What causes Apert syndrome?

Apert syndrome is a rare genetic disorder that primarily affects the normal development of the skull and limbs. It is caused by specific mutations in the fibroblast growth factor receptor 2 (FGFR2) gene.

The FGFR2 gene plays a crucial role in regulating cell growth, division, and the development of bones and tissues during embryonic development. Mutations in this gene lead to abnormal signaling, which disrupts the normal formation and growth of the skull, face, hands, and feet.

Apert syndrome is an autosomal dominant disorder, which means that only one copy of the mutated FGFR2 gene is required for the condition to occur. In most cases, the mutation occurs spontaneously and is not inherited from either parent. However, in a small percentage of cases (approximately 2%), the mutation can be passed down from an affected parent to their child.

The specific mutations that cause Apert syndrome are typically missense mutations, which involve the substitution of one amino acid for another in the FGFR2 protein. The two most common mutations responsible for Apert syndrome are:

1. Ser252Trp (S252W) mutation: This mutation accounts for approximately 67% of Apert syndrome cases.
2. Pro253Arg (P253R) mutation: This mutation accounts for around 32% of Apert syndrome cases.

These mutations cause the FGFR2 protein to be constantly active, leading to excessive and abnormal bone growth, particularly in the skull and limbs. As a result, individuals with Apert syndrome often have a distinctive skull shape (craniosynostosis), midface hypoplasia (underdeveloped middle part of the face), and syndactyly (fusion of fingers and toes).

While the specific genetic cause of Apert syndrome is well-established, the exact mechanism by which these mutations lead to the characteristic features of the condition is still an area of ongoing research. Early diagnosis and multidisciplinary management are essential for addressing the various medical and developmental challenges associated with Apert syndrome.

What are the symptoms of Apert syndrome?

Apert syndrome is characterized by several distinct physical features and symptoms that result from the abnormal development of the skull, face, and limbs. The main symptoms of Apert syndrome include:

1. Craniosynostosis: The premature fusion of one or more cranial sutures (fibrous joints in the skull) leads to an abnormal skull shape, often described as acrocephalic (cone-shaped) or oxycephalic (tower-shaped).
2. Midface hypoplasia: Underdevelopment of the midface region, resulting in a flat nasal bridge, sunken appearance of the middle part of the face, and possible breathing difficulties due to a narrow nasal airway.
3. Syndactyly: Fusion or webbing of fingers and toes, often referred to as “mitten hands” or “sock feet.” The severity can vary from partial to complete fusion.
4. Broad thumbs and toes: The thumbs and toes may appear wide and often deviate outward.
5. Cardiovascular abnormalities: Some individuals with Apert syndrome may have congenital heart defects, such as holes in the heart or abnormalities in the structure or function of the heart valves.
6. Hearing loss: Conductive hearing loss (caused by issues in the outer or middle ear) and, less commonly, sensorineural hearing loss (caused by issues in the inner ear or auditory nerve) can occur.
7. Developmental delays: Individuals with Apert syndrome may experience delays in reaching developmental milestones, such as sitting, crawling, and walking, due to the physical limitations imposed by the condition.
8. Intellectual disabilities: While intelligence can vary widely, many individuals with Apert syndrome may have intellectual disabilities ranging from mild to severe.
9. Other skeletal abnormalities: Additional skeletal abnormalities may include a curved spine (kyphosis or scoliosis), fused vertebrae, and abnormalities in the development of the shoulders, hips, and other joints.

The severity of symptoms can vary considerably among individuals with Apert syndrome, even within the same family. Early intervention with a multidisciplinary team of specialists, including craniofacial surgeons, geneticists, and other healthcare professionals, is essential to manage the various medical and developmental challenges associated with this condition.

How is Apert syndrome treated?

Apert syndrome requires a multidisciplinary approach to treatment, as it affects various aspects of development and bodily systems. The treatment plan is customized based on the individual’s specific symptoms and needs. Here are some of the common treatments and interventions for Apert syndrome:

1. Craniofacial surgery:

• Surgical release of the prematurely fused cranial sutures (craniosynostosis surgery) is often necessary to allow proper growth and development of the skull and brain.
• Surgeries may also be performed to correct midface hypoplasia, improve breathing, and address other facial deformities.

1. Hand and foot surgery:

• Surgical procedures may be required to separate fused fingers and toes (syndactyly release) and improve hand and foot function.
• Additional procedures, such as bone grafting or tendon transfers, may be necessary to enhance mobility and dexterity.

1. Orthopedic intervention:

• Braces, splints, or other orthopedic devices may be used to correct or prevent skeletal deformities, such as scoliosis or abnormal limb positioning.

1. Hearing aids and cochlear implants:

• Hearing aids or cochlear implants may be recommended to address hearing loss associated with Apert syndrome.

1. Speech and language therapy:

• Speech and language therapy can help improve communication skills and address any speech or language delays.

1. Developmental and educational support:

• Early intervention programs, special education services, and occupational and physical therapy can assist with developmental delays and support intellectual and motor skill development.

1. Genetic counseling:

• Genetic counseling can provide information about the genetic basis of Apert syndrome, the risks of recurrence, and available prenatal testing options.

1. Psychosocial support:

• Counseling and support groups can help individuals with Apert syndrome and their families cope with the emotional and social challenges associated with the condition.

1. Respiratory support:

• In severe cases, respiratory support or surgical interventions may be required to address breathing difficulties caused by midface hypoplasia or other airway obstructions.

1. Ongoing medical monitoring:
   • Regular follow-up with a multidisciplinary team of specialists, including craniofacial surgeons, geneticists, orthopedists, and other healthcare professionals, is essential to monitor the individual’s development and address any new or recurring issues.

The treatment approach for Apert syndrome is highly individualized and may involve multiple surgeries and interventions throughout childhood and into adulthood. Early diagnosis and coordinated care from a team of specialists are crucial for optimizing outcomes and improving the overall quality of life for individuals with this condition.