Introduction

Pfeiffer syndrome is a rare genetic disorder, affecting approximately 1 in every 100,000 children.¹ It causes premature fusion of certain bones in the skull, feet, and hands during child development.² The bones of the skull can fuse together too early, known as craniosynostosis. This usually leads to increased pressure around the brain, which causes changes to the shape of the face and head.

The skull is unable to grow normally, limiting the space for brain growth and often causing developmental delays.¹ Pfeiffer syndrome can vary in type and severity: whilst some children may present with mild facial or developmental differences, others may experience more severe complications, such as problems with vision or breathing.¹

Recognising how Pfeiffer syndrome affects skull growth and brain development helps ensure children receive timely care and tailored management, supporting the best possible quality of life for your child.

What causes Pfeiffer syndrome?

Pfeiffer syndrome is caused by a mutation in a gene that affects bone growth and formation. The mutation typically occurs in the FGFR2 (fibroblast growth factor receptor-2) or the FGFR1 (fibroblast growth factor receptor-1) genes, and results in early maturation and fusion of cells in the skull, hands, or feet.¹

Most children develop the genetic mutation sporadically, meaning the condition is caused by a new change in the gene that has occurred by chance.¹ However, the genetic mutation can also be passed down from parent to child following an autosomal dominant inheritance pattern.² This means that in some cases, a child has a 50% chance of inheriting the mutation if one parent has it.

Types of Pfeiffer syndrome

The features and severity of Pfeiffer syndrome can vary and are classified into three main types.

• Type 1 is recognised as the most classic form, presenting with mild physical symptoms such as a wider skull and head shape, a high forehead, broad thumbs, big toes, and wide-set eyes¹
  • Most children with Type 1 Pfeiffer syndrome have a normal life expectancy and display normal intelligence with successful treatment²
• Type 2 is a more severe form that presents with a characteristic cloverleaf head shape that bulges at the sides and front of the skull¹
  • This occurs due to extensive bone fusion in the skull and a build-up of fluid in the brain, known as hydrocephalus
  • Children with this type present with significant developmental delays, protruding eyes that can cause vision problems, and an overall shorter life expectancy^1,2
  • They also experience abnormal bone growth in the hands and feet, and limited mobility due to the fusion of the elbow, knee, or other joints¹
• Type 3 is similar to Type 2 in the severity of physical characteristics and developmental delays; however, this type presents without the cloverleaf head shape¹

Both Type 2 and Type 3 Pfeiffer syndrome have poor health outcomes. They often lead to significant learning difficulties, severe breathing difficulties, and neurological problems in affected children.¹ This can shorten their life expectancy and can be life-threatening if not treated successfully.¹

Effects on skull growth

A baby's skull is made up of several separate plates which are not completely joined together at birth. The seams where these plates meet are called 'sutures', and this flexible structure allows the skull to expand as the brain grows during early childhood. The sutures normally fuse together only after the baby's head has finished growing.

In children with Pfeiffer syndrome, some of these sutures fuse early and before birth. This restricts the space that the brain has to grow in, and the baby's head develops an altered shape with a flat midface.¹

If only one suture fuses, most commonly the sagittal suture, it is known as single-suture synostosis. Double-suture synostosis involves two skull sutures fusing. When more than two sutures are involved, it is referred to as 'complex craniosynostosis'. This is associated with the development of a cloverleaf head shape and more complex developmental delay than the fusion of a single suture.^3,4 In children living with Pfeiffer syndrome, certain sutures are affected: the coronal, lambdoid, and sagittal sutures are typically those involved in the fusion.¹

The type and degree of fusion between these sutures can vary from child to child. This results in a variety of skull growth patterns and head shapes, such as a tall or wide head. When the skull is unable to expand normally, this can affect brain growth and development.¹

Effects on brain development

The early fusion of multiple sutures in the skull creates limited space for the brain to grow. This can lead to increased pressure within the brain and subsequent changes in the brain's structure and function.¹

The effects on brain development can be primary or secondary.⁴ Primary differences occur as part of Pfeiffer syndrome itself. These include distorted shape and size of skull bones, as well as changes in the brain's white matter, which is responsible for learning and information processing.⁵ Secondary differences result from complications of an irregular skull and restricted brain growth that occur as a result of Pfeiffer syndrome. These complications can include hydrocephalus and Chiari Type 1 malformation.⁵ The latter can lead to a range of symptoms, such as severe headaches, neck pain, dizziness, muscle weakness, or vision problems.

These effects can overall cause significant developmental delay and learning difficulties in affected children. Severe forms of the condition, such as Type 2 Pfeiffer syndrome, may present more complex features or varied neurological symptoms, such as seizures or numbness in the arms or legs.^1,2

Other physical and developmental features

Aside from changes in skull growth and brain development, children with Pfeiffer syndrome may present with other features that vary in severity and can affect daily life.^1,2 These can include:

• Short and wide thumbs and big toes: often bent away from the rest of the hand or foot. This is a characteristic sign of Pfeiffer syndrome
• Webbed fingers and toes: fusion of the skin or underlying bone on one or both hands or feet, known as syndactyly²
• Protruding eyes: known as proptosis. This may cause difficulty in blinking, dry or irritated eyes, swollen eyelids, or a range of vision problems such as blurred, double, or loss of vision. In some complex cases, corneal ulcers may occur¹
• A flat midface: known as midface hypoplasia. This causes a sunken appearance of the middle of the face due to underdevelopment of the cheekbones, upper jaw, and eye sockets
• Breathing problems: often due to a narrower airway than usual. This can cause difficulty breathing through the nose and may lead to complications such as airway obstruction and sleep apnoea
• Hearing difficulty or loss
• Dental problems: typically crowded teeth
• Cognitive delay: including learning disabilities or problems with speech development

Diagnosis

Pfeiffer syndrome can be diagnosed through a combination of physical assessments, scans, and genetic testing.

• Before birth: detailed ultrasound scans may allow doctors to monitor changes in the shape and structure of your child's skull or limbs.² Genetic testing may also be used to confirm the diagnosis during pregnancy
• After birth: the condition is usually identified at birth based on the appearance of your child's facial features, skull, and limbs. The fusion of skull bones and abnormal thumbs and toes are key signs of Pfeiffer syndrome.^1,2
  • Specific diagnostic tests may therefore not be needed to confirm the diagnosis, but doctors may use imaging scans, such as CT scans and MRI, to check for abnormalities in bone formation and structure.
• Genetic tests are commonly used to identify the specific gene involved and the type of Pfeiffer syndrome your child has, as well as hearing tests to diagnose any hearing problems^1,2

Although Types 2 and 3 have sporadic causes and often present overlapping clinical symptoms that can make accurate diagnosis difficult, genetic testing can distinguish the underlying gene changes that result in the type of Pfeiffer syndrome.¹ Using multiple tests can effectively provide an early diagnosis and a positive outlook, helping families and healthcare professionals to establish a care plan and begin timely treatment.

Treatment and outlook

Treatment for Pfeiffer syndrome is centred around the specific physical and developmental challenges your child experiences, to support their needs and growth. As the condition can affect multiple parts of the body, care is best provided at a specialist children's centre by a team of various specialists, including craniofacial, hand, and neurosurgeons, as well as eye doctors, psychologists, and speech therapists.

Surgery is often recommended in early childhood to reshape the skull.² This involves carefully separating and restructuring the fused bones to create space for normal skull growth.^1,2 Surgery is also used in cases where there is a risk of eye damage or too much pressure inside the brain. Some children may need a shunt to drain excess fluid from the brain and relieve the internal pressure caused by hydrocephalus.²

Further surgery may also be required in late childhood to continue improving the skull shape and moving the midface forward, improving breathing and facial symmetry.¹ Imaging scans are frequently used before, during, and after surgical treatment to monitor bone structure during child development.¹

The outlook for children with Pfeiffer syndrome depends on the severity of symptoms, the impact on body functions, and how early treatment begins.^1,5 Whilst some may face ongoing challenges with breathing, hearing, or learning, many children thrive with timely surgical care, educational support, and ongoing encouragement, reaching their developmental milestones and living a meaningful quality of life.

Summary

Pfeiffer syndrome is a rare genetic condition that affects the growth of bones in the skull, hands, and feet. Early fusion of the skull bones can increase pressure in the brain as it grows, causing developmental problems with vision, learning, and breathing. With early diagnosis, timely surgery, and continuous monitoring, many children go on to reach their full potential and lead fulfilling lives. Families can find comfort and guidance through support groups and helplines, such as Headlines, in a safe space where they can share experiences, access emotional support, and connect with others who understand life with Pfeiffer syndrome. Understanding how the condition affects skull growth and brain development can ultimately help families and clinicians work together to support the best possible care and a positive health outlook.