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Home / Rare Diseases / Pfeiffer Syndrome

Pfeiffer Syndrome

Last updated: 7/25/2023

Years published: 1988, 1989, 1994, 1998, 1999, 2003, 2008, 2012, 2015,
2018, 2023

Acknowledgment
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.

Disease Overview Terms of Ser

Pfeiffer syndrome is a rare genetic disorder characterized by premature By contin
fusion of certain skull bones (craniosynostosis) and broad and medially Policy
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.)

Synonyms
acrocephalosyndactyly, type V

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ACSV

craniofacial-skeletal-dermatologic syndrome

Noack syndrome

Subdivisions
Pfeiffer syndrome type I

Pfeiffer syndrome type II

Pfeiffer syndrome type III

Signs & Symptoms

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 Terms of Ser
is usually some degree of hearing loss, which is more commonly
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conductive rather than sensorineural.
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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

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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. Terms of Ser

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Causes
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.

Affected populations
The incidence of all types of Pfeiffer syndrome is approximately

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1/100,000.

Disorders with Similar Symptoms

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, intellectual
disability 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 creates 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 Terms of Ser
bones within the second to the fourth fingers and the presence of a single
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common nail (“mitten-like” syndactyly). Apert syndrome is an autosomal
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dominant genetic condition associated with variants in FGFR2. (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 person to
person, 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 distinguishes Crouzon syndrome from Pfeiffer syndrome. Crouzon

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syndrome is an autosomal dominant genetic condition associated with

variants in FGFR2. (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 variants in FGFR3.

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 person to person,
including within affected family members (kindreds). Jackson-Weiss
syndrome is an autosomal dominant genetic condition associated with
variants in FGFR2. (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, skin abnormalities called cutis gyrata
Terms of Ser
and acanthosis nigricans and intellectual disability. Cutis gyrata are
patches of skin with a furrowed and wrinkled appearance and are found By contin
Policy
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 variants 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 variants. Muenke syndrome is an autosomal
dominant genetic condition associated with a specific single variant
in FGFR3. Some individuals with this specific FGFR3 variant 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 variants in FGFR2.

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Diagnosis
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.

Standard Therapies
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 Terms of Ser
craniosynostosis and, in the case of hydrocephalus, to insert a tube By contin
(shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and Policy
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.

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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.

Clinical Trials and Studies Terms of Ser

Information on current clinical trials is posted on the Internet By contin

at www.clinicaltrials.gov. All studies receiving U.S. government funding, Policy
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
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the
NORD website:
https://rarediseases.org/for-patients-and-families/information-
resources/news-patient-recruitment/

For information about clinical trials sponsored by private sources,

contact:
www.centerwatch.com

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For information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/

References
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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.
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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 Terms of Ser
patients with severe FGFR2-associated Pfeiffer syndrome. J Craniofac
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Surg. 2021;32(1):134-140Mahmud N, Abdul Latif H, Mohd Zaki F, Goh
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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
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Zimmerman CE, Sun J, Wes AM, et al. Long term speech outcomes
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Craniofac Surg. 2020;31(6):1775-1779.

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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
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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

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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.

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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 Terms of Ser
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INTERNET
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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
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18, 2023.

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