Pfeiffer syndrome

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Pfeiffer syndrome


Pfeiffer syndrome is one of a group of disorders defined by premature closure of the sutures of the skull, resulting in an abnormal skull shape. People affected with these conditions, known as craniosynostosis syndromes, may also have differences in facial structure and hand and foot abnormalities. The defining features of Pfeiffer syndrome are abnormalities of the hands, feet, and shape of the skull.


Pfeiffer syndrome is a complex disorder. Three subtypes of Pfeiffer have been defined based on symptoms. The syndrome is caused by a mutation (alteration) in either of two different genes. As the genes that cause craniosynostosis syndromes were discovered throughout the 1990s, scientists realized that these syndromes have overlapping underlying causes. Crouzon, Apert, Jackson-Weiss, and other syndromes are related to Pfeiffer syndrome by genetic causation as well as associated symptoms. Noack syndrome, once thought to be a separate condition, is now known to be the same as Pfeiffer syndrome. Acrocephalosyndactyly, Type V (ACS5) and Noack syndrome both refer to Pfeiffer syndrome.

Genetic profile

Pfeiffer syndrome is an autosomal dominant condition. Every person has two copies of every gene , one maternally inherited and one paternally inherited. Autosomal dominant conditions occur if a person has a change in one member of a gene pair. The chance for an affected individual to have an affected child is 50% with each pregnancy.

A person who has an autosomal dominant condition may have it because he or she inherited the altered gene from an affected parent or because of a new mutation. A new mutation occurs when the gene is altered for the first time in that individual. A person with an autosomal dominant condition due to a new mutation is the first person in his or her family to be affected.

Nearly all of the individuals with Pfeiffer syndrome types 2 and 3 described in the medical literature have new mutations. When a person has a new mutation, his or her parents are usually not at risk to have another child with the condition. The milder form, Pfeiffer syndrome type 1, is more likely to be inherited. When the mutation is inherited, the child's symptoms are often similar to those of the affected parent. Pfeiffer syndrome is fully penetrant. This means that all of the individuals who have the mutated gene associated with the condition are expected to have symptoms. In other words, the mutant gene is always expressed.

The two genes that cause Pfeiffer syndrome are called FGFR1 and FGFR2. FGFR1 is on chromosome 8. FGFR2 is on chromosome 11. These genes are members of a group of genes called the "fibroblast growth factor receptors."

Fibroblasts play an important role in the development of connective tissue (e.g. skin and bone). Fibroblast growth factors (FGFs) stimulate certain cells to divide, differentiate (specialize to perform a specific function different than the function of the original cell), and migrate. FGFs are important in limb development, wound healing and repair, and other biological processes. FGFs communicate with targeted cells through the action of the fibroblast growth factor receptors. Fibroblast growth factor receptors (FGFRs) on the targeted cells bind the FGFs and relay their message within the cell.

In 1999, 11 conditions were known to be caused by mutations in three of the four FGFR genes. However, only one condition is present in each affected family. Mutations in FGFR2 may cause Pfeiffer syndrome as well as Apert, Jackson-Weiss, and Crouzon syndromes. Nonetheless, a parent with Pfeiffer syndrome is at risk to have a child with Pfeiffer but is not at risk to have a child with Crouzon, Apert, or Jackson-Weiss syndromes. Because family members in multiple generations all have the same condition, the condition is said to "breed true" within families. A few exceptions—families with more than one FGFR-associated condition—are reported in the medical literature.

A given genetic condition may be associated with mutations in one particular gene, and mutations in a given gene may cause only one genetic condition. Alternatively, mutations in a gene may be associated with more than one genetic condition, and a particular genetic condition may be caused by any mutation in a number of multiple genes. FGFR2 causing both Pfeiffer and Apert syndromes is an example of the former; FGFR1 and FGFR2 causing Pfeiffer syndrome is an example of the latter. Various mutations of a particular gene are called alleles. Sometimes a gene causes different genetic conditions because each allele leads to a specific set of symptoms.

The exact same mutation in the FGFR2 gene may cause Pfeiffer syndrome in one family and cause a different craniosynostosis syndrome in another family. However, each family continues to have the same symptoms (the conditions breed true in each family). Differing effects of genes are sometimes explained by differing environmental influences and by differing interactions with other genes. However, the diverse effects of the FGFR2 gene probably have a more specific explanation/mechanism. The underlying reasons for these phenomena may be explained when fibroblast growth factors and their receptors are better understood. At that time, criteria defining various craniosynostosis syndromes (e.g. Pfeiffer, Crouzon, and Jackson-Weiss) may be reexamined and revised.


The incidence of Pfeiffer syndrome is approximately one in 100,000. The incidence of craniosynostosis is one in 2,000 to one in 2,500, which includes syndromic and nonsyndromic cases. In non-syndromic cases, the craniosynostosis is an isolated finding; no other abnormalities are present. Non-syndromic craniosynostosis is much more common than syndromic craniosynostosis. Usually isolated craniosynostosis is sporadic (not familial).

Signs and symptoms

Individuals with Pfeiffer syndrome have a high forehead, a "tower shaped" skull, and broad, deviated thumbs and great toes. The symptoms of type 1 are milder than those of types 2 and 3. Undergrowth of the midface leads to down-slanting, low-placed, widely spaced eyes; a small upper jaw bone; and a low nasal bridge. The larynx (voice organ below the base of the tongue) and the pharynx (tube that connects the larynx to the lungs) may be abnormal. Additional symptoms include a projecting chin, divergent visual axes, abnormalities of the passage between the nose and the pharynx, and hearing loss. Fingers and toes may be short and/or partially grown together. The palate may be especially high, and teeth may be crowded. In type 2, the elbow joint is frozen in place.

The skull is composed of many bones that fuse when the brain has finished growing. If the bones of the skull fuse prematurely (craniosynostosis), the skull continues to grow in an abnormal pattern. The places where the bones of the skull fuse are called sutures.

The suture that fuses prematurely in Pfeiffer syndrome is the coronal suture. This suture separates the frontal bone of the skull from the two middle bones (called the parietal bones). When the coronal suture closes prematurely, upward growth of the skull is increased and growth toward the front and back is decreased. Sometimes the sagittal suture will also be fused prematurely in individuals with Pfeiffer syndrome. This suture separates the right and left sides of the middle of the skull. If both the coronal and sagittal sutures fuse prematurely, the skull develops a somewhat clover-leaf shape. Individuals with Pfeiffer type 2 have clover-leaf skulls more often than individuals with types 1 and 3.

The coronal suture is also fused prematurely in Crouzon, Jackson-Weiss, Apert, and Beare-Stevenson syndromes. The thumbs and big toes are normal in Beare-Stevenson and Crouzon syndromes. Additional associated abnormalities distinguish Apert and Jackson-Weiss syndromes.

Serious complications of Pfeiffer syndrome include respiratory problems and hydrocephalus . Hydrocephalus is excessive fluid in the brain, which leads to mental impairment if untreated. Breathing problems may be caused by trachea abnormalities or be related to undergrowth of the midface. Some individuals may require an incision in the trachea (tracheostomy). Serious complications are more common in Pfeiffer types 2 and 3. Individuals with types 2 and 3 are severely affected, and often do not survive past infancy. Death may result from severe brain abnormalities, breathing problems, prematurity, and surgical complications. Even without accompanying hydrocephalus, developmental delays and mental retardation are common (in types 2 and 3). Lower displacement of the eyes may be so severe that the infant is unable to close his or her eyelids. Individuals with types 2 and 3 may also have seizures. Intellect is usually normal in Pfeiffer type 1.


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.

Treatment and management

Children with Pfeiffer syndrome usually see a team of medical specialists at regular intervals. This team typically includes plastic surgeons, neurosurgeons, orthopedists, ear, nose, and throat doctors (otolaryngologists), dentists, and other specialists. The affected person may see the specialists all at once in a craniofacial clinic at a hospital. Many physical problems must be addressed. Developmental, psychosocial, and financial issues are additional concerns. Unfortunately, treatment is aimed at the symptoms, not the underlying cause. Even if craniosynostosis is discovered prenatally, only the symptoms can be treated.

Multiple surgeries are usually performed to progressively correct the craniosynostosis and to normalize facial appearance. A team of surgeons is often involved, including a neurosurgeon and a specialized plastic surgeon. The timing and order of surgeries vary. Patients with syndromic craniosynostosis often require surgery earlier than patients with nonsyndromic craniosynostosis. The first surgery is usually performed early in the first year of life, even in the first few months.

Additional surgeries may be performed for other physical problems. Limb abnormalities often are not correctable. If the limb malformations do not lead to a loss of function, surgery is usually not required. Fixation of the elbow joints may be partially corrected, or at least altered to enable better functioning.

Hydrocephalus, airway obstruction, hearing loss, incomplete eyelid closure, and spine abnormalities require immediate medical attention.


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.



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Michelle Queneau Bosworth, MS, CGC