristic facial features described below.

Description

Other features of Crouzon syndrome include wide-set and prominent eyes. Individuals with this syndrome may also have a condition called strabismus, which means the eyes have difficulty focusing on objects. Other facial features may include an underdeveloped upper jaw, which causes tooth abnormalities. Individuals with Crouzon syndrome often have a beak-shaped nose and hearing loss. A skin condition, called acanthosis nigricans, occurs in approximately 5% of individuals with Crouzon syndrome. It is important to note that there is a wide range of severity in Crouzon syndrome. No two individuals with the condition will necessarily have all the listed features.

It is rare for individuals with Crouzon syndrome to have learning delays or mental impairments. Affected individuals often undergo several corrective surgeries, increasing the need for continual medical care throughout their lives. This can be very stressful and difficult for individuals and their families. Additionally, since people with Crouzon syndrome have significant facial differences, it may be difficult for them (and their parents) to feel accepted by society. There may be psychological implications, ranging from the affected person feeling bad for "looking different" to the parents having trouble bonding to their child for similar reasons. The psychological impact may be less if there are others in the family with Crouzon syndrome. Having more than one family member with this syndrome may help those affected feel less isolated and give them a stronger support system.

Genetic profile

Crouzon syndrome is caused by mutations in the FGFR2 (location 10q25.3-q26) and FGFR3 (location 4p16.3) genes. Crouzon syndrome is inherited in an auto-somal dominant manner. An affected individual has one copy of the FGFR mutation and has a 50% chance to pass it on to each of his or her children, regardless of that child's gender. As of 1997, about 75% of affected people have a family history of Crouzon syndrome, which is typically a parent with the condition. In the remaining 25%, the genetic mutation occurs as a new event in the affected individual, and there is no one in their family with the disease. These new mutations are thought to occur because of advancing paternal age, i.e. the age of the patient's father is a factor. Additionally, there is no increased recurrence risk for Crouzon syndrome above the general population risk when there is no family history of the condition.

FGFR2 and FGFR3 are responsible for the proper growth, movement, and creation of specific cells in the body, known as fibroblasts. Fibroblasts are often part of the bony structures in the body (such as the skull), so problems in fibroblast growth and movement would naturally lead to skull/bone problems. As of 1998, about 95% of patients have an FGFR2 mutation, and 5% have an FGFR3 mutation. However, nearly all of the affected individuals that also have acanthosis nigricans have one common FGFR3 mutation.

Demographics

As of 2000, Crouzon syndrome occurs in about one per 25,000 live births. It affects all ethnic groups equally.

Signs and symptoms

There commonly is bilateral (two-sided) coronal craniosynostosis in Crouzon syndrome. A cloverleaf skull may be present if the sagittal (long suture going from front to back of the head) and/or lambdoidal (short suture at very back of the head) sutures are involved. This causes the skull shape to be taller than usual, often described as "tower-shaped." The pattern looks like a cloverleaf because the skull is taller, and the sides of the skull and face bulge slightly from right to left. Additionally, the eye orbits are very shallow, causing the eyes to protrude significantly. This eye finding is always present in the condition. Strabismus may be present and eyes may be wide-set, making vision poor. Some individuals may have unexplained difficulties with their vision. The nose can be narrow and beak-shaped, forcing the individual to breathe through their mouth as a result.

The upper jaw may not be formed properly and can cause dentition problems, most commonly a missing tooth. The palate (upper ridge of the mouth) may be high and narrow, causing crowding of the existing teeth. Occasionally, clefting (improper closure) of the lip and palate may occur. Mild to moderate conductive hearing loss (due to abnormal ear structure formation) may occur in a proportion of cases.

Intellectual development is typically within normal limits. Only rare cases have been reported with significant mental deficiency. In about 30% of patients, hydrocephalus can occur. Hydrocephalus is an accumulation of fluid in the brain and skull, and this may progress or worsen with time. This typically shows up as a general enlarging of the skull. Sometimes the fluid can put increased pressure on various structures of the brain, limiting their growth and development. Hydrocephalus may be an explanation for the few reported cases of Crouzon syndrome with learning problems. Occasionally, seizures may occur in the condition.

Individuals with Crouzon syndrome may be shorter than the normal expected height. This seems to affect females with the condition more than males.

Diagnosis

Historically, Crouzon syndrome has been diagnosed after careful physical examination and further studies. A diagnosis of Crouzon syndrome can be made through observing several of the following features. The abnormally shaped head is typically seen right away, in the newborn period. It may sometimes be seen in the prenatal period with an ultrasound examination. X-ray or physical examination of the skull can diagnose craniosynostosis. Once craniosynostosis is seen, it is important to determine whether it occurred because of abnormal biology of the cranial suture, possibly caused by an FGFR mutation. This is known as primary craniosynostosis and would make Crouzon syndrome a possibility. Craniosynostosis may also be caused by abnormal outside forces (known as secondary craniosynostosis) such as decreased brain growth or abnormal fetal head positioning. This may have occurred in the prenatal period, and in these cases the abnormal head shape may correct itself with time. The next step is to determine the type of craniosynostosis. A cloverleaf skull makes Crouzon syndrome a possibility, but it is also seen more commonly in other genetic craniosynostosis syndromes.

Some babies with Crouzon syndrome have breathing problems in the newborn period, due to narrowed nasal passages. Protruding eyes are a hallmark feature for the condition, and can be seen almost immediately after birth. The lack of abnormalities in the extremities (hands and feet) are also considered part of the diagnosis of Crouzon syndrome versus another type of craniosynostosis.

As of 2001, molecular (DNA-based) genetic testing to diagnose Crouzon syndrome is available at a few laboratories. This testing is specific for the condition, separating it from other craniosynostosis syndrome possibilities. A blood or other type of sample (such as fetal cells from amniotic fluid) from the affected individual is provided, and the FGFR2 gene is analyzed.

Abnormal results occur when a mutation in the sequence of the FGFR2 DNA is identified from genetic analysis. This means that the mutation caused the symptoms in the individual, confirming the diagnosis of Crouzon syndrome. As mentioned earlier, not every person with Crouzon syndrome will have an FGFR2 mutation. Therefore, one could conceivably go through genetic testing and have no mutation found. This could mean that the person's symptoms are not caused by Crouzon syndrome.

As of 2001, only a little more than 50% of the mutations that cause Crouzon syndrome are known. Therefore, a negative result could also mean that the patient has a genetic mutation that is unable to be found by current technology. Once a mutation is found in a family, it is much easier (and less time-consuming) to test others in the same family. For people with the features of Crouzon syndrome and acanthosis nigricans, there is DNA-based testing to determine if they have the common FGFR3 mutation.

Prenatal testing is available for both FGFR2 and FGFR3 mutations, done via amniocentesis or chorionic villus sampling (CVS). This is only offered when there is a parent with a known mutation. However, knowing prenatally that an individual has a mutation tells nothing about the extent of the disease. The only way to determine the severity of Crouzon syndrome is by seeing the individual after birth, not by molecular testing. A prenatal ultrasound can sometimes make a possible diagnosis of a syndrome involving craniosynostosis, but it is not as accurate as direct DNA testing. Additionally, a cloverleaf skull seen on a prenatal ultrasound usually implies a more severe outcome for the baby than other types of craniosynostosis.

Treatment and management

Treatment of individuals with Crouzon syndrome often involves the coordinated efforts of several medical specialists in a team setting. The specialists may include a pediatrician, plastic surgeon, neurosurgeon, geneticist, genetic counselor, dentist, social worker, audiologist, speech pathologist, psychologist, and otolaryngologist.

Craniosynostosis is typically repaired through a series of operations. There is a major surgery performed as early as the first three months of life, followed by several others that may extend over the lifespan. Each series of operations is tailored to the individual, but it is rare for the correction to be "perfect" despite the interventions. Because the skull is continually growing in the early part of life, timing of these surgeries is critical for proper brain formation and better results. Surgeries after the skull has stopped growing rarely yield good results. Surgeries performed before various portions of the facial region have stopped growing also have a poor prognosis, and will require additional follow-up procedures.

For individuals with hydrocephalus, sometimes a shunt, or tube, needs to be placed in order to allow the fluid to drain from the affected area(s) of the brain.

For babies with respiratory distress, oxygen and ventilation are often provided. Occasionally, a tracheostomy (opening in the windpipe) is created to help the individual breathe.

Because their eyes protrude so significantly, people with Crouzon syndrome sometimes have trouble closing their eyes. Surgical eye closure may be necessary, which allows the eye and its various structures (such as the cornea) to remain protected.

Occasionally, surgeries to correct structural ear abnormalities (resulting in hearing loss) are necessary.

Prognosis

The most problematic complication in Crouzon syndrome is the craniosynostosis. Prognosis primarily depends upon the severity and extent of this skull abnormality. Consequently, the success of corrective surgeries often determines prognosis.

Resources

BOOKS

Charkins, Hope. Children with Facial Difference: A Parent's Guide. Bethesda, MD: Woodbine House, 1996.

ORGANIZATIONS

AboutFace USA. PO Box 458, Crystal Lake, IL 60014. (312) 337-0742 or (888) 486-1209. aboutface2000@aol.com. <http://www.aboutface2000.org>.

American Cleft Palate-Craniofacial Association. 104 South Estes Dr., Suite 204, Chapel Hill, NC 27514. (919) 993-9044. Fax: (919) 933-9604. <http://www.cleftline.org>.

Children's Craniofacial Association. PO Box 280297, Dallas, TX 75243-4522. (972) 994-9902 or (800) 535-3643. contactcca@ccakids.com. <http://www.ccakids.com>.

Crouzon Support Network. PO Box 1272, Edmonds, WA 98020. penny@crouzon.org. <http://www.crouzon.org>.

Crouzon's/Meniere's Parent Support Network. 3757 North Catherine Dr., Prescott Valley, AZ 86314-8320. (800) 842-4681. katy@northlink.com.

WEBSITES

"Craniofacial Anomalies." Columbia Presbyterian Medical Center Neurological Institute.<http://cpmcnet.columbia.edu/dept/nsg/PNS/Craniofacial.html>.

Deepti Babu, MS