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464
SECTION II
CHAPTER 19 • Facial transplant
understands the risks and benefits of face transplantation. The
transplantation team must also assess the patient’s ability to
adhere to life-long medication and to cope with the changes
of self-identity.
Once patients are identified to have facial disfigurement
that is not amenable to microsurgical reconstruction, they are
evaluated as potential candidates for face transplantation.
Identification of absent facial subunits, specific components
missing (such as bone, muscle, mucosa, etc.), and investiga­
tion of vascular integrity and anatomy are crucial in the initial
evaluation. The patient will also undergo rigorous psychoso­
cial evaluation including but not limited to:
a. Assessment of understanding and expectations of
procedure and alternatives
b. Patient quality of life, behavioral trends
c. Cognitive ability
d. Coping skills
e. Body image
f. Medical compliance
g. Social support network
h. History or risk of substance abuse.
Involvement of the transplant surgical service, infectious
disease specialty, radiologists, speech pathologists, social
services, and a nutritionist provide an all-encompassing
evaluation to optimize the patient selection process. Establish­
ing a patient–provider relationship early in the evaluation
process allows for the development of a sound relationship
among team members and a long-term relationship between
the patient and provider. A multidisciplinary approach cannot
be overemphasized.
Indications
Early in face transplantation, specifically defined indications
for performing the procedure were not defined, leaving most
discretion to the surgeon and patient. Nevertheless, as more
patients have undergone facial transplantation, a set a mul­
tiple conditions and patterns of facial defects have formed
tangible indications for face transplantation. Moreover,
enough time has elapsed since transplantation that complica­
tions associated with the care of face transplant patients have
helped guide various centers in developing indications and
contraindications. There are minor differences among the
indications of various institutions that perform facial trans­
plantation, but there is a broad consensus for most of the
indications, which are presented in this chapter.
The Brigham and Women’s Hospital institutional review
board has openly described their protocol in selecting face
transplant candidates. Indications for facial transplantation
involved the most difficult or impossible defects to recon­
struct, defects had to comprise greater than 25% of the facial
area or involve the central face such as the eyelids, nose, or
lips, and, lastly, patients had to have alternative reconstruc­
tive methods considered and deemed unfavorable or unsatis­
factory.16 Other groups have deviated from the 25% facial
defect as necessary for transplantation. Rather, a closer exami­
nation by all groups has focused on the etiology of the facial
deformity, which may vary considerably. Patients have under­
gone face transplants secondary to animal attacks (bear, dog,
non-human primate), tumor (malignant and benign), burn
(thermal and electrical), ballistic and blunt trauma (Table
19.1).1 Each select group of patients harbors inherent chal­
lenges. Preformed antibodies to multiple transfusions and
skin grafts can make burn patients and trauma patients more
difficult to find an ideal donor. Patients with malignancies are
at an increased risk for developing recurrence of their malig­
nancy, especially in the setting of chronic immunosuppres­
sion. As the field expands, the indications and set of injuries
are likely to converge onto a specific subset of patients. Once
outcomes become more predictable, surgeons may be more
cavalier to expand the indications to incorporate a broader
group of patients.
Absolute and relative contraindications
Indications for facial transplantation are largely balanced by
the patient’s benefit from the procedure outweighing the risks
of surgery and life with allograft. However, contraindications
vary amongst the various groups performing such procedures.
Chronic conditions such as HIV and malignancy within a
5-year period remain absolute contraindications, and blind­
ness is considered a controversial comorbidity to be trans­
planted.1,15 In the setting of immunosuppression, the infectious
complications and susceptibility to tumor growth and spread
is considered extremely high for patients with HIV and malig­
nancy.16 Many of this data has been gleaned from the solid
organ transplant literature, but also has been drawn from the
some of the early face transplants performed. The Spanish
group had transplanted an HIV-positive patient, which was
initially considered a success.17 Unfortunately, the patient
developed recurrence of the initial malignancy, which led to
his death.18 Other chronic conditions are also considered when
selecting patients for transplantation.
Blindness is considered a controversial topic among various
groups in their willingness to transplant such patients. The
condition in which a patient sustains facial deformity with
blindness poses significant challenges such as inability to
visualize biofeedback physiotherapy and the dangerous
inability to recognize early signs of acute rejection. On the
contrary, others19,20 describe the principle of justice mandating
that surgeons be obligated to provide facial reconstruction to
blind patients, ultimately leading to a blind patient receiving
a face transplant.19 The challenges to the blind patient must
be mitigated with extensive family support, which may limit
the reintegration into society. Furthermore, the cost of failing
to detect acute rejection or delayed presentation of acute rejec­
tion will result in decreased allograft longevity and is likely
to result in chronic rejection, as seen in upper extremity/hand
transplantation. This remains an ongoing controversy.
There are concerns of performing simultaneous upper
extremity and face transplantation. Two patients, one from
the French group21 and another from the Brigham group22,
have undergone simultaneous bilateral hand transplantation
and face transplantation. Both patients developed an early
postoperative Pseudomonas infection, ultimately resulting in
sepsis and death in one patient and sepsis leading to bilateral
hand amputations and facial allograft survival in the other
patient.22 The issues related to simultaneous hand and face
transplantation within a single stage surgery include a large
antigenic burden, prolonged anesthesia time, large-volume
Text continued on p. 469

465
Absolute and relative contraindications
Table 19.1  Face transplants performed worldwide
Team
leader(s)
Date
Location
Recipient
(age,
sex)
Indication
Extent of defect
Functional
deficit
Facial
allograft
Death (cause,
time from
transplant)
Acute
rejection
(episodes)
Chronic
rejection
  1
Devauchelle
and
Dubernard
November,
2005
Amiens,
France
38 years,
Female
Dog bite
Cheek, nose, lips,
chin
Labial
competence,
speech
Partial
Death
Yes (2)
Yes
  2
Guo
April, 2006
Xi’an, China
30 years,
Male
Bear bite
Cheek, nose,
upper lip,
maxilla, orbital
wall, zygoma
-
Partial
Death
(noncompliance,
-)
Yes (3)
No
  3
Lantieri
January,
2007
Paris, France
29 years,
Male
Neurofibromatosis
Forehead, brows,
eyelids, nose,
lips, cheeks
Labial
competence,
speech
Partial
Alive
Yes (2)
No
  4
Siemionow
December,
2008
Cleveland,
OH, USA
45 years,
Female
Ballistic trauma
Lower eyelids,
nose, upper lip,
orbital floor,
zygoma, maxilla
Speech, eating
Partial
Alive
Yes (3)
No
  5
Lantieri
March,
2009
Paris, France
27 years,
Male
Ballistic trauma
Nose, lips, maxilla,
mandible
Labial
competence,
speech
Partial
Alive
Yes (1)
No
  6
Lantieri
April, 2009
Paris, France
37 years,
Male
Third degree burn
Forehead, nose,
eyelids, ears,
cheek
Blink
Partial
Death (sepsis, 2
mo.)
No†
No
  7
Pomahac
April, 2009
Boston, MA,
USA
59 years,
Male
Electrical burn
Lower eyelid,
cheek, nose,
lips, maxilla,
zygoma
Labial
competence,
speech
Partial
Alive
Yes (3)
No
  8
Lantieri
August,
2009
Paris, France
33 years,
Male
Ballistic trauma
Cheek, nose, lips,
maxilla,
mandible
Labial
competence,
speech
Partial
Alive
Yes (1)
No
  9
Cavadas
August,
2009
Valencia,
Spain
42 years,
Male
Cancer/radiation
therapy
Lower lip, tongue,
floor of mouth,
mandible
Labial
competence,
speech
Partial
Death (cancer, -)
Yes (2)
No
Continued

466
SECTION II
CHAPTER 19 • Facial transplant
Team
leader(s)
Date
Location
Recipient
(age,
sex)
Indication
Extent of defect
Functional
deficit
Facial
allograft
Death (cause,
time from
transplant)
Acute
rejection
(episodes)
Chronic
rejection
10
Devauchelle
and
Dubernard
November,
2009
Amiens,
France
27 years,
Male
Ballistic trauma
Nose, lips,
mandible
Labial
competence,
speech, eating
Partial
Alive
Yes (8)
Yes
11
Gomez-Cia
January,
2010
Seville, Spain
35 years,
Male
Neurofibromatosis
Cheek, lips, chin,
mandible
Labial
competence,
speech
Partial
Alive
Yes (1)
No
12
Barret
March,
2010
Barcelona,
Spain
30 years,
Male
Ballistic trauma
Eyelids, nose, lips,
lacrimal
apparatus,
zygoma, maxilla,
mandible
Labial
competence,
speech
Full
Alive
Yes (3)
No
13
Lantieri
June, 2010
Paris, France
35 years,
Male
Neurofibromatosis
Eyelids, ears,
nose, lips, oral
mucosa
Blink, speech
Full
Alive
Yes (1)
No
14
Pomahac
March,
2011
Boston, MA,
USA
25 years,
Male
Electrical burn
Forehead, eyelids,
left eye, nose,
cheek, lips
Blink, speech
Full
Alive
Yes (3)
No
15
Lantieri
April, 2011
Paris, France
45 years,
Male
Ballistic trauma
Nose, mandible,
maxilla
Labial
competence,
speech
Partial
-
-
No
16
Lantieri
April, 2011
Paris, France
41 years,
Male
Ballistic trauma
Nose, mandible,
maxilla
Labial
competence,
speech
Partial
Death (suicide, 36
mo.)
-
No
17
Pomahac
April, 2011
Boston, MA,
USA
30 years,
Male
Electrical burn
Forehead, eyelids,
nose, cheek, lips
Labial
competence,
speech
Full
Alive
Yes (5)
No
18
Pomahac
May, 2011
Boston, MA,
USA
57 years,
Female
Animal attack
Forehead, eyelids,
eyes, nose, lips,
maxilla,
mandible
Blink, speech
Full
Alive
Yes (4)
No
Table 19.1  Face transplants performed worldwide—cont’d

467
Absolute and relative contraindications
Team
leader(s)
Date
Location
Recipient
(age,
sex)
Indication
Extent of defect
Functional
deficit
Facial
allograft
Death (cause,
time from
transplant)
Acute
rejection
(episodes)
Chronic
rejection
19
Blondeel
December,
2011
Ghent,
Belgium
54 years,
Male
Ballistic trauma
Eyes, eyelid,
cheek, nose,
maxillae,
mandible, lip
Speech, eating
Partial
Alive
Yes (1)
No
20
Ozkan
January,
2012
Antalya,
Turkey
19 years,
Male
Burn
Forehead, nose,
cheeks, lips
-
Full
Alive
Yes (7)
No
21
Nasir
February,
2012
Ankara,
Turkey
25 years,
Male
Burn
-
-
Full
Alive
-
No
22
Ozmen
March,
2012
Ankara,
Turkey
20 years,
Female
Ballistic trauma
Nose, upper lip,
maxilla,
mandible
-
Partial
Alive
-
No
23
Rodriguez
March,
2012
Baltimore,
MD, USA
37 years,
Male
Ballistic trauma
Forehead, eyelids,
nose, cheek,
lips, zygoma,
maxilla mandible
Speech, blink
Full
Alive
Yes (3)
No
24
Ozkan
May, 2012
Antalya,
Turkey
34 years,
Male
Thermal burn
Forehead, eyelids,
nose, cheeks,
lips
-
Full
Alive
Yes (-)
No
25
Devauchelle
and
Dubernard
September,
2012
Amiens,
France
-, Female
Vascular tumor
Lower eyelid,
maxilla, tongue
Eating
Partial
Alive
Yes (-)
No
26
Pomahac
February,
2013
Boston, MA,
USA
44 years,
Female
Chemical burn
Nose, lips, eyelids,
forehead, cheek,
ears, eyes, neck
Speech, blink,
labial
competence
Full
Alive
Yes (4)§
No
27
Maciejewski
May, 2013
Gliwice,
Poland
32 years,
Male
Blunt trauma
Nose, lips, eyelid,
cheek, maxilla
Speech
Partial
Alive
Yes (1)
No
28
Ozkan
July, 2013
Antalya,
Turkey
27 years,
Male
Ballistic trauma
Forehead, eyelids,
left eye, nose,
cheek, mandible
-
Full
Alive
Yes (-)
No
Table 19.1  Face transplants performed worldwide—cont’d
Continued

468
SECTION II
CHAPTER 19 • Facial transplant
Team
leader(s)
Date
Location
Recipient
(age,
sex)
Indication
Extent of defect
Functional
deficit
Facial
allograft
Death (cause,
time from
transplant)
Acute
rejection
(episodes)
Chronic
rejection
29
Ozkan
August,
2013
Antalya,
Turkey
54 years,
Male
Ballistic trauma
Scalp, forehead,
eyelids, nose,
left eye, maxilla,
mandible,
tongue
-
Full
Death (lymphoma
and respiratory
failure, 12 mo.)
Yes (2)‡
No
30
Maciejewski
December,
2013
Gliwice,
Poland
26 years,
Female
Neurofibromatosis
Forehead, eyelids,
nose, maxilla,
lips, mandible
Speech, eating
Full
Alive
Yes (-)
No
31
Ozkan
December,
2013
Antalya,
Turkey
22 years,
Male
Ballistic trauma
Forehead, lips,
nose, maxilla,
mandible
-
Partial
Alive
Yes (-)
No
32
Pomahac
March,
2014
Boston, MA,
USA
-, Male
Ballistic trauma
Forehead, nose,
lips, lower face
Speech, eating
Full
Alive
Yes (5)
No
33
Papay
September,
2014
Cleveland,
OH, USA
-, Male
Blunt trauma
Scalp, forehead,
eyelids, nose,
eye, maxilla,
cheeks
Speech
Partial
Alive
Yes (1)
No
34
Pomahac
October,
2014
Boston, MA,
USA
31 years,
Male
Ballistic trauma
-
-
Full
Alive
Yes (2)
No
35
Barret
February,
2015
Barcelona,
Spain
45 years,
Male
Arteriovenous
malformation
Lower face, neck,
lips, tongue,
pharynx
Speech
Full
Alive
-
No
36
-
May, 2015
St.
Petersburg,
Russia
-, Male
Electrical burn
Forehead, nose,
lips
Partial
Alive
-
-
37
Rodriguez
August,
2015
New York, NY,
USA
41 years,
Male
Thermal burn
Scalp, forehead,
eyelids, nose,
cheeks, lower
face, ears, lips,
neck
Labial
competence,
blink
Full
Alive
No
No
38
Mardini
June, 2016
Rochester,
MN, USA
32 years,
Male
Ballistic trauma
Nose, cheeks,
maxilla, lips,
mandible, teeth
-
Partial
Alive
-
No
Reprinted with permission from Sosin M, Rodriguez ED. The face transplantation update: 2016. Plast Reconstr Surg. 2016;137:1841–1850.
†Discrepancy between reports. The patient was described as having skin biopsy findings of grade I rejection with ongoing graft ischemia and another report stating no clinical rejection was evident.
‡Underwent removal of allograft and had an anterolateral thigh flap for coverage of the facial wound.
§Antibody-mediated rejection was observed in this patient.
Table 19.1  Face transplants performed worldwide—cont’d

469
Technical approach
resuscitation, and impaired cortical adaptation.23,24 However,
these issues are not supported by well conducted studies
and remain anecdotal explanations for such poor outcomes.
Interestingly, the other VCA experiences and animal models
offer refutable data to each of the aforementioned concerns.
The amount of transplanted tissue has shown to have a
positive impact in animal models25 and clinical solid organ
transplants26–28. Extensive face transplants with successful
outcomes29,30 continue to contradict the theory of antigenic
burden and the concerns of extended anesthesia time and
requirement of blood products during allograft procure­
ment.31 Both the France and Boston groups propose a more
cautious approach to patients requiring combined hand and
face transplants by performing staged transplantations.22
Other relative contraindications with a larger ethical
dilemma may surface. These issues include a recent history of
substance abuse or severe depression, which pose many chal­
lenges to the patient. A major psychological burden of face
transplantation on self-identity, impact on mental and physi­
cal health, and need for adherence to strict lifelong medication
may act as stressors that may cause substance abuse and
depression to resurface. Careful psychiatric evaluation must
elucidate whether depression is secondary to the facial defor­
mity or if the patient’s depression has an organic etiology
preceding the facial deformity. Despite the transformative
potential of face transplantation, prior depression and suicidal
attempts should limit the application of face transplantation.
This has been recognized firsthand by Lantieri et al. reporting
one of their patients (from a series of seven patients) eventu­
ally committing suicide after a prior attempt pre-transplant.32
However, the overwhelming positive outlook from patients
that undergo facial VCA is well-established. Following
face transplantation, patients have a decreased prevalence of
depression and verbal abuse, improved body image, quality
of life, sense of self, are able to reintegrate socially, and some
return to work.12,32–39
Once the patient has passed the screening process for facial
transplantation and is selected as a candidate recipient for
facial VCA, immunological testing is pursued. Once a poten­
tial donor is identified, HLA-testing, donor-recipient cross­
match, and donor specific antibody (DSA) titers are obtained.
Historically, partial HLA-compatibility with a negative cross­
match and low DSA reactivity was considered a universal
practice in VCA, but the last several years have challenged
these principles. Similar to kidney transplantation, a donor-
recipient crossmatch is completed with peripheral blood
using flow cytometry.40,41 However, peripheral blood cross­
matching may potentially have increased false negative
results, especially in patients exposed to multiple transfu­
sions.42 This has led to most VCA centers adopting the use of
donor lymph nodes in the majority of transplantation proce­
dures.40 Achieving an immunologically compatible donor
amongst a small donor pool is even further narrowed by skin
tone, hair color, cephalometrics, and age.
In addition to antigenic compatibility, the consequences of
Epstein–Barr virus (EBV) and cytomegalovirus (CMV) mis­
matches have elucidated themselves as important factors in
the immunosuppressed patient. It is postulated that the pro­
pensity of the skin endothelium to retain a greater viral load
relative to endothelial cells of the kidney, liver, or heart
allografts contributes to an increased risk of rejection.43 Hand
and kidney transplantation demonstrates a high incidence of
CMV infection.44 This been implicated as the nidus of an
immune response within the allograft and associated with
decreased graft survival.45–47 Cytomegalovirus mismatches
have been reported in at least nine face transplant patients47
leading to ganciclovir-resistant and valganciclovir-resistant
infection in two patients.35 Additionally, CMV seropositivity
is problematic because the treatment of CMV viremia involves
decreasing immunosuppression, which may itself predispose
the patient to rejection.47,48
The risk of de novo malignancy is increased in immunosup­
pressed solid organ transplant recipients approximately two
to four times compared with that of age-matched controls.49
Moreover, EBV naïve recipients receiving EBV-positive
allografts may carry an increased risk of developing a future
malignancy.47 The clinical VCA experience has largely focused
on technical aspects of surgery and viral status has poorly been
reported. Of two known recipients who were mismatched for
EBV,1,37 one patient (Amiens, France) developed a monoclonal
B-cell lymphoma at several months post-transplant, requir­
ing Rituximab and reduction of immunosuppression.50,51
Although EBV status was not reported, Ozkan reported one
patient that developed post-transplant lymphoproliferative
disorder (PTLD) (a known consequence of immunosup­
pression and EBV infection), which was followed by graft
failure requiring an ALT flap for coverage of the patient’s
facial wound and ultimately resulting in the patient’s death.1
With the limited experience of viral mismatching and poor
outcomes, it is recommended that CMV and EBV mismatch­
ing be avoided, particularly as patients require lifelong
immunosuppression.
Technical approach
Defect assessment
Evaluation of a potential face transplant recipient involves
conducting a thorough assessment of the craniomaxillofacial
injury. Commonly, patients with composite tissue loss will
have a deficit of bone and skin with variable involvement
of essential functional anatomy inevitably impacting degluti­
tion, respiration, oral competence, and blinking. Previously,
a classification system designed for oncologic midface
defects was proposed as a system to stratify patients being
evaluated for face transplantation. Although this system was
popularized for selection of free tissue transfer for midface
defects, there were shortcomings in its application for face
transplantation. Specifically, the defects of candidates being
evaluated for face transplantation seem to vary drastically as
compared with those defects created surgically from oncologic
resections.
A more encompassing classification system was described
by Mohan et al.52 with a goal of predicting the optimal trans­
plant design. This system was developed from the experience
of actual face transplants performed worldwide. Although
this algorithmic approach is broad, it serves as a primer to the
surgeon in considering pattern of injury, principles of aesthetic
subunit(s) design, and incorporates an already familiar Le
Fort-based classification scheme. The diagram in Fig. 19.1
details this classification system and illustrates the extent of
hard tissue and soft tissue defects.

470
SECTION II
CHAPTER 19 • Facial transplant
Fig. 19.1  Hard and soft tissue defects – a classification and guide to aid the surgeon in selecting a facial allograft for facial defects.
Type I
Type II
Type III
Type A
Type B
Type C
Imaging and operative planning
Preparation for facial allograft design and the completion of
a successful procedure involves the use of cutting edge tech­
nology, cadaveric surgical simulations, and anatomical perfu­
sion studies. In order to achieve optimal functional and
aesthetic outcomes, a planning process is essential. The prin­
ciples of craniofacial surgery, aesthetic surgery, and microsur­
gery help guide the allograft design process. Rigid fixation of
the facial buttress is the basis for soft tissue reconstruction.
Special attention should be made to preserve ligamentous and
canthal attachments to mitigate the degree of ptosis and
maintain muscular insertions to best sustain facial animation,
and, ultimately, allograft survival is dependent upon healthy
perfusion of the allograft.
Preparation for transplantation should incorporate multiple
radiologic and technological adjuncts. This includes a three-
dimensional craniomaxillofacial computerized tomographic
scan, a triple phase angiogram to evaluate arterial and
venous anatomy, and CAD/CAM technologies are strongly

471
Technical approach
recommended to precisely design osteotomy site location,
print cutting guides, and allow for re-evaluation of mock
transplantation for attaining optimal outcomes. With multiple
technical strategies of allograft preparation, recipient prepara­
tion, and allograft inset exist, the tenets of craniofacial,
microsurgical, and aesthetic surgery are reviewed below in
describing surgical principles of face transplantation.
Synchronization of teams
The ideal donor is able to provide multiple organs for life
saving procedures, in addition to providing a life-altering
facial allograft. Due to the nature of face transplantation being
the most novice specialty, the onus of establishing an organized
team approach for all transplant teams relies on the reconstruc­
tive surgeon. It is well-established that simultaneous allograft
preparation of the face, chest organs, and abdominal organs
is feasible and has technically been successful. However,
optimization of timing can minimize cold ischemia time and
it is recommended for the facial allograft to be harvested prior
to cross-clamping of the aorta, with immediate division of the
allograft pedicles prior to aortic cross-clamping.
Mask
Formulation of a silicone-based prosthetic mask is typically
fashioned prior to any allograft procurement (Fig. 19.2–19.5).
This allows for coverage of the donor defect upon completion
of the procedure, and it also provides a dignified means of
transportation from the operating room facilitating a dignified
return of the remains for the family of the deceased.
Surgical planning
Pre-operative computed tomography scans are obtained of the
donor and recipient to develop a virtual surgical plan. This
Fig. 19.2  Donor mask mold reservoir creation.
Fig. 19.3  Donor mask mold reservoir creation continued.
Fig. 19.4  Donor mask mold reservoir created. (Printed with permission from and
copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.)
provides optimal design of Le Fort III osteotomies, bilateral
mandibular sagittal split osteotomies, or uniquely designed
osteotomies specific to the patient’s specific bony deficit
(Figs. 19.6 & 19.7). Additionally, stereolithographic models of
the recipient can be manufactured for intraoperative use to
ascertain the precision of the allograft. Specific cutting-guides

472
SECTION II
CHAPTER 19 • Facial transplant
Fig. 19.5  Donor mask. (Printed with permission from and copyrights retained by
Eduardo D. Rodriguez, M.D., D.D.S.)
Fig. 19.6  Recipient osteotomy preparation using
computerized surgical planning to design cutting
guides. (Printed with permission from and
copyrights retained by Eduardo D. Rodriguez, M.D.,
D.D.S.)
are processed and manufactured for all recipient and donor
osteotomy sites to decrease operative time and foster more
precise apposition (Fig. 19.8).
Donor allograft recovery
The description of allograft preparation will vary based upon
patient defect. The description below provides an overview
of a total face allograft harvest with variation in anatomic
components included and excluded.
Neck and lower face
Markings are made on the donor to incorporate the neck and
total face, which should avoid inclusion of the tracheostomy
site. Skin markings are crucial to hide or camouflage, to better
foster an aesthetically pleasing result with inconspicuous
scars. Neck incisions are placed over the sternal notch extend­
ing bilaterally just above the clavicles, ascending along the
posterolateral portions of the neck to the pre-auricular region.
Markings are completed below the occipital groove of the
posterior hairline and sagittally in the midline, or in a coronal
fashion within the frontal hair bearing region depending on
whether the scalp is or is not included within the allograft,
respectively. An incision is made along the right neck and a
subplatysmal flap is elevated. The external vein is dissected
and ligated. If the greater auricular nerve is encountered, it is
dissected, divided, and saved for the inset of donor tissue as
a potential nerve allograft. The sternocleidomastoid muscle is
retracted laterally to identify the carotid sheath and its con­
tents. The internal jugular vein is identified and dissected
cranially to identify the thyrolingual facial trunk (Fig. 19.9).
All branch points of the external carotid artery are also dis­
sected cephalad to preserve the facial, occipital (if scalp is
included), and lingual arteries (if the tongue is incorporated
within the allograft). The sternocleidomastoid muscle may
then be sharply divided as the caudal dissection proceeds to
identify branches of the external carotid artery (Fig. 19.10). As
mentioned earlier, division of the superior thyroid, ascending
pharyngeal and associated arteries allow for mobilization of
the allograft. If the lingual artery is preserved, it should be
dissected to the tongue base throughout its trajectory within
the mylohyoid muscle. Sacrificing the posterior auricular
artery should only occur once the occipital artery has been
identified. Encountering the anterior and posterior bellies of
the digastrics muscle and hypoglossal nerve is expected, and
division is necessary to expose the tortuous course of the
facial artery (Fig. 19.11). Division of the digastric muscle later­
ally facilitates exposure of the submandibular gland, duct and

473
Neck and lower face
Fig. 19.7  Donor osteotomy preparation using
computerized surgical planning to design cutting
guides. (Printed with permission from and
copyrights retained by Eduardo D. Rodriguez, M.D.,
D.D.S.)
Fig. 19.8  Stereolithic 3D template of the donor for development of ideal cutting
guides.
Fig. 19.9  Donor dissection of the venous anatomy showing the internal jugular
vein and thyrolingual facial trunk.
Fig. 19.10  Donor dissection of the arterial anatomy showing the external carotid
artery and its branches.
Fig. 19.11  Encountering the digastric muscle during the donor dissection; this is
divided to expose the distal arterial branches.

474
SECTION II
CHAPTER 19 • Facial transplant
vessels, which are ligated and divided excluding the subman­
dibular gland from the allograft. The hypoglossal nerve
should be preserved as a potential nerve allograft during
inset. The posterior branch of the facial vein is dissected crani­
ally where the mandibular division of the facial nerve is
identified and protected.
The neck incision is extended to a pre-auricular incision or
around the neck laterally if the ears and scalp are incorporated
within the allograft. If the pre-auricular dissection is pursued,
it is carried down to the sub-superficial musculoaponeurotic
system plane to identify the parotidomasseteric fascia. Meticu­
lous dissection allows for visualization of Stensen’s duct,
which is ligated and divided, excluding the parotid duct from
the allograft. All facial nerve branches are identified and dis­
sected free individually (Fig. 19.12). If the ears and scalp are
included, the dissection continues cranially along the occipital
artery to identify its deeper course in the occipital groove
posterolateral to the mastoid process (Fig. 19.13). Extensive
retraction of a thick musculocutaneous flap is required later­
ally to expose the occipital vessels. The facial nerve, superficial
temporal artery, and internal maxillary artery are therefore
Fig. 19.12  Facial nerve dissection.
Fig. 19.13  Identification of the occipital artery. (Printed with permission from and
copyright retained by Eduardo D. Rodriguez, M.D., D.D.S.)
Fig. 19.14  Scalp elevation is completed bilaterally with an incision made down
the middle from the vertex caudad to reach the neck allowing for adequate elevation
of the allograft.
identified later in the dissection. For allografts incorporating
a bilateral sagittal split osteotomy of the mandible, the ptery­
gomasseteric sling is incised and stripped from the mandible.
The internal maxillary artery is ligated and divided at this
point to minimize blood loss during future Le Fort III osteoto­
mies. Each dissection must be completed bilaterally prior to
moving forward with allograft preparation.
If the tongue is included, an incision is made to the floor
of the mouth along the lingual mucosa bilaterally to the
tongue base. Dissection proceeds to identify the lingual nerves
and divide them, while avoiding any injury to the lingual
arteries. Lateral dissection allows for the alveolar ridge to be
exposed and a connecting incision of the soft palate cranially
allows for the pterygoids to be exposed. This perioral dissec­
tion is saved for a later point if the ears and scalp are included.
Following elevation of the ears and scalp, attention is then
drawn to the hair bearing scalp.
Scalp
Gentle elevation and flexion at the neck allows for the poste­
rior midline scalp to be incised down to the subperiosteal
layer. The scalp is elevated bilaterally (Fig. 19.14) and contin­
ues until the sub-superficial temporal fascia is reached. Care
is taken to not violate this plane as the superficial temporal
artery and vein are protected and maintained within the
allograft, while excluding the temporalis muscle from the
allograft. Subperiosteal elevation continues to the supraorbital
rim, and a portion of the zygomaticofrontal process, zygo­
matic arch, and lateral orbital rim are exposed. The supraor­
bital and supratrochlear neurovascular contents are ligated
and divided. Attention should then return to the posterior
periosteal scalp elevation which continues laterally to elevate
the occipital artery from the occipital groove and the ears
bilaterally if attachments still remain.
Periorbital region
The eyelid structures are dissected through a transconjuc­
tival incision. Dissection of the lower eyelid continues in a

475
Intraoral
subseptal plane down to the inferior orbital rim. The upper
eyelid dissection preserves the tarsus, levator palpebrae supe­
rioris, septum, and orbicularis oculi and meets the superior
orbital rim. The similar lower eyelid dissection is completed
to preserve the tarsal plate and orbicularis oculi meeting the
inferior orbital rim (Fig. 19.15–19.17).
A coronal incision is then made in the hair-bearing region
to connect the pre-auricular incisions bilaterally, if the ears
and scalp are excluded from the allograft. The soft tissue of
the forehead is caudally elevated in the subperiosteal plane to
expose the nasofrontal segment. Care is taken not to disrupt
the medial canthal attachments. The coronal incisions and the
eyelid incisions are connected and the inferolateral orbital rim
is stripped of soft tissue attachments. Additionally, the lateral
canthal tendons are tagged and cut. Le Fort III cutting-guides
are then placed over the nasofrontal and bilateral orbitozygo­
matic segments (Fig. 19.18).
If the ears and scalp are incorporated, the facial nerve,
superficial temporal artery, and internal maxillary artery are
identified via lateral access directed medially from the elevated
ears. Medial retraction of the allograft facilitates a deeper
dissection in the sub-superficial musculoaponeurotic system
Fig. 19.15  Eyelid dissection – transconjuctival dissection.
Fig. 19.16  Eyelid dissection – continued.
Fig. 19.17  Eyelid dissection – dissection proceeds to maintain the superior and
inferior tarsal plates along with underlying orbicularis oculi muscle.
plane of the superior pole of the parotid gland, without violat­
ing the parotid-masseteric fascia. The parotid duct and vascu­
lar branches are ligated and divided, and the facial nerve
trunk is tagged and divided to preserve maximum length. The
superficial temporal artery is also identified to avoid inadver­
tent injury. Typically, the internal maxillary artery is able to
be identified and divided during initial external carotid artery
branch dissection, but if it was unable to be identified, the
internal maxillary artery can be identified, ligated, and
divided at this point. At this juncture, prefabricated cutting-
guides must be approximated for appropriate fit, which can
only be ensured through adequate soft tissue exposure. Once
proper hardware engagement is achieved, screw fixation of
the cutting-guides is reserved for after the intraoral and eyelid
dissections are completed.
Intraoral
A circumferential intraoral incision is made along the gin­
givobuccal mucosal junction to preserve as much mucosa
as possible while avoiding the parotid papillae, bilaterally.
Fig. 19.18  Eyelid dissection – lateral canthii are identified with polypropylene
suture and divided allowing for completion of osteotomies.

476
SECTION II
CHAPTER 19 • Facial transplant
Fig. 19.19  An intraoral incision with elevation of a subperiosteal dissection of the
maxilla exposes the infraorbital neurovascular contents.
Fig. 19.20  Exposure of the mandibular symphasis and screw fixation of the cutting
guide allows for a precise chin osteotomy.
Fig. 19.21  Screw fixation of the maxillary cutting guide.
Fig. 19.22  Screw fixation of the mandibular cutting guide.
Fig. 19.23  Screw fixation of the orbitozygomatic and nasofrontal cutting guide.
The maxilla is exposed through elevation of an osteomucosal
flap to expose potential sites for osteotomies and/or cutting
guide placement. Exposure of the orbitozygomatic region
and anterior surface of the maxilla to expose the infraorbital
foramen content is then completed (Fig. 19.19). If exposure
is inadequate, snap-fit cutting guides may not be positioned
properly. Further exposure is achieved through flap elevation
to allow for engagement of hardware. Throughout the inferior
mucosal incision, the dissection continues to the submucosa
down to the mandibular symphysis for enough subperiosteal
elevation to accommodate a genial segment cutting-guide
(Fig. 19.20). Preservation of the mentalis muscle insertion is
attempted but not always possible depending on the size of
the cutting guides. The submucosal dissection must be com­
pleted laterally to divide all remaining circumferential attach­
ments of the buccinator to complete the intraoral mucosal
dissection.
Contour engagement of prefabricated cutting-guides con­
firms proper anatomic alignment, which is followed by
screw fixation and osteotomies of the orbitozygomatic, zy­
gomaticomaxillary, transverse maxillary, nasofrontal, and
genial regions (Fig. 19.21–19.25). Infrahyoid strap muscles are
then divided inferiorly liberating the allograft from all
soft tissue attachments besides the bilateral vascular ped­
icles. Bilateral ligation and division of the internal jugular
veins and external carotid arteries completes final allograft
liberation.

477
Osteotomies
Fig. 19.24  Nasofrontal osteotomy completion with the soft tissue of the allograft
protected.
Fig. 19.25  Completion of the mandibular osteotomy.
Osteotomies
Allografts encompassing bilateral sagittal split osteotomies
are completed through an intra- and extraoral approach. The
inferior alveolar nerve is identified and divided as proximally
as possible. As described earlier, Le Fort III cutting-guides can
be snap-fit into place or anatomic position can be checked
using an intraoperative navigation system to confirm precise
placement of osteotomies. Bone cuts are made anterior to the
zygomatic arches and posterior to the orbital rims. The naso­
frontal osteotomy is created posterior to the medial canthus
and the canalicular drainage system if possible. Completion
of the Le Fort III osteotomy involves the pterygomaxillary
junctions, which are cut to mobilize the bony segment of
maxillomandibular complex. This freely separates, although
the nasal septum may require trimming (Fig. 19.26). Any soft
tissue attachments must be divided (Fig. 19.27) to leave only
the vascular pedicles in continuity. At this juncture, the exter­
nal carotid arteries and the internal jugular veins are ligated
and divided bilaterally, ultimately liberating the allograft (Fig.
19.28–19.31). It is placed on the back table in an ice-water bath
of preservation solution and immediately irrigated with tissue
preservation solution (Figs. 19.32 & 19.33).
Fig. 19.26  Trimming of the allograft along the nasal septum.
Fig. 19.27  Strap muscles and submandibular soft tissue remain intact.
Fig. 19.28  Prior to division of the allograft pedicles.
Recipient preparation
The recipient preparation begins at the same time as the donor
operation, but there are several distinct differences that are
highlighted. Maximal preservation of neurovascular structures
are typically preserved within the recipient defect. Stensen’s

478
SECTION II
CHAPTER 19 • Facial transplant
Fig. 19.29  Elevation of the allograft with bilateral pedicles intact. (Printed with
permission from and copyright retained by Eduardo D. Rodriguez, M.D., D.D.S.)
Fig. 19.30  Allograft resting on the donor defect prior to elevation. (Printed with
permission from and copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.)
Fig. 19.31  A profile image of the allograft resting on the donor defect prior to
elevation. (Printed with permission from and copyrights retained by Eduardo D.
Rodriguez, M.D., D.D.S.)
Fig. 19.32  The allograft placed onto back table in an ice-water bath of preservation
solution.
Fig. 19.33  Preservation solution is infused into the allograft.
duct is also preserved when possible. The coronal incision is
carried to a more superficial plane to preserve the frontalis
and orbicularis oculi. If a coronal incision is not utilized, then
the defect is usually larger and accommodates the scalp and
ears. All skin of the donor is typically de-epithelialized and
scar tissue excised. All nerve branches are divided as distally
as possible including the zygomatic, buccal, and mandibular
branches of the facial nerve, as well as the sensory nerves,
including the infraorbital, supraorbital nerves, and supra­
trochlear nerves. Osteotomies will incorporate normal bone

479
Immunosuppression and rejection
along defect edges at the cost of achieving better anatomic
approximation with healthy wound edges (Figs. 19.34 &
19.35).
Allograft inset
Once both teams have completed their respective operative
portions, the allograft is transferred to the recipient operating
room where the allograft inset begins. Rigid fixations of bony
elements are completed, including the nasofrontal complex
(Fig. 19.36), the orbitozygomatic regions, and the mandibles
(if included). Next, nerve coaptations are completed. Nerves
Fig. 19.34  Recipient defect preparation includes de-epithelialization and scar
excision, and fixation of cutting guides.
Fig. 19.35  Recipient preparation after nasal and mandibular osteotomies have
been completed. (Printed with permission from and copyright retained by Eduardo
D. Rodriguez, M.D., D.D.S.)
Fig. 19.36  Allograft inset – nasofrontal allograft fixation.
repaired will vary depending on the recipient functional defi­
cits. Laying sensory nerves of the infraborbital and supraor­
bital nerves over their respective foramena may be required
if a nerve coaptation is not feasible. Following this, the vas­
cular anastomoses are completed with the arterial and venous
pedicles anastomosed on one side, then the other. The soft
tissue of the face is then re-draped and retaining sutures are
placed within areas of excess tissue laxity or mobility. The
lateral canthal tendons are fixed at the zygomaticofrontal
sutures approximately 1 mm above the medial canthal tendon.
The rest of the eyelid structures are gently re-draped and the
skin is sutured in place (Figs. 19.37 & 19.38).
Immunosuppression and rejection
The concepts of transplant immunology are beyond the scope
of this chapter, but an understanding of the breadth of medi­
cations and their timely use is crucial. Immunosuppression
Fig. 19.37  Allograft inset – intraoral trimming of the allograft to conceal the
incisional scar. (Printed with permission from and copyright retained by Eduardo D.
Rodriguez, M.D., D.D.S.)

480
SECTION II
CHAPTER 19 • Facial transplant
are CD3+/CD4+ T-cells with occasional CD8+ cytotoxic
T-cells, FoxP3+ T-regulatory cells, and CD68+ histiomonocytic
cells of recipient origin. Rejection from the dermis will pro­
gress to the epidermis and then to the hypodermis if left
untreated.47 As the severity of rejection increases, epidermal
findings will include keratinocyte apoptosis, necrosis, and
vacuolization. Microscopically, nonspecific changes involve
mainly dermis and epidermis, and gradations of involvement
medications can be divided into three categories: induc­
tion therapy, maintenance therapy, and rejection therapy.
Typically, prior to transplantation, patients will receive
an induction immunosuppressive regimen just prior to
the transplantation in an attempt to blunt a lymphocytic
response immediately post transplantation. Induction medi­
cations include antithymocyte globulin, or an anti-IL-2R α
chain antibodies (daclizumab or basiliximab), or anti-CD52
(alemtuzumab), with or without varying combinations of
mycophenolate mofetil (MMF) and FK506 (tacrolimus) and
corticosteroids. Recently, anti-CD20 has been incorporated in
the induction therapy protocol.30
Following induction therapy and completion of the trans­
plant, patients will begin maintenance therapy consisting of
tri-therapy combining mycophenolate mofetil (MMF) and
FK506 (tacrolimus) and steroids. The degree of tapering and
minimization of medications is tempered by the concern for
patients developing an episode of acute rejection. Addition­
ally, the metabolic side effect profile of these medications has
led to acute and chronic kidney injury, diabetes mellitus, and
infection.53,54 This has prompted groups to utilize different
strategies to avoid corticosteroids, and deviate from incorpo­
rating FK506 and implementing less nephrotoxic agents such
as sirolimus or everolimus.53 Despite attempts of maintenance
therapy, nearly all face transplants have manifested a process
known as acute rejection.
The skin has long been considered the most antigenic tissue
relative to other tissues of the human body.55 It has become
well-established that the skin of the allograft is the main target
of early acute rejection.56–59 Acute rejection is recognized clini­
cally via physical examination as erythematous macules,
diffuse redness, or asymptomatic papules over the trans­
planted skin.56,59,60 Early in the recovery process, residual
inflammation and edema may persist and confound the
physical exam (Figs. 19.39 & 19.40). Routine skin biopsies can
guide the surgical team regarding suspicion for acute rejec­
tion. Early evidence of rejection is seen with perivascular
lymphocytic infiltrates in the dermis. The predominant cells
Fig. 19.38  Allograft inset – intraoral apposition of mucosa. (Printed with
permission from and copyright retained by Eduardo D. Rodriguez, M.D., D.D.S.)
Fig. 19.39  Post-transplant acute rejection. (Printed with permission from and
copyrights retained by Eduardo D. Rodriguez, M.D., D.D.S.)
Fig. 19.40  Quiescence of allograft edema and erythema following acute rejection
treatment. (Printed with permission from and copyrights retained by Eduardo D.
Rodriguez, M.D., D.D.S.)

481
Case
important to optimize outcomes. Although tissue regenera­
tive medicine has long been touted as the next great recon­
structive technology, there have not been many advances to
help patients with devastating facial injury. To support expan­
sion of future transplantation, the worldwide experience must
continue to report their outcomes so the reconstructive trans­
plant community learns with each experience.68 Just as solid
organ transplantation evolved over the last 50 years, facial
VCA is on a fast path to mimic a similar trajectory.
Case
A 41-year-old male retired firefighter underwent a suc­
cessful total face, eyelids, ears, scalp, and skeletal subunit
transplant. The recipient endured full-thickness disfiguring
thermal facial injury (Figs. 19.41–19.43) while in the line of
duty in 2001. The extent of injury involved cartilaginous
destruction of the bilateral ears and nose. The perioral soft
tissue was contractured resulting in labial incompetence
and sialorrhea. Periorbital involvement led to impairment
of the blink mechanism and ultimately visual deteriora­
tion. The scalp sustained full thickness burns and the neck
developed contractures. The extent of soft tissue facial and
scalp tissue involved in transplantation constitutes the most
extensive face transplant performed to date. Early follow-up
has demonstrated encouraging results both functionally and
aesthetically (Figs. 19.44–19.46). Reflexive and volitional blink
remains intact, the patient is able to speak, retains oral compe­
tence, has regained his sense of smell, and has improved neck
range of motion. The patient satisfaction with his outcome
and his dramatic improvement in quality of life has been
remarkable.30
can complicate pathologic interpretation.61 Based on histologic
findings, a consensus scoring system known as the Banff clas­
sification56 has been established to assess the severity of acute
rejection, but there are limitations to relying on this system
for treating acute rejection in the context of facial VCA. Some
groups have investigated the utility of mucosal biopsies61,62
and sentinel skin graft.63 Both approaches have not replaced
the gold standard of the allograft skin biopsy.
Once recognized, the treatment of acute rejection involves
pulse intravenous steroids, and will typically require an
increase in the dosing of a maintenance immunosuppression
regimen. Adjunct FK506 topical based therapy has also been
utilized for directed therapy to the skin. Most rejection within
the face transplant literature focuses on acute rejection, its
frequency, and implication of severity. However, as time has
progressed, newer entities of rejection have declared them­
selves including: antibody-mediated rejection and chronic
rejection. These entities remain enigmatic and challenging to
treat.64,65
Pediatric facial VCA
The expansion of facial VCA to pediatric facial transplantation
has been proposed by several groups and remains controver­
sial. The largest hesitation of performing facial VCA in children
pertains to the lifelong requirement of immunosuppressive
medication and the long-term adverse risks of developing
hypertension, dyslipidemia, cardiovascular disease, malig­
nancy, osteoporosis, renal failure, and other systemic effects.
It is well-established that children burdened with craniofacial
deformity involving facial burns, capillary vascular malfor­
mations, hemifacial microsomia, and neurofibromatosis have
impaired quality of life early in life and into adulthood.66
Although allotransplantation of non-vital organs is a contro­
versial issue in part due to synchronized skeletal growth of
the patient and the allograft and development impairment
associated with transplantation,67 the principle drawback
of pediatric face transplantation is noncompliance. The need
for independence, known rebellious phase, and state of
invulnerability is typical of adolescence and early adulthood,
predisposing patients to a very high noncompliance rate.
Non-adherence is reportedly as high as 22%, the major cause
being graft loss or rejection in adolescent transplant recipi­
ents.65,66 Currently, pediatric face transplantation is regarded
as extremely controversial and, at present, there are no centers
that have performed a pediatric face transplant. However,
the future is evolving and recent arguments in support of
pediatric face transplantation have been made,65 especially
in light of a recent bilateral hand transplant performed at the
University of Pennsylvania with a remarkable result.66
Future directions
Apart from drugs, research protocols are directed towards
tolerance induction. This has been studied largely in animal
models to develop chimerism or even microchimerism, but
this has yet to be successfully demonstrated in humans.
Development of new drugs and donor specific tolerance
through various protocols is only one barrier to the expansion
of facial VCA. Choice selection of future candidates is just as
Fig. 19.41  (Frontal) A preoperative photo of a patient with thermal injury including
total face and scalp burns that underwent face transplantation. (Printed with
permission from and copyright retained by Eduardo D. Rodriguez, M.D., D.D.S.)

482
SECTION II
CHAPTER 19 • Facial transplant
Fig. 19.42  (Profile) A preoperative photo of a patient with thermal injury including
total face and scalp burns. (Printed with permission from and copyright retained by
Eduardo D. Rodriguez, M.D., D.D.S.)
Fig. 19.43  (Posterior) A preoperative photo of a patient with thermal injury
including total face and scalp burns. (Printed with permission from and copyright
retained by Eduardo D. Rodriguez, M.D., D.D.S.)
Fig. 19.44  (Frontal) An early postoperative result of the patient following face
transplantation. (Printed with permission from and copyright retained by Eduardo D.
Rodriguez, M.D., D.D.S.)
Fig. 19.45  (Profile) An early postoperative result of the patient following face
transplantation. (Printed with permission from and copyright retained by Eduardo D.
Rodriguez, M.D., D.D.S.)

483
Case
Fig. 19.46  (Posterior) An early postoperative result of the patient following face transplantation. (Printed with permission from and copyright retained by Eduardo D.
Rodriguez, M.D., D.D.S.)
1. Sosin M, Rodriguez ED. The Face Transplantation Update: 2016.
Plast Reconstr Surg. 2016;137:1841–1850.
12. Devauchelle B, Badet L, Lengele B, et al. First human face allograft:
early report. Lancet. 2006;368:203–209.
15. Pomahac B, Diaz–Siso JR, Bueno EM. Evolution of indications for
facial transplantation. J Plast Reconstr Aesthet Surg.
2011;64:1410–1416.
19. Pomahac B, Pribaz J, Eriksson E, et al. Three patients with full facial
transplantation. N Engl J Med. 2012;366:715–722.
26. Starzl TE, Demetris AJ, Murase N, et al. Cell migration, chimerism,
and graft acceptance. Lancet. 1992;339:1579–1582.
29. Dorafshar AH, Bojovic B, Christy MR, et al. Total face, double jaw,
and tongue transplantation: an evolutionary concept. Plast Reconstr
Surg. 2013;131:241–251.
30. Sosin M, Ceradini DJ, Levine JP, et al. Total face, eyelids, ears, scalp,
and skeletal subunit transplant: a reconstructive solution for the full
face and total scalp burn. Plast Reconstr Surg. 2016;138:205–219.
32. Lantieri L, Grimbert P, Ortonne N, et al. Face transplant: long-term
follow-up and results of a prospective open study. Lancet.
2016;S0140–6736(16)31138–2.
35. Lantieri L, Hivelin M, Audard V, et al. Feasibility, reproducibility,
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2011;67:309–314.
24. Farné A, Roy AC, Giraux P, et al. Face or hand, not both: perceptual
correlates of reafferentation in a former amputee. Curr Biol.
2002;12:1342–1346.
25. Zhong R, He G, Sakai Y, et al. Combined small bowel and liver
transplantation in the rat: possible role of the liver in preventing
intestinal allograft rejection. Transplantation. 1991;52:550–552.
26. Starzl TE, Demetris AJ, Murase N, et al. Cell migration, chimerism,
and graft acceptance. Lancet. 1992;339:1579–1582.
27. Nasir S, Bozkurt M, Klimczak A, et al. Large antigenic skin load in
total abdominal wall transplants permits chimerism induction. Ann
Plast Surg. 2008;61:572–579.
28. Gordon CR, Zor F, Siemionow M. Skin area quantification in
preparation for concomitant upper extremity and face
transplantation: a cadaver study and literature review.
Transplantation. 2011;91:1050–1056.
29. Dorafshar AH, Bojovic B, Christy MR, et al. Total face, double jaw,
and tongue transplantation: an evolutionary concept. Plast Reconstr
Surg. 2013;131:241–251.
30. Sosin M, Ceradini DJ, Levine JP, et al. Total face, eyelids, ears, scalp,
and skeletal subunit transplant: a reconstructive solution for the full
face and total scalp burn. Plast Reconstr Surg. 2016;138:205–219.
31. Brazio PS, Barth RN, Bojovic B, et al. Algorithm for total face and
multiorgan procurement from a brain-dead donor. Am J Transplant.
2013;13:2743–2749.
32. Lantieri L, Grimbert P, Ortonne N, et al. Face transplant: long-term
follow-up and results of a prospective open study. Lancet.
2016;S0140–6736(16)31138–2.
33. Dubernard JM, Lengele B, Morelon E, et al. Outcomes 18 months
after the first human partial face transplantation. N Engl J Med.
2007;357:2451–2460.
34. Gordon CR, Siemionow M, Papay F, et al. The world’s experience
with facial transplantation: what have we learned thus far? Ann
Plast Surg. 2009;63:572–578.
35. Lantieri L, Hivelin M, Audard V, et al. Feasibility, reproducibility,
risks and benefits of face transplantation: a prospective study of
outcomes. Am J Transplant. 2011;11:367–378.
36. Lantieri L, Meningaud JP, Grimbert P, et al. Repair of the lower and
middle parts of the face by composite tissue allotransplantation in a
patient with massive plexiform neurofibroma: a 1-year follow-up
study. Lancet. 2008;372:639–645.
37. Siemionow M, Papay F, Alam D, et al. Near-total human face
transplantation for a severely disfigured patient in the USA. Lancet.
2009;374:203–209.
38. Singhal D, Pribaz JJ, Pomahac B. The Brigham and Women’s
Hospital face transplant program: a look back. Plast Reconstr Surg.
2012;129:81e–88e.
39. Coffman KL, Gordon C, Siemionow M. Psychological outcomes
with face transplantation: overview and case report. Curr Opin
Organ Transplant. 2010;15:236–240.
40. Brandacher G. Composite tissue transplantation. Methods Mol Biol.
2013;1034:103–115.
41. Ashvetiya T, Mundinger GS, Kukuruga D, et al. Donor-recipient
human leukocyte antigen matching practices in vascularized
composite tissue allotransplantation: a survey of major
transplantation centers. Plast Reconstr Surg. 2014;134:121–129.
42. Paramesh AS, Sullivan K, Heneghan J, et al. A direct comparison of
donor peripheral blood vs. lymph nodes as a source of
crossmatching material for kidney transplantation. Am J Transplant.
2012;12:337.
43. Gordon CR, Avery RK, Abouhassan W, Siemionow M.
Cytomegalovirus and other infectious issues related to face
transplantation: specific considerations, lessons learned, and future
recommendations. Plast Reconstr Surg. 2011;127:1515–1523.
44. Schneeberger S, Lucchina S, Lanzetta M, et al. Cytomegalovirus-
related complications in human hand transplantation.
Transplantation. 2005;80:441–447.
45. Erdbruegger U, Scheffner I, Mengel M, et al. Impact of CMV
infection on acute rejection and long-term renal allograft function: a
systematic analysis in patients with protocol biopsies and indicated
biopsies. Nephrol Dial Transplant. 2012;27:435–443.

483.e2
SECTION II
CHAPTER 19 • Facial transplant
46. Dzabic M, Rahbar A, Yaiw KC, et al. Intragraft cytomegalovirus
protein expression is associated with reduced renal allograft
survival. Clin Infect Dis. 2011;53:969–976.
47. Sosin M, Woodall J, Schultz B, et al. Evolving concepts of skin and
mucosal biopsy in facial vascularized composite allotransplantation.
Curr Transplant Rep. 2014;1:197–202.
48. BenMarzouk–Hidalgo OJ, Cordero E, Gomez–Cia T, et al. First face
composite-tissue transplant recipient successfully treated for
cytomegalovirus infection with preemptive valganciclovir
treatment. Antimicrob Agents Chemother. 2011;55:5949–5951.
49. Burra P, Rodriguez–Castro KI. Neoplastic disease after liver
transplantation: Focus on de novo neoplasms. World J Gastroenterol.
2015;21:8753–8768.
50. Morelon E, Testelin S, Petruzzo P, et al. Face transplantation with
combined hematopoietic stem cell infusion and vascularized bone
marrow: first year of follow-up. Transpl Int. 2011;24:75.
51. Petruzzo P, Kanitakis J, Testelin S, et al. Clinicopathological findings
of chronic rejection in a face grafted patient. Transplantation.
2015;99:2644–2650.
52. Mohan R, Borsuk DE, Dorafshar AH, et al. Aesthetic and functional
facial transplantation: a classification system and treatment
algorithm. Plast Reconstr Surg. 2014;133:286–297.
53. Diaz–Siso JR, Fischer S, Sisk GC, et al. Initial experience of dual
maintenance immunosuppression with steroid withdrawal in
vascular composite tissue allotransplantation. Am J Transplant.
2015;15:1421–1431.
54. Diaz–Siso JR, Parker M, Bueno EM, et al. Facial allotransplantation:
a 3-year follow-up report. J Plast Reconstr Aesthet Surg. 2013;66:
1458–1463.
55. Murray JE. Organ transplantation (skin, kidney, heart) and the
plastic surgeon. Plast Reconstr Surg. 1971;47:425–443.
56. Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic features of
graft rejection of the first human hand allograft. Transplantation.
2003;76:688–693.
57. Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff 2007
working classification of skin-containing composite tissue allograft
pathology. Am J Transplant. 2008;8:1396–1400.
58. Morelon E, Kanitakis J, Petruzzo P. Immunological issues in clinical
composite tissue allotransplantation: where do we stand today?
Transplantation. 2012;93:855–859.
59. Landin L, Cavadas PC, Nthumba P, Ibañez J, Vera-Sempere F.
Preliminary results of bilateral arm transplantation. Transplantation.
2009;88:749–751.
60. Schneeberger S, Kreczy A, Brandacher G, Steurer W, Margreiter R.
Steroid- and ATG-resistant rejection after double forearm
transplantation responds to Campath-1H. Am J Transplant.
2004;4:1372–1374.
61. Chaudhry A, Sosin M, Bojovic B, et al. Defining the role of skin and
mucosal biopsy in facial allotransplantation: a 2-year review and
analysis of histology. Plast Reconstr Surg. 2015;136:559–567.
62. Bergfeld W, Klimczak A, Stratton JS, Siemionow MZ. A four-year
pathology review of the near total face transplant. Am J Transplant.
2013;13:2750–2764.
63. Kueckelhaus M, Fischer S, Lian CG, et al. Utility of sentinel flaps in
assessing facial allograft rejection. Plast Reconstr Surg. 2014;135:
250–258.
64. Chandraker A, Arscott R, Murphy GF, et al. The management of
antibody-mediated rejection in the first presensitized recipient of a
full-face allotransplant. Am J Transplant. 2014;14:1446–1452.
65. Petruzzo P, Kanitakis J, Testelin S, et al. Clinicopathological findings
of chronic rejection in a face grafted patient. Transplantation.
2015;99:2644–2650.
66. Marchac A, Kuschner T, Paris J, et al. Ethical issues in pediatric face
transplantation: should we perform face transplantation in
children? Plast Reconstr Surg. 2016;138:449–454.
67. Bartlett SP, Chang B, Levin LS. Discussion: ethical issues in
pediatric face transplantation: should we perform face
transplantation in children? Plast Reconstr Surg. 2016;138:455–457.
68. Mardini S. Facial Transplantation – The Rochester, Minnesota Clinical
Experience & Lessons Learned. AONA State of the Art: Facial
Reconstruction and Transplantation. May 19, 2017. New York, NY.

SECTION I • Clefts
20 
Embryology of the craniofacial complex
Jingtao Li and Jill A. Helms
SYNOPSIS
■ Analysis of human craniofacial development opens the door to
understanding the basis for craniofacial dysmorphologies.
■ Establishment of the craniocaudal and mediolateral axes is essential
for proper craniofacial development.
■ Neural crest cells are a multipotent, migratory mesenchymal population
of cells that give rise to the majority of the facial skeleton.
■ Facial clefting is a multifactorial disorder. Single mutations in multiple
signaling pathways can result in facial clefting.
■ Neurocranium is comprised of a cartilaginous and a membranous
portion. Cartilaginous neurocranium is derived from embryonic
mesoderm, while the membranous neurocranium is derived from
cranial neural crest.
■ Cranial sutures remain patent during infancy through an intricate
balance between maintenance of undifferentiated cells and cells that
have differentiated into osteoblasts.
■ Derivatives of the five pharyngeal arches form parts of the human face
and the neck.
■ Three well known teratogens, retinoic acid, alcohol, and cyclopamine,
affect craniofacial development.
Introduction
We come into this world primed to connect with the faces
around us; it is literally hardwired into our neural circuitry.
There is a specialized region in our brain located in the tem­
poral lobe in the fusiform gyrus that is filled with neurons
that preferentially fire when the individual is looking at a
face.1 Within minutes of birth, babies are using this facial
recognition domain; studies demonstrate that even very
young infants show a strong preference for looking at faces
over all other objects.2 So in a brain that is ultimately respon­
sible for coordinating every single activity that will maintain
all body functions and ensure survival, there is allocated some
terribly precious real estate whose only apparent purpose is
to respond to faces. Not an object, not a tree or a rock or a
banana or anything else, just a face. This is not a hominid
specialization, either; other mammals including sheep have
similar facial recognition sites.3
Our ability to “read a face” is essential for human survival.
The face is the means by which we communicate with the
world and each other. “The welfare of mankind depends on
the expression and recognition of emotion”, wrote Charles
Darwin in The Expression of the Emotions in Man and Animals.4
Support for Darwin’s statement can be found when observing
any adult with an infant: of all the motor skills that infants
must master, none is as important as mimicking the facial
gestures of people around them. Even at a very early age,
humans devote a great deal of attention and energy to teach­
ing infants the movements required for facial expression. In
fact, we know that children who are incapable or uninterested
in learning this task are often later diagnosed with conditions
such as autism. This focus on the face ultimately translates
into our faces becoming central to our sense of identity. This
chapter is devoted to an explanation of how this remarkable
part of our anatomy comes about. We begin at the beginning,
just after fertilization of the egg by the sperm, when the head
is first distinguished from the tail; we continue throughout
the embryonic, and then into the fetal periods. The explosion
of genetic research provides a framework for understanding
how mutations create asymmetries and imbalances in the
proportions of the human face. This wealth of new data rep­
resents an important step towards understanding the molecu­
lar, cellular, and environmental causes of craniofacial birth
defects; our next challenge is to figure out how to use this
information to reduce, ameliorate, or possibly even prevent
these birth defects from happening.
The craniofacial complex
Ralph Waldo Emerson wrote, “A man finds room in the
few square inches of the face for the traits of all his ancestors;
for the expression of all his history, and his wants”5 and in
doing so he succinctly summarized the significance of the

487
Genesis of the cranial neural crest
Patterning the craniofacial complex
Whereas gastrulation creates the three germ layers – ectoderm,
mesoderm, and endoderm – it is neurulation that creates the
fourth germ layer, the neural crest. During neurulation the flat
neural plate is transformed into a neural tube (Fig. 20.1). This
transformation has an important impact of facial develop­
ment, because the medial domain of the neural plate becomes
the ventral surface of the neural tube, and lateral domains of
the neural plate constitute the dorsal surface of the neural tube
(Fig. 20.1). Some of the most important signaling pathways
that control craniofacial development are actually involved in
specifying the medial and lateral domains of the neural plate.
For example, the medial domain of the anterior neural plate
is patterned by signals in the Hedgehog (HH) family of
secreted proteins. Sonic Hedgehog (SHH) is expressed in this
midline domain around the time of neurulation and there its
primary function is to repress activity of the transcription
factor PAX6 (Fig. 20.1). PAX6 is a master transcriptional regu­
lator of eye development.7 SHH normally represses PAX6
function in this medial domain where the expression domains
of the two molecules overlap; as a consequence, a single
PAX6-expressing eye domain separated into two, bilaterally
symmetrical PAX6-positive eye fields.8 When SHH signaling
is lost or blocked, such as happens in congenital cases of
holoprosencephaly (HPE), PAX6 expression persists in the
medial domain. Consequently, the single, PAX6-positive eye
field is not sub-divided and the affected fetus exhibits cyclo­
pia9,10 (Fig. 20.1). Other midline structures are also affected in
HPE:11 the nose may be completely absent or fetuses may have
in place of the nose a tubular-shaped structure called a pro­
boscis. In less severe cases of HPE, the affected fetus’ eyes can
be set very closely. In milder forms of HPE, the affected
individual can exhibit hypotelorism12; in a microform of HPE,
patients may only exhibit a single central incisor. All of these
anomalies share a common feature: they represent a collapse
in the mediolateral growth of the craniofacial complex, which
can be attributable to disruptions in midline Hedgehog
signaling.13
SHH is involved in specifying the medial domain of the
neural plate; the lateral domains of the neural plate are speci­
fied by signals in the bone morphogenetic protein (BMP)
family. Like HH proteins, BMPs are secreted growth factors,
and a gradient of BMP signaling is instrumental in defining
which region of the neural plate will give rise to neuroecto­
derm (and thus form the brain) and which region will give
rise to non-neural ectoderm (and thus form epidermis). Just
as loss of SHH can lead to HPE, so too can elevated BMP
signaling; BMP signals are normally restrained to the lateral
borders of the neural plate, but in cases where their domains
are expanded they can interrupt medial SHH function.
Embryos affected in this manner exhibit narrowing of the
midfacial region and microform versions of HPE (Fig. 20.1).14
BMPs are also critically important dorsal signals that specify
the roof plate of the developing forebrain.15
Genesis of the cranial neural crest
During neurulation, a new population of neural crest cells
form the dorsal region of the folding neural tube, specifically
craniofacial complex. This region of our anatomy is how
others distinguish us, and it is how we see ourselves and,
therefore, has been the study of intense investigation for
hundreds of years.
The craniofacial complex is primarily derived from cranial
neural crest cells and mesodermal cells that interact though
elaborately choreographed movements to form composite
tissues including the skeleton, the musculature, the connec­
tive tissues, and the epithelial specializations unique to the
head region. Both passive cell displacement and active cell
migration are involved in gastrulation and neurulation, which
establish the head region and the stage for craniofacial devel­
opment. As one might suspect, disruptions that affect the
timing, rate, or extent of cell migration often result in cranio­
facial defects; these will be discussed in detail later in the
chapter.
The craniofacial complex also houses the organs respon­
sible for sight, taste, smell, and sound and, therefore, must
integrate these sensory inputs into the architecture of the head.
Like other tissues, the craniofacial complex develops
through a synchronized series of reciprocal tissue–tissue
interactions. In the head, however, these interactions occur
between neural and non-neural ectoderm; between ectoderm
and endoderm; and between ectoderm, endoderm, and meso­
derm. The molecular signals mediating these interactions
have, in large part, been identified and, accordingly, there is
a growing understanding of how perturbations in a particular
signaling pathway manifest as a given craniofacial malforma­
tion. Clearly, decades of research have provided us with an
understanding of the etiologies of many craniofacial deforma­
tions, which has surely the stage set for developing therapeutic
interventions to treat – or perhaps prevent – such anomalies
in the future.
Distinguishing head from tail
Lewis Wolpert famously described not birth, marriage, or
death, but gastrulation as the most important phase of one’s
life6 and it is during this period that the “head” and “tail”
orientation of an embryo is firmly established. Prior to gas­
trulation, a newly formed zygote must generate sufficient
numbers of cells to eventually form an entire embryo. To that
end, the zygote divides repeatedly to generate a solid,
mulberry-like cell mass known as a morula. It is at this stage
that the morula traverses the fallopian tube and enters the
uterus. With further cell division, the morula becomes a
blastocyst, which itself has two components. The first compo­
nent is the trophoblast, which contributes to the formation of
placental structures that support and nourish the developing
embryo; the second component is the embryoblast that dif­
ferentiates into the embryo itself.
Gastrulation begins in the third week of human life and it is
an event that is restricted to the embryoblast, and it begins
when an invagination that spans the length of the pancake-like
human embryo is visible. This invagination is called the primi­
tive streak and cells from the ectoderm stream into this invagi­
nation in a head (cranial) to tail (caudal) gradient. As they
migrate past the most caudal extent of the primitive streak, the
cells pass by an anatomical landmark called Hensen’s node. It
is in this moment that cells are exposed to chemical morpho­
gens that will influence their ultimate behavior.

488
SECTION I
CHAPTER 20 • Embryology of the craniofacial complex
Fig. 20.1  (A,B) Expression pattern of Sonic hedgehog (SHH, yellow), WNT (red) and BMP (green) signaling during the process of neurulation. (C) SHH expression
(yellow) in the medial neural plate with Pax-6 expression (orange) in the dumbbell-shaped area which corresponds to the feature eye field. (D) Subdivision of Pax6
expression into two bilateral domains through expression of SHH. (E) Wild-type chick embryo. (F) Chick embryo exhibiting cyclopia. (G) Wild-type mouse embryo at
embryonic day 15.5. (H) Mouse embryo exhibiting cyclopia with proboscis as a result of loss of SHH in the neural plate which has led to persistence of a single Pax6
anterior midline. e=eye.
A
B
SHH
C
D
E
F
G
H
from a region called the neural folds; this neural fold defines
the boundary between neural and non-neural ectoderm (Fig.
20.1). Neural crest cells are generated at this boundary region
when columnar ectodermal cells detach and transform into
elongated mesenchymal cells (Fig. 20.2). This process is
referred to as an epithelial-to-mesenchymal transition (EMT)
and is a unique feature of normal neural crest cells; it is also
a feature shared by metastatic cells.16 Neural crest and meta­
static cells share other features, for example, both being highly
invasive.17 As a consequence of this similarity, considerable
effort has gone into understanding the molecular regulation
of neural crest cell migration.18 For example, neural crest cell
migration is specified in part by the action of the transcription
factor Slug and after migration is complete, Slug expression
is typically shut off.19 Highly invasive cancer cells, however,
continue to express high levels of Slug and what is more,
cancer cells derived from Slug-expressing neural crest cells
are much more invasive than cancer cells derived from meso­
dermal cells.20 When Slug is inactivated, even in neural crest-
derived cancer, cells become non-metastatic.21 These studies
demonstrate important parallels between the molecular pro­
grams governing neural crest behavior and cancer cell behav­
ior, and underscore how understanding the development of
the craniofacial complex can have direct implications for
understanding processes such as cancer metastasis.
The generation of neural crest cells is also intimately
dependent upon the Wnt pathway of secreted proteins. Wnt
proteins are first expressed in the neural folds; if Wnt signal­
ing is experimentally blocked at this stage then neural crest
cells fail to be generated.22 Wnt signals in turn drive expres­
sion of a number of transcription factors including Slug
(mentioned previously) as well as Sox9 and FoxD3.23 Disrup­
tions to these neural crest transcription factors result in a
range of severe congenital defects. For example, Sox9 is
expressed in neural crest cells,24 and mutations in this tran­
scription factor are associated with campomelic dysplasia,25 a
condition where the appendicular skeleton exhibits bowing
and angulation defects; in addition, affected infants exhibit
macrocephaly, hydrocephalus, hypertelorism, a small or flat
nasal bridge, micrognathia, and cleft palate.26
Mutations in the neural crest inducer Sox1027 cause periph­
eral demyelinating neuropathy, central dysmyelination,
Waardenburg syndrome, and Hirshsprung disease (PCWH28).
Clinical features of this condition include neurosensory deaf­
ness and extensive peripheral neuropathies. Given the impor­
tant role of neural crest cells in the generation of glia,29 a
basis for this complex congenital syndrome can readily be
appreciated.
Exodus of the neural crest
Once specified, cranial neural crest cells must begin an exten­
sive migration from the dorsal neural tube into the ventrally

489
Differentiation of the cranial neural crest
substance. Neural crest cells make use of a surface organelle
called the primary cilium to sense these “directive substances”.
These primary cilia are required for the transduction of HH
signals,36 and their importance in regulating neural crest cell
behavior has been demonstrated through loss-of-function
analyses. For example, loss of component of the intraflagellar
transport system, which moves proteins up and down
the primary cilia, leads to perturbations in HH signaling
and craniofacial defects including frontonasal dysplasias.13,37
Several other factors essential for neural crest migration,
including SDF-1, PDGF-AA, and VEGFA, have their receptors
positioned on the primary cilia. For an excellent review of the
subject, see Chang et al.38
Differentiation of the cranial
neural crest
Once their migration into the pharyngeal arches is complete,
neural crest cells must expand, through the process of prolif­
eration, and then differentiate. Neural crest cells have been
referred to as stem cells because of the enormous diversity of
cell types into which they differentiate.39 In the head region,
neural crest cells give rise to neural, odontogenic, and skeleto­
genic tissues, as well as melanocytes, some intrinsic eye
muscles, pericytes that encase blood vessels in the head, and
positioned pharyngeal arches (Fig. 20.2). A disruption in this
migratory process underlies the classification of malforma­
tions known as neurocristopathies.
CHARGE syndrome is a well-recognized example of a
neurocristopathy, which manifests as ocular coloboma, heart
defects, choanal atresia, and ear abnormalities. Mutations in
the gene CHD7 are responsible for 70–90% of CHARGE syn­
drome cases.30 Loss of CHD7 leads to activation of p53, a
tumor suppressor gene,31 and an increase in the expression of
the p53 protein inhibits genes related to neural crest migra­
tion, including SNAIL2 and ETS1. As a consequence of dis­
rupted neural crest migration, craniofacial morphogenesis
and heart development are perturbed.32
Clearly, the control of neural crest migration is important
but how do neural crest cells know which pathway to take,
and their ultimate destination? New data now demonstrate
that migrating neural crest cells contain receptors on their cell
surfaces that specifically recognize guidance cues found on
adjacent epithelial cells. Relative to neural crest, the epithelial
(i.e., endodermal and ectodermal) cells are stationary and
therefore can provide directions to the neural crest as they
make their way to the pharyngeal arches.33 Guidance cues can
function as positive (attractive) and negative (repulsive)
signals, and chief among them are the Ephrins.34 These same
guidance cues also direct axons to their correct targets.35
Efficient neural crest migration is governed in part by
chemotaxis, i.e., the movement of a cell towards a directive
Fig. 20.2  Neural crest migration in mouse embryo. (A) Specification of neural crest cells at embryonic day 7.
(B) Neural crest cells begin to migrate at embryonic day 8. (C) Coronal section and (D) wholemount sample
showing the migrated neural crest cells at embryonic day 9. mes=mesencephalon; f=frontal prominence; 1=first
pharyngeal arch; 2=second pharyngeal arch.
A
B
C
D

490
SECTION I
CHAPTER 20 • Embryology of the craniofacial complex
neural crest cells.42 Epigenomic mapping of neural crest cells
has been used to identify the enhancer “signatures” in human
neural crest cells predicting which genes will be turned on
and off as cranial neural crest cells differentiate,43 and even
which enhancer signatures are thought to be responsible for
creating the features of a human (versus primate) face.44,45
These studies have provided some of the first clues into how
craniofacial variation in primates is established.46
Organization of the pharyngeal arches
The neural crest pharyngeal arches are the starting material
from which the face develops (Fig. 20.4). The pharyngeal
arches are separated by pharyngeal clefts, each of which gives
adipocytes (Fig. 20.3). In the trunk region, neural crest cells
give rise to sensory neurons and glia of the peripheral nervous
system, including the enteric nervous system.40
The factors controlling this range of cellular phenotypes
have been the focus of considerable investigation. What is
clear from new studies is that epigenetics plays an important
role in the process (reviewed in Hu et al.41). For example,
craniofacial cartilage, bone, and muscle are all derived from
a single population of neural crest cells; but, until recently, it
was not clear how a set of cells that share the same genetic
information could differentiate into such a variety of cell
types. Joanna Wysocka and colleagues have now demon­
strated that regulatory elements in the DNA called enhancers
are responsible for the activity of transcription factors, which
in turn regulate the transcriptome in a given population of
Fig. 20.3  Differentiation of the cranial neural
crest.
Zygote
Epiblast
Ectoderm
Surface epithelium
Neural crest
Bone
Cartilage
Sensory ganglia
Schwann cells
Odontoblasts
Sk. muscle
Pericytes
Connective tissues
Trunk
Cranial
Neuroectoderm
Mesoderm
Endoderm
Fig. 20.4  (A) Migration pattern of neural crest from rhombomeres to corresponding branchial arches. Rhombomeres are color-matched to branchial arches, indicating
which rhombomere the neural crest cells in a particular arch or facial prominence comes from. (B) Scanning electron image of pharyngeal arches. The arches are indicated
by different colors. (C) The outgrowth of the pharyngeal clefts and pouches (Roman numerals). The arches (1,2,3,4) are composed of a core of neural crest (purple) and
mesoderm (orange) surrounded by both surface ectoderm (blue) and pharyngeal endoderm (green).
A
Frontonasal
r6
Maxilla
Mandible
1
2
3
r5
r4
r3
r2
r1
Mes
B
C
1
2
3
Neural crest
4
IV
I
II
III

491
Organization of the pharyngeal arches
bilateral malformations that include microtia, microphthal­
mia, and mandibular hypoplasia that can compromise the
airway. In the vast majority of cases, the etiology of craniofa­
cial microsomia is unknown, but there are several risk factors
including maternal use of vasoactive drugs, diabetes mellitus,
and second trimester bleeding. The molecular basis for this
malformation sequence is still under debate but some data
suggest that it is due to insufficient cranial neural crest pro­
liferation, leading to smaller than normal arches. The root
cause of the inadequate proliferation may arise from ischemia,
secondary to a defect in the stapedial artery that provides the
initial blood supply to this region.47
Another class of malformations that are attributable to
abnormal development of the first and second pharyngeal
arches is a spectrum of etiologically heterogeneous craniofa­
cial anomalies referred to as mandibulofacial dysostoses.
Mandibulofacial dysostosis are similar to craniofacial micro­
somia in that both are characterized by malar and mandibular
hypoplasia; the distinguishing feature, however, is that in
mandibulofacial dysostosis the manifestations of the syn­
drome are symmetrical.26 One well-studied mandibulofacial
dysostosis is Treacher–Collins syndrome, an autosomal domi­
nant genetic disorder characterized by bilateral deficiencies in
pharyngeal arch-derived structures that includes mandibular
and malar hypoplasia, microtia, and macrostomia. The genetic
basis for Treacher–Collins syndrome is due to perturbations
in the expression of nucleolar phosphoprotein, Treacle.48
Autosomal dominant mutations in the TCOF1 gene that
encodes Treacle interrupt neural crest cell formation and
proliferation, leading to hypoplastic features of Treacher–
Collins patients.48
Another example of mandibulofacial dysostosis is 22q11.2
deletion syndrome, also known as DiGeorge syndrome, which
is characterized by cleft palate, cardiovascular anomalies, and
agenesis or hypogenesis of the derivatives of the third and
fourth pharyngeal clefts (i.e., the thymus and parathyroid
glands). The 22q11.2 deletion syndrome is caused by haplo­
insufficiency of the TBX1 gene.49 TBX1 encodes a transcription
factor that regulates the expression of as-yet-unknown genes
rise to a variety of structures. Pharyngeal cleft 1 gives rise to
the auditory tube and middle ear, and part of the tympanic
membrane. Cleft 2 contributes to part of the middle ear and
the palatine tonsil, and cleft 3 gives rise to the inferior para­
thyroid glands and cells in the thymus. The fourth cleft con­
tributes to the superior parathyroid glands and to the thymus,
and along with cleft 6 contributes to the musculature and
cartilage of the larynx (Fig. 20.4). The pharyngeal arches form
in an anterior-to-posterior gradient: the first arch appears on
day 22; the second and third arches appear sequentially on
day 24; and the fourth through sixth arches appear sequen­
tially on day 29. A summary of the derivatives of each arch
and cleft is available in Table 20.1.
The face is predominantly derived from the first pharyngeal
arch. As neural crest cells within the arch proliferate, the
arch expands in an anterior (cranial) to posterior (caudal)
fashion. The cranial swelling gives rise to the maxillary promi­
nence, which will form the upper jaw and the caudal swelling
gives rise to the mandibular prominence, which will form
the lower jaw. As the upper and lower jaws develop, the
second pharyngeal arch (also known as the hyoid arch) serves
as a bracing element to support them. The third pharyngeal
arch forms the lower rim of the hyoid bone as well as the
root of the tongue, epiglottis, and thyroid and inferior para­
thyroid. The fourth and sixth arches together give rise to
the larynx.
Disorders of arch development
Underdevelopment of the first and second pharyngeal arches
lie at the foundation of one of the most common groups of
facial malformations, which are collectively referred to as
craniofacial microsomia. Clinical manifestations of craniofa­
cial microsomia include asymmetries due to hypoplasia of the
external and middle ear, the mandible, zygoma, maxilla,
temporal bone, facial muscles, muscles of mastication, palatal
muscles, tongue, and parotid gland.47 The severity of the
craniofacial macrosomia sequence can range from subtle
facial asymmetries with small preauricular skin tags to severe,
Table 20.1  Derivatives of the pharyngeal arches
Arch
Skeletal element
Musculature
Nerve
Artery
1st (mandibular
and maxillary)
Incus, malleus, zygomatic,
squamous. Part of the
temporal, mandible and maxilla
Muscles of mastication
Trigeminal
Maxillary artery
2nd (hyoid)
Stapes, styloid process of
temporal bone, stylohyoid
ligament. Lesser horn and
body of hyoid bone
Muscles of facial
expression
Facial
Stapedial artery
3rd
Greater horns and lower body of
hyoid
Muscles of the
stylopharyngeus (throat)
Glossopharyngeal
Common carotid/internal
carotid
4th and 6th
Cartilages of the larynx
Muscles of pharynx
constriction, muscles of
phonation,
palatoglossus (tongue),
muscles of upper
esophagus
Vagus
Arch of aorta, right
subclavian artery,
original sprouts of
pulmonary artery,
ductus arteriosus, roots
of pulmonary arteries
Modified from Moody SA (ed). Principles of Developmental Genetics. Burlington, MA: Academic Press; 2007, Ch. 30, Table 1).

492
SECTION I
CHAPTER 20 • Embryology of the craniofacial complex
phenotypic differences, the faces of human and mouse
embryos share a very similar blueprint at the phylotypic stage
of development (Fig. 20.5). Through selective cell prolifera­
tion, where one facial prominence expands relative to another
in a species-specific manner,55–57 the final phenotype of each
face is established.
As expected based on its moniker, the unpaired, midline
frontonasal (median nasal) prominence develops in the
midline of the embryo, and is characterized by a deep furrow
called the infranasal depression (Fig. 20.5). Structures derived
from the frontonasal prominence include the forehead, the
middle of the nose, the philtrum, septum, middle portion of
the upper lip, and primary palate (Fig. 20.5). Together, the
frontonasal-derived primary palate and nasal septum fuse
with the bilateral palatal shelves (derived from the maxillary
prominences, see below) to create the anterior portion of the
roof of the mouth.
During early craniofacial development, the lateral nasal
prominences are nearly equal in size to the frontonasal
prominence in both humans and mice (Fig. 20.5) but with
time, cell proliferation in the lateral nasal prominences is
significantly reduced compared to that in the frontonasal
prominence; as a consequence, the resulting structures to
which they give rise (i.e., the alae of the nose) are consider­
ably smaller (Fig. 20.5).
that are involved in controlling neural crest migration.50 TBX1
is not required in neural crest cells per se; rather, using a mouse
model of DiGeorge syndrome,51 scientists demonstrated that
aberrant neural crest cell migration was caused because
of a lack of guidance cues provided by pharyngeal pouch
endoderm.52 These analyses clearly demonstrate that neural
crest migration is intimately dependent on cues from the sur­
rounding ectoderm and endoderm,53 and that deficiencies in
neural crest cells – caused by disrupted migration, inadequate
proliferation, or excessive cell death – underlie many of the
craniofacial syndromes characterized by underdeveloped
structures.54
Building the face
The basic morphology of the face is established between the
fourth and 10th weeks of human development, and between
embryonic days 10–15 of murine development (Fig. 20.5). In
both mammals, the face is formed as a result of fusion of the
midline frontonasal prominence, and three paired promi­
nences, the maxillary, lateral nasal, and mandibular promi­
nences. Each of these prominences is filled with cranial neural
crest cells. Each of the prominences, and the structures that
arise from them, are discussed below. Despite their obvious
Fig. 20.5  Prominences of the vertebrate face
(A–D). Frontonasal prominence (purple)
contributes to the forehead, middle of the nose,
philtrum, and primary palate; maxillary prominence
(blue) contributes to the sides of the face and lip
and the secondary palate; lateral nasal prominence
(yellow) forms the sides of the nose; and the
mandibular prominence (red) produces the lower
jaw.
A
B
C
D

493
Palatogenesis
interferon regulatory factor IRF6 result in inappropriate adhe­
sions between the palatal shelves and the tongue, resulting in
palatal clefting phenotypes in mice and humans.59 Therefore,
disruptions in extent of growth of each facial prominence or
the process of fusion can result in facial clefting.
Clefts can be categorized in a number of ways; here we
present an embryologic point of view of the etiology of facial
clefting. When the frontonasal and maxillary prominences fail
to fuse, the result is cleft lip (Fig. 20.6). When the lateral nasal
and maxillary prominences fail to fuse, the result is an oblique
facial cleft (Fig. 20.6). When the frontonasal and lateral nasal
prominences fail to fuse the result is an alar cleft (Fig. 20.6).
The maxillary and mandibular prominences must fuse and,
in the absence of this event, the result is a transverse facial
cleft (Fig. 20.6). Other facial clefts can arise (e.g., median
upper lip cleft, median lower lip cleft) but these are
rarer events.
Palatogenesis
The secondary palate separates the nasal passage from the
mouth. In a stepwise manner, the palatal shelves extend verti­
cally on either side of the tongue then subsequently rotate to
a horizontal plane dorsal to the tongue, and fuse (Fig. 20.7).
Initially, the palatal shelves are lined by an epithelium (the
medial edge epithelium, MEE); as the shelves grow towards
the midline, the MEE of each shelf approximates and forms
the midline epithelial seam (MES). The MES is then removed
through the process of mesenchymal to epithelial transition
(MET, the opposite of EMT), which leads to a confluence
between the mesenchyme of the palatal shelves. Perturbations
caused by genetic, mechanical, or teratogenic factors can
occur at any of these steps, and frequently result in a cleft of
The maxillary prominences are initially equal in size to the
lateral nasal prominences (Fig. 20.5) but exuberant neural
crest proliferation ultimately results in the maxillary promi­
nences contributing to the upper cheek, the lateral upper lip,
maxilla, and the secondary palate (Fig. 20.5). The mandibular
prominence grows as a single unit from the first pharyngeal
arch with a separating notch in the center (Fig. 20.5). The
notch between bilateral mandibular prominences is obliter­
ated through mesenchyme proliferation and ectoderm migra­
tion, and the prominences eventually merge, rather than fuse,
with each other. Ultimately, the mandibular prominence
forms the lower cheek, the lower lip, the lower jaw including
the floor of the mouth and the submental area, as well as part
of the middle ear, and the anterior two-thirds of the tongue
(Fig. 20.5). Thus, in mammals, the blueprint of the face is
conserved, and selective neural crest cell proliferation leads
to species–specific variations in facial form.
Facial fusions and clefting defects
Cell proliferation results in growth of the facial prominences
and brings them into proximity to one another; the next criti­
cal step is to create a seamless unification of the prominences.
This process is achieved in two integrated steps: adhesion and
fusion. As they touch, the ectoderm enveloping each promi­
nence must “get out of the way” in order to create a unified
facial structure. One mechanism by which ectodermal cells
appear to be removed is through regional programmed cell
death that results in superficial layers of the ectoderm/
epithelium “peeling off” and leaving only a basal epithelial
layer intact.58 When the facial prominences fuse, cell connec­
tions are reinforced and stabilized by the formation of adhe­
sion junctions, such as desmosomes.58 Mutations in the
Fig. 20.6  Facial clefts associated with interrupted fusion between facial prominences. (A, A’) Cleft lip; (B, B’) oblique facial cleft; (C, C’) alar cleft; (D, D’) transverse
facial cleft.
A
A’
B
B’
C
C’
D
D’

494
SECTION I
CHAPTER 20 • Embryology of the craniofacial complex
between the frontal bones; the sagittal suture interposed
between the parietal bones; the coronal suture that separates
the frontal and parietal bones; and the lambdoid suture
that is positioned between the parietal and occipital bones
(Fig. 20.8).
Sutures remain patent (open) into postnatal life. The expan­
sion of the brain, which continues well into young adulthood,
stimulates the continued growth of the cranial vault bones.
The bones expand in size by adding new bone at their edges;
while this osteogenic differentiation is taking place, a subset of
cells between the cranial vault bone edges must be maintained
in a fibrous state in order to keep the sutures patent. This leads
to an interesting situation: cells in the middle of the suture
complex must remain undifferentiated while adjacent cells
differentiate into osteoblasts and add to the growing calvarial
bones. How these states of proliferation and differentiation are
so precisely synchronized is still unknown, but it is clear that
secondary palate. Another type of secondary palatal clefting
is palatal insufficiency, which is often caused by inadequate
outgrowth of the maxillary prominences.
The neurocranial base
The neurocranium comprises the bones that protect the brain.
The ventral portion of the neurocranium is called the basicra­
nium and includes the sphenoid and ethmoid bones, the
mastoid and petrous portions of the temporal bone, and the
base of the occipital bone. Using experimental manipulations60
and genetic fate-mapping approaches in mice61 the embryonic
origins of the bones of the basicranium have been established
as arising from mesodermal cells that originate as part of the
occipital somites and somitomeres. Skeletal elements that
comprise the basicranium form through endochondral ossifi­
cation, where a cartilaginous template or anlage is first
established and then is gradually replaced with a bony matrix
through the process of vascular invasion.
Cranial vault and sutures
The cranial vault is comprised of seven neural crest-derived60
bones: the paired frontal, squamosal, and parietal bones, and
the occipital bone. The majority of the cranial vault forms
through the process of intramembranous ossification, where
mesenchymal cells condense and directly differentiate into
osteoblasts without forming a cartilaginous intermediate. The
occipital bone is a composite structure where the inferior
portion forms via endochondral ossification and the superior
portion forms via intramembranous ossification.
The bones of the cranial vault are separated by fibrous
tissue called sutures, which include the frontal sutures lying
PS
T
A
PS
T
B
PS
T
C
Fig. 20.7  (A–F) Schematic diagram and coronal sections through a developing murine face demonstrating development of secondary palate. PS=palatal shelf (blue);
T=tongue (red).
D
E
F
Fig. 20.8  Cranial sutures.
Frontal
Lambdoid
Coronal
Fontanelle
Sagittal
P
F
O

495
Conclusions
mysteries than in cases where she shows tracings of her work­
ings apart from the beaten paths; nor is there any better way
to advance the proper practice of medicine than to give our
minds to the discovery of the usual law of nature, by careful
investigation of cases of rarer forms of disease”. Over hun­
dreds of years, physicians have followed this guidance
and carefully cataloged craniofacial anomalies in their
patients. Other than careful scrutiny of the phenotypes,
however, there was little additional help that physicians
and scientists could provide to affected patients and their
families.
The World Wars brought about horrific injuries, which
forced surgeons to make dramatic improvements in surgery
and patient care. These techniques and tools resulted in new
ways to save lives, which also had a profound influence on
the care of patients with craniofacial deformities. Some of
these techniques (i.e., free flaps, distraction osteogenesis,
tissue expansion) found direct application in the surgical
repair of congenital defects.
In 1966, another leap forward came with the work of
Victor McKusick, an internist and medical geneticist who
published that year the first catalog of all known genes and
genetic disorders. This critically important knowledgebase,
Mendelian Inheritance in Man (MIM), was made avail­
able online in 1987 as Online Mendelian Inheritance in Man
(OMIM) and is still updated daily. It remains the world’s
largest repository for genetic information on craniofacial
disorders, and as our understanding of the role of genet­
ics in many craniofacial anomalies improves, so too has the
ability to detect and discriminate among apparently similar
patient phenotypes. The last few decades have led to a
deep understanding of the molecular and cellular basis for
craniofacial conditions and, with it, a burgeoning concept
that some of these anomalies may be treatable by genetic
or cellular interventions. Coupling this information with
continued surgical innovation will undoubtedly lay the
groundwork for better management of the defects created
by nature.
destabilization of this balance is the basis for both craniosyn­
ostoses and cranium bifidum occultum (Fig. 20.9).
In pathological conditions such as cleidocranial dysplasia62
or frontonasal dysplasias13 the skull bones fail to grow ade­
quately. In these situations, the result is fibrous tissue covering
the cerebral hemispheres without the benefit of ossification,
clinically referred to as cranium bifidum occultum (Fig. 20.9).
Craniosynostoses, on the other hand, arise when cells in the
suture region prematurely differentiate into osteoblasts and
inadvertently fuse the cranial bones to one another. Cranio­
synostoses can be either inherited or isolated.63 Isolated,
non-syndromic craniosynostoses have a frustratingly obscure
etiology, but more is known about the molecular basis for the
craniosynostotic phenotypes that arise as a result of an inher­
ited mutation.
Patients with Saethre–Chotzen syndrome have mutations
in the transcription factor Twist.64 A mouse model of the
Saethre–Chotzen syndrome has been generated; and, based
on analyses of this animal, the premature suture fusion is a
result of inappropriate intermixing of neural crest-derived
cells in the frontal bone with mesoderm-derived cells in the
parietal bone.65 Humans with the same mutations exhibit
nearly identical skeletal defects,66 which suggests that inter­
ventions to prevent this suture fusion phenotype may be
tested on an appropriate animal model.
Mutations in the Wnt target gene, Axin2, are also associated
with a craniosynostotic phenotype67 and, in this case, in vitro
data indicate that cells in which Wnt signaling is amplified
have a tendency to differentiate prematurely into osteoblasts.67
Axin2 mutant mice have shorter snouts and premature fusion
of the metopic suture, data that argue for a tight balance on the
level of Wnt signaling for proper growth of the calvarial bones.
Conclusions
In 1657, the physician William Harvey wrote, “Nature is
nowhere accustomed more openly to display her secret
Fig. 20.9  Proliferation–differentiation balance at suture sites.
Proliferation
Proliferation
Proliferation < bone formation
Proliferation > bone formation
Differentiation
Differentiation
Differentiation
Craniosynostosis
Cranium bifidum occultum
Differentiation
Differentiation
Differentiation

496
SECTION I
CHAPTER 20 • Embryology of the craniofacial complex
9. Chiang C, Litingtung Y, Lee E, et al. Cyclopia and defective axial
patterning in mice lacking Sonic hedgehog gene function. Nature.
1996;383:407–413. Using targeted gene disruption model, this study
verified the critical role of Sonic hedgehog signaling in the patterning of
midline structures.
13. Brugmann SA, Allen NC, James AW, et al. A primary cilia-
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2010;19:1577–1592. This study demonstrated direct correlation between
Hedgehog signaling and the medial-lateral patterning and development,
especially in the craniofacial region. Over- and under-expression of Sonic
hedgehog signaling would respectively lead to hypertelorism and
hypotelorism.
17. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the
crossroads of development and tumor metastasis. Dev Cell.
2008;14:818–829. The epithelial-mesenchymal transition is a highly
conserved cellular program that allows polarized, immotile epithelial cells
to convert to motile mesenchymal cells. This review summarized major
signaling pathways that regulate the epithelial-mesenchymal transitions
during both development and tumor metastasis, which furthered our
molecular understanding of cell migration and morphogenesis.
22. Garcia–Castro MI, Marcelle C, Bronner–Fraser M. Ectodermal
wnt function as a neural crest inducer. Science. 2002;13:
13. Neural crest cells, which generate peripheral nervous system and facial
skeleton, arise at the neural plate/ectodermal border via an inductive
interaction between these tissues. Along with recognized role of Wnts and
BMPs in neural crest induction in amphibians and zebrafish, this study
showed that Wnt molecules are necessary and sufficient to induce neural
crest cells in avian embryos.
37. Brugmann SA, Cordero DR, Helms JA. Craniofacial ciliopathies: A
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2010;152A:2995–3006. This study examined a group of craniofacial
disorders that are the result of defects in primary cilia. Based on the
frequent appearance of craniofacial phenotypes in diseases born from
defective primary cilia, it proposed a new class of craniofacial disorders
referred to as craniofacial ciliopathies.
40. Couly GF, Coltey PM, Le Douarin NM. The triple origin of skull in
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1993;117:409–429. This study used the quail-chick chimera technique to
study the origin of the bones of the skull in the avian embryo. The data
obtained allow us to assign a precise embryonic origin from either the
mesectoderm, the paraxial cephalic mesoderm or the five first somites, to
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45. Prescott SL, Srinivasan R, Marchetto MC, et al. Enhancer divergence
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meninges, whereas ossification of the neural crest-derived frontal bone is
autonomous. These observations provided new perspectives on skull
evolution and on human genetic abnormalities of skull growth and
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33. Poliakov A, Cotrina M, Wilkinson DG. Diverse roles of eph
receptors and ephrins in the regulation of cell migration and tissue
assembly. Dev Cell. 2004;7:465–480.
34. Santiago A, Erickson CA. Ephrin-B ligands play a dual role in the
control of neural crest cell migration. Development. 2002;129:
3621–3632.
35. Wilkinson DG. Multiple roles of EPH receptors and ephrins in
neural development. Nat Rev Neurosci. 2001;2:155–164.
36. Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates hedgehog
signaling at the primary cilium. Science. 2007;317:372–376.
37. Brugmann SA, Cordero DR, Helms JA. Craniofacial ciliopathies: A
new classification for craniofacial disorders. Am J Med Genet A.
2010;152A:2995–3006. This study examined a group of craniofacial
disorders that are the result of defects in primary cilia. Based on the
frequent appearance of craniofacial phenotypes in diseases born from
defective primary cilia, it proposed a new class of craniofacial disorders
referred to as craniofacial ciliopathies.
38. Chang CF, Schock EN, Attia AC, Stottmann RW, Brugmann SA. The
ciliary baton: orchestrating neural crest cell development. Curr Top
Dev Biol. 2015;111:97–134.
39. Le Douarin NM, Creuzet S, Couly G, Dupin E. Neural crest cell
plasticity and its limits. Development. 2004;131:4637–4650.
40. Couly GF, Coltey PM, Le Douarin NM. The triple origin of skull in
higher vertebrates: a study in quail-chick chimeras. Development.
1993;117:409–429. This study used the quail-chick chimera technique to
study the origin of the bones of the skull in the avian embryo. The data
obtained allow us to assign a precise embryonic origin from either the
mesectoderm, the paraxial cephalic mesoderm or the five first somites, to
all the bones forming the avian skull.

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CHAPTER 20 • Embryology of the craniofacial complex
41. Hu N, Strobl–Mazzulla PH, Bronner ME. Epigenetic regulation in
neural crest development. Dev Biol. 2014;396:159–168.
42. Bajpai R, Chen DA, Rada–Iglesias A, et al. CHD7 cooperates with
PBAF to control multipotent neural crest formation. Nature.
2010;463:958–962.
43. Rada–Iglesias A, Bajpai R, Swigut T, et al. A unique chromatin
signature uncovers early developmental enhancers in humans.
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44. Rada–Iglesias A, Bajpai R, Prescott S, et al. Epigenomic annotation
of enhancers predicts transcriptional regulators of human neural
crest. Cell Stem Cell. 2012;11:633–648.
45. Prescott SL, Srinivasan R, Marchetto MC, et al. Enhancer divergence
and cis-regulatory evolution in the human and chimp neural crest.
Cell. 2015;163(1):68–83. This study used epigenomic profiling from
human and chimpanzee cranial neural crest cells to systematically and
quantitatively annotate divergence of craniofacial cis-regulatory
landscapes.
46. Rada–Iglesias A, Prescott SL, Wysocka J. Human genetic variation
within neural crest enhancers: molecular and phenotypic
implications. Philos Trans R Soc Lond B Biol Sci. 2013;368:20120360.
47. Heike CL, Luquetti DV, Hing AV. Craniofacial microsomia
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48. Dixon J, Jones NC, Sandell LL, et al. Tcof1/Treacle is required for
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49. Chieffo C, Garvey N, Gong W, et al. Isolation and characterization
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54. Hartsfield JK. Review of the etiologic heterogeneity of the oculo-
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55. Helms JA, Brugmann SA. The origins of species-specific facial
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insights into the molecular and cellular basis for craniofacial variation.
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species–specific facial pattern. Curr Top Dev Biol. 2006;73:1–42.
57. Tucker AS, Lumsden A. Neural crest cells provide species–specific
patterning information in the developing branchial skeleton. Evol
Dev. 2004;6:32–40.
58. Jiang R, Bush JO, Lidral AC. Development of the upper lip:
morphogenetic and molecular mechanisms. Dev Dyn. 2006;235:
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59. Richardson RJ, Dixon J, Jiang R, Dixon MJ. Integration of IRF6 and
Jagged2 signalling is essential for controlling palatal adhesion and
fusion competence. Hum Mol Genet. 2009;18:2632–2642.
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embryo. Development. 1988;103(suppl):101–113.
61. Jiang X, Iseki S, Maxson RE, Sucov HM, Morriss–Kay GM. Tissue
origins and interactions in the mammalian skull vault. Dev Biol.
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62. Mundlos S. Cleidocranial dysplasia: clinical and molecular genetics.
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SECTION I • Clefts
21.1 
Overview of the unilateral cleft lip and
nose deformity
Michael R. Bykowski and Joseph E. Losee
SYNOPSIS
■ A multidisciplinary team approach, including the craniofacial surgeon,
orthodontist, speech pathologist, otolaryngologist, social worker, and
psychologist.
■ Essential that this team builds a focused collaboration around the
patient from infancy to adulthood to achieve self-confidence, social
integration, and optimal functionality.
■ Cleft care can begin prior to the child being born when the cleft is
diagnosed prenatally.
■ Further treatment of the cleft can start before any surgical intervention
with different types of pre-surgical interventions.
■ The patient will undergo several stages of treatment through
adolescence to achieve excellent facial aesthetics, normal dental
occlusion, and normal speech.
■ These are the goals that are introduced in this chapter and are
expanded upon in the subsequent chapters by cleft surgeons who
seek to join the others who have previously pushed cleft care to its
modern limits.
Introduction
The repair of a bilateral cleft lip has been described as the
“most important day in the child’s life”,1 which is a sentiment
that extends to a unilateral cleft lip repair. The repair is a gift
to the infant, their family, and the surgeon. While the ancient
ignorance based on religion and superstition regarding the
etiology of this congenital deformity no longer exists, the
social stigma does. It has been the life work of many cleft
surgeons to identify deficiencies in treatment and, further, to
push the leading edges of new cleft lip treatment. Indeed, it
is the responsibility of current and future cleft surgeons to
persist and persevere to achieve excellent facial aesthetics,
normal dental occlusion, and normal speech. These are the
goals that are introduced in this chapter and are expanded
upon in the subsequent chapters by cleft surgeons who seek
to join the others who have previously pushed cleft care to its
modern limits.
Access the Historical Perspective section online at

Embryology
While the details of facial development are dynamic and
extremely complex, a general understanding is critical to the
craniofacial surgeon. In the first week following fertilization
of the ovum, the zygote divides repeatedly into a mulberry-
like cell mass known as the “morula”. While the morula
migrates through the fallopian tube and enters into the uterus
it continues to divide into a blastocyst – which is composed
of an inner and outer layer. The outer layer is the trophoblast,
which contributes to the placental structures. The inner layer
is the embryoblast, which develops into the embryo. During
the second week of development the blastocyst implants into
the uterine endometrium.
In the third week of human development, the embryoblast
divides into three layers through a process called “gastrula­
tion”, which leads to the three primary germ layers: ectoderm,
mesoderm, and endoderm. Due to its major role in develop­
ment, some refer to the neural crest as the “fourth germ layer”.
The neural crest is especially important in craniofacial devel­
opment and gives rise to the much of the neural, odontogenic,
and skeletogenic tissues of the craniofacial region.
The orofacial region can be identified in the fourth week
post-conception. At this point, an area of the trilaminar germ
disk (typically consisting of the ecto-, meso-, and endoderm)
lacks mesoderm, forming a bilaminar oropharyngeal mem­
brane. The cavity adjacent to the oropharyngeal membrane
marks the stomodeum (the primitive mouth), around which
five facial prominences swell during the fourth week of
embryogenesis. The stomodeum is bordered rostrally by the

497.e1
Historical perspective
Historical perspective
One of the oldest representations of a cleft lip dates to a
~3000-year-old “huaco” – a Peruvian piece of pottery linked
to burial sites, temples, or other ancient ruins.2 Not until the
Chin Dynasty (229–317 AD) in China, however, was the first
recorded surgical repair of a cleft lip.3 A story from this time
based on an 18-year-old Chinese man is recounted: “This
young man overcame his handicap and became Governor General
of six Chinese provinces”. Thereafter, the descriptions of surgi­
cal repair of cleft lip did not exist until approximately 950
AD, likely due to inadequate anesthesia, technical skill, and
inability to control bleeding. In 950 AD in a book entitled
The Leech Book of Bald, the first description of surgical cleft
lip was documented.4 The first illustration representing
unilateral cleft lip repair appears to be from the French surgeon
Ambroise Paré who coined the term “bec-de-lieure” or “lip of
the hare”.
In the nineteenth century, surgeons became more sophisti­
cated and advanced from simple straight-line lip repair to
reconstructing the subunits of the lip – specifically, the phil­
trum. Not until the latter half of the nineteenth century was
the nasal deformity addressed when M. H. Collins of Dublin
began to reconstruct the displaced alar base.5 In the early
twentieth century, Victor Veau – well-known today for wide-
spread use of the Veau Classification of cleft lip and palate –
began to address the clefted orbicularis oris muscle, known
as suture musculaire. Thankfully, surgeons persisted in their
ingenuity to advance the field of cleft lip repair – namely,
Charles Tennison, D. Ralph Millard, Peter Randall and Ross
H. Musgrave (to provide an incomplete list).

498
SECTION I
CHAPTER 21.1 • Overview of the unilateral cleft lip and nose deformity
rise to the upper jaw and the sides of the face, the sides of the
upper lip, and the secondary palate.
Formation of the secondary palate commences around 7–8
weeks and completes around the third month of gestation.
Three outgrowths appear in the oral cavity. The nasal septum
grows downward from the frontonasal process along the
midline. Two palatine shelves, one from each side, extend
from the maxillary processes toward the midline. At first, the
shelves are directed downward along each side of the tongue.
After the seventh week, the head of the embryo tilts back and
the tongue is withdrawn from between the shelves. The
shelves then elevate and fuse with each other above the
tongue and anteriorly with the primary palate. The septum
and the two shelves converge, fuse along the midline, and
hence separate the primary oro-nasal cavity into the nasal and
oral cavities.
The closure of the secondary palate proceeds gradually
from the primary palate in a posterior direction. The extent of
clefting found in a child reflects the time when closure of the
secondary palate was affected. Full clefting results from
interference at the start of closure and partial clefting later as
the process proceeds posteriorly.
As discussed above, clefts of the lip and the anterior maxilla
are a result of defective development of the embryonic
primary palate. Often when such clefts occur, the distortion
of the facial development prevents the palatine shelves from
making contact when they swing into the horizontal position.
Thus, clefts of the primary palate are often accompanied by
clefts of the secondary palate, both hard and soft.
Epidemiology
The genetics of cleft lip with or without a cleft palate, or an
isolated cleft palate, are complicated and do not follow a
Mendelian inheritance pattern. The etiology of cleft lip and
palate is thought to be multifactorial involving genetic and
environmental factors. This consensus is supported by the
concordance rate of 30–60% among monozygotic twins com­
pared to 1–5% among dizygotic twins. Families with “cleft lip
with or without palate” and “cleft palate only” are at a higher
risk of having another child with the deformity when com­
pared to the general population. Table 21.1.1 lists the increased
risk for having the next child having the deformities based
on current family members.6,7 A recent cohort study from
Denmark evaluating more than 54 000 relatives of cleft lip and
palate probands reports recurrence risks for first, second, and
third degree relatives, respectively: 3.5%, 0.8 %, and 0.6%.8
Individuals affected by the most severe oral cleft had a sig­
nificantly higher recurrence risk among both offspring and
median frontonasal prominence, laterally by the paired maxil­
lary prominences, and caudally by the paired mandibular
prominences (Fig. 21.1.1).
During the 4th through 10th weeks post-conception, the
basic morphology of the face is developed, which is formed
due to fusion of the frontonasal prominence and the maxillary,
lateral nasal, and mandibular prominences (Fig. 21.1.1).
The frontonasal prominence – as its name indicates – forms
the forehead, midline of the nose, the central lip (philtrum),
and the primary palate. Disruptions of the frontonasal devel­
opment can lead to a bilateral cleft lip with a “fly-away”
primary palate. On the inferior and lateral aspects of this
prominence form the bilateral nasal placodes, which then
submerge to form the nasal pits. Each nasal pit communicates
posteriorly with the stomodeum.
The medial nasal process of both sides gives rise to the
middle portion of the nose, the middle portion of the upper
lip, and anterior portion of the maxilla, as well as the primary
palate. The maxillary process grows medially and approaches
the lateral and medial nasal processes. As a result, the maxil­
lary process pushes the medial nasal process towards the
midline, which it then merges with its anatomic counterpart
from the opposite side (Fig. 21.1.1). The merging of the two
medial nasal processes results in the formation of that part of
the maxilla which carries the incisor teeth, and the primary
palate and the central upper lip. The upper lip is therefore
formed from the fusion of the maxillary process of each side
and the medial nasal process. Thus, clefting of the lip is a
result of failed fusion of the maxillary process and medial
nasal process. The lateral nasal prominences give rise to the
alae of the nose (Fig. 21.1.1). The maxillary prominences give
Fig. 21.1.1  Prominences of the face. Frontonasal prominence (FNP), maxillary
prominence (MXP), lateral nasal prominence (LNP), mandibular prominence (MNP).
FNP
MXP
LNP
MNP
Table 21.1.1  Risk of cleft lip and/or cleft palate
Family members
CL and CL/P
CP only
One child with a deformity
4%
2%
One parent with a deformity
4%
6%
One parent and one child with
deformities
17%
15%
Two children with deformities
9%

499
Presurgical infant orthopedics
rim, nasal septum, and nasal alar region. The maxillary denti­
tion is usually affected, often with a missing permanent lateral
incisor as well as frequent supernumerary teeth, which may
extrude into the cleft.
Presurgical infant orthopedics
Cleft lip deformities not only distort the soft tissues of the lip
but are associated with significant alveolar (bony tissues) and
nasal (cartilaginous tissues) deformities. While there are
several preoperative treatment modalities for cleft lip/nose,
the overall goals are similar: to more closely approximate the
cartilaginous, bony, and soft tissues to convert a complete cleft
lip/nose into an “incomplete” cleft lip/nose phenotype.
Historically, a head bonnet with an elastic strip had been used
to ventroflex the protruding premaxilla, in bilateral clefting,
to accomplish these goals. Currently, the most common
options for pre-surgical infant orthopedics (PSIO) include
simple lip taping, cleft lip-nose adhesion, the application of a
Latham appliance and naso-alveolar molding (NAM). Each
has its advantages, disadvantages, and different levels of
success.
Taping
The use of adhesive strips has the potential to apply a force
that slowly narrows the cleft gap. The DynaCleft® device
consists of an adhesive tape connected by an elastomeric strip
that bridges the cleft segments. It can be used for both unilat­
eral and bilateral clefts. The elastic core applies a constant
controlled force to better approximate the lip and alveolus.
Over time and serial applications of the device, the bony and
soft tissues are guided toward approximation, allowing for a
possibly easier primary repair of the lip. Placement of the
device occurs shortly after birth.
Lip–nose adhesion
Lip–nose adhesion (typically performed prior to 2–3 months
of age) involves creation of rectangular “book flaps” from the
medial and lateral cleft margins within the nostril sill and
upper lip. When the flaps along the medial edges of the cleft
lip and nostril sill are sewn together, an incomplete cleft
phenotype is created. The goals are to ultimately mold the
maxillary dental arch towards a more normal position, to
reposition the ala of the nose, and finally to release tension of
the lip in preparation of the definitive lip repair.10 This proce­
dure, however, is felt to be associated with additional scarring
and abnormal tethering of the lip and nasal elements.
Latham device
Although primarily used for bilateral clefts, the Latham device
is worth noting. The device is a form of active PSIO used to
align cleft tissues. The Latham device requires an additional
surgery for placement and is secured with surgical pins. This
device requires the child’s guardian to turn the screw daily as
well as weekly visits to the orthodontist. While effective, the
Latham device may have lost some popularity due to the
advent of naso-alveolar molding (NAM). Such active PSIO
has opponents who claim retraction of the premaxilla results
in adverse facial growth and occlusal outcomes.11,12
siblings – e.g., the recurrence risk for siblings of a proband
with isolated bilateral cleft lip with cleft palate was 4.6% (3.2
to 6.1) versus 2.5% (1.8 to 3.2) for a proband born with a
unilateral defect.
Anatomy
An in-depth understanding of the anatomic deformity of the
cleft lip and nose is critical to achieving successful surgical
correction. While the soft tissues of the upper lip and nose are
most visually affected and appreciated by peers, this defor­
mity is a composite tissue deformity involving skin, muscle,
cartilage, and bone. Early in the child’s life, the attention of
cleft surgeons is focused on all of these structures. The normal
upper lip is characterized by complex positioning of the
mucosa and vermillion, white roll, central tubercle, philtral
dimple, philtral columns, and columellar–labial junction.
The adult nose is made up of nine convex and concave
surfaces: the nasal subunits.9 However, because cartilaginous
and bony growth is not complete at the time of primary cleft
lip and nose repair, it is useful to appreciate that there are
differences in the nasal anatomy of the adult and a newborn.
The orbicularis oris is the main intrinsic muscle that
encircles the mouth, which consists of two functional com­
ponents – the superficial (pars superficialis) and the deep
(pars marginalis) components. The pars superficialis is
located under the skin of the lip and functions with nearby
facial muscles of expression primarily to retract the upper
lip. Furthermore, the pars superficialis consists of an upper
and lower muscle bundle. The lower bundle originates from
the depressor anguli muscle on each side, decussates in the
midline attaching its fibers into the skin, thus forming the
philtral columns on the contralateral side. The pars mar­
ginalis – which runs under the vermillion across from one
modiolus to the other – provides the sphincteric action of
the mouth.
Obviously, the cleft interrupts the continuous encirclement
of the mouth by the orbicularis oris. The abnormal muscular
attachments of the orbicularis oris contribute to the lip and
nasal deformity. On the cleft side, the orbicularis oris attaches
to the ipsilateral alar base, displacing the lower lateral carti­
lage inferiorly, posteriorly, and laterally, which produces the
collapsed, concave deformity. On the non-cleft or medial side,
the orbicularis oris attaches to the caudal septum and dis­
places it ipsilaterally.
As discussed above, the pars superficialis decussates in the
midline to form the philtral columns. However, on the cleft
side, the pars superficialis runs from the modiolus towards
the midline but redirects superiorly to abnormally attach to
the nasal ala and periosteum of the piriform rim. These attach­
ments are responsible for the lateral displacement of the
nostril, a lateral bulge when the muscle contracts, and the
underlying bony piriform rim’s inferior and lateral displace­
ment. On the non-cleft side, the pars superficialis continues
from the modiolus into the cleft edge perpendicularly. The
pars marginalis is interrupted by the cleft but largely does not
appear to cause further deformation.
The bony deformity is most pronounced by the alveolar
cleft, which usually extends from the incisive surface of the
alveolus, creating a greater and lesser cleft maxillary seg­
ments. The bony deformity extends cephalad to the piriform

500
SECTION I
CHAPTER 21.1 • Overview of the unilateral cleft lip and nose deformity
columella–lip junction. In Mohler’s repair, the marking for the
medial lip segment was modified in the superior portion, and
extends onto the columella, using columellar base tissue to
achieve adequate height to balance Cupid’s bow. The extended
Mohler repair is further described by Dr. Roberto Flores in
Chapter 1.2.
Fisher anatomic subunit repair
Similar to the Mohler repair, David Fisher described a tech­
nique that leaves the cleft side incision symmetric to the
unaffected philtral column.16 Moreover, borrowing from
Burget’s subunit principles in nasal reconstruction,9 Fisher
uses the concept of anatomic subunits of the lip. His technique
borrows from the Tennison–Randal technique where fre­
quently a small triangular flap is inside above the white roll
when needed to balance Cupid’s bow. The anatomic subunit
repair is described by Dr. David Fisher in Chapter 1.3.
Postoperative considerations
While postoperative management protocols for unilateral
cleft lip and nose repair vary between surgeons, there is a
short list of issues that must be considered, and these include
airway protection, analgesia, arm restraints, antibiotic use, lip
scar management and taping, and nasal stenting.
Early postoperative monitoring of the airway is required,
as blood and secretions, coupled with changes in the airway
from endotracheal intubation and alterations in the lip and
nose, put the infant at risk. As with any surgery, pain control
is an important aspect of postoperative care; nerve blocks
often decrease the need for analgesic medication.
The use of arm restraints has been a controversial subject.
However, one research group conducted a review of primary
cleft surgeries with different protocols for postoperative
restraints – one surgeon routinely used restraints whereas the
other did not.17 There was no difference in early complications
(i.e., infection, fistula, dehiscence) in patients who were
required to wear arm restraints versus those who were not.
As with most procedures in plastic surgery, there is no
consensus regarding the use of antibiotics in cleft surgery.
Given the nature of the lip and nose surgery, most surgeons
likely administer at least a preoperative dose of antibiotics.
Some surgeons performing more invasive nasal surgery prefer
to administer a postoperative course as well.18
There is no consensus regarding use of external skin sutures
on the cleft lip and nose repair. If external sutures are used,
their removal or dissolution protocol is unique to each
surgeon. If absorbable sutures are utilized, many surgeons
choose fast-absorbing sutures to minimize scarring. Absorp­
tion can be expedited by gently wiping the suture line with
normal saline or dilute hydrogen peroxide starting early
postoperatively. Due to an infant’s inability to cooperate, they
have been brought to the operating room for permanent
suture removal in the past. Others have removed permanent
sutures in the clinic during the initial postoperative visit. One
protocol instructs the caregiver to bring the child to clinic nil
per os (NPO) and hungry. The child is then placed supine with
the head in the surgeon’s lap. Giving the hungry child a bottle
allows for the sutures to be removed in a much more calm
and controlled fashion.
Naso-alveolar molding
Naso-alveolar molding (NAM) is a passive form of PSIO,
accomplishing a change to the alveolus and lip as well as
changes to the nose. NAM is most indicated in wide unilateral
clefts and for all complete bilateral clefts. The goal of NAM
is to narrow the cleft gap by aligning the maxillary arch;
and, this subsequently brings the edges of the clefted lips
together. As well, NAM addresses the cleft lip nasal defor­
mity, particularly with the bilateral cleft where it extends the
columella through tissue expansion, improves sagittal projec­
tion, as well as the size, shape, and symmetry of the nasal
apertures.
Surgical techniques
While differences between surgical techniques can be signifi­
cant and have evolved over years, the overall goal is similar
– to create a functional and aesthetically pleasing lip and nose.
Unilateral cleft lip and nose repair can be conceptualized as
“philtral subunit reconstruction” – with the goal of creating a
symmetric and normally shaped philtrum with a balanced
Cupid’s bow – placing the incision along the philtral column.
Basically, this can be accomplished with straight or curved
incisions, with or without the use of triangular flaps. In the
next three chapters, three common and unique techniques for
unilateral cleft lip and nose repair will be described. Four
techniques are briefly described here.
The Randall–Tennison repair
Charles Tennison initially described this triangular flap repair
in 1952,13 which was later modified by Peter Randall.14 Ten­
nison used a sterilized paper clip that he sculpted to determine
the position of a nearly equilateral triangular flap on the
lateral lip element superior to the vermillion. This lateral lip
based triangular flap is inset into the medial lip element above
the white roll, thereby lengthening the medial flap and bal­
ancing Cupid’s bow.
The rotation-advancement repair
The rotation-advancement technique was described by D.
Ralph Millard and has subsequently undergone many revi­
sions. In this technique, a curved rotation incision is created
on the medial lip element that allows for inferior rotation of
the central lip element, balancing Cupid’s bow. The lateral lip
is then advanced into the defect created by the rotation and
sewn in place. In its original conception, three flaps were
described: A, the medial rotation flap; B, the lateral advance­
ment flap carrying the alar base on the cleft side; and C, the
triangular flap attached to the columella that is advanced
across the nasal floor. The rotation-advancement repair is
further described by Dr. Philip Chen in Chapter 1.1.
Extended Mohler repair
Lester Mohler’s technique theoretically positions the scar to
simulate the “mirror image” of the unaffected philtral
column.15 This technique is compared to Millard’s repair
where the incision (and subsequent scar) approaches the
midline of the philtrum as it advances superiorly near the

501
Complications
a wide array of potential complications,19,20 which include:
airway obstruction, hematoma, infection, anesthesia-related
problems, and dehiscence. Longer-term potential complica­
tions include: stitch granuloma, hypertrophic scarring, nostril
floor breakdown with use of nasal stents, oronasal fistula, and
notching. Complications specific to nasal stenting include
infections, pressure necrosis, or soft tissue loss.18
Once the initial wound healing has commenced, many
surgeons employ various protocols for lip scar management
that include scar massage and scar taping. Some recommend
extended courses of lip scar taping with micropore tape and/
or silicone-impregnated tape. The authors recommend that
their patients receive 3 months of silicone-impregnated lip
scar taping. For hypertrophic scars that do not respond to
massage and taping, steroid impregnated tape and/or steroid
injections have been employed.
Some surgeons recommend a postoperative course of nasal
stents use (Fig. 21.1.2). Postoperative nasal stenting is utilized
to maintain the reconstructed nasal shape and prevent delete­
rious changes that result from wound scarring, cartilage
memory, and nasal scar contracture. Silicone nostril conform­
ers are placed at the time of primary rhinoplasty to maintain
the form and position of the reconstructed nasal deformity
and are used for weeks to months.
Complications
The above-mentioned postoperative considerations are insti­
tuted to prevent complications. Unfortunately, each surgery
is joined with a set of potential complications. These compli­
cations can be classified as early or late. Early complications
are those that occur within the hospital stay and may prolong
the hospital stay. A recent retrospective review demonstrates
Fig. 21.1.2  Nasal stent.
9. Burget GC, Menick FJ. The subunit principle in nasal
reconstruction. Plast Reconstr Surg. 1985;76:239.
13. Tennison CW. The repair of the unilateral cleft lip by the stencil
method. Plast Reconstr Surg. 1952;9:115–120.
14. Randall P. A triangular flap operation for the primary repair of
unilateral clefts of the lip. Plast Reconstr Surg. 1959;23:249–259.
15. Mohler LR. Unilateral cleft lip repair. Plast Reconstr Surg.
1987;80(4):511–517.
16. Fisher DM. Unilateral cleft lip repair: an anatomical subunit
approximation technique. Plast Reconstr Surg. 2005;116(1):
61–71.
17. Michelotti B, Long RE, Leber D, Samson T, Mackay D. Should
surgeons use arm restraints after cleft surgery? Ann Plast Surg.
2012;69(4):387–388.
18. Alef M, Irwin C, Smith D, et al. Nasal tip complications of primary
cleft lip nasoplasty. J Craniofac Surg. 2009;20(5):1327–1333.
19. Zhang Z, Fang S, Zhang Q, et al. Analysis of complications in
primary cleft lips and palates surgery. J Craniofac Surg. 2014;
25(3):968–971.
20. Schönmeyr B, Wendby L, Campbell A. Early Surgical Complications
after Primary Cleft Lip Repair: A Report of 3108 Consecutive Cases.
Cleft Palate Craniofac J. 2015;52(6):706–710.
Access the complete reference list online at

501.e1
References
References
1. Mulliken JB. Repair of bilateral cleft lip and its variants. Indian J
Plast Surg. 2009;42(suppl):S79–S90.
2. Landazuri H. History of plastic surgery in Peru. In: Hinderer U, ed.
X Congress of the International Confederation for Plastic and
Reconstructive Surgery. Madrid, Spain: Elsevier Science Publications;
1992:35–36.
3. Khoo B-C. An ancient Chinese text on a cleft lip. Plast Reconstr Surg.
1966;38:89–91.
4. Rogers BO. History of cleft palate treatment. In: Grabb WC,
Rosenstein SW, Bzoch KR, eds. Cleft Lip and Palate. Boston: Little
Brown and Company; 1971:142–169.
5. Millard DR Jr. Cleft Craft I. Boston: Little Brown and Co.; 1976.
6. Raymond GV. Craniofacial genetics and dysmorphology. In:
Achauer BM, Erikson E, Guyuron B, et al., eds. Plastic Surgery:
Indications, Operations, and Outcomes. St. Louis: Mosby; 2000
2:613–618.
7. Eppley BL, van Aalst JA, Robey A, Havlik RJ, Sadove AM. The
spectrum of orofacial clefting. Plast Reconstr Surg. 2005;115(7):
101e–114e.
8. Grosen D, Chevrier C, Skytthe A, et al. A cohort study of recurrence
patterns among more than 54 000 relatives of oral cleft cases in
Denmark: support for the multifactorial threshold model of
inheritance. J Med Genet. 2010;47(3):162–168.
9. Burget GC, Menick FJ. The subunit principle in nasal
reconstruction. Plast Reconstr Surg. 1985;76:239.
10. Hamilton R, Graham WP 3rd, Randall P. The fole of the lip
adhesion procedure in cleft lip repair. Cleft Palate J. 1971;Jan(8):1–9.
11. Berkowitz S, Mejia M, Bystrik A. A comparison of the effects of the
Latham–Millard procedure with those of a conservative treatment
approach for dental occlusion and facial aesthetics in unilateral and
bilateral complete cleft lip and palate: part I. Dental occlusion. Plast
Reconstr Surg. 2004;113(1):1–18.
12. Matic DB, Power SM. The effects of gingivoperiosteoplasty
following alveolar molding with a pin-retained Latham appliance
versus secondary bone grafting on midfacial growth in patients
with unilateral clefts. Plast Reconstr Surg. 2008;122(3):863–870,
discussion 871–873.
13. Tennison CW. The repair of the unilateral cleft lip by the stencil
method. Plast Reconstr Surg. 1952;9:115–120.
14. Randall P. A triangular flap operation for the primary repair of
unilateral clefts of the lip. Plast Reconstr Surg. 1959;23:249–259.
15. Mohler LR. Unilateral cleft lip repair. Plast Reconstr Surg.
1987;80(4):511–517.
16. Fisher DM. Unilateral cleft lip repair: an anatomical subunit
approximation technique. Plast Reconstr Surg. 2005;116(1):
61–71.
17. Michelotti B, Long RE, Leber D, Samson T, Mackay D. Should
surgeons use arm restraints after cleft surgery? Ann Plast Surg.
2012;69(4):387–388.
18. Alef M, Irwin C, Smith D, et al. Nasal tip complications of primary
cleft lip nasoplasty. J Craniofac Surg. 2009;20(5):1327–1333.
19. Zhang Z, Fang S, Zhang Q, et al. Analysis of complications in
primary cleft lips and palates surgery. J Craniofac Surg. 2014;
25(3):968–971.
20. Schönmeyr B, Wendby L, Campbell A. Early Surgical Complications
after Primary Cleft Lip Repair: A Report of 3108 Consecutive Cases.
Cleft Palate Craniofac J. 2015;52(6):706–710.

SECTION I • Clefts
21.2 
Rotation advancement cheiloplasty
Philip Kuo–Ting Chen, Jeremiah Un Chang See, and M. Samuel Noordhoff
SYNOPSIS
Pre-surgical nasoalveolar molding/nasal molding
Key steps in surgery
■ Determine the landmarks.
■ Determine the incision line for rotation: Mohler’s incision versus
traditional rotation incision.
■ Determine the incision lines for advancement including a white skin roll
flap, orbicularis marginalis flap, L-flap, and turbinate flap (if
necessary). Eliminate the perialar incision.
■ Adequate release of muscle in both the rotation and advancement
flaps. Adequate mobilization of the alar base on the cleft side.
■ Nasal floor reconstruction using mucosal flaps without leaving raw
surface. Overcorrection of the nostril width on the cleft side.
■ Anchoring of the advancement flap to nasal septum to centralize the
Cupid’s bow.
■ Approximate the orbicularis muscle in overlapping fashion for philtral
reconstruction.
■ Reconstruct the white skin roll according to subunit principle.
■ Correct central vermilion deficiency with triangular vermilion flap from
lateral lip.
■ Semi-open rhinoplasty with reverse U incision on the cleft side and rim
incision on the non-cleft side.
■ Atraumatic dissection to release the fibrofatty tissue from lower lateral
cartilages.
■ Advancement and fixation of the cleft side lower lateral cartilage to the
non-cleft side lower lateral cartilage and skin in an over-corrected
position.
■ Define the ala–facial groove with alar transfixion sutures.
Postoperative maintenance of over-correction with silicone nasal
conformer.
Introduction
The techniques presented here are based on the experiences
at Chang Gung Craniofacial Center over a period of 30 years
in a Taiwanese population. They have also been tested in
other racially diverse centers. The improved outcomes result
from an integrated approach with pre-surgical management,
surgical refinements, and post-surgical maintenance.
Preoperative plan
Multidisciplinary care
A multidisciplinary approach is essential to the satisfactory
treatment of cleft patients. This includes surgeons, orthodon­
tists, speech pathologists, pedodontists, prosthodontists,
otolaryngologists, social workers, psychologists, as well as a
photographer.1 In addition, the Center’s coordinator serves to
coordinate all these specialties for the benefit of the patients
as well as gathering and recording vital information. These
contribute to the comprehensive care of cleft patients from
infancy to adulthood.
First visit
At Chang Gung Craniofacial Center, the initial visit is made
as soon as possible after birth. An orthodontist and plastic
surgeon carefully examine the infant to record tissue deficien­
cies and distortion. The coordinator and social worker provide
psychological support to the patient’s family and essential
information regarding the subsequent care. The baby is also
evaluated by a pediatrician for other systemic abnormalities.
Nasoalveolar molding/nasal molding
Pre-surgical nasoalveolar molding (NAM, for complete cleft
lips) or nasal molding (for incomplete cleft lips) is started
soon after the first visit. Usually it takes 3–4 months for the
completion of the molding process.
During the past 28 years, several techniques have been
used for pre-surgical management. They vary from simple
to very sophisticated techniques. These include sleeping in
prone position,2 lip taping,3 pre-surgical orthopedics with an
Access video content for this chapter online at expertconsult.com

503
Operative techniques
Operative techniques
Treatment plan for lip repair in Chang Gung
Craniofacial Center
There are several different treatment plans leading to the
surgical correction of the deformity. With effective pre-surgical
nasoalveolar molding, definitive cheiloplasty with anterior
palate repair is done at the age of 3–5 months. Whenever
pre-surgical orthopedics is not available or if the child is older
than 3 months at presentation, cleft width determines the
protocol. If the cleft width is less than 12–15 mm, the child
proceeds to surgery. If there is a wide cleft (>12–15 mm) or
significant tissue deficiency, nasolabial adhesion cheiloplasty
is done at 3 months, followed by a definitive cheiloplasty at
about 9 months old.9
Rotation advancement cheiloplasty for
complete clefts (Videos 21.2.1 and 21.2.2 )
Markings
Cupid’s bow, vermilion, commissure, columellar base, and
alar base
The points of the Cupid’s bow (CPHR, LS, CPHL) are marked
on the epidermis–vermilion junction line along with the white
skin roll (WSR) as described by Millard. Usually, point CPHR
is easy to identify. Gentle upward lift on the nasal tip with a
finger helps to define point LS (Fig. 21.2.5A,B). This is essential
because it is easier to level the Cupid’s bow if LS is marked
toward CPHR, making Cupid’s bow somewhat narrower.
However, the shape of the Cupid’s bow can be partially
deformed. If one places point LS toward the cleft margin,
point CPHL will be moved higher, and it will be more difficult
to level the Cupid’s bow. The distance between LS and CPHL
is determined by the measurement between CPHR and LS.
The vermilion–mucosa junction line, the red line,10,11 is also
marked. This clearly defines the intervening vermilion below
the heights of the Cupid’s bow. It also identifies the vermilion
deficiency beneath the height of Cupid’s bow near the cleft
margin. Next, one marks out the midpoint of columella base
(SN), highest points of the philtral columns (CPHSR, CPHSL),
bilateral base of the ala (SBAR, SBAL) and commissure (CHR,
CHL). Lastly, the width of the WSR at point CPHR is marked
out. The width of the WSR is usually around 2 mm at the age
of 3–6 months old (Fig. 21.2.6A).
Base of philtral column on the cleft side
The base of the philtral column on the cleft side (CPHL′) is a
definite anatomic point but somehow difficult to identify. The
red line always converges and meets the WSR medially. Fre­
quently, there is a distinct point where the WSR changes
directions and makes a slight curve 3–4 mm before meeting
the red line. Point CHPL’ is where the WSR changes direction
and the vermilion first becomes widest which is usually
3–4 mm lateral to the converging point of red line and WSR.12
This is an important anatomic point for the cleft-side philtral
column and seldom requires adjustment unless there is a
severe discrepancy in the horizontal or vertical length (Fig.
21.2.6B). As mentioned earlier, the width of the WSR flap
acrylic plate4 with lip taping and three different NAM tech­
niques. Among these three techniques, modified Grayson’s
and Liou’s (modified Figueroa’s) are commonly used. Both
molding techniques require outpatient adjustments every
1–2 weeks.
Modified Grayson’s technique
A passive orthopedic appliance is used together with taping
of the lip. The alveolar molding is started first to narrow the
alveolar gaps while molding the premaxilla into a proper
position. Upon achieving a certain alveolar narrowing and
arch alignment, a nasal mold is added to the orthopedic
appliance. The nasal mold will lengthen the columella
and reshape the alar dome. Taping across the upper lip
also acts as a lip adhesion that decreases the nasal width
(Fig. 21.2.1A,B
).5
Fig. 21.2.1 appears online only.
Liou’s technique (Modified Figueroa technique)
This device is composed of a dental plate, nasal molding
components, and adhesive tape (Micropore™). The dental
plate is held to the palate with dental adhesive. Micropore™
tape is placed across the clefts to minimize the alveolar cleft,
retract the pre-maxilla, and keep both alar bases medial. The
nasal components project forward in a sagittal direction from
the dental plate. Columella lengthening is achieved by the
combined forces of backward movement of the premaxilla
and forward movement of the nasal tip. Both the alveolar and
nasal molding processes are performed simultaneously (Fig.
21.2.2A,B).6
A prospective randomized controlled trial showed there
were no differences between these two NAM techniques in
terms of frequency of clinical visit, total cost, nostril height,
and nostril area ratio. The modified Grayson technique
reduced nostril width more efficiently but caused more alveo­
lar ulceration. However, there was no difference in nostril
width following surgery. Overall, these two NAM techniques
produced similar nasal aesthetic outcomes.7
Nasoalveolar molding with a spring device
To decrease the burden of care for the parents, a new molding
device using the spring mechanism was developed from the
modification of Liou’s technique. The molding prongs are
made from 0.032-inch β-titanium wire with a helix. It only
needs four clinic visits before lip repair, thus significantly
decreasing the number of follow up visits. This can be very
important for patients with limited resources, as it saves cost
and travel time (Fig. 21.2.3A,B
).
Fig. 21.2.3 appears online only.
Nasal molding with silicone nasal conformer
For incomplete cleft lips, nasal molding can be achieved by
using silicone nasal conformers.8 Nasal conformers with dif­
ferent heights can gradually increase nasal dome height by
stretching the columella as well as molding the shape of
deformed lower lateral cartilage (LLC). Parents are instructed
to change to a larger size conformer every 2–3 weeks (Fig.
21.2.4A–D
).
Fig. 21.2.4 appears online only.

503.e1
Operative techniques
A
Fig. 21.2.1  (A) Modified Grayson molding device. (B) The device held in proper
position by elastics and tapes. Lip taping helps to approximate the alveolus.
B
A
Fig. 21.2.2  (A) Liou’s (modified Figueroa) molding device. (B) The device held in
proper position by dental adhesives. Lip taping is also used.
B

503.e2
SECTION I
CHAPTER 21.2 • Rotation advancement cheiloplasty
A
Fig. 21.2.3  (A) Liou’s molding device with spring mechanism. (B) The device held in place with dental adhesives. Lip taping is also used.
B
A
B
Fig. 21.2.4  (A) Nasal molding with silicone nasal conformer. (B) A set of nasal conformers with different heights for cleft side. (C) A 10-day-old baby with right
incomplete cleft lip. Nasal shape before the nasal molding. (D) Same baby at the age of 3 months old before lip repair. The nasal shape after nasal molding.
C
D

504
SECTION I
CHAPTER 21.2 • Rotation advancement cheiloplasty
corresponds to the measurement on the non-cleft side (Fig.
21.2.6C). The split point of the nasolabial groove (the point
where the skin-mucosal junction changes its direction at the
deepest point of the nasal vestibulum on the cleft side) is also
marked (Fig. 21.2.6D).
Proposed point of medial nasal sill
Gentle inward pressure on the cleft side ala base helps to
define the position and direction of the cleft side nasal sill.
The proposed point of the medial nasal sill, which is usually
the highest point of the philtral column on the cleft side
(CPHSL’), is the point where the nasal sill ends medially and
meets the base of columella during skin closure (Fig. 21.2.7).
This point is marked approximately 8 mm from a tangential
line on the ala–facial groove in a 3–6-month-old baby. This
distance helps to achieve an over-corrected nostril width on
the cleft side.
Measurements
Various measurements are made, based on the anthropometric
points marked (Fig. 21.2.8). Important measurements for the
A
Fig. 21.2.5  (A,B) The different shape of Cupid’s bow when pushing the nasal tip upward with a finger. This maneuver helps to define the point LS.
B
Fig. 21.2.6  (A) The points: CPHR, LS, CPHL, SN, CPHSR, CPHSL, SBAR, SBAL, CHR, CHL and the red lines.
(B) The point CPHL’. Although the horizontal lip length is shorter on the cleft side, this point is still chosen at its
anatomical position. (C) Besides the points in (D) shows the split point of nasolabial groove.
A
B
C
D
Fig. 21.2.7  The point CPHSL’, the proposed point of medial nasal sill on the cleft
side.

505
Operative techniques
surgeon to evaluate include the vertical length (5A, 5B) and
the horizontal width (6A, 6B) of the lip.
Peaking of Cupid’s bow
The discrepancy between the heights from the central colu­
mella base (SN) to the two peaks of the Cupid’s bow (CPHR
and CPHL) is critical for leveling the Cupid’s bow. The authors
favor Mohler’s incision for rotation if the discrepancy is over
2 mm. A shorter rotation incision from CPHL to CPSHL is
carried out if the discrepancy is less than 2 mm (Fig. 21.2.9A,B).
Lateral lip height and length
The short horizontal length on cleft side (HL) can be length­
ened by adjusting point CPHL′ medially; however, this would
shorten the vertical length (VL) (Fig. 21.2.10A). Vertical length
is more important aesthetically compared with the horizontal
length. Therefore, vertical length is seldom sacrificed for hori­
zontal length. The short vertical length can be increased by
adjusting point CPHL′ laterally, but this would result in an
even shorter horizontal length which is pre-existing (Fig.
21.2.10B). The traditional method of extending the upper
rotation-advancement incision around the ala can also increase
the short vertical length. However, this results in an unaccept­
able perialar scar and should be avoided. Point CPHL′ is as
10AB
1A
SBAR
5A
11A
7
CPHR
6A
CHR
2
SBAL
5B
10B'
CHL
6B
9B
9A'
10A'
9A
11B
CPHL
CPHL'
A
Fig. 21.2.8  (A) Unilateral complete cleft with anthropometric markings for
measurements. (B) Similar markings for unilateral incomplete cleft lip. (From
Noordhooff MS, Chen YR, Chen KT, Hong KF, Lo LJ. The surgical technique for the
complete unilateral cleft lip-nasal deformity. Opera Tech in Plast Reconstr Surg.
1995;2(3):167–174.)
10AB
3
1A
SBAR
5A
11A
7
CPHR
CPHL'
6A
CHR
2
SBAL
5B
CHL
6B
9B
9A'
9
11B
CPHL
1B
10A'B'
8
B
A
Fig. 21.2.9  (A) Markings for the Mohler incision if the height discrepancy is more
than 2 mm. (B) Marking for the simple rotation incision if the height discrepancy is
less than 2 mm.
B

506
SECTION I
CHAPTER 21.2 • Rotation advancement cheiloplasty
LS but becomes narrower toward point CPHL. The authors
routinely measure the width of WSR at point CPHR and
transfer this measurement to the cleft side. The measured
WSR at point CPHR is always wider (e.g., 2 mm wide at the
age of 3–6 months old) than the observed WSR at point CPHL’.
A triangular WSR flap is designed above point CPHL’. This
2 mm WSR flap helps to level Cupid’s bow and corrects the
WSR deficiency at point CPHL. In addition, it helps recon­
struct the upper lip contour line in accordance to the subunit
concept as advocated by Onizuka (Fig. 21.2.12A–D).13
Vermilion width
The vermilion width beneath point CPHL is always deficient
compared with the counterpart vermilion at point CPHR or
CPHL’. Inadequate reconstruction of this vermilion deficiency
will result in free border deformities like exposed mucosa,
color mismatching, and dry crusting as seen in a straight-line
vermilion closure (Fig. 21.2.13). Therefore, the vermilion
medial to point CPHL′ should be used to correct the vermilion
deficiency beneath the Cupid’s bow.10
important as other anatomic points and should not be adjusted
until all incisions, muscle dissection, and approximation are
completed. This is because an increase in vertical length – up
to 4 mm – can be achieved by adequate muscle dissection and
redraping of the skin over the muscle, thus eliminating the
need of perialar incisions or adjusting the point CPHL′. This
lengthening effect should be taken into consideration rather
than strictly observing the mathematically fixed points
marked during lip repair. The preoperative measurements
between points will differ after muscle release, muscle
approximation, and skin redraping; therefore, they must be
re-checked after muscle approximation.
Incomplete clefts often appear to have a vertically long
lateral lip. However, the measurement of the cleft side vertical
height is usually similar to the non-cleft side because the cleft
side lateral lip and the alar base are inferiorly displaced (Fig.
21.2.11A). Therefore, the vertically long lateral lip, seen in
incomplete clefts, is just an illusion. Adequate mobilization of
the cleft side alar base and lateral lip, prior to advancing the
entire lateral complex superiorly and medially, always levels
Cupid’s bow without vertically shortening the lateral lip (Fig.
21.2.11B).
White skin roll
The width of the WSR is usually widest above point CPHR.
The WSR remains quite prominent between points CPHR and
A
Fig. 21.2.10  (A) Moving point CPHL’ medially will increase the horizontal lip
length but shorten the vertical lip height. (B) Moving the point CPHL’ laterally will
have the opposite effect.
B
A
Fig. 21.2.11  (A) Although the vertical lip height seems longer on the cleft side,
the height measurement between the two sides shows a similar result. The long lip
is a false impression due to the downward displaced alar base. (B) Moving the
whole lateral lip/alar base upward can achieve a symmetrical lip without shortening
of the skin and muscle.
B