Crouzon syndrome

Genetic testing can be offered for other family members if a FGFR2 or FGFR3 gene mutation is identified in an affected person. If a child is found to be affected, testing should first be offered to parents. If a parent is found to be affected, testing can be offered to other children and first-degree relatives (siblings, parents).

If a FGFR2 or FGFR3 gene mutation is identified in a child and not in parents, the risk to siblings is very low and genetic testing is usually not recommended unless other sibling have features of the condition.

Each family’s situation is different, and it is beneficial to meet with a geneticist and genetic counselor to discuss risks to other family members and for whom testing is appropriate. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website . Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

In Crouzon syndrome, craniosynostosis is usually evident during the first year of life and progresses until about 2-3 years of age. In some cases, craniosynostosis is seen at birth. In some cases, craniosynostosis is not noticed until childhood.

To help understand what treatments may be needed, your doctor may want to do some or all of the following tests.

About 5-10% of people with Crouzon syndrome also have acanthosis nigricans. Acanthosis nigricans is a skin condition where the folds and creases in the skin are dark colored (brown to black), thickened, and velvety.

About 50% of cases of Crouzon syndrome are familial and are inherited from parents. About 50% of cases of Crouzon syndrome are de novo (spontaneously occurring) and appear in an individual for the first time due to a new gene change or mutation.

Crouzon syndrome is usually not abbreviated, but it can be referred to as CFD1 (Craniofacial Dysostosis Type I).

The prognosis for individuals with Crouzon syndrome is generally good but also variable; it all depends on the medical concerns and the severity of medical concerns in the affected person. Life-expectancy is typically normal.

Crouzon syndrome is a rare, genetic condition that causes the bones in the skull to fuse too early (craniosynostosis). This premature fusing causes the skull to grow abnormally and affects the head and the face. Many of the facial features seen in Crouzon syndrome are also the result of this early fusion and include abnormal growth of the bones that cause wide-set and bulging eyes, vision problems that may include strabismus (eyes that do not point in the same direction) and a jaw that is underdeveloped. Other common features of Crouzon syndrome include dental problems, hearing loss, narrow ear canals, and spine abnormalities. Signs and symptoms of Crouzon syndrome vary. The intelligence of people with Crouzon syndrome is typically normal.

Some people with Crouzon syndrome have hearing loss. Hearing loss can either be sensorineural, conductive, or mixed. Some individuals affected with Crouzon syndrome have narrow ear canals.

If a newborn baby is suspected to have Crouzon syndrome, both the FGFR2 and FGFR3 genes should be analyzed. Specific mutations in the FGFR2 gene cause Crouzon syndrome. One mutation in the FGFR3 gene (p.Ala391Glu, p. A391G, or c.1172C>A) causes Crouzon syndrome with acanthosis nigricans. Not all newborn babies with the specific FGFR3 mutation have acanthosis nigricans at birth, but may develop it later. If the baby is over 2 years old and does not have acanthosis nigricans, genetic testing for the specific FGFR3 gene mutation has very low yield.

Usually Crouzon is caused by a mutation in the FGFR2 gene. Everyone has two copies of the FGFR2 gene. The official name of this gene is "fibroblast growth factor receptor 2." This gene is located on chromosome 10. We get one FGFR2 gene from our mother and one FGFR2 gene from our father. Having a specific change (mutation) in one copy of the FGFR2 gene causes Crouzon syndrome.

In some cases, a specific mutation called p.Ala391Glu, p. A391G, or c.1172C>A in another gene called FGFR3 gene causes Crouzon syndrome together with a skin condition called acanthosis nigricans.

Facial differences typically seen in Crouzon syndrome include widely-spaced eyes (hypertelorism), shallow eye sockets, protusion or bulging of the eyeballs (exophthalmos), eyes that do not look in exactly the same direction at the same time (external strabismus), a beak-like nose, a short upper lip, and an underdeveloped jaw (hypoplastic maxilla) that faces more forward (mandibular prognathism).These facial differences are due to the early fusion of the skull bones.

Commonly seen eye differences in Crouzon syndrome include widely-spaced eyes (hypertelorism), eyes that do not look in exactly the same direction at the same time (external strabismus), bulging eyes, and poor vision. Poor vision is seen in about 50% of people with Crouzon syndrome. Less commonly seen eye differences include degeneration of the optic nerves, rapid recurring movements of the eyes that one cannot control (nystagmus), clouding of the lenses of the eyes (cataracts), and a hole in the colored part of the eye (iris coloboma). Blindness is seen in about 7% of people with Crouzon syndrome.

When a person inherits a "variant" in the FGFR2 gene for Crouzon syndrome, it means they have a change in the gene, but it is currently not known if this change actually causes Crouzon syndrome. These are often called variants of uncertain significance (VUS). Sometimes the interpretation of variants change as more people are tested and more data is received by the laboratory.

Because most people with Crouzon syndrome have an underdeveloped upper jaw, dental problems occur. Dental problems include crowding of the front teeth of the upper jaw and abnormal alignment of the upper and lower teeth.

People with Crouzon syndrome should see some medical specialists. They should see the following:

Each state has a newborn screen that includes a group of genetic conditions. Crouzon syndrome is not included in any newborn screening panels in the United States. If there is a family history of Crouzon syndrome or if Crouzon syndrome is suspected at birth, genetic testing can be performed using cord blood or another blood sample.

As of January 14, 2016, there is one main gene, FGFR2, currently known to be associated with Crouzon syndrome. The p.Ala391Glu, p. A391G, or c.1172C>A mutation in the FGFR3 gene is also associated with a smaller number of people with Crouzon syndrome and acanthosis nigricans. For FGFR2 genetic testing for Crouzon syndrome, there are a few different options depending the clinical situation. They are the following:

There are some things to be aware of at birth if someone is diagnosed with Crouzon syndrome. Some babies cannot breathe out of their nose and will require a breathing tube. Some babies have extra fluid on their brain (hydrocephalus). If someone has hydrocephalus, pressure inside the skull (intracranial pressure) may increase and a tube (shunt) may need to be surgically placed to drain the extra fluid from the brain. Infants who have premature fusion of many skull bones (craniosynostosis) and a severe skull deformity may need surgery early in the first year of life.

When the father is of older age (advanced paternal age), there is a higher risk to have a child with a de novo (brand new) mutation in the FGFR2 gene associated with Crouzon syndrome. This mutation is not inherited from a parent, but happens brands new in the sperm that creates the baby.

Sometimes there are findings on ultrasound if a baby has Crouzon syndrome. These include the following:

There is no cure for Crouzon syndrome. Treatment is limited to management and surveillance of medical concerns, and surgical intervention. For example, if someone has hydrocephalus, pressure inside the skull (intracranial pressure) may increase and a tube (shunt) may need to be surgically placed to drain the extra fluid from the brain. Infants who have premature fusion of many skull bones (craniosynostosis) and a severe skull deformity may need surgery early in the first year of life. There are published guidelines for management and surveillance for Crouzon syndrome on the website http://genereviews.org/.

People with Crouzon syndrome are affected differently and it is difficult to predict the severity of medical concerns at birth. Some people are more mildly affected and some people are more severely affected. Not all people affected with Crouzon syndrome in the same family are affected similarly.

Almost all people with a FGFR2 gene mutation associated with Crouzon syndrome are affected with the condition (complete penetrance). There has been only one family report in which two children and a father had a FGFR2 gene mutation associated with Crouzon syndrome, but two of these family members were mildly affected and one family member was not affected at all.

If you have Crouzon syndrome, your primary care provider should know the management and surveillance guidelines. Referrals to necessary specialists are typically needed early on, depending on the clinical features of the affected person. Some babies with Crouzon syndrome may have difficulty breathing through their nose and a breathing tube may be needed. A baby diagnosed with Crouzon syndrome should be seen by a plastic surgeon early on to discuss surgery. The primary care provider should look for signs of hydrocephalus (increased fluid on the brain) which can include a bulging "soft spot", crankiness, fatigue, and increasing head size. It will important for a person with Crouzon syndrome to have regular dental, hearing, and eye evaluations.

If a person is affected with Crouzon syndrome and has a known FGFR2 gene mutation, there is a 50% chance that each of his/her children will inherit the FGFR2 gene mutation and be affected. Clinical features and severity of these features cannot be predicted though.

It is a personal decision whether or not to pursue genetic testing during a pregnancy. Even if a mother and father are not found to have the same FGFR2 gene mutation previously found in their child, there is still the small possibility of gonadal mosaicism. Gonadal mosaicism is where some of the egg cells or some of the sperms cells have the FGFR2 gene mutation; this is unable to be detected through a blood draw. The recurrence risk for future pregnancies is low, likely less than 1%, but prenatal genetic testing can still be pursued if parents desire. If parents are interested, they can speak with a prenatal/reproductive genetic counselor. Genetic counselors can be found using the website http://nsgc.org.

If a mother or father is affected with Crouzon syndrome and has a known FGFR2 gene mutation, genetic testing can be performed during the pregnancy. Chorionic villus sampling (CVS) and amniocentesis are both available. CVS involves removing a piece of the placenta and sending the sample to a laboratory for genetic testing. CVS can be performed around 10-12 weeks of gestation. Amniocentesis involves taking a sample of amniotic fluid and sending it to the laboratory for genetic testing. This testing can be performed starting at 15 weeks of gestation. Testing involves looking for the specific FGFR2 gene mutation found in the mother or father. To note, clinical features cannot be predicted before birth. Because both CVS and amniocentesis are invasive, there is a small risk for miscarriage. If one is interested in this prenatal diagnostic testing, they can speak with a reproductive genetic counselor in their area. Genetic counselors can be found using the website http://nsgc.org It is best to talk with a genetic counselor before you become pregnant or as soon as you learn of your pregnancy as there is some pre-testing that will need to be organized prior to your day of testing the baby.

About 4.5% of people with craniosynostosis have Crouzon syndrome. Craniosynostosis or premature fusing of the skull bones causes the skull to grow abnormally and affect the head and the face. Many of the facial features seen in Crouzon syndrome are also the result of this early fusion and include abnormal growth of the bones that cause wide-set and bulging eyes, vision problems that may include strabismus (eyes that don’t point in the same direction) and a jaw that is underdeveloped.

There is currently no cure for Crouzon syndrome. However, many of the symptoms can be treated.

Treatment may include:
Surgery
There are a number of surgeries used to treat the symptoms of Crouzon syndrome. These include:

Crouzon syndrome is usually inherited in an autosomal dominant pattern. Everyone has two copies of their FGFR2 gene; one comes from your mother and one comes from your father. When a person has a specific harmful change known as a mutation in one copy of their FGFR2 gene, they have a genetic diagnosis of Crouzon syndrome. Sometimes a FGFR2 gene mutation associated with Crouzon syndrome is inherited from a parent, and sometimes it happens brand new (de novo) in a child for the first time. Crouzon syndrome with acanthosis nigricans caused by the specific FGFR3 gene mutation (p.Ala391Glu, p. A391G, or c.1172C>A) is also inherited in an autosomal dominant pattern.

There has been one reported family where a brother and sister were affected with Crouzon syndrome, but neither parent was affected. The individuals involved in this published paper suggested a recessive form of Crouzon syndrome.

Genetic testing for Crouzon syndrome is typically ordered by a geneticist and genetic counselor after seeing them for an appointment. A clinic appointment typically involves a complete review of the patient’s medical history, a three generation family history that documents health problems and genetic conditions, a detailed physical examination, discussion of recommended testing, and consent for genetic testing if the patient/guardian is interested. Sometimes this happens in one clinic visit, and sometimes this happens over the span of a few clinic visits. Each clinic is different. In terms of insurance, sometimes the clinic checks with your insurance, and sometimes it is your responsibility to call your insurance. As stated earlier, each clinic operates differently. If genetic testing is pursued, a blood sample and signed paperwork is sent to a laboratory that performs the testing. Results are then sent back to the geneticist and genetic counselor who contact the patient/guardian with results. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website . Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

The FGFR2 gene provides instructions for making a protein called "fibroblast growth factor receptor 2." This is a protein (building block) that is important for many processes in the body such as cell division, cell growth, wound heading, creation of blood vessels, and the development of a baby. This protein is located on the outside of our cells and communicates with other chemicals and proteins outside of the cell. This protein plays an important role in bone growth especially in the early stages. If the FGFR2 gene has a harmful change (mutation) in it, cell communication and overall bone development is disrupted, leading to the features seen in Crouzon syndrome.

Clinical research can be found on the following sites:

The incidence of Crouzon syndrome has been reported to be between 1 in 25,000 and 1 in 62,500 births. This incidence may be underestimated because some people with mild features may not be diagnosed.

Genetic testing for Crouzon syndrome typically involves using a blood sample. Some laboratories accept saliva samples; it is best to call the lab to see if they accept a saliva sample beforehand. Biopsy is typically not performed for Crouzon syndrome genetic testing. A medical geneticist or genetic counselor can help you organize tests and find appropriate labs. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website . Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

Crouzon syndrome appears to affect males and female equally.

Most people with Crouzon syndrome have normal intelligence. About 3% of people with Crouzon syndrome have intellectual disability.

Not all mutations in the FGFR2 gene cause Crouzon syndrome. Mutations in the FGFR2 gene can also cause Apert syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, lacrimo-auriculo-dento-digital syndrome, and Pfeiffer syndrome. Early fusion of the skull bones (craniosynostosis) is also seen in Apert syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, and Pfeiffer syndrome.

There are published guidelines for management and surveillance for Crouzon syndrome on the website GeneReviews.

There are other names for Crouzon syndrome. They include:

There are other medical concerns that are less common in Crouzon syndrome. These included an opening in the lip and roof of the mouth (cleft lip and palate), headaches, seizures, and accumulation of fluid in the brain that causes the head to enlarge (hydrocephalus). About 3% of people with Crouzon syndrome have intellectual disability. Some people have skeletal features such as fusion of some bones in the spine in the neck, and stiffness in the elbows. Sometimes, radiographic metacarpal-phalangeal (hand and finger) profile may reveal shortening although this cannot usually be noticed by the naked eye.

There are support groups for Crouzon syndrome. Some are specific for Crouzon syndrome, and some are for certain features of this condition. They are the following:

Only FGFR2 gene mutations are known to be associated with Crouzon syndrome. However, a specific mutation in the FGFR3 gene called p.Ala391Glu, p. A391G, or c.1172C>A causes Crouzon syndrome with acanthosis nigricans. Acanthosis nigricans is a skin condition where the folds and creases in the skin are dark colored (brown to black), thickened, and velvety.

There are other genetic conditions that are similar to Crouzon syndrome. Early fusion of the skull bones (craniosynostosis) is seen in many of these conditions. These include the following: