Craniofacial Syndromes: Learning Objectives: After Studying This Article, The Participant Should Be Able

CME
Craniofacial Syndromes
Edward P. Buchanan, M.D.
Learning Objectives: After studying this article, the participant should be able
Amy S. Xue, M.D.
to: 1. Recognize the clinical presentations of commonly seen craniofacial syn-
Larry H. Hollier, Jr., M.D.
dromes. 2. Understand the most serious complications associated with each
Houston, Texas 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 categories—syndromes with clefts and craniosyn-
origin to mean “run together.” Tradition- ostosis, and briefly discuss those associated with
ally, syndrome is a clinical diagnosis, char- atrophy.
acterized by a set of symptoms that consistently
present together. There are estimated to be over
SYNDROMIC CRANIOSYNOSTOSIS
500 syndromes with craniofacial anomalies.1
Most are morphologic, affecting the form and Craniosynostosis is a congenital disorder
function of the head and face. Many are asso- marked by premature fusion of one or more cra-
ciated with variations in the fibroblast growth nial sutures, resulting in abnormal cranial growth.
factor receptor (FGFR) genes, which direct the Children with craniosynostosis typically have cra-
development of bone and cartilage. The clinical nial expansion in the direction parallel to the
manifestations of these symptoms extend beyond fused suture, leading to abnormal head shape.
the craniofacial arena. Therefore, the best treat- Approximately one in 2500 infants is affected by
ment approach is one that is multidisciplinary this disorder.3 Most cases are nonsyndromic or
and takes into consideration physical and mental isolated. Syndromic craniosynostoses are those
development. conditions that have additional manifestations
Currently, there is no comprehensive classi- (craniofacial and/or extracraniofacial deformi-
fication system that encompasses all craniofacial ties); these account for 40 percent, or one in 6250
syndromes. Although the Whitaker classification2
(Table 1) is by no means perfect, it does pro-
vide an organized framework to initiate this dis- Disclosure: The authors have no financial interest
cussion. In this article, we focus on the first two to declare in relation to the content of this article.
From the Division of Plastic Surgery, Baylor College of Related Video content is available for this ar-
Medicine. ticle. The videos can be found under the “Re-
Received for publication April 22, 2013; accepted November lated Videos” section of the full-text article, or,
11, 2013. for Ovid users, using the URL citations pub-
Copyright © 2014 by the American Society of Plastic Surgeons lished in the article.
DOI: 10.1097/PRS.0000000000000308
128e www.PRSJournal.com
Volume 134, Number 1 • Craniofacial Syndromes
Table 1. Whitaker Classification of Craniofacial Anomalies*

Type Definition
I Clefts 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
I Synostoses Symmetric
• Metopic
• Coronal
• Sagittal
Asymmetric
• Unilateral coronal closure
• Lambdoid closure
III Atrophy (hypoplasia) Atrophy of skin, subcutaneous tissue, muscle, bone (e.g., Romberg syndrome,
coup de sabre)
IV Neoplasia (hyperplasia) Lymphangioma, hemangioma, fibrous dysplasia
V Unclassified Multiorgan involvement
Single-organ involvement
*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 clinical morphology, not genetic linkage; there-
single-suture synostosis are most likely not syn- fore, as genetic research further develops, this
dromic; however, many craniofacial syndromes classification system will likely be phased out of
present with single-suture synostosis. general use.
The majority of syndromic craniosynostoses
are associated with FGFR mutations, demonstrat- Apert Syndrome
ing autosomal dominant inheritance.5 The asso- First described in 1906 by Eugene Apert,
ciated mutations are typically gain-of-function the syndrome features craniofacial and hands/
mutations. Table 2 summarizes the common feet deformities. Genetically, it has been linked
presentations of the conditions we will discuss in to at least two missense, gain-of-function muta-
this section: Apert, Crouzon, Pfeiffer, Muenke, tions in the FGFR2 gene on chromosome 10:
Saethre-Chotzen, and Carpenter syndromes. Ser252Trp and Pro253Arg.6,7 The Ser252Trp
With the recent successes in molecular genetics mutation is more common (>60 percent of cases)
research, many had hoped that genetic testing and causes a less severe form of syndactyly but a
would provide more specific and accurate diag- higher frequency of cleft palates.8 The mutation
noses for these syndromes. Unfortunately, many causes an up-regulated response in the andro-
phenotypically distinct syndromes had been gen end-organ receptors, leading to diffuse early
linked to the same mutations, suggesting the exis- epiphyseal fusion (craniosynostosis, short stature,
tence of modifier genes and epigenetic factors, vertebral fusion, and syndactyly) and severe acne
yet undetermined. vulgaris.9,10 The mutation demonstrates autoso-
Table 3 summarizes the general terminology mal dominant inheritance, but most cases are
used in describing craniosynostosis. Although sporadic. Recent research demonstrated a strong
these terms are often used, they are more use- association with advanced paternal age.11 The
ful as descriptors of skull shape to aid commu- incidence is estimated to be approximately one
nication, and are not specific to each diagnosis. in 160,000 live births.12
Definitive diagnosis requires computed tomo- Major diagnostic features of Apert syndrome
graphic imaging demonstrating inappropriately include bicoronal craniosynostosis, midface
fused suture(s). It is also useful to briefly discuss hypoplasia, and complex syndactyly of the hands
the term “acrocephalosyndactyly,” which is a col- and feet7 (Fig. 1, above). As with most infants with
lection of craniofacial syndromes with craniofa- bicoronal synostosis, the anterior fontanel is large
cial dysmorphology and concurrent syndactyly and anteriorly displaced and the metopic suture
of the hands and feet. First used in the context remains open, as a compensatory mechanism to
of Apert syndrome (type I), it has since included accommodate brain growth13 (Fig. 1, below). The
other syndromes, such as Crouzon (type II), cranial shape is typically turribrachycephalic
Saethre-Chotzen (type III), and Pfeiffer (type V) and asymmetric. This may be the result of mega-
syndromes. The classification system is based on 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).
131e
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, intracranial pressure warrants further evaluation
the skull grows laterally, leading to telorbitism. and early operative management.
Crouzon has also been associated with other forms
of craniosynostosis, including metopic, lambdoid, Pfeiffer Syndrome
sagittal, and multisutural craniosynostoses.25 Nine Pfeiffer syndrome, or acrocephalosyndactyly
to 26 percent of patients suffer from hydroceph- type V, was first described in 1964 by Rudolph
alus, presenting with frequent headaches and Arthur Pfeiffer.27 The original description, which
seizures.15 As a result, any indication of elevated included a patient with bicoronal craniosynostosis,
133e
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- be one in 100,000 live births.12
fied the syndrome.28 Genetically, the syndrome Cohen classified Pfeiffer syndrome into three
is linked to mutation in the FGFR1 and FGFR2 major types28 (Table 4). Type I demonstrates
genes,29 and has an autosomal dominant inheri- bicoronal craniosynostosis with variable midface
tance pattern with incomplete penetrance and deformity. Proptosis in these patients is usually
Fig. 4. Kleeblattschädel (or cloverleaf skull) deformity characteristic of pansuture craniosynosto-

sis seen in Pfeiffer syndrome.
134e
Fig. 5. Patient with Saethre-Chotzen syndrome demonstrating bicoronal craniosynos-

tosis and small, inferiorly positioned ears.
minimal and they tend to demonstrate good including intestinal malrotation and prune belly
cranial growth. Type II is the most severe form, syndrome.
involving kleeblattschädel, or cloverleaf defor-
mity, with severe midface hypoplasia (Fig. 4). Muenke Syndrome
It is typically associated with broad thumbs and Muenke syndrome is another of the FGFR-
great toes, although these are not exclusive find- related craniosynostosis syndromes. This autoso-
ings for this type. Type III is similar to type II, but mal dominant syndrome occurs in one in 30,000
without kleeblattschädel deformity. Both types II live births.30 One hundred percent of the patients
and III are associated with severe mental devel- have a Pro250Arg mutation on the FGFR3 gene.30
opmental delay and shortened lifespan. There These patients normally present with either unicor-
have also been reports of visceral anomalies onal (29 percent) or bicoronal craniosynostosis
135e
(71 percent).31 They can also present with mega- intracranial pressure diagnosed by funduscopic
lencephaly without craniosynostosis. In a study examinations.35 Persistent elevation in intracra-
evaluating 72 individuals from 24 families, 12.5 nial pressure despite cranial vault remodeling sur-
percent of the patients had no evidence of cranio- gery has been seen in patients with this syndrome.
synostosis.31 Patients usually demonstrate mild to Woods et al. demonstrated a 42 percent elevation
significant midface hypoplasia with ocular hyper- of intracranial pressure after standard surgical
telorism.32 The extremities have normal hand and intervention requiring reoperation.41 Normally,
foot phenotypes; however, they can demonstrate these patients do not have developmental delay;
carpal or tarsal fusions.33 Neurosensorial hearing however, patients with TWIST1 microdeletion
loss of an unknown cause34 and strabismus35 are have an increased incidence.42
common. Developmental delay and intellectual In addition, patients can have partial syndac-
disabilities have been reported in approximately tyly of the fingers, most commonly between the
one-third of patients.33 web space of the index finger and long finger
(Level of Evidence: Diagnostic, V).43 A delta or
Saethre-Chotzen Syndrome duplicated distal phalanx of the hallux can be
Saethre-Chotzen syndrome, or acrocephalo- seen as well.
syndactyly type III, was first described in 1931 by
Saethre and Chotzen.36,37 In 1975, Pantke et al. Carpenter Syndrome
elaborated on the syndrome and named it after In 1909, Carpenter described a syndrome
its original authors.38 The inheritance pattern is affecting two sisters and a brother.44 Also called
autosomal dominant, with high penetrance and acrocephalopolysyndactyly type II, the deformity
variable expressivity, typically involving intragenic included acrocephaly, peculiar facies, symbrachy-
mutations, microdeletions, or translocations dactyly, and preaxial polydactyly of the toes. The
within the TWIST gene on chromosome 7.39 The mutations in the RAB23 gene on chromosome 6
incidence is estimated to range from one in 25,000 have been implicated,45 with autosomal recessive
to 50,000 live births,39 and it is one of the most and sporadic inheritance.46,47
common forms of syndromic craniosynostosis. The clinical characteristics include multisu-
Classic findings include unilateral or bilat- tural craniosynostosis, involving most commonly
eral coronal craniosynostosis, facial asymmetry if the sagittal and lambdoid sutures.48 Mental devel-
unicoronal, strabismus, ptosis, low frontal hair- opmental delay is common.49 The eyes demon-
line, and malformed ears38 (Fig. 5). The Saethre- strate either hypertelorism or hypotelorism, with
Chotzen ear typically has a small pinna with a shallow orbits, proptosis, and epicanthal folds.48
prominent superior crus. These patients can also Other ocular findings include blurring of the optic
present with deformities of the maxilla, including disc, corneal opacities, microcornea, and eyelid
a narrow and/or cleft palate or bifid uvula.40 Nasal ptosis. The ears are often hypoplastic and low set.
deformities include depressed nasal dorsum, flat- The nose is often flattened at the dorsum. The
tened frontal nasal angle, and beaked shaped nose maxilla demonstrates a high arching palate. The
(Fig. 5). A study by de Jong et al. demonstrated skeletal problems include preaxial polydactyly in
that 21 percent of individuals had increased the feet and symbrachydactyly of the hands.47
Table 5. Members of the Craniofacial Team Treatment of Syndromic Craniosynostosis

Audiology Treatment of syndromic craniosynostosis
Dental medicine/orthodontics should be performed by a multidisciplinary team
Geneticists and genetic counselors (Table 5). Ideally, the team would be coordinated
Neurosurgery
Nursing by a general pediatrician who is familiar with cra-
Nutrition niofacial conditions, and could function not only
Occupational/physical therapy as a primary care provider but also as a consistent
Ophthalmology
Oral and maxillofacial surgery patient liaison with medical specialists and social/
Otolaryngology community services. Timing is of utmost impor-
Pediatrics tance; therefore, it is essential that patients be
Plastic and reconstructive surgery
Psychiatry plugged into the right system at birth.
Respiratory care specialists
Social work Airway/Eye Care/Nutrition
Speech pathology The airway is the most immediate issue
Support staff requiring address postnatally. Many patients with
136e
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. strabismus, dental crowding, and hearing loss, are
lww.com/PRS/B24.) typically addressed after cranial vault remodeling
This procedure is performed at approximately and require referrals to the proper specialists.
6 months of age, before a fronto-orbital advance-
ment, to achieve a greater anteroposterior head
dimension. The ultimate goals of early cranial
SYNDROMES ASSOCIATED
vault surgery are to correct the retroposition of WITH CLEFTS
the frontal bar and forehead, to provide ocular Pierre Robin Sequence
protection, and to provide adequate volume for Originally described in 1923 by Robin, Pierre
brain development. After adequate cranial shape Robin sequence is a triad of symptoms that include
and volume have been achieved, surgery to close microgenia, glossoptosis, and upper airway
any full-thickness cranial defects can be per- obstruction.57 It is also associated with a U-shaped
formed at approximately 3 to 4 years of age. cleft palate. This collection of symptoms is theo-
Midface Hypoplasia/Orthognathic Surgery rized to be the result of one inciting event and is
Midface hypoplasia is typically corrected in late therefore referred to as a sequence rather than
childhood to early adolescence, with the excep- a syndrome. The actual event remains unproven
tion of those children with severe apnea (Level of but is believed to be either an intrinsic or extrinsic
Evidence: Therapeutic, IV).54 Because the major- growth disturbance of the mandible58,59 (Fig. 6).
ity of orbital growth normally occurs before early This disturbance arrests the rotation and advance-
adolescence, delaying midface surgery until this ment of the tongue that occurs as the mandible
time allows for maximum growth potential and develops embryologically. As a result, the tongue
fewer revisions.55 Regardless, coordination with does not descend from between the palatal shelves,
a sleep specialist is needed, as almost all of these leading to lack of palatal fusion and a U-shaped
children have some degree of obstructive sleep cleft palate. In addition, the Pierre Robin tongue
apnea.56 Depending on the position of the fore- remains pressed against the posterior pharynx
head, surgical correction of midface hypoplasia and leads to upper airway obstruction.60,61
may include either a Le Fort III osteotomy or a To date, there has been no specific human
monobloc advancement, by means of the tradi- gene associated with Pierre Robin sequence. How-
tional method or distraction osteogenesis with ever, the sequence has a strong correlation with
bone grafting. The ultimate goals are to correct other craniofacial syndromes,62,63 in particular,
the retropositioned orbit and provide maxillary Stickler, Nager, and Treacher Collins syndromes,
advancement. Once skeletally mature, orthogna- with Stickler syndrome being the most com-
thic surgery is planned to achieve normal occlu- mon.64,65 The incidence of Pierre Robin sequence
sion. This normally includes a Le Fort I osteotomy is between one in 8500 and one in 20,000 live
or bimaxillary surgery. Once the malocclusion has births, whereas the mortality associated with these
been corrected, the patient can be discharged symptoms is between 1.7 and 11.3 percent.63,64,66–68
from the craniofacial clinic as an adult. With the introduction of new treatments in the
Other Comorbid Issues past 20 years, this mortality rate has decreased.66
Patients with clefts should be addressed in
Treacher Collins Syndrome
relation to their other findings. If airway issues are
significant, cleft palate repair needs to be delayed Treacher Collins syndrome, or mandibulofa-
until it is safe to close a significant portion of their cial dysostosis, was first described in 1889 by Berry
nasopharynx. These decisions should be made in and later by Treacher Collins.69,70 In Europe, it is
conjunction with the ear, nose, and throat team, traditionally referred to as Franceschetti-Klein syn-
after a proper airway workup. If repair is deemed drome.71 Affecting approximately one in 50,000
safe, high vigilance is nonetheless essential, partic- live births, the condition demonstrates autoso-
ularly in the postoperative period. These patients mal dominant inheritance in 40 percent of the
should be monitored in the intensive care unit for patients and sporadic inheritance in the remain-
the first 24 hours and may remain intubated until ing 60 percent. Genetically, it has been linked to a
airway swelling has improved. A tongue stitch can mutation on the TCOF1,72 PLOR1C, and POLR1D
be used to assist with tongue retraction if early genes.73 Van der Meulen et al. postulated that the
extubation is planned. Other comorbid issues, condition results from fusion failure of the facial
such as complex syndactyly in Apert syndrome, and mandibular facial processes.74 Others have
138e
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 plasia often presents as Pierre Robin sequence.71
The major craniofacial abnormalities seen The combined effect of mandibular and maxil-
in this syndrome include bilateral zygomatic lary hypoplasia often leads to significant anky-
and malar hypoplasia, mandibular hypoplasia losis of the temporomandibular joint. The ears
including microgenia or retrogenia, external
are usually small and malformed, with atretic or
ear, and lower eyelid abnormalities71,72 (Fig. 7).
Patients typically have downward slanting of the stenotic external auditory canals, and are asso-
palpebral fissures because of the absence of the ciated with conductive hearing loss and speech
lateral orbital walls, and lower eyelid colobo- delay.71,77 Clefting of the secondary palate is seen
mas with absence of the eyelash in the medial in approximately 36 percent.77,78 Velopharyngeal
aspect.71 In addition, strabismus, vision loss, and insufficiency is common.
139e
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.
Fig. 7. Common presentation of a patient with Treacher Collins Stickler Syndrome

syndrome, including bilateral zygomatic hypoplasia, mandibu- Stickler syndrome, or hereditary arthro-oph-
lar hypoplasia, and downward slanting eyes with lower eyelid thalmopathy, was first described in 1965.85 It is a
colobomas requiring reconstruction. connective tissue disorder whose major clinical
manifestations occur in the eyes, craniofacial skel-
Nager Syndrome eton, ears, and joints. It has been linked to auto-
Nager syndrome, or acrofacial dysostosis, is somal dominant genes of collagen production,
characterized by deformities of the mandible and including the COL2A1, COL11A1, and COL11A2
the radial aspect of the hand.79 Common facial loci.86 Because the gene mutations affect col-
abnormalities include mandibular, malar, and lagen production, mainly collagen type II, the
maxillary hypoplasia (Fig. 8). Genetically, Nager syndrome affects multiple organ systems. Two
syndrome has been linked to mutations in chro- autosomal recessive genes have also been identi-
mosome 9,80–82 although no single gene(s) has fied, the COL9A1 and the COL9A2 genes.87,88 The
been isolated. The incidence of Nager syndrome incidence of Stickler syndrome is estimated to be
is unknown. one in 10,000 live births.64
Fig. 8. Common presentation of a patient with Nager syndrome, with similar phenotypic traits as Treacher Collins syndrome.
140e
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 Fig. 9. Van der Woude syndrome, demonstrating bilateral cleft
clefting. This syndrome accounts for approximately lip with one central lower lip pit.
2 percent of all cleft lip and palate cases.92 The inci-
dence of Van der Woude syndrome is estimated pursued given the autosomal dominant nature
to be one in 100,000 to 300,000, with autosomal and the high penetrance and expressivity of this
dominant inheritance.93–95 It demonstrates variable syndrome. Cleft lip and palate should be repaired
expressivity and high penetrance. Gene mutation at appropriate times. The lower lip pits can be
at the IRF6 gene, involved in interferon expression, addressed as well. It is important to note that if
is the most common genetic finding.96,97 these are excised, the full sinus should be tracked
Classic craniofacial findings include bilateral and excised. If any remnants are left, there is a
paramedian lower lip sinuses and orofacial clefts risk for mucocele development.
(Fig. 9). The types of clefts are similar to what is
witnessed in the normal cleft population. Of the Velocardiofacial Syndrome
patients presenting with lip pits, nearly two-thirds First described in 1978, the characteristics
will have cleft lip and palate, whereas the other of velocardiofacial syndrome, or Shprintzen syn-
one-third is split evenly between isolated cleft lip drome, include pharyngeal dysfunction, cardiac
or palate.98 anomalies, learning disabilities, and dysmorphic
The classic location of the lower lip sinuses is in facies.102 Deletion of chromosome 22q11.2 is found
the paramedian location (Fig. 9). There are usually in 100 percent of patients with velocardiofacial
two and symmetrical.99 Other locations for these syndrome.103,104 This same deletion is seen also in
pits include a single medial pit. The sinuses are patients who suffer from DiGeorge, CHARGE (col-
usually circular or slit like, and can present with a oboma of the eye, heart defects, atresia of the nasal
mucosal ridge or a conical elevation. The orifice is choanae, retardation of growth and/or develop-
usually lined with epithelial cells and extends down ment, genital and/or urinary abnormalities, and
through the orbicularis oris, to the level of the ver- ear abnormalities and deafness) syndrome, and
milion. It can also connect with the mucosal glands conotruncal face anomaly. The 22q deletion has an
of the lower lip. Usually, these pits are asymptom- autosomal dominant inheritance; however, most
atic, but can present with drainage of either clear patients who present for treatment usually have a
fluid or salivary secretions. The exact embryology sporadic mutation. The phenotypic heterogeneity
of the formation of these pits is unknown, but there of this mutation makes definitive diagnosis difficult.
has been much speculation regarding their forma- The incidence of velocardiofacial syndrome is
tion during the early embryonic stages.100 Other one in 2000 to 4500 live births.105 Diagnosis is usu-
associated features include hypodontia, syndactyly, ally a clinical one. Most infants will demonstrate
thumb hyperplasia, and syngnathia.93,101 significant developmental delay, characteristic
Treatment of these patients includes regular facies, palatal dysfunction, and feeding problems.
cleft team care. Genetic counseling should be The palatal dysfunction seen is often related to a
141e
secondary or a submucous cleft palate. In addi- largely similar as well. Management needs to be
tion, the palate can be immobile and short. These multidisciplinary (Table 5), and should be initi-
patients have speech difficulty and are usually in ated at birth.107,108 As most of these children have
speech therapy at an early age. Velocardiofacial Pierre Robin sequence, airway is the first and fore-
syndrome facies are characterized by a broad most issue to address.
nasal dorsum and a flattened midface. This facial
dysmorphology often will go unnoticed, making Airway: Pierre Robin Sequence
underdiagnosis a common problem. Children with Pierre Robin sequence will have
Viscerally, they can present with conotrun- persistent respiratory desaturation in the supine
cal cardiac abnormalities and medially displaced position, largely attributable to obstruction from
carotid arteries in the pharynx. The cardiac the tongue (tongue-based airway obstruction).
abnormalities commonly seen are ventricular sep- When oxygenation is a problem, monitoring in
tal defect, tetralogy of Fallot, or a right-sided aor- the neonatal intensive care unit is necessary. Poly-
tic arch.106 somnography and monitoring for carbon dioxide
Treatment of patients with velocardiofacial retention are necessary to evaluate for proper oxy-
syndrome starts with repair of any cardiac anom- genation and ventilation109–111 (Fig. 10).
alies. Given the association with DiGeorge syn- First-line therapy is side or prone position-
drome, calcium levels should be followed. At birth, ing, allowing the tongue to fall forward, out of
they should be introduced to a feeding specialist the airway. This maneuver is effective in over half
and followed until the patient is gaining weight of patients with Pierre Robin sequence.62,66,112,113
appropriately. If a cleft palate is present, it should If this does not improve respiratory effort and
be repaired during the first year of life. Speech oxygen saturation, placement of a nasopharyn-
difficulty is one of the most frustrating aspects of geal tube during airway evaluation has been
treating patients with a chromosome 22q deletion. advocated.114 This intervention can prevent more
These patients can have trouble with phonation invasive operations.115,116 The family needs to be
and language acquisition and comprehension. educated regarding appropriate home care of
Speech delay is common and management is very this nasopharyngeal airway. Most children grow
controversial, particularly with regard to whether out of airway problems as the mandible develops;
sign language should be introduced early or late. however, more invasive intervention, such as tra-
Language delay affects the quality of life of many cheostomy, may become necessary in those with
of these patients. They have trouble with school persistent difficulty despite a nasopharyngeal
and learning disabilities throughout their child- airway.
hood. It is also significantly stressful for families. The current surgical management of Pierre
In addition, patients with velocardiofacial syn- Robin sequence includes tongue-lip adhesion
drome can have significant behavioral problems, (glossopexy), mandibular distraction, or trache-
including psychiatric issues, which need to be ostomy. Glossopexy secures the anterior and pos-
addressed by a clinical specialist. Plastic surgeons terior portions of the tongue to the mandible,
provide a very small part of the care for these bringing the tongue out of the posterior phar-
patients. After cleft palate repair, they need to be ynx and thereby preventing obstruction.117 Man-
followed to assess for any velopharyngeal insuffi- dibular distraction is another option designed
ciency. Surgical correction of this can be helpful; to advance the base of the tongue forward. Bilat-
however, close observation by a speech therapist is eral mandibular osteotomies in either the rami
important, given the significant speech delay. Sur- or bodies are performed before application of
geons correcting a cleft palate or velopharyngeal internal or external distraction devices. These
insufficiency should be aware of the potential for devices are then activated postoperatively to pull
medially displaced carotid arteries. Preoperative the tongue from a vertical position to a horizontal
imaging is controversial but can be helpful when position and relieve the airway obstruction. The
it comes to locating the carotid arteries before any efficacy of this method is controversial because of
operative intervention. variations in obstructing anatomy and comorbid
conditions, such as gastric reflux. A small subset
Management of Cleft-Related Craniofacial of patients with Pierre Robin sequence may have
Syndromes micrognathia without cleft palate, but with sig-
As with syndromic craniosynostosis, most nificant respiratory difficulty unrelated to tongue
cleft-related craniofacial syndromes present with base obstruction. This patient population would
similar clinical features. Management is therefore not respond to mandibular distractions. This
142e
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- It is safe practice to consult the otolaryngology
ation early after birth and continuously through- team regarding appropriate timing to close the
out childhood and adolescence. Complications palate. Usually, this should be done around 1 year
associated with this treatment include facial scar- of age. Technique is according to routine for non-
ring, tooth bud disruption, facial or mental nerve syndromic cases. Speech therapy should be insti-
injury, and the need for repeated operations to tuted early so that velopharyngeal insufficiency
remove the devices. can be identified and treated. From age 3 years to
Tracheostomy is the definitive airway man- adolescence, patients with a cleft palate should be
agement for Pierre Robin sequence and is usu- evaluated by a speech therapist. Because patients
ally reserved as the last resort for severe cases or are beginning to integrate into the education sys-
patients with multilevel obstruction. Despite its tem and interact with their peers, this period is an
reliable results, it is not without its potential com- important time for social development. Psycho-
plications.118,119 Tracheostomies require a signifi- logical evaluation and counseling should be avail-
cant amount of maintenance and care from the able as well.
family. Home health assistance may be necessary.
Orbitozygomatic Hypoplasia
Complications related to decannulation, frequent
At 8 to 10 years, reconstruction of the orbitozy-
hospitalizations, and maintenance need to be
gomatic region should begin.120 Because the orbits
discussed with the family in great detail before
are nearing maturity by this time, full-thickness
discharge.
cranial bone grafts are contoured to create the
Cleft Palate malar and lateral orbital deficiency. Other options
Cleft palate in the setting of craniofacial syn- for malar reconstruction have been described,
dromes needs to be addressed in the context of the including rib grafts and vascularized calvarial
airway. If airway management were suboptimal, flaps.121,122 Deficiency in this region is particularly
palatal closure could be potentially detrimental. challenging to correct. As a result, most patients
143e
will undergo multiple revision procedures. At the arch consists of three different layers: the endo-
same time, lateral canthoplasty can be secured to derm, ectoderm, and mesoderm. Disturbances of
the reconstructed malar complex in an attempt to this migration lead to deformities of the face, ear,
correct the antimongoloid slant. The lower eyelid and maxilla.77 Patients typically present with facial
colobomas can be addressed after reconstruction asymmetry related to deformities in the facial
of the orbital framework. This can be done with a skeleton and soft tissue. The skeletal deformities
number of techniques, the most common being include mandibular and maxillary hypoplasia.
bipedicled or unipedicled upper to lower eyelid Soft-tissue defects, such as microtia and hypoplas-
musculocutaneous flaps.123,124 tic subcutaneous tissue, further contribute to the
Microtia facial asymmetry.129
Timing for ear reconstruction for microtic The diagnosis of craniofacial microsomia is
ears depends on the technique used. For advo- a clinical one. Genetically, craniofacial micro-
cates of the four-stage Brent technique, surgery somia usually occurs sporadically, even though
begins at approximately age 7 years, or when the there have been some families that demonstrate
child is old enough to understand and contrib- an autosomal dominant inheritance pattern.130,131
ute to their treatment.125 For advocates of Nagata The incidence of craniofacial microsomia is one
ear reconstruction, surgery is delayed until later, in 3500 to 5600 live births.129,132 Boys are affected
when there is enough costal cartilage for the ear more commonly than girls, with a 3:1 preva-
framework.126 lence.132 The right side of the face is usually more
severely affected than the left. Craniofacial micro-
Orthognathic Surgery somia is marked by phenotypic variability, ranging
At skeletal maturity, 16 to 18 years of age, from simple preauricular skin tags to severe facial
orthognathic surgery is considered to correct any asymmetry with microtia or anotia.133
malocclusion. These cases are some of the most Clinical manifestations of craniofacial micro-
complex, and require precise presurgical plan- somia include the craniofacial region and other
ning to achieve normal occlusion and correct areas of the body. There have been many classifi-
the facial profile. Early mandibular distraction is cation systems proposed to describe patients with
endorsed by some groups in an attempt to increase this disease.129,134 The most comprehensive system
the vertical height of the ramus.127 This helps treat used to date is the Orbit, Mandible, Ear, Nerve,
airway difficulties caused by micrognathia but also and Soft tissue–Plus classification135 (Table 6).
increases the amount of bone stock for future This particular assessment tool takes into account
orthognathic procedures.128 Mandible distraction the major anomalies, including orbital, mandible,
in craniofacial syndromes is a controversial topic, ear, nerve, and soft tissue, and any extracranial
and the ideal timing is still being debated. manifestations of the disease. Orbital manifesta-
Other Skeletal Deformities tions can include dystopia caused by ipsilateral
Children with craniofacial syndromes asso- maxillary hypoplasia. Soft-tissue findings include
ciated with extracranial deformities, such as shortening of the palpebral fissures and colobo-
Nager syndrome, need to be seen by the appro- mas of the upper eyelid.
priate specialists as early as possible. Radial- Micrognathia can be seen, and these patients
side hand hypoplasia should be treated by a can suffer from Pierre Robin sequence. Most com-
pediatric hand surgeon who specializes in cor- monly, there is an asymmetric mandible with only
rection of these rare and complex problems. unilateral involvement. Normally, the ascending
Hand reconstruction should be undertaken at ramus and condyle are affected. This mandibu-
approximately 1 year of age, to allow adequate lar hypoplasia has been classified into three types
growth for reliable results. according to Pruzansky et al.136 Type I presents
with a small glenoid fossa, condyle, and ramus.
OTHER FACIAL SYNDROMES Type II affects the temporomandibular joint and
glenoid fossa. Type IIA patients demonstrate a
Craniofacial Microsomia symmetrical mouth opening, whereas in type IIB
Craniofacial microsomia, or oculoauriculover- patients there is an abnormally formed and posi-
tebral spectrum, is an anomaly arising from the tioned temporomandibular joint. Type III patients
first and second branchial arches. During week 4 have the worst malformation, with a hypoplastic
of gestation, the neural crest cells from the neu- ramus, glenoid fossa, and temporomandibular
ral tube migrate into the pharyngeal arches. Each joint. Ankylosis of the temporomandibular joint
144e
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 The spectrum of nasomaxillary hypoplasia
issue. Treatment of epibulbar dermoids (Fig. 11), is quite broad, and the deformities range from
as seen in Goldenhar syndrome, is led by an expe- subtle to quite severe. Some believe there are eth-
rienced pediatric ophthalmologist. nic differences associated with Binder syndrome.
If facial paralysis is involved, management Certain ethnicities have a tendency for flat nasal
should be at centers that have experts in facial bridges and poor projection of the nasal tip.
reanimation surgery. Foremost, ocular protection When evaluating a patient with suspected Binder
from corneal desiccation and ulceration is a major syndrome, the patient’s ethnicity should be taken
priority. Initial treatment includes eye lubrication into consideration. Preoperative workup for these
and rewetting drops. To assist with upper lid clo- patients should include imaging of the cervi-
sure, gold weights can be embedded in the pre- cal spine, given the tendency for malformations.
tarsal area but need to be sized correctly so that Treatment for Binder syndrome is controversial
extrusion does not occur. and dependent on the practitioner. Treatment
can involve nasomaxillary augmentation and
Binder Syndrome nasal reconstruction or traditional orthognathic
Maxillofacial dysplasia, originally described in surgery.151,152
1939, was characterized as a distinct syndrome by Traditional orthognathic surgery includes
Von Binder in 1962.146,147 The syndrome is charac- orthodontic treatment, with extraction of the
terized by particular facial appearance: short nose, maxillary bicuspids and retrusion of the incisors
flat nasal bridge, short columella, acute nasal as indicated. A Le Fort I osteotomy can then be
labial angle, convex upper lip, a tendency for a performed to provide for greater piriform vol-
class III malocclusion, and malar and perialar flat- ume. This is then followed by dorsal augmenta-
ness (Fig. 12). Patients often display a “dish face,” tion of the nose. The downside to this approach is
or concave facial profile. The incidence of Binder the failure to address the deficiency in the malar
syndrome is not well established and it is believed and nasal frontal regions. Others will advocate
to demonstrate autosomal recessive inheritance for a higher Le Fort osteotomy, including a high
with incomplete penetrance.148 The exact cause is Le Fort I or a Le Fort II osteotomy to correct the
unknown, but some speculate an underdevelop- entire piriform deficiency.152–154 Augmentation of
ment of the osteogenic center at the nasomaxil- the premaxillary and piriform areas can also be
lary spine.149 Patients can have skeletal findings in achieved with onlay bone grafting.151
the cervical spine, particularly abnormally formed Timing of nasal reconstruction in Binder syn-
or fused C1 to C2 vertebrae.150 drome patients has also been controversial. The
146e
Fig. 12. Binder syndrome, characterized by short nose, flat nasal bridge, short
columella, and malar and perialar flatness.
indications for early childhood nasal reconstruc- dominant and recessive familial patterns have
tion most commonly include pressure from the been reported.159
parents and peers. Future revision surgery needs Möbius syndrome can have a number of
to be discussed if early rhinoplasty is considered. clinical features, but bilateral congenital abdu-
If the decision is made to wait until the nose is cens and facial nerve palsies are the classic find-
fully grown, the optimal reconstruction material ings. Other cranial nerves can be involved, the
becomes controversial. Successful use of dorsal most common of which are the hypoglossal and
onlay bone grafting and columellar struts has vagus nerves.159,160 Musculoskeletal deformities
been described.155 However, one long-term study are commonly seen, with clubfeet being the most
reported the need to avoid bone grafts because of frequent. Cardiac defects, including ventricular
resorption.156 Others advocate rib cartilage graft- septal defects and transposition of the great ves-
ing and columellar struts in an L-shaped construct sels, have been documented.161,162 Oropharyngeal
for nasal bridge reconstruction.157 Columellar malformations, including cleft palate, retrogenia,
lengthening can be achieved with a V-Y advance- and microstomia, have been described.163–165
ment flap and provide adequate space for colu- Clinical presentation associated with facial
mellar and nasal tip grafting. The nasal soft tissue nerve palsies includes incomplete eye closure dur-
is usually not an issue, and local flaps do not need ing sleep and oral incompetence. Drooling and
to be incorporated. the inability to suck significantly impact the infant
years. As a result, these children often require hos-
Möbius Syndrome pitalization to optimize nutritional status. Patients
Möbius syndrome was first described in 1880 develop a classic “mask-like facies” because of the
but further defined by Paul Möbius in 1888. He inability to produce any facial expressions. This
compared a number of his patients who suffered weakness is asymmetric, and the upper face is usu-
from a combined abducens and facial nerve palsy ally more affected than the lower. The abducens
with those already reported in the literature.158 nerve palsy creates bilateral horizontal gaze palsy.
This nonprogressive and congenital condition Facial nerve palsies in infants can be caused
mostly occurs sporadically, although autosomal by birth trauma or some form of supranuclear
147e
abnormality.166 The cause of Möbius syndrome is Parry-Romberg Syndrome (Disease)

currently unknown; however, a common hypoth- Parry-Romberg disease was originally
esis suggests either hypoplasia of the central ner- described in 1825 by Parry and, later, by von Rom-
vous system, atrophy or degeneration of nuclear berg.172,173 The incidence and prevalence of this
centers, or a vascular disruption during devel- disease are unknown, given its rare presentation.
opment resulting in restricted development of Patients present with a progressive hemifacial
normal brain stem structures.167 Furthermore, atrophy that usually starts between 5 and 15 years
prenatal exposure to certain medications may be of age and lasts for approximately 2 to 10 years.
the inciting factor leading to disruption of normal This is usually a hemifacial disease affecting the
vascular cerebral anatomy.168–170 skin, soft tissue, muscle, and bone. Involved areas
Goals of treatment for Möbius patients include of the face usually are within the dermatomes of
eye protection from an early age, the ability to the trigeminal nerve. Unlike Möbius syndrome,
smile, and oral competence. Protection of the eyes patients with Parry-Romberg disease have nor-
should be started during infancy. Vigilance by the mal facial appearance and function at birth and
practitioner and the family needs to be stressed to during most of childhood until insult occurs.
prevent dry eye and chronic conjunctivitis. Treat- Cutaneous discoloration of the skin, including
ment includes continuous eye lubrication. More hypopigmentation and depigmentation, is often
aggressive interventions include temporary or seen. This disease is associated with neurologic
permanent tarsorrhaphy sutures to close the pal- symptoms, the most common of which is focal
pebral fissure and prevent corneal exposure. Gold epilepsy.174
weights can be added to the upper eyelid to pro- Although the exact cause is unknown, an
vide for dynamic eyelid closure. This is a simple, autoimmune type of disease has been strongly
reliable, and reversible operation commonly used implicated.175 Other possible causes include
to assist with upper lid closure. viral, neural, or traumatic.176,177 Some distinguish
Facial reanimation to provide patients with a Parry-Romberg syndrome from a similar form
smile and oral competence has remained a chal- of scleroderma known as linear scleroderma.177
lenge for the reconstructive surgeon. Older meth- This is also referred to as scleroderma “en coup
ods for facial reanimation include static slings with de sabre.” This form of linear scleroderma usually
tendon or fascia. These operations were designed only affects the frontoparietal area and does not
to restore symmetry between the facial sides, but extend below the eyebrow.
because Möbius is normally bilateral, these opera- Treatment for Parry-Romberg disease includes
tions did not achieve most patient goals. It was microinjections of fat or microvascular trans-
not until the introduction of microsurgery that plantation of free tissue.178,179 Traditionally, the
dynamic reconstruction of Möbius syndrome treatment for Parry-Romberg disease was micro-
became possible.171 The current treatment of vascular transplantation of tissue to restore facial
choice includes microvascular free muscle trans- symmetry. More recently, progressive and serial
fer, coapted to local functioning nerves. The most
fat injections have been introduced to change
commonly used muscle is the gracilis, because of
the vascular architecture of the face in the areas
its reliable neurovascular pedicle, ease of harvest,
involved. It is important to begin these fat injec-
and low morbidity. Neurorrhaphy to the nerve to
tions when the course of the patient’s disease has
masseter, partial hypoglossal, or spinal accessory
burnt out. This usually involves multiple rounds
is commonly used for reinnervation of the trans-
of grafting, and preferred donor sites include
ferred muscle. Nerve-to-masseter coaptation often
lower abdomen, buttocks, and inner thighs for
can provide for spontaneous smiling because of
extremely thin children.
cerebral plasticity.
Whereas treatment of eye issues needs to be Larry H. Hollier, Jr., M.D.
started immediately after birth, facial reanima- Division of Plastic Surgery
tion operations are usually delayed until after Baylor College of Medicine
6701 Fannin, Suite CC610.00
the age of 5 years. Patients need to be of a cer- Houston, Texas 77030
tain size before their facial structures can sup- larryh@bcm.edu
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 PATIENT CONSENT
spaced 3 to 6 months apart, or until recovery Parents or guardians provided written consent for
has occurred. use of patients’ images.
148e
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153e

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CME

Table 1. Whitaker Classification of Craniofacial Anomalies*

skull base.14 Mental and developmental delay is

blurring of optic discs,

corneal opacity, high-

stature, mental delay

(II/III), prune belly

loss, mental delay

The presence of skeletal anomalies is a defin-

ing characteristic in Apert syndrome, particularly

have multilevel vertebral fusion, with C5 and C6

I is described as having the thumb and part of the

fifth finger separate from a syndactylous mass.

Type II has just the little finger separated from

the mass, whereas type III includes all fingers.

There is a similar classification system described

are described together, because morphologically,

Crouzon syndrome is Apert syndrome without

the hand/feet anomalies. Recent development of

thus further confirming the close linkage.

FGFR1 (AD), 5%; FGFR2

FGFR3 (AD), Pro250Arg

plays complete penetrance with variable expres-

RAB23 (AR, sporadic)

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

acanthosis nigricans,24 which is considered a dis-

anteroposterior direction and causes a shortened

anterior cranial base. The phenotypic conse-

quence is a brachycephalic cranium, shallow orbits

(appearance of proptosis), and midface hypo-

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

Table 3. Terminology Commonly Used to Describe Head Shape*

Trigonocephaly Triangular forehead Metopic

Plagiocephaly Asymmetric Unilateral coronal

Turricephaly Tall, towering Bilateral coronal

Brachycephaly Short in the anteroposterior Bilateral coronal

Turribrachycephaly Tall, short, and broad Bilateral coronal

Oxycephaly Conical/pointed Bilateral coronal (delayed

Kleeblattschädel Cloverleaf shaped Pansynostosis

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

Table 4. Cohen Classification of Pfeiffer Syndrome*

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

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

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

Table 5. Members of the Craniofacial Team Treatment of Syndromic Craniosynostosis

syndromic craniosynostosis have significant mid-

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

Phenotypically, the craniofacial features of

Fig. 7. Common presentation of a patient with Treacher Collins Stickler Syndrome

Diagnosis is made clinically, based on the

Van der Woude Syndrome

Fig. 11. Patient with Goldenhar syndrome, characterized by unilateral man-

abnormality.166 The cause of Möbius syndrome is Parry-Romberg Syndrome (Disease)

REFERENCES mutations in fibroblast growth factor receptor (FGFR)2

119. Bath AP, Bull PD. Management of upper airway

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