Khe Hở Môi Và Vòm Miệng: Chẩn Đoán Và Quản Lý Điều Trị (Cleft Lip and Palate)

281
11 Airway Management in Patients with Robin Sequence
oxygen supplement, or TLA in Fig. 11.1 .
Among the cohort requiring tracheostomy, 14
patients (56 %) were isolated and 11 patients
(44 %) were syndromic as shown in Fig. 11.2 .
Overall, the median time to decannulation was
97 months in Fig. 11.3 . The few patients with
syndromic RS who were successfully decan-
nulated required a median time >73 months as
compared to patients with isolated RS who had
a median time to decannulation of 19 months in
Fig. 11.4 . In total, 13 out of 25 infants (52 %)
were successfully decannulated without fur-
ther surgical intervention; only two patients
were syndromic and the remaining 11 patients
were isolated.
At mean follow-up of 4 years, the rate of
tracheostomy-speci fi c complications (e.g., cannula
obstruction or accidental decannulation, delays in
speech and language development, tracheomalacia
( fl accidity of the tracheal support cartilage)/
tracheitis, pneumonia) was 52 % and tracheostomy-
speci fi c mortality was 8 %. Patients with syndromic
RS stayed in the hospital signi fi cantly longer than
patients with isolated RS (50 versus 28 days,
respectively). There was one death in each group;
however, patients with syndromic RS had
signi fi cantly more events of end-organ dysfunction
(neurogenic, gastrointestinal, and/or cardiopulmo-
nary) per patient than patients with isolated RS
(2.08 versus 0.69, p = 0.005).
11.4
Discussion
Based upon the literature, approximately 2/3 of
patients with RS can be successfully managed
with conservative therapies (Kochel et al. 2011 ;
Gozu et al. 2010 ; Evans et al. 2006 ; Horikiri et al.
2010 ) . Prone positioning is often suf fi cient in less
severely affected patients but may result in pro-
longed hospitalization (Kochel et al. 2011 ; Sher
1992 ; Bhat et al. 2006 ) . NPA can be effective in
during the early clinical course to avoid emergent
tracheostomy, but dif fi cultly maintaining proper
position for an extended period of time has lim-
ited its use (Chang et al. 2000 ; Sher 1992 ; Kochel
et al. 2011 ; Masters et al. 1999 ; de Buys Roessingh
et al. 2007 ) . Lastly, orthopedic devices have been
61 RS Patients with obstructive events
25 Required Tracheostomy
11 Syndromic RS 14 Isolated RS
36 Managed with positioning,
non-invasive airways, or TLA
Fig. 11.1 Of 61 patients with obstructive events, 25
required tracheostomy, of which 11 were syndromic
(Stickler syndrome (a group of genetic disorders affecting
connective tissue), Treacher Collins (congenital craniofa-
cial syndrome), and others) and other 14 patients had iso-
lated Robin sequence
Robin Patients Treated with Tracheostomy
20%
4%
20%
56%
Stickler
Treacher collins
Other
Isolated
Fig. 11.2 Of 25 patients treated with tracheostomy, 44 %
(11 cases) were syndromic, of which 45 % (5 cases) was
either Stickler or other syndromes and 10 % (1 case) was
Treacher Collins and the other 56 % (14 cases) had iso-
lated RS
100
80
60
40
20
0
0
50
100
13 (52%) decannulated
Median Time: 97 months
All Patients
Months
Percent tracheotomized
150
200
Fig. 11.3 Of 25 infants treated with tracheostomy, 13
infants (52 %) were eventually decannulated with median
time to decannulation of 97 months

282
K.D. Han et al.
tried with success in a few small studies but these
devices are often expensive (Hotz and Gnoinski
1982 ; Buchenau et al. 2007 ; Kochel et al. 2011 ) .
More recently, Kochel et al. described the usage
of newer orthopedic devices as another noninva-
sive way to treat upper airway obstruction. Three
major types (plate with a posterior wire spur,
plate with a posterior acrylic extension, and plate
with a pharyngeal tube) of orthopedic devices
were used in seven patients based on their mecha-
nisms of the obstruction (Sher’s classi fi cations;
see Sect. 11.4 ). All of the seven patients had nor-
mal oxygen saturation upon discharge and at the
end of study period, fi ve out seven patients toler-
ated the removal of the orthopedic devices
(Kochel et al. 2011 ) .
Surgical modalities such as glossopexy or
TLA, mandibular distraction, mandibular exten-
sion, and subperiosteal release of fl oor of mouth
muscle have been studied extensively for their
effectiveness in avoiding or delaying tracheo-
stomy, improving polysomnographic results,
facilitating feeding, and bypassing or correct-
ing the anomalous anatomy. TLA, subperiosteal
release of fl oor of mouth muscle, and mandibular
distraction have been described most frequently
in the recent literature. TLA temporarily bypasses
the obstruction by creating a stable airway with
reported success rates between 70 and 100 %
(Denny et al. 2004 ; Bijnen et al. 2009 ; Kirschner
et al. 2003 ) . Dehiscence (breaking down of the
incision) still ranges between 0 and 57 % with a
mean of 30 % (Sher 1992 ; Marques et al. 2001 ;
Bookman et al. 2011 ) . Based on a few studies, the
need for a secondary invasive airway procedure
such as tracheostomy after subperiosteal release
ranges between 10 and 100 % (Delorme et al.
1989 ; Caouette-Laberge et al. 1996 ; Breugem
et al. 2008 ; Siddique et al. 2000 ) . Mandibular dis-
traction has been shown to improve polysomno-
graphic outcome, to avoid or delay tracheostomy,
and to expedite decannulation of a tracheostomy
(Scott et al. 2011 ; McCarthy et al. 1992 ; Denny
et al. 2001 ; Lin et al. 2006 ; Schaefer et al. 2004 ;
Schaefer and Gosain 2003 ) . Nevertheless, com-
plications such as infection, device failure, and
nonunion occur from 2.5 to 52 % (Caouette-
Laberge et al. 1994 ; McCarthy et al. 2002 ; Shetye
et al. 2009 ) . One large retrospective review of 141
infants with RS who underwent mandibular dis-
traction reported a 52 % overall complication rate
with a 5 % major complication rate – a complica-
tion that necessitated a secondary invasive therapy
(Shetye et al. 2009 ) .
Indications for surgical airway management
are also highly debated. While many clinicians
rely on a “gestalt” impression of airway obstruc-
tion, some have proposed data-driven clinical
parameters for airway management. Caouette-
Laberge et al. and Cole and colleagues proposed
grading systems based on the settings of respira-
tory obstruction (Caouette-Laberge et al. 1994 ;
Cole et al. 2008 ) . Caouette-Laberge grouped
125 infants with RS into three categories: (1)
adequate respiration in prone position and regu-
lar bottle-feeding, (2) adequate respiration in
prone position and dif fi culty with feeding, and
(3) endotracheal intubation (Caouette-Laberge
et al. 1994 ) . Parsons and Smith provided rule
of thumb criteria for TLA in infants with RS;
those who had progressive weight/strength gain
over a 7-day period did not require TLA, while
those infants who needed more than 3 days of
endotracheal airway support should receive TLA
(Parsons and Smith 1982 ) . Freed et al. reported on
the use of bedside monitoring and polysomnog-
raphy to objectively guide airway management
for infants with RS (Freed et al. 1988 ) . Criteria
for TLA included (1) an average transcutaneous
O 2 level below 60 mmHg or transcutaneous CO 2
Isolated RS: 19 months
Syndromic RS: >73 months
p = 0.019
Syndromic
Non-syndromic
0
0
20
40
60
80
100
Percent tracheotomized
50
100
Months
150
200
Fig. 11.4 Patients with syndromic RS had a median
time to decannulation of >73 months versus patients
with isolated RS had a median time to decannulation
of 19 months, p = 0.019

283
11 Airway Management in Patients with Robin Sequence
level over 50 mmHg for a minimum of 8 h, (2)
obstructive episodes on sleep study, and (3) oxy-
gen saturation below 80 %.
More recently, Rogers et al. described the
GILLS scoring system where one point was
assigned to each of the fi ve variables: g astroe-
sophageal re fl ux, i ntubation preoperatively, l ate
operation, l ow birth weight, and s yndromic diag-
nosis. TLA was 100 % successful in infants with
a GILLS score of 2 or less but failed in 43 % of
infants with a score of 3 or more (Rogers et al.
2011 ) . Sher detailed the use of fl exible fi ber optic
endoscopy to guide the form of surgical treatment
in infants with RS failing conservative measures.
Based upon nasopharyngoscopy and identi fi cation
of the site of obstruction, infant airways were
classi fi ed into four groups. Type I represented
airway obstruction solely due to glossoptosis,
while types II–IV had additional components of
obstruction. Regardless of airway classi fi cation,
all patients were initially treated with NPA place-
ment for up to 8 weeks. If conservative therapy
failed, type I patients received TLA and types
II–IV underwent tracheostomy (Sher 1992 ) .
Schaefer et al. described an algorithm for
approaching respiratory and nutritional dysfunc-
tion in infants with RS. Management decisions
were based upon the ability to maintain progress
on the growth curve, continuous pulse oximetry
and bedside polysomnography, and the site of
airway obstruction (Schaefer et al. 2004 ) . Finally,
data from our own institution (Fig. 11.5 ) from a
retrospective review of airway management in
patients with RS from 1994 to 2010 found that
four clinical factors ( MIST criteria) were most
associated with surgical airway management:
m aximum CO 2 > 62 mmHg, apnea–hypopnea
i ndex (index of sleep apnea severity) > 23.0
events/h, minimum O 2 s aturation < 79.4 %, and
greater than 5.7 % total sleep t ime with O 2 satura-
tion less than 90 %. Each of these parameters
identi fi ed operative intervention with 75–85 %
accuracy (Seruya et al. 2011 ) .
Despite the various procedures described for
surgical airway management, tracheostomy
remains the most de fi nitive treatment for infants
with severe respiratory obstruction that is not
compatible with life. In many cases, tracheos-
tomy is believed to be a temporary measure until
“natural” mandibular growth permits decannula-
tion. The topic of mandibular growth in patients
with RS has been heavily debated yet remains
poorly de fi ned. Some authors have documented
diminished mandibular size and proportions
compared age-adjusted norms while others have
cited evidence to the contrary (Shen et al. 2010 ;
Hermann et al. 2003 ; Daskalogiannakis et al.
2001 ; Figueroa et al. 1991 ) . Rogers et al. found
that mandibular length was shorter in all patients
with RS irrespective of the type of airway
management, and the differences in both man-
dibular length and sagittal position varied
signi fi cantly among all the syndromic subtypes
(Rogers et al. 2009 ) . Maalouf et al. found that
60 % of patients who received bilateral mandibu-
lar distraction maintained proportionate facial
symmetry at the median follow-up time of
57 months; mandibular size, however, was not
evaluated (Maalouf and Lehman 2011 ) . Finally,
Pruzansky and Richmond demonstrated the
opportunity for “catch-up” growth of the mandi-
ble without the need for invasive procedures aside
MIST Criteria for Surgical Airway Management
Apnea-hypopnea Index > 23.0 events/hr
Minimum oxygen Saturation < 79.4%
Total sleep Time with O2 saturation less then 90% > 5.7%
Maximum CO2 > 62 mm Hg
•
•
•
•
Fig. 11.5 MIST criteria for
surgical airway management
of patients with Robin
sequence ( RS )

284
K.D. Han et al.
from a temporary tracheostomy (Pruzansky and
Richmond 2005 ) . Overall, these studies highlight
the phenotypic heterogeneity of patients with RS,
which may stem from the dissimilar mandibular
growth kinetics of isolated versus syndromic
patients.
In our retrospective study of 61 infants with
RS, 25 patients required tracheostomy (14 cases of
isolated RS and 11 cases syndromic RS). This is
one of the largest published cohorts of RS children
with tracheostomy that have been followed to ana-
lyze rates of eventual decannulation due to man-
dibular growth without other ancillary surgical
interventions. The median time to decannulation
in our cohort was longer (97 months) than what
other smaller series have reported (Tomaski et al.
1995 ; Demke et al. 2008 ) . Patients with syndromic
RS largely contributed to this extended time
course, as most of them could not be decannulated
by the completion of the study. Outcomes follow-
ing tracheostomy were signi fi cantly poorer in
patients with syndromic RS as compared to those
with isolated RS: patients with syndromic RS had
longer hospital stay and more long-term complica-
tions as compared to patients with isolated RS.
Summary and Conclusion
Airway management in patients with RS and
severe airway obstruction remains controver-
sial. The bene fi ts of various surgical airway
procedures, as well as indications for inter-
vention, are unclear and based upon imperfect
data. Our experience with these complex
patients has documented some factors associ-
ated with the need for surgical intervention,
but these criteria await validation in a random-
ized prospective trial. We have also found that
although tracheostomy was intended to be a
temporary airway for these patients, the time
to natural decannulation was longer than
expected. This may be partially explained by
the mandible’s inability to “catch up” in
growth, especially in syndromic patients. We
are planning further study into these issues by
means of a prospective trial that will incorpo-
rate serial lateral cephalograms to document
mandibular growth as well as offer mandibu-
lar distraction as a surgical modality to patients
with severe airway obstruction. Based on our
experience, we believe that all potential treat-
ment options should be exhausted before
offering tracheostomy to syndromic patients
with Robin sequence.
Financial Disclosure Information The authors have no
fi nancial or commercial interests to disclose.
Con fl ict of Interest
None
References
Bhat RY, Hannam S, Pressler R, Rafferty GF, Peacock JL,
Greenough A (2006) Effect of prone and supine posi-
tion on sleep, apneas, and arousal in preterm infants.
Pediatrics
118(1):101–107.
doi: 118/1/101
[pii]
10.1542/peds.2005-1873
Bijnen CL, Don Griot PJ, Mulder WJ, Haumann TJ, Van
Hagen AJ (2009) Tongue-lip adhesion in the treatment
of Pierre Robin sequence. J Craniofac Surg 20(2):315–
320. doi: 10.1097/SCS.0b013e31819ba5ce
Bookman LB, Melton KR, Pan BS, Bender PL, Chini BA,
Greenberg JM, Saal HM, Taylor JA, Elluru RG (2011)
Neonates with tongue-based airway obstruction: a sys-
tematic review. Otolaryngol Head Neck Surg.
doi: 0194599811421598 [pii] 10.1177/0194599811421598
Breugem CC, Olesen PR, Fitzpatrick DG, Courtemanche DJ
(2008) Subperiosteal release of the fl oor of the mouth in
airway management in Pierre Robin sequence. J Craniofac
Surg 19(3):609–615. doi: 10.1097/SCS.0b013e31816aab0b
00001665-200805000-00009 [pii]
Buchenau W, Urschitz MS, Sautermeister J, Bacher M,
Herberts T, Arand J, Poets CF (2007) A randomized
clinical trial of a new orthodontic appliance to improve
upper airway obstruction in infants with Pierre Robin
sequence. J Pediatr 151(2):145–149. doi: S0022-
3476(07)00234-X [pii] 10.1016/j.jpeds.2007.02.063
Bull MJ, Givan DC, Sadove AM, Bixler D, Hearn D
(1990) Improved outcome in Pierre Robin sequence:
effect of multidisciplinary evaluation and manage-
ment. Pediatrics 86(2):294–301
Bush PG, Williams AJ (1983) Incidence of the Robin
Anomalad (Pierre Robin syndrome). Br J Plast Surg
36(4):434–437. doi: 0007-1226(83)90123-6 [pii]
Caouette-Laberge L, Bayet B, Larocque Y (1994) The
Pierre Robin sequence: review of 125 cases and evolu-
tion of treatment modalities. Plast Reconstr Surg
93(5):934–942
Caouette-Laberge L, Plamondon C, Larocque Y (1996)
Subperiosteal release of the fl oor of the mouth in
Pierre Robin sequence: experience with 12 cases. Cleft
Palate Craniofac J 33(6):468–472

285
11 Airway Management in Patients with Robin Sequence
Chang AB, Masters IB, Williams GR, Harris M, O’Neil MC
(2000) A modi fi ed nasopharyngeal tube to relieve high
upper airway obstruction. Pediatr Pulmonol 29(4):
299–306.
doi:10.1002/(SICI)1099-0496(200004)29:4
<299::AID-PPUL10>3.0.CO;2-U [pii]
Cole A, Lynch P, Slator R (2008) A new grading of Pierre
Robin sequence. Cleft Palate Craniofac J 45(6):603–
606. doi: 07-129 [pii] 10.1597/07-129.1
Cruz MJ, Kerschner JE, Beste DJ, Conley SF (1999) Pierre
Robin sequences: secondary respiratory dif fi culties and
intrinsic feeding abnormalities. Laryngoscope 109(10):
1632–1636. doi: 10.1097/00005537-199910000-00016
Daskalogiannakis J, Ross RB, Tompson BD (2001) The
mandibular catch-up growth controversy in Pierre
Robin sequence. Am J Orthod Dentofacial Orthop
120(3):280–285. doi: S0889-5406(01)02513-6 [pii]
10.1067/mod.2001.115038
de Buys Roessingh AS, Herzog G, Hohlfeld J (2007) Respiratory
distress in Pierre Robin: successful use of pharyngeal tube. J
Pediatr Surg 42(9):1495–1499. doi: S0022-3468(07)00270-9
[pii] 10.1016/j.jpedsurg.2007.04.024
Delorme RP, Larocque Y, Caouette-Laberge L (1989)
Innovative surgical approach for the Pierre Robin
anomalad: subperiosteal release of the fl oor of the
mouth musculature. Plast Reconstr Surg 83(6):960–
964; discussion 965–966
Demke J, Bassim M, Patel MR, Dean S, Rahbar R, van
Aalst JA, Drake A (2008) Parental perceptions and
morbidity: tracheostomy and Pierre Robin sequence.
Int J Pediatr Otorhinolaryngol 72(10):1509–1516.
doi: S0165-5876(08)00316-9
[pii]
10.1016/j.
ijporl.2008.07.002
Denny AD, Talisman R, Hanson PR, Recinos RF (2001)
Mandibular distraction osteogenesis in very young
patients to correct airway obstruction. Plast Reconstr
Surg 108(2):302–311
Denny AD, Amm CA, Schaefer RB (2004) Outcomes of
tongue-lip adhesion for neonatal respiratory distress
caused by Pierre Robin sequence. J Craniofac Surg
15(5):819–823. doi: 00001665-200409000-00023 [pii]
Dykes EH, Raine PA, Arthur DS, Drainer IK, Young DG (1985)
Pierre Robin syndrome and pulmonary hypertension.
J Pediatr Surg 20(1):49–52. doi: S0022346885000069 [pii]
Evans AK, Rahbar R, Rogers GF, Mulliken JB, Volk MS
(2006) Robin sequence: a retrospective review of 115
patients. Int J Pediatr Otorhinolaryngol 70(6):973–
980. doi: S0165-5876(05)00499-4 [pii] 10.1016/j.
ijporl.2005.10.016
Figueroa AA, Glupker TJ, Fitz MG, BeGole EA (1991)
Mandible, tongue, and airway in Pierre Robin
sequence: a longitudinal cephalometric study. Cleft
Palate Craniofac J 28(4):425–434. doi:10.1597/1545-
1569(1991) 028<0425:MTAAIP>2.3.CO;2
Freed G, Pearlman MA, Brown AS, Barot LR (1988)
Polysomnographic indications for surgical interven-
tion in Pierre Robin sequence: acute airway manage-
ment and follow-up studies after repair and take-down
of tongue-lip adhesion. Cleft Palate J 25(2):151–155
Gozu A, Genc B, Palabiyik M, Unal M, Yildirim G,
Kavuncuoglu S, Ozsoy Z (2010) Airway management
in neonates with Pierre Robin sequence. Turk J Pediatr
52(2):167–172
Hermann NV, Kreiborg S, Darvann TA, Jensen BL, Dahl E,
Bolund S (2003) Early craniofacial morphology and
growth in children with nonsyndromic Robin Sequence.
Cleft Palate Craniofac J 40(2):131–143. doi:10.1597/1545-
1569(2003) 040<0131:ECMAGI>2.0.CO;2
Hoffman S, Kahn S, Seitchik M (1965) Late problems in
the management of the Pierre Robin syndrome. Plast
Reconstr Surg 35:504–511
Horikiri M, Park S, Kinoshita M, Matsumoto D (2010)
Respiratory management of Pierre Robin sequence using
nasopharyngeal airway with Kirschner wire. J Plast Reconstr
Aesthet Surg 63(4):e390–e394. doi: S1748-6815(09)00720-7
[pii] 10.1016/j.bjps.2009.09.023
Hotz M, Gnoinski W (1982) Clefts of the secondary pal-
ate associated with the “Pierre Robin syndrome”.
Management by early maxillary orthopaedics. Swed
Dent J Suppl 15:89–98
Kapp-Simon KA, Krueckeberg S (2000) Mental develop-
ment in infants with cleft lip and/or palate. Cleft Palate
Craniofac J 37(1):65–70
Kirschner RE, Low DW, Randall P, Bartlett SP, McDonald-
McGinn DM, Schultz PJ, Zackai EH, LaRossa D
(2003) Surgical airway management in Pierre Robin
sequence: is there a role for tongue-lip adhesion? Cleft
Palate Craniofac J 40(1):13–18
Kochel J, Meyer-Marcotty P, Wirbelauer J, Bohm H,
Kochel M, Thomas W, Bareis U, Hebestreit H, Speer
C, Stellzig-Eisenhauer A (2011) Treatment modalities
of infants with upper airway obstruction-review of the
literature and presentation of novel orthopedic appli-
ances. Cleft Palate Craniofac J 48(1):44–55.
doi: 10.1597/08-273
Lin SY, Halbower AC, Tunkel DE, Vanderkolk C (2006)
Relief of upper airway obstruction with mandibular dis-
traction surgery: long-term quantitative results in young
children. Arch Otolaryngol Head Neck Surg 132(4):437–
441. doi: 132/4/437 [pii] 10.1001/archotol.132.4.437
Maalouf M, Lehman JA (2011) Long term outcome of
mandibular distraction for airway obstruction. In:
American Cleft Palate-Craniofacial Association, San
Juan, March 2011
Marques IL, de Sousa TV, Carneiro AF, Barbieri MA,
Bettiol H, Gutierrez MR (2001) Clinical experience
with infants with Robin sequence: a prospective study.
Cleft Palate Craniofac J 38(2):171–178
Masters IB, Chang AB, Harris M, O’Neil MC (1999)
Modi fi ed nasopharyngeal tube for upper airway
obstruction. Arch Dis Child 80(2):186–187
Matsas R, Thomson A, Goodacre T (2004) Management
of infants with Pierre Robin sequence. Cleft Palate
Craniofac J 41(2):219. doi: 03-208 [pii]
McCarthy JG, Schreiber J, Karp N, Thorne CH, Grayson BH
(1992) Lengthening the human mandible by gradual dis-
traction. Plast Reconstr Surg 89(1):1–8; discussion 9–10

286
K.D. Han et al.
McCarthy JG, Katzen JT, Hopper R, Grayson BH (2002)
The fi rst decade of mandibular distraction: lessons we
have learned. Plast Reconstr Surg 110(7):1704–1713.
doi: 10.1097/01.PRS.0000036260.60746.1B
Moyson F (1961) A plea against tracheostomy in the
Pierre-Robin syndrome. Br J Plast Surg 14:187–189.
doi: S0007-1226(61)80035-0 [pii]
Parsons RW, Smith DJ (1982) Rule of thumb criteria for
tongue-lip adhesion in Pierre Robin anomalad. Plast
Reconstr Surg 70(2):210–212
Pruzansky S, Richmond JB (2005) Pierre Robin sequence.
In: Berkowitz S (ed) Cleft lip and palate: diagnosis and
management, 2nd edn. Springer, New York, pp 215–222
Rogers GF, Lim AA, Mulliken JB, Padwa BL (2009)
Effect of a syndromic diagnosis on mandibular size and
sagittal position in Robin sequence. J Oral Maxillofac
Surg 67(11):2323–2331. doi: S0278-2391(09)01330-5
[pii] 10.1016/j.joms.2009.06.010
Rogers GF, Murthy AS, LaBrie RA, Mulliken JB (2011)
The GILLS score: part I. Patient selection for tongue-
lip adhesion in Robin sequence. Plast Reconstr Surg
128(1):243–251. doi: 10.1097/PRS.0b013e318217420d
00006534-201107000-00036 [pii]
Sadewitz VL (1992) Robin sequence: changes in thinking
leading to changes in patient care. Cleft Palate
Craniofac J 29(3):246–253
Schaefer RB, Gosain AK (2003) Airway management in
patients with isolated Pierre Robin sequence during
the fi rst year of life. J Craniofac Surg 14(4):462–467
Schaefer RB, Stadler JA 3rd, Gosain AK (2004) To distract or
not to distract: an algorithm for airway management in iso-
lated Pierre Robin sequence. Plast Reconstr Surg 113(4):
1113–1125. doi: 00006534-200404010-00001 [pii]
Scott AR, Tibesar RJ, Lander TA, Sampson DE, Sidman
JD (2011) Mandibular distraction osteogenesis in
infants younger than 3 months. Arch Facial Plast Surg
13(3):173–179. doi: archfacial.2010.114 [pii] 10.1001/
archfacial.2010.114
Seruya M, Kureshi S, Sarhaddi D, Han KD, Goldstein JA,
Baumgart S, Preciado DA, Oh AK (2011) Clinical fac-
tors associated with surgical airway management of
patients with Robin sequence. Children’s National
Medical Center, Washington, D.C
Shen Y, Vargervik K, Oberoi S, Chigurupati R (2010)
Facial skeletal morphology in growing children with
Pierre Robin sequence. Cleft Palate Craniofac
J. doi: 10.1597/09-154
Sher AE (1992) Mechanisms of airway obstruction in
Robin sequence: implications for treatment. Cleft
Palate Craniofac J 29(3):224–231
Shetye PR, Warren SM, Brown D, Gar fi nkle JS, Grayson
BH, McCarthy JG (2009) Documentation of the inci-
dents associated with mandibular distraction: introduc-
tion of a new strati fi cation system. Plast Reconstr Surg
123(2):627–634. doi: 10.1097/PRS.0b013e3181956664
00006534-200902000-00025 [pii]
Siddique S, Haupert M, Rozelle A (2000) Subperiosteal
release of the fl oor of the mouth musculature in two
cases of Pierre Robin sequence. Ear Nose Throat
J 79(10):816–819
Tomaski SM, Zalzal GH, Saal HM (1995) Airway obstruc-
tion in the Pierre Robin sequence. Laryngoscope 105(2):
111–114. doi: 10.1288/00005537-199502000-00001
Wagener S, Rayatt SS, Tatman AJ, Gornall P, Slator R
(2003) Management of infants with Pierre Robin
sequence. Cleft Palate Craniofac J 40(2):180–185

287
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DOI 10.1007/978-3-642-30770-6_12, © Springer-Verlag Berlin Heidelberg 2013
12
12.1 Growth of Mandible in Infants
with Micrognathia (Pruzansky
and Richmond 1954 )
Since Pierre Robin fi rst described the syndrome
of hypoplasia of the mandible, cleft palate,
glossoptosis, inspiratory retraction of the ster-
num, cyanosis, and malnutrition which has come
to bear his name (Robin 1929, 1934 ) , numerous
reports of cases have appeared in the literature.
The fatal termination of some cases is a testimony
of the serious nature of the syndrome. Although
a variety of mechanical and surgical therapeutic
procedures have been suggested (Eley and Farber
1930 ; Davis and Dunn 1933 ; Callister 1937 ;
Lleweyllyn and Biggs 1943 ; Douglas 1946 ;
Nisenson 1948 ; Longmire and Sandford 1949 ;
May and Chun 1948 ) , a rationale for the proper
management of individual patients has not been
adequately presented. It is the purpose of this
communication to present observations from the
serial studies of patients with this disorder, upon
which a physiologic approach to management
may be based.
It is generally agreed that the pathophysiologic
events in this syndrome are as follows: the reced-
ing chin fails to support the tongue in its normal
forward relationship and hence fosters the
glossoptosis. The retroposed tongue impinges
against the posterior wall of the pharynx, obstruct-
ing inspiration and impeding feeding. Slight
excess in mucus or saliva tends to enhance the
pharyngeal obstruction and may precipitate severe
cyanotic seizures, resulting in death. Starvation
and respiratory infections, or both, may follow as
a consequence of the chronic glossoptosis.
Since the major symptoms are de fi nitely
related to the micrognathia, it was of special
interest to focus our attention upon the growth of
the mandible in these infants. In reviewing the
published case reports, it appeared that two ques-
tions, basic to an understanding of a more appro-
priate management of these cases, remained
unanswered. The fi rst question could be phrased
as follows: How soon would mandibular growth
be suf fi cient to accommodate the tongue and
hence insure a more adequate airway? This is
assuming that the infant could be placed in an
adequate metabolic climate. The answer to this
question would have an important baring on
immediate management. The second question is
related to whether or not mandibular growth
would be suf fi ciently sustained to provide an
esthetically satisfactory facial pro fi le.
The answer to these questions had to await the
development of accurate roentgenographic tech-
niques for measuring the growth of the head in
infants, which made it possible to undertake a
Pierre Robin Sequence
Samuel Pruzansky and Julius B. Richmond
With some additional photographs by Samuel Berkowitz, DDS, MS
S. Pruzansky , DDS, (Deceased)
Cleft Palate Craniofacial Center,
University of Illinois ,
Chicago , IL , USA
J. B. Richmond , M.D. (Deceased)
Department of Plastic Surgery , University of Illinois ,
Chicago , IL , USA

288
S. Pruzansky and J.B. Richmond
serial study of the growth of the micrognathic
mandible. The results of these investigations have
provided useful information as a basis for therapy
and prognosis.
During the past 25 years, cephalometric
roentgenography has produced valuable infor-
mation pertaining to the growth of the head in
normal (Brodie 1941a, b ) and pathologic con-
ditions (Brodie 1941a, b ) in man. In addition
to the cephalometric roentgenographic mea-
surements, dental impressions of the maxil-
lary arch were obtained at regular intervals.
The impressions were cast in dental stone and
then subjected to various measurements. The
infants were recalled for study every 3 months
during the fi rst year of life and twice annually
until the age of 5 years. Thereafter, they were
observed annually.
From a large series of similar cases now under
longitudinal study at the Cleft Palate Center of
the University of Illinois (Pruzansky 1953 ) , we
have selected three cases for presentation. At
birth, each of these infants presents an isolated
cleft of the palate and mandibular micrognathia.
Despite these similarities, certain important dif-
ferences existed to vary the management and
progress of each infant. The differences to be
described in each of these cases represent the
major variations which we have encountered in
our experience with this syndrome. For the sake
of brevity, the case history will be con fi ned to
such information as is directly pertinent to the
purpose of this chapter.
12.1.1 Case 1
At 2 months of age, D.R.P., a small white dehy-
drated baby girl, was admitted to the Research
and Educational Hospital, with the principal
complaint of intermittent pneumonitis for the
previous 5 weeks. After a normal full-term spon-
taneous delivery, it was noted that the baby had
an isolated cleft palate and a small mandible. The
birth weight was 5 lb 13 oz (2,640 g). Feeding
had been dif fi cult because of the tendency of the
baby’s tongue to fall back into the pharynx. There
was no history of a cleft on either side of the fam-
ily. The mother gave no history of being exposed
to a contagious disease or other illness during her
fi rst trimester of pregnancy (Fig. 12.1 ) .
Because of the patient’s congenital defects,
she presented primarily a feeding problem. An
attempt was made to design an obturator so that
the baby could be bottle-fed. This was met with
failure, and gastric gavage was necessary.
However, the patient did not gain weight and
continued to do poorly. Approximately 1 month
after admission, it was considered that a trache-
otomy was the only procedure which might
Fig. 12.1 ( a ) Serial cephalometric tracing of a child with
Pierre Robin sequence showing a severely micrognathic
mandible. At 3–4–13, there is a big increase in the
pharyngeal space ( darkened area ). ( b ) Superimposed
tracings at 2 months and 10 days (0–2–10) and 3 years,
4 months, and 13 days (3–4–13) shows a rapidly growing
micrognathic mandible (Reprinted with permission from
Pruzansky ( 1953 ) )

289
12 Pierre Robin Sequence
possibly save the baby’s life. After the tracheot-
omy, respiration was greatly facilitated, and soon
the patient was removed from the oxygen tent.
Her improvement thereafter was constant. The
patient was discharged from the hospital 3 months
after admission, at 5 months of age.
Growth Studies: Oral examination disclosed a
cleft involving the one-half of the hard palate and
extending posteriorly throughout the length of
the soft palate. Ptosis of the tongue was evident.
On the fi fth day following the tracheotomy, at
the age of 3 months 1 day, the fi rst lateral fi lm
was obtained without sedation. A tracing of this
fi lm revealed that the head was in slight
dorsi fl exion, the position of greatest comfort for
the infant. The relative smallness of the mandible
and its effect on the facial pro fi le was self-evi-
dent. In relation to contiguous anatomical struc-
tures, the posture of the tongue was abnormal. It
projected through the cleft in the palate into the
nasal cavity (Fig. 12.2 ).
In the lateral head plate, the dorsum of the
tongue was visible at a level above the palatal
plane. Posteriorly, the tongue impinged on the
airway. The posterior surface of the tongue, just
above the epiglottis, was in close approximation
to the posterior outline of the pharyngeal wall. At
this level, the airway was almost completely
occluded. The tracheotomy tube was in place.
The airway in its posteroanterior dimensions is
Fig. 12.2 Pierre Robin sequence. A series of tracings of the
lateral fi lm from 3 months, 1 day of age (0–3–1) to 3 years,
5 months, 12 days (3–5–12). The pharyngeal airway is fi lled
in ( black ), and the stippled area denotes the border of the
tongue. A tracheotomy tube is visible in the fi rst two fi lms.
Soon after birth (3 and 4 months of age), the dorsum of the
tongue is visible at a level above the palatal plane within the
palatal cleft space. Posteriorly, the tongue just above the
epiglottis impinged on the airway. At this level, the airway
was almost completely occluded. Comparison with the
remaining three fi gures, ages 0–8–10, 1–1–0, and 3–5–12,
reveals the con fi guration of these structures under normal
circumstances after closure of the cleft. The airway in its
posteroanterior dimensions is fairly wide, and the tongue
occupies a more protrusive relationship to the mandible
(Reprinted with permission from Pruzansky ( 1954 ))

290
S. Pruzansky and J.B. Richmond
fairly wide, and the tongue occupies a more pro-
trusive relationship to the mandible.
The second fi lm in Fig. 12.2 , obtained less than
6 weeks later, at the age of 4 months 13 days,
revealed considerable enlargement of the airway.
At the same time, a considerable increment in the
growth of the head and, above all, of the mandible
was recorded. Subsequent fi lms, up to the age of
3 years 5 months 12 days, gave proof of the gradual
and continued growth of the lower jaw in relation
to the total face and the increase in the dimensions
of the pharyngeal airway. At 8 months following
removal of the tracheotomy tube, the air passage
was demonstrated to be quite adequate (Fig. 12.2 ).
The superimposed tracings, from 3 months 1 day
of age to 3 years 5 months 12 days, reveal the pro-
gressive growth of the cranial vault, the maxilla, and
the middle face and the increase in length and height
of the mandible (Fig. 12.1b ). Gradual improvement
in the facial pro fi le was recorded by the changes in
the facial angle and in the angle of convexity. The
facial angle is a measure of the degree of protrusion
or recession of the chin. In this instance, the facial
angle increased from 64°, at 3 months of age, to
70°, at the age of 3 1/2 years, indicating a reduction
by 6° in the recessiveness of the chin. While the
mandible is still in a retrusive relation to the rest of
the face, the potential for further improvement with
continued growth still exists.
The changes in the angle of convexity were more
interesting. This measurement relates the maxilla
to the total facial pro fi le. At 3 months of age, the
angle of convexity was 140°, and at 3 1/2 years
it measured at 154°. The integrated growth of the
several areas of the face was such as to improve
the overall con fi guration of the facial pro fi le. Serial
photographs at 2 months, at 13 months, and at
3 years of age further testify to the changes in this
child’s face. In the last photograph, the patient is
posed beside her older sibling.
The changes in the position of the hyoid bone
are of particular interest, insofar as they re fl ect a
change in the relative position of the tongue. The
tongue is composed of several individual muscles
originating from the base of the skull, the mandi-
ble, the hyoid bone, and the walls of the pharynx.
Changes in the position of any of its bony or
fi brous attachments would tend to re fl ect on the
position of the tongue. Conversely, changes in the
posture of the tongue would re fl ect on the spatial
relations of the mandible and hyoid bone.
Therefore, to study the position of the hyoid bone
is, in a sense, to study the position of the tongue.
With growth, there occurs a forward and downward
migration of the hyoid bone from the base of the
skull. The pattern of changes in the posture of the
hyoid bone observed in this patient sheds further
light on the favorable adjustments consequent to
growth. During the fi rst 5 months of our studies,
the hyoid bone migrated downward and forward.
This resulted in an increase in the angle S-N-H.
But, from 8 months onward, this angle became
fairly stable and the hyoid bone began to descend
principally in a downward direction.
Comment: This case was selected to typify the
fi ndings in several similar cases, one of which has
been followed to the age of 7 years. Not all cases
of Pierre Robin syndrome present such acute his-
tories. When clinical evaluation suggests that
there will be no improvement or that possibly
death may ensue, tracheotomy should be under-
taken without hesitation to prevent further aggra-
vation of the symptoms. Once an adequate
respiratory exchange was made possible, improve-
ment in oxygenation and feeding followed. In
such instances, we have recorded rapid growth
and favorable changes in the facial appearance.
12.1.2 Case 2
J.G, a white girl, was referred to the outpatient
clinic of the Cleft Palate Center at the age of
2 months with a diagnosis of cleft palate and man-
dibular micrognathia. Following an uneventful
pregnancy, the delivery was normal and at full term.
The birth weight was 6 lb 11 oz (3,030 g). The
infant had some dif fi culty in breathing, but this was
relieved by placing her in a prone position. Tube
feeding was employed for the fi rst few days after
which she was given bottle feedings. At 6 days of
age, the infant was discharged from the hospital.
There was no family history of cleft palate. The
mother suffered no illness during her pregnancy.
Oral examination revealed an unusually small
tongue closely attached to the fl oor of the mouth.
In the course of our fi rst examination under seda-
tion, the infant became cyanotic and failed to initi-
ate mandibular movements suf fi cient to permit
the passage of air. This was relieved immediately

291
12 Pierre Robin Sequence
by maintaining forward traction on the tongue and
mandible. After about 5 min, the infant recovered
control of mandibular movements and respiration
normally. Aside from this isolated episode, which
occurred under sedation, the parents did not report
any similar dif fi culties. The child has continued to
grow and develop at a satisfactory rate.
Growth Studies: The casts disclose symmet-
rical cleft of the hard and soft palate, extending
distally from the region of the nasopalatine
foramen. Additional casts obtained at regular
intervals revealed that the cleft had narrowed,
so that it now presents a narrow V-shaped defect
(Figs. 12.3 and 12.4 ).
a
b
0.2.10
1.2.2.3
2.1.5
2.10.7
3.11.6
6.1.1
Fig. 12.3 ( a , b ) Palatal growth changes in a child with a
Pierre Robin sequence. This sequence is characterized by
glossoptosis, micrognathia, and isolated cleft palate. In
many cases, the cleft palate which is initially wide at birth
can spontaneously narrow with palatal growth. ( a ) Computer-
generated tracings of the isolated cleft of the hard palate
from 2 months and 10 days (0–2–10) to 6 years, 1 month,
and 1 day (6–1–1). The palate was closed at 4 years,
2 months. ( b ) Superimposed tracings of each cast (on
the baseline created by connecting postgingivale points (the
posterior limits of the hard palate) and registered at the
bisector of the line) show that the length of the cleft increases
with palatal growth and narrows due to spontaneous growth
at the medial border of the palatal processes. Obturators
which interfere with tongue posturing within a relatively
small intraoral space are contraindicated (Berkowitz 1996 )

292
S. Pruzansky and J.B. Richmond
The earliest lateral head palate, at 2 months
10 days of age, displayed a small mandible and
small tongue. The latter was positioned high and
above the fl oor of the nose, but relatively remote
from the posterior wall of the pharynx. The air-
way appeared suf fi cient to sustain respiration
without any undue effort on the part of the infant.
Progressive growth changes recorded up to the
age of 3 years, 4 months, 13 days disclosed man-
dibular growth and generalized growth in all
areas of the face and cranial vault. Mandibular
growth was continuous and progressively down-
ward and forward. During the period studied,
from 2 to 40 months of age, the facial angle
increased from 61.5, becoming more obtuse. The
angle of convexity increased from 147° to 155°.
Altogether, the changes were in a direction
tending to minimize the recessiveness of the chin
in relation to the rest of the face.
Comment: Micrognathia by itself is not
suf fi cient to produce glossoptosis and respira-
tory embarrassment. If the tongue is large or
even normal in size, the small recessive man-
dible will tend to displace the tongue distally
and superiorly. It is this displacement that
produces the respiratory obstruction both into
the hypopharynx and into the posterior choa-
nae. On the other hand, if the tongue is small,
there will be no obstruction of the airway even
in the presence of a micrognathic mandible.
In this instance, the simultaneous occurrence
of micrognathia and microglossia averted the
respiratory dif fi culties commonly experienced
in such instances.
The tendency to lose re fl ex control of the mus-
cles of respiration and deglutition under anesthe-
sia or sedation renders such procedures unusually
hazardous in these patients because of the limited
reserve. It is, therefore, important that such pro-
cedures be undertaken with full knowledge and
anticipation of possible respiratory obstruction,
in order that adequate emergency provisions for
the establishment of an airway be available.
12.1.3 Case 3
E.C., a white boy aged 5 weeks, was referred to
the outpatient clinic of the Cleft Palate Center for
longitudinal growth studies. The delivery had
been normal and at full term. His birth weight
was 7 lb 8 oz (3,400 g). There was no history of
Fig. 12.4 A series of cast of
the maxillary arch from
2 months 10 days of age to
6 years 1 month. Note the
progressive narrowing in the
lateral dimension of the cleft
(Reprinted with permission
from Pruzansky ( 1954 ))

293
12 Pierre Robin Sequence
cleft on either side of the family. No dif fi culty in
breathing was encountered, and the infant was
discharged from the hospital on the sixth day.
After a brief adjustment period, the infant was
readily fed by a combination of a hard nipple and
by means of a premature baby bottle nipple.
Some snoring sounds were heard, especially
as the infant was placed on its back and the head
elevated with slight ventro fl exion on the chest.
The infant preferred to sleep on either side, and in
these positions, the snoring sounds were at a min-
imum. This baby showed progressive improve-
ment, and at the age of 5 months, he weighed
15 lb 8 oz (7,030 g).
Growth Studies: Two sets of records are avail-
able in this case. The fi rst was obtained at the age
of 1 month 7 days, and the second at 3 months
25 days of age.
The fi rst cast of maxilla revealed a wide para-
bolic cleft extending distally from the nasopala-
tine foramen. The widest portion of the cleft, at
the level of the maxillary tuberosities, measured
16 mm. Although the second cast exhibited an
increase in the length and width of the palate,
there was a decrease of 1.5 mm in the width of
the cleft at its widest portion. During the fi rst
examination, the tongue was observed to occupy
at rest the opening into the nasal chambers
provided by the cleft in the palate. This was fur-
ther con fi rmed by examining the frontal and lat-
eral views of the head plates. The second series
of fi lms indicated that the tongue was now pos-
tured in a more inferior position and no longer
occupied the nasal cavity to the same extent pre-
viously noted. This new position of the tongue
could be explained by the downward and forward
growth of the mandible that had occurred in the
interim.
In the fi rst lateral fi lm, the recessive chin, the
distally and superiorly malposed tongue, and rel-
atively restricted airway were clearly observed.
Two and one-half months later, considerable
growth in the mandible had occurred to improve
the facial pro fi le, alter the posture of the tongue,
and increase the anteroposterior diameter of the
airway. The tongue was no longer in close apposi-
tion to the posterior pharyngeal wall, and its supe-
rior margin did not extend into the nasal cavity to
the degree previously observed. Coincidentally,
the mother reported a diminution of the stertor-
ous breathing that had been present.
Superimposition of the tracings of the bony
structures revealed the rapid growth character-
istic of this early period in life. In 2 1/2 months,
that cranial vault and all parts of the face
exhibited proportionate increases. Particularly
encouraging was the amount and direction of
growth displayed by the lower jaw. Mandibular
growth was responsible not only for reducing
the glossoptosis and increasing the airway but
for the improvement in the appearance of this
baby’s face.
Comment: The problem presented by this
baby was unique and different from the two pre-
vious cases of the partial obstruction of the air-
way. Diligent nursing care to determine the most
comfortable position for breathing and feeding
may be suf fi cient to tide such cases through their
critical period. In some instances, the prone posi-
tioning and orthostatic feeding suggested in the
literature are most successful. Again, one is
impressed by the remarkable potential for proli fi c
growth during this period of life; a potential that
is shared by the small mandible. It follows then
that every effort must be made to permit the real-
ization of the baby’s potential for growth by
providing an adequate airway, which, in turn,
facilitates feeding. The clinical course to be fol-
lowed is varied and depends on the severity of the
symptoms and principally upon the degree of
obstruction of the airway.
12.2
Comment
The representative sampling of cases presented
provides an answer to the questions which the
study was designed to solve. It is observed from
the data presented that the mandible possesses
remarkable potentialities for growth in patients
with the Pierre Robin syndrome. Thus, all efforts
should be directed toward sustaining life in a
metabolically favorable climate in order that a
more physiologic airway may be established as
growth proceeds. With growth, the glossoptosis
is minimized and spontaneous resolution of the

294
S. Pruzansky and J.B. Richmond
respiratory and feeding problems occurs. It is
our opinion that tracheotomy should be resorted
to promptly if respiratory embarrassment is
signi fi cant in order to achieve a suf fi cient airway
to provide adequate oxygenation. This is undoubt-
edly a lifesaving procedure in some patients.
On the basis of our longitudinal growth stud-
ies, certain prognostications concerning the future
growth of the micrognathic mandible are permis-
sible. In most instances, the increment in man-
dibular growth, as related to total facial growth, is
suf fi cient to overcome the extreme recessiveness
of the chin that is observed at birth. Since man-
dibular growth continues until late adolescence, it
is possible to hope for an esthetically pleasing
pro fi le in adulthood. The management of the cleft
palate has been in keeping with the established
criteria for the treatment of palatal defects.
The lateral cephalometric fi lm served as a
valuable diagnostic tool in estimating the degree
of obstruction of the airway as a result of the
glossoptosis. In our experience, there was a high
positive correlation between the degree of
obstruction revealed in the x-ray fi lm and the
incidence and severity of the respiratory
dif fi culties. When obstruction of the air passage
was complete and the tongue was practically in
contact with the posterior wall of the pharynx,
tracheotomy was recommended as a lifesaving
procedure. If the obstruction was incomplete,
more conservative measures were employed.
Care was taken to ascertain the most comfortable
postures for breathing and feeding for the indi-
vidual case, and the nurse or parent was carefully
instructed in the care of the infant. Appropriate
nipples were selected to minimize the energy
expended by the infant in the feeding process.
In the course of these studies, we were aware
of an obvious objection to placing so much reli-
ance on these roentgenograms. Since many of
these fi lms were obtained under mild sedation,
was it not possible that the posture of the mandi-
ble or of the tongue might have been altered by
the sedative? Secondly, the fi lm depicted a static
view of the airway and represented only two
dimensions. Did this view properly re fl ect the
kinetic ability of the infant to manipulate the
tongue and jaw hence the consistent correlation
between the fi ndings in our fi lms and the clinical
state? Moreover, when the fi lms were repeated in
the same infant without sedation, similar postures
were recorded for the structures under analysis. It
was important that the postures of the head in
relation to the neck be kept constant. Dorsi fl exion
or ventro fl exion of the head varied to posture of
the mandible and tongue and produced changes
in the con fi guration of the airway. To indicate
alterations in the posture of the head to the neck,
our tracings purposely included at least the fi rst
two cervical vertebrae.
We recognize that few institutions possess
cephalometric
roentgenographic
equipment.
Therefore, we would like to point out that an
ordinary lateral fi lm obtained by carefully posi-
tioning the infant can provide useful diagnostic
data. To minimize enlargement, a target-object
distance of at least 3 ft (90 cm) is recommended.
For the sake of de fi nition and to further decrease
enlargement, the object fi lm distance should be
kept at a minimum. Sjölin ( 1950 ) has published
interesting fi lms to describe his experiences with
a case of micrognathia. Although his fi lms did
not permit quanti fi cation of the growth changes,
they were adequate for diagnostic purposes.
A number of papers in the literature claim to
“stimulate” the growth of the mandible by a vari-
ety of mechanical devices or surgical procedures.
For example, a special nursing bottle was
designed to force the infant to protrude his jaw in
order to obtain nourishment and, by this protru-
sion, to stimulate mandibular growth (Eley and
Farber 1930 ) . From our data, we would conclude
that the nursing care enabled the infant to survive
until mandibular growth was suf fi cient to provide
a more adequate airway.
In another report, continuous traction on the
mandible was maintained by circumferential wir-
ing around the symphysis. The authors claimed
growth-stimulating properties for this procedure
(Longmire and Sandford 1949 ) . From the fi ndings
in our series, it would seem that mandibular growth
probably occurred spontaneously and not because
of the stimulus provided by surgical traction.
The important and prime objective in the care
of these children is to provide an airway. If possi-
ble, this should be accomplished with a minimum

295
12 Pierre Robin Sequence
of trauma. Secondly, the infant’s total needs should
be assessed to provide optimal conditions for
somatic growth. As the potential for growth is per-
mitted to express itself, the chin grows downward
and forward away from the base of the skull. With
this pattern of growth, adequate space for the
tongue is provided, the airway enlarges, and there
follows a spontaneous resolution of the symptoms.
Also, there are progressive improvements in the
facial appearance.
There is another dimension to the abnormal
posture of the tongue, as observed in these
patients, that merits discussion. Not only does the
tongue block the pharyngeal processes and hence
prevent their fusion. The high incidence of
micrognathia in the population of clefts involving
only the hard and soft palate lends support to this
theory. Mandibular micrognathia is a physiologi-
cal fi nding in early intrauterine life. If for some
reason the micrognathia persists and fails to carry
the tongue down and out of the nasal cavity, a
cleft in the palate might result.
In early postnatal life, the tongue acts to keep
the cleft palatal processes apart. As the tongue
descends with mandibular growth and no longer
forcefully intrudes itself into the nasal cavity, the
palatal processes tend to approximate in the mid-
line. Fusion of the palatal processes cannot occur,
but the narrowing in the clefts is recorded fact.
Summary and Conclusions
The development of the accurate techniques for
cephalometric roentgenography of infants has
made possible a longitudinal study of the growth
of the micrognathic mandible. As a result of
these studies, useful diagnostic and prognostic
information has been obtained to provide a ratio-
nale for the management of individual cases.
The lateral cephalometric roentgenogram is
a valuable diagnostic aid in assessing the sever-
ity of the glossoptosis and its obstruction of the
airway. A de fi nite correlation exists between
the degree of constriction of the airway and the
severity of the clinical state. On the basis of
these fi ndings, it is possible to recommend
either conservative management or tracheot-
omy in extreme situations, or distraction osteo-
genesis. Three cases, out of a larger series of
similar cases, were presented to indicate the
spectrum of variations to be encountered.
In all instances, it was found that where an
adequate metabolic situation was provided
and the infant gained weight, mandibular
growth during the fi rst few months was
suf fi cient to provide for a natural resolution of
the symptoms attending the glossoptosis.
Longitudinal records have indicated that
mandibular growth is proportionally adequate
to reduce the retrognathic pro fi le and provide
an esthetically harmonious facial appearance.
Based on investigations performed during the
tenure of Special Research Fellowship from the
National Institute of Dental Research Institutes
of Health (Dr. Pruzansky, Senior Assistant
Dental Surgeon [R], United States Public Health
Service, National Institute of Dental Research,
Department of Health, Education, and Welfare).
References
Berkowitz S (1996) Cleft lip and Palate – perspectives in
management. 1st ed. Singular Publishing Group, San
Diego, Ca. USA
Brodie AG (1941a) On the growth pattern of the human
head from the 3rd month to the 8th year of life. Am
J Anat 68:209–262
Brodie AG (1941b) Behavior of normal and abnormal
facial growth patterns. Am J Orthod 27:633–655
Callister AC (1937) Hypoplasia of the mandible (microg-
nathy) with cleft palate: treatment in early infancy
with skeletal traction. Am J Dis Child 53:1057–1064
Davis AD, Dunn R (1933) Micrognathis: a surgical treat-
ment for correction in early infancy. Am J Dis Child
45:799–806
Douglas B (1946) The treatment of micrognathia associated
with obstruction by plastic procedure. Plast Reconstr
Surg 1:300
Eley RC, Farber S (1930) Hypoplasia of the mandible
(micrognathy) as a cause of cyanotic attack in newly born
infant: report of 4 cases. Am J Dis Child 39:1167–1175
Lleweyllyn JS, Biggs AD (1943) Hypoplasia of the mandible:
report of case, with resume of literature and suggestions
for modi fi ed form treatment. Am J Dis Child 65:440
Longmire WP Jr, Sandford MC (1949) Stimulation of
mandibular growth in congenital micrognathia by trac-
tion. Am J Dis Child 78:750–755
May H, Chun LT (1948) Congenial ankyloglossia
(tongue-tie) associated with glossoptosis (retruded
mandible) and palatum fi ssum (cleft palate). Pediatrics
2:685–687

296
S. Pruzansky and J.B. Richmond
Nisenson A (1948) Receding chin and glossoptosis: cause
of respiratory dif fi culty in infant. J Pediatr 32:397–401
Pruzansky S (1953) Description, classi fi cation and analy-
sis of unoperated clefts of the lip and palate. Am
J Orthod 39(8):590
Pruzansky S, Richmond JB (1954) Growth of mandible in
infants with micrognathia. Am J Dis Child 88:29–42
Robin P (1929) La glossoptose: un grave danger pour nos
enfants. Gaston Doin, Paris
Robin P (1934) Glossoptosis due to atresia and hypoplasia
of the mandible. Am J Dis Child 48:541–547
Sjolin S (1950) Hypoplasia of the mandible as a cause of
respiratory dif fi culties in the infant. Acta Paediatr
39:255–261

Part IV
Audiology/Otology

299
S. Berkowitz (ed.), Cleft Lip and Palate,
DOI 10.1007/978-3-642-30770-6_13, © Springer-Verlag Berlin Heidelberg 2013
13
Children with cleft palate and other craniofacial
anomalies are at risk for a variety of otopatholo-
gies including otitis media and structural defor-
mities of the outer and middle ear. These
conditions are usually associated with conductive
hearing impairment; however, when hearing loss
occurs as part of a syndrome, there may be sen-
sorineural or mixed hearing loss. This chapter
will review the etiology of these conditions and
their medical management. We will also examine
the assessment of hearing and various technolo-
gies available for treatment of hearing loss.
13.1
Etiology and Medical
Management of Middle
Ear Disease
Because of the shared embryological origins of
the ear and other craniofacial structures, patients
with cleft palate and craniofacial anomalies are
at increased risk for a variety of otopathologies
including otitis media, cholesteatoma, and struc-
tural abnormalities of the outer and middle
ear. Otitis media is, by far, the most prevalent
otopathology seen in patients with cleft palate
(Paradise et al. 1969 ; Moller 1975 ; Hubbard
et al. 1985 ; Rynnel-Dagoo et al. 1992 ; Sheahan et al.
2003, 2004 ; Flynn et al. 2009 ; Zheng et al.
2009 ) ; however, a few may require tympano-
plasty, tympanomastoidectomy, or ossicular
chain reconstruction (Goudy et al. 2006 ) . The
high prevalence of otitis media in this population
is due primarily to poor Eustachian tube function
during swallow (Doyle et al. 1980 ; Takahashi
et al. 1994 ) . In the normal swallow, the velopha-
ryngeal sphincter, which includes the levator veli
palatini and tensor veli palatini muscles, closes
the nose from the oral cavity to prevent re fl ux
of oral secretions and food into the nasophar-
ynx. The tensor veli palatini, the primary muscle
responsible for opening the Eustachian tube,
originates from the Eustachian tube and inserts
on the palate where it joins muscles from the
contralateral side to form a supporting sling for
the palate. In patients with cleft palate, the sling
is poorly developed and follows a more vertical
orientation resulting in greater risk of re fl ux into
the middle ear. The outcome is poor aeration of
the middle ear and a high prevalence of otitis
media (Bluestone 1971 ; Fria et al. 1987 ; Flynn
et al. 2009 ) . Although the prevalence decreases
with age, some patients continue to experience
otitis media as adults (Handzic-Cuk et al. 1996,
2001 ; Sheahan et al. 2003 ) .
Management of Otopathology
and Hearing Loss in Children with
Cleft Palate and Craniofacial Anomalies
Amelia F. Drake and Jackson Roush
A. F. Drake , M.D., FACS ()
Department of Otolaryngology ,
The University of North Carolina School of Medicine,
UNC Hospitals , CB#7070 , Chapel Hill ,
NC 27599-7070 , USA
e-mail: amelia_drake@med.unc.edu
J. Roush , Ph.D.
Division of Speech and Hearing Sciences,
Department of Allied Health Sciences ,
University of North Carolina School of Medicine ,
CB 7190 3100 Bondurant Hall, 301 S. Columbia St. ,
Chapel Hill , NC 7190-27599 , USA
e-mail: jroush@med.unc.edu

300
A.F. Drake and J. Roush
Diagnosis of acute otitis media (AOM)
requires (1) a history of acute onset of signs and
symptoms; (2) middle ear effusion based on evi-
dence of a bulging tympanic membrane, limited
or absent mobility of the tympanic membrane,
observation of an air- fl uid level behind the tym-
panic membrane, or otorrhea; and (3) signs and
symptoms of middle ear in fl ammation with evi-
dence of otalgia (ear pain) or erythema of the
tympanic membrane (AAP 2004 ) . Otitis media
with effusion (OME) is de fi ned as the presence of
fl uid in the middle ear without signs or symptoms
of AOM. It is more dif fi cult to detect than AOM
because in most cases, the only overt symptom is
fl uctuating hearing loss.
Otoscopy refers to examination of the eardrum
or tympanic membrane using an otoscope and is
part of any complete physical examination (Stool
2006 ) . Tympanometry, an important adjunct to
otoscopy, is a physiologic measure that provides
information concerning the mobility of the tym-
panic membrane and middle ear system as well
as middle ear pressure and estimates of equiva-
lent volume, each of which may be associated
with various middle ear conditions (Roush and
Grose 2006 ) . Figure 13.1 shows a series of tym-
panograms and their clinical interpretation.
Acute otitis media, when treated medically, is
treated with antibiotics to cover for H. in fl uenzae ,
S. pneumoniae , or M. catarrhalis . For most peni-
cillin-resistant organisms, amoxicillin/clavulanate
has proven effective (AAP 2004 ) . When middle
ear effusion persists for more than 3 months, as it
often does in children with cleft palate, it is con-
sidered chronic. Tympanostomy tube placement is
a common practice for those children, and improve-
ments in hearing have been noted (Gould 1990 )
with relatively few complications (Curtin et al.
2009 ) ; however, multiple tube insertions have been
associated with persistent conductive hearing loss
(Goudy et al. 2006 ) . Although it is unclear whether
this is due to the placement of the tympanostomy
tubes or to middle ear damage from the
in fl ammation associated with otitis media, some
clinicians have favored hearing aids over multiple
tube placements (Maheshwar et al. 2002 ) .
Complications from middle disease, although
relatively rare, include perforation or retraction
of the tympanic membrane, resulting in choleste-
atoma. Cholesteatoma refers to a benign but
locally erosive mass of squamous cells that often
begins with a tympanic membrane retraction
pocket or perforation. It is a potentially serious
condition that warrants evaluation by an otolar-
yngologist and subsequent surgery.
Surgical repair of the palate has been
shown to improve Eustachian tube function
and decrease the frequency of otitis media
and need for tympanostomy tubes (Bluestone
1971 ) ; however, it may take several years
for Eustachian tube function to fully recover
(Smith et al. 1994 ; Goudy et al. 2006 ) . As with
Fig. 13.1 Tympanometric patterns associated with nor-
mal middle ear function ( a ), middle ear effusion ( b ), nega-
tive middle ear pressure ( c ), and reduced middle ear
mobility ( d ) (Reprinted with permission from Roush and
Grose ( 2006 ) , p. 378)
−300
−200
−100
0
−100 −200
Ear canal air pressure (daPa)
Acoustic admittance (mmho)
a
b
c
d

301
13 Management of Otopathology and Hearing Loss in Children with Cleft Palate
the non-cleft palate population, the likelihood
of hearing loss decreases with age (Gordon
et al. 1988 ) ; however, hearing loss persists in
adulthood for some patients.
13.2
Assessment of Hearing
Newborn hearing screening is now a standard of
care throughout the United States (JCIH 2007 ).
Two technologies are used for newborn screening
and both employ physiologic methods; that is,
they involve physiologic measurement of audi-
tory function obtained without the infant’s active
participation. The fi rst involves the measurement
of otoacoustic emissions (OAEs) which are low-
intensity sounds produced by the inner ear in
response to acoustic stimuli (tones or clicks) and
detected by a sensitive microphone placed in the
ear canal. Successful recording of OAEs con fi rms
a healthy inner ear (cochlea) and is consistent
with normal or near-normal hearing sensitivity.
Since the middle ear is involved in both the con-
duction of acoustic stimuli to the inner ear and
reverse transmission of OAEs to the ear canal,
their presence also con fi rms normal middle ear
function. OAEs are “preneural” so their inclusion
in the test battery makes it possible to evaluate
the auditory system at the level of the inner ear
without involving higher auditory centers.
However, absent OAEs may be due to a variety of
conditions ranging from middle ear dysfunction
to profound cochlear hearing loss; other tests are
needed to resolve their absence. OAE screening
may be performed by a variety of professionals
or support personnel, while diagnostic OAE test-
ing is performed by an audiologist as part of a test
battery. Another physiologic test used for both
hearing screening and diagnosis of hearing loss is
the auditory brainstem response (ABR). Like
OAEs, ABRs are elicited by acoustic stimuli pre-
sented in the ear canal; however, ABRs are neu-
rological responses obtained from surface
electrodes attached to the head and provide infor-
mation regarding the functional integrity of the
auditory nerve and brainstem pathway. When
used in a diagnostic test battery, audiologists use
frequency-speci fi c ABR testing to estimate hear-
ing threshold levels.
Although OAE and ABR tests provide valu-
able information regarding the auditory system at
the preneural, auditory nerve, and brainstem lev-
els, they are not considered true tests of hearing in
the perceptual sense. Comprehensive assessment
of hearing requires behavioral tests, that is, pro-
cedures that involve observation of a listener’s
response to sound. Methods used for behav-
ioral assessment of hearing vary depending on
the child’s age and developmental status. When
infants reach a developmental age of approxi-
mately 6 months, most can be tested using an
operant conditioning procedure known as visual
reinforcement audiometry. By age 3–4 years,
behavioral testing can be accomplished using
conditioned play procedures, and by 5 years of
age, typically developing children respond by
raising their hand or pressing a response button.
To summarize, newborn hearing screening is
conducted using physiologic measures: otoa-
coustic emissions or auditory brainstem responses,
alone or in combination. Infants who do not pass
the newborn hearing screening are referred to an
audiologist for comprehensive assessment using
these and other specialized procedures to deter-
mine if hearing impairment is present and, if so,
to ascertain the type and degree of hearing loss.
When infants reach a developmental age of
approximately 6 months, they can be tested using
behavioral methods. When permanent hearing
loss is diagnosed, most children bene fi t from
acoustic ampli fi cation (hearing aids). Those with
severe-profound hearing loss are likely to bene fi t
from a cochlear implant.
The initial goal of the audiologic assessment,
whether conducted using physiologic or behav-
ioral methods, is to obtain a frequency-speci fi c
estimate of the child’s hearing thresholds for
each ear, based on detection levels for air- and
bone-conducted test stimuli. Air conduction
audiometry involves the presentation of pure
tones from an earphone or insert receiver; bone
conduction audiometry involves the presentation

302
A.F. Drake and J. Roush
of signals through a bone vibrator placed behind
the ear on the mastoid process. Testing is usually
performed at octave intervals from 250 to
8,000 Hz for air conduction and 250–4,000 Hz
for bone conduction. Thresholds are displayed
on an audiogram which plots threshold levels in
decibels hearing level (dB HL) as a function of
frequency, using standard symbols (Fig. 13.2 ).
The degree of hearing loss can be summarized
by averaging the pure-tone air conduction thresh-
olds in the mid-frequencies. Terms used to clas-
sify hearing levels include normal (0–15 dB HL),
borderline normal (16–25 dB HL), mild (26–
45 dB HL), moderate (46–75 dB HL), severe
(76–0 dB HL), and profound hearing loss (>90+
dB HL). Borderline categories may be described
using a combination of terms, such as moderate
to severe (Roush and Grose 2006 ) .
When pure-tone air conduction thresholds are
abnormally elevated, bone conduction testing is
performed to differentiate problems with sound
transmission lateral to the inner ear. As shown in
Fig. 13.2a , when air and bone conduction thresh-
olds are equally elevated, the loss is described as
sensorineural. Conductive hearing loss, illustrated
in Fig. 13.2b , is characterized by normal or near-
normal bone conduction thresholds with elevated
air conduction thresholds. A mixed hearing loss,
shown in Fig. 13.2c , is characterized by abnor-
mal responses to both air conduction and bone
conduction signals, with air conduction thresholds
poorer than bone conduction thresholds.
Fig. 13.2 Audiograms illustrating mild to moderate sensorineural hearing loss ( a ), mild conductive hearing loss
( b ), and moderate-to-severe mixed hearing loss ( c ) (Reprinted with permission from Kramer ( 2008 ), p. 153)
a
b
c

303
13 Management of Otopathology and Hearing Loss in Children with Cleft Palate
13.3
Hearing Loss in Children with
Cleft Palate and Craniofacial
Anomalies
As noted earlier, most hearing losses that occur
with cleft palate and craniofacial anomalies are
conductive in nature. That is, incoming sounds
are attenuated by aural atresia or middle ear dis-
ease. When cleft palate or craniofacial anomalies
occur as part of a syndrome, they may include
cochlear or labyrinthine dysplasias that result in
sensorineural or mixed hearing loss. These
include Treacher-Collins syndrome, Goldenhar
syndrome (oculoauriculovertebral or OAV spec-
trum), and craniofacial microsomia. CHARGE
syndrome may involve abnormalities of the outer,
middle, and inner ear, while Stickler syndrome,
which is often identi fi ed by a Pierre Robin
sequence, has been associated with progressive
sensorineural hearing loss. Velocardiofacial syn-
drome (chromosome 22 deletion syndrome) may
include sensorineural hearing loss, and when
accompanied by cleft palate, Eustachian tube
dysfunction, and otitis media, a mixed hearing
impairment. Syndromes involving craniosynos-
tosis may include auricular dysplasias, canal
atresia, ossicular fi xation, and sensorineural hear-
ing loss. Tympanostomy tube placement may be
indicated if feasible, and some patients will be
candidates
for
ossicular
reconstruction.
Jarhsdoerfer et al. ( 1992 ) developed criteria to
predict the success of atresia surgery based on
otologic fi ndings that include the presence of
ossicles, an oval window, round window, facial
nerve, and external ear. Unfortunately, only about
half of patients with aural atresia are candidates
for surgical repair, and many of those will require
revision surgeries (Jarhsdoerfer et al. 1992 ).
13.4
Management of Hearing Loss
in Children with Cleft Palate
and Craniofacial Anomalies
The challenge of determining hearing status for
these children often begins at birth. Many infants
with cleft palates do not pass the newborn hearing
screening because of middle ear effusion and
require referral to a pediatric audiologist for fol-
low-up assessment. Although most will not be
found to have a permanent, underlying sensorineu-
ral or conductive hearing loss, it is important to
determine the child’s hearing status early as pos-
sible. For typically developing infants, the test
used to make this determination, diagnostic ABR,
can be easily accomplished in natural sleep. But
for infants born with cleft palate, the test is often
complicated by middle ear effusion. Although
ABR testing can be completed using bone-
conducted as well as air-conducted stimuli, it is
preferable to perform the ABR when the middle
ear is free of effusion. Another potential complica-
tion is the noisy breathing of some young infants
with cleft palate, which may result in artifacts that
affect the quality of the ABR when recorded in
natural sleep. If an adequate ABR study cannot be
performed in natural sleep, it must be completed
with sedation or under general anesthetic. Sedated
or operating room procedures add additional time
and expense but enable the high-quality assess-
ment needed for prompt, accurate diagnosis. The
clinician must decide whether a separate proce-
dure for diagnostic ABR is warranted or if the test
can be performed at the time of cleft repair or tym-
panostomy tube placement, being mindful of the
importance of avoiding excessive delay between
screening and diagnostic ABR evaluation.
When hearing loss is diagnosed, timely and
appropriate intervention are essential. In many
cases, medical management will resolve a tran-
sient middle ear disorder and restore normal
hearing. But hearing loss in children with cleft
palate and craniofacial anomalies is often chronic,
even with appropriate medical management.
When conductive hearing loss cannot be resolved
through medical intervention, hearing aid use
should be considered. For children, hearing aids
worn behind the ear are preferred whenever pos-
sible because they allow fl exibility in program-
ming, and they work well with assistive listening
devices used at home and in the classroom. When
acoustic ampli fi cation is precluded by aural atre-
sia or chronic otorrhea, a bone conduction device
is usually indicated. Most bone conduction hear-
ing aids consist of an oscillator fi tted to a headband
that maintains pressure of the bone vibrator

304
A.F. Drake and J. Roush
against the scull (Fig. 13.3 ). Because the inner
ear is often unaffected by aural atresia, the bone
oscillator is able to bypass the impaired outer
and/or middle ear and deliver sound directly to
the cochlea. Older children may be candidates for
a percutaneous, bone-anchored device that deliv-
ers vibrotactile stimulation from a hearing instru-
ment mounted to a titanium abutment surgically
implanted in the temporal bone (Fig . 13.4 ). The
surgically implanted, bone-anchored device pro-
vides stable retention and ef fi cient transmission
of vibrotactile signals, making it usable with
mixed hearing impairment.
As noted earlier, although most hearing losses
in children with cleft palate or craniofacial anom-
alies are conductive in nature, it is important to
provide comprehensive audiological assessment
to rule out a sensorineural or mixed impairment.
When sensorineural hearing loss is identi fi ed, the
audiologist and otolaryngologist will determine
the best approach to hearing technology. An ear-
level, air conduction hearing aid may be appro-
priate, or in cases of severe-profound hearing
loss, a cochlear implant may be indicated.
Cochlear implants bypass the inner ear, providing
electrical stimulation from an external sound pro-
cesser and coil that transmit digital signals across
the skin to an internally implanted electrode that
provides direct stimulation of the auditory nerve.
13.5
Summary
Hearing is vital for speech, language, cognitive,
and social development. Nearly all children with
cleft palate and craniofacial anomalies will expe-
rience middle ear disease and/or conductive hear-
ing loss, and some are at risk for sensorineural or
mixed hearing impairment. Careful monitoring
of ear and hearing status by an otolaryngologist
and audiologist are essential. With appropriate
management, conductive hearing loss can often
be avoided or ameliorated. When there is perma-
nent (sensorineural) or chronic conductive
impairment, several hearing technologies are
available for delivery of sound via air conduc-
tion, bone conduction, or electrical stimulation.
References
American Academy of Pediatrics (2004) Clinical practice
guidelines: diagnosis and management of acute otitis
media. Pediatrics 113(5):1451–1465
Bluestone CD (1971) Eustachian tube obstruction in infants
with cleft palate. Ann Otol Rhinol Laryngol 80:1–30
Fig. 13.3 A 3-year-old child with Treacher-Collins
syndrome using a Baha softband bone conduction device.
A vibrotactile transducer, held in place by an elastic strap,
transmits vibrations from incoming sounds directly to the
inner ear, bypassing the outer and middle ear
Fig. 13.4 The implanted bone-anchored hearing device
consists of an external sound processor attached to a tita-
nium abutment that is surgically implanted into the skull
(Courtesy of Cochlear Corporation)

305
13 Management of Otopathology and Hearing Loss in Children with Cleft Palate
Curtin G, Messner AH, Chang KW (2009) Otorrhea in
infants with tympanostomy tubes before and after sur-
gical repair of cleft palate. Arch Otolaryngol Head
Neck Surg 135(8):748–751
Doyle WJ, Cantekin EI, Bluestone CD (1980) Eustachian
tube function in cleft palate children. Ann Otol Rhinol
Laryngol 89(Suppl 68):34–40
Flynn T, Moller C, Jonsson R, Lohmander A (2009) The
high prevalence of otitis media with effusion in children
with cleft lip and palate as compared to children without
clefts. Int J Pediatr Otorhinolaryngol 73(10):1441–1446
Fria TJ, Paradise JL, Sabo DL, Elster BA (1987)
Conductive hearing loss in infants and young children
with cleft palate. J Pediatr 111:84–87
Gordon AS, Jean-Louis F, Morton RP (1988) Late ear
sequelae in cleft palate patients. Int J Pediatr
Otorhinolaryngol 15:149–156
Goudy S, Lott D, Canady J, Smith R (2006) Conductive
hearing loss and otopathology in cleft palate patients.
Otolaryngol Head Neck Surg 134:946–948
Gould HJ (1990) Hearing loss and cleft palate: the per-
spective of time. Cleft Palate J 27:36–39
Green DR, Gaffney M, Devine O, Grosse SD (2007)
Determining the effect of newborn hearing screening
legislation: an analysis of state hearing screening rates.
Public Health Rep. Mar-Apr;122(2):198–205
Handzic-Cuk J, Cuk V, Risavi R, Katusic S, Stajner-
Katusic S (1996) Hearing levels and age in cleft palate
patients. Int J Pediatr Otorhinolaryngol 37:227–242
Handzic-Cuk J, Cuk V, Gluhinic M, Risavi R, Stajner-Katusic
S (2001) Tympanometric fi ndings 464 in cleft palate
patients: in fl uence of age and cleft type. J Laryngol Otol
115:91–96
Hubbard TW, Paradise JL, McWilliams BJ, Elster BA,
Taylor FH (1985) Consequences of unremitting mid-
dle-ear disease in early life. Otologic, audiologic, and
developmental fi ndings in children with cleft palate. N
Engl J Med 312:1529–1534
Jahrsdoerfer RA, Yeakley JW, Aguilar EA, et al. (1992)
Grading system for the selection of patients with con-
genital aural atresia. American Journal of Otology
13:6–12
Kramer S (2008) Audiology: Science to Practice. San
Diego: Plural Publishing
Maheshwar AA, Milling MAP, Kumar M, Clayton MI,
Thomas A (2002) Use of hearing aids in the manage-
ment of children with cleft palate. Int J Pediatr
Otorhinolaryngol 66:55–62
Moller P (1975) Long-term otologic features of cleft
palate patients. Arch Otolaryngol 101:605–607
Paradise JL, Bluestone CD, Felder H (1969) The univer-
sality of otitis media in 50 infants with cleft palate.
Pediatrics 44:35–42
Roush J, Grose J (2006) Principles of audiometry. In: Van
De Water T, Staecker H (eds) Otolaryngology: basic
science and clinical review. Thieme Medical Publishers,
New York, pp 374–384, Chapter 30
Rynnel-Dagoo B, Lindberg K, Bagger-Sjoback D, Larson O
(1992) Middle ear disease in cleft palate children at three
years of age. Int J Pediatr Otorhinolaryngol 23:201–209
Sheahan P, Miller I, Sheahan JN, Earley MJ, Blayney AW
(2003) Incidence and outcome of middle ear disease in
cleft lip and/or cleft palate. Int J Pediatr Otorhinolaryngol
67:785–793
Sheahan P, Miller I, Earley MJ, Sheahan JN, Blayney AW
(2004) Middle ear disease in children with congenital
velopharyngeal insuf fi ciency. Cleft Palate Craniofac J 41(4):
364–367
Smith TL, DiRuggiero DC, Jones KR (1994) Recovery of
Eustachian tube function and hearing outcome in
patients with cleft palate. Otolaryngol Head Neck Surg
111(4):423–429
Stool S (2006) Diseases of the ear in children with cleft
palate and craniofacial anomalies. In: Berkowitz S
(ed) Cleft lip and palate – diagnosis and management,
2nd edn. Springer-Verlag, Heidelberg/Germany
Takahashi H, Honjo I, Fujita A (1994) Eustachian tube
compliance in cleft palate – a preliminary study.
Laryngoscope 104:83–86
Zheng W, Smith JD, Shi B, Li Y, Wang Y, Li S et al (2009)
The natural history of audiologic and tympanometric
fi ndings in patients with an unrepaired cleft palate.
Cleft Palate Craniofac J 46(1):24–29

Part V
Effects of Surgery and How It Was Utilized

309
S. Berkowitz (ed.), Cleft Lip and Palate,
DOI 10.1007/978-3-642-30770-6_14, © Springer-Verlag Berlin Heidelberg 2013
14
14.1
Introduction
Cleft palate patients often develop growth
disturbances of the midfacial region after primary
surgery. Factors such as intrinsic developmental
de fi ciencies and functional distortions are initially
involved, but palatal repair seems to be a main
factor in these growth disturbances (Ross 1987a,
b, c, d, e, f, g ) . A strong indication for the involve-
ment of iatrogenic factors is the largely undis-
turbed maxillary growth in untreated patients
(Derijcke et al. 1994 ; Mars and Houston 1990 ;
Ortiz-Monasterio et al. 1966 ) . In treated patients,
the healing of surgical wounds originating from
palatal repair is probably responsible for the
growth disturbances (Kuijpers-Jagtman and Long
2000 ) . This chapter gives an overview of the
wound healing process with emphasis on wound
contraction and scar formation since they are con-
sidered to be key events. Some speci fi c features of
the palatal wound healing process are highlighted.
Further, the effects of palatal repair on growth of
the maxilla and development of the dentition are
reviewed, as well as possible means to improve
the clinical outcome. This review is based on clin-
ical evaluations, experimental research in animal
models, and on in vitro experiments using cell
culturing and tissue engineering techniques.
14.2
Wound Healing
14.2.1 Skin and Oral Mucosa
The general function of wound healing is to restore
the integrity and function of the tissue. In tissues
like skin and oral mucosa, wound healing involves
a partly overlapping sequence of in fl ammation,
tissue formation, and tissue remodeling (Fig. 14.1 ).
During in fl ammation, hemostasis is restored and
bacteria and debris are removed from the wound.
Subsequently, the defect is closed by the formation
of new tissues and by wound contraction. Finally,
tissue remodeling takes place during maturation of
the newly formed tissues, which generally leads to
the formation of a scar.
In intraoral wounds, the wound healing pro-
cess is generally faster than in skin and gener-
ates less scar tissue. Therefore, intraoral wounds
are sometimes considered to be more simi-
lar to fetal wounds (Okazaki et al. 2002 ) . This
may be related to the presence of lower levels
of pro-in fl ammatory and pro- fi brotic cytokines
in mucosal wounds (Szpaderska et al. 2003 ) .
The intraoral wound healing process is also
in fl uenced by the presence of saliva and large
numbers of bacteria (Zelles et al. 1995 ) . Saliva
Palatal Wound Healing: The Effects
of Scarring on Growth
Johannes W. Von den Hoff , Jaap C. Maltha ,
and Anne Marie Kuijpers-Jagtman
J. W. Von den Hoff , Ph.D. () • J. C. Maltha , Ph.D.
Department of Orthodontics and Craniofacial Biology ,
Radboud University Nijmegen Medical Centre ,
6500 HB, Nijmegen , The Netherlands
e-mail: h.vondenhoff@dent.umcn.nl
A. M. Kuijpers-Jagtman , DDS, Ph.D.
Department of Orthodontics and Craniofacial Biology,
Cleft Palate Craniofacial Unit ,
Radboud University Nijmegen Medical Centre ,
6500 HB , Nijmegen , The Netherlands

310
J.W. Von den Hoff et al.
contains many growth factors such as epidermal
growth factor (EGF). In addition, phenotypic dif-
ferences between skin and mucosal fi broblasts
may be involved (Lepekhin et al. 2002 ) . These
considerations, however, mainly apply to buccal
mucosa, which has a quite different morphology
than the palatal mucosa (Fig. 14.2 ).
In contrast to buccal mucosa, the palatal
mucosa is a mucoperiosteum, which means that
mucosa and periosteum are merged and attached
to the palatal bone (Squier and Finkelstein 2003 ) .
The palatal mucoperiosteum is also much stiffer
than buccal mucosa, and it contains less elastin
fi bers, as was also shown for the gingival muco-
periosteum (Bourke et al. 2000 ) . Furthermore,
the epithelium of palatal mucosa is generally
thicker than in the buccal areas, and it is kerati-
nized. All this implies that the physiological and
mechanical characteristics of this tissue are quite
different from buccal mucosa, which might
explain differences in the outcome of the wound
healing process.
Nevertheless, the general outline of both the
palatal and the buccal wound healing process is
similar to that of skin, which is described below
(Clark 1996 ) . It is important to stress that the
phases of wound healing described here are not
discrete episodes but they overlap in time
(Fig. 14.1 ). In addition, the progress of healing in
the outer wound area is more advanced than in
the center, which means that subsequent phases
of the wound healing process may be found in
adjacent areas. This, of course, concerns only
open wounds with a tissue defect in which heal-
ing takes place by second intention.
a
b
Fig. 14.2 ( a , b ) The palatal mucoperiosteum. The muco-
periosteum of the palate contains an epithelium and a sub-
mucosal connective tissue and is fi rmly attached to the
palatal bone
0
5
10
15
20
25
Time (days)
Activity (au)
Inflammation
Tissue formation
Remodeling
Scar formation
Contraction
Fig. 14.1 Phases in wound
healing. The wound healing
process can be divided into
three partly overlapping phases.
Wound contraction is an early
phenomenon, while scar
formation is a late phenomenon
in wound healing ( arrows )

311
14 Palatal Wound Healing: The Effects of Scarring on Growth
14.2.2 Phases in Wound Healing
Tissue injury causes disruption of blood vessels
and bleeding. Within seconds, the coagulation
cascade starts, leading to the formation of a
fi brin-rich blood clot that contains numerous
platelets. These platelets are reservoirs of cytok-
ines and growth factors such as transforming
growth factors (TGFs) and platelet-derived
growth factor (PDGF) that attract in fl ammatory
cells, especially neutrophils and macrophages.
The blood clot forms a provisional matrix for the
migration of those cells. Proteins such as
fi bronectin, fi brinogen, and vitronectin allow cell
attachment and migration by their interaction
with integrins, which are transmembrane cell sur-
face receptors (Yamada and Clark 1996 ) .
Neutrophils and macrophages subsequently clear
the wound bed of debris and bacteria. In addition,
the relative blood volume at the site of injury
increases by dilation of the capillary vessels in
the surrounding tissue and also by an increase of
their permeability, which leads to redness and
swelling. This phase is called the in fl ammatory
phase and usually subsides several days after
wounding (Fig. 14.1 ).
In the next phase, the tissue formation phase ,
keratinocytes, fi broblasts, and endothelial cells in
the wound edge start to proliferate. They migrate
into the wound bed and start to form the neo-
epithelium and the underlying granulation tissue
(Clark 1996 ) . This phase already starts a few days
after wounding, before the in fl ammatory phase
has come to an end. Keratinocytes seem to be
activated by the partial loss of cell–cell contacts
at the wound edge and by locally produced
growth factors such as epidermal growth factors
(EGFs) and fi broblast growth factors (FGFs).
Fibroblasts, endothelial cells, and more mac-
rophages migrate into the wound bed. Their
migration and other activities are regulated by
complex interactions with growth factors and
extracellular matrix components within the pro-
visional matrix (Yamada and Clark 1996 ) . Again,
integrins play a major role in the interaction
between cells and the extracellular matrix. The
binding of matrix proteins to integrins is required
for attachment and migration, and it also leads to
the transmission of additional regulatory signals
into the cells (Rojas and Ahmed 1999 ) . Cell
migration furthermore requires the activity of
matrix metalloproteinases (MMPs), enzymes that
pave the way for cells by cleaving extracellular
matrix proteins (McPherson 1992 ) .
During migration into the wound, fi broblasts
gradually switch to a more synthetic phenotype, a
switch that involves the action of TGF b . The
fi broblasts start to produce large quantities of col-
lagen, with collagen type III as the main species,
but elastin is not synthesized in the wound. Within
this matrix, endothelial cells form numerous
capillaries to nourish the newly formed tissue.
This process is called neo-angiogenesis and
FGFs, vascular endothelial growth factor (VEGF),
and many other growth factors are implicated in
its regulation as shown by in vitro studies (Clark
1996 ) . As soon as the wound is fi lled with granu-
lation tissue and the neo-epidermis is formed, the
collagen production is reduced, which requires
interferon- g (IFN g ). A negative feedback mecha-
nism based on the accumulated collagen may
also contribute to the decrease in collagen syn-
thesis. This event marks the beginning of the
third and last phase, the remodeling phase .
The remodeling phase starts within 1 week
after wounding and will ultimately lead to the
formation of scar tissue. The remodeling of the
extracellular matrix is mainly carried out by
fi broblasts. It involves the degradation of colla-
gen type III by matrix metalloproteinases
(Mignatti et al. 1996 ) and the concurrent deposi-
tion of type I collagen by fi broblasts. In the sec-
ond week after injury, fi broblasts also start to
produce proteoglycans. The mechanical proper-
ties of the tissue are not only determined by col-
lagens but to a large extent also by these
proteoglycans, since they can bind large amounts
of water. In addition, many proteoglycans have
been shown to regulate cell function, either by
direct modulation of cell adhesion and prolifera-
tion or indirectly through the binding or release
of growth factors (Nakato and Kimata 2002 ) .
At the start of the remodeling phase, part of
the fi broblasts within the granulation tissue dif-
ferentiates into myo fi broblasts that possess con-
tractile properties. These specialized cells are

312
J.W. Von den Hoff et al.
strongly involved in the process of wound con-
traction. Their differentiation seems to be gov-
erned mainly by mechanical tension within the
matrix, by TGF b and by a speci fi c variant of
fi bronectin, the ED-A fi bronectin (Tomasek et al.
2002 ) . Wound contraction causes a rapid reduc-
tion of the surface area of the wound and a con-
comitant rearrangement of the collagen fi bers. In
the mean time, the neo-epidermis is maturing
into a fully differentiated strati fi ed epithelium.
After 1–2 weeks, no further contraction takes
place
because
the
myo fi broblasts
have
disappeared, probably by apoptosis (Desmouliere
et al. 1995 ) . The induction of apoptosis is not
completely understood, but several genes are
known to govern the process. The expression of
these genes is regulated by growth factors as
well as by changes in the interaction between the
cells and their extracellular matrix. In the next
several months, many of the fi broblasts, but also
endothelial cells, disappear by apoptosis, which
gradually renders the tissue less vascularized
and less cell rich. The slow remodeling of the
collagen fi bers by remaining fi broblasts, which
is part of the transition to scar tissue, can go on
for a long time.
14.2.3 Contraction and Scarring
Wound contraction and scarring seem to be the
two main processes in wound healing responsible
for the growth disturbances after cleft palate
repair and are therefore reviewed here in more
detail. Wound contraction is the reduction of the
wound surface area by approximation of the
wound edges, and it may account for up to
80–90 % of wound closure (McGrath and Simon
1983 ) . The evolutionary function of this feature
obviously is to speed up wound closure and
thereby reduces the risk of infection and dehydra-
tion. Scar formation might be a negative side
effect of this primarily bene fi cial process.
The cause of wound contraction is not yet
exactly known. Two main theories have been
described in literature. The fi rst one states that
fi broblasts, which migrate from the wound mar-
gins into the wound bed, cause traction in the
extracellular matrix. This tensional force would
be suf fi cient to contract the wound (Ehrlich and
Rajaratnam 1990 ) . This theory does not require
specialized cells to explain wound contraction.
The second theory assumes that a specialized
subtype of fi broblasts, the myo fi broblast, is
responsible for wound contraction (Desmouliere
and Gabbiani 1996 ; Gabbiani 2003 ) . During
wound
contraction,
fi broblasts,
containing
intracellular stress fi bers are found within the
granulation tissue. These stress fi bers have been
shown to contain alpha-smooth muscle actin
(ASMA), a cytoskeletal protein also present in
smooth muscle cells. This protein seems to be
required for the contraction of myo fi broblasts
within the granulation tissue. The coordinated
contraction of myo fi broblasts, attached to the
extracellular matrix, causes the reduction of the
wound surface.
Nowadays, the two theories have merged into
a consensus theory stating that both fi broblasts
and myo fi broblasts are involved in wound con-
traction (Tomasek et al. 2002 ) . Initially, migrat-
ing fi broblasts in the wound area generate
tension within the matrix. The resulting strain
within the matrix triggers the differentiation
of fi broblasts into myo fi broblasts, which also
requires the presence of TGF b 1 . The coordinated
action of myo fi broblasts strongly increases
tension within the wound tissue, which subse-
quently contracts. Thus, in the consensus theory,
both fi broblasts and myo fi broblasts contribute to
wound contraction.
During contraction of the granulation tissue,
extensive collagen remodeling takes place in
which MMPs play a prominent role (Mignatti
et al. 1996 ) . As a consequence of this remodel-
ing, collagen type III is gradually replaced by
collagen type I. The new collagen is deposited in
an orientation that is guided by the main lines of
tension within the extracellular matrix (Huang
et al. 1993 ; Rudolph et al. 1992 ) . The reorienta-
tion of collagen fi bers and the substitution of type
I collagen for type III collagen mark the start of
scar tissue formation. If a uniform direction of
tension exists within the contracting granulation
tissue, the new collagen fi bers will also be depos-
ited in a uniform orientation. Consequently, the

313
14 Palatal Wound Healing: The Effects of Scarring on Growth
resulting tissue will develop the properties of a
scar, a process that may slowly progress for sev-
eral months to years (Rudolph et al. 1992 ) .
During scar tissue formation, the number of
endothelial cells and fi broblasts within the devel-
oping scar tissue slowly decreases, a process in
which apoptosis is involved. The fi nal scar tissue
therefore is poorly vascularized and has a low
cell density. In addition, elastin fi bers, which pro-
vide elasticity to normal mucosa and skin, are not
resynthesized during wound healing and scar tis-
sue formation. Their absence and the presence of
highly oriented collagen fi bers make the scar a
rigid and stiff tissue. A speci fi c feature of palatal
wound healing is the attachment of the scar tissue
to the palatal bone (see Sect. 14.4.1 ). This may
cause palatal repair to have considerable effects
on maxillary growth.
14.3
Effects of Palatal Repair
on Growth
Apart from embryonic distortions and intrinsic
growth de fi ciencies, facial growth in cleft lip and
palate patients may be affected by surgical repair,
orthodontic treatment, and functional adaptations
(Kuijpers-Jagtman and Long 2000 ; Ross 1987a,
b, c, d, e, f, g ; Rygh and Tindlund 1982 ; Semb
and Shaw 1996 ) . Since the landmark studies of
Graber ( 1949 ) and Dahl ( 1970 ) , numerous
descriptive cephalometric studies have been pub-
lished (for an overview, see Semb and Shaw
1996 ) . It is reasonably well established that cleft
surgery, in particular lip and palate repair, can
disturb normal growth and development of the
maxilla in cleft patients (Berkowitz 1977 ;
Kuijpers-Jagtman and Long 2000 ) . However, the
possible growth effects of surgery should be eval-
uated in relation to the intrinsic abnormalities of
craniofacial growth in cleft palate patients. This
requires that unoperated cleft lip and palate
patients should be studied as well (Capelozza
Filho et al. 1996 ; Derijcke et al. 1994 ; Lambrecht
et al. 2000 ; Mars and Houston 1990 ) .
Of all surgical procedures that are used in cleft
lip and palate patients, palatal surgery has
attracted the greatest amount of attention. The
reason is that during this procedure, mucope-
riosteal fl aps are created on the palate to close the
cleft, leaving areas of denuded bone. The scar tis-
sue that is formed during healing might be a
potential inhibitor of subsequent maxillary
growth and dental arch development. Many stud-
ies over the past 50 years have focused on the
effects of speci fi c techniques of primary palate
repair on midfacial growth and development. The
effects of palatal closure seem to be mainly
con fi ned to the maxillary base and arch (Kuijpers-
Jagtman and Long 2000 ; Semb and Shaw 1998 ) .
The maxilla is shown to be narrower, shorter, and
displaced posteriorly relative to the cranial base.
The dentoalveolar processes are often de fl ected
to the median, resulting in anterior and transverse
cross bites. However, since both lip and palatal
surgery are generally performed, it is dif fi cult to
distinguish between the effects of the two types
of surgery.
A problem with the evaluation of the literature
on this subject is that the majority of the publica-
tions suffer from major methodological draw-
backs, which minimizes their value (Ross 1987f ;
Kuijpers-Jagtman and Long 2000 ) . Hardly, any
studies are available that directly compare two
types of treatment in a prospective research
design. In contrast, there is a vast amount of ret-
rospective studies available that all attempted to
relate speci fi c maxillary growth effects to partic-
ular surgical procedures. The most comprehen-
sive study of this type is the multicenter study by
Ross ( 1987a, b, c, d, e, f, g ) . By comparing lateral
cephalometric radiographs collected from 15
cleft palate centers from around the world, they
concluded that it was dif fi cult to isolate the effects
of individual palate repair techniques. However,
an inhibition of anterior growth and translation of
the maxilla was a common fi nding. Another
problem that is only addressed by few is that not
only the surgical technique but in particular the
skills of the surgeon are very important for the
long-term outcome in terms of growth and devel-
opment (Kuijpers-Jagtman and Long 2000 ; Shaw
et al. 2000 ) .
In conclusion, strong consensus exists that
primary surgery is a major factor in the impair-
ment of dentomaxillary growth. The extent of

314
J.W. Von den Hoff et al.
growth impairment may be in fl uenced by the
speci fi c techniques, the timing and sequence of
operations, the use of orthopedic appliances, and
possibly the most important of all, the skills of
the surgeon. No particular technique has been
shown to produce consistently better growth
results than any other. Assuming that scar tissue
is a primary etiological factor in maxillofacial
growth disturbances, most contemporary repair
techniques attempt to minimize scarring. Animal
experiments are very well suited to determine the
exact effects of speci fi c surgical procedures. For
a better understanding of the biological mecha-
nisms in wound healing, and for the goal-directed
modulation of healing, experimental studies are
of major importance. Results of such studies are
discussed in the next section.
14.4
Experimental Research
Extensive research in animal models has been
performed to evaluate the effects of cleft surgery
on growth and development of the maxilla and to
study the wound healing process. Animal models
are also used to develop new surgical techniques
that may reduce the unfavorable effects of sur-
gery. Tissue-engineered constructs are being
developed to prevent attachment of scar tissue to
the bone or as a substitute for the lacking mucosal
tissue. A lot of in vitro research is also aimed at
the elucidation of aspects of the oral wound heal-
ing process.
14.4.1 Effects of Surgery on Growth
Since suitable animal models for congenital
clefts are not available, the effects of reconstruc-
tive surgery are evaluated with surgically created
clefts in dogs, rabbits, and rats. Two different
approaches have been used to evaluate the effects
of surgery on midfacial growth and development
of the dentition. The fi rst approach is to create
a cleft in the soft tissue and the palatal bone by
surgical means. This cleft is subsequently closed
again as the actual experimental intervention.
It is obvious, however, that a surgically created
cleft is different from a congenital one. Such a
cleft creates a surgical trauma that might act as
a confounding factor for the interpretation of the
results. Only if the bony cleft is considered to be
essential for evoking the disturbances in growth
and development does this approach make sense.
Bardach and coworkers have used this model
since 1975. They performed some of the earli-
est experiments on the possible negative effect
of lip repair (Bardach 1989, 1990 ; Bardach and
Eisbach 1977 ; Bardach et al. 1979, 1980, 1993 ) .
Lip repair in rabbits and beagle dogs with surgi-
cally created complete unilateral clefts was found
to result in a signi fi cant increase in lip pressure
and a corresponding maxillary growth de fi ciency.
The authors therefore suggested a causal relation-
ship between the two.
The second approach is based on the assump-
tion that the soft tissue intervention is crucial
for the growth disturbances after cleft palate
surgery. Already in the late 1960s, Kremenak
and coworkers performed mucoperiosteal exci-
sions without affecting the palatal bone in young
beagle dogs as a model for the clinical situation
after cleft palate repair (Kremenak et al. 1970 ) .
This approach led to growth disturbances that
were similar to those after surgical cleft closure
in children. Kremenak therefore concluded that
“in this model, mucoperiosteal denudation of
palatal shelf bone adjacent to deciduous molars
is the single surgical variable responsible for the
maxillary growth disturbances seen” (Kremenak
et al. 1970 ) . This is in agreement with later dog
studies in which a midpalatal soft tissue cleft
was created that was subsequently closed by von
Langenbeck technique (e.g., (Wijdeveld et al.
1989, 1991 ) ). Their results not only show the
same effects on growth but also that the extent
of this effect is related to the age at which sur-
gery is performed. Growth disturbances turned
out to be most prominent when surgery is per-
formed before shedding of the deciduous den-
tition. Furthermore, these studies, as well as
recent studies in rats (Kim et al. 2002 ) , show that
the deviations in maxillary arch dimensions are
not only caused by a decreased sutural growth
but also by a palatal tipping of the teeth in the
lateral areas. In dogs, this tipping is especially

315
14 Palatal Wound Healing: The Effects of Scarring on Growth
prominent when surgery is performed at a young
age, and it becomes apparent only after shedding
of the deciduous dentition.
An explanation for this effect can be found in
the healing of the soft tissue wounds and more
speci fi cally in wound contraction and scar tis-
sue formation. Wound contraction in dog muco-
periosteum is most prominent in the fi rst week
after surgery. In palatal wounds in rats, it has
been shown that the number of myo fi broblasts
increases
considerably
in
that
period
(Cornelissen et al. 2000b ) , which also seems to
be the case in dogs. Thereafter, the maturing
granulation tissue is characterized by a gradual
decrease in the number of fi broblasts and
in fl ammatory cells and an increase in number
and thickness of collagen type I fi bers (Searls
et al. 1979 ) . Elastic fi bers are not present in the
granulation tissue or in the scar tissue at later
stages (Wijdeveld et al. 1991 ) .
A speci fi c feature of the healing of open
wounds in the mucoperiosteum is the deposi-
tion of callus-like cancellous bone on the pal-
ate. The granulation tissue adjacent to the palatal
bone acquires an osteogenic potential, or osteo-
genic cells migrate into that area from adja-
cent periosteal tissues, and new bone is formed
(Wijdeveld et al. 1991 ) . This phenomenon is also
known from other craniofacial bones and from
long bones, where removal or mobilization of
the periosteum leads to callus formation. Most of
the collagen fi bers of the scar are oriented in a
transverse direction, but many fi bers also show a
vertical orientation. These vertical fi bers become
embedded in the cancellous palatal bone as
Sharpey’s fi bers, generating a strong attachment
of the scar tissue to the underlying palatal bone
(Wijdeveld et al. 1991 ) (Fig. 14.3 ).
The transverse fi bers appear to be continu-
ous with the cervical periodontal ligament, thus
Fig. 14.3 ( a – d ) Palatal scar tissue. ( a ) shows the scar
tissue adjacent to the teeth. The organization of the tissue
is shown schematically in ( b ). ( c , d ) Shows an enlargement
of the squared section. Note the thick perpendicular
collagen fi bers (Sharpey’s fi bers) running into the bone,
which are more clear when seen in polarized light ( d )

316
J.W. Von den Hoff et al.
forming a mechanical connection between the
teeth and the mucoperiosteal scar tissue (Kim
et al. 2002 ; Wijdeveld et al. 1991 ) . At the end
of the growth period, the teeth alongside the scar
tissue show a palatal tipping which is probably
caused by the traction of the scar tissue on the
erupting permanent dentition (Wijdeveld et al.
1988, 1989 ) . These fi ndings have led to the
hypothesis that the iatrogenic effects of palatal
surgery are initially caused by wound contrac-
tion, but scar tissue formation and the accompa-
nying attachment of the scar tissue to the palatal
bone and the teeth are probably the most impor-
tant features. This leads to a restriction of maxil-
lary growth and to a palatal tipping of erupting
teeth in that region.
14.4.2 Modi fi cation of Surgical
Techniques
Several researchers have tried to modify cleft pal-
ate surgery in order to avoid the appearance of
denuded bone areas and the subsequent growth
impairment. Perko was the fi rst to use a mobi-
lized mucosal split fl ap for palatal closure (Perko
1974 ) . The disadvantage of his technique was
the high risk of necrosis because the fl ap was
only pedicled at the dorsal side. This technique
has been modi fi ed by Leenstra et al. to obtain
a fl ap that is pedicled both at the dorsal and the
ventral side (Leenstra et al. 1995a, 1996 ) . They
used a partially split fl ap, leaving the lateral bone
covered with the osteogenic layer of the muco-
periosteum, without impairment of the major
neurovascular bundles (Leenstra et al. 1995a ) .
In dogs, this technique was promising, since it
led to less attachment of the mucoperiosteum
to the underlying bone, and an improved trans-
versal growth and development of the dentition
(Leenstra et al. 1995a, b ) , and also in a clinical
setting, the results were promising (Leenstra
et al. 1996 ) .
The denuded bone can also be covered with
a biomaterial, which can either be applied as
such or supplemented with cultured cells. This
type of approach belongs to the fi eld of tissue
engineering.
14.4.3 Tissue Engineering
Tissue engineering has been de fi ned in the late
1980s as “the application of principles and meth-
ods of engineering and life sciences toward fun-
damental understanding of structure-function
relationships in normal and pathological mam-
malian tissues and the development of biological
substitutes to restore, maintain or improve tissue
functions” (Skalak and Fox 1988 ) .
With respect to cleft palate surgery, a variety
of approaches have been chosen to improve the
outcome of the wound healing process. Firstly,
biocompatible membranes have been used to pre-
vent attachment of the scar tissue to the palatal
bone or to reduce contraction and scar formation.
A second approach is the engineering of mucosal
substitutes to replenish the tissue defects. To this
end, thin layers of keratinocytes have been cul-
tured that can be used as epithelial grafts.
Alternatively, keratinocytes have been cultured
on top of a dermal substrate to produce a bilay-
ered or composite graft, which is a substitute for
the entire mucosa. The dermal substrate may
consist of a collagenous matrix without cells or a
matrix with cultured fi broblasts.
14.4.3.1 Biocompatible Membranes
Biocompatible synthetic membranes have been
used to inhibit the attachment of scar tissue to the
palatal bone by covering the denuded bone areas
after surgery. Initially, the principles of guided
tissue regeneration were used by inserting mem-
branes in the mucoperiosteal defects (In de Braekt
et al. 1992 ) . These membranes were supposed to
cover the palatal bone, inhibit osteogenic pro-
cesses, and thereby prevent the formation of
Sharpey’s fi bers. Bio-resorbable Poly-L-lactic
acid membranes and non-resorbable polymer
membranes yielded unsatisfactory results. This
was caused by an uncontrollable degradation of
the lactic acid membranes and exfoliation or
incomplete coverage of the bone by the non-
resorbable membranes (Leenstra et al. 1998 ) .
Next to synthetic membranes, collagen-based
membranes have been used for intraoral surgery.
Atelocollagen membranes have been success-
fully used to improve gingival healing in a rat

317
14 Palatal Wound Healing: The Effects of Scarring on Growth
model (Minabe et al. 1989 ) . Similar membranes
were used later in a model for cleft palate repair
in young rabbits (Fujioka and Fujii 1997 ) . In a
split-mouth
design,
the
membranes
were
implanted on the denuded palatal bone at the
experimental side, while the control side was left
open. The authors report that implantation
reduced contraction and allowed more favorable
growth of the palatal bone and normal develop-
ment of the dentition.
To further improve collagen-based mem-
branes, suitable growth factors might be added to
promote angiogenesis and regeneration of the
submucosa and the overlying epithelium (Nimni
1997 ; Jansen et al. 2009 ) .
14.4.3.2 Epithelial Sheets
Oral keratinocytes, obtained from a mucosal
biopsy, can be cultured to form an epithelial sheet.
The keratinocytes are generally expanded using
the Rheinwald and Green method or a modi fi cation
thereof (Rheinwald and Green 1975 ) . Grafts cul-
tured from autologous keratinocytes seem to
behave as a permanent epithelial substitute after
transplantation (Bodner and Grossman 2003 ; Tsai
et al. 1997 ) . If allogeneic keratinocytes are used,
however, the graft behaves as a temporary wound
dressing that only accelerates reepithelialization
(Sumi et al. 1999 ) . Similar results were obtained
after skin grafting with cultured epidermal kerati-
nocytes. Several studies indicate that wound con-
traction and scar formation may still occur after
the application of a cultured epidermal graft
(Cooper et al. 1993 ; Williamson et al. 1995 ) . In
addition, the epithelial sheets are very fragile and
dif fi cult to handle.
14.4.3.3 Composite Substitutes
An approach that is more widely used nowadays
was developed for the grafting of full-thickness
burn wounds on the skin. In this approach, the
epithelium is cultured on a dermal substrate to
produce a composite graft (Pomahac et al. 1998 ;
Liu et al. 2010 ) . The presence of a dermal sub-
strate is supposed to diminish contraction and
subsequent scar formation. It can be derived from
human dermis or prepared from puri fi ed collagen
and additional extracellular matrix components.
Also, fi broblasts and growth factors may be
included within the dermal substrate to improve
vascularization and epithelial differentiation. An
overview of the production of a composite cul-
tured graft is given in Fig. 14.4 .
If dog palatal keratinocytes are cultured on skin-
derived substrates, they form an epithelium similar
to that in vivo (Ophof et al. 2002 ) (Fig. 14.5 ). Such
Mucosa
Fibroblasts
Keratinocytes
Dermal substrate
Composite graft
Implantation
Tissue
engineering
Fig. 14.4 Tissue engineering
of palatal mucosa. A mucosal
biopsy is taken and divided
into epithelium and submu-
cosa. Keratinocytes are
cultured from the epithelium,
and fi broblasts from the
submucosa. The fi broblasts
are seeded into a dermal
substrate, and the keratino-
cytes are cultured on top to
construct a composite graft
for implantation

318
J.W. Von den Hoff et al.
a composite graft containing human keratinocytes
showed a good clinical take rate after intraoral
grafting. Compared to a substrate without cells, the
composite graft showed enhanced epithelialization
and maturation of the submucosa (Izumi et al.
2003 ) . Grafts composed of a collagen substrate and
human keratinocytes inside the matrix have been
implanted in full-thickness skin wounds in
immunode fi cient mice (Butler et al. 2002 ) . They
showed a reduced wound contraction and a stimu-
lation of epithelial maturation.
Composite grafts for skin and oral mucosa
containing both keratinocytes and fi broblasts
have also been constructed (El Ghalbzouri et al.
2004 ; Liu et al. 2008 ) . The fi broblasts within the
dermal substrate seem to enhance the differentia-
tion of the overlying epithelium. Preliminary
studies have shown that keratinocytes cultured on
a collagen gel containing fi broblasts form a well-
differentiated epithelium (Igarashi et al. 2003 ) .
Transplantation of such a graft into skin wounds
in immunode fi cient mice reduced wound con-
traction (Moriyama et al. 2001 ) . Up to now, com-
posite grafts have not been evaluated extensively
for intraoral transplantation. However, their sug-
gested capacity to reduce wound contraction and
subsequent scarring makes them good candidates
for application in cleft palate surgery. The use of
tissue engineering techniques may well lead to
the development of suitable grafts for the
improvement of cleft palate repair.
14.4.4 Mechanisms of Wound Healing
(In Vivo Studies)
Recent animal experiments on cleft palate sur-
gery focus mainly on the biological processes
during intraoral wound healing and the possibili-
ties of reducing contraction and subsequent scar-
ring. Observational research aims at a more
detailed description of the cytokines and growth
factors involved in the intraoral wound healing
process. Most of these studies have been per-
formed in rats. Several pro-in fl ammatory factors
such as interleukins (ILs) are involved in palatal
wound healing. For example, IL-1 seems to be
essential for intraoral wound healing but not for
dermal wound healing. Its effects are probably
mediated by an increase of the antibacterial activ-
ity of PMNs and monocytes (Graves et al. 2001 ) .
On the other hand, oral wounds contain less IL-6
than skin wounds, while the expression of IL-10
in both types of wounds is similar (Szpaderska
et al. 2003 ) .
TGF b s and FGFs are also very important in
the early phases of wound healing, as they are
involved in the differentiation of myo fi broblasts.
TGF b 1 is supposed to upregulate FGF receptor-1
and FGF receptor-2 on palatal fi broblasts and
thus increasing the susceptibility of these cells to
FGFs. The latter factors are mainly produced by
macrophage-like cells and cause an increase in
the number of myo fi broblasts (Funato et al. 1999 ;
Kanda et al. 2003 ; Yokozeki et al. 1997 ) . On the
other hand, IFN g inhibits the differentiation of
myo fi broblasts from rat palatal fi broblasts
in vitro (Yokozeki et al. 1997 ) and in vivo
Fig. 14.5 ( a , b ) Tissue-engineered mucosa. Dog palatal
keratinocytes were cultured on a de-epidermized dermis
(DED) for 3 weeks. ( a ) Shows normal dog palatal
mucoperiosteum. ( b ) Shows the cultured graft. Note that
the cultured graft has a much thicker keratinized layer due
to the absence of mechanical abrasion

319
14 Palatal Wound Healing: The Effects of Scarring on Growth
(Cornelissen et al. 2000a ) . FGF2 is also involved
in the reepithelialization of palatal mucosa since
a single topical application already speeds up this
process (Oda et al. 2004 ) . After the completion of
wound
contraction
and
reepithelialization,
myo fi broblasts disappear, probably through
apoptosis that again is in fl uenced by TGF b 1 and
FGF2 (Funato et al. 1999 ) . The same processes
have been described for skin wounds, but they
seem to proceed at a slower pace (Nukumi et al.
2004 ) .
In the later phases of palatal wound healing,
the number of cells and the amount of collagen
are higher than in the normal mucoperiosteum.
The collagen type I fi bers are densely packed and
transversely aligned, indicating a distinct scar tis-
sue (Cornelissen et al. 1999 ) with a decreased
vascular density (Chu et al. 2000 ) . Since IFNs
possess anti fi brotic and anticontractive proper-
ties, they have been used for experimental
research on skin wound contraction and the
reduction of keloids. IFN a inhibits wound con-
traction (Nedelec et al. 1998 ) , IFN b downregu-
lates collagen synthesis of dermal fi broblasts
in vitro (Duncan et al. 1995 ) , and IFN g down-
regulates collagen synthesis in skin wounds
(Granstein et al. 1989 ) .
Strong evidence for the involvement of growth
factors in the regulation of wound contraction
and scar formation has been obtained from stud-
ies on fetal wound healing. Intrauterine wound
healing in mammalian fetuses occurs without
contraction and scar formation up to a certain
gestational age (Longaker and Adzick 1991 ) . In
this early phase of gestation, myo fi broblasts do
not occur during wound healing, and the regener-
ated tissue is indistinguishable from normal tis-
sue. This scarless healing seems to depend on a
speci fi c growth factor pro fi le within the wound
and on the typical intrauterine environment.
Several researchers have utilized these character-
istics of fetal wound healing to perform prenatal
cleft palate surgery in animals (Kaban et al. 1993 ;
Sullivan 1989 ; Zelles et al. 1995 ) . These studies
are debatable since they involve only surgically
created clefts.
Recently, a model for congenital cleft palate in
goats was described in which clefting was induced
by the teratogen anabasine (Weinzweig et al.
2002 ) . In affected fetuses, palatoplasty was per-
formed in utero using a modi fi ed von Langenbeck
technique at 85 days gestation. At 6 months of
age, the mucoperiosteum of the palate had healed
without scarring, and the function of the soft pal-
ate and the architecture of the velum were similar
to that of unclefted controls. However, it is highly
unlikely that prenatal surgery for cleft palate
repair will soon be common practice because of
diagnostic and ethical problems (Molsted 1999 ) .
The effects of speci fi c growth factors that are
possibly involved in scarless fetal healing can be
further investigated by in vitro studies.
14.4.5 Mechanisms of Wound Healing
(In Vitro Studies)
Several cell culture models are exploited to inves-
tigate aspects of fi broblast and keratinocyte biol-
ogy that are relevant to the oral wound healing
process. These studies often aim to elucidate the
differences between oral and dermal wound heal-
ing or to fi nd pharmacological means to modify
the oral wound healing process. Two-dimensional
monolayer cultures are suitable to study the
expression of certain proteins or the proliferation
and migration of cells. However, to study the
interactions of cells with their extracellular matrix,
a three-dimensional culture model is required. An
additional advantage of three-dimensional culture
models is that the physiology of the cells is more
similar to that in vivo (Mio et al. 1996 ) .
In two-dimensional monolayer cultures,
human oral keratinocytes constitutively express
higher levels of hepatocyte growth factor and
keratinocyte growth factor than skin keratino-
cytes (Okazaki et al. 2002 ) . In addition, they
express higher levels of IL-6 after stimulation
with other cytokines (Li et al. 1996 ) . These dif-
ferences may contribute to the preferential heal-
ing of mucosal wounds in comparison with skin
wounds. For rat palatal wound fi broblasts, it was
shown that interferons can reduce their collagen
synthesis, which seems to be favorable in the
light of scar reduction (Cornelissen et al. 1999 ) .
Oral fi broblasts have also been shown to possess

320
J.W. Von den Hoff et al.
a lower migration capacity in vitro compared
with skin fi broblasts (Lepekhin et al. 2002 ) .
Fibroblasts, taken from subsequent phases in rat
palatal wound healing, show distinct expression
patterns of integrins and cytoskeletal proteins
(van Beurden et al. 2003 ) . This indicates that
speci fi c subpopulations of fi broblasts may be
responsible for wound contraction and scarring.
Fibroblasts cultured in three-dimensional col-
lagen lattices contract this lattice in a time-
dependent way (Grinnell 1994 ) . The contraction
is caused by attachment of the cells to the collagen
and their migration through the lattice. This
model therefore represents some aspects of the
wound contraction process in vivo. Several inves-
tigators have used this model to compare the con-
traction capacity of oral and dermal fi broblasts
(Irwin et al. 1998 ; Lee and Eun 1999 ; Stephens
et al. 1996, 2001 ) . In general, these studies show
that oral fi broblasts have a higher contraction
capacity than dermal fi broblasts, similar to that of
fetal fi broblasts (Irwin et al. 1998 ) . The contrac-
tion of all three types of fi broblasts is inhibited by
IL-1b. Fibroblast-populated collagen lattices
were also used to investigate the migration of
fi broblasts into a wound (al-Khateeb et al. 1997 ) .
To this end, an experimental wound was made in
the lattice, and the migration of fi broblasts into
the wound was measured. Wound repopulation
by mucosal fi broblasts was greater than that by
age-matched dermal fi broblasts. These in vitro
models contribute to the understanding of cellu-
lar processes during oral wound healing and the
identi fi cation of factors with potential therapeutic
value. Eventually, this may lead to new strategies
to reduce intraoral wound contraction and scar-
ring and subsequent growth disturbances.
14.5
Application of Experimental
Results
The available data from clinical as well as experi-
mental research clearly indicate that primary
palatal surgery is an important factor in the max-
illary growth disturbances in cleft palate patients.
Experimental research in animal models shows
that wound contraction and subsequent scarring
in the surgical wounds are key events. More
speci fi cally, the attachment of the scar tissue to
the palatal bone and the periodontal fi ber system
inhibits sutural growth and normal development
of the dentition. This can only be partially pre-
vented by modi fi cations of the surgical technique
such as the split fl ap technique, which avoids the
denudation of palatal bone. Another development
is the use of tissue engineering techniques to con-
struct a substitute for oral mucosa, which can be
used to cover the denuded bone areas. There are
some indications that this may reduce contraction
and subsequent scarring on the palate. Whether
this approach will yield better growth parameters
after palatal surgery remains to be established.
A third approach might be the pharmacological
reduction of contraction and scarring after palatal
surgery. In vitro studies have shown that some
cytokines have the capacity to inhibit speci fi c
aspects of scar formation such as the differentia-
tion of myo fi broblasts and excessive collagen
deposition. Only few of these factors have also
shown favorable effects in vivo. However, the
ef fi cient delivery of the factor into the wound and
the targeting to speci fi c cells are practical prob-
lems that have to be solved.
References
al-Khateeb T, Stephens P, Shepherd JP, Thomas DW
(1997) An investigation of preferential fi broblast
wound repopulation using a novel in vitro wound
model. J Periodontol 68(11):1063–1069
Bardach J (1989) Lip repair and facial growth in beagles.
Plast Reconstr Surg 83(6):1079–1080
Bardach J (1990) The in fl uence of cleft lip repair on facial
growth. Cleft Palate J 27(1):76–78
Bardach J, Eisbach KJ (1977) The in fl uence of primary
unilateral cleft lip repair on facial growth. Cleft Palate
J 14(1):88–97
Bardach J, Klausner EC, Eisbach KJ (1979) The relation-
ship between lip pressure and facial growth after cleft
lip repair: an experimental study. Cleft Palate J
16(2):137–146
Bardach J, Roberts DM, Yale R, Rosewall D, Mooney M
(1980) The in fl uence of simultaneous cleft lip and pal-
ate repair on facial growth in rabbits. Cleft Palate J
17(4):309–318
Bardach J, Kelly KM, Salyer KE (1993) A comparative
study of facial growth following lip and palate repair
performed in sequence and simultaneously: an experi-

321
14 Palatal Wound Healing: The Effects of Scarring on Growth
mental study in beagles. Plast Reconstr Surg 91(6):
1008–1016
Berkowitz S (1977) Cleft lip and palate research: an
updated state of the art. Section III. Orofacial growth
and dentistry. Cleft Palate J 14(4):288–301
Bodner L, Grossman N (2003) Autologous cultured
mucosal graft to cover large intraoral mucosal defects:
a clinical study. J Oral Maxillofac Surg 61(2):169–173
Bourke KA, Haase H, Li H, Daley T, Bartold PM (2000)
Distribution and synthesis of elastin in porcine gingiva
and alveolar mucosa. J Periodontal Res 35(6):361–368
Butler CE, Navarro FA, Park CS, Orgill DP (2002)
Regeneration of neomucosa using cell-seeded colla-
gen-GAG matrices in athymic mice. Ann Plast Surg
48(3):298–304
Capelozza Filho L, Normando AD, da Silva Filho OG (1996)
Isolated in fl uences of lip and palate surgery on facial
growth: comparison of operated and unoperated male
adults with UCLP. Cleft Palate Craniofac J 33(1):51–56
Chu S, Ishikawa H, Kim T, Yoshida S (2000) Analysis of
scar tissue distribution on rat palates: a laser Doppler
fl owmetric study. Cleft Palate Craniofac J 37(5):
488–496
Clark RAF (1996) Wound repair: overview and general
considerations. In: Clark RAF (ed) The molecular and
cellular biology of wound healing. Plenum Press, New
York, pp 3–35
Cooper ML, Andree C, Hansbrough JF, Zapata-Sirvent
RL, Spielvogel RL (1993) Direct comparison of a cul-
tured composite skin substitute containing human
keratinocytes and fi broblasts to an epidermal sheet
graft containing human keratinocytes on athymic
mice. J Invest Dermatol 101(6):811–819
Cornelissen AM, Maltha JC, Von den Hoff HW, Kuijpers-
Jagtman AM (1999) Palatal mucoperiosteal wound
healing in the rat. Eur J Oral Sci 107(5):344–351
Cornelissen AM, Maltha JC, Von den Hoff JW, Kuijpers-
Jagtman AM (2000a) Local injection of IFN-gamma
reduces the number of myo fi broblasts and the collagen
content in palatal wounds. J Dent Res 79(10):1782–1788
Cornelissen AM, Stoop R, Von den Hoff HW, Maltha JC,
Kuijpers-Jagtman AM (2000b) Myo fi broblasts and
matrix components in healing palatal wounds in the
rat. J Oral Pathol Med 29(1):1–7
Dahl E (1970) Craniofacial morphology in congenital
clefts of the lip and palate. An x-ray cephalometric
study of young adult males. Acta Odontol Scand
28(Suppl 57):11+
Derijcke
A,
Kuijpers-Jagtman
AM,
Lekkas
C,
Hardjowasito W, Latief B (1994) Dental arch dimen-
sions in unoperated adult cleft-palate patients: an anal-
ysis of 37 cases. J Craniofac Genet Dev Biol 14(1):
69–74
Desmouliere A, Gabbiani G (1996) The role of the
myo fi broblast in wound healing and fi brocontractive
diseases. In: Clark RAF (ed) The molecular and cel-
lular biology of wound healing. Plenum Press, New
York, pp 391–414
Desmouliere A, Redard M, Darby I, Gabbiani G (1995)
Apoptosis mediates the decrease in cellularity during
the transition between granulation tissue and scar. Am
J Pathol 146(1):56–66
Duncan MR, Hasan A, Berman B (1995) Pentoxifylline,
pentifylline, and interferons decrease type I and III
procollagen mRNA levels in dermal fi broblasts: evi-
dence for mediation by nuclear factor 1 down-regula-
tion. J Invest Dermatol 104(2):282–286
Ehrlich HP, Rajaratnam JB (1990) Cell locomotion forces
versus cell contraction forces for collagen lattice con-
traction: an in vitro model of wound contraction.
Tissue Cell 22(4):407–417
El Ghalbzouri A, Hensbergen P, Gibbs S, Kempenaar J,
van der Schors R, Ponec M (2004) Fibroblasts facili-
tate re-epithelialization in wounded human skin equiv-
alents. Lab Invest 84(1):102–112
Fujioka M, Fujii T (1997) Maxillary growth following
atelocollagen implantation on mucoperiosteal denuda-
tion of the palatal process in young rabbits: implica-
tions for clinical cleft palate repair. Cleft Palate
Craniofac J 34(4):297–308
Funato N, Moriyama K, Baba Y, Kuroda T (1999)
Evidence for apoptosis induction in myo fi broblasts
during palatal mucoperiosteal repair. J Dent Res 78(9):
1511–1517
Gabbiani G (2003) The myo fi broblast in wound healing
and fi brocontractive diseases. J Pathol 200(4):
500–503
Graber TM (1949) Craniofacial morphology in cleft pal-
ate and cleft lip deformities. Surg Gynecol Obstet
88(3):359–369
Granstein RD, Deak MR, Jacques SL, Margolis RJ, Flotte
TJ, Whitaker D, Long FH, Amento EP (1989) The
systemic administration of gamma interferon inhibits
collagen synthesis and acute in fl ammation in a murine
skin wounding model. J Invest Dermatol 93(1):
18–27
Graves DT, Nooh N, Gillen T, Davey M, Patel S, Cottrell
D, Amar S (2001) IL-1 plays a critical role in oral, but
not dermal, wound healing. J Immunol 167(9):
5316–5320
Grinnell F (1994) Fibroblasts, myo fi broblasts, and wound
contraction. J Cell Biol 124(4):401–404
Huang D, Chang TR, Aggarwal A, Lee RC, Ehrlich HP
(1993) Mechanisms and dynamics of mechanical
strengthening
in
ligament-equivalent
fi broblast-
populated collagen matrices. Ann Biomed Eng 21(3):
289–305
Igarashi M, Irwin CR, Locke M, Mackenzie IC (2003)
Construction of large area organotypical cultures of
oral mucosa and skin. J Oral Pathol Med 32(7):
422–430
In de Braekt MM, van Alphen FA, Kuijpers-Jagtman AM,
Maltha JC (1992) Wound healing and wound contrac-
tion after palatal surgery and implantation of poly-(L-
lactic) acid membranes in beagle dogs. J Oral
Maxillofac Surg 50(4):359–364; discussion 365–356
Irwin CR, Myrillas T, Smyth M, Doogan J, Rice C, Schor
SL (1998) Regulation of fi broblast-induced collagen
gel contraction by interleukin-1beta. J Oral Pathol
Med 27(6):255–259

322
J.W. Von den Hoff et al.
Izumi K, Feinberg SE, Iida A, Yoshizawa M (2003)
Intraoral grafting of an ex vivo produced oral mucosa
equivalent: a preliminary report. Int J Oral Maxillofac
Surg 32(2):188–197
Jansen RG, van Kuppevelt TH, Daamen WF, Kuijpers-
Jagtman AM, Von den Hoff JW (2009) FGF-2-loaded
collagen scaffolds attract cells and blood vessels in rat
oral mucosa. J Oral Pathol Med 38(8):630–638
Kaban LB, Dodson TB, Longaker MT, Stern M, Umeda
H, Adzick S (1993) Fetal cleft lip repair in rabbits:
long-term clinical and cephalometric results. Cleft
Palate Craniofac J 30(1):13–21
Kanda T, Funato N, Baba Y, Kuroda T (2003) Evidence
for fi broblast growth factor receptors in myo fi broblasts
during palatal mucoperiosteal repair. Arch Oral Biol
48(3):213–221
Kim T, Ishikawa H, Chu S, Handa A, Iida J, Yoshida S
(2002) Constriction of the maxillary dental arch by
mucoperiosteal denudation of the palate. Cleft Palate
Craniofac J 39(4):425–431
Kremenak CR Jr, Huffman WC, Olin WH (1970)
Maxillary growth inhibition by mucoperiosteal denu-
dation of palatal shelf bone in non-cleft beagles. Cleft
Palate J 7:817–825
Kuijpers-Jagtman AM, Long RE Jr (2000) State of the art:
the in fl uence of surgery and orthopedic treatment on
maxillofacial growth and maxillary arch dimensions
in patients treated for orofacial clefts. Cleft Palate
Craniofac J 37:527/1–527/12
Lambrecht JT, Kreusch T, Schulz L (2000) Position,
shape, and dimension of the maxilla in unoperated
cleft lip and palate patients: review of the literature.
Clin Anat 13(2):121–133
Lee HG, Eun HC (1999) Differences between fi broblasts
cultured from oral mucosa and normal skin: implica-
tion to wound healing. J Dermatol Sci 21(3):176–182
Leenstra TS, Kuijpers-Jagtman AM, Maltha JC, Freihofer
HP (1995a) Palatal surgery without denudation of
bone favours dentoalveolar development in dogs. Int
J Oral Maxillofac Surg 24(6):440–444
Leenstra TS, Maltha JC, Kuijpers-Jagtman AM, Spauwen
PH (1995b) Wound healing in beagle dogs after pala-
tal repair without denudation of bone. Cleft Palate
Craniofac J 32(5):363–369; discussion 369–370
Leenstra TS, Kohama G, Kuijpers-Jagtman AM, Freihofer
HP (1996) Supraperiosteal fl ap technique versus
mucoperiosteal fl ap technique in cleft palate surgery.
Cleft Palate Craniofac J 33(6):501–506
Leenstra TS, Kuijpers-Jagtman AM, Maltha JC (1998)
The healing process of palatal tissues after palatal sur-
gery with and without implantation of membranes: an
experimental study in dogs. J Mater Sci Mater Med
9(5):249–255
Lepekhin E, Gron B, Berezin V, Bock E, Dabelsteen E
(2002) Differences in motility pattern between human
buccal fi broblasts and periodontal and skin fi broblasts.
Eur J Oral Sci 110(1):13–20
Li J, Farthing PM, Ireland GW, Thornhill MH (1996) IL-1
alpha and IL-6 production by oral and skin keratino-
cytes: similarities and differences in response to cytokine
treatment in vitro. J Oral Pathol Med 25(4):157–162
Liu J, Lamme EN, Steegers-Theunissen RP, Krapels IP,
Bian Z, Marres H, Spauwen PH, Kuijpers-Jagtman
AM, Von den Hoff JW (2008) Cleft palate cells can
regenerate a palatal mucosa in vitro. J Dent Res
87(8):788–792
Liu J, Bian Z, Kuijpers-Jagtman AM, Von den Hoff JW
(2010) Skin and oral mucosa equivalents: construction
and performance. Orthod Craniofac Res 13(1):11–20
Longaker MT, Adzick NS (1991) The biology of fetal
wound healing: a review. Plast Reconstr Surg
87(4):788–798
Mars M, Houston WJ (1990) A preliminary study of facial
growth and morphology in unoperated male unilateral
cleft lip and palate subjects over 13 years of age. Cleft
Palate J 27(1):7–10
McGrath MH, Simon RH (1983) Wound geometry and
the kinetics of wound contraction. Plast Reconstr Surg
72(1):66–73
McPherson JM (1992) The utility of collagen-based
vehicles in delivery of growth factors for hard and soft
tissue wound repair. Clin Mater 9(3–4):225–234
Mignatti P, Rifkin DB, Welgus HG, Parks WC (1996)
Proteinases and tissue remodeling. In: Clark RAF (ed)
The molecular and cellular biology of wound healing.
Plenum Press, New York, pp 427–461
Minabe M, Kodama T, Hori T, Watanabe Y (1989) Effects
of atelocollagen on the wound healing reaction follow-
ing palatal gingivectomy in rats. J Periodontal Res
24(3):178–185
Mio T, Adachi Y, Romberger DJ, Ertl RF, Rennard SI
(1996) Regulation of fi broblast proliferation in three-
dimensional collagen gel matrix. In Vitro Cell Dev
Biol Anim 32(7):427–433
Molsted K (1999) Treatment outcome in cleft lip and pal-
ate: issues and perspectives. Crit Rev Oral Biol Med
10(2):225–239
Moriyama T, Asahina I, Ishii M, Oda M, Ishii Y, Enomoto
S (2001) Development of composite cultured oral
mucosa utilizing collagen sponge matrix and con-
tracted collagen gel: a preliminary study for clinical
applications. Tissue Eng 7(4):415–427
Nakato H, Kimata K (2002) Heparan sulfate fi ne structure
and speci fi city of proteoglycan functions. Biochim
Biophys Acta 1573(3):312–318
Nedelec B, Dodd CM, Scott PG, Ghahary A, Tredget EE
(1998) Effect of interferon-alpha2b on guinea pig
wound closure and the expression of cytoskeletal pro-
teins in vivo. Wound Repair Regen 6(3):202–212
Nimni ME (1997) Polypeptide growth factors: targeted
delivery systems. Biomaterials 18(18):1201–1225
Nukumi K, Masuda M, Obata A, Yumoto E (2004)
Differences in expression of basic fi broblast growth
factor during wound healing between oral mucosa and
skin. Wound Repair Regen 12(1):A7
Oda Y, Kagami H, Ueda M (2004) Accelerating effects of
basic fi broblast growth factor on wound healing of rat
palatal mucosa. J Oral Maxillofac Surg 62(1):73–80

323
14 Palatal Wound Healing: The Effects of Scarring on Growth
Okazaki M, Yoshimura K, Uchida G, Harii K (2002)
Elevated expression of hepatocyte and keratinocyte
growth factor in cultured buccal-mucosa-derived
fi broblasts
compared
with
normal-skin-derived
fi broblasts. J Dermatol Sci 30(2):108–115
Ophof R, van Rheden RE, Von den HJ, Schalkwijk J,
Kuijpers-Jagtman AM (2002) Oral keratinocytes cul-
tured on dermal matrices form a mucosa-like tissue.
Biomaterials 23(17):3741–3748
Ortiz-Monasterio F, Serrano A, Barrera G, Rodriguez-Hoffman
H, Vinageras E (1966) A study of untreated adult cleft pal-
ate patients. Plast Reconstr Surg 38(1):36–41
Perko MA (1974) Primary closure of the cleft palate using
a palatal mucosal fl ap: an attempt to prevent growth
impairment. J Maxillofac Surg 2(1):40–43
Pomahac B, Svensjo T, Yao F, Brown H, Eriksson E
(1998) Tissue engineering of skin. Crit Rev Oral Biol
Med 9(3):333–344
Rheinwald JG, Green H (1975) Serial cultivation of strains of
human epidermal keratinocytes: the formation of kerati-
nizing colonies from single cells. Cell 6(3):331–343
Rojas AI, Ahmed AR (1999) Adhesion receptors in health
and disease. Crit Rev Oral Biol Med 10(3):337–358
Ross RB (1987a) Treatment variables affecting facial
growth in complete unilateral cleft lip and palate, part
1:treatment affecting growth. Cleft Palate J 24(1):5–23
Ross RB (1987b) Treatment variables affecting facial
growth in complete unilateral cleft lip and palate. Part
2: presurgical orthopedics. Cleft Palate J 24(1):24–30
Ross RB (1987c) Treatment variables affecting facial growth
in complete unilateral cleft lip and palate. Part 3: alveo-
lar repair and bone grafting. Cleft Palate J 24(1):33–44
Ross RB (1987d) Treatment variables affecting facial
growth in complete unilateral cleft lip and palate. Part
4: repair of the cleft lip. Cleft Palate J 24(1):45–53
Ross RB (1987e) Treatment variables affecting facial
growth in complete unilateral cleft lip and palate. Part
5: timing of palate repair. Cleft Palate J 24(1):54–63
Ross RB (1987f) Treatment variables affecting facial
growth in complete unilateral cleft lip and palate. Part 6:
techniques of palate repair. Cleft Palate J 24(1):64–70
Ross RB (1987g) Treatment variables affecting facial
growth in complete unilateral cleft lip and palate. Part
7: an overview of treatment and facial growth. Cleft
Palate J 24(1):71–77
Rudolph R, Vande Berg J, Ehrlich HP (1992) Wound con-
traction and scar contracture. In: Cohen IK, Diegelman
RT, Lindblad WJ (eds) Wound healing: biochemical
and physical aspects. WB Saunders, Philadelphia,
pp 96–114
Rygh P, Tindlund R (1982) Orthopedic expansion and
protraction of the maxilla in cleft palate patients–a
new treatment rationale. Cleft Palate J 19(2):104–112
Searls JC, Kremenak CR, Rittman BR (1979) Quantitative
characterization of changes in cellularity and collagen fi ber
size in contracting palatal wounds. Cleft Palate J 16(4):
373–380
Semb G, Shaw WC (1996) Facial growth in orofacial cleft-
ing disorders. In: Turvey TA, Vig KWL, Fonseca RJ
(eds) Facial clefts and craniosynostosis. Principles and
management. WB Saunders, Philadelphia, pp 28–56
Semb G, Shaw WC (1998) Facial growth after different
methods of surgical intervention in patients with cleft
lip and palate. Acta Odontol Scand 56(6):352–355
Shaw WC, Semb G, Nelson P, Brattström V, Prahl-
Andersen B (2000) The Eurocleft project 1996–2000.
Ios Press, Amsterdam
Skalak R, Fox CF (1988) Preface. In: Skalak R, Fox CF
(eds) Tissue engineering. Alan R Liss, New York
Squier CA, Finkelstein MW (2003) Oral mucosa. In:
Nanci A (ed) Ten Cate’s oral histology: development,
structure, and function, 6th edn. Mosby, St. Louis,
pp 329–375
Stephens P, Davies KJ, al-Khateeb T, Shepherd JP, Thomas
DW (1996) A comparison of the ability of intra-oral
and extra-oral fi broblasts to stimulate extracellular
matrix reorganization in a model of wound contrac-
tion. J Dent Res 75(6):1358–1364
Stephens P, Davies KJ, Occleston N, Pleass RD, Kon C,
Daniels J, Khaw PT, Thomas DW (2001) Skin and oral
fi broblasts exhibit phenotypic differences in extracel-
lular matrix reorganization and matrix metalloprotei-
nase activity. Br J Dermatol 144(2):229–237
Sullivan WG (1989) In utero cleft lip repair in the mouse
without an incision. Plast Reconstr Surg 84(5):723–
730; discussion 731–722
Sumi Y, Hata KI, Sawaki Y, Mizuno H, Ueda M (1999)
Clinical application of cultured oral epithelium for
palatal wounds after palatoplasty: a preliminary report.
Oral Dis 5(4):307–312
Szpaderska AM, Zuckerman JD, DiPietro LA (2003)
Differential injury responses in oral mucosal and cuta-
neous wounds. J Dent Res 82(8):621–626
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA
(2002) Myo fi broblasts and mechano-regulation of connec-
tive tissue remodelling. Nat Rev Mol Cell Biol 3(5):349–363
Tsai CY, Ueda M, Hata K, Horie K, Hibino Y, Sugimura
Y, Toriyama K, Torii S (1997) Clinical results of cul-
tured epithelial cell grafting in the oral and maxillofa-
cial region. J Craniomaxillofac Surg 25(1):4–8
van Beurden HE, Snoek PA, Von den Hoff JW, Torensma
R, Kuijpers-Jagtman AM (2003) Fibroblast subpopu-
lations in intra-oral wound healing. Wound Repair
Regen 11(1):55–63
Weinzweig J, Panter KE, Spangenberger A, Harper JS,
McRae R, Edstrom LE (2002) The fetal cleft palate:
III. Ultrastructural and functional analysis of palatal
development following in utero repair of the congeni-
tal model. Plast Reconstr Surg 109(7):2355–2362
Wijdeveld MG, Grupping EM, Kuijpers-Jagtman AM,
Maltha JC (1988) Growth of the maxilla after soft tis-
sue palatal surgery at different ages in beagle dogs: a
longitudinal radiographic study. J Oral Maxillofac
Surg 46(3):204–209
Wijdeveld MG, Grupping EM, Kuijpers-Jagtman AM,
Maltha JC (1989) Maxillary arch dimensions after
palatal surgery at different ages on beagle dogs. J Dent
Res 68(6):1105–1109

324
J.W. Von den Hoff et al.
Wijdeveld MG, Maltha JC, Grupping EM, De Jonge J,
Kuijpers-Jagtman AM (1991) A histological study of tis-
sue response to simulated cleft palate surgery at different
ages in beagle dogs. Arch Oral Biol 36(11):837–843
Williamson JS, Snelling CF, Clugston P, Macdonald IB,
Germann E (1995) Cultured epithelial autograft: fi ve
years of clinical experience with twenty-eight patients.
J Trauma 39(2):309–319
Yamada KM, Clark RAF (1996) Provisional matrix. In:
Clark RAF (ed) The molecular and cellular biology
of wound healing. Plenum Press, New York,
pp 51–82
Yokozeki M, Moriyama K, Shimokawa H, Kuroda T
(1997) Transforming growth factor-beta 1 modulates
myo fi broblastic phenotype of rat palatal fi broblasts
in vitro. Exp Cell Res 231(2):328–336
Zelles T, Purushotham KR, Macauley SP, Oxford GE,
Humphreys-Beher MG (1995) Saliva and growth fac-
tors: the fountain of youth resides in us all. J Dent Res
74(12):1826–1832

325
S. Berkowitz (ed.), Cleft Lip and Palate,
DOI 10.1007/978-3-642-30770-6_15, © Springer-Verlag Berlin Heidelberg 2013
15
For the foreseeable future, clefts of the lip and
palate will continue to be managed by surgical
closure and thus will be accompanied by an ines-
capable degree of surgical trauma. Surgery will
be considered successful when, without undue
burden, favourable outcomes have been achieved
with respect to nasolabial appearance, speech and
hearing and facial growth, thus optimising per-
sonal development and social integration.
As far as facial growth is concerned, surgi-
cally induced growth impairment has been recog-
nised for more than 60 years (Graber 1949 ;
Slaughter and Brodie 1949 ) . But despite the
intervening years, controversy remains about the
importance of surgical technique, timing and
sequence, ancillary procedures and surgical skill.
And there is as much doubt about the mecha-
nisms of facial growth in the absence of clefts,
individual variability in response to surgery, the
validity of theories that have determined the
selection of some techniques over others and the best
way to resolve these uncertainties. In this chapter,
these issues will be reviewed with respect to
complete unilateral and bilateral cleft lip and
palate (UCLP and BCLP).
15.1
The Characteristics of Facial
Development in Individuals
with Repaired Complete Cleft
Lip and Palate
15.1.1 UCLP
A previous review of facial development in
individuals with repaired complete cleft lip and
palate revealed general consensus on the associ-
ated characteristics (Semb and Shaw 1996 ) . Facial
form in adult individuals with repaired UCLP and
BCLP is similar and, in comparison with the facial
form of non-cleft subjects, is characterised by a
progressive retrusion of the pro fi le relative to the
cranial base involving the nasal bone, the mandi-
ble, but especially the maxilla (Fig. 15.1 ). Both
the maxilla and mandible are shorter and retru-
sive, and the incisors in both jaws are retroclined.
There is severe reduction in posterior but only
slight reduction in anterior maxillary height. The
mandible has an increased gonial angle and a
steeper mandibular plane, and there is an increase
in lower facial height. The bony nasopharynx is
smaller. There is a tendency for facial growth to
be more severely affected in males.
The pattern of growth is different from that in
non-cleft individuals. Semb ( 1991a ) found only
a small increase between 5 and 18 years of age
in the length of the maxilla measured to the ante-
rior outline of the alveolar process in a mixed
longitudinal study of 257 subjects with com-
plete UCLP. There was a concomitant reduction
in maxillary prominence at the dentoalveolar
Facial Growth Related to Surgical
Methods
Gunvor Semb and William C. Shaw
G. Semb , DDS, Ph.D. () • W. C. Shaw , BDS, Ph,D.
Department of Orthodontics,
University of Manchester, School of Dentistry ,
Room G.009, Coupland III Building, Coupland Street ,
Manchester M13 9PL , UK
e-mail: gunvor.semb@manchester.ac.uk;
bill.shaw@manchester.ac.uk

326
G. Semb and W.C. Shaw
level, as seen in Fig. 15.2 . The excessive lower
face angulation changed little over time in the
UCLP sample (approximately 3° greater than
the Bolton standards at age 5 years), whereas
it was reduced by 5° in the non-cleft sample.
The gradual reduction of maxillary prominence
over time and increased lower face height has
also been described in several long-term stud-
ies (Enemark et al. 1990 ; Paulin and Thilander
1991 ; Smahel et al. 1993 ; Friede and Enemark
2001 ; Brattström et al. 2005 ; Nollet et al. 2008 ;
Meazzini et al. 2008 ; Friede et al. 2011 ) .
15.1.2 BCLP
A mixed longitudinal study of 90 patients with
complete BCLP from 5 to 18 years (Semb 1991b )
found the maxilla in BCLP to be relatively prom-
inent in early childhood (4° more prominent at
5 years), but it steadily receded so that by 7 years,
it was similar to the value for non-cleft subjects
Fig. 15.1 Average facial shape in adult patients with
unilateral complete cleft lip and palate compared with a
non-cleft sample (Courtesy of Dr. E. Dahl, University of
Copenhagen)
90
89
88
87
86
85
83
84
81
80
82
75
73
76
77
72
78
74
79
71
70
0
1
3
2
4
5
6
7
8
9
10 11 12 13 14 15 16 17
20
18 19
Age in years
Reduced maxillary prominence (SNA)
UCLP and BCLP compared to non-cleft
BCLP n = 90
Non-Cleft
UCLP
n = 257
Fig. 15.2 Changes in maxillary prominence (SNA) for 257 patients with complete unilateral cleft lip and palate
(UCLP) and 90 patients with complete bilateral cleft lip and palate (BCLP) compared with a non-cleft sample

327
15 Facial Growth Related to Surgical Methods
(Broadbent et al. 1975 ) and by 18 years, it was 6°
less (see Fig. 15.2 ). Throughout the period of
observation, the mandible was less prominent (4°
less at 5 years and 6° less at 18 years). Vertically,
lower facial angulation remained higher in BCLP
(2° at 5 years and 9° at 18 years). Similar fi ndings
have been reported (Heidbüchel et al. 1994 ;
Gnoinski and Rutz 2009 ) .
Thus, the growth pattern is different between
UCLP and BCLP groups in one obvious respect.
In comparison with UCLP patients, subjects with
BCLP displayed greater maxillary prominence in
early childhood (SNA was 5.3° larger at 5 years),
but this difference reduced with time so that by
18 years, the maxilla was only slightly (1.4°)
more prominent on average. In other respects,
facial growth patterns were similar in both con-
ditions, although the gonial angle was somewhat
greater (3°) in BCLP throughout the period of
observation.
15.1.3 Late Deterioration
Impairment of maxillary development continues
into the late teens and early adulthood while
mandibular growth continues (Enemark et al.
1990 ; Paulin and Thilander 1991 ; Semb 1991a,
b ; Friede and Enemark 2001 ; Brattström et al.
2005 ; Gnoinski and Rutz 2009 ; Myklebust et al.
2009 ; Friede et al. 2011 ; Semb et al. 2011 ) . Thus,
the anteroposterior jaw relationship worsens over
time and with it the occlusion.
Since there are few publications of longitudinal
follow-up beyond age 20, it is not possible to say
when this growth differential ends. Enemark et al.
( 1990 ) followed 57 patients with UCLP from birth
to 21 years of age. The cephalometric study
showed that from 16 to 21 years, the maxillary
prominence reduced by 1.1° while the mandibular
prominence increased by 1.0°. The same was
found in a longitudinal cephalometric study of 60
patients with UCLP from Oslo studied at 16, 18
and 21 years of age (Myklebust et al. 2009 ) .
Maxillary prominence (SNA) is reduced by 0.3°
from 16 to 18 years and by 0.3° from 18 to 21 years;
maxillary length (condylion to A-point) is increased
by 0.6 mm from 16 to 18 years and by 0.5 mm
from 18 to 21, while the mandibular length is
increased by 2.3 mm from 16 to 18 years and with
1.1 mm from 18 to 21 years. A deterioration of the
occlusion in the late teens/early adulthood has
been reported by Lilja et al. ( 2006 ) , Marcusson
and Paulin ( 2004 ) , and Semb et al. ( 2011 ) .
15.2
Intrinsic Facial Differences
Not Attributable to Surgery
It would be surprising if the catastrophic events
leading to failed union of the facial processes
were not associated with dysmorphology beyond
the cleft site. Some indication of the extent to
which the variations in facial form in UCLP and
BCLP described above are intrinsic can be
obtained by comparing individuals with unre-
paired clefts and normal controls.
On anteroposterior cephalograms, increased
width of various facial parts in unoperated infants
with UCLP and BCLP has been found (Hermann
et al. 2000, 2004 ) . On lateral cephalograms, the
maxilla in the UCLP group was smaller, though
more protrusive at the alveolar level and at the
level of the anterior nasal spine in the male sub-
jects. The mandible was also smaller, the gonial
angle was increased, the mandibular plane was
steeper and the lower incisors were retroclined in
the UCLP group. There was a reduced posterior
height and a tendency towards increased anterior
lower facial height. These differences in mandib-
ular shape were more marked in females. The
nose was less protruded, but as a result of the
maxillary protrusion, there was an increase in
pro fi le convexity (Capelozza et al. 1993 ; Mars
and Houston 1990 ) . Differences likely to be intrin-
sic in nature also include abnormalities in the size
and form of the cranial base (although the litera-
ture is contradictory on this point). One consistent
fi nding is the smaller craniofacial dimensions
(including size of the maxilla) found in both unop-
erated and operated individuals with UCLP and
BCLP compared with non-cleft subjects, though
this may relate to a smaller overall stature in indi-
viduals with clefts (Jensen et al. 1983 ) .
Evidence that the prominence of the cleft
maxilla is similar to that of the non-cleft is a key

328
G. Semb and W.C. Shaw
issue in the debate concerning surgical iatrogen-
esis. Therefore, it is noteworthy that the compari-
sons between individuals without cleft and
individuals with unoperated cleft have revealed
similar anterior projection of the basal maxilla on
the greater segment (Capelozza et al. 1993 ; Mars
and Houston 1990 ) , and the same is true preop-
eratively for infants with complete clefts com-
pared to infants with cleft lip and alveolus
(Hermann et al. 2000, 2004 ) .
A variety of reports including twin and fetal
studies point to intrinsically reduced nasal airway
volume in individuals with clefts, repaired or not.
This in turn may contribute the mandibular abnor-
malities that are observed (Semb and Shaw 1996 ) .
15.2.1 Individuality of Patients
Lastly, it must remembered that children, whether
or not they have clefts, tend to resemble their par-
ents and that inheritance, especially with regard to
Class II or Class III predisposition, will be an
in fl uential background factor in post-surgical facial
development. Furthermore, each child entering the
operating room will have other inherited traits that
may impact on healing and recovery and on a wide
range of later development. This individuality is a
key factor in explaining the wide variability of out-
come demonstrated by any study cohort and the
consequent need for adequate sample size in
research. As Pruzansky observed, “Within certain
de fi ned limits, the success or failure of the surgical
procedure depends more on the initial state than on
the variables inherent in the manoeuvre. To put it
another way, we expect that subtle differences
among patients will be more prognostic of the sub-
sequent state than differences between surgeons”
Nordin ( 1957 ) .
15.3
Surgical Iatrogenesis
Surgery has a great impact on maxillary growth
that becomes progressively apparent as patients
reach maturity with reduced prominence of the
maxilla at the basal (anterior nasal spine) and den-
toalveolar (A point) level (Liao and Mars 2005a, b ) .
The mandibular growth pattern is unaffected by the
surgical repair of complete clefts (da Silva et al. 1992 ) .
It is conceivable that patients with a signi fi cant
de fi ciency of tissue are most at risk for post-oper-
ative maxillary distortion and restraint. However,
the speci fi c cause of growth disturbance remains
unclear, but lip closure as well as palate closure
has been implicated (Ross and Johnston 1972 ;
Mars and Houston 1990 ; Normando et al. 1992 ) .
It is possible that the iatrogenic effects of
lip closure may have been underestimated.
Experimental animal studies have reported
that increased pressure from the repaired cleft
lip is the primary cause of maxillary growth
restraint (Bardach et al. 1984a ) . Lip pressure in
infants with UCLP has been measured after lip
repair and until 2 years of age and found to be
signi fi cantly higher than in a non-cleft control
group. Furthermore, follow-up of partially oper-
ated human subjects with complete UCLP and
BCLP where only the lip has been repaired, in
comparison to individuals with both lip and palate
repair, points to the signi fi cant role of lip closure.
Indeed, increased lip pressure probably continues
to mould the anterior dentoalveolar region and
reduce the SNA angle into adulthood.
Two studies have focused on this question on
relatively large samples of subjects with UCLP
(Mars and Houston 1990 ; Capelozza et al. 1996 ) .
The length of the maxilla (Ar-ANS) was reduced
after lip surgery by 6.3 and 4.0 mm, respectively,
in the Sri Lankan and Brazilian lip-only samples,
an effect that appears to be largely due to mould-
ing of the anterior alveolus (Liao and Mars
2005b ) . In the samples where lip surgery and
subsequent palate surgery were performed, pala-
tal surgery appeared responsible for only a small
additional amount of retrusion, 1.0 mm in the Sri
Lankan sample and 0.7 mm in the Brazilian sam-
ple. The same effect was seen in the prominence
of the anterior alveolar process. Dahl ( 1970 ) also
found a substantial reduction in maxillary promi-
nence in patients with UCLP who had undergone
lip surgery only. However, because individuals
with complete clefts who have undergone only
palatal surgery are not available, this experiment
cannot be considered complete. It is by no means
certain that the effect of palatal repair alone

329
15 Facial Growth Related to Surgical Methods
would be limited to 1 or 2 mm (i.e. whichever
operation is undertaken fi rst could have the major
restraining effect).
The transverse dimension of the basal maxilla
does not seem to be affected by surgery, but the
dental arches are highly affected. Palatal closure
often includes incisions alongside the dental
arches, and the scars produced may induce an
inward de fl ection of the dentoalveolar processes,
resulting in anterior and traverse crossbites (Ross
and Johnston 1972 ; Bergland and Sidhu 1974 ;
Dahl et al. 1981 ) . It is therefore likely that differ-
ent surgical techniques for closing the palate give
rise to malocclusions of different extent without
necessarily altering the neighbouring structures.
15.4
Clinical Uncertainty
Considerable ingenuity has been applied in the
development and modi fi cation of primary surgical
protocols for closing UCLP and BCLP. And if one
takes the technique, timing and sequence of opera-
tions into account, the variations in practice between
centres can be extreme. One survey funded by the
European Union found that 201 cleft teams
employed a total of 194 different protocols in the
closure of UCLP (Shaw et al. 2001 ) . The total
number of primary operations to close the cleft var-
ied from 1 to 4; a total of 17 possible sequences of
operation for closing the cleft were practised; lip
closure was performed at all possible points
between birth and 12 months; the timing of hard
palate closure ranged from birth to 13 years. Almost
half the centres used presurgical orthopaedics. In
fact, all of the 201 teams would have differed in
their protocols had not seven of them previously
agreed to participate in a randomised trial.
15.5
Theories That Have In fl uenced
Surgical Management
In general, developments of new or modi fi ed
surgical protocols have been founded on one or
other theoretical premise, and disappointment
with current results. Examples of these would
include assumptions concerning the underlying
mechanisms of maxillary growth, the presence
and location of growth centres (to be avoided
during surgery) or the role of muscular function
in optimising growth potential. However, pres-
ent understanding of the controlling mechanisms
of facial growth is incomplete and derives from
observational work and speculation in earlier
decades.
However, this fi eld of research no longer
seems popular with craniofacial biologists, and
understanding of the mechanisms of facial growth
has not advanced in recent years. Current research
mostly focuses on genetic causation, on gene
environment interaction and on Hox genes,
growth factors and signalling molecules that
in fl uence facial embryogenesis, providing, at this
stage, few options for surgical manipulation.
Examples of theories that have in fl uenced sur-
gical management in a quest for better maxillary
growth include:
Delaying closure of the hard palate.
•
“Later” lip repair may reduce early growth
•
impairment.
Designing fl aps to minimise denuded bone,
•
for example, avoiding pushback techniques
and using minimal lateral releasing incisions.
Avoiding use of the vomerine fl ap in order to
•
safeguard septal and the vomero-premaxillary
suture development and in turn growth.
Performing extensive facial muscle dissection
•
to optimise function and, in turn, growth.
Reducing the extent of trauma at any one time
•
by performance of surgical closure in small
incremental stages, such as three or four oper-
ations rather than one or two.
Assuming early bene fi ts of repairing the alve-
•
olar cleft by bone grafting or other osteogenic
technique in infancy would not harm growth.
Assuming that presurgical orthopaedics/soft
•
tissue moulding would facilitate surgery and
improve the long-term result in better or equal
growth.
Assuming that concentrating surgery on high-
•
volume surgeons would achieve better
growth.
As we shall see below, however, most of these
theories and assumptions have proved unreliable
in actual practice, except possibly in the case of

330
G. Semb and W.C. Shaw
the last. The following appraisal is based upon
earlier reviews (Semb and Shaw 1996, 1998 ) ,
three more recent comprehensive reviews (Liao
and Mars 2006 ; Friede 2007 ; Yang and Liao 2010 )
and reports of additional studies that set out to
make explicit intra- or intercentre comparisons of
different surgical protocols using cephalometry
and/or indices of dental arch relationship.
15.6
Clinical Evidence to Support
or Refute Theories Concerning
Surgery and Growth
15.6.1 Delayed Hard Palate Closure
Delayed hard palate closure is by no means a
recent development having been proposed at
least 90 years ago (Gillies and Fry 1921 ) . It is
still relatively popular; in the last survey, 16.5 %
of European centres delayed closure till the
child was older (range 3–13 years). But it has
not been without critics. In their review of the
rationale and supporting evidence for this pro-
cedure, Witzel and co-workers ( 1984 ) proposed
that the bene fi cial effect on facial growth had
not been proved (unless surgery is delayed until
after 12 years of age) and deleterious effects on
speech had been largely disregarded. Recent
fi ndings from a randomised trial con fi rm this risk
(Willadsen 2011 ) . By 3 years of age, the group
where hard palate repair was delayed to 3 years
had a more restricted phonological system and
produced more cleft speech characteristics than
the group repaired at 1 year.
Earlier data from single-centre studies indicate
that maxillary prominence does not systematically
differ between centres practicing early closure of
the hard palate with a vomer fl ap or by different
forms of one-stage palatoplasty, including push-
back, and those who delay hard palate closure
(Semb and Shaw 1996 ) . Only the exceptional delay
of hard palate closure in Marburg sample until
mean age 13.2 years (range 8–22 years) con fi rmed
a bene fi cial long-term effect on maxillary growth
while assessment of speech development revealed
signi fi cant speech impairment (Schweckendiek
and Doz 1978 ; Bardach et al. 1984b ) .
However, earlier reports of very good maxillary
growth with delayed closure (till age 8) were recently
con fi rmed by Friede and co-workers ( 2011 ) in a
cephalometric follow-up of 50 patients to age 19
and an assessment of dental arch relationship at age
19 (Lilja et al. 2006 ) . Liao et al. ( 2010 ) also found
better maxillary prominence at age 20 in a delayed
closure group compared with an early closure group
treated in different time periods at the same centre
in Taiwan, though delayed closure was abandoned
because of poor speech outcome. Noverraz et al.
( 1993 ) found no advantage for delayed closure
in an intracentre comparison, while Gaggl et al.
( 2003 ) compared two groups from the same cen-
tre at 18 years, and found maxillary prominence
to be worse in the delayed closure group, while
another intracentre study, despite use of the original
Schweckendiek protocol including obturation and
hard palate closure at 7 years, reported very nega-
tively on delayed closure as it led to severe speech
problems, deleterious growth and a high rate of
retrusion calling for orthognathic surgery (Holland
et al. 2007 ) . Negative speech and outcomes for
delayed closure were also reported from yet another
intracentre study (Rohrich et al. 2000 ) .
Inter centre comparisons including at least
one delayed hard palate closure group have been
reported. Friede and Enemark ( 2001 ) compared
growth outcome between Gothenburg and Aarhus
samples of 30 patients. The fi rst group had soft
palate closure at 8 months and hard palate clo-
sure at 8.5 years (mean) while the second had
anterior palate closure at 3 months (vomer fl ap)
and soft palate closure at 22 months (pushback).
Cephalometric values at three intervals from the
early to mid-teens for maxillary prominence were
better for the delayed closure group, though less
so with age.
Swennen et al. ( 2002 ) , however, found no dif-
ferences in a comparison between a delayed clo-
sure and an early closure centre, nor did Stein
et al. ( 2007 ) in a similar study. Comparison of
delayed with early closure in the same centre
revealed no difference in dental arch relationship
(Noverraz et al. 1993 ) . This was also the case in
a subsequent Eurocleft comparison of records
with another centre practising delayed closure
(Nollet et al. 2005a ) . Nor did delayed closure

331
15 Facial Growth Related to Surgical Methods
surpass early closure in a small four-centre
Scandinavian comparison (Friede et al. 1991 ) .
Robertson and Jolleys ( 1974 ) conducted a ran-
domised trial involving two groups of 20 patients
where one group’s hard palate closure was delayed
until 5 years of age. No bene fi t for dentofacial
growth was found in delaying hard palate closure
when the children reached 11 years of age.
One exception to this pattern is the report of a
meta-analysis where regression analysis sug-
gested delayed closure to be bene fi cial for growth
(Nollet et al. 2005b ) . One explanation may be
inclusion of a high proportion (65 %) of patients
from the UK (where delayed closure is not prac-
tised), mainly drawn from a series of studies
revealing historical de fi ciencies of cleft surgical
services in general (Bearn et al. 2001 ) .
An alternative approach to the timing question
is presented by Berkowitz et al. ( 2005 ; see also
Chap. 7 ). This multicentre three-dimensional
analysis of study casts found that the velocity of
growth decreases over the fi rst 2 years and then
plateaus. It was concluded that the optimal time
for closure was when the ratio of the posterior
cleft space to the total palatal surface area is
10 % or less, generally occurring between 18 and
24 months.
The present overview leads us to concur with
the comprehensive reviews of Liao and Mars
( 2006 ) and Yang and Liao ( 2010 ) who noted that
the great heterogeneity in reports precludes reli-
able conclusions at this time and makes the case
that well-designed prospective studies are neces-
sary to resolve this uncertainty; Friede ( 2007 )
also drew attention to the forthcoming fi ndings of
three randomised trials in the Scandcleft series
(Semb 2001 , described below).
15.6.2 Later Lip Closure
In truth, not much consideration has been given
to the timing of lip closure, but we include it here
for consideration as factor that may have been
overlooked in interpreting outcomes. Bardach
et al. ( 1984a ) drew attention to the high lip pres-
sure that follows repair, and lip surgery on its
own is associated with considerable moulding of
the anterior maxilla (Liao and Mars 2005a, b )
and possibly restraint of the basal maxilla
(Capelozza et al. 1996 ) .
Almost one third of European centres perform
lip repair at 6 months or later (Shaw et al. 2001 ) .
There are no comparative studies of early versus
late lip repair that we are aware of, but it is interest-
ing that several diverse protocols that include late
lip repair have achieved good growth outcomes.
These include “all-in-one repair” undertaken at
9 months (Fudalej et al. 2009 ) , soft palate repair
at 3 months followed by lip and hard palate repair
at 6 months (Trotman and Ross 1993 ) and the
Zurich protocol with lip repair at 6 months (Perko
1990 ) . Another variation is the Gothenburg pro-
tocol where lip adhesion is done at 2 months and
de fi nitive repair is deferred to 18 months (Friede
and Enemark 2001 ) . Substantial postponement of
lip closure of course may raise important socio-
logical issues.
15.6.3 Efforts to Minimise Trauma
and Scarring
It does seem probable that minimising trauma and
scarring by delicate tissue handling and judicious
fl ap design can only be bene fi cial and that suitable
forms of tissue engineering or pharmaceutical
modulation of scarring offer promise for the future
(see Chap. 5 ). Much has been written about the
harmful effect of palatal scars that form on areas
of the palate denuded during primary surgery
(Palmer et al. 1969 ; Blocksma et al. 1975 ) , and it
has been postulated especially that scar tissue
located in the region of the maxillary/palatine and
palatine/pterygoid sutures acts to prevent the
maxilla’s normal downward and forward transla-
tion (Ross and Johnston 1972 ) . Avoidance of the
vomero-premaxillary suture has also been recom-
mended (Friede and Morgan 1976 ) .
Ross ( 1987 ) hypothesised that early soft tissue
closure of the alveolus might also lead to some
growth impairment compared to those who had
had no alveolar repair.
Perko ( 1974 ) developed a mucosal split fl ap to
avoid elevation of the periosteum. A modi fi ed
version of this achieved more arch depth than the

332
G. Semb and W.C. Shaw
previously used Wardill-Kilner technique in a
Japanese comparison (Leenstra et al. 1996 ) .
Jonsson et al. ( 1980 ) used a vomer fl ap covered
with an autogenous skin graft in UCLP but with-
out signi fi cant bene fi t. Also, no or minimal
releasing incisions for closure of the palate
(except in patients with very wide clefts) have
been proposed (Brusati and Mannucci 1994 ;
Sommerlad 2009 ) .
15.6.4 Vomer Flap
Scott’s theories on the primacy of the nasal septum
probably did much to underpin concerns about sur-
gical harm to the vomer, and different opinions have
been held regarding the disadvantages and bene fi ts
of the use of a single-layer vomer fl ap to close the
hard palate (Friede and Johanson 1977 ; Jonsson
et al. 1980 ; Bütow and Steinhauser 1984 ; Delaire
and Precious 1985 ; Friede and Pruzansky 1985 ;
Enemark et al. 1990 ; Semb 1991a, b ; Hay and
Sommerlad 2008 ) . However, again, the available
clinical evidence contradicts the theory. As noted
above, and in an earlier review (Semb and Shaw
1996 ) , single-centre cephalometric studies incorpo-
rating vomer fl ap show no systematic evidence of
growth disturbance, and several have some of the
highest values. Likewise, in a series of different
intercentre comparisons involving analysis of den-
tal arch relationship and/or cephalometry, alterna-
tive methods have equalled but not surpassed vomer
fl ap (combined with modi fi ed von Langenbeck pos-
terior palate closure) samples at statistically
signi fi cant levels (Friede et al. 1991 ; Brattström
et al. 1991 ; Mars et al. 1992 ; Mølsted et al. 1992 ,
2005 ; MacKay et al. 1994 ; Roberts-Harry et al.
1996 ; Gaukroger et al. 2002 ; Brattström et al. 2005 ;
Nollet et al. 2005a ; Flinn et al. 2006 ; Meazzini et al.
2008 ; Fudalej et al. 2009 ; Meazzini et al. 2010 ) .
15.6.5 Extensive Orofacial Muscle
Dissection
Anatomical study of the orofacial and oronasal
musculature led Delaire to propose extensive
“functional repair” of the musculature as a
solution to midface growth inhibition (Joos 1995 ) ;
however, although the theory was put into
practice by Delaire and others for a time, little
evidence for its validity has since emerged. One
single-centre study reported UCLP outcomes at
a mean age 6.5 years and found outcomes bet-
ter than a historical control group treated by
a different surgeon (Joos 1995 ) . No conven-
tional cephalometric data or study cast index
was reported. Others have drawn attention to
the possible paradox that more extensive sur-
gery to achieve normal anatomy may incur the
penalty of greater scarring and growth restraint
(Kuijpers-Jagtman and Long 2000 ) .
15.6.6 Single or Multiple Stages
of Closure
In the European survey referred to above, the
total number of operations taken to complete clo-
sure of complete unilateral clefts varied from one
(5 %), two (71 %), three (22 %) and four (2 %)
with multiple stages often part of a delayed hard
palate program. The economy and reduction of
the burden of care clearly favour the “all-in-one”
approach, but that could be offset with a per-
ceived greater challenge of post-operative man-
agement and worries about iatrogenic growth
disturbance, as evidenced in animal studies
(Bardach et al. 1993 ) .
Interestingly, the evidence available from
intercentre comparisons suggests that varying
the number of stages may actually be neutral
in terms of growth. In the Americleft study
(Chap. 18 ), Centre C who performed three-
stage closure (lip, then hard palate with vomer
fl ap, then soft palate) ranked highest for growth
(Daskalogiannakis et al. 2011 ; Hathaway et al.
2011 ) . An “all-in-one” sample from Poland has
also compared well with mainstream staging in
intercentre comparisons (Fudalej et al. 2009 ) .
De Mey et al. ( 2009 ) reported a prospective
cohort study in a single centre, where a two-
stage Malek protocol was compared with an
“all-in-one” Malek protocol. Entry to the lat-
ter group was limited to patients with a poste-
rior palate width less than 10 mm. Both groups
were followed till age 10 and 15 and had good
cephalometric outcomes.