longitudinal craniofacial growth in pierre robin …...dr. sunjay suri, thesis supervisor, director...

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Longitudinal Craniofacial Growth in Pierre Robin

Sequence in Comparison with Isolated Cleft Palate and

Unaffected children

By

Fay Pereira BSc, D.D.S

A thesis submitted in conformity with the requirements for the degree of Master of Science (Orthodontics)

Graduate Program in Orthodontics Faculty of Dentistry, University of Toronto

© Copyright by Fay Pereira 2017

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Longitudinal Craniofacial Growth in Pierre Robin Sequence in

Comparison with Isolated Cleft Palate and Unaffected Children

Fay Pereira

Master of Science Degree, 2017

Graduate Program in Orthodontics, Faculty of Dentistry, University of Toronto

Toronto, Ontario, Canada

Abstract

Background: Pierre Robin Sequence (PRS) is defined at birth by the presence of mandibular

micrognathia, glossoptosis and airway insufficiency with or without cleft palate.

Objectives/hypothesis: Analyze craniofacial morphology and facial growth patterns in non-

syndromic PRS and compare them to isolated cleft palate (ICP) and unaffected children. Materials

& Methods: Craniofacial characteristics were examined at three time points by comparing

digitized tracings of subjects with PRS and ICP and unaffected class I subjects. Between-group

and longitudinal differences across the time points were analyzed. Results: PRS and ICP groups

had significantly small maxillas compared to the unaffected group and displayed a vertical pattern

of growth. PRS group had the smallest mandibles (by 8%; 9.7mm) followed by the ICP group (by

4%; 4.2mm) when compared to the unaffected group. Conclusions: Craniofacial morphology and

longitudinal facial growth in subjects with PRS and ICP are similar in many areas but differ

significantly from comparable unaffected children.

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Acknowledgements

I would like to thank and express my gratitude to the following people for their support

throughout the course of the investigation:

Dr. Sunjay Suri, Thesis supervisor, Director of the Graduate Specialty Program in Orthodontics,

Faculty of Dentistry, University of Toronto; for your guidance, encouragement, and advice from

conception of the project to the last edit of the manuscript, including every presentation in

between. Your passion and expertise in this area of study exuded throughout the process.

Dr. David Fisher, Committee member, Medical Director and Plastic Surgeon, Hospital for Sick

Children, Toronto; for your advice and for sharing your extensive knowledge and experience in

managing patients with Pierre Robin Sequence.

Dr. Wendy Lou, Committee member, Division Head of Biostatistics, Dalla Lana School of

Public Health, University of Toronto; for your guidance and statistical expertise throughout this

project.

Ms. Lynn Cornfoot, former digitizer, Department of Dentistry, Hospital for Sick Children,

Toronto; Thank you for lending me your cephalometric tracing expertise throughout this

investigation.

Fred F. Schudy Memorial Research Award 2015-2016 awarded to Dr. Sunjay Suri from the

AAO Foundation that supported this project.

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Table of Contents

Acknowledgements ..................................................................................................................................... iii

List of Tables ................................................................................................................................................ vi

List of Figures .............................................................................................................................................. vii

List of Abbreviations ................................................................................................................................. viii

1. Introduction and Statement of the Problem ........................................................................................... 1

1.1 Introduction ........................................................................................................................................ 1

1.2 Statement of the Problem ................................................................................................................. 4

2. Review of the literature ........................................................................................................................... 5

2.1 Pierre Robin Sequence (PRS) ............................................................................................................. 5

2.1.1. Prevalence ................................................................................................................................... 6

2.1.2. Etiology ....................................................................................................................................... 7

2.1.3. Embryopathogenesis................................................................................................................... 8

2.1.4. Management .............................................................................................................................. 9

2.2. Isolated Cleft Palate (ICP) ............................................................................................................... 11

2.2.1. Prevalence ................................................................................................................................. 12

2.2.2 Etiology and Embryopathogenesis ............................................................................................. 12

2.2.3 Cleft palate repair ...................................................................................................................... 13

2.3. Effects on Craniofacial Growth ....................................................................................................... 14

2.3.1. Pierre Robin Sequence compared to Isolated Cleft Palate ........................................................ 15

2.3.2. Pierre Robin Sequence and Isolated cleft palate compared to Normal .................................... 16

3. Purpose of the study, Research Objective and Hypothesis .................................................................. 20

3.1. Purpose of the study ....................................................................................................................... 20

3.2. Research Objectives ........................................................................................................................ 21

3.3. Hypotheses ...................................................................................................................................... 22

4. Materials and Methods .......................................................................................................................... 23

4.1. Sample Description ......................................................................................................................... 23

4.1.1. Pierre Robin Sequence group: ................................................................................................... 23

4.1.2. Isolated Cleft Palate group – control group .............................................................................. 24

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4.1.3. Unaffected children – control group: ........................................................................................ 25

4.2. Cephalometric Analysis ................................................................................................................... 26

4.3. Statistics ........................................................................................................................................... 29

4.4. Reliability Analysis .......................................................................................................................... 30

5. Results..................................................................................................................................................... 31

5.1. PRS vs Normal: ................................................................................................................................ 40

5.2. PRS vs ICP: ....................................................................................................................................... 42

5.3. ICP vs Normal: ................................................................................................................................. 43

6. Discussion ............................................................................................................................................... 44

7. Conclusions ............................................................................................................................................. 51

8. References .............................................................................................................................................. 53

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List of Tables

Table 1. Summary of the Literature: Catch-up mandibular growth in patients with PRS (Suri, 2014) ...... 18

Table 2. Summary of the Literature: Craniofacial growth characteristics in patients with PRS and ICP in

comparison with normal samples ............................................................................................................... 19

Table 3. Mean ages: PRS group .................................................................................................................. 24

Table 4. Mean ages: Isolated Cleft Palate group ........................................................................................ 25

Table 5. Mean Ages: Unaffected Group ..................................................................................................... 26

Table 6. Cephalometric Analysis: Definitions of the cephalometric landmarks ......................................... 28

Table 7. Cephalometric Analysis: Definitions of the linear and angular measurements ........................... 29

Table 8. Intraexaminer repeatability of cephalometric measurements of 15 randomly selected subjects.

.................................................................................................................................................................... 30

Table 9. Mean values with and without adjustment for gender of the cephalometric measurements at

T1. ............................................................................................................................................................... 35


T2. ............................................................................................................................................................... 36


T3. ............................................................................................................................................................... 37

Table 12. Pairwise comparisons of mean measurements adjusted for gender using Tukey’s comparison

at T1 ............................................................................................................................................................ 38


at T2. ........................................................................................................................................................... 39


at T3 ............................................................................................................................................................ 40

Table 15. Linear mixed model analysis of growth differences between PRS and Normal groups. ............ 41

Table 16. Linear mixed model analysis of growth differences between PRS and ICP groups .................... 42

Table 17. Linear mixed model analysis of growth differences between ICP and Normal groups .............. 43

Table 18. Averaged percentage differences in maxillary and mandibular lengths found in this study in

comparison with those reported in the literature. ..................................................................................... 51

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List of Figures

Figure 1. Illustration of a lateral cephalogram labelled with the custom landmarks (Suri et al., 2010b) .. 27

Figure 2. A digitized lateral cephalogram ................................................................................................... 27

Figure 3. Superimposition of averaged tracings of PRS, ICP and normal groups at T1. ............................. 32



Figure 6. Superimposition of averaged tracings of the PRS group at T1, T2 and T3 .................................. 33

Figure 7. Superimposition of averaged tracings of the ICP group at T1, T2 and T3 ................................... 33

Figure 8. Superimposition of averaged tracings of the normal group at T1, T2 and T3 ............................. 34

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List of Abbreviations

BGC Burlington Growth Centre

EMD Estimated mean difference

HSC Hospital for Sick Children

ICCC Intra-class Correlation Coefficient

ICP Isolated cleft palate

OSA Obstructive sleep apnea

PEBP Pre-epiglottic baton plate

PRS Pierre Robin Sequence

UAO Upper airway obstruction

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1. Introduction and Statement of the Problem

1.1 Introduction

Craniofacial anomalies relate to abnormalities in growth patterns and development of the face

and the skull. Development of these abnormalities can primarily be attributed to interruptions in

the normal embryonic growth process occurring in utero, resulting in defects seen at birth. They

can also occur secondary to trauma or pathologic processes that occur after birth (Figueroa and

Friede, 2000). Pierre Robin Sequence (PRS) is a craniofacial disorder defined at birth by the

presence of a core triad - mandibular micrognathia, glossoptosis and upper airway obstruction

(Robin, 1934). Although the presence of palatal clefting is not necessary for the diagnosis of

PRS, it is present in 84.5% to 95% of these patients (Latham and Van der Molen, 1966,

Anderson et al, 2011; van Lieshout et al, 2014). This condition is referred to as a ‘sequence’

because the primary anomaly of a micrognathic mandible sets into motion a cascade of events

that gives PRS its characteristic features. The small mandible prevents the tongue from

descending adequately during the fusion of the palatal shelves resulting in a cleft in the palate

(Opitz, 1979). The small mandible is also unable to provide adequate space and support for the

tongue musculature resulting in glossoptosis and a congested airway, often requiring emergency

airway management in the delivery room (Robin, 1934; Opitz, 1979).

The incidence of PRS reported in the literature varies between 1 in 8,500 and 1 in 20,000 births,

making it a rare condition (Bush, 1983; Printzlau and Anderson, 2004). The characteristic

micrognathic mandible of PRS is etiologically heterogeneous and can result from either an

intrinsic dysplasia or secondary to intrauterine compression and teratogenic influences during

fetal development (Poswillo, 1966; Cohen, 1999). Recent developments in genetic testing have

revealed numerous genetic associations that can lead to PRS, where it may form part of a larger

syndrome such as, Stickler syndrome or Treacher Collins syndrome. Although the exact genetic

causes of PRS as a non-syndromic anomaly are not yet known, its occurrence has been

associated with a family history of clefting in 27% of cases (Jakobson et al, 2006).

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In syndromic PRS, because the etiology is usually intrinsic and related to genetic defects, the

ability of the mandible to ‘catch-up’ to normal is reported to be quite limited (Shprintzen, 1992).

In non-syndromic PRS, because the etiology was thought to be mostly extrinsic, mandibular

growth was expected to improve significantly and attain normal or near normal lengths. This is

not the case as reported widely in the literature (Randall et al., 1965; Shen et al., 2012). In the

time immediately following birth, infants with PRS do show an accelerated percentage of

growth, however, this is not enough to ‘catch-up’ to normal and completely resolve the

retrognathic and convex profile retained into adulthood (Figueroa et al., 1991; Vegter et al.,

1999; Hermann et al., 2003; Erikson et al., 2006).

In the literature, PRS is often compared to isolated cleft palate groups (ICP) in order to take into

consideration the effect of the cleft palate and its surgical repair on growth of the facial skeleton

and overall craniofacial morphology (Figueroa et al., 1991). It is known that the maxillary

lengths of subjects with palatal clefts are smaller than normal (Shibasaki and Ross, 1969;

Laitinen and Ranta, 1998). Some studies suggest that the deficiency in length is due to post-

surgical scar tissue formation since un-operated subjects are reported to have maxillas that are

comparable to normal (Ortiz-Monasterio et al., 1966; Mars and Houston, 1990). Others suggest

that the deficiency in maxillary length is a combination of an innate developmental defect in

addition to the surgical cleft repair, since un-operated subjects had maxillas that were smaller

than normal (Coupe and Subtelny, 1960; Ross and Coupe, 1965; Capelozza et al., 1993). Bishara

(1973) and daSilva et al. (1989, 1992) found no significant differences in the maxillary lengths

of patients with ICP that received surgical cleft repair compared to those that did not receive

surgery, suggesting that the deficiency in maxillary length might be due to an innate

developmental defect.

The effect of cleft palate on the mandible is also a subject of controversy. Some studies have

refuted a significant influence of the cleft palate repair on morphology and spatial positioning of

the mandible (Bishara, 1973; daSilva et al., 1992). However, other studies show that the

presence of palatal clefting and the repair thereof, does have an effect on mandibular growth.

Shibasaki and Ross (1969) compared patients with ICP to normal subjects and found that

although patients with ICP have normal mandibular lengths, their mandibles are posteriorly

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rotated resulting in a large gonial angle. However, rat studies as well as human studies have

shown that the mandibular growth pattern is normal but the length of the mandible is shorter than

normal (Warkany et al., 1943; Warkany and Schraffenberger, 1947; Borden 1957).

A review of the literature comparing PRS and ICP suggests that there is a difference in the rate

of craniofacial growth and morphology when paralleling to each other and to unaffected subjects.

Although PRS and ICP have mandibles that might have some morphogenetic similarities, PRS

have mandibles that are smaller, both in body length and ramus height, more retrognathically

positioned and posteriorly rotated leading to a soft tissue profile that is more convex than ICP

(Laitinen and Ranta, 1992). The pattern of growth also tends to be more vertical as suggested by

steeper mandibular plane angles in subjects with PRS (Laitinen and Ranta, 1992;

Daskalogiannakis et al., 2001).

Aside from a micrognathic mandible when comparing to unaffected children, patients with PRS

have been shown to have a smaller maxilla with a steep palatal plane angle and smaller cranial

base lengths (Suri et al., 2010a). The detailed analysis of craniofacial morphology of PRS

conducted by Suri et al. (2010a) provides a quantitative comparison between patients with PRS

and unaffected children. A custom comprehensive cephalometric analysis using internal

landmarks as well as conventional landmarks were used for this study (Suri et al., 2006, 2010b).

The mandible in subjects with PRS was found to be 60 retrognathic, 100 steeper and 6.5% shorter

in length than unaffected normal children. As well, the maxilla in subjects with PRS was found

to be 12% shorter than normal subjects. This information is clinically relevant in order to

accurately plan both orthodontic and surgical treatment that is often required in patients with

PRS. It is important to note how this detailed analysis of PRS craniofacial morphology compares

to that of ICP craniofacial morphology, in order to identify the role that the cleft palate and its

repair might play on growth of the craniofacial complex. This will help not only to verify the

ideology that patients with PRS present with a more severe but morphogenetically similar

developmental anomaly as those with ICP, but also allow us to learn more about the specific

differences between ICP and normal

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1.2 Statement of the Problem

Although PRS is a well-recognized craniofacial anomaly, several aspects of this condition still

remain poorly understood. Till date, PRS has several definitions and agreed-on clinical features,

making comparisons of the results in the literature, a difficult task (Breugem et al., 2016). Most

of what is known regarding the craniofacial growth and morphology of children and adolescents

with PRS is based on small sample sizes, case reports, mixed racial samples, cross sectional

studies, short-term longitudinal studies and mixed longitudinal studies. As well, some studies

have used mixed groups of syndromic and non-syndromic PRS. Rogers et al (2009) reported that

mandibular morphology and position varies depending on the association of PRS with a

syndrome, as well as the type of syndrome that is present. All of these factors have introduced

variability in the results reported in the literature, limiting its applicability to treatment of all

patients with PRS. It is important to understand craniofacial growth and morphology in this

group of patients in order to confidently plan and execute dentofacial treatment.

In order to shed some light on the craniofacial growth patterns of patients with PRS, the aim of

this study was to evaluate and identify differences in craniofacial morphology and growth

patterns in patients diagnosed with non-syndromic PRS in comparison with patients diagnosed

with isolated cleft palate and unaffected subjects. This evaluation was to be carried out by using

the comprehensive cephalometric analysis reported by Suri et al. (2006, 2010b) focussing on

regional detail with internal landmarks.

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2. Review of the literature

2.1 Pierre Robin Sequence (PRS)

This craniofacial disorder is named after the French stomatologist, Pierre Robin, who described

its defining features in 1923. Previous associations between micrognathia and airway obstruction

were described as early as 1822 by St-Hilaire, followed by Fairbain in 1846 and Shukowsky in

1911 (Scott and Mader, 2014). However, Pierre Robin was able to identify that the respiratory

difficulties experienced by infants and children with hypoplastic mandibles were due to

glossoptosis. In his initial observations of 6-7 year old children with retruded mandibles, he

found that even after adenoidectomies, they still experienced breathing difficulties. He explained

that retracted mandibles caused the base of the tongue to be pushed back against the epiglottis,

creating an airway obstruction. As soon as their mandibles were forced forward, these children

were able to breathe with ease. He also observed that in some extreme cases, babies born with

severely hypoplastic mandibles did not survive past 16 to 18 months due to breathing and

feeding difficulties. He called this mechanical effect “glossoptosis” and the condition,

“glossoptotic syndrome” (Robin, 1934). By the 1960s, other clinicians added further information

through their own observations, and it began to be called Pierre Robin Syndrome (Randall, 1965;

Shprintzen, 1992). Over the years, several terms have been used to diagnose this condition

including, Robin Syndrome, Robin Anomalad and, Pierre Robin Triad. More recently it has been

described as a sequence rather than a syndrome because the abnormal mandible begins a cascade

of events that leads to the characteristic features of this condition (Opitz, 1979; Cohen, 1981).

Aside from the varied nomenclatures used to identify this condition, there is universal confusion

with regard to the key characteristic features that define PRS making diagnosis difficult (Van der

Haven et al, 1997; Breugem and Van der Molen, 2009). Today, the all-encompassing definition

for PRS is, a craniofacial disorder diagnosed at birth by the presence of a core triad of

mandibular micrognathia or retrognathia, glossoptosis and upper airway obstruction with or

without cleft palate (Breugem et al, 2016). Although the presence of palatal clefting is not

necessary for the diagnosis of PRS, it has been reported to be present in 84.5% to 95% of these

patients (Latham and Van der Molen, 1966, Anderson et al, 2011; van Lieshout et al, 2014).

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Even though micrognathia is a key feature of this condition, a specific definition for what

constitutes micrognathia is lacking in the literature and is currently based on subjective criteria

(Izumi et al, 2012).

2.1.1. Prevalence

Pierre Robin Sequence is a relatively rare disorder with a reported prevalence range of 1 in 8,500

to 1 in 20,000 live births (Bush, 1983; Printzlau and Anderson, 2004). The wide range in

prevalence reported in the literature can be attributed to the pathogenetic and phenotypic

variability of the condition making it difficult to clearly define and diagnose this disorder. As

well, prevalence has been shown to differ in various populations and racial groups (Basart et al,

2015; Cohen, 2001). Asians are reported to have the lowest prevalence, while Caucasians are

reported as having the highest prevalence of PRS (Tolarova and Cervenka, 1998). In terms of a

gender related predilection, there is no difference in incidence of PRS reported in males and

females (Printzlau and Anderson, 2004).

PRS is commonly classified as a syndromic or non-syndromic entity. In syndromic PRS, the

triad of features forms part of a larger syndrome accounting for 35% of PRS cases (Holder-

Espinasse et al, 2001). There are over 40 syndromes associated with PRS, the most common of

which are Stickler Syndrome (44%), velocardiofacial Syndrome (7%), Treacher Collins

Syndrome (5%) and craniofacial microsomia (3%) (Evan et al, 2006; Rogers et al, 2009; Evans

et al, 2011). Other associated syndromes include 22q11.2 deletion syndrome, Marshall

syndrome, Van der Woude syndrome, oculo-auricular-vertebral spectrum, Moebius syndrome,

and Nager syndrome (Izumi et al, 2012). It can also be associated with environmentally-induced

or teratogenic syndromes such as Fetal Alcohol Syndrome and Fetal Hydantoin Syndrome

(Gorlin et al, 1990). In non-syndromic PRS, the triad of features may occur in isolation, as it

does in 48% of cases. It may also occur in association with a wide spectrum of anomalies

involving the eyes and/or ears, as it does in 17% of cases (Holder-Espinasse et al, 2001; Ozcan et

al, 2004).

There is a possibility that cases of syndromic PRS have been underreported in the literature

because a syndromic diagnosis is often difficult to make in the neonatal period (Al-Samkari et al,

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2010). Change in diagnosis from non-syndromic to syndromic PRS often occurs after the

neonatal period because syndrome-specific facial features and syndrome-specific medical

complications are rarely noted during this time, becoming more pronounced with growth. As

well, in order to accurately diagnose a patient with syndromic or non-syndromic PRS, genetic

testing, family history, prenatal exposure to teratogenic agents as well as ophthalmologic and

audiologic evaluations are necessary, which might be difficult to do during the neonatal period

(Izumi et al, 2012). In terms of treatment, it is important to make this distinction as patients with

syndromic PRS typically require more aggressive airway and feeding management than patients

with non-syndromic PRS (Al-Samkari et al, 2010; Izumi et al, 2012).

2.1.2. Etiology

Pierre Robin Sequence is known as an etiologically heterogeneous condition. The characteristic

mandibular micrognathia can occur as a result of inherent defects in mandibular outgrowth and

elongation due to genetic aberrations. It can also occur from causes that are external to the

mandible but secondarily impact its growth during fetal development. These interruptions can be

caused by intrauterine compression and restriction of mandibular growth or by the influence of

environmental teratogens (Poswillo, 1966; Cohen, 1999; Tan et al., 2013).

There are several instances that point to the genetic etiology of PRS. Family members of patients

with PRS often have cleft lip or palate (Marques et al., 1998; Holder-Espinasse et al., 2001). As

well, PRS may be associated with other syndromes that have a genetic basis such as Stickler

syndrome, velo-cardio-facial syndrome and Treacher Collins syndrome, suggesting that

syndromic PRS is due to aberrations in the patient’s genetic make-up (Evans et al, 2006). PRS

has been linked to SOX9 enhancer deletions (17q24.3–q25.1), rearrangements of certain

chromosome loci such as, 2q24.1–q33.3 (GAD67), 4q32-ter, 11q21–q23.1 (PVRL1) and (SOX9)

and, mutations in collagen genes such as, COL2A1 and COL11A1 (Cohen, 1999; Jakobsen et al,

2006).

Non-genetic causes of PRS have been linked to intrauterine constriction, oligohydramnios,

breech position, abnormal uterine anatomy, or multiple births (Jakobsen et al, 2006; Amarillo et

al, 2013). In any of these situations, the posture of the embryo is altered such that the normal

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extension of the cervical spine that occurs after the 6th week is prevented, delayed or greatly

reduced, interfering with development of normal cranial flexure. The chin becomes compressed

against the sternum, forcing the mandible against the nasal capsular region and arresting

intramembranous ossification of the body of the mandible (Poswillo, 1966). Furthermore,

teratogens such as alcohol, tobacco, and drugs such as tamoxifen have been implicated in the

development of Pierre Robin Syndrome (Prows and Bender, 1999; Holder – Espinasse et al,

2001; Berger and Clericuzio, 2008).

2.1.3. Embryopathogenesis

In the early 4th week of embryonic development, neural crest cells that originate in the mid- and

hindbrain regions of the neural folds migrate into the future head and neck regions to initiate

formation of the branchial arches (Praveen and Barbara, 2007). It is the first branchial arch that

gives rise to the cartilage and bones of the mandibular skeleton. Mandibular hypoplasia can

result from insufficient or defective neural crest cell production or migration into the first

branchial arch during the 4th week of embryonic development (Praveen and Barbara, 2007). In

between the 7th and 11th weeks, the presence of a hypoplastic mandible sets into motion the

sequence of events that produces the characteristic features of this craniofacial condition

(Figueroa et al, 1991). Normally, during the 7th week of embryological development, the tongue

migrates downward as the mandible continues to develop allowing the secondary palatal shelves

to elevate and begin fusion from the anterior end by the 9th week to the posterior end by the 12th

week (Ferguson, 1988; Gorlin et al, 1990). In a fetus with a hypoplastic mandible, there is

inadequate space and support for the tongue musculature resulting in an elevated and retruded

tongue posture or glossoptosis. The elevated tongue posture prevents fusion of the palatal

shelves, resulting in a cleft in the palate, while the retruded tongue position blocks the

pharyngeal space resulting in varying degrees of airway obstruction (Shen et al, 2012). Normal

palatal closure occurs in a ‘zipperlike’ manner from the anterior aspect to the posterior aspect of

the palate. Thus, if a primary failure of fusion occurs, it should result in a V-shaped defect, as it

does in patients with isolated cleft palate. However, in patients with PRS, majority exhibit U-

shaped clefts that are generally wider and longer than patients with isolated cleft palate due to the

mechanical interference of palatal closure provided by the elevated tongue posture (Latham and

Van der Molen, 1966; Printzlau and Anderson, 2004; Godbout et al, 2014).

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2.1.4. Management

Mortality rates in patients with PRS range from 5% to 30% and is mainly attributed to upper

airway obstruction (UAO) (Robin, 1934; Caouette-Laberge et al, 1994). Along with UAO, the

presence of the cleft palate and primary oropharyngeal dysmotility impairs the infant’s ability to

feed and often leads to gastroesophageal reflux, aspiration and malnutrition (Baudon et al, 2002;

Kochel et al, 2011). Supplemental tube feedings are often required and initially given through

nasogastric tubes. In cases with persistent and chronic feeding difficulties, a surgically placed

gastronomy tube is used (Cohen et al, 2017). Gastroenterologists and feeding specialists monitor

the infant to ensure adequate nutrition, management of gastroesophageal reflux, good pulmonary

protection from aspiration and adequate development during the first years of life.

In order to improve the infant’s chances of survival and maintain adequate nutrition, upper

airway obstruction, which is most significant during the first 8 weeks of life, requires continuous

monitoring by neonatologists, pediatricians and sleep medicine professionals (Daniel et al, 2013;

Cohen et al, 2017). The obstruction is not always caused by glossoptosis alone, as previously

thought by Pierre Robin. It is multifactorial, related to anatomical abnormalities of the mandible,

impaired function of the genioglossus in holding the tongue out of the pharyngeal space and

neuromuscular function of the pharynx (Sher, 1992). Nasopharyngoscopy studies show that

airway obstructions can be classified into four types depending on the cause: type 1 is posterior

movement of the dorsum of the tongue against the posterior pharyngeal wall, type 2 is posterior

movement of the tongue compressing the soft palate, type 3 is medial collapse of the lateral

pharyngeal wall and type 4 is sphincteric constriction of the pharynx (Sher, 1986). The method

and success of the airway management strategy depends on the type of airway obstruction

present in the patient. Patients with isolated PRS often display type 1 and/or type 2 obstructions,

while syndromic patients can display all four types of obstruction, making airway management a

challenge (Sher, 1992).

The consequences of UAO range from hypoxia to cor pulmonale, neurodevelopmental delay,

failure to thrive and sudden death (Bacher et al, 2011). Some infants can maintain a patent

airway while awake but fail to do so during sleep, thus developing obstructive sleep apnea

(OSA). Others may not be able to maintain a patent airway when awake or asleep and require

10

more aggressive management (Sher, 1992). Although evidence based management

recommendations are lacking in the literature and treatment is mainly carried out based on

institutional preferences, some basic recommendations do exist. The first step in airway

management involves conservative strategies such as prone positioning and placement of

nasopharyngeal tubes, both of which have shown a success rate of 45-69.2% (Caouette-Laberge

et al, 1994; Kirschner et al, 2003). Surgical interventions might be required for severe cases and

include procedures such as tongue-lip adhesion, mandibular traction, and mandibular distraction

osteogenesis, with the most aggressive intervention being tracheostomy (Evans et al, 2006;

Izumi et al, 2012). Continuous positive airway pressure (CPAP) can also be used in the

management of OSA. Oral appliances such as the pre-epiglottic baton plate with velar extension

(PEBP) supports the pharyngeal wall and shifts the base of the tongue forward, widening the

hypopharyngeal space and improving the ability to breathe (Kochel et al, 2011). These

appliances have been shown to be an effective treatment strategy for respiratory distress, feeding

difficulties and OSA management (Hotz and Gnoinski, 1982; Oktay et al, 2006; Bacher et al,

2011, Müller-Hagedorn et al, 2017). A randomized clinical trial by Buchenau et al (2007)

showed that apnea index was reduced by 70% in patients given the PEBP appliance.

During the first few months of post-natal life, the mandibles of some infants will grow improving

tongue position along with maturation of pharyngeal neuromuscular function which helps in

resolution of the airway and feeding insufficiencies (Sher, 1992). In most isolated, non-

syndromic cases, 6-8 weeks of intervention is adequate because of the catch-up mandibular

growth that occurs during this time (Pruzansky and Richmond, 1954; Sher 1992). However, in

other cases that display minimal or delayed mandibular growth, airway and deglutition problems

can continue for years. Further intervention and monitoring with polysomnography, airway

endoscopy and clinical assessments are necessary throughout infancy and into adulthood (Sher,

1992; Cohen et al, 2017).

After infancy, the management of patients with PRS involves the monitoring of general growth

and development by pediatric specialists. Normally, cognitive, motor and psychosocial

development of children with PRS is similar to unaffected children. Therefore, any deviations

from typical development should be investigated. A common developmental challenge however,

11

is speech, which is helped with early and consistent speech therapy. After palatal cleft repair,

speech and language pathologists generally evaluate these children on a yearly basis for the

development of speech and velopharyngeal insufficiency which may require additional surgical

procedures (Cohen et al, 2017). Another complication of the palatal clefting that children with

PRS experience is increased episodes of serous otitis media and subsequent hearing problems

requiring additional surgeries (Glynn et al, 2011). A significant majority of children will require

myringotomy and placement of ventilation tubes to minimize liquid build-up in the middle ear

(Dhillon, 1988).

Aside from speech therapy and myringotomies, a patient with PRS receives regular evaluation of

their facial growth by the orthodontist from childhood into late adolescence. Primary concerns

are the severity of the class II malocclusion due to the hypoplastic mandible, hypodontia as well

as the possibility of damaged tooth buds after mandibular distraction therapy, if applicable

(Evans et al., 2011; Cohen et al., 2017). Patients with PRS have a characteristic vertical

craniofacial growth pattern along with hypoplasia of both, the maxilla and the mandible. In

severe skeletal dysplasias and/or severe OSA situations, orthognathic surgery is required and is

performed at skeletal maturity (Cohen et al, 2017). Based on what is known in the literature, the

craniofacial growth pattern of patients with PRS is compared and contrasted to the growth

pattern of patients with ICP and unaffected children in Section 3.

2.2. Isolated Cleft Palate (ICP)

Clefting of the orofacial complex is one of the most commonly reported birth defects. Minor

deviations in the developmental process or in the precise timing of the events involved, can lead

to the disruptions and clefting (Ross and Johnston, 1972). Orofacial clefts can be broadly

classified as syndromic or non-syndromic depending on the presence of major and/or minor

anomalies. Although non-syndromic clefts do not involve major anomalies, they may be

associated with two or fewer minor malformations of minimal functional or esthetic significance

(Wyszynski, 2002). Anything more would suggest the association of the cleft with a syndrome

(Tolarova and Cervenka, 1998). Clefts are also further classified based on the tissues involved –

12

lip and/or alveolar process with or without palate and palate alone (Ross and Johnston, 1972).

Isolated cleft palate is the rarest form of orofacial clefting and can be associated with other

anomalies or syndromes about 50% of the time (Kirschner and LaRossa, 2000; Vieira, 2008;

Burg et al, 2016). The most common syndrome associated with cleft palate is 22q11.2 deletion

syndrome caused by deletion of a small segment of the long arm of chromosome 22. Other

associated syndromes include Fetal Alcohol Syndrome, Treacher Collins syndrome and Stickler

Syndrome among others (Praveen and Barbara, 2007). For the purposes of this investigation, the

focus is on isolated non-syndromic cleft palate.

2.2.1. Prevalence

The prevalence of orofacial clefting shows wide variability depending on geographic location,

ethnic group and socioeconomic conditions. It has been reported to be as high as 1:500 live

births in Asian and Native American populations, to 1:1,000 live births in Caucasian populations

and, 1:2,500 live births in African populations (Christensen and Mitchell, 1996; Beaty et al,

2010). Among those presenting with orofacial clefting, isolated cleft palate accounts for 33% of

the diagnoses, while the majority are diagnosed with cleft lip and palate (46%) (Hopper et al,

2007). The reported incidence of cleft palate varies from 1 in 2,000 to 1 in 2,500 live births

(Natsume et al, 2000; Vieira, 2008).

Variability in prevalence is also influenced by gender. Females are 66% more likely to be

diagnosed with isolated cleft palate than males (Kirschner and LaRossa, 2000; Stanier and

Moore, 2004). As well, females have been shown to present with more severe clefting than males

(Christensen and Mitchell, 1996). This difference has been attributed to a longer palatal closure

process in females thus increasing the period of vulnerability to teratogens (Burdi and Faist,

1967).

2.2.2 Etiology and Embryopathogenesis

Isolated cleft palate is considered an etiologically heterogeneous condition since multiple genetic

and environmental factors have been implicated in its development (Christensen and Mitchell,

1996). Mutations in genes encoding various transcription factors, growth factor receptors,

extracellular matrix components, and cell surface adhesion molecules have been reported to

13

cause cleft palate (Wilkie and Morriss-Kay, 2001). Mutations in the MSX1 gene have been

associated with non-syndromic isolated cleft palate (Smith et al, 2012). Aside from genetic

factors, environmental teratogens such as tobacco, alcohol, anticonvulsants, and retinoic acid

have been associated with orofacial clefting (Hopper et al, 2007).

Cleft palate can result from a defect or interruption during one of the three stages of palatal

formation - palatal shelf outgrowth, elevation of the palatal shelves and, fusion of the palatal

shelves (Kaartinen et al, 1995). This critical period for palatogenesis begins at the end of the 5th

week and lasts until the 12th week of embryonic development (Kirschner and LaRossa, 2000). In

normal palatogenesis, during the 6th week of gestation, two palatal shelf-like processes emerge

from the maxillary prominences and grow vertically on either side of the tongue. In the 7th week,

the palatal shelves start to elevate and move towards each other assuming a horizontal

orientation. Fusion begins by the end of the 9th week starting at the incisive foramen and moving

posteriorly until the formation of the uvula by the 12th week (Ferguson, 1988; Gorlin et al, 1990).

Any disruptions occurring during this period can cause clefting in the palate. The severity of the

cleft depends upon the point at which the disruption occurred in palatal development. Palatal

clefting may involve soft palate only or both hard and soft palate (Smith et al, 2012).

2.2.3 Cleft palate repair

Cleft palate repair involves the use of nasal and oral mucoperiosteal flaps to achieve palatal

closure and velopharyngeal competence with minimal impact on maxillary growth (Nierzwicki

and Daifallah, 2015). A successful outcome is dependent on the timing and the technique

involved in the repair (Kirschner and LaRossa, 2000). Establishing an optimal time for the

surgery has been a matter of controversy throughout the literature. It is believed that while early

palatal repair benefits speech development, it may restrict midfacial growth. Dorf and Curtain

(1982), demonstrated that palatal repair done before 12 months of age allows for significantly

better speech articulation. Randall et al (1983) went further and specified that the age range at

which palatal repair would provide the most speech benefit was 3-7 months. However, a recent

study by Luyten et al (2014), found no significant differences in speech articulation and

resonance characteristics in children who had palatal repair before 6 months of age (mean age - 3

months) and those that had the repair after 6 months of age (mean age - 11.1 months). Friede and

14

Pruzansky (1972) investigated effects of surgery on maxillary growth and demonstrated that as

long as the surgical intervention did not utilize primary bone grafting procedures, palatal closure

did not interfere with growth. However, restricted maxillary growth following surgical repair has

been documented in the literature (Liao et al, 2002; Lu et al, 2007). Due to lack of conclusive

evidence, the current recommendation is ‘before two years of age,’ more specifically 18 months

of age, and is based on expert opinion (Follmar et al, 2015).

Currently, there is no consensus on the best surgical technique or protocol for cleft palate repair.

Originally it was thought that since the Von Langenbeck technique produces less denuded palatal

bone than the push-back technique, it results in less restriction of maxillary growth especially in

the transverse dimension (Palmer et al, 1969). Jonsson and Thilander (1979) demonstrated a

reduction in frequency of crossbite occlusion after using Von Langenbeck technique for their

palatal closures. Several reports have shown that push-back technique has a significant influence

on the shape of the maxilla causing reduction in the maxillary width and dental arches, with

more severe restriction occurring in more severe cleft cases (Nystrom and Ranta, 1994;

Heliovaara et al, 1993). Animal experimentation conducted by Leenstra et al (1995) also

supported the observation that keeping denuded palatal bony surfaces to a minimum reduces the

negative impact of palatal repair on maxillary growth. Additionally, the areas denuded at palatal

surgery should be kept as medial as possible to minimize the inhibitory effects of the post-

surgical scar tissue formation (Ishikawa et al, 1998).

2.3. Effects on Craniofacial Growth

Growth of the mandible in patients with PRS has been a topic of controversy for many years.

The major area of disagreement is whether or not “catch up” mandibular growth occurs in these

patients after birth. Variable findings have been reported in the literature because most studies

consist of small sample sizes, variable methodology and fail to separate subjects with syndromic

and non-syndromic PRS. Rogers et al. in 2009 reported that mandibular morphology and

position varies depending on whether PRS is associated with a syndrome or is occurring as an

isolated entity. Therefore, combining syndromic and non-syndromic PRS in a study sample can

15

also lead to inaccuracies in the results. A summary of the literature review pertaining to catch up

mandibular growth is presented in Table 1.

Aside from differences in growth of the mandible, the growth pattern of the maxilla and cranial

base are also noted to be different when compared to unaffected children. Maxillary retrusion has

been consistently found in subjects with PRS which could be attributed to scar tissue formation

after surgical cleft palate repair or due to intrinsic growth deficiency of a clefted maxilla. Bishara

(1973) examined 20 Caucasian females with isolated cleft palate where 12 were operated and 8

were obturated. When compared to 32 unaffected Caucasian females, he found that the cleft

group had smaller, posteriorly positioned maxillas and posteriorly positioned mandibles. The

operated and unoperated cleft subgroups had no significant differences in maxillary and

mandibular morphology, thus suggesting that surgical repair of the cleft may not be the only

reason for altered craniofacial growth.

A summary of the findings in the literature are presented in Table 2 and in the following sections

where craniofacial growth in patients with PRS is compared to patients with isolated cleft and

normal control growth values.

2.3.1. Pierre Robin Sequence compared to Isolated Cleft Palate

Craniofacial morphology and pattern of growth for patients diagnosed with PRS and ICP are

different in many ways to normal growth but similar in many ways to each other. Hermann et al

(2003) compared craniofacial characteristics of 7 Danish children diagnosed with PRS to 53

Danish children diagnosed with ICP between the ages of 2 months to 22 months. They concluded

that PRS had shorter posterior cranial bases, smaller mandibles in terms of length but similar in

terms of height and width, and an increased mandibular plane angle although the gonial angles

were similar. When comparing growth patterns, they found that the maxilla did not grow to the

same extent in PRS children as it did in ICP children and the PRS group also tended to have a

more vertical pattern of growth. Laitinen and Ranta (1991) compared 35 children diagnosed with

non-syndromic PRS to 30 children diagnosed with ICP at approximately 9 years of age.

Consistent with the previous study, at this age as well, the PRS group was found to have a

slightly smaller maxilla with a steeper palatal plane, and a much smaller mandible with similar

16

gonial angles compared to the ICP group. In a mixed longitudinal study, Daskalogiannakis et al

(2001) compared 96 children with non-syndromic PRS to 50 children with ICP of various racial

backgrounds at the approximate ages of 5.5 years. Of the 96 children with PRS, 38 of them were

compared with the same 50 ICP children at the approximate ages of 10.5 years and 16.9 years.

They found that throughout the 3 time points, mandibular length remained deficient in the PRS

group. Although the differences in maxillary measurements (SNA and Ba-N-ANS) were not

significant between the two groups, the midface depth (Ba-ANS) was shorter in the PR group.

As well, consistent with the aforementioned studies, palatal plane and mandibular plane were

steeper in the PRS group.

Evaluating growth and craniofacial form beyond 16 years of age, Laitinen et al (1997) compared

30 Finnish young adults with non-syndromic PRS to 116 Finnish young adults with ICP of

approximately 17 years and older. Similarities to the aforementioned studies were found along

with the observation that the PRS group had shorter ramal length compared to the ICP group.

2.3.2. Pierre Robin Sequence and Isolated cleft palate compared to Normal

Figueroa et al (1991) analyzed mandibular size during the first 2 years of life (3 months to 2

years) in 17 children with non-syndromic PRS, 26 children with ICP and 26 unaffected children.

They found that the greatest difference in mandibular length between the groups was at the

earliest time point. This difference reduced over time owing to a spike in mandibular growth rate

in the PRS infants during the early months of life. Over the two years, although mandibular

length increased by 53% in the PRS group compared to 42% for ICP and 38% in the normal

group, this was not enough to eliminate the differences seen in lengths, indicating only a partial

catch-up in mandibular growth. PRS mandibles remained the smallest, followed by ICP and then

normal mandibles. Shen et al (2012) compared 13 children diagnosed with non-syndromic PRS

to 14 children with ICP and normative cephalometric values measured at approximately 5 years

of age and 12 years of age. Their comparison involving PRS to ICP was similar to other

literature findings reported in the section above. Comparing PRS to normal values, they

concluded that cranial base length, mandibular length and maxillary length were deficient at both

time points. The mandible was also found to have a steeper mandibular plane angle. They also

compared ICP to normal and found that although mandibular length in children with ICP started

17

out much smaller than normal at 5 years, at 12 years the lengths became almost similar (ICP still

remained slightly shorter but not significantly shorter than normal). The maxillary length

however, remained shorter than normal at both ages leading to sagittal jaw discrepancies as

evidenced by negative ANB values.

Craniofacial characteristics of subjects with PRS in their adolescent years were investigated by

Suri et al in 2010a. They compared 34 Caucasian children with non-syndromic PRS with age-

and sex-matched unaffected controls at approximately 12 years and 16 years of age. They found

that, in addition to deficiencies in cranial base, maxillary and mandibular lengths, subjects with

PRS had steeper palatal planes, vertical pattern of growth and bimaxillary retrognathism. More

specifically within the mandible, deficiencies were found in the mandibular body length and

height, ramal length and width and anterior basal thickness.

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Table 1. Summary of the Literature: Catch-up mandibular growth in patients with PRS (Suri, 2014)

Author Study Design PRS Sample size Comparison Group Catch up growth

Pruzansky and Richmond - 1954

Case report N - 3 (2mo – 4y)

None Yes

Beers and Pruzansky - 1955

Case report N - 1 (10d – 15mo)

None Yes

Randall et al - 1965

Longitudinal case series

N - 22 (birth) N - 18 (1y)

None 1/3 caught up by year 1 1/2 improved with later growth

Pruzansky - 1969 Case report N - 2 None Yes

Hotz and Gnoinski - 1982

Cross sectional N - 7 (5y) ICP - 7 No

Figueroa et al – 1991

Longitudinal N - 17 (3mo – 21.5mo)

ICP: N - 26 Normal: N - 26

Increased rate of growth in PRS mandibles - Partial catch-up

Vegter et al – 1999

Longitudinal case series

N - 7 (2mo – 22mo) Normal: N - 100 (0mo) 42 (6mo) 32 (1y)

No

Daskalogiannakis et al – 2001

Retrospective longitudinal

N - 96 (5.5y) 38 (10.3y) 38 (16.8y)

ICP: N - 50 (5.5y) 50 (10.5y) 50 (17y)

No

Herman et al – 2003

Longitudinal N - 7 (2mo – 22mo) ICP: N - 53 (2mo – 22mo) UCLP: N - 48 (2mo – 22mo)

No

Matsuda et al – 2006

Case series N - 5 None Yes. Improved growth with treatment during adolescence

Ericson et al – 2006

Longitudinal N - 7 (2mo – 22mo) ICP: N - 66 No

Shen et al – 2012

Mixed longitudinal

N - 13 (4y – 7y and 10y – 13y)

ICP: N -14 (4y – 7y and 10y – 13y)

No

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Table 2. Summary of the Literature: Craniofacial growth characteristics in patients with PRS and ICP in comparison with normal samples

Author Study Design Sample size Comparison

group

Findings

Shibasaki and Ross – 1967

Retrospective Part I: ICP: N - 30 @ avg age 6yrs Part II: ICP: N - 36 @ 6y, 9y, 12y, 15y

Part I: Normal: N - 30 @ 6y Part II: Normal: N - 30 @ 6y, 9y, 12y, 15y

Part I: Normal mandibular length but chin posteriorly displaced, increased gonial angle and mandibular inclination, retruded maxillary incisors, increased lower face height and increased freeway space Part II: retruded facial growth pattern

Figueroa et al – 1991


PRS: N - 17 @ 0-2y

Normal: N - 26 @ 0-2y ICP: N - 26 @ 0-2y

Craniofacial morphology differs between PRS, ICP and normal. More so between PRS and normal than ICP and normal. Rate of change/growth higher in PRS than ICP and N and inversely related to age. Change in airway dimension and tongue area: PRS>ICP>N Lower hyoid position in PRS

Ranta and Laitinen - 1992

Longitudinal PRS: N - 35 @ avg. age 9.1y and 13.3y

ICP: N - 30 age and sex matched @ avg. age 7.1y and 12.4y

PRS: smaller and more retrognathically positioned mandibles Morphogenetically similar mandibular development to ICP

Daskalogiannakis et al - 2001

Retrospective mixed longitudinal

PRS: N - 96 @ 5.5y, 38 @ 10.3y, 38 @ 16.8y

ICP: N - 50 @ 5.7yrs, 50 @ 10.6yrs, 50 @ 17yrs

PRS: retrognathic mandible, shorter mandibular length, steep mandibular plane, steep palatal plane. Dental: retroclined max incisors, proclined mandibular incisors, deep overbite and large overjet

Suri et al – 2010a


PRS: N - 34 @ avg age 11.8 and 16.6

Normal: N - 34 age, sex and ethnicity matched

PRS: Bimaxillary retrognathism, steep palatal plane, vertical growth pattern, reduced lengths of maxilla, cranial base and mandible, and large gonial angles

Horsewell and Gallup – 1992


ICP + UCLP + BCLP + CL/A: N - 542 @ ages 7y-18y

Normal: N - 277 @ ages 7y-18y

ICP: Anterior cranial base length was smaller than Normal As well posterior cranial base length shorter from 12-18. Acute cranial base angle – signifies nasopharynx deficiency and midface retrusion

daSilva, Normando and Capelozzo – 1992

Retrospective ICP: N - 43 operated cases

ICP: N - 43 non-operated cases

ICP: no significant difference between operated and unoperated cases in terms of mandibular length and spatial position

20

3. Purpose of the study, Research Objective and Hypothesis

3.1. Purpose of the study

The purposes of this retrospective longitudinal study are:

To characterize the differences in craniofacial morphology and growth in patients with

PRS and unaffected children from childhood to late adolescence

To characterize the differences in craniofacial morphology and growth in patients with

PRS and patients with ICP from childhood to late adolescence

21

3.2. Research Objectives

The objectives of this study are:

To longitudinally evaluate craniofacial growth and identify morphological differences in

the maxilla, mandible and cranial base of patients with non-syndromic PRS in

comparison to patients with isolated cleft palate at 3 time points: 6 years, 12 years and 18

years.

To longitudinally evaluate craniofacial growth and identify morphological differences in

the maxilla, mandible and cranial base of patients with PRS in comparison to unaffected

subjects with class I skeletal growth patterns and occlusions at 3 time points: 6 years, 12

years and 18 years.

22

3.3. Hypotheses

To address the research objectives, the following null hypotheses were formulated:

Null hypothesis 1:

There are no significant differences in craniofacial morphology and growth patterns of patients

with non-syndromic PRS in comparison to unaffected children.

Null hypothesis 2:

There are no significant differences in craniofacial morphology and growth patterns of patients

with non-syndromic PRS in comparison to patients with isolated cleft palate.

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4. Materials and Methods

This retrospective longitudinal cephalometric study was approved by the Hospital for Sick

Children’s Research Ethics Board as well as the University of Toronto Research Ethics Board.

The plan for the study was to assess longitudinal craniofacial growth in the same patient from the

age of 6 years to 18 years. For this purpose, three time points were selected to approximate

prepubertal and pubertal growth phases, as well as the end of the active facial growth phase:

T1 or average age of 6 years, the beginning of the transitional dentition period and before

any orthodontic interventions

T2 or average age of 12 years, when the patient entered the permanent dentition stage of

dental development and before any orthodontic interventions.

T3 or average age of 18 years, when the patient reaches adulthood, after completion of

orthodontic treatment but before orthognathic surgery.

4.1. Sample Description

4.1.1. Pierre Robin Sequence group:

The Hospital for Sick Children (HSC) receives approximately 7-18 patients per year of various

racial backgrounds, who are diagnosed with Pierre Robin Sequence. These children are either

born at the hospital itself or sent from other birth centres across the province of Ontario. The

diagnosis of PRS at HSC is based on the following criteria:

Presence of mandibular micrognathia

Cleft palate

At least 1 episode of respiratory distress in the neonatal period

Patients with PRS are under the care of a multi-disciplinary team which involves regular

orthodontic evaluations at the HSC orthodontic clinic. As part of this evaluation, they receive

lateral cephalometric imaging and panoramic imaging at regular intervals to evaluate growth and

plan for future orthodontic treatment.

24

The inclusion criteria for the PRS group were:

Caucasian descent – in order to maintain racial homogeneity and eliminate variations

introduced by race-specific craniofacial features.

Diagnosis of non-syndromic PRS - Mandibular size, morphology, and position are

significantly variable in children with a syndromic PRS (Rogers et al, 2009). Hence,

separating syndromic and non-syndromic PRS is important to maintain homogeneity and

reduce variations in the study sample.

Have lateral cephalometric radiographs at approximately 6 years, 12 years and 18 years

since these were the time points selected for the study.

After applying the inclusion criteria to patients diagnosed with PRS at HSC, the final PRS study

group included patients who were born between 1954 and 1991. A total of 43 patients consisting

of 18 males and 25 females were selected and their mean ages at each time point are summarized

in Table 3. These patients had surgical cleft palate repair at a mean age of 17.7 months (+/- 1.8

months) using Von Langenbeck or push-back palatoplasty techniques.

Lateral cephalometric images had been acquired using standard equipment and methodology

adhering to the protocols of the hospital. These images were imported into the Dolphin Imaging

software (version 11.8.06.24 Premium; Patterson Dental Supply Inc., Richmond, WA) for the

purposes of cephalometric tracing and analysis.

Table 3. Mean ages: PRS group Time point Male Female

T1 6y5m (range: 5y2m-7y8m) 6y (range: 5y-8y3m)

T2 11y8m (range: 9y2m-13y10m) 12y3m (range: 9y2m – 13y7m)

T3 16y5m (range: 14y11m – 19y9m) 16y10m (range: 14y – 18y11m)

4.1.2. Isolated Cleft Palate group – control group

As part of their treatment, patients with ICP receive regular orthodontic evaluations at the HSC

orthodontic clinic. Lateral cephalometric imaging and panoramic imaging are taken at regular

intervals to evaluate growth of the jaws and need for orthodontic treatment and future

orthognathic surgery.

25

After applying the same inclusion criteria used for the PRS group, a total of 43 patients

consisting of 18 males and 25 females were selected such that their lateral cephalometric

radiographs had been taken at ages that closely matched the PRS sample. The final non-

syndromic ICP group consisted of patients born between 1949 and 1980. Table 4 summarizes the

mean ages of the ICP group at each of the three time points. These patients had surgical palatal

repair at a mean age of 20.4 months (+/- 7.1 months) using Von Langenbeck or push-back

palatoplasty techniques.

Lateral cephalometric images were then imported into the Dolphin Imaging software (version

11.8.06.24 Premium; Patterson Dental Supply Inc., Richmond, WA) for the purposes of

cephalometric tracing and analysis.

Table 4. Mean ages: Isolated Cleft Palate group Time point Male Female

T1 6y8m (range: 5y1m - 7y10m) 6y8m (range: 5y4m – 7y11m)

T2 12y10m (range: 9y6m – 13y5m) 12y1m (range: 9y7m – 13y10m)

T3 17y1m (range: 14y4m – 19y6m) 16y10m (range: 14y7m - 21y)

4.1.3. Unaffected children – control group:

The Burlington Growth Centre (BGC) study is a collection of longitudinal craniofacial growth

records of a predominantly Caucasian, and mostly Anglo-Saxon, group of individuals that made

up the local population at that time. An original sample of 1258 children representing 90% of the

Burlington children, were separated into 5 study groups:

Serial experimental group at age 3 (SE) (N – 312): Records taken annually from age 3-20

Serial control at age 6 (C-6) (N: 295): Records taken at ages 6, 9, 12, 14, 16 and 20

Serial control at age 8 (C-8) (N: 219): Records taken at age 8



For the current investigation, 18 male and 25 female children were selected from the SE and C-6

groups who had lateral cephalometric images taken at ages that closely matched the sample of

26

non-syndromic PRS. As well, to be selected, the subject’s growth pattern and occlusion should

have been recorded in the archives as class I. The mean ages of the final control group of

unaffected children is presented in Table 5. The digital lateral cephalometric images taken in

centric occlusion, were then imported into the Dolphin Imaging software (version 11.8.06.24

Premium; Patterson Dental Supply Inc., Richmond, WA) for the purposes of cephalometric

tracing and analysis.

Table 5. Mean Ages: Unaffected Group Time point Male Female

T1 6y4m (range: 5y-7y) 6y5m (range: 5y-8y)

T2 11y7m (range: 9y-14y) 12y (range: 9y-14y)

T3 16y5m (range: 15y-19y) 16y10m (range: 14y-18y)

4.2. Cephalometric Analysis

Using Dolphin Imaging software, lateral cephalometric records were analyzed using a custom

cephalometric analysis previously described by Suri et al (2006, 2010b). This consisted of

measurements from conventional analyses, as well as, additional landmarks and measurements to

study regional detail of the maxilla, mandible and cranial base. Figure 1 illustrates the unique

cephalometric landmarks involved in this analysis. Landmark and measurement descriptions are

summarized in Table 6 and Table 7. In order to maintain consistency, a single technician traced

and digitized all radiographs in the manner presented in Figure 2.

27

Figure 1. Illustration of a lateral cephalogram labelled with the custom landmarks (Suri et al.,

2010b)

Figure 2. A digitized lateral cephalogram

28

Table 6. Cephalometric Analysis: Definitions of the cephalometric landmarks Landmark Definition

Ba (Basion) Most inferior posterior point of the occipital bone at the anterior margin of the occipital foramen

Na (Nasion) Intersection of the internasal suture with the nasofrontal suture in the midsagittal plane

S (Sella) Center of the pituitary fossa of the sphenoid bone

Po (Porion) Highest point of the external auditory meatus

O (Orbitale) Lowest point of the external border of the orbital cavity

ANS (Anterior Nasal Spine) The tip of the anterior nasal spine

PNS (Posterior Nasal Spine) Tip of the posterior nasal spine

Sn Most posterior midline point on the premaxilla between the anterior nasal spine and prosthion

A (A point) A point – Deepest point of the curve of the maxilla between the ANS and dental alveolus

Pr (Prosthion) Most anterior and inferior point on the alveolar process between the maxillary central incisors

Co (Condylion) The most posterior superior point of the condyle

Go (Gonion) Most convex point along the inferior border of the ramus

Me (Menton) Most inferior point of the symphysis

Gn (Gnathion) Midpoint between the most anterior and inferior point on the bony chin

B (B point) Most posterior point in the concavity along the anterior border of the symphysis

Pg (Pogonion) Most anterior point on the mid-sagittal symphysis

Id (Infradentale) Most superior and anterior point on the alveolar process in between the mandibular central incisors

Idl (Lingual infradentale) Directly opposite Id on the lingual surface

Prl (Lingual prosthion) Directly opposite Pr on the lingual surface

Al (Lingual A point) Directly opposite A point on the lingual surface

Pamaxj (palate-anterior maxillary junction) Most superoanterior point on palatal contour of basal anterior maxilla

Mamax (midpoint of anterior maxillary base) Midpoint of line drawn from pamaxj to Sn

Amaxaj (anterior maxilla-alveolar junction) Midpoint of line drawn from Al to A

Malvmx (midpoint of anterior alveolus, maxillary)

Midpoint of line drawn from Prl to Pr

PAPmd (posterior alveolar point, mandibular) Most posteroinferior mid planed point on the anterior border of the ascending ramus

Inf Go (inferior gonion) Mid planed point on the lower border of the mandible where the convexity at gonion merges with the concavity of the antegonial notch

RBS (ramus body syncline) Point of intersection of a line drawn from Inf Go to PAPmd with the cortical outline of the mid planed mandibular nerve

Bl (Lingual point B) Point of intersection of a line drawn from RBS to B with the lingual contour of the symphysis

Saj (symphysis alveolar junction) Midpoint of a line drawn from Bl to B

Pgl (lingual point pogonion) Most prominent point on the lingual contour of the symphysis, as located by the greatest perpendicular distance from a line drawn from Saj to Me

Malvmd (midpoint of anterior alveolus, mandibular)

Midpoint of line drawn from Id(l) to Id

29

Table 7. Cephalometric Analysis: Definitions of the linear and angular measurements Measurement Description

Anterior cranial base length Length of line drawn from S to N

Cranial base angle Internal angle Ba-S-Na

Maxillary length Length of line drawn from ANS to PNS

Maxillary anterior basal width Length of line drawn from pamaxj to Sn

Maxillary anterior apical width Length of line drawn from Al to A

Anterior maxillary height Length of perpendicular dropped from amaxaj to PNS-ANS

Maxillary anterior alveolar height Length of line drawn from amaxaj to malvmx

Palatal/anterior maxillary deflection Internal angle between the palatal plane (ANS-PNS) and line drawn from amaxaj to mamax

Mandibular length Length of line drawn from Co to Gn

External ramal length Length of line drawn from Co to Go

Internal ramal length Length of line drawn from Co to RBS

External body length Length of line drawn from Go to Gn

Internal body length Length of line drawn from RBS to Gn

Gonial angle Internal angle Co-Go-Gn

Internal mandibular deflection Internal angle Co-RBS-Gn

Mandibular posterior alveolar height Length of the perpendicular dropped from PAPmd to RBS-B

Mandibular posterior body height Length of the perpendicular dropped from Inf Go to RBS-B

Mandibular anterior alveolar height Length of the line drawn from malvmd to saj

Symphyseal height Length of line drawn from saj to Me

Symphyseal thickness Sum of the lengths of perpendiculars dropped from Pg and Pgl to a line drawn from saj to Me

Mandibular plane/symphyseal deflection Internal angle between Go-Gn and the line drawn from saj to Me

Ramal width Length of the line drawn from the mid planed deepest points on the posterior and anterior borders of the ramus

Mandibular anterior apical base width Length of the line drawn from Bl to B

ANB angle Difference between SNA and SNB angles indicating the skeletal relationship between the maxilla and the mandible

4.3. Statistics

Statistical analysis of the data was completed using the Statistical Package for the Social

Sciences software (IBM SPSS v. 20; SPSS Inc., Chicago, IL.). Pairwise comparisons were

conducted using Tukey’s correction adjusted for gender effects. Longitudinal comparisons across

all time points were made using linear mixed models adjusted for age and gender effects.

Measurements with p-values of less than 0.05 were reported as statistically significant.

30

4.4. Reliability Analysis

To assess intraexaminer repeatability of the cephalometric method, 5 patients from each group

were randomly selected. Their radiographs at all three time points were retraced and redigitized 3

months after the initial digitization was completed. Repeatability was assessed through linear and

angular measurements recorded at both times and correlated by the intraclass correlation

coefficient analysis. Table 8 summarizes the results of the repeatability assessment and shows a

highly significant agreement between the measurements recorded at the initial tracing phase and

the repeated tracing phase. This demonstrates excellent repeatability of the cephalometric

method used in this study.

Table 8. Intraexaminer repeatability of cephalometric measurements of 15 randomly selected subjects.

Measurements Mean SD Mean SD

Cranial Base

Cranial base angle (o) 130.55 5.4 130.32 5.33 0.96

Anterior Cranial Base (SN) (mm) 69.23 4.45 69.03 4.49 0.99

Maxilla

Maxillary length (ANS-PNS) (mm) 48.11 5.35 48.85 5.05 0.95

Maxillary anterior basal width (mm) 17.78 2.78 17.68 2.3 0.87

Maxillary anterior apical width (mm) 11.42 1.88 11.31 1.82 0.89

Anterior maxillary height (mm) 7.92 1.63 8.02 1.69 0.9

Maxillary anterior alveolar height (mm) 17.42 2.43 17.71 2.49 0.95

Palatal/anterior maxillary deflection (o) 146.64 14.3 145.69 13.72 0.95

Mandible

Internal mandibular deflection (o) 148.79 7.79 147.42 6.86 0.95

Condylion - Gonion - Anatomical Gnathion (o) 122.18 7.36 121.71 6.06 0.96

Mandibular length (Co-Gn)(mm) 108.84 12.08 108.53 12.01 0.99

Internal body length (mm) 54.74 8.02 54.9 8.06 0.98

Co-Go (mm) 54.11 7.66 53.9 7.78 0.98

Internal ramal length (mm) 58.43 6.72 58.45 6.5 0.98

Ramal width (mm) 30.35 2.98 30.27 2.83 0.95

Mandibular posterior alveolar height (mm) 15.06 2.9 15.65 3.24 0.91

Mandibular posterior body height (mm) 9.19 2.51 8.56 2.08 0.84

Mandibular anterior alveolar height (mm) 11.83 2.2 11.79 2.39 0.91

Mandibular anterior apical base width (mm) 8.27 1.49 8.48 1.4 0.9

Symphyseal height (mm) 20.76 2.84 20.75 2.94 0.93

Symphyseal thickness (mm) 13.38 2.17 13.33 2.16 0.94

Mandibular plane/symphyseal deflection (o) 72.93 7.17 73 7.58 0.97

Trial 1 Trial 2

ICCC

31

5. Results

Following digitization of all radiographs, an averaged tracing for each group at each time point

was created. These tracings were superimposed on each other for comparison of craniofacial

growth patterns at each time point (Figures 3, 4, and 5). As well, the averaged tracings of each

group at the three time points were superimposed on each other, to visually appreciate the growth

patterns within the group (Figures 6, 7, and 8). Across the three time points, the growth patterns

of the PRS group and the ICP group were similar to each other, however, they were quite

different from the unaffected group. For overall comparison of craniofacial growth, the tracings

were superimposed on anterior cranial base, registered at Sella. The maxilla and mandible of the

PRS and ICP groups appear to be retrognathic when compared to the unaffected group. The

length of the mandible appears to be most deficient in the PRS group, followed by the ICP group

and then the unaffected group. This is also confirmed from the mandibular superimpositions of

the three groups at each time point, which was done by overlaying the tracings on the lingual

outline of the symphysis. The PRS group also appeared to have the most vertical pattern of

growth compared to the other two groups. Anterior cranial bases were indifferent between the

three groups. For comparison of the maxilla, the tracings were superimposed on the palatal

plane, registered at ANS. It can be noted that the maxillary length of the PRS and ICP groups

were similar to each other but shorter when compared to the unaffected group.

Averaged PRS Tracing Averaged ICP Tracing Averaged Normal Tracing

32

Figure 3. Superimposition of averaged tracings of PRS, ICP and normal groups at T1.



Averaged PRS Tracing Averaged ICP Tracing Averaged Normal Tracing

Averaged PRS Tracing

Averaged ICP Tracing

Averaged Normal Tracing

33

Figure 6. Superimposition of averaged tracings of the PRS group at T1, T2 and T3

Figure 7. Superimposition of averaged tracings of the ICP group at T1, T2 and T3

T1 T2 T3

T1 T2 T3

34

Figure 8. Superimposition of averaged tracings of the normal group at T1, T2 and T3

T1 T2 T3

35

For each group, the mean values (with and without adjustment for gender) of each cephalometric

measurement at each time point are presented in Tables 9, 10 and 11. Results of the pairwise

comparisons using Tukey’s correction with adjustments for gender are presented in Tables 12,

13, and 14. Comparisons across time were conducted using linear mixed models with

adjustments for age and gender effects and are summarized in Tables 15, 16, and 17.

Table 9. Mean values with and without adjustment for gender of the cephalometric measurements at T1.

T1

Measurements Mean STD Adj Mean Mean STD Adj Mean Mean STD Adj Mean

Cranial Base

Cranial base angle (o) 130.335 4.374 130.231 129.819 5.38 129.714 131.328 5.201 131.224

Anterior Cranial Base (SN) (mm) 67.488 2.504 67.769 66.73 4.345 67.011 66.74 3.109 67.02

Maxilla

Maxillary length (ANS-PNS) (mm) 46.805 2.793 46.949 42.87 2.617 43.014 41.828 3.045 41.972

Maxillary anterior basal width (mm) 16.974 2.002 17.079 16.114 1.653 16.219 15.795 1.686 15.9

Maxillary anterior apical width (mm) 11.084 1.526 11.134 10.302 1.494 10.353 10.047 1.571 10.097

Anterior maxillary height (mm) 7.205 1.023 7.222 6.735 1.03 6.752 7.256 1.127 7.273

Maxillary anterior alveolar height (mm) 16.502 1.548 16.549 16.879 1.67 16.926 16.363 2.127 16.409

Palatal/anterior maxillary deflection (o) 144.009 9.544 144.108 143.428 12.266 143.527 141.637 14.616 141.736

Mandible

Internal mandibular deflection (o) 152.019 5.414 151.996 154.523 5.702 154.5 162.281 6.535 162.258

Condylion - Gonion - Anatomical Gnathion (o) 124.249 4.507 124.309 129.621 5.511 129.681 133.653 6.215 133.713

Mandibular length (Co-Gn)(mm) 100.656 4.183 100.961 96.891 6.429 97.196 92.323 5.617 92.628

Internal body length (mm) 50.028 3.098 50.09 48.074 4.006 48.136 43.542 3.504 43.604

Co-Go (mm) 48.056 3.207 48.346 45.107 4.568 45.397 44.693 4.472 44.983

Internal ramal length (mm) 53.853 2.999 54.098 51.395 4.059 51.64 50.07 3.476 50.315

Ramal width (mm) 29.293 2.033 29.341 27.288 3.387 27.336 27.019 2.395 27.066

Mandibular posterior alveolar height (mm) 12.074 1.616 12.149 13.04 1.864 13.115 12.116 2.3 12.191

Mandibular posterior body height (mm) 8.567 1.458 8.549 6.747 1.166 6.728 7.433 2.207 7.414

Mandibular anterior alveolar height (mm) 10.149 1.902 10.194 9.677 1.739 9.722 10.028 1.752 10.073

Mandibular anterior apical base width (mm) 8.667 1.536 8.715 7.733 1.262 7.78 7.663 1.507 7.711

Symphyseal height (mm) 18.458 1.829 18.493 18.595 2.095 18.63 19.214 2.491 19.249

Symphyseal thickness (mm) 13.76 1.473 13.822 12.616 1.341 12.678 12.335 1.453 12.397

Mandibular plane/symphyseal deflection (o) 78.279 5.657 78.235 76.8 6.058 76.756 75.019 6.465 74.975

Normal ICP PRS

36


T2


Cranial Base

Cranial base angle (o) 129.821 4.562 129.717 129.833 5.57 129.728 131.102 5.69 130.998


Maxilla







Mandible





Co-Go (mm) 54.844 4.694 55.134 51.005 4.754 51.295 50.553 4.338 50.844


Ramal width (mm) 30.407 2.106 30.455 28.14 3.401 28.187 28.744 3.096 28.792








ICP PRSNormal

37


T3


Cranial Base

Cranial base angle (o) 130 4.66 129.896 129.507 5.935 129.403 131.277 5.923 131.173


Maxilla







Mandible





Co-Go (mm) 61.779 5.929 62.069 57.577 5.864 57.867 57.233 6.558 57.523


Ramal width (mm) 31.847 3.571 31.894 29.533 3.526 29.58 29.028 2.859 29.075








Normal ICP PRS

38

Table 12. Pairwise comparisons of mean measurements adjusted for gender using Tukey’s comparison at T1

T1

Measurements Mean(SE) pvalue Sig Mean(SE) pvalue Sig Mean(SE) pvalue Sig

Cranial Base

Cranial base angle (o) 0.993 (1.134) 0.994 No 1.509 (1.134) 0.921 No -0.516 (1.134) 1 No

Anterior Cranial Base (SN) (mm) -0.749 (0.750) 0.986 No 0.009 (0.750) 1 No -0.758 (0.750) 0.985 No

Maxilla

Maxillary length (ANS-PNS) (mm) -4.977 (0.704) <0.001 Yes -1.042 (0.704) 0.864 No -3.935 (0.704) <0.001 Yes

Maxillary anterior basal width (mm) -1.179 (0.433) 0.144 No -0.319 (0.433) 0.998 No -0.860 (0.433) 0.553 No

Maxillary anterior apical width (mm) -1.037 (0.311) 0.027 Yes -0.256 (0.311) 0.996 No -0.781 (0.311) 0.232 No

Anterior maxillary height (mm) 0.051 (0.268) 1 No 0.521 (0.268) 0.582 No -0.470 (0.268) 0.711 No

Maxillary anterior alveolar height (mm) -0.140 (0.392) 1 No -0.516 (0.392) 0.926 No 0.377 (0.392) 0.989 No

Palatal/anterior maxillary deflection (o) -2.372 (2.689) 0.994 No -1.791 (2.689) 0.999 No -0.581 (2.689) 1 No

Mandible

Internal mandibular deflection (o) 10.263 (1.222) <0.001 Yes 7.758 (1.222) <0.001 Yes 2.505 (1.222) 0.511 No

Condylion - Gonion - Anatomical Gnathion (o) 9.405 (1.210) <0.001 Yes 4.033 (1.210) 0.027 Yes 5.372 (1.210) <0.001 Yes

Mandibular length (Co-Gn)(mm) -8.333 (1.303) <0.001 Yes -4.567 (1.303) 0.016 Yes -3.765 (1.303) 0.096 No

Internal body length (mm) -6.486 (0.878) <0.001 Yes -4.533 (0.878) <0.001 Yes -1.953 (0.878) 0.392 No

Co-Go (mm) -3.363 (1.036) 0.035 Yes -0.414 (1.036) 1 No -2.949 (1.036) 0.107 No

Internal ramal length (mm) -3.784 (0.860) <0.001 Yes -1.326 (0.860) 0.835 No -2.458 (0.860) 0.105 No

Ramal width (mm) -2.274 (0.645) 0.015 Yes -0.270 (0.645) 1 No -2.005 (0.645) 0.053 No

Mandibular posterior alveolar height (mm) -0.042 (0.500) 1 No 0.923 (0.500) 0.65 No -0.965 (0.500) 0.592 No

Mandibular posterior body height (mm) -1.135 (0.394) 0.099 No 0.686 (0.394) 0.721 No -1.821 (0.394) <0.001 Yes

Mandibular anterior alveolar height (mm) -0.121 (0.397) 1 No 0.351 (0.397) 0.994 No -0.472 (0.397) 0.958 No

Mandibular anterior apical base width (mm) -1.005 (0.291) 0.018 Yes -0.070 (0.291) 1 No -0.935 (0.291) 0.039 Yes

Symphyseal height (mm) 0.756 (0.491) 0.835 No 0.619 (0.491) 0.941 No 0.137 (0.491) 1 No

Symphyseal thickness (mm) -1.426 (0.349) 0.002 Yes -0.281 (0.349) 0.997 No -1.144 (0.349) 0.032 Yes

Mandibular plane/symphyseal deflection (o) -3.260 (1.413) 0.341 No -1.781 (1.413) 0.941 No -1.479 (1.413) 0.981 No

ICP vs NormalPRS vs Normal PRS vs ICP

39

Table 13. Pairwise comparisons of mean measurements adjusted for gender using Tukey’s comparison at T2.

T2


Cranial Base

Cranial base angle (o) 1.281 (1.134) 0.969 No 1.270 (1.134) 0.971 No 0.012 (1.134) 1 No

Anterior Cranial Base (SN) (mm) -1.628 (0.750) 0.427 No -0.153 (0.750) 1 No -1.474 (0.750) 0.568 No

Maxilla


Maxillary anterior basal width (mm) -1.370 (0.433) 0.045 Yes -0.200 (0.433) 1 No -1.170 (0.433) 0.152 No

Maxillary anterior apical width (mm) -0.742 (0.311) 0.297 No -0.560 (0.311) 0.682 No -0.181 (0.311) 1 No

Anterior maxillary height (mm) -0.656 (0.268) 0.261 No 0.437 (0.268) 0.785 No -1.093 (0.268) 0.002 Yes

Maxillary anterior alveolar height (mm) -0.751 (0.392) 0.603 No -1.121 (0.392) 0.104 No 0.370 (0.392) 0.99 No

Palatal/anterior maxillary deflection (o) -1.398 (2.689) 1 No -5.305 (2.689) 0.564 No 3.907 (2.689) 0.876 No

Mandible

Internal mandibular deflection (o) 9.170 (1.222) <0.001 Yes 6.870 (1.222) <0.001 Yes 2.300 (1.222) 0.627 No

Condylion - Gonion - Anatomical Gnathion (o) 8.558 (1.210) <0.001 Yes 2.305 (1.210) 0.611 No 6.253 (1.210) <0.001 Yes

Mandibular length (Co-Gn)(mm) -9.721 (1.303) <0.001 Yes -5.374 (1.303) 0.002 Yes -4.347 (1.303) 0.027 Yes

Internal body length (mm) -8.037 (0.878) <0.001 Yes -5.049 (0.878) <0.001 Yes -2.988 (0.878) 0.022 Yes

Co-Go (mm) -4.291 (1.036) 0.002 Yes -0.451 (1.036) 1 No -3.840 (1.036) 0.008 Yes

Internal ramal length (mm) -3.977 (0.860) <0.001 Yes -1.893 (0.860) 0.409 No -2.084 (0.860) 0.277 No

Ramal width (mm) -1.663 (0.645) 0.202 No 0.605 (0.645) 0.991 No -2.267 (0.645) 0.015 Yes

Mandibular posterior alveolar height (mm) 0.158 (0.500) 1 No 0.535 (0.500) 0.978 No -0.377 (0.500) 0.998 No

Mandibular posterior body height (mm) -1.763 (0.394) <0.001 Yes 1.147 (0.394) 0.091 No -2.909 (0.394) <0.001 Yes

Mandibular anterior alveolar height (mm) 0.119 (0.397) 1 No -0.060 (0.397) 1 No 0.179 (0.397) 1 No

Mandibular anterior apical base width (mm) -0.619 (0.291) 0.457 No 0.600 (0.291) 0.501 No -1.219 (0.291) 0.001 Yes

Symphyseal height (mm) -0.688 (0.491) 0.896 No 0.358 (0.491) 0.998 No -1.047 (0.491) 0.453 No

Symphyseal thickness (mm) -1.444 (0.349) 0.002 Yes -0.053 (0.349) 1 No -1.391 (0.349) 0.003 Yes

Mandibular plane/symphyseal deflection (o) -3.072 (1.413) 0.426 No -1.135 (1.413) 0.997 No -1.937 (1.413) 0.908 No


40

Table 14. Pairwise comparisons of mean measurements adjusted for gender using Tukey’s comparison at T3

5.1. PRS vs Normal:

Cranial base angle and anterior cranial base length were not significantly different at any of the

three time points that were analyzed. Although, the difference in growth increment from T1 to

T2 in the anterior cranial base length was statistically significant, the overall difference in growth

increment was not statistically significant.

Maxillary length in the PRS group remained significantly smaller than the normal group at all

three time points. Horizontal maxillary growth was significantly deficient between T1 and T2.

The overall amount of growth in maxillary anterior basal width and maxillary anterior apical

width were significantly smaller in the PRS group. All other maxillary measurements were

similar between the two groups.

T3


Cranial Base

Cranial base angle (o) 1.277 (1.134) 0.97 No 1.770 (1.134) 0.825 No -0.493 (1.134) 1 No

Anterior Cranial Base (SN) (mm) -2.021 (0.750) 0.155 No -0.198 (0.750) 1 No -1.823 (0.750) 0.271 No

Maxilla


Maxillary anterior basal width (mm) -0.291 (0.433) 0.999 No 0.870 (0.433) 0.538 No -1.160 (0.433) 0.16 No

Maxillary anterior apical width (mm) -0.872 (0.311) 0.12 No -0.209 (0.311) 0.999 No -0.663 (0.311) 0.455 No

Anterior maxillary height (mm) 0.165 (0.268) 1 No 0.779 (0.268) 0.091 No -0.614 (0.268) 0.349 No

Maxillary anterior alveolar height (mm) -1.109 (0.392) 0.112 No -1.358 (0.392) 0.018 Yes 0.249 (0.392) 0.999 No

Palatal/anterior maxillary deflection (o) -3.260 (2.689) 0.953 No -4.121 (2.689) 0.839 No 0.860 (2.689) 1 No

Mandible

Internal mandibular deflection (o) 8.305 (1.222) <0.001 Yes 3.756 (1.222) 0.059 No 4.549 (1.222) 0.007 Yes

Condylion - Gonion - Anatomical Gnathion (o) 8.123 (1.210) <0.001 Yes 1.384 (1.210) 0.967 No 6.740 (1.210) <0.001 Yes

Mandibular length (Co-Gn)(mm) -9.472 (1.303) <0.001 Yes -5.014 (1.303) 0.005 Yes -4.458 (1.303) 0.02 Yes

Internal body length (mm) -8.165 (0.878) <0.001 Yes -5.186 (0.878) <0.001 Yes -2.979 (0.878) 0.022 Yes

Co-Go (mm) -4.547 (1.036) <0.001 Yes -0.344 (1.036) 1 No -4.202 (1.036) 0.002 Yes

Internal ramal length (mm) -4.014 (0.860) <0.001 Yes -0.988 (0.860) 0.966 No -3.026 (0.860) 0.015 Yes

Ramal width (mm) -2.819 (0.645) <0.001 Yes -0.505 (0.645) 0.997 No -2.314 (0.645) 0.012 Yes

Mandibular posterior alveolar height (mm) -0.912 (0.500) 0.666 No -0.040 (0.500) 1 No -0.872 (0.500) 0.717 No

Mandibular posterior body height (mm) -2.191 (0.394) <0.001 Yes 0.072 (0.394) 1 No -2.263 (0.394) <0.001 Yes

Mandibular anterior alveolar height (mm) 0.226 (0.397) 1 No -0.098 (0.397) 1 No 0.323 (0.397) 0.996 No

Mandibular anterior apical base width (mm) -0.837 (0.291) 0.099 No 0.644 (0.291) 0.399 No -1.481 (0.291) <0.001 Yes

Symphyseal height (mm) 0.030 (0.491) 1 No 0.677 (0.491) 0.905 No -0.647 (0.491) 0.925 No

Symphyseal thickness (mm) -1.784 (0.349) <0.001 Yes 0.051 (0.349) 1 No -1.835 (0.349) <0.001 Yes

Mandibular plane/symphyseal deflection (o) -5.086 (1.413) 0.011 Yes -1.721 (1.413) 0.952 No -3.365 (1.413) 0.299 No


41

Mandibular length, symphyseal thickness and ramal length in the PRS group remained

significantly smaller than the normal group at all three time points. The difference in ramal

width, however, was only statistically significant at T1 and T3 with most of the deficiency in

growth occurring between T2 and T3. Although the mandibular posterior body height was

smaller in PRS subjects at T1, the difference was not statistically significant. This difference

became significantly larger at T2 and T3 with overall statistically significant deficiency in

growth increments in PRS subjects. PRS subjects displayed a vertical growth pattern with a

significantly larger gonial angle and internal deflection angle at all three time points. Although

the mandibular plane-symphyseal deflection was consistently smaller in the PRS group, it was

only statistically significant at T3.

Table 15. Linear mixed model analysis of growth differences between PRS and Normal groups.

Measurements EMD SE P value Sig EMD SE P value Sig EMD SE P value Sig

Cranial Base

Cranial base angle (o) -0.3 0.529 0.57 No -0.02 0.529 0.97 No 1.193 1.081 0.514 No

Anterior Cranial Base (SN) (mm) 0.827 0.398 0.039 Yes 0.286 0.399 0.473 No -1.427 0.682 0.096 No

Maxilla

Maxillary length (ANS-PNS) (mm) 2.803 0.669 <0.001 Yes -0.244 0.669 0.716 No -6.811 0.542 <0.001 Yes

Maxillary anterior basal width (mm) 0.173 0.469 0.712 No -1.115 0.469 0.018 Yes -0.933 0.321 0.012 Yes

Maxillary anterior apical width (mm) -0.307 0.361 0.395 No 0.106 0.361 0.771 No -0.875 0.22 <0.001 Yes

Anterior maxillary height (mm) 0.698 0.259 0.008 Yes -0.839 0.26 0.001 Yes -0.14 0.213 0.788 No

Maxillary anterior alveolar height (mm) 0.596 0.352 0.092 No 0.326 0.352 0.356 No -0.655 0.324 0.111 No

Palatal/anterior maxillary deflection (o) -0.902 3.403 0.791 No 2.011 3.404 0.555 No -2.397 1.766 0.366 No

Mandible

Internal mandibular deflection (o) 1.163 0.978 0.235 No 1.008 0.978 0.304 No 9.194 1.046 <0.001 Yes

Condylion - Gonion - Anatomical Gnathion (o) 0.889 0.694 0.202 No 0.521 0.695 0.454 No 8.664 1.127 <0.001 Yes

Mandibular length (Co-Gn)(mm) 1.233 0.848 0.147 No -0.566 0.849 0.506 No -9.06 1.158 <0.001 Yes

Internal body length (mm) 1.464 0.646 0.024 Yes -0.049 0.647 0.94 No -7.498 0.763 <0.001 Yes

Co-Go (mm) 0.836 0.829 0.314 No 0.069 0.83 0.933 No -3.999 0.877 <0.001 Yes

Internal ramal length (mm) 0.111 0.709 0.876 No -0.13 0.709 0.855 No -3.864 0.719 <0.001 Yes

Ramal width (mm) -0.602 0.537 0.264 No 1.176 0.538 0.03 Yes -2.259 0.547 <0.001 Yes

Mandibular posterior alveolar height (mm) -0.176 0.469 0.708 No 1.119 0.469 0.018 Yes -0.283 0.399 0.759 No

Mandibular posterior body height (mm) 0.619 0.42 0.142 No 0.41 0.421 0.331 No -1.689 0.297 <0.001 Yes

Mandibular anterior alveolar height (mm) -0.243 0.443 0.583 No -0.115 0.443 0.796 No 0.077 0.291 0.962 No

Mandibular anterior apical base width (mm) -0.391 0.275 0.156 No 0.209 0.275 0.448 No -0.817 0.233 0.002 Yes

Symphyseal height (mm) 1.43 0.456 0.002 Yes -0.748 0.457 0.103 No 0.043 0.397 0.993 No

Symphyseal thickness (mm) 0.012 0.223 0.959 No 0.325 0.223 0.146 No -1.546 0.318 <0.001 Yes

Mandibular plane/symphyseal deflection (o) -0.158 0.903 0.861 No 2.076 0.904 0.022 Yes -3.829 1.282 0.009 Yes

T1 vs T2 T2 vs T3 T1 vs T3

Growth differences PRS vs Normal - Mixed model

42

5.2. PRS vs ICP:

There were no significant differences in the cranial bases of the PRS and ICP groups.

Maxillas of the PRS and ICP groups were similar in most aspects. Maxillary anterior alveolar

height remained deficient in the PRS group at all three time points, however, this difference was

statistically significant only at T3. There was also a significantly reduced overall growth

increment in maxillary anterior alveolar height and anterior maxillary height in the PRS group.

The major difference between the two groups lay in the length of the mandible. The internal

mandibular body length and mandibular length were significantly smaller in the PRS group

across all three time points. PRS subjects appear to grow more vertically than ICP subjects,

however the difference in gonial angle was only statistically significant at T1 and internal

mandibular deflection at T1 and T2. Unlike the gonial angle, there was a significantly greater

overall growth increment in internal mandibular deflection in the PRS group.

Table 16. Linear mixed model analysis of growth differences between PRS and ICP groups


Cranial Base

Cranial base angle (o) 0.246 0.529 0.642 No -0.459 0.53 0.387 No 1.532 1.081 0.335 No

Anterior Cranial Base (SN) (mm) 0.19 0.398 0.633 No 0.222 0.399 0.579 No -0.047 0.682 0.997 No

Maxilla

Maxillary length (ANS-PNS) (mm) 0.73 0.669 0.276 No -0.798 0.67 0.235 No -1.044 0.543 0.136 No

Maxillary anterior basal width (mm) -0.109 0.468 0.816 No -1.01 0.469 0.032 Yes 0.14 0.321 0.901 No

Maxillary anterior apical width (mm) 0.311 0.361 0.39 No -0.31 0.362 0.392 No -0.326 0.22 0.303 No

Anterior maxillary height (mm) 0.088 0.259 0.733 No -0.311 0.26 0.232 No 0.591 0.213 0.017 Yes

Maxillary anterior alveolar height (mm) 0.613 0.352 0.082 No 0.291 0.353 0.409 No -0.978 0.324 0.009 Yes

Palatal/anterior maxillary deflection (o) 3.476 3.402 0.308 No -1.431 3.408 0.675 No -3.833 1.767 0.08 No

Mandible

Internal mandibular deflection (o) 0.851 0.978 0.385 No 2.876 0.98 0.004 Yes 6.038 1.046 <0.001 Yes

Condylion - Gonion - Anatomical Gnathion (o) 1.706 0.694 0.015 Yes 0.778 0.696 0.265 No 2.519 1.127 0.069 No

Mandibular length (Co-Gn)(mm) 0.889 0.848 0.295 No 0.168 0.85 0.844 No -4.785 1.158 <0.001 Yes

Internal body length (mm) 0.562 0.646 0.385 No 0.432 0.648 0.506 No -4.811 0.763 <0.001 Yes

Co-Go (mm) 0.086 0.829 0.918 No 0.204 0.831 0.807 No -0.285 0.878 0.943 No

Internal ramal length (mm) 0.611 0.709 0.39 No -0.626 0.711 0.38 No -1.296 0.719 0.173 No

Ramal width (mm) -0.88 0.537 0.103 No 1.076 0.539 0.047 Yes -0.069 0.547 0.991 No

Mandibular posterior alveolar height (mm) 0.376 0.469 0.424 No 0.492 0.47 0.297 No 0.442 0.4 0.513 No

Mandibular posterior body height (mm) -0.456 0.42 0.279 No 1.105 0.421 0.009 Yes 0.646 0.297 0.079 No

Mandibular anterior alveolar height (mm) 0.414 0.443 0.351 No 0.05 0.444 0.91 No 0.069 0.291 0.969 No

Mandibular anterior apical base width (mm) -0.667 0.274 0.016 Yes -0.028 0.275 0.92 No 0.398 0.233 0.208 No

Symphyseal height (mm) 0.268 0.456 0.557 No -0.269 0.458 0.557 No 0.57 0.397 0.325 No

Symphyseal thickness (mm) -0.224 0.223 0.315 No -0.081 0.223 0.718 No -0.085 0.318 0.961 No

Mandibular plane/symphyseal deflection (o) -0.663 0.903 0.464 No 0.483 0.906 0.595 No -1.585 1.282 0.434 No

Growth differences PRS vs ICP - Mixed model


43

5.3. ICP vs Normal:

There were no significant differences in the cranial bases of the ICP and normal groups.

Maxillary lengths of the ICP groups were significantly deficient compared to the normal group at

all three time points, with the most deficient growth increment occurring between T1 and T2.

ICP subjects had shorter mandibular lengths and internal body lengths which were statistically

significant at T2 and T3 and significantly deficient overall growth from T1-T3. Symphyseal

thickness, ramal length and width, anterior apical base width and posterior body height were

deficient throughout growth. Subjects with ICP tended to grow more vertically than normal

subjects with a significantly larger gonial angle at all three time points and significantly greater

overall growth increments in gonial angle from T1 to T3. Internal mandibular deflection was

significantly greater only at T3 with a statistically significant increase in the deflection between

T2 and T3.

Table 17. Linear mixed model analysis of growth differences between ICP and Normal groups


Cranial Base

Cranial base angle (o) -0.528 0.529 0.319 No 0.505 0.529 0.341 No -0.333 1.079 0.949 No

Anterior Cranial Base (SN) (mm) 0.716 0.419 0.088 No 0.349 0.419 0.406 No -1.352 0.698 0.133 No

Maxilla

Maxillary length (ANS-PNS) (mm) 2.193 0.707 0.002 Yes 0.981 0.707 0.166 No -5.724 0.549 <0.001 Yes

Maxillary anterior basal width (mm) 0.309 0.47 0.511 No -0.009 0.47 0.984 No -1.064 0.322 0.004 Yes

Maxillary anterior apical width (mm) -0.6 0.363 0.099 No 0.481 0.363 0.186 No -0.542 0.22 0.04 Yes

Anterior maxillary height (mm) 0.623 0.261 0.018 Yes -0.479 0.261 0.067 No -0.726 0.212 0.002 Yes

Maxillary anterior alveolar height (mm) 0.007 0.356 0.984 No 0.121 0.356 0.734 No 0.332 0.321 0.558 No

Palatal/anterior maxillary deflection (o) -4.488 3.412 0.19 No 3.047 3.412 0.373 No 1.395 1.76 0.708 No

Mandible

Internal mandibular deflection (o) 0.205 0.998 0.838 No -2.249 0.998 0.025 Yes 3.118 1.043 0.009 Yes

Condylion - Gonion - Anatomical Gnathion (o) -0.881 0.705 0.212 No -0.486 0.705 0.491 No 6.122 1.119 <0.001 Yes

Mandibular length (Co-Gn)(mm) 0.581 0.958 0.544 No 0.112 0.958 0.907 No -4.19 1.148 0.001 Yes

Internal body length (mm) 1.035 0.694 0.137 No -0.009 0.694 0.989 No -2.64 0.757 0.002 Yes

Co-Go (mm) 0.891 0.871 0.307 No 0.363 0.871 0.677 No -3.664 0.875 <0.001 Yes

Internal ramal length (mm) -0.374 0.749 0.617 No 0.942 0.749 0.21 No -2.522 0.717 0.002 Yes

Ramal width (mm) 0.263 0.537 0.625 No 0.047 0.537 0.931 No -2.195 0.547 <0.001 Yes

Mandibular posterior alveolar height (mm) -0.588 0.472 0.214 No 0.495 0.472 0.295 No -0.738 0.402 0.162 No

Mandibular posterior body height (mm) 1.088 0.421 0.01 Yes -0.647 0.421 0.126 No -2.331 0.296 <0.001 Yes

Mandibular anterior alveolar height (mm) -0.651 0.442 0.142 No -0.144 0.442 0.745 No 0.01 0.291 0.999 No

Mandibular anterior apical base width (mm) 0.284 0.274 0.301 No 0.263 0.274 0.338 No -1.212 0.234 <0.001 Yes

Symphyseal height (mm) 1.184 0.457 0.01 Yes -0.4 0.457 0.382 No -0.519 0.397 0.395 No

Symphyseal thickness (mm) 0.247 0.223 0.27 No 0.444 0.223 0.048 Yes -1.457 0.318 <0.001 Yes

Mandibular plane/symphyseal deflection (o) 0.458 0.904 0.613 No 1.428 0.904 0.115 No -2.26 1.285 0.188 No

Growth differences ICP vs Normal - Mixed model


44

6. Discussion

The aim of this study was to investigate the craniofacial morphology and facial growth patterns

in non-syndromic PRS and compare them longitudinally to race-, age- and sex-matched ICP and

unaffected children during their active growth period. A true longitudinal analysis of such a long

duration involving such a large sample size is lacking in the literature. Based on the results of our

cephalometric analysis, significant differences in craniofacial growth patterns and morphology

were found between the three groups, thus leading to the rejection of the null hypotheses.

The subjects diagnosed with PRS and ICP selected for this study were treated at the Hospital for

Sick Children, where a large interdisciplinary team of experts including surgeons, orthodontists,

pediatricians, syndromologists and clinical geneticists is involved in managing craniofacial

abnormalities. Because of this, it was possible to confidently select patients with PRS and ICP

who did not have any associated syndromes. In order to limit variability in the PRS and ICP

groups and make sure that the craniofacial features seen were not due to any associated

syndromes, it was important to separate syndromic from non-syndromic patients. Although none

of the patients received orthognathic surgery or functional appliance treatment during the study

period, they did receive fixed orthodontic appliance treatment at the center’s orthodontic clinic.

For this reason, no dental measurements were included and evaluated in this study.

For the purposes of comparison and to serve as controls for different aspects of growth, an ICP

group and an unaffected group were selected. The reason for selection of an ICP group was to

control for aspects of craniofacial growth that may be affected by the presence of cleft palate and

its surgical management. Maxillary dimensions in subjects with ICP have been noted to be

smaller than normal before and after surgical repair (Shibasaki and Ross, 1969; Laitinen and

Ranta, 1998). The deficiency in the maxilla may partly be due an innate developmental defect

and partly due to fibrotic scar tissue formation as a result of surgical cleft repair (Ross and

Coupe, 1965). Ross and Coupe (1965) as well as Shibasaki and Ross (1969) also identified that

mandibles in patients with ICP displayed a positional change, most likely due to the altered

maxillary complex. Palatal clefts result in Mandibles displaying a clockwise, downward and

backward rotation resulting in increased gonial angles and increased lower face heights. These

45

mandibular changes are thought to be a characteristic of craniofacial growth in patients with

isolated cleft palate since similar findings were seen in operated and un-operated subjects

(Bishara, 1973; Dahl et al., 1982, 1989; daSilva et al., 1989; daSilva et al., 1992, 1993).

The unaffected group served as a second control group and was selected from the Burlington

Growth Center archives. This group included subjects with class I occlusions and skeletal growth

patterns as evaluated by mean ANB measurements of 3.24O + 1.34O by T3. In a survey

conducted by Proffit et al. (1998), normal population consists of a range of occlusions, Class I –

80% - 85%, Class II – 15%, Class III – 1%. In spite of this range of malocclusions in the normal

population, unaffected children with a Class I skeletal pattern and occlusion were selected for

comparison to the PRS sample. This is because, during orthodontic treatment, the goal is ideally

to achieve a class I occlusion and skeletodental relation. Therefore, in order to formulate a

realistic treatment plan, it is important to know the discrepancies that exists between patients

with PRS and the ultimate goal of such a class I occlusion and relation. Additionally, in order to

reduce variability in the study sample that is attributable to race, the subjects in all three groups

were limited to the Caucasian race.

Several studies investigating the craniofacial growth patterns of patients with PRS and ICP have

consistently found that the greatest difference is between the PRS and the normal groups. The

ICP group tends to be in between with more similarities to the PRS group than to the normal

group (Figueroa and Friede, 2000). The superimposed averaged tracings of the three groups at

each time point show that a similar trend was found in this study sample as well (Figure 3, 4 and

5). Through these images, it is apparent that the PRS group had the most retrusive mandibles that

remained retrusive throughout the active facial growth period. However, their intermaxillary

relationships appear to be harmonious. This is also evident from the mean ANB values

(unadjusted) recorded in the PRS group over the three time points (T1: 5.83O + 2.93O, T2: 4.39O

+ 3.04O, T3: 4.00O + 3.4O). The presence of a deficient maxilla significantly alleviates the

appearance of the underdeveloped mandible, creating a bimaxillary retrognathic profile type.

This facial profile pattern has also been reported by Matsuda et al, 2006; Suri et al, 2010a; Shen

et al, 2012. As well, the PRS and ICP groups displayed the characteristic vertical growth pattern

seen in subjects with palatal clefts, as described earlier.

46

Cranial base angle and anterior cranial base length was not an area of noteworthy difference

between the three groups in this study. Although the anterior cranial base length measurement

was shorter than normal in the PRS and ICP groups, this difference did not reach statistical

significance at any of the three time points. Suri et al. (2010a) and Shen et al. (2012) found a

significantly shorter anterior cranial base length in their PRS group when compared to normative

values. Similar to the results of this study, Suri et al. (2010a) did not find a significant difference

in angular cranial base measure between PRS and unaffected subjects. Comparable to the

findings in the literature which generally reports no differences in the cranial bases of patients

with PRS and ICP, this study found no differences in the cranial bases of subjects with PRS and

ICP (Laitinen and Ranta, 1992; Laitinen et al., 1997; Daskalogiannakis et al., 2001; Shen et al.,

2012).

Since patients with PRS and ICP undergo surgical palatal repair procedures, it is expected that

their maxillary growth will be interrupted and their maxillary lengths, deficient. In this study, the

maxillary lengths of PRS and ICP groups were not significantly different from each other,

however, they were significantly shorter than the normal group. The averaged maxillary lengths

of the PRS and ICP groups were approximately 10.8% (6.0mm) shorter than the normal group.

The greatest maxillary growth differential occurred between T1 and T2, with an insignificant

growth difference between T2 to T3. The maxillas of subjects with ICP and PRS grew at

approximately half the rate of the maxillas of the unaffected group between T1 to T2 (2.7mm,

3.67mm and 6.55mm respectively). These findings are corroborated by several studies reported

in the literature (Table 18) (Laitinen and Ranta, 1991, Bacher et al., 2000; Suri et al., 2010a;

Shen et al., 2012). Several causes for deficient maxillary growth in cleft patients have been cited

in the literature, most common of which are related to the surgical repair of the cleft and scar

tissue formation. Other causes include, type and severity of the cleft, quality of pre- and post-

operative care including orthodontic and prosthodontic intervention, lack of primary palatal

tissue to support adequate midfacial growth, inability to perform normal functions which is a

stimulus for normal maxillary growth and genetic abnormalities (Bishara, 1973; Satokata and

Maas, 1994).

47

Generally, PRS and ICP were smaller in other areas of the maxilla as well, although, this

difference was not always statistically significant. Alveolar portions of the maxilla were

demarcated from the basal portions of the maxilla, showing reduced heights and widths in the

alveolus of the PRS and ICP groups when compared to the unaffected group. The general

reduction in maxillary volume could be attributed to bone and tissue deficiencies due to clefting

and growth disruption due to post-surgical scar tissue formation. Another possible explanation

for underdevelopment of the alveolus could be an abnormality in the MSX1 gene. The MSX1

gene, commonly implicated in cleft palate formation, is responsible for epithelial-mesenchymal

interactions during embryogenesis. Aside from clefting of the palate, abnormality in the MSX1

gene also results in deficiency in the alveolar bone development of the maxilla and the mandible

as well as tooth bud malformation and consequently hypodontia (Satokata and Maas, 1994). ICP

and PRS populations have a higher rate of permanent tooth agenesis compared to the normal

population. About 30% - 50% of patients with PRS and 30% of patients with ICP have

congenitally missing teeth, the most common being the mandibular 2nd premolar followed by the

maxillary lateral incisor (Margareta et al., 1998; Antonarakis and Suri, 2014). The absence of

permanent tooth development could further contribute to reduced alveolar development in the

anterior maxilla.

Laitinen and Ranta (1992) found that patients with PRS present a more severe but

morphogenetically similar developmental anomaly of the mandible than patients with ICP. These

findings are supported by the results of this study as well. When comparing the mandibles of the

PRS and ICP groups with each other, the most remarkable difference that was seen consistently

throughout growth was in the length of the mandible. Mandibular length (Co-Gn) in the PRS

group was 4.7% shorter than the ICP group at T1, getting better with growth and ending at 4.2%

shorter than the ICP group at T3. The averaged deficiency in mandibular length of the PRS

group was 4.6% (5.0mm) compared to ICP group. Although Daskalogiannakis et al (2001) did

not find that the mandibular length of their PRS group got better with time, the averaged

percentage deficiency in mandibular length of their PRS group was also 4.6% (T1: 4.23%, T2:

5.3%, T3: 4.1%) compared to the ICP group (Table 18). When the mandible is separated into

ramal and body components, the difference in mandibular length can be mostly attributed to

deficiencies in the mandibular body. While the ramal width essentially remained the same in

48

both groups, the internal body length (RBS-Gn) of the PRS group was 9.4% shorter than the ICP

group at T1, ending at 8.6% shorter than the ICP group at T3. Another area of difference

between the PRS and ICP groups was in the degree of the vertical growth of the face. The gonial

angle (Co-Go-Gn) and internal mandibular deflection angle (Co-RBS-Gn) of the PRS group

were greater than the ICP group. This suggests an increased vertical pattern of growth in subjects

with PRS compared to subjects with ICP, as supported by several studies in the literature

(Daskalogiannakis et al., 2001; Shen et al., 2012).

As expected, mandibular morphology of the PRS and ICP groups significantly differed from the

normal group at all three time points. The internal mandibular deflection angles, gonial angles

and ramal height measures of the PRS group were significantly different from the normal group.

Increased gonial angle and internal mandibular deflection angle along with reduced ramal length

(7.4%) suggests a reduced posterior face height and a vertical pattern of growth. These results

are in agreement with the associations made in the literature regarding palatal clefts and a

vertical pattern of facial growth resulting in increased gonial angles and consequently, a

posteriorly rotated mandible (da Silva et al., 1993; Suri et al., 2010a). Bishara (1973) and da

Silva et al (1989 and 1992) found that these differences were not attributed to surgical repair of

the cleft, but rather were a part of the craniofacial characteristics of cleft palate patients. True to

form, the mandibular length of the PRS group was significantly shorter than the normal group

and remained at approximately 92% (9.7mm) of normal mandibular length throughout the

growth period. When the mandible is separated into ramal and body components, most of the

deficiency appears to be in the body of the mandible. The internal body length of the PRS group

remained approximately 13% shorter than the normal group, while the ramal width was 7.4%

shorter than the normal group. Suri et al. (2010a) reported similar results with their PRS group

displaying a 6.5% deficiency in mandibular length, 11.1% deficiency in internal body length and

a 10.7% deficiency in ramal width compared to their normal group.

Compared to the normal group, the pattern of diminished mandibular growth did not change

throughout T1 to T3. This is illustrated by the similar amount of mandibular growth experienced

by both groups from T1 to T3 (23.1mm in the normal group vs 21.9mm in the PRS group). The

findings from Figueroa et al (1991) suggest that the mandibles of babies with PRS experience a

49

greater change in mandibular length during the first 2 years of life than normal babies (53.5%

change vs 38% change). However, this mandibular growth spurt is only enough to allow partial

catch-up in mandibular length. Even though this growth spurt is limited, it is extremely important

in improving the airway dimension and resolving the respiratory distress that infants with PRS

experience immediately after birth.

Aside from a deficient mandibular length in the PRS group, it was also evident that their

mandibles had significantly reduced bony volume. Symphyseal width (10.5%), mandibular

posterior body height (16.3%) and mandibular anterior apical base width (9.2%) were all

deficient compared to the normal group. Suri et al. (2010a) also found a significant reduction in

mandibular bony volume when comparing the mandibles of the PRS group to the normal group.

They found a symphyseal width deficiency of 9.6%, a posterior body height deficiency of 12.9%

and mandibular anterior apical base width deficiency of 12%. In this study, the ICP group also

displayed significant deficiencies in their mandibular bony volume (9.8% deficiency in

symphyseal width, 22.8% deficiency in mandibular posterior body height and 13.4% deficiency

in mandibular apical base width), suggesting that these deficiencies seen in both groups may be

due to growth disturbances attributed to the palatal clefts.

Some of the strengths and limitations of this study should be considered when interpreting the

results. Even though this study involves the largest racially homogenous sample of PRS to be

reported in the literature till date (43 subjects), it is still a relatively small sample population. A

major strength of this study was the use of a comprehensive cephalometric analysis that was not

restricted to the use of external measurements. The analysis previously described by Suri et al

(2006, 2010b) involves internal measurements that are not affected by remodelling changes

caused by muscle attachments on the surface. Using this analysis also allowed description of

morphological features that have previously not been described, such as anterior maxillary basal

and apical heights and widths, among several other measurements. Measurements such as

internal ramal length, internal body length, posterior and anterior mandibular alveolar heights,

posterior mandibular body height, symphyseal height, internal mandibular deflection and

mandibular plane/symphyseal deflection were possible using the RBS point. Ramus Body

syncline (RBS) is an internal geometrically constructed landmark that was used to differentiate

50

between the ramal components and body components of the mandible. It is the point of

intersection between the mid-planed cortical outline of the inferior alveolar nerve canal and a

line going through the posterior alveolar point on the mandible (PAPmd) and the inferior gonion

(Inf Go). Using inferior gonion avoids the use of gonion and antegonial notching which can both

affected by muscular attachments. A possible direction for similar future studies could involve

taking into account the morphological aspects of general somatic growth when considering the

inclusion criteria of their sample.

The results of this study do not support the decision for early treatment of patients with PRS

when it relates solely to their long term jaw relationship. Infants with PRS often require

treatment to resolve respiratory difficulties encountered at birth. On average, their maxillas and

mandibles both become retrognathic with growth, displaying a harmonious but bimaxillary

retrognathic profile type. Furthermore, the tendency for vertical growth and clockwise rotation of

the mandible implies that orthodontic mechanics increasing lower face height should be avoided.

Orthognathic surgery at the completion of growth may be useful for patients with PRS to

improve esthetics and facial balance, as well as to correct retrognathia in one or both jaws.

51

Table 18. Averaged percentage differences in maxillary and mandibular lengths found in this study in comparison with those reported in the literature.

Measurement Author Study Design Comparison

Group

Sample Size Age

Range

%

Difference

Maxillary

Length

Pereira et al.

(2017)

Retrospective

Longitudinal

PRS vs

Normal

N - 43 6y-17y 10.8%

Suri et al. (2010a) Retrospective

Longitudinal

N - 34 11y-17y 12.3%

Shen et al. (2012) Longitudinal N - 13 4y-13y 13.4%

Pereira et al.

(2017)

Retrospective

Longitudinal

PRS

vs ICP

N - 43 6y-17y 2.4%

Shen et al. (2012) Longitudinal PRS: N -13

ICP: N -14

4y-13y 1.4%

Mandibular

Length

Pereira et al.

(2017)

Retrospective

Longitudinal

PRS vs

Normal

N - 43 6y-17y 8.1%

Suri et al. (2010a) Retrospective

Longitudinal

N - 34 11y-17y 6.5%

Shen et al. (2012) Longitudinal N - 13 4y-13y 10.5%

Pereira et al.

(2017)

Retrospective

Longitudinal

PRS

vs ICP

N - 43 6y-17y 4.6%

Shen et al. (2012) Longitudinal PRS: N -13

ICP: N -14

11y-17y 4.6%

Daskalogiannakis et

al. (2001) Mixed Longitudinal

PRS: T1: 96; T2

& T3: 38

ICP: 50

6y-17y 4.6%

* Some subjects included in the current study were also included in the studies by Daskalogiannakis et al. (2001) and Suri et al. (2010a)

52

7. Conclusions

In this true longitudinal study of the largest, racially homogenous PRS sample to be reported on

to date, the following conclusions can be drawn:

The craniofacial morphology and longitudinal facial growth in subjects with PRS and

ICP differ significantly from comparable unaffected Class I children.

The significant morphological differences lie in the mandible:

Mandibular length, ramal length, ramal width, symphyseal thickness and internal

body length are significantly smaller in PRS and ICP groups in comparison to the

unaffected group.

Maxillary length is also remarkably deficient in both PRS and ICP subjects.

The craniofacial morphology of PRS and ICP are similar in many areas except for an

exaggerated deficiency in mandibular length and vertical growth pattern.

Many of these morphological differences are seen at the 6yr time point and continue to be

deficient throughout the active growth period, with little improvement over time.

53

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longitudinal craniofacial growth in pierre robin …...dr. sunjay suri, thesis supervisor, director...

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