Última actualización:
7/25/2023
Años publicados: 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.
Treatment
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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TEXTBOOKS
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.
JOURNAL ARTICLES
Noble AR, Cunningham ML, Lam A, et al. Complex airway management in patients with tracheal cartilaginous sleeves. Laryngoscope. 2022;132(1):215-221.
Lu X, Forte AJ, Allam O, et al. Nasopharyngeal airway and subcranial space analysis in Pfeiffer syndrome. Br J Oral Maxillofac Surg. 2021;59(5):592-598.
Kilcoyne S, Potter KR, Gordon Z, et al. Feeding, communication,hHydrocephalus, and intracranial hypertension in patients with severe FGFR2-associated Pfeiffer syndrome. J Craniofac Surg. 2021;32(1):134-140Mahmud N, Abdul Latif H, Mohd Zaki F, Goh BS. Tracheal cartilaginous sleeve in Pfeiffer syndrome: lesson learnt from its rarity. BMJ Case Rep. 2021;14(4):e236888. Published 2021 Apr 2.
Mavridis IN, Rodrigues D. Nervous system involvement in Pfeiffer syndrome. Childs Nerv Syst. 2021;37(2):367-374.
Raposo-Amaral CE, Denadai R, Máximo G, Raposo-Amaral CA, Ghizoni E. Pfeiffer Syndrome: A Therapeutic algorithm based on a modified grading scale. Plast Reconstr Surg Glob Open. 2020;8(4):e2788. Published 2020 Apr 29.
Zimmerman CE, Sun J, Wes AM, et al. Long term speech outcomes following midface advancement in syndromic craniosynostosis. J Craniofac Surg. 2020;31(6):1775-1779.
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.
Vogels A and Fryns J-P. Pfeiffer Syndrome. Orphanet Journal of Rare Diseases. 2006;1:19. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-19
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.Mavridis, Rodriguez. Nervous system involvement in Pfeiffer syndrome
INTERNET
Wenger T, Miller D, Evans K. FGFR Craniosynostosis Syndromes Overview. 1998 Oct 20 [Updated 2020 Apr 30]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1455/ Accessed July 18, 2023.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Pfeiffer Syndrome. Entry No: 101600. Last Edited 08/11/2017. Available at: https://omim.org/entry/101600 Accessed July 18, 2023.
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Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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