CME

Craniofacial Syndromes
Edward P. Buchanan, M.D.
Amy S. Xue, M.D.
Larry H. Hollier, Jr., M.D.
Houston, Texas
Learning Objectives: After studying this article, the participant should be able
to: 1. Recognize the clinical presentations of commonly seen craniofacial syn-
dromes. 2. Understand the most serious complications associated with each
syndrome. 3. Formulate the best age-appropriate surgical plans.
Summary: Craniofacial syndromes fall into two major categories—those as-
sociated with craniosynostosis, and those associated with clefts. Each has a
different set of potential complications requiring a unique approach for sur-
gical management. Craniosynostosis is a congenital disorder in which one or
more of the cranial sutures fuses prematurely. The most common syndromes
associated with this condition include Crouzon, Apert, Pfeiffer, Muenke, and
Saethre-Chotzen syndromes. Surgical management of these children requires
a multidisciplinary approach and close involvement of the family. Operations
must take into consideration the growing potential of the bony structures.
Common syndromes associated with clefts include Pierre Robin, Treacher
Collins, Nager, Binder, and Stickler syndromes. Many of these children have
severe airway issues requiring immediate address before operative reconstruc-
tion. As with syndromes associated with craniosynostosis, the key to manage-
ment is a multidisciplinary approach focused on the right timing. The purpose
of this article is to review the clinical presentation, care, and treatment of
these patients.  (Plast. Reconstr. Surg. 134: 128e, 2014.)

T
he word syndrome translates from its Greek
origin to mean “run together.” Tradition-
ally, syndrome is a clinical diagnosis, char-
acterized by a set of symptoms that consistently
present together. There are estimated to be over
500 syndromes with craniofacial anomalies.1
Most are morphologic, affecting the form and
function of the head and face. Many are asso-
ciated with variations in the fibroblast growth
factor receptor (FGFR) genes, which direct the
development of bone and cartilage. The clinical
manifestations of these symptoms extend beyond
the craniofacial arena. Therefore, the best treat-
ment approach is one that is multidisciplinary
and takes into consideration physical and mental
development.
Currently, there is no comprehensive classi-
fication system that encompasses all craniofacial
syndromes. Although the Whitaker classification2
(Table 1) is by no means perfect, it does pro-
vide an organized framework to initiate this dis-
cussion. In this article, we focus on the first two
categories—syndromes with clefts and craniosyn-
ostosis, and briefly discuss those associated with
atrophy.
SYNDROMIC CRANIOSYNOSTOSIS
Craniosynostosis is a congenital disorder
marked by premature fusion of one or more cra-
nial sutures, resulting in abnormal cranial growth.
Children with craniosynostosis typically have cra-
nial expansion in the direction parallel to the
fused suture, leading to abnormal head shape.
Approximately one in 2500 infants is affected by
this disorder.3 Most cases are nonsyndromic or
isolated. Syndromic craniosynostoses are those
conditions that have additional manifestations
(craniofacial and/or extracraniofacial deformi-
ties); these account for 40 percent, or one in 6250
Disclosure: The authors have no financial interest
to declare in relation to the content of this article.

From the Division of Plastic Surgery, Baylor College of
­Medicine.
Received for publication April 22, 2013; accepted November
11, 2013.
Copyright © 2014 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0000000000000308
Related Video content is available for this ar-
ticle. The videos can be found under the “Re-
lated Videos” section of the full-text article, or,
for Ovid users, using the URL citations pub-
lished in the article.

128e www.PRSJournal.com
Volume 134, Number 1 • Craniofacial Syndromes
Table 1.  Whitaker Classification of Craniofacial Anomalies*
Type
I Clefts
I Synostoses
III Atrophy (hypoplasia)
IV Neoplasia (hyperplasia)
V Unclassified
*Modified from Whitaker LA, Pashayan H, Reichman J. A proposed new classification of craniofacial anomalies. Cleft Palate J. 1981;18:161–176.
births.4 As a general rule of thumb, children with
single-suture synostosis are most likely not syn-
dromic; however, many craniofacial syndromes
present with single-suture synostosis.
The majority of syndromic craniosynostoses
are associated with FGFR mutations, demonstrat-
ing autosomal dominant inheritance.5 The asso-
ciated mutations are typically gain-of-function
mutations. Table 2 summarizes the common
presentations of the conditions we will discuss in
this section: Apert, Crouzon, Pfeiffer, Muenke,
Saethre-Chotzen, and Carpenter syndromes.
With the recent successes in molecular genetics
research, many had hoped that genetic testing
would provide more specific and accurate diag-
noses for these syndromes. Unfortunately, many
phenotypically distinct syndromes had been
linked to the same mutations, suggesting the exis-
tence of modifier genes and epigenetic factors,
yet undetermined.
Table 3 summarizes the general terminology
used in describing craniosynostosis. Although
these terms are often used, they are more use-
ful as descriptors of skull shape to aid commu-
nication, and are not specific to each diagnosis.
Definitive diagnosis requires computed tomo-
graphic imaging demonstrating inappropriately
fused suture(s). It is also useful to briefly discuss
the term “acrocephalosyndactyly,” which is a col-
lection of craniofacial syndromes with craniofa-
cial dysmorphology and concurrent syndactyly
of the hands and feet. First used in the context
of Apert syndrome (type I), it has since included
other syndromes, such as Crouzon (type II),
Saethre-Chotzen (type III), and Pfeiffer (type V)
syndromes. The classification system is based on
Definition
Centric (surrounding structures are displaced laterally, require reposition)
 • Facial clefts, nos. 0, 1, 2, and 3
 • Cranial extensions, nos. 14, 13, 12, and 11
Acentric
 • Facial clefts, nos. 4, 5, 6, 7, and 8
 • Cranial clefts, nos. 10 and 9
Symmetric
 • Metopic
 • Coronal
 • Sagittal
Asymmetric
 • Unilateral coronal closure
 • Lambdoid closure
Atrophy of skin, subcutaneous tissue, muscle, bone (e.g., Romberg syndrome,
coup de sabre)
Lymphangioma, hemangioma, fibrous dysplasia
Multiorgan involvement
Single-organ involvement
clinical morphology, not genetic linkage; there-
fore, as genetic research further develops, this
classification system will likely be phased out of
general use.
Apert Syndrome
First described in 1906 by Eugene Apert,
the syndrome features craniofacial and hands/
feet deformities. Genetically, it has been linked
to at least two missense, gain-of-function muta-
tions in the FGFR2 gene on chromosome 10:
Ser252Trp and Pro253Arg.6,7 The Ser252Trp
mutation is more common (>60 percent of cases)
and causes a less severe form of syndactyly but a
higher frequency of cleft palates.8 The mutation
causes an up-regulated response in the andro-
gen end-organ receptors, leading to diffuse early
epiphyseal fusion (craniosynostosis, short stature,
vertebral fusion, and syndactyly) and severe acne
vulgaris.9,10 The mutation demonstrates autoso-
mal dominant inheritance, but most cases are
sporadic. Recent research demonstrated a strong
association with advanced paternal age.11 The
incidence is estimated to be approximately one
in 160,000 live births.12
Major diagnostic features of Apert syndrome
include bicoronal craniosynostosis, midface
hypoplasia, and complex syndactyly of the hands
and feet7 (Fig. 1, above). As with most infants with
bicoronal synostosis, the anterior fontanel is large
and anteriorly displaced and the metopic suture
remains open, as a compensatory mechanism to
accommodate brain growth13 (Fig. 1, below). The
cranial shape is typically turribrachycephalic
and asymmetric. This may be the result of mega-
lencephaly combined with synchondrosis of the
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 Plastic and Reconstructive Surgery • July 2014

skull base.14 Mental and developmental delay is

neurosensorial hearing

blurring of optic discs,

Conductive hearing loss

corneal opacity, high-

Soft palate/uvula cleft,

stature, mental delay

present to varying degrees. Ventricular enlarge-

(II/III), prune belly

Intestinal malrotation

hairline, strabismus
Facial asymmetry, low
acne vulgaris, short

syndrome (II/III),
ment is found in 40 to 90 percent of patients

loss, mental delay

epicanthal folds,
with Apert syndrome,15,16 and the incidence of

hypotelorism,
Hypertelorism/

arched palate
Other

mental delay
elevated intracranial pressure is as high as 45

Strabismus,
percent.17 Midface hypoplasia in Apert patients
is often associated with a V-shaped maxillary
dental arch18 (Fig. 2) and a shorter than normal
hard palate. As a result, the secondary palate is
both thicker and longer than normal, often with
Pan-syndactyly, thumbs free

Symbrachydactyly of hands,
Partial syndactyly (IF/LF),
delta phalanx, duplicate clefting in approximately 75 percent of cases.19
Broad thumbs/halluces

Carpal/tarsal fusions

preaxial polydactyly of
Speech delay may therefore be a potential issue
to address.
Hands/Feet

The presence of skeletal anomalies is a defin-

distal phalanx
—

ing characteristic in Apert syndrome, particularly

syndactyly of the hands and feet (Fig. 1, above,
left).20 In addition, 68 percent of Apert patients
toes

have multilevel vertebral fusion, with C5 and C6

being the most common.20 The classification sys-
tem for Apert hand ranges from type I to III. Type
moderate to severe (III)

I is described as having the thumb and part of the

Table 2.  Summary of Clinical Features Seen in Craniofacial Syndromes with Craniosynostosis
Midface Hypoplasia

fifth finger separate from a syndactylous mass.

Mild to moderate

Type II has just the little finger separated from

Mild to none

ACS, acrocephalosyndactyly; AD, autosomal dominant; AR, autosomal recessive; IR, index finger; LF, long finger.
Moderate
Moderate

Moderate (I/II),

the mass, whereas type III includes all fingers.

—

There is a similar classification system described

for the feet. Management of these skeletal issues
is beyond the scope of this article.

Crouzon Syndrome
Traditionally, Apert and Crouzon syndromes
kleeblattschädel (II/III)

are described together, because morphologically,

Bicoronal synostosis (I),
Bicoronal synostosis

Bicoronal synostosis

Unicoronal/bicoronal

Unicoronal/bicoronal

Crouzon syndrome is Apert syndrome without

Synostosis Type

Sagittals/lambdoid

the hand/feet anomalies. Recent development of

genetic research found that both are related to a
mutation of the FGFR2 gene on chromosome 10,21
synostosis
synostosis

synostosis

thus further confirming the close linkage.

Crouzon syndrome was first described in 1912
by the French physician Octave Crouzon22 based
on the phenotypic similarity of a mother and a
daughter. This autosomal dominant disorder dis-
FGFR2 (AD), FGFR3 plus
Ser252Trp, Pro253Arg

FGFR1 (AD), 5%; FGFR2

FGFR3 (AD), Pro250Arg

plays complete penetrance with variable expres-

FGFR2 (AD, sporadic),

acanthosis nigricans

RAB23 (AR, sporadic)

Genetic Findings

sivity, and has an incidence of one in 25,000 live

births.23 Most cases are associated with mutations
in FGFR2; FGFR3 has been implicated in cases with
(AD), 95%

TWIST (AD)

acanthosis nigricans,24 which is considered a dis-

tinctive syndrome.
The clinical manifestations of Crouzon syn-
drome result from bicoronal craniosynostosis,
which leads to arrest of cranial growth in the
Crouzon (ACS II)

anteroposterior direction and causes a shortened

Saethre-Chotzen
Pfeiffer (ACS V)

anterior cranial base. The phenotypic conse-

Apert (ACS I)

quence is a brachycephalic cranium, shallow orbits

(ACS III)

Carpenter

(appearance of proptosis), and midface hypo-

Muenke
Name

plasia25,26 (Fig. 3). As with all craniosynostoses,

the skull expands in the direction parallel to the

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Table 3.  Terminology Commonly Used to Describe Head Shape*

Term Description Suture Morphology
Scaphocephaly Elongated in the anteroposterior Sagittal
direction, boat-shaped
Dolichocephaly Elongated in the anteroposterior Sagittal
direction, long and narrow

Trigonocephaly Triangular forehead Metopic

Plagiocephaly Asymmetric Unilateral coronal

(anterior), lambdoid
(posterior)

Turricephaly Tall, towering Bilateral coronal

Brachycephaly Short in the anteroposterior Bilateral coronal

direction, broad

Turribrachycephaly Tall, short, and broad Bilateral coronal

Oxycephaly Conical/pointed Bilateral coronal (delayed

onset)

Kleeblattschädel Cloverleaf shaped Pansynostosis

AP, anteroposterior.
*Diagnosis of craniosynostosis requires computed tomographic imaging to confirm inappropriate fusion of suture(s) (head faces toward end
of the page in transverse views, left in lateral views, and front in anteroposterior views).

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 Plastic and Reconstructive Surgery • July 2014

Fig. 1. Typical type III hand (above) presentation of a patient with Apert syndrome. (Below)
Maxillofacial computed tomographic scan with three-dimensional reconstruction of a child
with bicoronal craniosynostosis leading to turricephaly. As shown here, patients typically have
an anteriorly displaced anterior fontanel with an open metopic suture, allowing some com-
pensatory growth.

Fig. 2. V-shaped dental arch secondary to maxillary hypoplasia.

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Fig. 3. Preoperative (left) and postoperative (right) images of a patient with Crouzon
syndrome. Typical characteristics of Crouzon syndrome include brachycephaly caused
by craniosynostosis, ocular proptosis, telorbitism, and midfacial hypoplasia. Although
craniosynostosis is commonly bicoronal, it may involve any of the other major sutures.

affected suture. In this case, as the brain develops,
the skull grows laterally, leading to telorbitism.
Crouzon has also been associated with other forms
of craniosynostosis, including metopic, lambdoid,
sagittal, and multisutural craniosynostoses.25 Nine
to 26 percent of patients suffer from hydroceph-
alus, presenting with frequent headaches and
seizures.15 As a result, any indication of elevated
intracranial pressure warrants further evaluation
and early operative management.
Pfeiffer Syndrome
Pfeiffer syndrome, or acrocephalosyndactyly
type V, was first described in 1964 by Rudolph
Arthur Pfeiffer.27 The original description, which
included a patient with bicoronal craniosynostosis,

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 Plastic and Reconstructive Surgery • July 2014

Table 4.  Cohen Classification of Pfeiffer Syndrome*

Type Major Characteristics Associated Anomaly Prognosis Inheritance
I Turribrachycephaly, midface retrusion, broad Cervical spine fusions, Survival to Sporadic, autosomal
thumbs and great toes, brachydactyly, and visceral anomaly adulthood dominant
variable syndactyly   (low incidence)
II Cloverleaf skull, ocular proptosis, severe mid- Spine anomaly, elbow Poor Sporadic
face retrusion, digital anomaly synostoses, intellectual
delay, intracranial
anomaly
III Severe midface retrusion, no cloverleaf skull, Elbow/knee synostoses, Poor Sporadic
ocular proptosis, class III malocclusion, visceral anomaly, intel-
digital anomaly lectual delay, intracra-
nial anomaly
*Modified from Cohen MM Jr. Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. Am J Med Genet.
1993;45:300–307.

turribrachycephaly, and maxillary hypoplasia, variable expressivity. Its incidence is estimated to

was later modified by Cohen, who further classi-
fied the syndrome.28 Genetically, the syndrome
is linked to mutation in the FGFR1 and FGFR2
genes,29 and has an autosomal dominant inheri-
tance pattern with incomplete penetrance and
be one in 100,000 live births.12
Cohen classified Pfeiffer syndrome into three
major types28 (Table 4). Type I demonstrates
bicoronal craniosynostosis with variable midface
deformity. Proptosis in these patients is usually

Fig. 4. Kleeblattschädel (or cloverleaf skull) deformity characteristic of pansuture craniosynosto-

sis seen in Pfeiffer syndrome.

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Fig. 5. Patient with Saethre-Chotzen syndrome demonstrating bicoronal craniosynos-

tosis and small, inferiorly positioned ears.

minimal and they tend to demonstrate good
cranial growth. Type II is the most severe form,
involving kleeblattschädel, or cloverleaf defor-
mity, with severe midface hypoplasia (Fig. 4).
It is typically associated with broad thumbs and
great toes, although these are not exclusive find-
ings for this type. Type III is similar to type II, but
without kleeblattschädel deformity. Both types II
and III are associated with severe mental devel-
opmental delay and shortened lifespan. There
have also been reports of visceral anomalies
including intestinal malrotation and prune belly
syndrome.
Muenke Syndrome
Muenke syndrome is another of the FGFR-
related craniosynostosis syndromes. This autoso-
mal dominant syndrome occurs in one in 30,000
live births.30 One hundred percent of the patients
have a Pro250Arg mutation on the FGFR3 gene.30
These patients normally present with either unicor-
onal (29 percent) or bicoronal craniosynostosis

135e

(71 percent).31 They can also present with mega-
lencephaly without craniosynostosis. In a study
evaluating 72 individuals from 24 families, 12.5
percent of the patients had no evidence of cranio-
synostosis.31 Patients usually demonstrate mild to
significant midface hypoplasia with ocular hyper-
telorism.32 The extremities have normal hand and
foot phenotypes; however, they can demonstrate
carpal or tarsal fusions.33 Neurosensorial hearing
loss of an unknown cause34 and strabismus35 are
common. Developmental delay and intellectual
disabilities have been reported in approximately
one-third of patients.33
Saethre-Chotzen Syndrome
Saethre-Chotzen syndrome, or acrocephalo-
syndactyly type III, was first described in 1931 by
Saethre and Chotzen.36,37 In 1975, Pantke et al.
elaborated on the syndrome and named it after
its original authors.38 The inheritance pattern is
autosomal dominant, with high penetrance and
variable expressivity, typically involving intragenic
mutations, microdeletions, or translocations
within the TWIST gene on chromosome 7.39 The
incidence is estimated to range from one in 25,000
to 50,000 live births,39 and it is one of the most
common forms of syndromic craniosynostosis.
Classic findings include unilateral or bilat-
eral coronal craniosynostosis, facial asymmetry if
unicoronal, strabismus, ptosis, low frontal hair-
line, and malformed ears38 (Fig. 5). The Saethre-
Chotzen ear typically has a small pinna with a
prominent superior crus. These patients can also
present with deformities of the maxilla, including
a narrow and/or cleft palate or bifid uvula.40 Nasal
deformities include depressed nasal dorsum, flat-
tened frontal nasal angle, and beaked shaped nose
(Fig. 5). A study by de Jong et al. demonstrated
that 21 percent of individuals had increased
Table 5.  Members of the Craniofacial Team
Audiology
Dental medicine/orthodontics
Geneticists and genetic counselors
Neurosurgery
Nursing
Nutrition
Occupational/physical therapy
Ophthalmology
Oral and maxillofacial surgery
Otolaryngology
Pediatrics
Plastic and reconstructive surgery
Psychiatry
Respiratory care specialists
Social work
Speech pathology
Support staff
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Plastic and Reconstructive Surgery • July 2014
intracranial pressure diagnosed by funduscopic
examinations.35 Persistent elevation in intracra-
nial pressure despite cranial vault remodeling sur-
gery has been seen in patients with this syndrome.
Woods et al. demonstrated a 42 percent elevation
of intracranial pressure after standard surgical
intervention requiring reoperation.41 Normally,
these patients do not have developmental delay;
however, patients with TWIST1 microdeletion
have an increased incidence.42
In addition, patients can have partial syndac-
tyly of the fingers, most commonly between the
web space of the index finger and long finger
(Level of Evidence: Diagnostic, V).43 A delta or
duplicated distal phalanx of the hallux can be
seen as well.
Carpenter Syndrome
In 1909, Carpenter described a syndrome
affecting two sisters and a brother.44 Also called
acrocephalopolysyndactyly type II, the deformity
included acrocephaly, peculiar facies, symbrachy-
dactyly, and preaxial polydactyly of the toes. The
mutations in the RAB23 gene on chromosome 6
have been implicated,45 with autosomal recessive
and sporadic inheritance.46,47
The clinical characteristics include multisu-
tural craniosynostosis, involving most commonly
the sagittal and lambdoid sutures.48 Mental devel-
opmental delay is common.49 The eyes demon-
strate either hypertelorism or hypotelorism, with
shallow orbits, proptosis, and epicanthal folds.48
Other ocular findings include blurring of the optic
disc, corneal opacities, microcornea, and eyelid
ptosis. The ears are often hypoplastic and low set.
The nose is often flattened at the dorsum. The
maxilla demonstrates a high arching palate. The
skeletal problems include preaxial polydactyly in
the feet and symbrachydactyly of the hands.47
Treatment of Syndromic Craniosynostosis
Treatment of syndromic craniosynostosis
should be performed by a multidisciplinary team
(Table 5). Ideally, the team would be coordinated
by a general pediatrician who is familiar with cra-
niofacial conditions, and could function not only
as a primary care provider but also as a consistent
patient liaison with medical specialists and social/
community services. Timing is of utmost impor-
tance; therefore, it is essential that patients be
plugged into the right system at birth.
Airway/Eye Care/Nutrition
The airway is the most immediate issue
requiring address postnatally. Many patients with
Volume 134, Number 1 • Craniofacial Syndromes

syndromic craniosynostosis have significant mid-

face hypoplasia and lack of functional nasophar-
ynx, and are therefore obligate oral breathers.
If retrognathia or other upper airway issues also
exist, tracheostomy may be indicated. Eye care is
the second issue requiring urgent consideration.
Although most children have adequate eyelid
closure to protect the eyes from desiccation and
corneal abrasions, the ophthalmologist should
nevertheless be involved early. Most ocular issues
are preventable with constant vigilance and appro-
priate ocular lubrication. Tarsorrhaphies may be
indicated in more severe cases. Nutrition needs
to be coordinated by the dietician, particularly in
children with gastrointestinal comorbidities, as in
Pfeiffer syndrome. If oral intake remains poor, a Video 1. Supplemental Digital Content 1 displays anterior vault
nasogastric or gastrostomy tube needs to be con- remodeling with fronto-orbital advancement. This video is avail-
sidered early. able in the “Related Videos” section of the full-text article on PRS-
Journal.com or, for Ovid users, at http://links.lww.com/PRS/B23.
Intracranial Pressure
Elevated intracranial pressure is more com-
mon in children with multisuture craniosynostosis treated with this intervention. The literature dem-
(Pfeiffer with kleeblattschädel), and needs to be onstrated a higher incidence of revisionary opera-
addressed within the first year of life. There con- tions to further expand the cranial volume in these
tinues to be significant debate regarding the opti- patients (References 50 and 51, Level of Evidence:
mal treatment strategy; however, consensus exists Therapeutic, IV).50,51 Some postulate that this is
regarding the need for cranial vault expansion related to the premature fusion of the cranial base
within the first year of life to allow for brain growth. sutures, preventing the growth of the midface
Whether this is done through posterior expansion and the cranium. Because of this growth arrest,
followed by anterior expansion, or vice versa, still
and the need for repeated surgery, some groups
depends on surgeon preference. The neurosur-
geon is an essential member of this operative team. have had some success with posterior vault expan-
Although elevated intracranial pressure is one sion by means of distraction osteogenesis (Refer-
possible cause of developmental delay in children ence 52, Level of Evidence: Therapeutic, III).52,53
with syndromic craniosynostosis, its supporting (See Video, Supplemental Digital Content 2,
evidence at this time is limited. Excluding direct which displays posterior vault expansion with dis-
mechanical insults such as Chiari malformations or traction osteogenesis. This video is available in the
tonsillar herniations, there has not been any clear “Related Videos” section of the full-text article on
causal link. In addition, most patients, such as those
with Apert syndrome, have additional primary dis-
orders of the central nervous system (e.g., agenesis
of the corpus callosum, septum pellucidum).
Craniosynostosis
Most patients with syndromic craniosynostosis
present with bicoronal craniosynostosis. Tradition-
ally, this is treated at 9 to 12 months of age with
an anterior cranial vault expansion by means of
fronto-orbital advancement. (See Video, Supple-
mental Digital Content 1, which displays anterior
vault remodeling with fronto-orbital advancement.
This video is available in the “Related Videos” sec-
tion of the full-text article on PRSJournal.com or, Video 2. Supplemental Digital Content 2 displays posterior vault
for Ovid users, at http://links.lww.com/PRS/B23.) expansion with distraction osteogenesis. This video is available
Most patients with syndromic craniosynostosis in the “Related Videos” section of the full-text article on PRSJour-
and bicoronal craniosynostosis will be effectively nal.com or, for Ovid users, at http://links.lww.com/PRS/B24.

137e

PRSJournal.com or, for Ovid users, at http://links.
lww.com/PRS/B24.)
This procedure is performed at approximately
6 months of age, before a fronto-orbital advance-
ment, to achieve a greater anteroposterior head
dimension. The ultimate goals of early cranial
vault surgery are to correct the retroposition of
the frontal bar and forehead, to provide ocular
protection, and to provide adequate volume for
brain development. After adequate cranial shape
and volume have been achieved, surgery to close
any full-thickness cranial defects can be per-
formed at approximately 3 to 4 years of age.
Midface Hypoplasia/Orthognathic Surgery
Midface hypoplasia is typically corrected in late
childhood to early adolescence, with the excep-
tion of those children with severe apnea (Level of
Evidence: Therapeutic, IV).54 Because the major-
ity of orbital growth normally occurs before early
adolescence, delaying midface surgery until this
time allows for maximum growth potential and
fewer revisions.55 Regardless, coordination with
a sleep specialist is needed, as almost all of these
children have some degree of obstructive sleep
apnea.56 Depending on the position of the fore-
head, surgical correction of midface hypoplasia
may include either a Le Fort III osteotomy or a
monobloc advancement, by means of the tradi-
tional method or distraction osteogenesis with
bone grafting. The ultimate goals are to correct
the retropositioned orbit and provide maxillary
advancement. Once skeletally mature, orthogna-
thic surgery is planned to achieve normal occlu-
sion. This normally includes a Le Fort I osteotomy
or bimaxillary surgery. Once the malocclusion has
been corrected, the patient can be discharged
from the craniofacial clinic as an adult.
Other Comorbid Issues
Patients with clefts should be addressed in
relation to their other findings. If airway issues are
significant, cleft palate repair needs to be delayed
until it is safe to close a significant portion of their
nasopharynx. These decisions should be made in
conjunction with the ear, nose, and throat team,
after a proper airway workup. If repair is deemed
safe, high vigilance is nonetheless essential, partic-
ularly in the postoperative period. These patients
should be monitored in the intensive care unit for
the first 24 hours and may remain intubated until
airway swelling has improved. A tongue stitch can
be used to assist with tongue retraction if early
extubation is planned. Other comorbid issues,
such as complex syndactyly in Apert syndrome,
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Plastic and Reconstructive Surgery • July 2014
strabismus, dental crowding, and hearing loss, are
typically addressed after cranial vault remodeling
and require referrals to the proper specialists.
SYNDROMES ASSOCIATED
WITH CLEFTS
Pierre Robin Sequence
Originally described in 1923 by Robin, Pierre
Robin sequence is a triad of symptoms that include
microgenia, glossoptosis, and upper airway
obstruction.57 It is also associated with a U-shaped
cleft palate. This collection of symptoms is theo-
rized to be the result of one inciting event and is
therefore referred to as a sequence rather than
a syndrome. The actual event remains unproven
but is believed to be either an intrinsic or extrinsic
growth disturbance of the mandible58,59 (Fig. 6).
This disturbance arrests the rotation and advance-
ment of the tongue that occurs as the mandible
develops embryologically. As a result, the tongue
does not descend from between the palatal shelves,
leading to lack of palatal fusion and a U-shaped
cleft palate. In addition, the Pierre Robin tongue
remains pressed against the posterior pharynx
and leads to upper airway obstruction.60,61
To date, there has been no specific human
gene associated with Pierre Robin sequence. How-
ever, the sequence has a strong correlation with
other craniofacial syndromes,62,63 in particular,
Stickler, Nager, and Treacher Collins syndromes,
with Stickler syndrome being the most com-
mon.64,65 The incidence of Pierre Robin sequence
is between one in 8500 and one in 20,000 live
births, whereas the mortality associated with these
symptoms is between 1.7 and 11.3 percent.63,64,66–68
With the introduction of new treatments in the
past 20 years, this mortality rate has decreased.66
Treacher Collins Syndrome
Treacher Collins syndrome, or mandibulofa-
cial dysostosis, was first described in 1889 by Berry
and later by Treacher Collins.69,70 In Europe, it is
traditionally referred to as Franceschetti-Klein syn-
drome.71 Affecting approximately one in 50,000
live births, the condition demonstrates autoso-
mal dominant inheritance in 40 percent of the
patients and sporadic inheritance in the remain-
ing 60 percent. Genetically, it has been linked to a
mutation on the TCOF1,72 PLOR1C, and POLR1D
genes.73 Van der Meulen et al. postulated that the
condition results from fusion failure of the facial
and mandibular facial processes.74 Others have
Volume 134, Number 1 • Craniofacial Syndromes

Fig. 6. (Above) Patient with Pierre Robin sequence exhibiting severe microretrognathia. (Below) Craniofacial com-
puted tomographic scan with three-dimensional reconstruction. Expectedly, she was born with airway obstruc-
tion requiring tracheostomy.

suggested that it is manifestation of a combined amblyopia are common.76,77 Mandibular hypo-

Tessier 6, 7, and 8 facial clefts.75
The major craniofacial abnormalities seen
in this syndrome include bilateral zygomatic
and malar hypoplasia, mandibular hypoplasia
including microgenia or retrogenia, external
ear, and lower eyelid abnormalities71,72 (Fig. 7).
Patients typically have downward slanting of the
palpebral fissures because of the absence of the
lateral orbital walls, and lower eyelid colobo-
mas with absence of the eyelash in the medial
aspect.71 In addition, strabismus, vision loss, and
plasia often presents as Pierre Robin sequence.71
The combined effect of mandibular and maxil-
lary hypoplasia often leads to significant anky-
losis of the temporomandibular joint. The ears
are usually small and malformed, with atretic or
stenotic external auditory canals, and are asso-
ciated with conductive hearing loss and speech
delay.71,77 Clefting of the secondary palate is seen
in approximately 36 percent.77,78 Velopharyngeal
insufficiency is common.

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Fig. 7. Common presentation of a patient with Treacher Collins
syndrome, including bilateral zygomatic hypoplasia, mandibu-
lar hypoplasia, and downward slanting eyes with lower eyelid
colobomas requiring reconstruction.
Nager Syndrome
Nager syndrome, or acrofacial dysostosis, is
characterized by deformities of the mandible and
the radial aspect of the hand.79 Common facial
abnormalities include mandibular, malar, and
maxillary hypoplasia (Fig. 8). Genetically, Nager
syndrome has been linked to mutations in chro-
mosome 9,80–82 although no single gene(s) has
been isolated. The incidence of Nager syndrome
is unknown.
Fig. 8. Common presentation of a patient with Nager syndrome, with similar phenotypic traits as Treacher Collins syndrome.
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Plastic and Reconstructive Surgery • July 2014
Phenotypically, the craniofacial features of
Nager syndrome are similar to those of Treacher
Collins syndrome, as both result from hypoplasia
of the zygoma, maxilla, and mandible. Other asso-
ciated deformities include a high nasal bridge,
long upper lip philtrum, and ectopic hair on
the cheek.79 As with Treacher Collins syndrome,
mandibular hypoplasia derives from Pierre Robin
sequence, and is almost always associated with
cleft palate and velopharyngeal insufficiency.83
Intelligence is typically within normal limits.84 The
upper limb abnormalities seen with Nager syn-
drome include preaxial deficits and hypoplasia,79
commonly affecting the thumb and the radius.
Defects such as camptodactyly, syndactyly, and
clinodactyly are also seen.
Stickler Syndrome
Stickler syndrome, or hereditary arthro-oph-
thalmopathy, was first described in 1965.85 It is a
connective tissue disorder whose major clinical
manifestations occur in the eyes, craniofacial skel-
eton, ears, and joints. It has been linked to auto-
somal dominant genes of collagen production,
including the COL2A1, COL11A1, and COL11A2
loci.86 Because the gene mutations affect col-
lagen production, mainly collagen type II, the
syndrome affects multiple organ systems. Two
autosomal recessive genes have also been identi-
fied, the COL9A1 and the COL9A2 genes.87,88 The
incidence of Stickler syndrome is estimated to be
one in 10,000 live births.64
Volume 134, Number 1 • Craniofacial Syndromes
Diagnosis is made clinically, based on the
affected organs. Ophthalmologically, these
patients often present with early-onset cataract,
vitreous anomalies, retinal detachment, and
myopia of greater than 3 diopters.89 Eye find-
ings are usually nonprogressive and are found in
neonates. From a craniofacial standpoint, these
patients can present with micrognathia and suffer
from Pierre Robin sequence. Midface hypoplasia,
malar bridge depression, bifid uvula, and submu-
cous cleft palate are commonly seen. Neural or
conductive hearing loss is common.90 Joint defor-
mities include early-onset degenerative changes
and spondylolisthesis and hypermobility.85
Van der Woude Syndrome
Originally described in 1845, this syndrome
was extensively researched and its full description
was provided by Van der Woude in 1954.91,92 He
described the association of lower lip pits with facial
clefting. This syndrome accounts for approximately
2 percent of all cleft lip and palate cases.92 The inci-
dence of Van der Woude syndrome is estimated
to be one in 100,000 to 300,000, with autosomal
dominant inheritance.93–95 It demonstrates variable
expressivity and high penetrance. Gene mutation
at the IRF6 gene, involved in interferon expression,
is the most common genetic finding.96,97
Classic craniofacial findings include bilateral
paramedian lower lip sinuses and orofacial clefts
(Fig. 9). The types of clefts are similar to what is
witnessed in the normal cleft population. Of the
patients presenting with lip pits, nearly two-thirds
will have cleft lip and palate, whereas the other
one-third is split evenly between isolated cleft lip
or palate.98
The classic location of the lower lip sinuses is in
the paramedian location (Fig. 9). There are usually
two and symmetrical.99 Other locations for these
pits include a single medial pit. The sinuses are
usually circular or slit like, and can present with a
mucosal ridge or a conical elevation. The orifice is
usually lined with epithelial cells and extends down
through the orbicularis oris, to the level of the ver-
milion. It can also connect with the mucosal glands
of the lower lip. Usually, these pits are asymptom-
atic, but can present with drainage of either clear
fluid or salivary secretions. The exact embryology
of the formation of these pits is unknown, but there
has been much speculation regarding their forma-
tion during the early embryonic stages.100 Other
associated features include hypodontia, syndactyly,
thumb hyperplasia, and syngnathia.93,101
Treatment of these patients includes regular
cleft team care. Genetic counseling should be
Fig. 9. Van der Woude syndrome, demonstrating bilateral cleft
lip with one central lower lip pit.
pursued given the autosomal dominant nature
and the high penetrance and expressivity of this
syndrome. Cleft lip and palate should be repaired
at appropriate times. The lower lip pits can be
addressed as well. It is important to note that if
these are excised, the full sinus should be tracked
and excised. If any remnants are left, there is a
risk for mucocele development.
Velocardiofacial Syndrome
First described in 1978, the characteristics
of velocardiofacial syndrome, or Shprintzen syn-
drome, include pharyngeal dysfunction, cardiac
anomalies, learning disabilities, and dysmorphic
facies.102 Deletion of chromosome 22q11.2 is found
in 100 percent of patients with velocardiofacial
syndrome.103,104 This same deletion is seen also in
patients who suffer from DiGeorge, CHARGE (col-
oboma of the eye, heart defects, atresia of the nasal
choanae, retardation of growth and/or develop-
ment, genital and/or urinary abnormalities, and
ear abnormalities and deafness) syndrome, and
conotruncal face anomaly. The 22q deletion has an
autosomal dominant inheritance; however, most
patients who present for treatment usually have a
sporadic mutation. The phenotypic heterogeneity
of this mutation makes definitive diagnosis difficult.
The incidence of velocardiofacial syndrome is
one in 2000 to 4500 live births.105 Diagnosis is usu-
ally a clinical one. Most infants will demonstrate
significant developmental delay, characteristic
facies, palatal dysfunction, and feeding problems.
The palatal dysfunction seen is often related to a
141e

secondary or a submucous cleft palate. In addi-
tion, the palate can be immobile and short. These
patients have speech difficulty and are usually in
speech therapy at an early age. Velocardiofacial
syndrome facies are characterized by a broad
nasal dorsum and a flattened midface. This facial
dysmorphology often will go unnoticed, making
underdiagnosis a common problem.
Viscerally, they can present with conotrun-
cal cardiac abnormalities and medially displaced
carotid arteries in the pharynx. The cardiac
abnormalities commonly seen are ventricular sep-
tal defect, tetralogy of Fallot, or a right-sided aor-
tic arch.106
Treatment of patients with velocardiofacial
syndrome starts with repair of any cardiac anom-
alies. Given the association with DiGeorge syn-
drome, calcium levels should be followed. At birth,
they should be introduced to a feeding specialist
and followed until the patient is gaining weight
appropriately. If a cleft palate is present, it should
be repaired during the first year of life. Speech
difficulty is one of the most frustrating aspects of
treating patients with a chromosome 22q deletion.
These patients can have trouble with phonation
and language acquisition and comprehension.
Speech delay is common and management is very
controversial, particularly with regard to whether
sign language should be introduced early or late.
Language delay affects the quality of life of many
of these patients. They have trouble with school
and learning disabilities throughout their child-
hood. It is also significantly stressful for families.
In addition, patients with velocardiofacial syn-
drome can have significant behavioral problems,
including psychiatric issues, which need to be
addressed by a clinical specialist. Plastic surgeons
provide a very small part of the care for these
patients. After cleft palate repair, they need to be
followed to assess for any velopharyngeal insuffi-
ciency. Surgical correction of this can be helpful;
however, close observation by a speech therapist is
important, given the significant speech delay. Sur-
geons correcting a cleft palate or velopharyngeal
insufficiency should be aware of the potential for
medially displaced carotid arteries. Preoperative
imaging is controversial but can be helpful when
it comes to locating the carotid arteries before any
operative intervention.
Management of Cleft-Related Craniofacial
Syndromes
As with syndromic craniosynostosis, most
cleft-related craniofacial syndromes present with
similar clinical features. Management is therefore
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Plastic and Reconstructive Surgery • July 2014
largely similar as well. Management needs to be
multidisciplinary (Table 5), and should be initi-
ated at birth.107,108 As most of these children have
Pierre Robin sequence, airway is the first and fore-
most issue to address.
Airway: Pierre Robin Sequence
Children with Pierre Robin sequence will have
persistent respiratory desaturation in the supine
position, largely attributable to obstruction from
the tongue (tongue-based airway obstruction).
When oxygenation is a problem, monitoring in
the neonatal intensive care unit is necessary. Poly-
somnography and monitoring for carbon dioxide
retention are necessary to evaluate for proper oxy-
genation and ventilation109–111 (Fig. 10).
First-line therapy is side or prone position-
ing, allowing the tongue to fall forward, out of
the airway. This maneuver is effective in over half
of patients with Pierre Robin sequence.62,66,112,113
If this does not improve respiratory effort and
oxygen saturation, placement of a nasopharyn-
geal tube during airway evaluation has been
advocated.114 This intervention can prevent more
invasive operations.115,116 The family needs to be
educated regarding appropriate home care of
this nasopharyngeal airway. Most children grow
out of airway problems as the mandible develops;
however, more invasive intervention, such as tra-
cheostomy, may become necessary in those with
persistent difficulty despite a nasopharyngeal
airway.
The current surgical management of Pierre
Robin sequence includes tongue-lip adhesion
(glossopexy), mandibular distraction, or trache-
ostomy. Glossopexy secures the anterior and pos-
terior portions of the tongue to the mandible,
bringing the tongue out of the posterior phar-
ynx and thereby preventing obstruction.117 Man-
dibular distraction is another option designed
to advance the base of the tongue forward. Bilat-
eral mandibular osteotomies in either the rami
or bodies are performed before application of
internal or external distraction devices. These
devices are then activated postoperatively to pull
the tongue from a vertical position to a horizontal
position and relieve the airway obstruction. The
efficacy of this method is controversial because of
variations in obstructing anatomy and comorbid
conditions, such as gastric reflux. A small subset
of patients with Pierre Robin sequence may have
micrognathia without cleft palate, but with sig-
nificant respiratory difficulty unrelated to tongue
base obstruction. This patient population would
not respond to mandibular distractions. This
Volume 134, Number 1 • Craniofacial Syndromes
Fig. 10. Airway management algorithm developed based on data from Table 2 in Evans KN, Sie KC, Hopper RA, Glass RP, Hing AV,
Cunningham ML. Robin sequence: From diagnosis to development of an effective management plan. Pediatrics 2011;127:936–948.
again reiterates the need for proper airway evalu-
ation early after birth and continuously through-
out childhood and adolescence. Complications
associated with this treatment include facial scar-
ring, tooth bud disruption, facial or mental nerve
injury, and the need for repeated operations to
remove the devices.
Tracheostomy is the definitive airway man-
agement for Pierre Robin sequence and is usu-
ally reserved as the last resort for severe cases or
patients with multilevel obstruction. Despite its
reliable results, it is not without its potential com-
plications.118,119 Tracheostomies require a signifi-
cant amount of maintenance and care from the
family. Home health assistance may be necessary.
Complications related to decannulation, frequent
hospitalizations, and maintenance need to be
discussed with the family in great detail before
discharge.
Cleft Palate
Cleft palate in the setting of craniofacial syn-
dromes needs to be addressed in the context of the
airway. If airway management were suboptimal,
palatal closure could be potentially detrimental.
It is safe practice to consult the otolaryngology
team regarding appropriate timing to close the
palate. Usually, this should be done around 1 year
of age. Technique is according to routine for non-
syndromic cases. Speech therapy should be insti-
tuted early so that velopharyngeal insufficiency
can be identified and treated. From age 3 years to
adolescence, patients with a cleft palate should be
evaluated by a speech therapist. Because patients
are beginning to integrate into the education sys-
tem and interact with their peers, this period is an
important time for social development. Psycho-
logical evaluation and counseling should be avail-
able as well.
Orbitozygomatic Hypoplasia
At 8 to 10 years, reconstruction of the orbitozy-
gomatic region should begin.120 Because the orbits
are nearing maturity by this time, full-thickness
cranial bone grafts are contoured to create the
malar and lateral orbital deficiency. Other options
for malar reconstruction have been described,
including rib grafts and vascularized calvarial
flaps.121,122 Deficiency in this region is particularly
challenging to correct. As a result, most patients
143e

will undergo multiple revision procedures. At the
same time, lateral canthoplasty can be secured to
the reconstructed malar complex in an attempt to
correct the antimongoloid slant. The lower eyelid
colobomas can be addressed after reconstruction
of the orbital framework. This can be done with a
number of techniques, the most common being
bipedicled or unipedicled upper to lower eyelid
musculocutaneous flaps.123,124
Microtia
Timing for ear reconstruction for microtic
ears depends on the technique used. For advo-
cates of the four-stage Brent technique, surgery
begins at approximately age 7 years, or when the
child is old enough to understand and contrib-
ute to their treatment.125 For advocates of Nagata
ear reconstruction, surgery is delayed until later,
when there is enough costal cartilage for the ear
framework.126
Orthognathic Surgery
At skeletal maturity, 16 to 18 years of age,
orthognathic surgery is considered to correct any
malocclusion. These cases are some of the most
complex, and require precise presurgical plan-
ning to achieve normal occlusion and correct
the facial profile. Early mandibular distraction is
endorsed by some groups in an attempt to increase
the vertical height of the ramus.127 This helps treat
airway difficulties caused by micrognathia but also
increases the amount of bone stock for future
orthognathic procedures.128 Mandible distraction
in craniofacial syndromes is a controversial topic,
and the ideal timing is still being debated.
Other Skeletal Deformities
Children with craniofacial syndromes asso-
ciated with extracranial deformities, such as
Nager syndrome, need to be seen by the appro-
priate specialists as early as possible. Radial-
side hand hypoplasia should be treated by a
pediatric hand surgeon who specializes in cor-
rection of these rare and complex problems.
Hand reconstruction should be undertaken at
approximately 1 year of age, to allow adequate
growth for reliable results.
OTHER FACIAL SYNDROMES
Craniofacial Microsomia
Craniofacial microsomia, or oculoauriculover-
tebral spectrum, is an anomaly arising from the
first and second branchial arches. During week 4
of gestation, the neural crest cells from the neu-
ral tube migrate into the pharyngeal arches. Each
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Plastic and Reconstructive Surgery • July 2014
arch consists of three different layers: the endo-
derm, ectoderm, and mesoderm. Disturbances of
this migration lead to deformities of the face, ear,
and maxilla.77 Patients typically present with facial
asymmetry related to deformities in the facial
skeleton and soft tissue. The skeletal deformities
include mandibular and maxillary hypoplasia.
Soft-tissue defects, such as microtia and hypoplas-
tic subcutaneous tissue, further contribute to the
facial asymmetry.129
The diagnosis of craniofacial microsomia is
a clinical one. Genetically, craniofacial micro-
somia usually occurs sporadically, even though
there have been some families that demonstrate
an autosomal dominant inheritance pattern.130,131
The incidence of craniofacial microsomia is one
in 3500 to 5600 live births.129,132 Boys are affected
more commonly than girls, with a 3:1 preva-
lence.132 The right side of the face is usually more
severely affected than the left. Craniofacial micro-
somia is marked by phenotypic variability, ranging
from simple preauricular skin tags to severe facial
asymmetry with microtia or anotia.133
Clinical manifestations of craniofacial micro-
somia include the craniofacial region and other
areas of the body. There have been many classifi-
cation systems proposed to describe patients with
this disease.129,134 The most comprehensive system
used to date is the Orbit, Mandible, Ear, Nerve,
and Soft tissue–Plus classification135 (Table 6).
This particular assessment tool takes into account
the major anomalies, including orbital, mandible,
ear, nerve, and soft tissue, and any extracranial
manifestations of the disease. Orbital manifesta-
tions can include dystopia caused by ipsilateral
maxillary hypoplasia. Soft-tissue findings include
shortening of the palpebral fissures and colobo-
mas of the upper eyelid.
Micrognathia can be seen, and these patients
can suffer from Pierre Robin sequence. Most com-
monly, there is an asymmetric mandible with only
unilateral involvement. Normally, the ascending
ramus and condyle are affected. This mandibu-
lar hypoplasia has been classified into three types
according to Pruzansky et al.136 Type I presents
with a small glenoid fossa, condyle, and ramus.
Type II affects the temporomandibular joint and
glenoid fossa. Type IIA patients demonstrate a
symmetrical mouth opening, whereas in type IIB
patients there is an abnormally formed and posi-
tioned temporomandibular joint. Type III patients
have the worst malformation, with a hypoplastic
ramus, glenoid fossa, and temporomandibular
joint. Ankylosis of the temporomandibular joint
Volume 134, Number 1 • Craniofacial Syndromes

Table 6.  OMENS-Plus Classification of Craniofacial canal is seen, with an associated conductive hear-
Microsomia* ing loss. Neurosensorial and/or conductive hear-
Description
ing losses can also be seen. Nerve involvement
primarily affects the cranial nerves, most com-
Orbital classes monly the facial nerve. Often, this is associated
 O0 Normal orbital size and position
 O1 Abnormal orbital size with an absent parotid gland. Failure of fusion
 O2 Abnormal orbital position of the facial processes can lead to macrostomia.
 O3 Abnormal orbital size and position Extracranial manifestations include cervical spine
Mandibular
classes fusions, most commonly at the C2 to C3 level.137
 M0 Normal mandible Spina bifida has been described, as have congeni-
 M1 Mandible and glenoid fossa are small tal heart disease and pulmonary anomalies.138 Cleft
with short ramus
 M2 Mandibular ramus is short and palate is a common finding in these patients, with
abnormally shaped a 35 percent prevalence of velopharyngeal insuf-
 M2a Glenoid fossa in anatomically ficiency.139 Goldenhar syndrome is a more severe
acceptable position in relation to
opposite TMJ presentation of the oculoauriculovertebral spec-
 M2b TMJ inferiorly, medially, and anteriorly trum, including mandibular hypoplasia, cervical
displaced with hypoplastic condyle anomalies, and epibulbar dermoids140 (Fig. 11).
 M3 Complete absence of ramus, glenoid
fossa, and TMJ Treatment of craniofacial microsomia
External ear depends on the severity of the disease. In milder
anomaly cases, in which only skin tags are present, removal
classes
 E0 Normal ear at an appropriate age is warranted. It is important
 E1 Mild hypoplasia and cupping with all to be wary of the facial nerve when removing skin
structures present tags because the cartilage remnants can be closely
 E2 Absence of external auditory canal
with variable hypoplasia of the associated. If microtia is present, ear reconstruc-
concha tion with autologous material should be delayed
 E3 Malpositioned lobule with absence of until the patient is age appropriate, between 7 and
auricle
Facial nerve 10 years, depending on the technique used.125,126
classes Patients presenting with mandibular hypopla-
 N70 No facial nerve involvement sia provide a particular challenge to the craniofa-
 N71 Upper facial nerve involvement
(temporal and zygomatic branches) cial team, mostly because of the optimal timing
 N72 Lower facial nerve involvement of surgical management. Some prefer a more
(buccal, mandibular, and cervical conservative approach, waiting until skeletal
branches)
 N73 All branches of facial nerve affected maturity to correct malocclusion with traditional
Soft-tissue orthognathic procedures.141,142 This is universally
deficiency believed to be the best treatment for patients with
classes
 S0 No obvious soft-tissue or muscle milder forms of mandibular and maxillary hypo-
deficiency plasia, such as in Pruzansky types I and IIA. For
 S1 Minimal subcutaneous/muscle the more severe deformities, as seen with types
deficiency
 S2 Moderate deficiency IIB and III, earlier surgical intervention with man-
 S3 Severe soft-tissue deficiency caused dibular distraction and orthodontic techniques
by subcutaneous and muscular may be indicated.143 Patients with Pruzansky type
hypoplasia
OMENS-Plus Any associated extracranial anomaly III mandibles usually require early intervention,
TMJ, temporomandibular joint: OMENS, Orbital, Mandible, Ear, such as bone grafting followed by mandibular dis-
Nerve, and Soft tissue. traction.144 This allows for appropriate bone stock
*Modified from Cohen SR, Levitt CA, Simms C, Burstein FD.
Airway disorders in hemifacial microsomia. Plast Reconstr Surg.
so that subsequent traditional orthognathics can
1999;103:27–33. be attempted. The skin and soft-tissue hypoplasia
needs to be considered in relation to the skeletal
caused by abnormal development of the maxilla problems. Traditionally, microvascular free tissue
and mandible can occur. transfer has been performed to achieve better
Preauricular facial tags or pits can extend facial symmetry. Recently, serial fat grafting has
from the level of the ear to the oral commissure. been advocated whenever these children undergo
They often contain cartilage remnants that can be any operation, to achieve a more symmetric
intimately involved with the facial nerve. Exter- soft-tissue envelope.145 Although this technique
nal ear anomalies such as microtia and anotia are requires multiple operations to achieve adequate
common findings. Atresia of the external auditory symmetry, given the number of procedures these

145e

Fig. 11. Patient with Goldenhar syndrome, characterized by unilateral man-
dibular hypoplasia, facial cleft, and epibulbar dermoid.
patients undergo, this has not been a significant
issue. Treatment of epibulbar dermoids (Fig. 11),
as seen in Goldenhar syndrome, is led by an expe-
rienced pediatric ophthalmologist.
If facial paralysis is involved, management
should be at centers that have experts in facial
reanimation surgery. Foremost, ocular protection
from corneal desiccation and ulceration is a major
priority. Initial treatment includes eye lubrication
and rewetting drops. To assist with upper lid clo-
sure, gold weights can be embedded in the pre-
tarsal area but need to be sized correctly so that
extrusion does not occur.
Binder Syndrome
Maxillofacial dysplasia, originally described in
1939, was characterized as a distinct syndrome by
Von Binder in 1962.146,147 The syndrome is charac-
terized by particular facial appearance: short nose,
flat nasal bridge, short columella, acute nasal
labial angle, convex upper lip, a tendency for a
class III malocclusion, and malar and perialar flat-
ness (Fig. 12). Patients often display a “dish face,”
or concave facial profile. The incidence of Binder
syndrome is not well established and it is believed
to demonstrate autosomal recessive inheritance
with incomplete penetrance.148 The exact cause is
unknown, but some speculate an underdevelop-
ment of the osteogenic center at the nasomaxil-
lary spine.149 Patients can have skeletal findings in
the cervical spine, particularly abnormally formed
or fused C1 to C2 vertebrae.150
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Plastic and Reconstructive Surgery • July 2014
The spectrum of nasomaxillary hypoplasia
is quite broad, and the deformities range from
subtle to quite severe. Some believe there are eth-
nic differences associated with Binder syndrome.
Certain ethnicities have a tendency for flat nasal
bridges and poor projection of the nasal tip.
When evaluating a patient with suspected Binder
syndrome, the patient’s ethnicity should be taken
into consideration. Preoperative workup for these
patients should include imaging of the cervi-
cal spine, given the tendency for malformations.
Treatment for Binder syndrome is controversial
and dependent on the practitioner. Treatment
can involve nasomaxillary augmentation and
nasal reconstruction or traditional orthognathic
surgery.151,152
Traditional orthognathic surgery includes
orthodontic treatment, with extraction of the
maxillary bicuspids and retrusion of the incisors
as indicated. A Le Fort I osteotomy can then be
performed to provide for greater piriform vol-
ume. This is then followed by dorsal augmenta-
tion of the nose. The downside to this approach is
the failure to address the deficiency in the malar
and nasal frontal regions. Others will advocate
for a higher Le Fort osteotomy, including a high
Le Fort I or a Le Fort II osteotomy to correct the
entire piriform deficiency.152–154 Augmentation of
the premaxillary and piriform areas can also be
achieved with onlay bone grafting.151
Timing of nasal reconstruction in Binder syn-
drome patients has also been controversial. The
Volume 134, Number 1 • Craniofacial Syndromes
Fig. 12. Binder syndrome, characterized by short nose, flat nasal bridge, short
columella, and malar and perialar flatness.
indications for early childhood nasal reconstruc-
tion most commonly include pressure from the
parents and peers. Future revision surgery needs
to be discussed if early rhinoplasty is considered.
If the decision is made to wait until the nose is
fully grown, the optimal reconstruction material
becomes controversial. Successful use of dorsal
onlay bone grafting and columellar struts has
been described.155 However, one long-term study
reported the need to avoid bone grafts because of
resorption.156 Others advocate rib cartilage graft-
ing and columellar struts in an L-shaped construct
for nasal bridge reconstruction.157 Columellar
lengthening can be achieved with a V-Y advance-
ment flap and provide adequate space for colu-
mellar and nasal tip grafting. The nasal soft tissue
is usually not an issue, and local flaps do not need
to be incorporated.
Möbius Syndrome
Möbius syndrome was first described in 1880
but further defined by Paul Möbius in 1888. He
compared a number of his patients who suffered
from a combined abducens and facial nerve palsy
with those already reported in the literature.158
This nonprogressive and congenital condition
mostly occurs sporadically, although autosomal
dominant and recessive familial patterns have
been reported.159
Möbius syndrome can have a number of
clinical features, but bilateral congenital abdu-
cens and facial nerve palsies are the classic find-
ings. Other cranial nerves can be involved, the
most common of which are the hypoglossal and
vagus nerves.159,160 Musculoskeletal deformities
are commonly seen, with clubfeet being the most
frequent. Cardiac defects, including ventricular
septal defects and transposition of the great ves-
sels, have been documented.161,162 Oropharyngeal
malformations, including cleft palate, retrogenia,
and microstomia, have been described.163–165
Clinical presentation associated with facial
nerve palsies includes incomplete eye closure dur-
ing sleep and oral incompetence. Drooling and
the inability to suck significantly impact the infant
years. As a result, these children often require hos-
pitalization to optimize nutritional status. Patients
develop a classic “mask-like facies” because of the
inability to produce any facial expressions. This
weakness is asymmetric, and the upper face is usu-
ally more affected than the lower. The abducens
nerve palsy creates bilateral horizontal gaze palsy.
Facial nerve palsies in infants can be caused
by birth trauma or some form of supranuclear
147e

abnormality.166 The cause of Möbius syndrome is
currently unknown; however, a common hypoth-
esis suggests either hypoplasia of the central ner-
vous system, atrophy or degeneration of nuclear
centers, or a vascular disruption during devel-
opment resulting in restricted development of
normal brain stem structures.167 Furthermore,
prenatal exposure to certain medications may be
the inciting factor leading to disruption of normal
vascular cerebral anatomy.168–170
Goals of treatment for Möbius patients include
eye protection from an early age, the ability to
smile, and oral competence. Protection of the eyes
should be started during infancy. Vigilance by the
practitioner and the family needs to be stressed to
prevent dry eye and chronic conjunctivitis. Treat-
ment includes continuous eye lubrication. More
aggressive interventions include temporary or
permanent tarsorrhaphy sutures to close the pal-
pebral fissure and prevent corneal exposure. Gold
weights can be added to the upper eyelid to pro-
vide for dynamic eyelid closure. This is a simple,
reliable, and reversible operation commonly used
to assist with upper lid closure.
Facial reanimation to provide patients with a
smile and oral competence has remained a chal-
lenge for the reconstructive surgeon. Older meth-
ods for facial reanimation include static slings with
tendon or fascia. These operations were designed
to restore symmetry between the facial sides, but
because Möbius is normally bilateral, these opera-
tions did not achieve most patient goals. It was
not until the introduction of microsurgery that
dynamic reconstruction of Möbius syndrome
became possible.171 The current treatment of
choice includes microvascular free muscle trans-
fer, coapted to local functioning nerves. The most
commonly used muscle is the gracilis, because of
its reliable neurovascular pedicle, ease of harvest,
and low morbidity. Neurorrhaphy to the nerve to
masseter, partial hypoglossal, or spinal accessory
is commonly used for reinnervation of the trans-
ferred muscle. Nerve-to-masseter coaptation often
can provide for spontaneous smiling because of
cerebral plasticity.
Whereas treatment of eye issues needs to be
started immediately after birth, facial reanima-
tion operations are usually delayed until after
the age of 5 years. Patients need to be of a cer-
tain size before their facial structures can sup-
port the transfer of a muscle for reanimation.
If both sides of the face are to be corrected,
the operations are staged and surgery is usually
spaced 3 to 6 months apart, or until recovery
has occurred.
148e
Plastic and Reconstructive Surgery • July 2014
Parry-Romberg Syndrome (Disease)
Parry-Romberg disease was originally
described in 1825 by Parry and, later, by von Rom-
berg.172,173 The incidence and prevalence of this
disease are unknown, given its rare presentation.
Patients present with a progressive hemifacial
atrophy that usually starts between 5 and 15 years
of age and lasts for approximately 2 to 10 years.
This is usually a hemifacial disease affecting the
skin, soft tissue, muscle, and bone. Involved areas
of the face usually are within the dermatomes of
the trigeminal nerve. Unlike Möbius syndrome,
patients with Parry-Romberg disease have nor-
mal facial appearance and function at birth and
during most of childhood until insult occurs.
Cutaneous discoloration of the skin, including
hypopigmentation and depigmentation, is often
seen. This disease is associated with neurologic
symptoms, the most common of which is focal
epilepsy.174
Although the exact cause is unknown, an
autoimmune type of disease has been strongly
implicated.175 Other possible causes include
viral, neural, or traumatic.176,177 Some distinguish
Parry-Romberg syndrome from a similar form
of scleroderma known as linear scleroderma.177
This is also referred to as scleroderma “en coup
de sabre.” This form of linear scleroderma usually
only affects the frontoparietal area and does not
extend below the eyebrow.
Treatment for Parry-Romberg disease includes
microinjections of fat or microvascular trans-
plantation of free tissue.178,179 Traditionally, the
treatment for Parry-Romberg disease was micro-
vascular transplantation of tissue to restore facial
symmetry. More recently, progressive and serial
fat injections have been introduced to change
the vascular architecture of the face in the areas
involved. It is important to begin these fat injec-
tions when the course of the patient’s disease has
burnt out. This usually involves multiple rounds
of grafting, and preferred donor sites include
lower abdomen, buttocks, and inner thighs for
extremely thin children.
Larry H. Hollier, Jr., M.D.
Division of Plastic Surgery
Baylor College of Medicine
6701 Fannin, Suite CC610.00
Houston, Texas 77030
larryh@bcm.edu
PATIENT CONSENT
Parents or guardians provided written consent for
use of patients’ images.
Volume 134, Number 1 • Craniofacial Syndromes
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