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SPECIAL TOPIC
The Spectrum of Median Craniofacial Dysplasia
Karam A. Allam, M.D.
Derrick C. Wan, M.D.
Henry K. Kawamoto, M.D.,
D.D.S.
James P. Bradley, M.D.
Heddie O. Sedano, D.D.S.
Samia Saied, M.D.
Los Angeles, Calif.; and Nasser City,
Sohag, Egypt
Summary: Given the multiple permutations in craniofacial malformations, classification of median craniofacial dysplasia or midline Tessier no. 0 to 14 clefts
has been difficult and disjointed. In this review, the authors present a summary
of normal embryology, prior terminology, and their proposed new classification
system. Median craniofacial dysplasia has tissue agenesis and holoprosencephaly
at one end (the hypoplasias), frontonasal hyperplasia and excessive tissue (the
hyperplasias) at the other end, and abnormal splitting or clefting and normal
tissue volume (dysraphia) occupying the middle portion of the spectrum. These
three distinct subclassifications have different forms of anomalies within their
groups. (Plast. Reconstr. Surg. 127: 812, 2011.)
NORMAL EMBRYOLOGY
T
horough knowledge of embryologic development in the craniofacial region is of paramount importance for understanding, classifying, and treating median craniofacial defects. In
the third week of gestation, primitive tissues of the
trilaminar embryo give rise to notochordal and prechordal mesoderm (Fig. 1). Simultaneously, the rostral ectoderm differentiates to form highly specialized neural crest cells, which are responsible for
ultimate development of the brain and midline facial structures.1 The dual role of the prechordal mesoderm forms the median facial skeleton and induces the rostral neural ectoderm to develop into
the prosencephalon.2
Starting at the fourth week of gestation, various
processes appear and the face assumes a more recognizable form.3,4 A bewildering coordination of cell
proliferation, migration, and interaction occurs.
The correct amount of tissue must be present at the
right time in a proper three-dimensional relationship. Any breakdown in this intricate program can
produce disastrous consequences.5
By the end of the fourth week, the double-layer
stomodeal membrane creates an opening for the
primitive mouth. An overhanging frontonasal
prominence represents the superior border of the
stomodeum.5 On either side of the frontonasal
prominence, just above the stomodeum, a localFrom the Division of Plastic and Reconstructive Surgery,
Department of Surgery, University of California, Los Angeles
Medical Center; the Department of Plastic and Reconstructive Surgery, Sohag University School of Medicine; and the
University of California, Los Angeles School of Dentistry.
Received for publication June 15, 2010; accepted July 19,
2010.
Copyright ©2011 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0b013e318200aa08
812
ized thickening of ectoderm forms the nasal or
olfactory placodes. During the fifth week, the margins of the nasal placodes elevate while the central
portion deepens to form the olfactory pits. The
olfactory pit is actually a groove because it communicates inferiorly with the stomodeum. The
raised margins of the placode become the medial
and lateral nasal processes. These processes, together with the frontonasal prominence, constitute the frontonasal process.
During the sixth week, the medial nasal processes enlarge and coalesce in the midline. The
caudal extensions of the medial nasal processes,
the globular processes, are united with the developing maxillary processes to form the upper
lip. The medial nasal process gives rise to the
nasal tip, the columella, the philtrum, and the
premaxilla. The nasal alae are derived from the lateral nasal processes. The frontonasal process contributes the bridge and the root of the nose.5
Forebrain development is closely associated
with the midline facial structures, which consist of
the ethmoid, crista galli, nasal and vomerine
bones, nasal septum, premaxilla with four incisors,
triangular component of the primary hard palate,
and the philtrum of the upper lip.6 The neural
crest cells migrate at the time of neural fold closure and prosencephalon cleavage.7 Most of the
median facial structures form from these neural
crest cells. Defects or deficiencies in the median
Disclosure: The authors have no financial interest
to declare in relation to the content of this article. All
sources of funds supporting the completion of this
article are under the auspices of the University of
California, Los Angeles.
www.PRSJournal.com
Volume 127, Number 2 • Median Craniofacial Dysplasia
part of the anterior neural plate and neural crest
cells, from whatever cause, intrinsic or extrinsic,
result in abnormal development (dysplasia) of the
forebrain and/or medial facial structures.8
NEW MEDIAN CRANIOFACIAL
DYSPLASIA CLASSIFICATION
Classification of frontonasal malformations remains confusing. We believe that the median
craniofacial malformations should be studied
from the embryologic point of view. With tissue
agenesis and holoprosencephaly at one end (the
hypoplasias), and frontonasal hyperplasia and excessive tissue (the hyperplasias) at the other end,
median anomalies with separation or clefting and
normal tissue volume (dysraphia) occupy the middle portion of the spectrum. We prefer use of the
term “dysplasia” rather than “dysgenesis.” Also, we
agree with Noordhoff et al. in limiting the term
holoprosencephaly to cases of alobar brain.8 Thus,
our modified median craniofacial dysplasia classification is based on both previous descriptions
and severity of the anomaly (Table 1). The three
main divisions are as follows:
Fig. 1. Facial development of the human embryo. Drawings depict (above, left) a 5-week embryo (6.5 mm), (above, right) a
6-week embryo (9 mm), (below, left) a 6.5-week embryo (12 mm),
and (below, right) a 7-week embryo (19 mm).
I. Median craniofacial hypoplasia (tissue deficiency or agenesis).
II. Median craniofacial dysraphia (normal tissue volume but clefted).
III. Median craniofacial hyperplasia (tissue excess or duplication).
Table 1. Modified Median Craniofacial Dysplasia Classification
Subclassification
I. Median craniofacial hypoplasia
A. Holoprosencephalic spectrum
(alobar brain)
1. Cyclopia
2. Ethmocephaly
3. Cebocephaly
4. Primary palate agenesis
B. Median cerebrofacial hypoplasia
(lobar brain)
C. Median facial hypoplasia
D. Microforms of median facial
hypoplasia
II. Median craniofacial dysraphia
A. True median cleft
B. Anterior encephalocele
III. Median craniofacial hyperplasia
Description
Tissue deficiency
Single holistic brain with midline facial hypoplasia or agenesis. Four
subclassifications: cyclopia, ethmocephaly, cebocephaly, primary palate
agenesis.
1. Single eye in a single orbit, arhinia with proboscis often located above the
single orbit and microcephaly (Fig. 2).
2. Severe hypoteloribtism but separate orbits. Arhinia with proboscis located in
between the orbits (Fig. 3).
3. Severe hypoteloribtism. Proboscis-like rudimentary nose (Fig. 4).
4. Premaxillary segment missing or hypoplastic (Fig. 5).
Separate lobes to brain but with midline cerebral malformation; midline facial
hypoplasia (Fig. 6).
Midline facial hypoplasia without gross cerebral involvement (Fig. 7).
1. Binder anomaly (maxillonasal dysplasia) (Fig. 8).
2. Central maxillary incisor anomaly (Fig. 9).
3. Absent upper lip frenulum/incisors.
Normal tissue volume but clefted
Isolated cleft of the upper lip or abnormal split between the median
globular process. It can be an incomplete (Fig. 10, left) or complete form
(Fig. 10, right).
Cystic malformation in which central nervous structures are abnormally
displaced or herniated through a defect in the cranium (Fig. 11).
Tissue excess or duplication. All forms of excess tissue starting from just
thickened or duplicated nasal septum to the more severe forms of
frontonasal dysplasia (Fig. 12).
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Plastic and Reconstructive Surgery • February 2011
Under each division, further subclassifications
are used to describe the specific anomalies.
I. Median Craniofacial Hypoplasia
The first category of median craniofacial dysplasia, median craniofacial hypoplasia, occurs
with tissue deficiency or agenesis.
A. Holoprosencephalic Spectrum (Alobar Brain)
1. Cyclopia: This is described by a single eye in
a single orbit. Arhinia exists with a proboscis
often located above the single orbit. Microcephaly is also a component (Fig. 2).
2. Ethmocephaly: Severe hypoteloribtism exists
but the orbits are separate anatomically.
Again, arhinia is present; however, the proboscis is located in between the orbits (Fig. 3).
3. Cebocephaly: Moderate to severe hypoteloribtism is noted. There is a “proboscis-like” rudimentary nose in a more typical nasal position (Fig. 4).
4. Primary palate agenesis: The primary palate,
including the premaxillary segment and associated midline structures, is absent or severely
deficient. Hypoteloribtism is seen (Fig. 5).
Fig. 3. Severe form of median craniofacial hypoplasia with hypoteloribtism, and proboscis in between orbits.
B. Median Cerebrofacial Hypoplasia
(Lobar Brain)
In this condition, midline facial hypoplasia
and midline cerebral malformations exist. Unilateral or bilateral cleft lip and palate may be present
(Fig. 6).
Fig. 4. A patient with cebocephaly.
Fig. 2. A patient with cyclopia. Note the rudimentary proboscis
above the single orbit.
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C. Median Facial Hypoplasia
Midline facial hypoplasia exists without gross
cerebral involvement. Unilateral or bilateral cleft
lip and palate may again be present (Fig. 7).
D. Microforms of Median Facial Hypoplasia
Microform variants of median facial hypoplasia may occur when there are mild deficiencies from maldevelopment of the median facial
structures. Unilateral or bilateral cleft lip and
palate can also be found. This group includes
the following:
1. Binder syndrome or anomaly (maxillonasal
dysplasia): Binder syndrome patients have a
characteristic flat nasomaxillary facial region
with deficient or absent anterior nasal spine
Volume 127, Number 2 • Median Craniofacial Dysplasia
Fig. 5. A patient with primary palate agenesis.
Fig. 7. Frontal view of patient with median facial hypoplasia, median cleft, nasal hypoplasia, and no gross cerebral involvement.
II. Median Craniofacial Dysraphia
Median craniofacial dysraphia describes a midline anomaly that has normal tissue volume but clefting, or when an abnormal separation of midline
structures is present. Within the spectrum of median
craniofacial dysplasia, there is a group of malformations that have normal tissue volume but have abnormally split (true median cleft lip) or are displaced (encephalocele). This group is better
categorized as median tissue defects midway between hypoplasia and hyperplasia.9
Fig. 6. Frontal view of patient with median cerebrofacial hypoplasia with median cleft, rudimentary columella, and absent
premaxillary segment.
and negative overjet from a class III anterior
incisor relationship (Fig. 8).
2. Abnormalities of the maxillary central incisors
(Fig. 9): three variants of this include:
a. Absent central maxillary incisors.
b. Single maxillary central incisor.
c. Hypoplastic central maxillary incisors.
3. Absence of upper lip frenulum.
A. True Median Cleft
A true median cleft may manifest as an isolated
cleft of the upper lip “0 cleft” not associated with
either hypoplasia or hyperplasia (Fig. 10). Alternatively, a true median cleft may have tissue deficiency or agenesis (e.g., absent nasal septum). A
true median cleft may also occur with tissue excess
(e.g., duplicated nasal septum).
With median craniofacial dysraphia, a true median cleft has separated but retains a normal tissue
amount. The upper lip deformity is a true median
cleft lip with a split between the median globular
processes. This is opposed to a “false” median cleft
with agenesis of the globular processes. With true
median cleft, the separation passes between central incisors. The cleft may continue posteriorly as
a cleft of the primary and/or secondary palate.
When the cleft encroaches into the interorbital
region, orbital hypertelorbitism may be seen.5
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Plastic and Reconstructive Surgery • February 2011
Fig. 8. (Left) Frontal and (right) lateral views of a patient with Binder syndrome.
phologic classification.12 Basal encephaloceles are
associated with a defect at or behind the crista galli
and, in some cases, may protrude through a defect
in the sphenoid bone and are called transsphenoidal encephaloceles.13
Fig. 9. Patient with a single central maxillary incisor.
B. Anterior Encephaloceles
An encephalocele is a cystic congenital malformation in which central nervous system structures
herniate through a defect in the cranium in communication with cerebrospinal fluid pathways.10
They occur between normally developed zones,
where a weakness permits brain to escape. The mass
further pushes fields apart.9
Anterior encephaloceles are divided into
frontoethmoidal and basal groups (Fig. 11). In
frontoethmoidal encephaloceles, the defect occurs at the junction of the frontal and ethmoidal
bones (the foramen cecum).11 Nasoethmoidal
encephaloceles are considered Tessier no. 14
clefts or frontonasal dysraphia in Mazzola’s mor-
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III. Median Craniofacial Hyperplasia (Tissue
Excess or Duplication)
This spectrum of anomalies includes all forms of
excess tissue starting from just a thickened or duplicated nasal septum and extends toward the more
severe forms of frontonasal dysplasia (Fig. 12).
“Frontonasal dysplasia” is the most widely
known of these types of hyperplasias.14 Objections
are raised about the terminology of this condition.
Typically, the term “dysplasia“ refers to the whole
spectrum of abnormal tissue development starting
from tissue agenesis and hypoplasia all the way to
the other end of hyperplasia and excess tissue.
The basic defect of median craniofacial hyperplasia is not known. Embryologically, if the
nasal capsule fails to develop properly, the primitive brain vesicle fills the space normally occupied
by the capsule, thus producing an anterior cranium bifidum occultum. This leads to morphokinetic arrest in the positioning of the eyes and
nostrils, which tend to maintain their relative fetal
positions.15 Experiments have shown that a reduction in the number of migrating neural crest cells
results in these multiple defects.16
Other nasal findings may range from a notched
broad nasal tip to completely divided nostrils with
Volume 127, Number 2 • Median Craniofacial Dysplasia
Fig. 10. Frontal views of (left) a boy with incomplete isolated cleft of the upper lip and (right)
of a boy with complete isolated midline cleft of the upper lip.
orbitism is severe, or when extracephalic anomalies
occur, mental deficiency appears to be more likely
and more severe.14,17
PREVIOUSLY DESCRIBED
TERMINOLOGY AND CLASSIFICATIONS
Fig. 11. Frontal view of a patient with a frontonasal encephalocele and hypertelorbitism.
hypoplasia and even absence of the prolabium and
maxilla with a median cleft lip. In addition, variable
notching of the ala is described. Occasional associated abnormalities include accessory nasal tags, lowset ears, conductive hearing loss, mild to severe retardation, basal encephalocele, and agenesis of the
corpus callosum. Importantly, a high incidence of
ocular abnormalities is described. When hypertel-
Historically, Kundrat was the first to use the
term “arhinencephaly” to describe absence of olfactory buds and failed development of the
prosencephalon and associated structures.18 DeMyer and Zeman later restricted the term arhinencephaly to absence of olfactory bulbs and designated the undifferentiated prosencephalon as
holoprosencephaly.19 Brucker et al. suggested the
term “median cerebrofacial dysgenesis” to encompass the whole spectrum of anomalies affecting
the central part of the face and forebrain.20
DeMyer proposed the “median cleft face syndrome” and classified patients into four facial
types based on orbital hypertelorbitism and
other associated craniofacial abnormalities: cranium bifidum occultum, V-shaped frontal hairline, primary telecanthus, median cleft nose, median cleft prolabium, median cleft premaxilla, and
median cleft palate.21 Sedano et al. modified DeMyer’s classification, preferring the designation of
“frontonasal dysplasia” and categorized abnormality into four types depending on embryologic
derivation.22,23 They considered frontonasal dysplasia and holoprosencephaly to be at the opposite ends of the median facial anomaly spectrum.5
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Plastic and Reconstructive Surgery • February 2011
Fig. 12. (Left) A patient with a thickened nasal septum representing a mild form of median facial hyperplasia. (Center) A child with
a bifid nose and hypertelorbitism. (Right) A patient with a severe form of median facial hyperplasia, hypertelorbitism, and bifid nose
associated with other facial clefts.
In contrast, Pfeifer offered a morphologic classification dividing the head of the embryo into three
topographic areas: a frontonasal region and two
lateral-posterior regions.12 Mazzola subsequently
modified Pfeifer’s classification, with anomalies
in (i) upper face region including holoprosencephaly, frontonasal dysplasia, nasal duplication,
and nasal aplasia; and (ii) midcephalic borderline
region including paramedian anomalies.12
Tessier considered a cleft to be at the basis of
each malformation. He established a numeric system for each malformation depending on its relationship to the sagittal midline.24 The no. 0 to
no.14 Tessier facial cleft passes through the
midline of the face and embraces most of the
midline deformity described in the other classifications.21,22,25,26 Based on Tessier’s classification, Kawamoto separated the median facial
anomalies into two broad categories: (1) those
in which the volume of tissue is deficient (hypoplasia), and (2) those in which the amount of
tissue is near normal or in excess (hyperplasia).5
Tessier’s classification is a descriptive, clinical
classification that is related to the embryopathogenesis. Use of the term “cleft,” however, creates confusion where no cleft exists, as in hypertelorbitism
and nasal aplasia.27 For these reasons, van der
Meulen et al. proposed a new classification based on
embryology and introduced new nomenclature.27
They preferred to use the term “dysplasia” instead of
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“cleft.” They distinguished two main groups of malformations: (1) cerebral craniofacial defects involving the brain and/or eyes, and (2) defects of the face
and cranium (“craniofacial defects”).
In 1993, Noordhoff et al., based on the classification of van der Meulen et al., introduced the
term “median cerebrofacial dysplasia” to describe
the holoprosencephalic dysplasia spectrum.8,27
Their classification primarily distinguishes the
group of patients with deficient midline tissues
and did not include the other end of the midfacial
spectrum with excessive tissue.
After Kundrat first described arhinencephaly, DeMyer and Zeman coined the term “holoprosencephaly” to describe the arrest in cleavage of the prosencephalon into two cerebral
hemispheres.18,19 The resulting various skull and
facial defects with brain abnormalities were classified into five categories:
I.
II.
III.
IV.
Cyclopia.
Ethmocephaly.
Cebocephaly.
Median cleft lip with total absence of the
primary palate (premaxillary agenesis).
V. Facial dysmorphism, median philtrumpremaxilla anlage with bilateral complete
lateral cleft of the primary palate with rudimentary intermaxillary segment.
Volume 127, Number 2 • Median Craniofacial Dysplasia
Groups I to IV were described as alobar,
whereas group V was described as lobar. The term
“holoprosencephaly,” however, refers to cerebral
defects and makes no reference to the invariably
present median facial deformity.2
Brucker et al. suggested the term “median cerebrofacial dysgenesis” to describe this spectrum
of anomalies that ranges from severe (e.g., cyclopia) to cerebral and facial development approaching normality.20 Gruss and Matthews added group
VI to the above five categories for patients with a
unilateral complete cleft of the primary palate
with a prolabium-premaxillary anlage.2
In 1983, van der Meulen et al. introduced the
term “interophthalmic dysplasia” as a subdivision
of “cerebral craniofacial dysplasia” to describe
agenesis or hypodevelopment of the midline
structures of the face and brain.27 They recommended changing the term dysgenesis (which is
abnormal morphogenesis) to dysplasia to denote
abnormal development or growth.
In 1992, Elias et al., with the help of new advances in computed tomography and magnetic resonance imaging, proposed a revised classification
system taking into account the wide range of midline
facial anomalies seen in those patients with otherwise normal brains.1 Proposed primarily from a
prognostic point of view to aid treatment planning,
Elias and colleagues left DeMyer groups I through
III unchanged, with surgical intervention being contraindicated because of severe brain abnormality.21 A
redefined group IV included patients with a false
median cleft, hypoteloribtism, and abnormal cerebral morphology. Further subdivision of group IV
separated those with severe brain malformation
(group IVA) from those with moderate (group IVB)
involvement. Group V was changed to include only
those patients with anatomically normal brains. Subdivision of group V distinguished those with false
median clefts (group VA) from those without a false
median cleft but still with hypoteloribtism and midface hypoplasia. Patients in group IVA may live several years but are severely neurologically compromised and rarely benefit from operation. Group IVB
patients are candidates for lip and palate repair.
Groups VA and VB are also surgical candidates for
more definitive procedures.
Noordhoff et al. preferred to limit the term
“holoprosencephaly” to those malformations with
a single holistic brain.8 They used the term “median cerebrofacial malformations,” and based on
the recommendations of van der Meulen et al.,
classified these malformations into four groups
(one alobar and three lobar brain anomalies):
I. “Holoprosencephalic dysplasias” included
those with alobar brain and agenesis of the
primary palate and associated midline
structures.
Patients with a lobar brain were further classified into:
I. Median cerebrofacial dysplasia: if there is
dysplasia of the median cerebral structures
associated with dysplasia of the midline facial structures.
II. Median facial dysplasia: if there is no gross
anomalies of the brain.
III. Microforms of median facial dysplasia: included microforms of deficient development of the median facial structures.
Unilateral or bilateral cleft lip and palate can
be found in any of the last three groups.
The essential features of maxillonasal dysplasia
were first described by Noyes and then later considered a true clinical entity by Binder.28,29 Although he
originally described it as a form of arhinencephaly,
it actually does not have brain abnormalities, and
patients have a normal sense of smell. The hypoplastic midface has characteristic features including
absent nasofrontal angle, nasal hypoplasia, flattened
nose, short columella, palpable depression in the
anterior nasal floor, localized alar base maxillary hypoplasia, and a convex upper lip with a broad philtrum. Radiographically, there is aplasia or hypoplasia of the anterior nasal spine, increase in the
nasomaxillary angle, and often hypoplastic/absent
frontal sinuses. Cephalometrically, sella-nasion distance and anteroposterior maxillary length are
reduced.17 The cause is considered to be a disturbance of the prosencephalic induction center during embryonic growth.30,31
Basal encephalocele (transsphenoidal and transethmoidal) is rare, and its incidence has been
estimated at one in 35,000 live births.32 The true
incidence of basal encephalocele is probably
higher because it may be asymptomatic and is not
detectable externally.33,34 Previously asymptomatic
basal encephaloceles with an intact palate may
even be detected by imaging for examination of
headache in adults.35
Basal encephaloceles may be reported in association with median cleft face anomaly, accompanied by ocular hypertelorbitism in 90 percent of
cases, median facial cleft in 79 percent of cases,
and bifid nose in 25 percent.11,23 Association of
basal encephaloceles with cleft lip and palate is
well documented in the literature. A large anterior
encephalocele has been reported with frontonasal
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Plastic and Reconstructive Surgery • February 2011
dysplasia.23,36 Guion-Almeida et al. reported 10
cases of basal encephaloceles in a series of 21 patients with frontonasal dysplasia.14 The anterior basal
encephalocele is frequently associated with coexisting anomalies in the face, optic system, and brain.
The most common anomalies are median cleft facial
syndrome, optic dysplasia, and agenesis of the corpus callosum.37 Hilaire proposed a theory for development of basal encephaloceles, postulating that the
anterior neuropore of the neural tube does not
close, and the anterior part of neuroectodermal
layer remains attached to the germinal layer of surface ectoderm. This adhesion interferes with the
mesoderm’s interposition between neuroectodermal and ectodermal layers, which is necessary for the
formation of skull base bones.38
“Median craniofacial hyperplasia” (tissue
excess or duplication) has also been called
“median cleft face syndrome, “frontonasal syndrome,” “frontonasal dysostosis,” and “frontonasal malformation.”17,21,22,39 The term “median
face cleft syndrome” implies clefting, which may
or may not be present in any given case. The
condition may also not present as a syndrome.
The term “dysostosis” is usually defined as a
malformation of bones; thus, the term “frontonasal dysostosis” overemphasizes the bony aspects without consideration of the brain. Finally,
the term “frontonasal malformation” implies a
developmental field defect or sequence. However, the condition may be pathogenetically heterogeneous and better thought of as a regional
defect.14
CONCLUSIONS
As can be witnessed through the historical classification of median craniofacial dysplasias, the
terminology and descriptions have been confusing and somewhat convoluted. This revised classification system has attempted to clarify these
midline anomalies by providing three main subclassifications of (1) hypoplasias, (2) dysraphias,
and (3) hyperplasias with related subtypes.
Henry K. Kawamoto, M.D., D.D.S.
Division of Plastic and Reconstructive Surgery
University of California, Los Angeles Medical Center
1301 20th Street, Suite 460
Santa Monica, Calif. 90404
[email protected]
PATIENT CONSENT
Parents or guardians provided written consent for
the use of patient images.
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Contribute to Plastic Surgery History
The Journal seeks to publish historical photographs that pertain to plastic and reconstructive surgery. We
are interested in the following subject areas:
• Departmental photographs
• Key historical people
• Meetings/gatherings of plastic surgeons
• Photographs of operations/early surgical procedures
• Early surgical instruments and devices
Please send your high-resolution photographs, along with a brief picture caption, via email to the Journal
Editorial Office ([email protected]). Photographs will be chosen and published at the Editor-inChief’s discretion.
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