What is Pfeiffer Syndrome?
Pfeiffer syndrome is a genetic disorder that affects the shape of the face and skull, and can also cause broad thumbs and toes, and webbing (or fusion) of the skin between the fingers and toes. This condition is linked with the premature fusion of skull bones, known as primary craniosynostosis. It can also lead to facial features such as underdevelopment of the midface (midface hypoplasia) and, commonly, causes a type of hearing loss that occurs when sound is blocked from reaching the inner ear (conductive hearing loss).
The condition was first identified by Rudolf Pfeiffer in 1964 when he observed a pattern of characteristics including abnormal skull shape, widely-spaced eyes (hypertelorism), downward slanting eye openings, broad thumbs and toes, and normal intelligence in eight family members across three generations. The fact that the condition was passed from father to son twice suggested that it is inherited in an ‘autosomal dominant’ way, which means that a child would only need to inherit the altered gene from one parent to be affected.
Pfeiffer syndrome is sometimes referred to as type V acrocephalosyndactyly, craniofacial-skeletal-dermatologic dysplasia, or Noack syndrome. The name ‘acrocephalosyndactyly’ refers to a group of conditions where the skull bones fuse early and the fingers or toes are webbed. Other conditions that come under this group include:
- Type I: Apert syndrome
- Type II: Vogt/Crouzon syndrome
- Type III: Saethre–Chotzen syndrome
- Type IV: Waardenburg syndrome
Type V is Pfeiffer syndrome. Each variant has its unique symptoms and is caused by different genetic changes.
What Causes Pfeiffer Syndrome?
PS, or Pfeiffer Syndrome, features a typical pattern of inheritance that’s called autosomal dominant. This means a person only needs a copy of the abnormal gene from one parent to inherit the disease. Even though everyone who inherits the gene will have the syndrome (this is called ‘complete penetrance’), the severity of the symptoms can vary widely among individuals, especially when it comes to syndactyly, or when fingers or toes are fused together.
Pfeiffer Syndrome has different types: Type I is linked with changes in two genes, FGFR1 and FGFR2. Types II and III, however, are associated only with changes in FGFR2. Most commonly, Pfeiffer Syndrome is caused by changes in the FGFR2 gene, which is located on chromosome 10q26.13. Only a small percentage of Type I Pfeiffer Syndrome cases are caused by changes in the FGFR1 gene, which is located on chromosome 8p11.23; this gene usually has no connection with other types of Pfeiffer Syndrome.
So, what do these genes do? The FGFR1 and FGFR2 genes have a major role in creating fibroblast growth factor receptors 1 and 2. These receptors are primarily involved in embryonic development, helping transform flexible stem cells into bone-building cells, or osteoblasts. If these genes have mutations or changes, it can lead to prolonged signaling of a protein, which in turn leads to the early fusion of skull bones and improper development of bones in the limbs.
Certain major changes in the FGFR2 gene – specifically p.W290C, p.Y340C, p.C342R, and p.S351C – can cause severe forms of Pfeiffer Syndrome, whereas a change in the FGFR1 gene, specifically p.P252R, usually results in a milder form of the syndrome.
In addition, researchers have identified a specific change in the FGFR1 gene (Pro252Arg) in exon 5 – an important section of this gene – as one found in Pfeiffer Syndrome.
Finally, a significant risk factor for developing Pfeiffer Syndrome is an older paternal age. If one parent has the syndrome, there’s a 50% chance their child will also have the syndrome with each pregnancy. Equal risks exist for both male and female offspring.
Risk Factors and Frequency for Pfeiffer Syndrome
Pfeiffer Syndrome (PS) is a condition that affects about 1 in 100,000 newborn babies. It’s one of the most common types of disorders known as “acrocephalosyndactyly syndromes”. The most common syndrome in this group is known as Apert syndrome.
Signs and Symptoms of Pfeiffer Syndrome
Type I PS condition is characterized by signs like a flat head due to a condition called bi-coronal synostosis, a smaller upper jaw, eyed spaced farther apart than usual, protruding jaw, dental irregularities, broad thumb and big toes, along with varying abnormalities of the fingers or toes. People with this condition generally have normal mental abilities.
When it comes to type II PS condition, it includes a feature known as the cloverleaf skull, which is often associated with fluid build-up in the brain. Other symptoms include a smaller upper jaw that can make the eyes appear to bulge, a nose shaped like a beak, low-set ears, and stiff elbow joints. This condition is commonly associated with mental and neurological impairment as well as irregularities in the internal organs.
Type III PS condition has many of the same features as Type II, except for the cloverleaf skull shape. There are additional symptoms such as a shorter foremost part of the skull, teeth present at birth, bulging eyes, and other abnormal features related to internal organs like kidney problems and a smaller-than-normal gallbladder. People with this condition often have developmental delays, neurological problems, and may experience seizures after being born.
Tracheal cartilaginous sleeve (TCS) is a condition often seen in PS, where the normal rings in the windpipe are not present. Instead, there is a continuous segment of cartilage from below the voice box to the point where the windpipe splits. This abnormality can also be found in Apert and Crouzon syndromes. The presence of TCS can worsen the prognosis due to the potential for breathing complications.
Furthermore, PS patients may also have related health conditions such as a cleft palate, choanal atresia, tracheomalacia, a congenital fusion of vertebrae, Arnold-Chiari malformation, and imperforate anus. Common eye conditions seen in PS are proptosis, squint, swelling of the optic disk, and iris colobomas.
Testing for Pfeiffer Syndrome
When it comes to diagnosing Pfeiffer syndrome (PS), a rare genetic disorder resulting in early fusion of certain skull bones and abnormal growth of the hands and feet, the main clues come from physical signs or symptoms. Doctors can make a preliminary diagnosis based on a combination of these key features like the premature fusion of skull bones (called craniosynostosis) and abnormal shortness and webbing of fingers and toes (known as brachysyndactyly), alongside other identified characteristics.
If a child is suspected to have PS, they will typically be recommended for genetic testing. This testing checks for changes, or mutations, in specific parts of certain genes (termed ‘exons’) within the FGFR1, FGFR2, and FGFR3 genes. These changes can indicate that PS is the cause of the symptoms being seen.
Another method for spotting signs of Pfeiffer syndrome is through an ultrasound scan, which uses sound waves to create images of the inside of the body. Ultrasound can reveal specific physical abnormalities that are often found with Pfeiffer syndrome. These can include a variety of craniofacial (or head and face) abnormalities such as brachycephaly (a flat or shortened back of the head), acrocephaly (a high, towering skull), and hypertelorism (widely spaced eyes). Other abnormalities like a small nose and a low nasal bridge might also be present.
Similarly, the ultrasound may also show certain abnormalities of the hands and feet such as syndactyly (fusion of fingers or toes), a broad thumb, and a large big toe. For this reason, an ultrasound is now being recommended as a strategy for early diagnosis of Treacher Collins Syndrome (TCS, a condition that causes facial deformities), particularly in patients who also have Pfeiffer syndrome.
Treatment Options for Pfeiffer Syndrome
Corrective surgery for certain conditions requires very specialised experience and is mainly performed to relieve pressure on the brain by creating enough room within the skull, to create enough space in the eye socket for the eyeball, and to open up the airway wider by shifting forward the facial structures just below and either side of the nose.
Usually, patients with these types of conditions are treated with several surgeries performed at different times. In the first year of life, a surgery called a suturectomy is performed to create more room inside the skull which enables the brain to grow normally. After this, more surgeries can be done to fix any other physical abnormalities.
In certain cases, the patients may need a procedure called a tracheostomy. This is mainly needed to treat sleep apnea, which is caused by an underdeveloped upper jawbone, narrowed nasal passages, and an unusually large tongue – all of which can cause breathing difficulties. In this surgery, a tube is put into the windpipe to allow air to get into the lungs. However, inserting the right size tube can be challenging because these patients often have a stiff windpipe, which can lead to complications like excessive growth of tissue around the tube insertion site.
However, it’s important for parents to be aware that a tracheostomy can be critical, potentially influencing their child’s future health and quality of life.
What else can Pfeiffer Syndrome be?
When a doctor is trying to determine if a patient has Pfeiffer Syndrome (PS), they will often look at other conditions that can cause similar symptoms. These conditions include:
- Apert Syndrome
- Crouzon Syndrome
- Muenke Syndrome
- Saethre-Chotzen Syndrome
- Jackson-Weiss Syndrome
- Antley-Bixler Syndrome
Apert Syndrome is similar to PS, but they don’t share the same genetic markers. Additionally, with Apert Syndrome, the patient typically doesn’t have a misshapen skull (commonly known as a “cloverleaf” skull) or bulging eyes, which are characteristic features of PS. Crouzon Syndrome doesn’t result in any abnormalities of the hands or feet as seen in PS.
The symptoms of PS can overlap with Muenke Syndrome, though the cause of Muenke Syndrome is known to be a specific genetic mutation. People with Saethre-Chotzen Syndrome and Jackson-Weiss Syndrome may have similar features to those of PS, particularly in the appearance of the toes.
Antley-Bixler Syndrome is a less common condition that might be confused with PS, especially the type II variant. It’s associated with a mishappen skull, but not the “cloverleaf” pattern and fusion of certain bones in the forearm and the elbow, as well as bowed legs. This syndrome may also include internal abnormalities, usually related to the genitals.
What to expect with Pfeiffer Syndrome
Type I Pfeiffer Syndrome (PS) typically has positive outcomes regarding intellectual development. However, types II and III of the syndrome often lead to severe complications in brain development, frequently resulting in death during childhood.
The outlook for a patient depends on the severity of their syndrome. Yet, the appearance of the face and skull often improve as the individual grows older. A recent study by Robin and colleagues reviewed the health journey of seven children with Pfeiffer Syndrome type III. Despite having severe symptoms, these children showed positive outcomes when they were given thorough medical and surgical treatments.
Possible Complications When Diagnosed with Pfeiffer Syndrome
The syndrome can lead to a variety of complications, including:
- Slowed brain development
- Mental disability
- Pneumonia caused by inhaling food or drink (aspiration pneumonia)
- Corneal ulcers and damage due to an abnormal bulging of the eye (proptosis)
- Difficulty breathing during sleep (obstructive sleep apnea)
- Seizures
Preventing Pfeiffer Syndrome
The only way to prevent PS, or Pfeiffer Syndrome, from happening is through genetic counseling. This means talking with a health professional who is trained to help people understand about how genes, diseases, and conditions are passed down through families. This can help you understand the risks and what can be potentially done to prevent it.
