|55 Kenosia Avenue
Danbury, CT 06810
Toll Free: 1.800.999.6673
The National Organization for Rare Disorders (NORD) web site, its databases, and the contents thereof are copyrighted by NORD. No part of the NORD web site, databases, or the contents may be copied in any way, including but not limited to the following: electronically downloading, storing in a retrieval system, or redistributing for any commercial purposes without the express written permission of NORD. Permission is hereby granted to print one hard copy of the information on an individual disease for your personal use, provided that such content is in no way modified, and the credit for the source (NORD) and NORD’s copyright notice are included on the printed copy. Any other electronic reproduction or other printed versions is strictly prohibited.
The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.
Copyright 1988, 1989, 1994, 1998, 1999, 2003, 2008, 2012
NORD is very grateful to 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 abnormally broad and medially deviated thumbs and great toes. Most affected individuals also have an abnormal midface, with 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 mutations in the fibroblast growth factor receptor-2 (FGFR2) gene and the fibroblast growth factor receptor-1 (FGFR1) gene.
Pfeiffer syndrome is now known to be a member of a group of conditions caused by mutations 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 in the AP diameter and tall (turribrachycephaly). Additional craniofacial abnormalities 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.
Pfeiffer syndrome type II is characterized by a more severe form of craniosynostosis (Cloverleaf skull), and more severe hand and foot anomalies, as well as 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 inhibition of the normal flow of cerebrospinal fluid (CSF) and abnormal widening (dilatation) of the spaces around the brain (ventricles) may cause accumulation of CSF in the skull and increased pressure on the brain. Characteristic craniofacial abnormalities 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. Affected infants may also exhibit abnormal fixation and lack of mobility (ankylosis) of the elbow joints and/or, in some cases, various malformations of certain internal organs in the abdominal area (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 airway problems. Without appropriate treatment, the physical abnormalities associated with the disorder may lead to life-threatening complications during infancy.
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 abnormal 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 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 affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Pfeiffer syndrome type I is associated with mutations in the FGFR1 gene and the FGFR2 gene. Pfeiffer syndrome type II and type III are associated with mutations in the FGFR2 gene.
The incidence of all types of Pfeiffer syndrome is approximately 1/100,000.
Apert syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the head that lead to distinctive facial features. In addition, the hands and/or feet may be webbed (syndactyly) and in some cases, mental retardation may also be present. Babies born with Apert syndrome have fibrous joints between bones of the skull (sutures) that close prematurely (craniosynostosis). The pressure of continued brain growth distorts various bones of the skull and the face. The skull is forced into one of several characteristic shapes. Often the head appears abnormally pointed at the top (acrocephaly). The distortion of the skull plates create changes in the facial bones leading to characteristic facial abnormalities, such as widely spaced eyes (ocular hypertelorism), abnormal protrusion of the eyes (exophthalmos), underdevelopment of midfacial regions (midface hypoplasia), and/or a narrow roof of the mouth (palate).
Malformations of the hands and feet may include unusually broad thumbs and great toes, short fingers, and/or partial to complete fusion (syndactyly) of certain fingers and toes (digits). Most commonly, there is complete fusion of bones within the second to the fourth fingers and the presence of a single common nail ("mitten-like" syndactyly). Apert syndrome is an autosomal dominant genetic condition associated with mutations in the FGFR2 gene. (For more information on this disorder, choose "Apert" as your search term in the Rare Disease Database.)
Crouzon syndrome is a rare genetic disorder that may be evident at birth (congenital) or during infancy. The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) region. Such abnormalities may vary greatly in range and severity from case to case, including among affected family members. However, in most infants with Crouzon syndrome, the fibrous joints between certain bones of the skull (cranial sutures) close prematurely (craniosynostosis). In addition, facial abnormalities typically include unusual bulging or protrusion of the eyeballs (proptosis) due to shallow eye cavities (orbits); outward deviation of one of the eyes (divergent strabismus or exotropia); widely spaced eyes (ocular hypertelorism); and a small, underdeveloped upper jaw (hypoplastic maxilla), with protrusion of the lower jaw (relative mandibular prognathism). The presence of normal appearing hands and feet distinguish Crouzon syndrome from Pfeiffer syndrome. Crouzon syndrome is an autosomal dominant genetic condition associated with mutations in the FGFR2 gene. (For more information on this disorder, choose "Crouzon as your search term in the Rare Disease Database.)
Crouzon syndrome with acanthosis nigricans is a rare genetic disorder characterized by the signs and symptoms of Crouzon syndrome in combination with thick, dark areas in the skin folds (acathosis nigricans). This condition follows autosomal dominant inheritance and is associated with specific mutations in the FGFR3 gene.
Jackson-Weiss syndrome is an extremely rare genetic disorder characterized by craniosynostosis; an unusually flat middle portion of the face (midface hypoplasia); abnormally broad great toes; and/or webbing or fusion (syndactyly) of the second and third toes. The range and severity of symptoms and findings may vary greatly from case to case, including within affected family members (kindreds). Jackson-Weiss syndrome is an autosomal dominant genetic condition associated with mutations in the FGFR2 gene. (For more information on this disorder, choose "Jackson Weiss" as your search term in the Rare Disease Database.)
Beare-Stevenson syndrome is an extremely rare genetic disorder characterized by craniosynostosis, particular skin abnormalities called cutis gyrata and acanthosis nigricans and mental retardation. Cutis gyrata are patches of skin with a furrowed and wrinkled appearance and are found most often on the face, near the ears and on the palms of hands and soles of feet. Acanthosis nigricans are patches of thick, dark areas in the skin folds. Genital and anal abnormalities may also be present. Beare-Stevenson syndrome is an autosomal dominant genetic condition associated with mutations in the FGFR2 gene.
Muenke syndrome is a rare genetic disorder characterized by premature fusion of skull bones over the top of the head from ear to ear (coronal craniosynostosis). Other symptoms can be similar to those of other disorders caused by FGFR gene mutations. Muenke syndrome is an autosomal dominant genetic condition associated with a specific single mutation in the FGFR3 gene. Some individuals with this specific FGFR3 mutation do not have symptoms of the disorder.
FGFR2-related isolated coronal synostosis is an autosomal dominant genetic disorder characterized by premature fusion of skull bones over the top of the head from ear to ear (coronal craniosynostosis) and no other major abnormalities. Many children also have hypertelorism as well.This condition follows autosomal dominant inheritance and is associated with mutations in the FGFR-2 gene.
The diagnosis of Pfeiffer syndrome is based on clinical findings. Molecular genetic testing for the FGFR1 and FGFR2 genes 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; specialists who assess and treat hearing problems (audiologists); and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
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 abnormalities (e.g., midface hypoplasia, facial asymmetry, nasal abnormalities, ocular proptosis due to shallow orbits). According to the medical literature, the results of such craniofacial surgery may vary.
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 addition, in some cases, 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, 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., craniofacial malformations, digital and skeletal abnormalities, hearing loss, etc.].)
Muenke M, Wilkie AOM. Craniosynostosis Syndromes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; 2002:245.
Hackett A, Rowe L. FGFR1 Pfeiffer syndrome without craniosynostosis: an additional case report. Clin Dysmorphol. 2006;15:207-10.
Stevens CA, Roeder ER. Ser351Cys mutation in the fibroblast growth factor receptor 2 gene results in severe Pfeiffer syndrome. Clin Dysmorphol. 2006;15:187-8.
Oliveira NA, Alonso LG, Fanganiello RD, Passos-Bueno MR. Further evidence of association between mutations in FGFR2 and syndromic craniosynostosis with sacrococcygeal eversion. Birth Defects Res A Clin Mol Teratol. 2006;76:629-33.
Quintero-Rivera F, Robson CD, Reiss RE, et al. Apert syndrome: what prenatal radiographic findings should prompt its consideration? Prenat Diagn. 2006;26966-72.
Itoh S, Nojima M, Yoshida K. Usefulness of magnetic resonance imaging for accurate diagnosis of Pfeiffer syndrome type II in utero. Fetal Diagn Ther. 2006;21:168-71.
Lajeunie E, Heuertz S, El Ghouzzi V, et al. Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome. Eur J Hum Genet. 2006;14:289-8.
Glaser RL, Jiang W, Boyadjiev SA, et al. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet. 2000;66:768-77.
Kress W, Collmann H, Busse M, Halliger-Keller B, Mueller CR. Clustering of FGFR2 gene mutations in patients with Pfeiffer and Crouzon syndromes (FGFR2-associated craniosynostoses). Cytogenet Cell Genet. 2000;91:134-7.
Robin NH, Scott JA, Arnold JE, et al. Favorable prognosis for children with Pfeiffer syndrome types 2 and 3: implications for classification. Am J Med Genet. 1998;75:240-4.
Tartaglia M, Di Rocco C, Lajeunie E, Valeri S, Velardi F, Battaglia PA. Jackson-Weiss syndrome: identification of two novel FGFR2 missense mutations shared with Crouzon and Pfeiffer craniosynostotic disorders. Hum Genet. 1997;101:47-50.
Winter RM, Reardon W. Lumpers, splitters, and FGFRs. Am J Med Genet. 1996;63(3):501-2.
Moore MH, Cantrell SB, Trott JA, David DJ. Pfeiffer syndrome: a clinical review. Cleft Palate Craniofac J. 1995;32:62-70.
Muenke M, Schell U, Robin NH. et al. Variable clinical spectrum in Pfeiffer syndrome: correlation between phenotype and genotype. Proc Green Genet Ctr. 1995;15:126.
Cohen MM Jr. Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. Am J Med Genet. 1993;45:300-7.
Robin NH, Falk MJ, Haldeman-Englert CR. (Updated June 7, 2011). FGFR-Related Craniosynostosis Syndromes. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed April 5, 2012.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. http://omim.org/geneMap/8/158?start=-3&limit=10&highlight=158Pfeiffer Syndrome. Entry No: 101600. Last Edited June 10, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed April 5, 2012.
Vogels A and Fryns J-P. Pfeiffer Syndrome. In: Orphanet Journal of Rare Diseases. http://www.ojrd.com/content/1/1/19. June 1, 2006. Accessed April 5, 2012.
Report last updated: 2012/04/05 00:00:00 GMT+0