Orphanet Journal of Rare Diseases

BioMed Central

Review Open Access

Pfeiffer syndrome
Annick Vogels and Jean-Pierre Fryns*

Address: Center for Human Genetics, University Hospital Leuven, Herestraat 49, B-3000 Leuven, Belgium
Email: Annick Vogels - [email protected]; Jean-Pierre Fryns* - [email protected]
* Corresponding author

Published: 01 June 2006 Received: 05 May 2006

Accepted: 01 June 2006
Orphanet Journal of Rare Diseases 2006, 1:19 doi:10.1186/1750-1172-1-19
This article is available from: http://www.OJRD.com/content/1/1/19
© 2006 Vogels and Fryns; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Pfeiffer syndrome is a rare autosomal dominantly inherited disorder that associates
craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly on hands and feet.
Hydrocephaly may be found occasionally, along with severe ocular proptosis, ankylosed elbows,
abnormal viscera, and slow development. Based on the severity of the phenotype, Pfeiffer
syndrome is divided into three clinical subtypes. Type 1 "classic" Pfeiffer syndrome involves
individuals with mild manifestations including brachycephaly, midface hypoplasia and finger and toe
abnormalities; it is associated with normal intelligence and generally good outcome. Type 2 consists
of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis,
developmental delay and neurological complications. Type 3 is similar to type 2 but without a
cloverleaf skull. Clinical overlap between the three types may occur. Pfeiffer syndrome affects
about 1 in 100,000 individuals. The disorder can be caused by mutations in the fibroblast growth
factor receptor genes FGFR-1 or FGFR-2. Pfeiffer syndrome can be diagnosed prenatally by
sonography showing craniosynostosis, hypertelorism with proptosis, and broad thumb, or
molecularly if it concerns a recurrence and the causative mutation was found. Molecular genetic
testing is important to confirm the diagnosis. Management includes multiple-staged surgery of
craniosynostosis. Midfacial surgery is performed to reduce the exophthalmos and the midfacial
hypoplasia.

Disease name and synonyms Definition

Pfeiffer syndrome (OMIM 101600) Pfeiffer syndrome is a rare autosomal dominantly inher-
ited disorder that associates craniosynostosis, broad
Acrocephalosyndactyly, type V (ACS5) thumbs and big toes, and partial syndactyly on hands and
feet.
ACS V
History
Noack syndrome (included) In the original article, Pfeiffer described a syndrome with
skull and limb anomalies in eight persons from a three-
Craniofacial-skeletal-dermatologic dysplasia (included) generation family [1]. Since then, several reports have
documented its high clinical variability and genetic heter-
ogeneity.

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Epidemiology the diagnosis difficult to establish. Types 2 and 3 have

Pfeiffer syndrome affects about 1 in 100,000 individuals. occurred only in sporadic cases, and have an increased risk
for early death due to severe neurological compromise
Clinical description and respiratory problems.
A craniosynostosis in association with short, broad
thumbs and big toes are the major diagnostic clues for Clinical overlap between the three types may occur.
Pfeiffer syndrome.
Diagnosis
Patients have premature fusion of the coronal and lamb- The diagnosis of Pfeiffer syndrome is based on the pres-
doid sutures and occasionally of the sagittal sutures, lead- ence of craniosynostosis and abnormal thumbs and/or
ing to an abnormal skull shape. There is a characteristic first toes. Because of the large clinical variability even
facial appearance: disproportionally wide head with flat within the same family, molecular data may be an impor-
occiput, full high forehead, underdeveloped midface with tant complement to the clinical phenotype to confirm the
receded cheekbones (midfacial hypoplasia), a small nose diagnosis. Children with a suspected complex craniofacial
with low nasal bridge and widely spaced eyes (ocular syndrome should be referred for clinical genetic investiga-
hypertelorism). Patients often show prominence of the tions including mutation analysis of FGFR 1 (exon 7),
eyes (ocular proptosis) due to very shallow orbits. FGFR 2 (exon 8), FGFR 2 (exon 10) and FGFR 3 (exon 7).

The thumbs and big toes are short and broad. There is a Etiology
typical deviation of thumbs and great toes away from the Mutations in the fibroblast growth factor receptor (FGFR)
other digits and webbing (syndactyly) of the second and genes cause Pfeiffer syndrome: FGFR1 (on chromosome
third fingers and toes. Additional abnormalities may 8p11.2-p11) and FGFR2 (on chromosome 10q26) [4].
include mental retardation, aqueductal stenosis with The FGFR1 and FGFR2 genes play an important role in sig-
ensuing hydrocephaly, cerebellar and brain stem hernia- naling the cell to respond to its environment, perhaps by
tion, low-set ears, external auditory canal stenosis of dividing or maturing. A mutation in either gene causes
atresia, recurrent ear infections, and infrequently, internal prolonged signaling, which can promote early maturation
anomalies such as hydronephrosis, pelvic kidneys and of bone cells in a developing embryo and the premature
hypoplastic gallbladder [2]. Visual abnormalities may be fusion of bones in the skull, hands and feet.
a feature, either primary, due to the proptosis or second-
ary, due to increased intracranial pressure. Type 1 Pfeiffer syndrome is caused by mutations in either
the FGFR1 or FGFR2 gene. Types 2 and 3 are caused by
Patients with Pfeiffer syndrome may manifest upper air- mutations in the FGFR2 gene. Mutations in FGFR1 there-
way obstruction related to midface hypoplasia and sec- fore usually give a milder phenotype.
ondary nasal obstruction; tracheal anomalies have been
infrequently reported [3]. Differential diagnosis
The main differential diagnosis includes the syndromes
Based on the severity of the phenotype, the Pfeiffer syn- that are characterized by craniosynostosis (Apert, Carpen-
drome has been divided into three clinical subtypes [2]: ter, Crouzon, isolated cloverleaf skull, and Thanatophoric
dysplasia). Interestingly, mutations in the same FGFR
• Type 1 Pfeiffer or "classic" Pfeiffer syndrome involves (either FGFR1, FGFR2 or FGFR3) can result in different
individuals with mild manifestations including brachyc- craniosynostosis syndromes, thus implicating a common
ephaly, midface hypoplasia, and finger and toes abnor- pathologic mechanism with FGFR gain of function in
malities. It is associated with normal neurological and Pfeiffer, Apert, Muenke, and Beare-Stevenson syndromes
intellectual development, and generally has a good out- [5]. Pfeiffer syndrome and Apert syndrome are notewor-
come. thy for some similarities but the two disorders are nosolo-
gically and genetically distinct. Crouzon syndrome is
• Type 2 consists of trilobated skull deformity (cloverleaf phenotypically similar to Pfeiffer syndrome but lacking
skull), extreme proptosis, finger and toes abnormalities, the hand and foot anomalies. Phenotypic overlap occurs
elbow ankylosis or synostosis, developmental delay and with Muenke syndrome, which is caused by a specific
neurological complications. The cloverleaf skull can cause FGFR3 mutation. Sometimes Pfeiffer syndrome has been
limited brain growth, and the extreme proptosis can cause confused with Saethre-Chotzen and Jackson-Weiss syn-
severe visual impairments. dromes, since broad toes may occur in both.

• Type 3 is similar to type 2 but without the cloverleaf

skull. The absence of cloverleaf skull in type 3 can make

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Prenatal diagnosis 7. Nazzaro A, Della Monica M, Lonardo F, Di Blasi A, Baffico M, Baldi M,

Nazzaro G, De Placido G, Scarano G: Prenatal ultrasound diag-
The condition is usually detected in the newborn period nosis of a case of Pfeiffer syndrome without cloverleaf skull
or later, and not prenatally. Prenatal diagnosis has only and review of the literature. Prenat Diagn 2004, 24:918-922.
been reported 6 times, mainly based on the presence of a 8. Soekarman D, Fryns JP, van den Berghe H: Pfeiffer acrocephalo-
syndactyly syndrome in mother and son with cloverleaf skull
cloverleaf skull deformity [6]. A careful three-dimensional anomaly in the child. Genet Couns 1992, 3:217-220.
ultrasound examination can lead to an early prenatal 9. Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Mal-
diagnosis also in cases without cloverleaf skull [7]. The dergem L, Johnson D, Walsh S, Oldridge M, Wall SA, Wilkie AO, Jabs
EW: Paternal origin of FGFR2 mutations in sporadic cases of
large clinical variability of Pfeiffer syndrome even within Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet
the same family, as well as other causes of craniosynosto- 2000, 66:768-777.
10. Kroczek RA, Mühlbauer W, Zimmermann I: Cloverleaf skull asso-
sis, can make the prenatal diagnosis on sonography alone ciated with Pfeiffer syndrome: pathology and management.
difficult. Subsequent molecular analysis should be per- Eur J Pediatr 1986, 145:442-445.
formed to verify the diagnosis by identifying a FGFR
mutation.

Genetic counseling
Pfeiffer syndrome is an autosomal dominantly inherited
disorder meaning that children of a person with Pfeiffer
have a 50% chance of inheriting the syndrome. Recom-
mendations for the evaluation of parents of a proband
with an apparent de novo mutation include clinical, radio-
graphic and molecular genetic evaluation. All cases of
Pfeiffer syndrome type 3 and all but one case of Pfeiffer
syndrome type 2 [8] have resulted from de novo gene
mutations. Advanced paternal age was noted for the
fathers of patients with Pfeiffer syndrome [9].

Management
The primary treatment of craniofacial abnormalities asso-
ciated with craniosynostosis is surgical reconstruction that
usually require a series of staged procedures. In the first
year of life the synostotic sutures of the skull are released.
In syndromic craniosynostosis the first surgery is often as
early as at three months of age. The aim of this surgery is
decompression of the brain and remodeling of the skull,
and if necessary, elongation and expansion of the bony
orbits [10]. As the child grows, skull remodeling may be
required. Early treatment may reduce the risk for second-
ary complications such as hydrocephaly. In a second
stage, midfacial surgery is performed to reduce the exoph-
thalmos and the midfacial hypoplasia.

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