Years published: 1988, 1989, 1994, 1998, 1999, 2003, 2008, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Nathaniel H. Robin, MD, Professor of Genetics and Pediatrics, University of Alabama at Birmingham, for assistance in the preparation of this report.
Pfeiffer syndrome is a rare genetic disorder characterized by premature fusion of certain skull bones (craniosynostosis) and broad and medially deviated thumbs and great toes. Most affected individuals also have differences to their midface (protruding eyes) and conductive hearing loss. Three forms of Pfeiffer syndrome are recognized, of which types II and III are the more serious.
Pfeiffer syndrome is an autosomal dominant condition associated with changes (pathogenic variants or mutations) in the genes fibroblast growth factor receptor-2 (FGFR2) and fibroblast growth factor receptor-1 (FGFR1).
Pfeiffer syndrome is now known to be a member of a group of conditions caused by variants in the FGFR genes including Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans and Muenke syndrome. (For more information on these conditions, please see the Related Disorders section below.)
Infants with Pfeiffer syndrome type I have craniosynostosis that causes the head to appear short and tall (turribrachycephaly). Additional features may include a high, full forehead; underdeveloped midfacial regions (midface hypoplasia); widely spaced eyes (ocular hypertelorism); an underdeveloped upper jaw (hypoplastic maxilla), with a prominent lower jaw; and dental abnormalities. Intelligence is usually normal. There is usually some degree of hearing loss, which is more commonly conductive rather than sensorineural.
Pfeiffer syndrome type II is characterized by a more severe form of craniosynostosis (cloverleaf skull), with more severe hand and foot anomalies and additional malformations of the limbs. In infants with Pfeiffer syndrome type II, premature closure of the fibrous joints (cranial sutures) between several bones in the skull causes the skull to have a “tri-lobed” appearance (cloverleaf skull deformity, or Kleeblattschadel type craniosynostosis). In addition, this form of craniosynostosis is often associated with hydrocephalus, a condition in which the normal flow of cerebrospinal fluid (CSF) is altered, leading to abnormal widening (dilatation) of the spaces within the brain (ventricles) causing accumulation of CSF in the skull and increased pressure on the brain. Characteristic craniofacial features associated with Pfeiffer syndrome type II may include an abnormally high, broad forehead; severe protrusion of the eyes (ocular proptosis); an unusually flat middle portion of the face (midface hypoplasia); a “beak-shaped” nose; and downwardly displaced ears. Besides craniofacial features, some may have abnormalities in the structure of segments of the spinal column. Affected infants may also exhibit fixation and lack of mobility (ankylosis) of the elbow joints and/or, in some people, various malformations of certain internal organs in the abdomen (visceral anomalies). In addition, infants with Pfeiffer syndrome type II often experience impaired mental development and neurological problems due to severe involvement of the brain, and/or hypoxia due to problems with breathing. Without appropriate treatment, the physical abnormalities associated with the disorder may lead to life-threatening complications during infancy. Severe obstructive sleep apnea is common. Additionally, closure of the tracheal cartilage (tracheal cartilaginous sleeve) can worsen breathing problems.
Individuals with Pfeiffer syndrome type III have symptoms and findings similar to those present in Pfeiffer syndrome type II, with the exception of the cloverleaf skull deformity. Additional characteristics associated with Pfeiffer syndrome type III include a shortened base of the skull (anterior cranial base); the abnormal presence of certain teeth at birth (natal teeth); severe protrusion of the eyes (ocular proptosis) due to shallowness of the bony cavities that accommodate the eyeballs (orbit); and/or various malformations of certain internal organs in the abdominal area (visceral anomalies). As in type II, individuals with Pfeiffer syndrome type III often experience impaired mental development and severe neurological problems and may develop potentially life-threatening complications early in life without appropriate treatment.
Pfeiffer syndrome type I is associated with variants in FGFR1 and FGFR2. Pfeiffer syndrome type II and type III are associated with variants in FGFR2.
Pfeiffer syndrome is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Essentially all cases of Pfeiffer syndrome type II and type III have resulted from new mutations. Advanced paternal age is associated with an increased risk for new mutations for Pfeiffer syndrome. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
The incidence of all types of Pfeiffer syndrome is approximately 1/100,000.
The diagnosis of Pfeiffer syndrome is based on clinical findings. Molecular genetic testing for FGFR1 and FGFR2 gene variants is available if the diagnosis is uncertain.
The treatment of Pfeiffer syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; surgeons; physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists); neurologists; ophthalmologists; specialists who assess and treat hearing problems (audiologists); and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.
Specific therapies for Pfeiffer syndrome are symptomatic and supportive. Because craniosynostosis and, in some cases, associated hydrocephalus may result in abnormally increased pressure within the skull (intracranial pressure) and on the brain, early surgery may be advised to correct craniosynostosis and, in the case of hydrocephalus, to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Early corrective and reconstructive surgery may also be performed in infants with Pfeiffer syndrome to help correct certain associated craniofacial differences (e.g., midface hypoplasia, facial asymmetry, nasal abnormalities, ocular proptosis due to shallow orbits). The results of such craniofacial surgery may vary, but often produce a significant decrease in ocular symptoms and breathing problems. These surgeries can temporarily worsen velopharyngeal insufficiency, making speaking and swallowing more difficult, but this resolves with time.
Airway compromise can also occur, especially in very young children. This causes low oxygen levels that can, if unrecognized and untreated, result in brain damage. In many cases, particularly those with a tracheal cartilaginous sleeve, a surgical airway (tracheostomy) may be necessary.
In addition, in some affected individuals, reconstructive surgery may be performed to help correct ear malformations and/or specialized hearing aids may be used to improve conductive hearing loss.
In some individuals with Pfeiffer syndrome, surgery may also be conducted to help correct syndactyly and/or other skeletal malformations and improve function and mobility. Physical therapy and additional orthopedic and supportive measures may also be used to help further improve an affected individual’s mobility. The surgical procedure(s) performed to correct certain craniofacial, audiological, digital, and/or skeletal abnormalities associated with the disorder will depend upon the severity and location of the anatomical abnormalities and their associated symptoms.
Early intervention may be important to ensure that children with Pfeiffer syndrome reach their potential. Special services that may be beneficial to affected children include special social support, physical therapy, speech therapy, and other medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families. In addition, thorough clinical evaluations may be important in family members of diagnosed individuals to detect any symptoms and physical characteristics that may be potentially associated with Pfeiffer syndrome.
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