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Patient with Apert Syndrome

Apert Syndrome, also known as acrocephalosyndactly (ak″ro-sef″ah-lo″sin-dak´tĭ-le) or "acrocephaly" (deformity of head) and "syndactaly" (webbed fingers and toes), is a rare genetic disorder that is caused by a premature fusion of skull bones. Its key features include a distinct malformation of the head and webbed hands and/or feet. The disorder is apparent at birth, with findings of incidence of occurrence ranging from an estimated 1 of every 65,000 to 1 out of every 160,000 live births. It has no sex preference between male or female and it is detected in the newborn prior to craniostinosis and syndactly. Almost all cases of Apert Syndrome are causes by new cases of genetic mutations, but in rare cases, Apert Syndrome can be inherited as an autosomal dominant trait with a sporadic cause.

In Apert Syndrome, the pressure of continued brain growth distorts various bones of the skull and face into various categorizable shapes.The shape of the head is often formed in a manner that is pointed at the top, with a sunken appearance in the middle of the face, bulging and wide-set eyes and a nose that is beaked shape and an underdeveloped jaw. These deformities are caused by the skulls inability to grow properly due to a premature fusion in the skull bones.The cause of Apert Syndrome is a rare mutation that occurs on a single gene, FGFR2, which normally guides the bones of the skull to fuse together at the right time. In the case of Apert syndrome, the mutation causes a premature fusion of skull bones resulting in the various symptoms associated with Apert Syndrome.

Mechanism:

The mutation that occurs on FGFR2 is responsible for the presentation of Apert Syndrome in an individual. FGFR2 is the gene responsible for providing instructions for the production of fibroblast growth receptor 2, which is one of the many growth factor receptors that are involved in regulation of critical processes like cell division, growth and maturation as well as the formation of blood vessels and embryonic development. FGFR2 plays an important role in bone growth throughout embryonic development. It is involved in signaling the immature cells present to develop and become bone cells in the hands, head, feet and other tissues. Without this factor, proper formation cannot occur.

Apert Syndrome mutations involved missense substitution in one of two amino acids, S252W or P253R which are located on the linker region between Ig-like domains II and III of FGFR2. The two main mutations known to occur are when the amino acid, serine is replaced with tryptophan at protein position 252 or the second mutation in which the amino acid, proline, replaces arginine at position 253. The altered FGFR2 proteins cause a stronger signaling which causes the premature fusion of the skull, hands and feet to occur. FGF signaling has an important role in cranial development because it is a critical aspect needed to maintain the balance between cell proliferation and cell differentiation. In the case of Apert Syndrome, the increased FGFR2 activity that occurs causes a fusion of the sutures of the skull before the brain is fully developed, so as the brain continues to grow, the pressure causes the bones of the skulls and face to become distorted.

Studies have found that while most cases of Apert Syndrome are linked to the missence mutation at serine 252 or proline 253, there are rare cases of Apert Syndrome. These case which have been identified de novo are due to Alu-insertions that affect the alternative splicing of Fgfr2. This results in an ectopic expression of FGFR2b and causes cells to become sensitive to locally expressed ligand FGF7 or FGF10. S252W or P253T mutations in FGFR2 allow FGFR2c to be activated by FGF7 or FGF10 and result in the activation of FGFR by mesenchymally expressed FGF(s) which explains why both the rare Alu-insertion mutations and the missence mutations that occur with S252W or P252R both result in the same physical characteristics being displayed in individuals living with Apert Syndrome.

Symptoms

The major symptoms associated with Apert Syndrome are:

Syndactaly of hands

Cranial and Facial Features resulting from abnormal skull growth

• Misshapen head: A head that is long with a high forehead
• Depressed forehead: sunken appearance to the middle of the face
• Wide set, bulging eyes often with eyelids that close poorly

Other Symptoms of Apert Syndrome

• Webbed (mitten shaped) bones of hand and feet (syndactaly)
• Poor intellectual development and intellectual disability: intellectual development that is below to severely behind normal level
• Sleep Apnea: breathing that repeatedly stops and starts during sleep
• Repeated sinus infections due to impaired development of frontal sinus
• Hearing Loss due to deformity of the stapes
• Heart, gastrointestinal or urinary symptom issues

Misshapen head in Apert Syndrome

The areas of the body that are infected include the head, hands and feet, eyes, heart, and gastrointestinal areas.

Diagnosis:

Apert Syndrome can be diagnosed during pregnancy by an obstetrician/gynecologist. An abnormality is usually detected on a sonogram first. If a cranial, facial, congenital heart disease, cleft palate, or urogenital disease or other abnormality associated with Apert Syndrome is detected on a sonogram, a fetal MRI may be necessary to further confirm the diagnosis. An MRI is considered the gold standard to detect central nervous system(CNS) abnormalities after 19 weeks of gestation. Diagnosis by MRI is recommended for a pregnancy in the third trimester since the cranial and facial abnormalities may be subtle or difficult to detect prior to this point.

If Apert Syndrome is not detected during pregnancy, a doctor will confirm the diagnosis at birth by examination of the Apert Syndrome related abnormalities. A key indication of Apert Syndrome that distinguishes it from other similar diseases with cranial and facial abnormalities is the webbing of the hands. An x-ray may also be needed to confirm diagnosis and prepare a treatment plan. Depending on the abnormalities present, the child will be referred to the necessary specialist. Effective care may require a multidisciplinary approach combining specialist from various fields.

Apert Syndrome is largely a clinical diagnosis made by the identification of its key symptoms, so genetic testing is usually unnecessary. However, if a doctor finds it necessary or if the family requests, genetic testing can be done to identify a mutation in FGFR2 by a geneticist.

Cause and Prevention:

There is no known way to prevent Apert Syndrome since it is usually caused by a sporadic mutation of FGFR2 and research has yet to determine why this mutations occurs. There are no known food, medication or activities during pregnancy that can lead to Apert Syndrome. Due to its autosomal dominant mechanism, Apert Syndrome can be inherited genetically and individuals living with Apert Syndrome have a 50% chance of passing it on to their offspring.

Treatment and Prognosis:

There is no known cure to the disease but surgery can be done to correct the abnormalities between bones. Treatment of Apert Syndrome is largely focused on lessening the symptoms associated and ensuring that proper developmental growth can occur. Treatment varies among individual but a team of specialist that that is necessary for the individual will be established. Individuals with Apert Syndrome will need to be monitored throughout their life in order to treat any symptoms that may arise. A team of physicians that specialize in disorders of the ears, nose, throat, heart abnormalities and other health care professionals may be necessary.

Children with Apert Syndrome usually require surgery in order to release the skull bones and allow the brain to develop normally. The earlier this surgery is done, the better the chance that the child will reach normal intellectual ability. Surgery to correct the syndactly of the hands and feet is usually desired by the patient and family. Life expectancy varies between children with Apert Syndrome but children that survive past childhood without any heart problems can be expected to live a normal life expectancy due to advances in surgical technique and individual follow-up care.

Recent Research:

Recent research has indicated that Paternal age can have an effect on Apert Syndrome developing in individuals. The incidence of the disease is thought to increase with the increase in the age of the father of an individual with Apert Syndrome. In a 2009 study that tested the mutation incidence occurrence with both sperm donors and live births of individuals with older fathers, it was found that

This is the recent research