Pfeiffer syndrome is a genetic disorder characterized by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. Pfeiffer syndrome also affects bones in the hands and feet. Pfeiffer syndrome is divided into 3 subtypes (type 1, type 2 and type 3) based on the presence and severity of specific features.
Pfeiffer syndrome affects about 1 in 100,000 individuals. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Signs and symptoms can include craniosynostosis, which prevents normal skull growth and affects the shape of the head and face; distinctive facial features including bulging and wide-set eyes, a high forehead, an underdeveloped upper jaw, and a beaked nose; hearing loss; and dental problems. Other features may include broad and deviated thumbs and great toes; brachydactyly; and syndactyly.
The presence and severity of features of Pfeiffer syndrome may differ depending on the type of Pfeiffer syndrome a person has. Type I is considered mild compared to types II and III.
In Pfeiffer syndrome type I, infants have craniosynostosis that causes the head to appear vertically elongated. Distinctive facial features may include a high, full forehead; underdeveloped mid-facial regions (midface hypoplasia); widely spaced eyes (ocular hypertelorism); an underdeveloped upper jaw (hypoplastic maxilla) with a prominent lower jaw; and dental abnormalities. People with type I usually have normal intelligence and a good prognosis with a normal life span.
In Pfeiffer syndrome type II, people typically have more severe craniosynostosis, more severe hand and foot abnormalities, and additional malformations of the limbs. Infants with type II have a form of craniosynostosis that causes the skull to have a "tri-lobed" appearance (called a "cloverleaf skull" deformity). This is often associated with hydrocephalus, which causes increased pressure on the brain. Distinctive facial features may include an abnormally high, broad forehead; severe protrusion of the eyes (ocular proptosis); midface hypoplasia; a "beak-shaped" nose; and low-set ears. Infants may also have lack of mobility of the elbow joints and/or various abnormalities in some of the internal organs (visceral anomalies). Infants with type II often have intellectual disabilities and neurological problems due to severe brain involvement. The physical abnormalities associated with type II can lead to life-threatening complications without appropriate treatment.
Pfeiffer syndrome type III is very similar to type II, but people with type II do not have the cloverleaf skull deformity. The features associated with type III may include a shortened base of the skull ; the abnormal presence of teeth at birth (natal teeth); ocular proptosis; and/or various visceral anomalies. As in type II, people with type III often have intellectual disabilities and severe neurological problems.
The cause of Pfeiffer Syndrome, like many of the other syndromal craniosynostosis, has been found to be linked to a gene alteration. Specifically Pfeiffer syndrome results from mutations in the FGFR1 or FGFR2 gene and is inherited in an autosomal dominant manner. These genes provide instructions for making proteins known as fibroblast growth receptors 1 and 2. Among their multiple functions, these proteins signal immature cells to become bone cells during embryonic development. A mutation in either the FGFR1 or FGFR2 gene alters protein function and causes prolonged signaling, which can promote the premature fusion of skull bones and affect the development of bones in the hands and feet.
The diagnosis of Pfeiffer syndrome is based primarily on clinical findings (symptoms). Although genetic testing is available, the diagnosis is usually made based on physical examination and radiological testing. Often the doctor can determine which cranial suture closed prematurely by physical examination. For confirmation, an x ray or computerized tomography (CT) scan of the head may be performed. Determining which suture is involved is crucial in making the correct craniosynostosis diagnosis. Craniosynostosis may be caused by an underlying genetic abnormality, or it may be due to other, nongenetic factors. In Pfeiffer syndrome, the tissue itself is abnormal and causes the suture to fuse prematurely. The doctor will consider nongenetic causes of craniosynostosis. These secondary causes include external forces such as abnormal head positioning (in the uterus or in infancy) and a small brain. Genetic testing may be useful for prenatal diagnosis, confirmation of the diagnosis, and to provide information to other family members. Mutations are not detected in all individuals with Pfeiffer syndrome. Approximately one-third of affected individuals with Pfeiffer syndrome do not have an identifiable mutation in the FGFR1 or FGFR2 gene. People with Pfeiffer syndrome due to a mutation in the FGFR1 gene may have less severe abnormalities than people who have Pfeiffer due to mutations in the FGFR2 gene. Prenatal diagnosis is available by chorionic villus sampling (CVS) or amniocentesis if a mutation has been identified in the affected parent. Amniocentesis is performed after the fifteenth week of pregnancy and CVS is usually performed in the tenth and twelfth weeks of pregnancy. Craniosynostosis may be visible by fetal ultrasound. Conditions caused by mutations in the FGFR genes account for only a small portion of craniosynostosis. Therefore, assuming that the fetus does not have a family history of one of these conditions, genetic testing for the FGFR genes is unlikely to provide useful additional information.
The prognosis for an individual is based on the symptoms he or she has. Individuals with Pfeiffer syndrome type 1 have a better prognosis than individuals with types 2 or 3. But the designation of type is based on that person's symptoms. Although people with Pfeiffer syndrome may not obtain a completely normal appearance, significant improvement is possible. Timing the surgeries correctly is an important factor in whether they are successful and whether repeat surgeries are required. Although Pfeiffer syndrome is rare, craniosynostosis is relatively common. Multiple agencies and organizations exist to help families face the challenges of having a child with craniosynostosis and facial differences. The identification of the FGFR genes that cause Pfeiffer (and other) craniosynostosis syndromes has promoted research into the underlying process that causes Pfeiffer syndrome. It will be another enormous challenge to go from understanding the process to treating the process. But better understanding is a big first step. Also, when the process that causes Pfeiffer and related conditions is better understood, a much clearer knowledge of human development in general will be established.
Management typically includes various surgical interventions.