IDEAS AND INNOVATIONS

Airway Analysis in Apert Syndrome

Antonio J. Forte, M.D.,
Background: Apert syndrome is frequently combined with respiratory insuf-
Ph.D.
ficiency, because of the midfacial deformity which, in turn, is influenced by
Xiaona Lu, M.D.
the malformation of the skull base. Respiratory impairment resulting from
Peter W. Hashim, M.D. Apert syndrome is caused by multilevel limitations in airway space. Therefore,
Derek M. Steinbacher, M.D., this study evaluated the segmented nasopharyngeal and laryngopharyngeal
D.M.D. anatomy to clarify subcranial anatomy in children with Apert syndrome and
Michael Alperovich, M.D. its relevance to clinical management.
John A. Persing, M.D.
Downloaded from https://journals.lww.com/plasreconsurg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3svV2EAJi192prX/P2vETAbkjHSlA+yqN3fS+IOXHYeM= on 09/03/2019

Methods: Twenty-seven patients (Apert syndrome, n = 10; control, n = 17)

Nivaldo Alonso, M.D., Ph.D.
Jacksonville, Fla.; Beijing, People’s
Republic of China; New Haven, Conn.;
and São Paulo, Brazil
were included. All of the computed tomographic scans were obtained from
the patients preoperatively, and no patient had confounding disease comor-
bidity. Computed tomographic scans were analyzed using Surgicase CMF. Cra-
niometric data relating to the midface, airway, and subcranial structures were
collected. Statistical significance was determined using t test analysis.
Results: Although all of the nasal measurements were consistent with those of
the controls, the nasion-to–posterior nasal spine, sphenethmoid-to–posterior
nasal spine, sella-to–posterior nasal spine, and basion-to–posterior nasal spine
distances were decreased 20 (p < 0.001), 23 (p = 0.001), 29 (p < 0.001), and 22
percent (p < 0.001), respectively. The distance between bilateral gonions and
condylions was decreased 17 (p = 0.017) and 18 percent (p = 0.004), respec-
tively. The pharyngeal airway volume was reduced by 40 percent (p = 0.01).
Conclusion: The airway compromise seen in patients with Apert syndrome
is attributable more to the pharyngeal region than to the nasal cavity, with a
gradually worsening trend from the anterior to the posterior airway, resulting
in a significantly reduced volume in the hypopharynx.  (Plast. Reconstr. Surg.
144: 704, 2019.)

P
atients with Apert syndrome frequently pres-
ent with respiratory function compromise,
even obstructive sleep apnea. In addition,
Apert syndrome results in a high-arched palate and
central groove, associated cleft palate, and bifid
uvula, all of which complicate breathing problems.
The correlation of the limited airway diameter,
volume, and respiratory function has been widely
studied in patients with craniosynostosis and in
individuals without craniosynostosis.1 The obstruc-
tive sleep apnea experienced by patients with Apert
syndrome is usually attributed to the extent of mid-
facial hypoplasia, which characterizes Apert syn-
drome among other syndromes.2,3 Theoretically,
the anteroposterior shortened midface length
should result in a shorter nasopharyngeal space,
which should alleviate some of the breathing com-
promise in syndromic patients based on airflow
dynamics analysis. That is, as airflow is measured
as it goes through a shorter tube, it diminishes the
potential energy expended (work) in comparison
with a longer tube with the same properties (same
diameter and texture). Apert syndrome patients,
however, with evident midfacial retrusion, develop
worsening airway obstruction over time. Dentino
et al.4 documented that syndromic craniosyn-
ostosis patients actually have a longer upper air-
way pathway, and there seems to be a correlation
between the severity of midfacial retraction and

From the Division of Plastic Surgery, Mayo Clinic; the

­Chinese Academy of Medical Sciences, Peking Union Medi-
cal College, Plastic Surgery Hospital; the Division of Plastic
and Reconstructive Surgery, Yale School of Medicine; and
the Department of Plastic Surgery, University of São Paulo.
Received for publication August 3, 2018; accepted February
6, 2019.
Copyright © 2019 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0000000000005937
Disclosure: The authors have no financial interest
to declare in relation to the content of this article.
Related digital media are available in the full-
text version of the article on www.PRSJournal.
com.

704 www.PRSJournal.com
Copyright © 2019 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
 Volume 144, Number 3 • Airway Analysis in Apert Syndrome
airway compromise. Doerga et al. considered that
the respiratory impairment of Apert syndrome was
attributable more to multilevel limitation of airway
space than to a single level,5 and there are varieties
of potential restriction sites. Therefore, the pur-
pose of this study was to evaluate nasopharyngeal
and laryngopharyngeal anatomy in children with
Apert syndrome and its relationship with subcra-
nial structure development using three-dimen-
sional measurements.
PATIENTS AND METHODS
This retrospective analysis was performed in
concordance with the Yale University Human
Investigation Committee (no. 1101007932). We
obtained computed tomographic scans of patients
without previous surgical intervention to correct
midfacial retrusion. Clinically diagnosed patients
with Apert syndrome and age- and sex-matched
controls without confounding abnormality were
included in the study.
Digital Imaging and Communications in Med-
icine data were measured using Surgicase CMF
software (version 5.0.0.32; Materialise, Leuven,
Belgium). Following segmentation, craniomet-
ric and volumetric analyses were performed fol-
lowing the same technique used in our previous
work.6–9 Volumetric and linear measurements are
described. (See Table, Supplemental Digital Con-
tent 1, which lists definitions of nasal measure-
ments, http://links.lww.com/PRS/D650. See Table,
Supplemental Digital Content 2, which lists defi-
nitions of airway measurements, http://links.lww.
com/PRS/D651.) An interobserver analysis was
performed in a series of test patients before the
completion of data analysis, and the intraclass cor-
relation coefficients were greater than 0.94. The
Mann-Whitney U test was used for age compari-
son, and the chi-square test was used for gender
comparison (IBM SPSS Version 24.0; IBM Corp.,
Armonk, N.Y.). A two-tailed t test was used for sta-
tistical analysis, and values of p ≤ 0.05 were con-
sidered significant. Two-tailed statistical power
analysis (alpha = 0.05) was performed for statisti-
cally significant values to ensure reliability.
RESULTS
Demographics
Twenty-seven patients were included in this
study, 10 in the Apert syndrome group (mean
age, 5.31 ± 5.04 years) and 17 in the control group
(mean age, 5.87 ± 3.62 years) (p = 0.77). Patients
with Apert syndrome consisted of four boys and
Copyright © 2019 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
six girls, and the control group had 10 boys and
seven girls (Table 1).
Nasal Cephalometry
Patients with Apert syndrome developed a 2
percent (p = 0.81) increase in nasal bone length
and an 11 percent (p = 0.15) increase in nasal bone
width. Nasal base width was decreased by 6 per-
cent (p = 0.40) in patients with Apert syndrome.
In addition, nasal tip projection and length were
increased by 9 (p = 0.24) and 2 percent (p = 0.73),
respectively. (See Table, Supplemental Digital
Content 3, which shows nasal measurements of
Apert syndrome patients versus controls, http://
links.lww.com/PRS/D652.)
Airway
The nasion-to–posterior nasal spine, sphen-
ethmoid-to–posterior nasal spine, and sella-to–
posterior nasal spine distances decreased 20
(p < 0.001), 23 (p = 0.001), and 29 percent
(p < 0.001), respectively. The distance between
basion and posterior nasal spine diminished by 22
percent (p < 0.001) as well (Fig. 1 and Table 2).
For the space around the oropharyngeal and
laryngopharyngeal space, the distance between
bilateral gonions and the distance between bilat-
eral condylions became proportionately short-
ened, by 17 (p = 0.017) and 18 percent (p = 0.004),
respectively, indicating a reduced bony diameter
in the mediolateral direction throughout the
length of oropharyngeal and laryngopharyngeal
airway. The distance from the posterior tongue
to the posterior pharyngeal wall was decreased
13 percent in patients with Apert syndrome com-
pared with the control group (1.00 ± 0.33 mm
versus 1.15 ± 0.32 mm), suggesting an antero-
posteriorly reduced diameter. [See Figure, Sup-
plemental Digital Content 4, which shows the
tongue-to-pharynx distance of 1-year-old male
control (left) and Apert syndrome (right) patients
(sagittal plane). The distance between the pos-
terior tongue and the posterior pharyngeal wall
of patients with Apert syndrome is insignificantly
Table 1.  Demographic Information
Apert
Syndrome Control p
Mean age ± SD, yr 5.31 ± 5.04 5.87 ± 3.62 0.505*
Sex
 Male 4 10
 Female 6 7 0.484†
 Total 10 17
*Mann-Whitney U test.
†χ2 test (Pearson χ2 = 0.490).
705
 Plastic and Reconstructive Surgery • September 2019

Fig. 1. Bony structure distance (with posterior nasal spine as a reference) developed significant shortening in a patient with Apert
syndrome (right) compared with a control patient (left) aged 6 years; male control and Apert syndrome patients are representative.

decreased compared with controls, http://links.
lww.com/PRS/D653.]
Correspondingly, the pharyngeal airway vol-
ume (Fig. 2) was significantly decreased in the
Apert syndrome group by 40 percent (2.54 ±
1.19 cm3) compared with the control group (4.20
± 1.97 cm3; p = 0.01). Nasal airway volume was also
decreased in the Apert syndrome group by 18 per-
cent (p = 0.25).
DISCUSSION
Previous studies have explored the use of
computed tomographic scan analysis when exam-
ining craniofacial malformation in patients with
Apert syndrome.10–14 This study is unique in that
it simultaneously measures cephalometric dis-
tances to integrate such data with both airway
volumetric analysis and bony structure cephalom-
etry. This better describes the overall deformity,
leading to a substantiated hypothesis on the etio-
pathogenesis of the significant functional airway
impairment.
Midfacial hypoplasia of bony structures in
patients with Apert syndrome is associated with
cranial base malformation and misshapen subcra-
nial anatomy.6,15,16 These abnormities could con-
tribute to deformed airway structures.17 Initially,
airflow begins at the nose, then the nasophar-
ynx, oropharyngeal, and hypopharynx area. Both
bony and soft-tissue analysis adds to the discussion
regarding the anatomical influences on patients
with respiratory insufficiency caused by Apert syn-
drome. Although soft-tissue movement during
inspiration and expiration is readily appreciated,
sleep-related muscle relaxation also contributes

Table 2.  Airway Measurements of Apert Syndrome Patients versus Controls

Variables Apert Syndrome Controls p Statistical Power (%)
Mean GOR-GOL ± SD, mm 64.54 ± 11.59 77.60 ± 9.62 0.017* 94.6
Mean COR-COL ± SD, mm 64.72 ± 9.34 79.19 ± 11.67 0.004* 99.8
Mean N-PNS ± SD, mm 47.13 ± 6.04 58.84 ± 7.45 <0.001* 100.0
Mean ES-PNS ± SD, mm 27.27 ± 4.12 35.22 ± 5.99 0.001* 100.0
Mean S-PNS ± SD, mm 27.35 ± 4.69 38.55 ± 5.05 <0.001* 100.0
Mean BA-PNS ± SD, mm 31.23 ± 4.91 40.07 ± 3.23 <0.001* 100.0
Mean tongue-pharynx distance ± SD, mm 1.00 ± 0.33 1.15 ± 0.32 0.29 —
Mean pharyngeal airway volume ± SD, cm3 2.54 ± 1.99 4.20 ± 1.97 0.01† 75.1
Mean nasal airway volume ± SD, cm3 8.02 ± 4.76 11.36 ± 4.08 0.1 —
GOR, right gonion; GOL, left gonion; COR, right condylion; COL, left condylion; N, nasion; PNS, posterior nasal spine; ES, ethmosphenoid
synchondrosis; S, sella; BA, basion.
*p < 0.01.
†p < 0.05.

706
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 Volume 144, Number 3 • Airway Analysis in Apert Syndrome

Fig. 2. Pharyngeal airway volume and nasal airway volume measurements represented on sagittal view show significantly less
pharyngeal airway volume in patients with Apert syndrome compared with controls. Computed tomographic scans of a 6-year-
old male control subject (left) and an Apert syndrome patient (right) were used as representative examples.

to understanding airway function.18 Segmented
structural analysis is beneficial in that it may pro-
vide individualized surgical planning for patients
with Apert syndrome with airway restriction
symptomatology.
Apert syndrome patients in this study basically
had normal nasal length, width, and projection,
which are consistent with the study by Rosenberg
et al. and our previous study.19,20 Consequently,
the nasal airway volume of patients with Apert
syndrome was similar to that of the control group.
Therefore, nasal surgery is likely not helpful for
improving the breathing function for this group
of patients.21
Doerga et al. considered that the respiratory
impairment of Apert syndrome was attributable
more to multilevel limitation of airway space than
to single-level limitation.5 Dentino et al. docu-
mented more evident posterior airway dimen-
sional limitation.4 Their study was supported by
the subcranial dimensions documented in this
study, illustrating that the bony structures around
the nasal and the nasopharyngeal space, from
anterior to posterior, become progressively more
reduced, which in turn results in significantly less
pharyngeal airway overall. These findings were in
accord with the clinical observation of patients
with Apert syndrome having more severe and fre-
quent breathing obstruction symptoms related
more to the laryngopharyngeal region than to the
nasopharyngeal region.5
The soft-tissue volume correlated with the
growth-restricted bony structure, to a certain
extent. The smaller mandible size, defined by
the proportionately shortened distance between
bilateral gonions and the distance between bilat-
eral condylions, was consistent with reduced bony
diameters. This was evident in the mediolateral
dimension throughout the entire length of the
oropharyngeal and the laryngopharyngeal air-
way. Considered together, the shortened distance
between the posterior nasal spine and basion indi-
cates an anteroposterior shortening of the laryn-
geal diameter. Therefore, the data support the
concept that airway compromise is related to the
bony structures in many horizontal dimensions.
Of note, the distance between the poste-
rior tongue and the posterior pharyngeal wall
in patients with Apert syndrome, compared with
controls, is only slightly decreased. It is noted
that the tension and movement of the surround-
ing soft-tissue structure changed with inspiration
and expiration and with patient head orientation
during computed tomography.22,23 These could be
influencing factors in this measurement. A stan-
dard protocol of positioning while obtaining com-
puted tomographic scans of patients with Apert
syndrome and controls is recommended for more
accurate comparison of this distance, including
the standard head orientation and hyoid bone
position (inspiration or expiration, with or with-
out swallowing, and with or without endotracheal
intubation).18,24

707
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 Plastic and Reconstructive Surgery • September 2019
However, the deviation and the reduced
distance between the posterior tongue and the
posterior pharyngeal wall suggest that soft-tissue
flaccidity, or insufficiency, may be more of an
influencing factor to patients with airway com-
promise caused by Apert syndrome. Therefore,
significant airflow improvement in patients after
maxillomandibular advancement, compared
with preoperatively, according to both poly-
somnographic findings and patients’ subjective
reports, likely relates to the enlarged pharyngeal
volume in the anteroposterior direction and
change in the relative position of surrounding
soft tissue.25,26 Furthermore, the facial bipartition
variation of Le Fort III osteotomy, or combining
bipartition with monobloc distraction, in young
children and adolescents, could yield additional
benefits. One could increase the mediolateral
width of the midface, and increase the width
of the mandible, by the complementary growth
mechanisms. Furthermore, the mediolateral
dimension of the pharyngeal airway may be
increased.1,12,27–30
The limitations of this study consist of its
small sample size (10 patients), as we included
only patients without confounding operations in
this study. In addition, there is a lack of correla-
tion with genetic and clinical data, as we focused
only on the natural history of patients with Apert
syndrome structural airway development. More-
over, the age variability, ranging from 11 months
to 12 years, may challenge the interpretations
despite the use of age-matched controls in this
study. There is also a wide phenotypic presen-
tation for Apert syndrome; correlation analysis
of real-time respiratory function detection, and
longitudinal airway volumetric measurement
could be more constructive for individualized
surgical planning. However, real-time moni-
toring and longitudinal study are not readily
performed.
CONCLUSIONS
The airway compromise of Apert syndrome
is attributable more to the pharyngeal region
than to the nasal cavity. Airway stenosis gradu-
ally worsens from anterior to posterior, result-
ing in significantly reduced volume in the
hypopharynx.
John A. Persing, M.D.
Section of Plastic and Reconstructive Surgery
Yale School of Medicine
330 Cedar Street, 3rd Floor Boardman Building
New Haven, Conn. 06520
john.persing@yale.edu
708
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