CEPHALOMETRIC COMPARISON OF THE

CRWlOFAClAL SMLETAL MORPHOLOGY BETWEEN

MOBIUS SYNDROME A N D NON-SYNDROMIC CONTROLS

Susette M. lnstrum

A thesis submitted in conformity with the requirements for the

Degree of Master o f Science, Department o f Orthodonties.

Faculty of Dentistry, The University of Toronto

O Copyright by Susette M. Instrum 1999

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The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts ~ o m it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation.

1 would like to thank my cornmittee rnembers Dr. Ross. Dr. Rossouw. Dr. Tompson. and

Dr. Zuker for their assistance and suidance with this project. 1 would like to offer a special

acknowledgment to Dr. Ross for always challen$ng rny ideas and Dr. Tompson for

supportin; me unconditionally.

Thank you to The Burlington Growth Center. Derek Stephens for his statistical expertise.

Lynn Cornfoot for her assistance with the cephalometric tracing. and Dr Faille t'or

providing the additional sample.

Completing this last year has been very cliallenginy and would not have been possible

without my husband who always believed in my abilities and always reminded me to l ive

life to the fullest. 1 would also like to acknowledge rny daughter Karhryn Rene who added

an extra chailense to the year but has proven to be my yreatest accomplishment.

TABLE OF CONTENTS PP.

Abstract 1 *.

Acknowledgments 11 *. .

Table of Contents III

List of Tables

List of Figures

List of Appendices

Introduction

Literature Review

Facial Paralysis

Diagnostic Criteria

Pathogenesis

E tio logy

Craniofacial Morphology and Orofacial Manifestations

Other Features

Radiographie Findings

Surgical interventions

Conclusions

Statement of the Problem

Objectives

Hypo theses

Methods and Materials

Resu 1 ts

Discussion

Conclusions

Further Research

References

iv

LIST OF TABLES Pe,

Table 1 : Differential diagnosis of facial paralysis

Table 7: Surnrnary of features associated with Mobius syndrome

Table 3: Necrospy reports

Table 4 a: Environmental causes of Mobius syndrome

Table 4 b: Genetic cases of Mobius svndrorne

Table 4 c: Proposed location of gene for Mobius syndrome

Table 5: Sumrnary of cranial nerves and associated functions

Table 6: Distribution of cranial nerve palsies in Mobius syndrome (Engler et al 1979)

Tab

Tab

Tab

e 7: Distribution of cranial nerve palsies in Mobius syndrome (Carr et al. 1997)

e 8: Muscle of the face innervated by cranial nenie (VU) and associated actions

e 9: Muscles of mastication innervated by cranial nerve (V) and associated actions

Table 10: Staternents of micrognathia in Mobius syndrnrne and respective references

Table 1 1 : Craniofacial assessments of 186 cases of Mobius syndrome

Table 12: Reports of micrognathia in young individuais with Mobius syndrome

Table 13 : Mobius sample: ase. yender, cranial nerve and time of lateral cephalogram

Table 14: Age and sex distribution of sample and control

Table 15: Results of Univariate Anova for primary Mobius sample and control

Table 16: Means and standard deviations for secondary Mobius sarnple versus control

Table 17: Means for rnavillary length, mandibular length and unit length difference

\

- LIST OF FIGURES

Figure 1 a: Mobius syndrome - frontal view

Figure 1 b: Mobius syndrome - profile view

Figure 2: Skeletal components of Class I I blalocclusions

Figre 3 : Flap pnor to gracilis muscle transfer

Figure 4: Superficial location of graci l is muscle

Figure 5a: klobius syndrome - smile prior to reanimation surgery

Figure 5b: Mobius syndrome - smile after reanirnation surgery

Figure 6a: blobius syndrome - smile after reanimation surgery - right

Figure 6b: Mobius syndrome - smile after reanimation surgery - right and left

Figure 7: Skeletal landmarks on lateral cephalograri;

Figure 8a: Linear measurements on lateral cephalogram

Figure 8b: Anyular measurements on lateral cephalogram

Figure 8c: Proportional measurements on lateral cep halogram

Figure 9a: hlaxillary length of primary sample and control

Figure 9b: Mandibular iength of prirnary sample and control

Figure IOa: Mean tracing; primary sample superimposed on control on Ba-Na

Figure lob: Mean tracing; primary sample superimposed on control on ANS-PNS

Figure 1Oc: Mean tracing; primary sample superimposed on conrrol on MP

Figure 1 1 : Lateral cephalometric radiograph- primary sample

Figure 12: Lateral cephalometric radioyraph- secondary sample

Figure D a : Mean tracing; secondary sample superimposed on control on Ba-Na

Figure 13b: Mean tracing; secondary sample superimposed on control on ANS-PNS

Figure 13c: Mean tracing; secondary sample superimposed on control on MP

Pe.

LIST OF APPENDICES PP. -

Appendix A: Operational Definitions 79

Appendix B Raw Data - Primary Sample 52

Xppendix C: Raw Data - Secondary Sample S5

Appendix D: Raw Data - Control for Primary Sample 87

Appendix E: Raw Data - Control for Secondary Sample 92

Appendix F : Cephalometric Tracings - Primary Sarnple 94

Appendis G: Crphalometric Tracings - Sacondaq Sampla 98

Appendix H: Statistical Data 1 O0

INTRODUCTION

Mobius syndrome is a rare form of conjenital non-progressive facial paralysis which was

first reported by Mobius in 1888. Although the seventh cranial nerve is always involved,

cranial nerves III, IV, V, VI, VIII, IX, X, XI and X I may also be affected. Craniofacial and

orofacial abnormalities are included in the diagnostic criteria for Mobius syndrome and

include: microstornia, cleft palate, bi fid uvula, high arched palate. palatal palsy, high nasal

bridge, midface prominence, l i p incorn petency with an evened and prominent lower 1 ip,

hypoplasia and/or paralysis of the tongue, exremal ear defects and micrognathia. Eye, limb

and muscle abnonalities may also be present. This literature review provides a detailed

overview of the syndrome, dong with the reported etiology and pathogenesis. The

diagnostic criteria and associated features of the syndrome are reviewed and the current lack

of evidence to include micrognathia. alonj with the need for controlled cephalometric

studies, is explained. Finallv, the surgical interventions for individuals with Mobius

syndrome are described and future studies to determine their potential morphological

benefits with respect to growth and development are proposed.

LITERATURE REVIEW

Facial Paralvsis

The differential diagnosis of facial paralysis is extensive and includes: metabolic, vascular,

imrnunologic. traumatic, infectious, toxic, neoplastic, idiopathic, and congenital (Hora &

Elwell 1966, May & Klein 1994, Cwach et al. 1997) (Table 1 ).

Congeni ta1 Facial Paralvsis

Congenital Facial paralysis occurs in approximately 1.4 70 of live binhs (Carr et al. 1997)

and is associated with obstetric or spontaneoushon-obstetric causes (Bonar & Owens 1929.

Carr et al. 1997). Obstetric cases of facial paralysis may be caused by forceps delivery or

inherent pressure factors such as antepartum and intrapartum compression. Spontaneous or

non-obstetric causes of facial paralysis include: Myotonic dystrophy, Facioscapulohumeral

dystrophy. materna1 ingestion of Thalidomide. and Mohius syndrome (Cwach et al. 1997).

Mdbius Svndrome

Mobius syndrome was originally described by von Graefe in 1880, but Illobius was the first

to report the syndrome in 1888 (Engler et ai. 1979). Mobius collected 43 cases of acquired

and congenital nerve paisies and classified them into seven groups. One group consisted of

six cases of congenital bilateral abducens and facial palsy. Mobius believed that the

condition was due to degeneration and atrophy of the invoived nuclei and was unable to find

a single case of abducens-facial paralysis which developed during childhood (Thomas

1898). The term "Mobius syndrome" has been used by medical historians but other terms

include: congenital facial diplegia, congenital abducens-facial paralysis, congenital

oculofacial paralysis, congenital nuclear agenesis, congenital paralysis of the sixth and

seventh nerve, infantile Kemschwund. akinesia alegra, and infantile nuclear atrophy

(Cadwalader 1927, Masaki 1971, Engler et al. 1979). Although Evlobius was the first to

report the syndrome in 1888, the syndrome has been referred to as both "Mobius" and

"Moebius" syndrome.

Table 1: Diffcrcntiiil Diagnosis of Facial Pmlysis (May and Klein 1994. Cwacli et al. 1997)

Ditibstcs nicllitus Acutc interniittcnt porpliyria Wcniicke-Korsrrkoff Syndroiiie H~~pcrthyro idism

rraumatic 3asilar skull frxturc 3ilatcr+,l mandibulx frdctures 3ilatcwl tcmponl bone fractures Utitude parilysis ;cuba diving

ï'osic 3thylenc glycol ingestion 4rsenic intoxication Z d o n monoside

[nfcctious Lynie disease Aquired immune deficienq syndrome Mristoiditis Syphilis Leuospirosis Otitis nicdia Tctmus Diphthcria Sculet fcver Tuberculosis Leprosy Mycoplasmli pncuinonili Malaria Trichinosis Herpes siniples virus Epstein-Barr virus Varicella-zoster virus Cossakic vims

Immunoloric Multiple sclerosis My sisthenia gravis

Polyrirtcritis nodosa Tcinponl artertitis Sysieniic Lupus Eqdiriialosus Sclerodernia Sjogren's syndrome iMelkersson-Roscntfr31 sy ndroiiic Pontine Iieniorrtiage or iscficniia

Ncoplasm Pontine glionias Xeurofibromatosis Meningeal carcinonia ptosis Leukemia Ly mphoma Fibrous dysplrisiri

Con~eni td biobius s~ndronie Myotonic dystroptiy Facioscapulohumenl dystrophy Materna1 injestion of Tlialidomide Birth tmunta

Othcr - Bell's pais' Benign intrxranial Iiypencnsion Sarcodosis Stevens Jolmson syndrome Amyuophic laterd sclcrosis Polomy clitis Murnps Influenza .4rôovirus kleningitis Encephalitis Botulism Guillaine Barre

Diagnostic Criteria

Mobius syndrome is usually diagnosed soon after birth. The facial palsy is typicall y noticed

by the parents during the first few days of life due to the child's difficulty in nursing and

incomplete closure of the eyelids during sleep. The parents becorne concemed with their

child's inability to smile and the lack of facial expression when crying (Henderson 1939).

The criteria for diagnosis rernains difficult to define. This dificulty is most likely due to the

variable expressivity of the syndrome and the low incidence of reported cases. There are

approximately 200 reported cases to date (MacDermot et al. 1990) with males and females

being equally affected (Gorlin et al. 1990). The diagnostic criteria of Mobius syndrome has

stemmed from a collaboration of the most typically found features described in the cases

reported (Table 2). Controlled studies to determine the diagnostic criteria have not been

conducted and thus little scientific evidence has rmerged.

Accordhg to Mobius (1888). the syndrome consisted of bilateral facial weakness and

bilateral abducens palsies. Richards ( 1953) reviewed the published papers up to 1953 and

described the essential features of Mobius syndrome as :

1. unilateral or bilateral, complete or incomplete facial weakness;

2. unilateral or bilateral loss of abduction of the eye;

3. primas, or secondary congenital abnomalities of the extremities; and

4. possible other involvement of the branchial musculature.

6

Although Richards (1953) included unilateral facial paralysis in his diagnostic criteria,

Kumar ( 1990), Zuker ( 1990) and May & Klein ( 1 994) felt that bilatera

more typical of Mobius syndrome.

1 facial paralysis was

Roger's ( 1 969) additions to the diagnostic criteria included oculomotor, motor branch of the

trigem inal. glossopharyngeal and h y poglossal cranial nerve palsies. dong with ear

anomalies and mental retardation. Baraitser (1977) insisted that limb malformations be

included in the diagnostic criteria. Kumar (1990) established guidelines for diagnosing

Mobius syndrome based on previously published case reports of Henderson (1 93 9),

Richards (1953) and Baraitser (1977). Along with the "essential" complete or partial facial

paralysis and the often present limb malformations. Kumar ( 1990) also described additional

clinical features which could be present and would be helpful in making a clinical diagnosis

of blobius syndrome. These additional features included bilateral or unilateral ocular nerve

palsies. hypoplasia of the tongue. speech and swallowing problerns. malformations of the

orofacial complex and anomalies of the musculoskeletal system.

+ . . - . . - =cniq.f$diii - :, -

" '

* mask-like facies

* high nasal bndgc

* rnicrostonii~

* uppcr micifacc prominencc

* micrognüthia

* e ~ t r t c d and proniincni 101s cr lip

* lip inconipetcncy

* bifid u\+ulri

* clcft palatc

* p m l j sis of the tongue

hypoplasiii of tlie tongue

* cstcrnril ear defccts

* absent digits

inability to abdiici the eyc Iritcrally

11' pcrtclorisiii

incoiiipicic clostirc of e> clids

sniall palpcbrdl fissures

cpicmthic folds

I O*.. :. .-. .-. . . : . . . . .>:< .?: . . .. . , , - F+on& ,...,+y... . , . -. . . Pro ... b h s : . ~ . . ~ : ~ s ~ ~ s - T. .z ....-.\,a ;:;--.-.œ &->.-..a?:~:--, . ... S . * :.. .. .,., .. . . - .. .. ~ . I . i * . - - . ~ . . . - d . - ' . r.4-

* nicntal rctardation

* ribscncc of stcmai hcad of

pecioralis riitiscle

* brmcliial niusclc dcf'ccts

* rib defccts

* Klippcl-Fcil rinotrialy

* Polarid- Mobiiis s> ndrornc

ps~~chosocial concems

speech problctns

fccding roblcins

sucking problems

swllo\ving diffïctiliies

;isp ira t ion

potcntial for poor growtti

niirsing bottle caries

otitis niedia

drooling

Table 2: S u m r n q of i ~ t m rissociated ivith Mobius syndrome (Haderson 1939, Evans 1955. R e d & Griit 1957. ct al. 1985. Koroluk el al. l%Y. Gorlin et al. 1990. Kumar 19'30. Zuktlr IYYO. Sltx et üI. 199 1. and Chester & Zukcr I 992)

Pathoeenesis

The pathogenesis of Mobius syndrome remains controversial. Necropsy repons sugsest that

at least four pathological explanations for the clinical signs of Mobius syndrome exist.

These include: ( 1 ) hypoplasia or absence of the central brain stem nuclei, (2) destructive

degeneration of the central brain stem nuclei, (3) peripheral nerve involvernent and, (4)

myopathy (MacDermot et al. 1990). Supporters of the ectodermal defect theory daim that

the defect is primarily located in the brain involving the sixth and seventh cranial nerve

nuclei, with secondary muscle dysplasia (Mobius 1888. Rainy & Fowler 1903. Spatz &

Ullrich 193 1. Fenyes 1937. Sprotkin et al. 19%. Van Allen & Blodi 1960). Supporters of

the rnesodennic defect theory daim that the defect is prirnarily due to muscle aplasia leading

to secondary nerve atrophy and state that the high incidence of rnusculoskeletal anomalies

support this theory (Richard 1953. Evans 1935. Wallis 1960. Pitner et al. 1965).

Pathological evidence is scarce and contlicting (Hanson et al. 1971). There are thineen

reponed autopsies of blobius syndrome cases (Heubner 1900. Rainy & Fowler 1903. Spatz

& Ullrich 1903, Fenyes 1937, Richter 1958, Riggs 1958, Wallis 1960, Pitner et al. 1965,

Hanissian et al. 1971, Sudanhan & Goldie 1985, and Iaradeh et al. 1996). According to

Pitner et al. ( 1965). as of 1965 there existed only four undisputed histological examinations

of Mobius syndrome. These examinations were done by Heubner (1900), Spatz & Ullrich

(1931), Wallis (1960), and Pitner et al. (1965). Pathological repons by Fenyes (1937) and

Riggs (1958) were challenged by Henderson (1939) and Richter (1958) who believed that

the facial paralysis represented intrapartum brain-stem hemorrhage rather than a tNe

congenital anomaly (Pitner et al. 1965). Hendenon (1939) and Richter (1958) also

challenged Rainy & Fowler's (1903) case report stating that the obsewed facial paralysis

was due to trauma of both facial nerves by obstetrical forceps. Only autopsies reported by

Pitner et al. ( 1 965). Hanissian et al. ( 197 1). and Sudarshan & Goldie ( 1985) are known to

have examined both the brain and paralytic musculature (Table 3). Isolated examinations of

involved extra-ocular and facial muscles rvere reponed by Richards (1953). Yasuna &

Schlezinger ( 1955). Reed & Grant ( 1957). Van Allen Rr Blodi ( 1960). and Graham ( 1964).

but these authors had no opponunity to examine the brain (Pitner et al. 1965)

A completr review of the iiterature indicates that nuclear agenesis. with or without an intact

nrrve tmnk, intact nuclei with dysplastic or aplastic nerve trunk. or a pure muscle dysplasia

with an intact nerve tmnk and nucleus may be the pathogenetic rnechanism responsible for

Mobius syndrome (Hanissian et ai. 197 1) . Pitner et al. (1965) stated that the static course of

blobius syndrome is in itself indirect rvidence ajainst a degenerative process which would

be expected to continue into post-natal iife. Although Pitner et al. (1963) believed that

Mobius syndrome. in their report. was due to a primary dysplasia of the facial muscles. they

also stated that the histological observations of Heubner ( 1 WO), and Spatz & Ullrich ( 193 I ),

revealed a primary neuronal dysplasia. Mobius syndrome may have more than one etiology

and may involve the musculature derived from the branchial arches and/or the brain stem in

the same way that arthrogryposis can involve the musculature derived from somites and/or

the spinal cord (Pitner et al. 1965).

Table 3- Necropsy Reports

Pitner et al. ( 1965)

imdeh et al. ( I996)

and

abnormal crriniai nerves III. VI. Vil. XI and XII

rcmtiining iirrvts lacking or Ljegtl~~er~trd

Ioircr part oitncdulla u~idcrrlcvtIopcd

rn histologicril changes in nuclei ofcrriniül ncrvrs III. IV. VI. and VI1

central nrrvous systrm rtpofled as nornial

d l cranitil nsrvss apprrired nomal

increast. in subcutanrous t'lit \\.ith dmost total absence o i tlw ilicilil muscles

crrinial nrnres III. IV. Vi ahsrnt

v e n thin lüciül nervrs

rn mürksd symrnstricd hypoplasia oi' the pons ruid rnedulla

0 no evidence of degentmion or dy splasiü o i hct craniul nervr: nuclri but fewèr

nucki in the right h?po$ossal nervr

0 prripherlil muscles not esamined

0 craniiil nswes VII. IV. VI. XII i ib~rnt

nurnbcr oi' neurons in al1 crlinial n w e nuclri were comparrible to u sirnilx

ape control

no rvidrncr of degrnerition t'oiind but the Ict't side ot' the toneue.

strrnocleidornüstoid. pectord. m d h c i d muscles displuyd adipose changes

simillir to Pimer et al.'s case ( 1965)

mild enlu-gernent of the vcntricular s'stati and a hypopliistic appezirrincr of

the Io\\.er brriin s t m

rnidline necrosis and ctilcitictition within thc tlaor o i the J~ ventricle ivith

mild @sis

nuclri of ci-mial nenres UI. IV. V. VI. and ViI intact. necrosis in the media1

longitudinal fasciculus ünd genu of the facial nenre

O no miçmscopic svidence of rnyopathy

O relative hjpoplrisia of riIl c m i a i ncnve nuclei at the mzdulla and pontinr

Ievrls

detailrd muscle esamination not p r r t ' o m d

o çerebral htmispheres normal but atrophie bnin stem

absent abducens nmfe ruid nudei

0 facial nrrvr a p p w r d strophic

Etiology

The etiology of the suggested pathogeneses remains unclear. Environmental and heredi tary

mechanisms have been proposed (Table 4 a .b. c).

(i) fiiviru~rrnrnfnl

Mobius (1888) believed that the syndrome was due to a degeneration of the brain-stem

caused by a toxic insult, while Reed Rr Grant (1957) considered a developrnental defect of

the cranial nuclei and the posterior longitudinal bundle. Cranial nerves III. V (motor), VI,

VI!, and XII al1 lie in close proximity in the floor of the founh ventricle. A noxious

influence acting upon these nuclei, in such a restricted area, could account For many of the

manifestations of Mobius syndrome (Carr et al. 1997). Rubin ( 1 976) suggested

1 influences during the development of the fetus and listed "culprits" such as

, drugs, aicohol. smoking or poor placental placemenr. Rubin (1976) also

environmenta

bacteria, viri,

hypo thesized that a built-in hormonotrophic influence "_rone astray" could trigger an

ectodrrmal or mesodemal rnaldeveloprnent. Elsahy (1973) reported a case of Mobius

syndrome in which the mother took Thalidomide during her pregnancy. but Cwach et al.

(1997) described materna1 ingestion of Thalidomide as a separate etiology of congenital

bilateral facial paralysis. Bouwes-Bavinck & Weaver (1986) proposed that Mobius

syndrome results from an interruption of embryonic blood supply by premature regression,

obstruction, or disniption of the primary trigeminal arteries prior to the establishment of

sufficient blood supply for the brain stem and that the extent and nature of the associated

defects was dependent on the specific locations of vascular insufficiency. Harbord et al.

(1989) described a child with Mobius syndrome who also had unilateral cerebellar

hypoplasia and suggested that the abnomalities were secondary to a vascular disruption

involving the basilar artery between 33 and 40 days of gestation. Lipson et al. (1990)

indicated signiticant events of pregnancy in eight of fifteen cases including hypothermia,

electric shock, failed abortion, previous uterine surgery, prolonged rupture of the

membranes, and alcohol abuse. The use of Misoprostol, as an unsuccessful attempt to

terminate pregnancv. has been associated with an increased risk of Mobius syndrome.

Pastuszak et al. ( 1998) identified 96 infants with Mobius syndrome born between 1990 and

1996 from 7 hospitals in Brazil. Forty-seven of the 96 rnothers (499'0). of infants born with

illobius syndrome. had used Misoprostol in the tirst trimester of pregnancy.

(ii) Hrredilory

Xccording to Baraitser (1977). Terntany & McKusick (1978) and Legum et al. ( 198 1).

Mobius syndrome has a heterojeneous etiology . Genetic studies have supponed the

heterogeneity concept in that both autosomal dominant (Fontanier & S pejer 193 5. Harrison

& Parker 1950. van der Wiel 1957, Krueger & Fredrich 1963, Hanissian et al. 1970, Masaki

197 1. Ziter et al. 1977. Stabile et al. 1984, iblacDermot et al. 1990) and recessive pedigrees

(Thomas 1898, Cadwalader 1922) have been reported. The recessive form of ilIobius

syndrome does not appear to be more severe than the dominant form (Legum et al. 1981).

An x-linked recessive trait has also been proposed by Joumel et al. (1989) who described

Mobius syndrome in two brothen and a male first cousin who were sons of sisters

(McKusick 1994). Mobius syndrome may be caused by mutant alleles at one or more gene

loci and the variable expressivity and decreased penetrance couid explain the Iack of clear

Mendelian inheritance patterns. Also, the association with other neuro-muscular and limb

bud disorders may be explained by the pleiotropism of some of these genetic mutations

affecting the developrnent of certain mesodemal structures (Legum et al. 198 1 ).

Ziter et al. ( 1977) reported the clinical and cytogenic data of Mobius syndrome on seven

family members from three generations. Karyotype analysis revealed a uniform

chromosome abnorrnality in al1 clinically affected individuals. Giemsa banding revealed a

reciprocal translocation between chromosomes 1 and 13. The authors admined that their

pedigree size was srnall and that the observations did not resolve the controversy

surrounding the pathological basis underlying the iMobius syndrome. Donahue et al. (1993)

found an association between chromosomes 1 and 1 1 in one individual with Mobius

syndrome. Slee et al. (1996) presented a 2.5 year old child with Mobius syndrome with a

deletion of chromosome 13q and proposed that a pene for Mobius syndrome was located on,

or near. band q12.7 on chromosome 13, Kremer et al. (1996). described the performance

linkaje analysis in a large Dutch family with autosomal dominantly inherited Mobius

syndrome. These authors excluded Slee et ai's (1996) candidate region for Mobius

syndrome on l3q 12.2-q 13 and localized the gene to chromosome 3q2 1-22. indicating

jenetic heterogeneity. According to Nishikawa et al. ( 1997). almost al1 of Kremer et al.'s

(1996) subjects had unilateral Facial paralysis which diffus from the phenotypes described

by Ziter et al. (1977) and Slee et al. (1991). Nishikawa et a h (1997) report of a 15 month

old male with Mobius syndrome described a reciprocal translocation between the short am

of chromosomes 1 and the long arm of chromosome 2. The karyotypes of the parents were

nomal, indicating that the translocation was de rtovo. Despite the chromosome

investigations on reponed cases o f Mobius syndrome, the chromosomal abnonnalities in

these individuais remains unclear.

Table 4 a: Environmental causes of Miihiuu spdramc Mohius 18XX * clcgtncmtion ot'hmin-stcrii crtusrd by tosic insult Rcrd A Graril 1 'J57 r dcvclopnicntrtl dtiïtxt in crdnitrl nuclcii and posicnor

Iongitmiiniil hiindlc. criiiscd by nosioiis inllucii~rs EIsdiy 1 Y73 * llialicloini~l~. during prtgiiaiic y Rubin 1976 * ciivironnirntd intlucnces during drvclopmrrit o i the ktus

{hacteriü. vin. aicohol. smoking. poor placcntiil plriccmrlnt ) BOUN es-Bav irick dk Wwvrr I 986 * interruption of embnonic bloocl suppl y b y premature regrrssion.

obstruction. or di sruption of the primüry trigeminal artcrics prior to establishment ol' siitticient blood suppl! for the bmin

Hrirbord ct al. iLHY vcisculrir disniption Lipson clt ai. ! LNO sigtiific:int txsnts JuRng pregnitnc?. such ris hpxhemiiri.

&ctric shock. L'tiilcd ribort~on. prrtViolis utcrine surgep. proIorigd nipturt. o i mrmbrmes. B I I ~ alcohd abuse

Pristiisztik cf d. I 998 * use ot'h.lisopro~fol in tint trirnestcr oi'pregnrinc!

Table 4 h: Cenctic cases of hliibius syndrome

imilial Iiistcirirs in 3 crises Sh cast.s in 6 grnerdtiotis 3 grnerations ol 'aifectd mmhers mo~iozygot ir: hvtns 3 c.3st.s in 2 grneration 7 uses in 3 2cnt.mtions -7 cascs in one tiniily inothcr KL son. mothcr's itiatcrn~l aunt ml sou

S-Linked Joumri et al. 198Y 2 brothers & male cousin (sons oisistrrs)

Table 1 c: Proposed location of gene for Miibius syndrome Zitrr et al. I Y 7 7 recipmçal trrinslocation betwesn chromosomr 1 k 13 Slse et al. 199 1 * 13q12.2 Donahue et al. 1993 recipmcal ~rmslocrition brnveen chromosome 1 k I I kernr r et al. t 996 -3 (11 bq22 Nishikma et ai. t 997 * reciprocd rmsiocrition bchveen chromosome 1 2

[

According to Kumar (1990). malformations of the orofacial complex rnay be present in

Mobius syndrome and their presence may aid in the diagnosing the syndrome. Detailed

descriptions of the craniofacial rnorphology and malformations of the orofacial cornplex are

extrernely rare despite their inclusion in the diagnostic criteria. The craniohcial morphology

can be described in terms of nerve and muscle involvement, soft tissue assessment, facial

anomalies. oral manitèstations. skeletal morphology. and dental malocclusions.

(i) Nerva-

The cranial nerves affected in blobius syndrome include cranial nerves III, IV, V (motor),

VI. VII, VIII, LX. .Y. XI, and XII. Cranial nerve VI1 is always affected to some degree, with

cranial nerve VI beins the second most cornmoniy affected (Kumar 1990, Carr et al. 1997).

According to von Zimrnerman (1966), taste and lacrimation are usually normal. The

hypoglossal nerve is the third most frequently involved nerve and is affected in

approxirnately 75% of the cases (Van Allen and Blodi 1960). The extent of the cranial nerve

involvement determines the clinical manifestations observed (Table 5). The incidence of

cranial nerve involvement from Engler et al.'s (1979) review of 106 cases and Carr et A.'s

(1997) review of 156 reported cases is listed in Table 6 and 7 respectively.

17

Table 5: Sumrnary of Crinial nenes and associrited funcrions (Liebgott 1986. Wilson-Pauwels et al. 1988)

N e ~ e .. . ' 1; Fùnction .. . , . - .

. - r - Olfacton (1) 1 Scnsc of siiicll

1 Parxynpalhetic supply to cilia? and pupillaq constrictor niuscles Trochlcar (IV) * [ r Motor supply to supenor oblique Trigeniinal (V) * 1 r Moior to niiiscles of mastication (V3) tensor tynipani. tensor palati.

- . 1

1 mierior belly of digastric. and rnyloh~oid muscle

Optic ( I I ) Oculoniotor (Ill) *

1 r Estcroceptive: skin of ihc bcc. oral :uid nasal iiiucosa. iiieningcs. ;ind

' Vision Motor to al1 csu-aocular rtiusclcs csccpt supenor oblique and lateral recrus

- Pmqrnpathetic nipply to ail glands of the head escept the parotid and intcgunientriry glands

Abduccns ( IV) * Facial (VII)*

9 Proprioccpti\~c: pcriodontiurii. pallitil1 niucosri. niusclcs of niristicrition. and teiiiporoiiiiindibulrirjoint Motor to Iiitcrril rcctus nitisclc

r Motor to niiiscles of Fxiril expression. platymi. stylohyoid. posterior bclly of digastric. and siapedius muscle

(LW * 1 r Parasympathetic supply to parotid gland

Vsstibulocochlear (VIII) * Glossop h;in-ngeal

1 a Sensoq recepton in die skin of the riuncle. iiiiicous nienibnne of

- Cutanco~is rcceptors in conclia of aiiriclc œ Triste rmtcrior Zi3 of tonguc 0 Balancc

Hcriring - blotor to sty lophaqngcus tnusck

1 postcrior l/3 of tongiic. pliiu)ns and rniddle ur

1 supenor. niiddle. infenor constrictor n~usclcs of the pliüqms. Vagis (‘O*

1 palatoph;uygeiis. levator palaii. palatoglosnis. and inuinsic muscles of

œ Tastc postcrior 213 of totig~~c œ Supplies ; i l1 ~ t n i i t ~ d niusclc supplicd by the branches of the ~ a g m n e n c

1 r Sniooth iiiuscle of rlic broncliinl trce. hcm. stomacli. srniil1 and large intestine up [O die lcft colic llesurc. sccrctornotor fibcrs to glands of the respintory and digestive systems

1 r Senson reccptors in the meninges of the postcnor manial fossa. skin of

1 the estenial auditory nieÿtus. mucous membrane of the 1-nx and

1 viscemrecepton of the lhoncic and abdoniinal riscen

pliuyns- pa l a top l~~ngeus nluscle. levator pa1ati muscle. palatoglossus muscle. and intrinsic muscles of the I q n s

Accessory (XI)* œ Taste receptor arowid the inlet of the l w n s and epiglottis œ Cranial portion: superior. middle. inferior constrictor muscle of the

palatoglossus Hypoglossal (XII)*

Spinal portion: stemocleidotnastoid and tnpezius muscle Motor to inuinsic and esuinsic muscles of the tangue escept

Table 6: Engler et al.'s (1979) distribuiion of cranial nenle pafsies in 1116 rcportcd cases of Mobius syndrome

Cranial Nerve Palsies C m i a l Nervc VI1

Cranid Ncrvt. VI Cranid Ncrvc 111 Cranid Nervc XII

Cranid Nerve VI1 unil3tcd Cranid Nene VI bilaterd Cranial Nerve VI u n i l a t d

Percent of Reported Cases 10094,

6 i '4

23%

22%

Cranid Nervc: IX Cranial Nerve XII Cmid Nerve X C m i a l Nervc I I I Cranid Nerve IV Cranid Nerve V

Table 7: C m et sl.'s (1997) distribution of cnnial ncnc palsies in 186 rcponed crises of Mobius syndroiiie

(ii) hhrsc./e.s

a) Muscles of facial expression

The muscles of facial expression are derived from the second branchial arch and are

supplied by the facial nerve (cranial nerve MI). The muscles of facial expression are found

within the superficial fascia around the facial orifices and have two basic functions: 1 )

dilators and sphincters controlling the openings of the orifices, and 2) movers of the

overlying skin enabling various facial expressions to be perfoned (Liebgott 1986). The

elevator of the upper eyelid and the muscles of mastication are the only muscles of the face

that are not innervated by the seventh cranial nerve. (Rubin 1976) The muscles around the

mouth lips, cheek. chin. nose. eye, and forehead and their associated actions are listed in

Table 8.

According to Kumar ( 1990). complete or partial congenital facial nerve paralysis is essential

for the diagosis of Mobius syndrome. The facial paralysis is non-progressive (Mitter et al.

1983) and may be unilateral. but is more typically bilateral (Kumar 1990). The incidence of

bilateral and unilateral facial paralysis was found to be 85% and 1596 respectively in Carr et

al.'s (1997) review of 186 reponed cases in the literature. The lower pan of the face is

usually less affected than the upper part if the paralysis is incornplete (Henderson 1939.

Edgenon et al. 1975). Xccording to Henderson (1939), the frontalis muscles are most

constantly paralyzed. whereas the muscles which draw the corners of the mouth ouward and

downward. including the platysmae. mav be spared. The peri-orbital muscles are usually

cornpleteiy affected. but may occasionally contain a few tiring fibers.

Electromyography results reponed by Hellstrorn ( 1949). Van Allen & Blodi ( 1960). von

Zimrnerman ( 1966). McHugh et al. (1969). Olsen et al. ( 1970). Masaki (1 97 1). and lamal et

al. (1988) have shown little if any evidence of electrical activity in the facial muscles.

b) Muscles of mastication

The muscles of mastication are derived €rom the first branchial arch and are supplied by the

motor component of the trigeminal nerve. The muscles of mastication are comprised of four

main pairs of muscles attached to the mandible, as well as accessory muscles. These muscles

are responsible for elevating, protruding, retruding and moving the rnandible laterally

(Liebgott 1986). The muscles of mastication and their associated actions are listed in Table

9.

..MUSClee:.-- ---.---- . - --+ > . ,' . . A&On,--f-f. - . . --.. - . -.- CI -- ... < . .-W. .-. -*. . . a. . \ .- -. . ... . .. - <-..-_ . * ., .+ % , .' " - ,,.;. - . . . , . . . + .

Obicularis oris compresses lips against anterior teeth. closes niouth. prouudes lips 1

Dcpressor anguli oris 1 depresses angle of mouth 1 1

Levator anguli oris 1 elevatcs angle of mouth I 1

Zygomaticus m j o r 1 drarvs angle of rnouth up and back 1 1 Zygomaticus minor

I

1 cir-ws angle of mouth up I 1

Risorius 1 draws mgle of mouth latenlly 1 1

Levator labii mpcnoris 1 elevates uppcr lip. flares nosuil 1 I

Depressor labii inferions 1 depresses lotver lip 1 I

Buccinator 1 compresses dieek against rnolar teeth. sucking and blowing 1 1

klentalis ( pucken skin of chin. proinides lower lip 1 1

Nasalis 1 cornpressor n m : compresses. dihtor nÿres: flares nosiril 1 1

Orbiculriris ocitli ( orbital: closes eye forcefully. palpcbnl: closcs eye gently 1 1 Procrnis 1 u i i s e r s e rvrinkling of bridge of nose I

Comgator 1 ~rrtical wrinkling of bridge of nose

Fronirilis 1 pulls scalp up and bnck 1 Ysma Pht- 1 tenses skin of neck. ciids in depression of niandible

Table 8: bluscles of the hcc inncnated by crmial nen7e VI1 ruid associated actions (Liebgott 1986)

1 Mssseter 1 elmation. prouusion. remsion and ipsilateral excursions 1 1

Temporalis 1 elevation. retrusion and ipsilateral escursions

1 Medial Pterygoid 1 elmation. pminision and contralateral escunions 1 1

Lateral Ptelgoid 1 pmtrusion. depression and conm1atenl excursions 1 Table 9: Muscies of mastication innervrited by cranilil neme (V) and rtssociated actions (Liebgott 1986)

(iii) Sofi Îis~mes

Individuals with Mobius syndrome are described as having a high nasal bridge (Reed &

Grant 1957) which extends down to include the nasal tip resulting in a midface prominence

(Gorlin et al. 1990). The prominent upper lip and prominent and everied lower lip is a

striking feature in adults (Henderson 1939). Lip incompetency has been reported by Chester

& Zuker (1992). Whether the lip incornpetency is associated with excessive incisor

protrusion, or an increased vertical face height growth. has not been investigated (Figure 1 a,

1 b).

Evans ( 1 955), Reed & Grant ( 1957), Elsahy ( 1973). Sugarman et al. ( 1973). Federman et al.

(1975). Wedgwood (19781, Gutman et al. ( 1973). Meyerson & Foushee ( 1 978). Hopper et

al. ( 1 985), Legum et al. ( 198 l) , Parker et al. ( 195 1 ), Sudarshan et al. ( 1985). Rubin ( 1986).

Kuhn (1988). Harbord et al. ( 1989). Joumel et al. ( 1989). Koroluk et al. ( 1989). Slee et al.

(199 1 ), Donahue et al. ( 1993), Jaradeh et al. ( 1993). and Sherer & SpafFord ( 1994) reported

a micrognathic appearance of the mandible. but these were soft tissue assessments.

(iv) Fac*icd A,iomo/ies

Extemal ear defomities. hypenelorism, and epicanthic folds have been reponed by Gorlin

et al. ( 1990).

Figure la: Mobius syndrome - frontal vietv Figure Lb: Mobius syndrome - profile view

Ornl Mariifk-infiorls

Henderson (1939) listed bifid uvulas as an associated feature of the syndrome, but this

feature was only observed in 2 of the 61 cases he reviewed. Cleft palates were reported by

Meyerson & Foushee ( 1978)- Bergstrom et al. ( 198 1 ), Sudarshan & Goldie ( l985), Donahue

et al. ( 1993). and Jaradeh et a1.(1996). Microstomia was reported by Meyerson & Foushee

( I978). Gorlin et al. ( 1986) and Rizos et al. ( 1998).

Henderson ( 1939). Meyerson & Foushee ( 1978). Slee et al. ( 199 l ) , and Sherer & Spafford

(1994) observed high arched palates. Slee et al. ( 1990) observed a small tonsue with

hypoglossal weakness. while Sherer & Spafford ( 1994) observed a normally proportioned

tongue. The extent of rnaxillary constriction and the relationship to the presence or extent of

tongue hypoplasia or paralysis h a not been investigated.

Speech. feeding and swallowing difficuities rnay occur as a result of hypoglossal (XII).

trigeminal (V). glossopharyngeal (IX) and vagus (X) nerve involvement. Unilateral tongue

hypoplasia is more frequent (Evans 1955), but bilateral tongue hypoplasia c m occur (Evans

1955, Reed & Grant 1957, Hanissian et al. 1970). Speech may be defective due to the

involvement of the lips, tongue, palate and larynx (Evans 1955). According to Chester &

Zuker (1992), speech is always affected to some degree. Patients are usually unable to

produce bilabial sounds due to their lip incompetency. The hypoglossal nerve involvement

with resultant tongue hypoplasia leads to restricted tongue rnovement and affects vowel

sounds. Speech may be affected by velopharyngeal incornpetence caused by

glossopharyngeal paralysis alone or in combination with paralysis of the vagus and

accessory nerves. Paralysis of the tensor veli palatini muscle may lead to chronic otitis

media and further affect speech development. The incidence of mental retardation is

approximately lO?/o. but is typically overestimated due to the child's lack of facial

expression and poor speech (Chester & Zuker 1992). Sucking and feeding problems usually

persist into childhood. Affected children may be bottle fed to a later than normal ase due to

their feeding and sucking difticulties, and nursing bottle caries may result (Koroluk et al.

1989). Poor growth may occur due to poor feeding during the first years of life (Godin et al.

1990).

(vi) Skr le ta/ C7muiofncic~l iL101pholu~

The craniofacial rnorphology associated with Mobius syndrome has not been established via

controlled cephalornetric studies. The inclusion of micrognathia has persisted although this

inclusion has not been substantiated by the literature. Also. the inclusion of micrognathia has

been based on clinical soft tissue examinations rather than cephalometric skeletal analyses,

and micrognathia was most often reponed from soft tissue profile assessrnents of younger

individuais.

The etiology of the reported micrognathia has not been investigated although Smith (1976)

and Jones (1988) reported that the observed micrognathia in Mobius syndrome was not a

primas, dysmorphic feature but rather secondary tu a neurological defect in the early

movement of the mandibte in utero.

Micrognathia has been listed as an associated feature of Mobius syndrome by the following

authors (Table 10):

I I 1 occurs. but Ins frcquentl! hm 0 t h 1

Reîierence +- -7 :: - .--

not referenced

1 ~ederman et al.

; Mierognatbia in Mabius Syndrome. .: :, * micrognathia is an momaly which

:- Apthov: . - -.*' A !.bar "

Pitner et al.

Gutman et al.

Reed & Grmt

* States that nian! riuthors have dcscribed patients with mmdibuar

1957

1965

t 973

* retrognülhiri is an lissocirited rinonialy I tg7 j 1 inMdbiusswdroriie

not refcrcnced

Godin et al. 1964

associated anomalies rnicrognathia is a deformity associated with Mobius syndronie

* the underde\.elopnienr of Lfic nirindible could be relittcd to tlic parcsis

not referenccd

not refcrenced

Banitser

Meyerson & Foushee

Sugarmrin & Stark

Wedgwood

1 1 1 Mobius svndrome 1

1977

Engler et 31.

1978

1973

1978

defomiities nich as micrognathia * micrognathia is an associated feature

of Mobius svndrome

1970

/ Bergstrorn ci al. * niicropatliiri is an mociatcd t'cmre 1 14" 1 of Mdbius iyndronie

Table 10: Statements of micrognathia in Mobius syndrome and respective references

not refercnced

* mandibular hypogencsis is a fcaturc of Mobius syndrome

* micrognaihia is an associatcd abnorniality in i'vlobius syndrome

* micrognathia is a clinical

Gorlin et al. 1976

Gorlin et al. 1976

not referenced

Henderson 1939 manifestation in Mobius syndrome

* micrognathia is an associrited defcct in

Hopper et al.

Bccrbowcr et al.

Jones

Gorlin et al.

Kurnar

Sherer & Spafford

Kremer et al.

Rizos et al.

not rcfcrcnced

* micrognathia is an associated rraniofacisl anomaly in hdobius syndrome

* micrognatiiia is an associatcd fcature of Mobius syndrome

* micrognathia is an associated feature of Mobius syndrome

* maridible is frequenily mildly to moder~tely h)popiastic

* rnicrognathia is a malformation of the orofacial structure which may be present and aid in the diagnosis of Mobius qmdrome

* Mobius syndrome is frequently acconipanied by micrognathia

* micrognathirt and other mriiformations of the jaws as orofacial maiformations present in Mobius syndronie

* micrognathia is a sign associated with Mobius svndrome

1985

1986

1988

1990

1990

1994

1996

1998

Gorlin et al. 1976

Pitner et al. 1965

not rcfcrenced

Evans 1955. Reed & Grant 1957 Gorlin et al. 1 YS6

Meyerson & Foushee 1978. Jones 1988. Mobius 1888. Henderson 1939. Richards 1953. Bmitser 1977. Kurnar 1990. MacDermot et ai. 1990 Sherer & Spafford 1994

Aithough Henderson (1939) has been cited as a reference for the presence of rnicrognathia

in individuals with Mobius syndrome, there was no description of the mandible in his

review of 6 1 case reports.

Godin et al. ( 1964, 1976. 1986, 1990) have been frequently cited as a reference for the

inclusion of micrognathia as a craniofacial manifestation of Mobius syndrome. They

described the mandible as mildly to moderately hypoplastic. Godin et al. (1990) cited Evans

(1955) and Reed & Grant (1957) as a reference for this latter statement. Interestingly

enough, Reed & Grant (1957) reponed micrognathia in the three cases they described and

stated that microjnathia was a developmental anomaly which occurred less frequently in

individuals with Mobius syndrome. Evans ( 1955) stated that micrognathia was not regarded

as a constituent of Mobius syndrome. Five of nine cases reponed by Evans (1955) were

described as having micrognathia at an early are. Threr of these five cases of micrognathia

showed improved growth of the mandible as the children matured. Evans (1955) felt that

significant mandibular growth was evident resulting in a "less obvious" degree of

mandibular hypoplasia. He also stated that mandibular hypoplasia might be expected to

occur with hypoplasia of the muscles, but that a coincidence of hypomandibulism may have

exis ted.

A review of literature of 186 case repons from 1888 to 1998 by this author (Table 11)

showed that micrognathia or retrognathia was reponed in 75 of the 186 reponed cases

(13.4%). Eighteen of the 25 subjects were exarnined at a young age (Table 12).

Table 11: Cmniofacial tisscssnients of 186 cises of Mobius syndrome reportcd in the litenturc

1 1988 F L 1989 F 7Jno 1 1989 \i habu 1 19R9 F 45 nio

\I son 1991 2-

tr 1932 F vrr

The normal fetal mandible at rest occupies a relative posterior or distal position and a

considerable increase in size is seen between fetal life and three years of age. Mandibular

yrowth then increases at a slow rate until adulthood (Scott 1961). The inclusion of

micrognathia, as an associated feature of Mobius syndrome, may be based on observations

of normal distally positioned mandibles.

1 Evans 1 Evans

Evans

--

Rccd & Grant Reed & Grant Sugman et al. Federman et al. Meyerson & Foushee Mcyerson & Foushee Leguni

loumel ct al.

.Year -.' 1

1955 1955

Gender b!

1950

1955

1957 1957

1973

b1 F

1975 1978 1978 1981

1994 I F 1 prenatal 1 inicrognathia

Age 10 weeks

M bl F F M

Table 12: Reports of micrognathic or retrognathic mandibles in Young individuals with Mobius syndrome fiom 1888 - 1998. 18 of 25 reports of micrognathia in 186 case rcports of Mobius syndrome

Description of theMandiMe . ' ; ' . micrognrithia

4.5 years LO weeks

M M M F

1

Engler et al. ( 1979) listed micrognathia as an associated feature of Mobius syndrome. They

reviewed 106 cases reponed by Fontanier et al. ( 1 939 , Henderson (1 939), Hicks ( 1 943).

Danis (1 945). Murphey et al. ( 1947), Van Buskirk ( 195 1 ), Stansbury ( 1952). Richards

(1953), Evans (1959, Nisenson (1955), Sprofkin et al. ( 1956), Reed & Grant (1957), Van

micrognatliia micro grtathia

J weeks 5 months 3 years 2.5 yc,m 5 y e m

nc\t8born 45 niontlis baby 2.5 !.en 3 v e m

1985

1989

1989

1991

3

- micrognathia micrognathia moderate micrognathia ~narked micrognathia micrognaiiiic

3 y e m

2 years 6 y e m babv -

micrognilthic small mandible microreirognnthia micrognathic micro-gnathic & reuognathic

? F kI F F

retrognathic 4

mi1d micrognrithia mild micrognaîhia

, modemtely micrognathic

Allen & Blodi (1960), Masaki ( 197 1). and Becker-Christensen & Lund (1 974). Of the 106

cases of Mobius syndrome, 6% (approxirnately 5 cases) had micrognathia. These five cases

were those described by Evans ( 1955) and Reed & Grant ( 1957).

Sherer & Spafford's (1994) case report consisted of a prenatal sonographic examination of a

fetus with Mobius syndrome. The sonographic examination revealed micrognathia. The

infant also had respiratory difficulties which was thought to be secondary to the

micrognathia.

Except the three cases reponed by Briggs (1965) Gutman et al. (1973). and Rizos et al.

(1998). assessments of mandibular position and size were performed clinically without

radioçraphic analyses. Mcrognathia continues to be listed as an associated feature of

Mobius syndrome despite the lack of controlled clinical and radiogaphic studies. Analyses

of the actual size and position of the mavilla and mandible are currently lacking. Clinical

observations of "micrognathic" mandibles rnay be misleading, especially for examiners who

are not familiar with the potential variation in position and size of the mandible. When the

skeletal components of a Class II malocclusion are measured and assessed on cephalometric

radiographs, one may observe: (1) a micrognathic or retrognathic rnandible with a normal

size and/or positioned rnaxilla, (2) a normal sized and normally positioned mandible with a

proynathic mailla, (3) a normal shed mandible rotated downwards and backwards or, (4) a

combination of the above (Woodside 1976) (Figure 2).

Figure 2: Skrletal Components of Clxs I I klalocciusions (A) micrognathic or retrognathic mandible. (B) prognathic midface. (C) normal simd mandible rotated downward and backwrud, (D) Combination. Adripted from Woodside: Ccphalometnc Roentgenognphy. p 6. 1976.

Class III skeletal patterns have been described by Thomas ( 1898). Briggs (1965) and

Chester & Zuker ( 1992). Thomas ( 1898) described a 19 year old male with a prognathic

rnandible and a negative overjet who undenvent a bilateral mandibular osteotomy in order to

improve the patients lip incompetency. Briggs ( 1965). described an eight year old female

with a "de finite skeletal Class III" malocclusion. Measurements to assess the vertical

dimension were not included in Briçgs' ( 1 965) cephalometric analysis.

Due to ( 1 ) the lack of controlied cephalometric studies. (2) the inclusion of micrognathia

being based on soft tissue assessments. and (3) micrognathia being reported more frequently

in newboms, infants and young children, furher comprehensive cephalometric studies are

required.

vii) Dr n t d Mai m.*c/usion

Various dental malocclusions in individuals with Mcbius syndrome have been reported.

Case reports by Wedgwood (1978) and Gutman et ai. ( 1973) described Class II

malocclusions, whereas Briggs (1965) described an eight year old female with an Angle

Class I malocclusion on a Class 1 to mild Class 111 skeletai base. Chester & Zuker (1992),

described two cases of Mobius syndrome with Class I I I malocclusions and stated that this

type of malocclusion was not usuaily associated with blobius syndrome. Maxillary incisor

prominence and linguoversion of the rnandibular incisors were observed in Federman and

Stoopack's (1975) case repon. while an anterior crossbite was seen in Briggs's case report

( 1965) F o g ~ ( 1980) described a 17 year old kmale with excellent occlusion. while Rizos et

al. (1998) described a 17 year old fernale who had multiple congenitally missing primary

teeth and was also congenitally missing the Following teeth: 1 . 1 , 1 2, 1.3, 3.1, 3 2, 4.1, 4.2.

1.3. 1.8. She also had a Class II molar relationship on the right and a Class III molar

relationship on the left along with a 12 mm anterior open bite and bilateral posterior

crossbites.

Other Fentures

Oczrlar rVercv Palsies

The ocular involvement of Mobius syndrome includes bilateral or unilateral ocular nerve

palsies. The abducens nerve (VI) i s the most commonly involved ocular nerve with the

trochlear (IV) and oculomotor (III) nerves being affected less frequently (Kumar 1990).

Lim b Mai furmat iom

Limb malformations such as syndactyly. brachydactyly, absent digits. hypoplasia of digits,

and talipes are often present in individuals with Mobius syndrome (Henderson 1939.

Richards 1953). In Engler et a l . 3 ( 1979) review of 106 cases of Mobius syndrome, 28%

had associated limb anomalies and according to Temtany et al. (1978). club foot is the most

common limb malformation with the Requency being approximately 33%. According to

Baraitser (1977). limb malformations must be included in the diagnostic criteria of Mobius

syndrome. Based on his observations in 15 subjects, along with 50 subjects previously

reponed in the literature. Baraitser ( 1977) cnncluded that when the definition of Mobius

syndrome included skeletal malformations. the risk of the offspring having similar

characteristics was approximately 2%. According to MacDermot et al. (1990). a higher

recurrence risk of 25941 to 30% seems reasonable when skeletal defects are absent.

Orhrr il~l~i.scrrio.~~ke/ti~~~/ .-lrror~in/ie.s

According CO Kumar (1990). anomalies of the niusculoskeletal system such as Klippel-Fei1

anomaly, absence of the sternal head of the Pectoralis muscle. rib defects, and branchial

muscle defects may be associated with Mobius syndrome. Poland syndrome has also been

associated wi th Mobius syndrome. This corn bination has been referred to as Poland-Mobius

syndrome (Hopper et al. 1985). Poland-Mobius syndrome is estimated to have a prevalence

of 1:500.000 (Hemnann et al. 1976) and is manifested by bilateral paralysis of the sixth and

seventh cranial nerves. absence of the Pectoralis major muscle. and ipsilateral hand and digit

anomalies (Hopper et al. 1985).

Radio~ra~hic Findines

According to Beerbower et al. (1986). CT scans are useful in evaluating the features of

Mobius syndrome and may be used to document any malformations that indicate a more

extensive CNS process not clinically evident in the newborn. CT scans can aid in the

identification of concomitant brain malformations and exclude possible treatable or

progressive disorders such as infection. hemorrhage. trauma. hydrocephalus. or tumors that

could mimic Mobius syndrome. Most patients with blobius syndrome have normal CT scans

except for the media1 gaze of the eye as a result of' the lateral rectus paralysis. One would

expect no characteristic brain findings with CT scans given that the fundamental

pathological lesion remains unknown (Kuhn 1988).

According to Kuhn ( l988), congenital anomalies of the branchial musculature and

extremities including talipes equinovanis. digital anomalies. congenital hip dislocations,

unilateral hypoplasia or aplasia of the pectoralis musculature, S-shaped scoliosis. and

anhrogryposis have been observed radiographicall y, but the spectrum of radiological

findings in EvIobius syndrome has never been iilustrated

Cephalometric analysis results in a quantatative examination of craniofacial growth and

development (Steiner 1953). Although lateral cephalogams were taken on the three cases

reported by Briggs (1965), Gutman et al. (1973), and Rizos et al. (1998), there are no

controlled cephalometric studies describing the craniofacial morphology of individuals with

Mobius syndrome. Briggs observed a "definite skeletal Class III" malocclusion while

Gutman et al. ( 1973) described a micrognathic rnandible. Rizos et al. (1998) described a

Class II skeletal apical base relationship with a hyperdivergent growth pattern. Gutman et al.

( 1973) also observed a rather small appearing sella turcica with an enlarged anterior and

posterior clinoid process partially connecting the saddle. The Findings described from the

skull series performed on Sugarman & Stark's case (1973) showed an average size cranial

vault with the sella turcica having a normal appearance and the mandibular angles were

described as "quite obtuse". Although ail three subjects reponed by Reed & Grant ( 1957)

were clinicall y described as having micrognathia, the skull radiographs were described as

normal.

Sureical Interventions

i) Oi'r l~o.~~inthi~~ S ~ q q v

Thomas ( 1898) described bilateral rnandibular osteotomies to correct a prognathic rnandible

while Gutman et al. (1973) described an individual who underwent an Obwegeser sagittal

osteotomy with anterior repositioning of the mandible and chin to correct a retrognathic

mandible. Gutman et al. (1973) described an individual with Mobius syndrome with the

muscle of mastication also being affected. Although the individual described by Gutman et

al. (1973) had an "elongated face", mavillary impaction was not performed. The incidence

of orthognathic surgery and the incidence of surgical relapse due to the paralytic

musculature, is unknown.

ii) Sirraen> for Rranirnntioii

Facial reanimation has always been an important issue with Mobius syndrome. Early

corrective procedures for paresis of the facial muscles included static suspensions of the lips

and nasolabial folds. Materials used included fascia from the thigh. srainless steel strips. and

silicone ribbon. The surgical results were static and immobile and had minimal effect on the

patients blank. fixed facial expression (Rubin 1976).

In 1933. Gilles transplanted the anterior portions of the temporalis muscle to activate the

nasolabial folds and the corners of the mouth. In 1952, McLaughlin detached the coronoid

process of the mandible and left the bones Fastened to the temporalis tendon. .A sling of

facia lata was placed around the lips in order to sirnulate an orbicularis oris muscle. This

sling was then insened into a hole in the coronoid process and was in mm elevated by the

entire temporalis muscle. McLaughlin's technique was prirnarily used in unilateral Facial

paralysis (Rubin 1976).

In 1 976. Rub in described bilateral tem poralis transplantation. with tem poralis facia as added

tendons. to activate the cheeks. upper lips. nasolabial folds and eyelids. Rubin's (1976)

procedure could only be used if the fifth nerve was present. Later, Rubin et al. (1986)

described his state of the art reanimation technique which included shonening or plication of

the weakened facial muscle and replacing individual degenerated muscles with strips of

temporalis, rnasseter and frontalis muscle. According to Rubin et al. (1986), the expectations

for obtaining good results with this technique were reasonable, but total reanimation

remained impossible.

Edgerton et al. (1975) described two surgicai techniques used for reanimation in the Mobius

syndrome patient. Edgerton et al. ( 1975) used muscle transfers from either the functionin~

platysrna muscle or the ternporalis muscle. Edgenon et al. (1975) believed that when

Mobius syndrome spared the platysma muscle. strong consideration should be given to using

this valuable tme "mirnetic" muscle.

Although facial movernents were achieved through local muscle transfer procedures such as

those postulated by Rubin et al. ( 1986). insufficient excursions with these techniques were

noted (Zuker Rr Manktelow 1989). .Accordin_r to O'Brien et al. (1980) and Tolhurst & Bos

(1982). the seventh nerve is the only nerve which provides the desired spontaneity of

activity with emotional expression. Zuker ( 1990). described a stage-setting cross-face nerve

graft in unilateral facial paralysis in order to provide seventh neme input to the affected side.

Innervation by a non-seventh motor nerve. such es the hypoglossal nerve (XII) or the motor

nerve (V) to the masseter muscle. was used in bilateral facial paralysis therefore spontaneous

and synchronous activity, along with ernotional expression of the transplant muscle, was not

possible. Intricate and complex movernents of the upper lip and commisure was not possible

with the utilization of a single muscle but asymmetries at rest were corrected by positioning

the muscles under appropriate tension. Synchronous and spontaneous movement of the

upper lip and commisure in the desired direction was also achieved (Zuker 1990). Although

absolute symmetry could not be expected. nor fine variations in expression, the muscle

activity resulted in a symmetrical srnile.

Zuker and Manktelow (1989) performed vascularized muscle transplantation in seven

patients with blobius syndrome (Figure 3. 4). Five patients had bilateral facial paralysis and

two patients had unilateral facial paralysis. resulting in twelve transplant procedures. A

single-fascicle functioning motor unit was used in al1 subjects. A gracilis muscle was used in

eleven transplants and a segment of the latissimus dorsi muscle was used in one transplant.

The facial vesse1 was used for revascularization in al1 twelve subjects. Reinnervation was via

the hypoglossal nerve in nine transplants, the rnotor nerve to the masseter muscle in two

transplants and a transfacial nerve graft in one transplant. According to the authors, eleven

of the twelve transplant areas demonstrated sufficient movernent to meet their initial surgical

expectations and muscle transplantation offered excellent potential for smile reconstruction

and improved social habilitation for individuals with Mobius syndrome (Figure Sa, 5b. 6%

6b).

Facial reanimation surgrry is ideally performed at age 5-6 years for psychosocial concerns

(Zuker 1990) An evaluation of the potential improvements in craniofacial qowth and

development is required if controlled cephalometric studies confirm an altered craniofacial

morphoiogy in individuals with Mobius syndrome.

Figure 3: Flap prior to placement of graciiis muscle

Figure 4: Superficial location of gracilis muscle

Figure Sb: MSbitis syidrome - m i l e a tkr right ~ ind Ieti gncilis transftr

Figure 6a: Mdbius syndrome - smile aArr right Figure 6b: Mdbius syndrome - srnile atler righr and leR gncilis tnnsfer

Conclusions

Mobius syndrome was first reported by Mobius in 1888 and approximately 200 cases have

since been reponed. Many questions regarding the syndrome remain unanswered. The

pathogenesis and the etiology of the syndrome continue to be debated. Autopsies have

indicated that the primary lesion may be of both ectodermic or mesodermic origin and,

environmental. as well as familial cases. have been reponed. Chrornoson~al studies continue

to search for the Mobius syndrome gene but differing opinions exist regarding its location.

The dental and orthodontic literature regarding Mobius syndrome is extremely rare. The

maloccIusion associated with Mobius syndrome has not yet been investigated and no

controlled cephalometric studies have been conducted in order to assess the skeietal

craniofacial morpholo~y The inclusion of micrornathia and midface prominence has been

based on anecdotal evidence based on soft tissue assessments.

Facial reanimation continues to be performed with expected success. but the potential

benefits for improved facial growth have not been assessed. Studies to compare the

craniofacial skeletal rnorphology OP non-reanimated to reanimated cases are indicated if

facial growth and developrnent proves to be affected by the paralysis involved in Mobius

syndrome.

STATEMENT OF THE PROBLEM

Mobius syndrome is a form of congenital paralysis of the muscles of facial expression due to

the involvement of the seventh cranial nerve. I t may also involve cranial nenies Ill, IV, V.

VI, VIII, IX, X, Xi, XII and their associated functions (Kumar 1990, Carr et al. 1997). There

are approximately 200 cases of Mobius syndrome reported in the literature (MacDennot et

al. 1990) but there have been no studies to determine the craniofacial skeletal morphologv.

Abnormalities such as micrognathia and midface prominence have been claimed as Features

of Mobius syndrome (Engler et al. 1979. Gorlin et al. 1990. Kurnar et al. 1990) but they have

been based on anecdotal descriptions with no supponing evidençe. Mobius syndrome could

serve as a mode1 to evaluate the effects of congenital paraiysis of the facial musculature on

the facial skefeton.

The influence on facial growth and developrnent. with the additional involvement of cranial

nerve V. has not been reported and the amount of vertical growth of the face has not

previousl y been considered.

Finally. if the craniofacial skeletal morphology of individuals with Mobius syndrome is

significantly different than controls, future studies are indicated to detemine whether gracilis

muscle transfer results in changes in the craniofacial morphology.

OBJECTIVES

The objectives of the study were:

1 . To determine the craniofacial skeletal rnorphology associated with Mobius syndrome. via

Iateral cephalometric analyses.

2. To describe the craniofacial skeletal morphology associated with Mobius syndrome

involving cranial nerve V. in addition to cranial nerve VU, via lateral cephalometric

analyses.

HYPOTHESES

1. The craniofacial skeletal morphology of individuals with Mobius syndrome is

significantly different than normal controls.

2. The craniofacial skeletal morpholopy of individuals with Mobius syndrome is more

severely altered if cranial nerve V is also involved.

M A T E W L S AND METHODS

Samplr

This study was cross-sectional and rerrospective. Thiny lateral cephalornetric radiographs of

individuals with Mobius syndrome were available for the study. Twenty-seven were obtained

from the Orthodontic and Plastic Surgery Depanments at The Hospital for Sick Children,

Toronto and 3 frorn the Orthodontic Depanment at the Montreal Children's Hospital.

Montreal. The diagnosis of blobius syndrome and cranial nerve involvernent were confirmed

through medical records. lnclusion criteria consisted of Caucasians with Mobius syndrome

wi th bilateral facial paral ysis who had cephalom etric radiographs taken prior to onhodontic

treatment. All had cranial nerve VI1 involvement while four had cranial nerve V involvement

as well (Table 13). The individuals with trigeminal nerve

separately as a subgroup for analysis. The primary samp

involvement were considered

le therefore consisted of 26

individuals with bilateral facial newe paralysis and the secondary sample consisted of 4

individuals with bilateral facial nerve and trigeminal nerve involvement. Details of age and

sex distribution are provided in Table 14.

Ten subjects had recently undergone gracilis muscle transfers by Dr. R.T. Manktelow and

Dr. R.M. Zuker at The Hospital for Sick Children. Toronto, Canada at or close to the time of

the lateral cephalometric radioyraphs but no later than 6 months (range: 3 days-6 months)

post-operatively to preciude any effects of the surgery on the skeletal morphology.

Control groups were randomly selected from a pool of 1632 normal individuals from the

Burlington Growth Center. University of Toronto. Canada. The primary and secondary

sarnple were matched for age. sex and race to 52 and 8 normal controls respectively (Table

14).

hk thocko/om

Lateral cephalometric radiographs, taken in occlusion. were used in the analysis. The

cephalometric radiographs of the sample were taken at the Hospital for Sick Children and

The Montreal's Children's Hospital. The cephalornetric radiographs of the control yroup

were taken from the Burlington Growth Study The enlargement factor at the rnidsasittal

plane was similar for al1 three cephalornetric units. Skeletal landmarks on ali lateral

cephalometric radiographs were identified. traced and dijitized using the Dentofacial Planner

7.0 software. Inter-examiner reliability of the traced cephaloyrams and the corresponding

landmark identification was performed in the Onhodontic Departrnent at The Hospital for

Sick Children. Intra-examiner reliability for digitization was also confinned through

intraclass correlation. .A total of 20 landmarks were identified (Figure 7) from which 30

angular, linear and proportional values were obtainrd (Figure 8 a. b. c). A description of the

cephalornetric measurements is located in Appendix A. The measured values are located in

Appendices B. C, D. E and the cephalornetric tracings are located in Appendices F and G.

The statistical analysis was performed in the Research Institute at the Hospital for Sick

Children using the MiniTab 12.0 Statistical Analysis Package and SAS 6.12. Repeated

measures analysis of variance for factors of age (0 - 1 1 .1 1 years, 12 years - 14.1 1 years, IS

years - 2 l years). sex (male and fernale). and group (Mobius and Control) were conducted. A

preliminary analysis of the data using Manova revealed no overall agdsex, sedgroup or

agelgroup di fferences therefore the sample was col lapsed into 2 groups. Subsequentl y a

Univariate Anova was perfomed on each individual measurement. A significance level of

p= 0.05 was applied to al1 analyses.

The prirnary sample of individuals with Mobius syndrome was assessed separately from the

secondary sample. Complete statistical analysis on the secondary sample yroup was not

performed due to the small sample size. but means and standard deviations were used to

describe aiid to compare the rneasured variables to their respective matched controls.

Table 13: Mobius sample listing gender, age. cranial nerve VI1 involvement *, cranial nerve V involvement *. and time of lateral cephalogram.

Sample Cender Age C.N. VI1 C.N. V Time o f Lateral Cephalogram

J.B. b1 4. X * prc-trcritmcnt P . F 5.6 * prc-treritmcnt K.M. F 6.4 * 5 rno post-op grricilis transfer M.R. F 7. J * pre-treatmen t D.D. M 7.4 * pre-treatment B.M. .M 8.0 * * prc-trecitment

T.G. F 8.4 * pre-treatmcnt E.S. kf 9.6 t prc-treritnicnt K . . F 9.1 l 1; 4 rno post-op gnciiis t m s k r T.W. F 10.6 t pre-treatmcnt C.G. F 1 1 . 1 1 * prc-treatment B.V. F t 2.0 * 3 rno post-op gncilis t m s f c r T.H. F 12.2 * pre-treatment L. P . kt 12.7 t prc-trcatmcnt R.C. ,CI 13.1 * 3 d a 3 post-op gracilis tr:msfcr R.K. ,LI 14.1 t pre-treritrncnt R.S. bl 14.3 1i: 4 mo post-op gncilis transfer W.M. ,LI 14.1 1 * * pre-treatmcnt P.R. hl 15.3 * 4 mo post-op gncilis transtkr A D .LI 15.3 t prç-trccitmsnt T.bI. ,LI 15.0 * J mo post-op gncilis transfer X.H. F 15.10 * 5 mo post-op gncilis transfcr J.D. F 16.6 * prc-trcritrncnt C M . kt 15.9 * prc-trcatment B.H. F 16.2 * 6 mo post-op gncilis t m s f e r K.H. F 16.3 * J mo post-op gncilis transfer H.M. F 16.7 * * pre-treatment

J.B. M 16. I l t * pre-treatment

C. S. .hl 17.1 * pre-treritment S.M. F 20.6 * pre-treatment

Table 14 : Sample and control distribution

Primary Primary Secondary Secondary Sample Controls Sample Con trol

Total number 26 52 4 S Overnll mean [years) Overdl range (years) Number of males Male mean age (years) Male age range (years) Number of females Female mean age (years) Female age range (years)

Ficure 7: Shelctal Ianilmürks on the Iütenil crpli;ilugram: S. sella. Fieurr Hu: Linru measurernenls on Iülrr~l sephrilogrnm: 1. S. nasion: .\. :\ point; B. F3 point; (in, gnlithiun; lie. nienton; ( i i i , I1;trvold m;isilIün lrngth (Co-Sn). 2 Flantild m~ndihii1;ir Iength gonion: .L. ~niciil;irr; Co. ~undvlilin; Ba. hasion; PSS. postcrior (Co-Ch). 3. fI;in.olJ nisxillün-mandihular unit lcngth ditkence. nasal .ipinc: :\>S. anterior nwd ïpinr: Sn. whnasüle; Sn' 4 Ba-PSS. 5 . PSS-.A point. o . C'o-Cio. 7. Gu-Cin. 8. Sri-Xlc. 9 .iuhnasdr'. ('IX uppcr incisor ~ p t s ; LIE. uppcr incisur dp: { ' F N IO. 1-FH. I l . [ ' t !O NF. 12. LI to JtP. 1.3. t ) v e r j e ~ 14. LI.4. loner incisot ripes: LIE. lowct inciser edgc: t'ti. uppcr tint iwrbitc. 15. I 'ci to SF. 16. 1-6 to )!P. 17. Ba-S;i molar edge: L6 I w r r tim molar dgr .

Figure Nb: . h g u l u mrrisurements on Ititenl crphülugmm: 1. SNA. 2. SNB. 3. ;\NB. 4. Ba-S-Sa. 5. gonial angle. 6. interincisa1 mgle. 7. 1'1 to NF. 8. LI to MP. 9. Ba-Sa-Co-(in. 10. Bo-Nd-.-\ point

Flrure Ilc: Roponiond measurrmcnrs on laiitnl cephalogram: C T H : LRI. L1 -me: Nri-mc

RESULTS

The intraclass correlation showed excellent digitization reliability (ICC > 0.99). thus there

was no significant intra-examiner error (Landis & Koch 1977). blultivariate tests of

agelsedgroup and their 3 way interaction showed significance of the main effects only. The

p-value for age, sex and yroup were 0.000 1 . 0.0007. and 0.0002 respectively. The interaction

p-values were 0.56 for ageisex. 0.47 for ayeigroup and 0.46 for sedgroup. The results of the

Univariate Anova for the skeletal landmarks of the primary sample (n=26) and control group

(n=52), aiong with the means and p-vaiues. are surnrnarized in Table 15. The means and

standard deviations for the skeletal landmarks for the secondary sample (n=4) and control

group (n=8) are presented in Table 16. The statistical data is located in Appendix H.

The laterai cephalometric analysis showed significant differences (p < 0.05) for I O of the 30

measured variables for the primary Mobius sample. The cranial base lengh (Ba-Na) was

significantly shoner (p <0.O 1 ) while the craniai base angle (Ba-S-Na) was not signitïcantly

different. In the anteroposterior dimension. the ANB angle was signiticantl y larger (p< 0.05).

The Harvold maxillary length to mandibular unit length difference was significantly smaller

(p< 0.05) but no siynificant difference was observed with SNA, S N B and Ba-Na-A point.

The Harvold mandibular length (Co-Gn) and the lower border of the mandible (Go-Gn) were

significantly smaller (p < 0.01) while the posterior border of the mandible (Co-Go) and the

gonial angle were not signi ficantl y di fferent. The Harvold maxi1 lary length (Co-Sn), Ba- A

point and pharyngeal space (Ba-PNS) were significantly srnaller (p < 0.05. p < 0.01, p < 0.01

respectively) but PNS-A point was not significantly different. With respect to the vertical

dimension, the upper face height (WH) was significantly shoner (p < 0.05) while the total

face height (Na-Me). lower face height (LFH). upper to lower face height ratio (UFH:LFH),

and the angle between the cranial base and the mandible (Ba-Na-Co-Gn) were not

signi ficantly different. No signi ficant differences were noted in the angular and l inear

measurements of the maxillary and mandibular incisors and first molars (U1 to NF

degreeslmm, L1 to MP degreesimm. overjet. overbite, interincisal angle. U6 to NF. L6 to

MP).

Due to the small sample size. statistical analyses were not performed on the secondary

sample, but several findings were noted. The cranial base length (Ba-Na) was also shorter. In

the anteroposterior dimension. no difference was noted in the ANB angle as compared to the

primary sample versus control. The Harvold mandibular length (Co-Gn). posterior border of

the mandible (Co-Go) and gonial angle were larger than the measured controls. The Harvold

rnaxillary length (Co-Sn). Ba-A point. PNS-A point and pharyngeal space (Ba-PNS) were

smaller and the Harvold maxillary length to mandibular length difference was larser.

Measurement in the vertical dimension ( Na-Me. WH. LFH. üFH: LFH, and Ba-Na-Co-Gn)

al1 indicated a more vertical pattern of growth. Measurements describing the angular and

vertical position of the maxillary and mandibular incisors and first molars (U1 to NF

degreedmm. L 1 to MP degrees/mm. U6 to NF, L6 to MP) indicated that the maxillary and

mandibular incisors were overempted but the rnaxillary and rnandibular first molars were

even more overerupted. This was also confirmed by the lack of overbite.

iii

DISCUSSION

There are approxirnately 200 cases of Mobius syndrome reponed in the literature

(iMacDerrnot et al. 1990) but there have been no studies to determine the craniofacial

skeletal morpholoyy . Abnormalities such as micrognathia and midface prominence have

been claimed as features of Mobius syndrome. but they have been based on anecdotal

descriptions with no supporthg evidence.

Microgathia has been the most frequently mentioned craniofacial skeletal abnormality in

the literature (Table 10). Except for the 3 cases reported by Bnggs (1965), Gutman et al.

(1973) and Rizos et al. ( 1998). reports of associated craniofacial findings have been based

on clinical examinations rather than standardized cephalometric studies. The incidence of

micrognathia associated with Mobius syndrome may have been overestimated in the

literamre due to the use of soft tissue assessments with the iack of distinction between a

reduced size and reduced or rotated position of the mandible and its position relative to the

maxilia. Clinical assessments of the soft tissue do not accurately differentiate these

di fferences.

Micrognathia is a reduced size of the jaw whereas retrognathia irnplies a retruded position.

The size and position of the mandible is more accurately assessed on a lateral cephalometric

radiograph where it is possible to assess whether the mandible, in profile. is 1 ) micrognathic

relative to the other structures of the craniofacial cornplex, 2) normal size and position but

retognathic relative to a prognathic or normal maxilla, and (3) normal sized but wiih a

clockwise rotation, thus functioning in a retrognathic position relative to a normal maxilla.

Althcugh the use of lateral cephalometric radiographs to determine the skeletal craniofacial

morphology is more accurate than soft tissue assessments. there is an inherent danger in

using linear measurements when comparing an affected group of individuals to a non-

affected control group. The affected group may be larger or smaller individuals in al1

dimensions than the controls, and thus incorrect conclusions can be drawn from the

measurements. If the individuals with Mobius syndrome in this sample are smaller overall as

a group than the Burlington control group. then measurements which are proportionately the

same will appear to be srnaller. and may even have statistical significance. There are two

ways to overcome this problern: either use angular and proponionai measurements, or size-

adjust the samples One method of accomplishing the latter is to accept the cranial base

length (Na-Ba) as a standard length in the skull that is not affected by the anomaly being

studied. This rnethod is accurate in studies involvin_r individuals with a cleft lip and palate,

where the cranial base is not affected by the presence of the cleft (Ross 1987). The mean

cranial base lensth (Na-Ba) of the Mobius group is smaller. and it would appear justifiable to

size adjust al1 skeletal linear measurements to reflect this. If this was done as in colurnn 7 of

Table 15. many of the differences between the samples disappear. There is no proof,

however, that size-adjusting For these individuals is valid. Although it seems a sensible

method to improve the accuracy of these results. it can only be considered a hypothetical

improvement.

Primary Samole - Craniofacial Findines

The results from the lateral cephalometric analysis for the primary sample showed significant

differences (p <0.05) for I O of the 30 measured variables. Eight of the 10 measured variables

were linear. one was angular and one was proportional. Although not proven statistically.

size-adjustment of the linear measurernents accordin3 to the cranial base length (Na-Ba)

suggests that individuals with Mobius syndrome have a smaller craniofacial corn plex overall

and that the anteroposterior positions of the maxilia and rnandible are proportionately sized

to the craniofacial size (Table 15).

Without size-adjustments, the results of this study indicate that the Harvold mandibular

length (Co-Gn) and the size of the lower border of the mandible (Go-Gn) were significantly

smaller (p ~ 0 . 0 1 ) ihan the control group but the length of the posterior border of the

mandible (Co-Go) was not significantly differenr. The results also indicate that the Harvold

maxillary length (Co-Sn) was significantly smaller ( p <0.05) than the controls but not PNS-

A point. The Harvold mavillary length to mandibular unit length difference was si~nificantly

smaller (p <0.05) by 2.5 mm.

It should be noted that the rneasured values for the Harvold mavillary length, Harvold

mandibular length and Harvold maxillary io mandibular unit length difference for the

primary sample are comparable to the Harvold mean values (Harvold 1974) and even more

so when these values are size-adjusted (Table 17). Therefore. the mandible should not be

considered rnicrognathic or abnormaily small based on these measurements (Figure 9 a, b).

The anteroposterior position of A point and B point (SNA, Ba-Na-A point and SM3) were

sirnilar to the controls indicating a similar anteroposterior position of the maxilla and

mandible relative to the cranial base. Therefore, the previous suggestions of a rnidface

prominence (Henderson 1939, Gorlin et al. 1990) could be attributed to erroneous clinical

observations or to soft tissue characteristics. The on1 y significantly different angular

measurement was ANB ( p < 0.05) but a siynificantlv larger ANB angle does not imply a

micrognathic mandible but rather indicates a relative spatial difference between A point, Na,

and B point.

Tiihle 17: Hmold mcms (H'wold 1974). control group nieans. priniiq sample mcms and size-adjusted means for Hmold niiisillary length. Hmold rnandibiilar length and HmoId rnrisillary to mandibulw unit length difference

Croup Gender Age Hun.c)ld muxilliiry Humold mrindihular Hünfold muxillury tci SUF [yeurs) Icngth (Co-Sn) length (Ci)-Gn) mandihular unit

length diffwcncc Harwld Meun ,CI t 2 LI? inm 2 3.73 I l 4 mm 24.9 72 nlin

F 12 mm 2 4.07 Il.? nim 25.2 23 mm Contrd Croup hl / F' 12.4 li 1 .h mm 2 7 .2 I 1J.H mni I l0.I 24.0 mm + 4.7 Primury Sample M / F If.? W.4 mm i 7.4 1 Iii.2 mm I I 1 . R 21.3 mm f 7.2 Size-Adiurted fibr Nu-Bu M f F 1 . 3 92.4 nim 1 1-3.9 mm 72.2 mm

Except for a significantly shorter (p <0.05) upper face height (UFH), no significant

difference was noted with respect to vertical face height. Again, size-adjustment resuits in

comparable values for this variable (Table 15).

Figure 9a: Harvold m a u i l l w length (Co-Sn) of prirnanl sample and control group

60 ------- . -.-- ---- ---- -- . .----

4 b X 10 12 I - l Ici 1 S ?O 12

Figure 9b: Harcold mandibulx Icngth (Co-Gn) of primary sanipk and control group

H a n o l J i+lundihul:ir Length (Co-Gn)

, Primury .\lubius Sumple ,

, Control Gmun

Primary S a m ~ l e - Dents1 Findines

The findings of this study indicated that the maxillary incisors were not protrusive as

reported by Federman and Stoopack (1975). Although not statistically significant, the

angular positions of the mavillary and mandibular incisors (U1 to M. L I to MP and

interincisal angle) suggested a more upright positioning. Paralysis of the muscles of facial

expression may in Fact cause a constant direct force on the maxillary and mandibular incisors

similar to orthodontic forces and thus could result in a more upriyht positioning of the

anterior teeth.

An anterior open bite was reponed by Rizos et al. (1998). but the amount of overbiie

observed in the study was identical to the normal controls and the maxillary and mandibular

incisors and first molars were not over or underenipted.

S i ~ r ~ ~ r n m - t , of Pritmrv Jilri~pie

In summary, this lateral cephalornetric study showed that the craniofacial morphology

associated with Mobius syndrome was significantly different (p ~ 0 . 0 5 ) than the control

group for 10 of the 30 measured variables. However, this study sugyested that individuais

with Evlobius syndrome may have a smailer craniofacial complex given the significantly

smaller cranial base length (Na-Ba). Without sire-adjustment, this study suggested the

presence of a smaller maxillary and mandibular length (Co-Sn, Co-Gn) but the measured

values fell within the range of the normal Harvold means and standard deviations (Table 17).

Also, the anteroposterior position of the maxilla and mandible was simiiar to normal

controls. Using only angular measurements, it appean there are no real differences between

the two groups and there is no evidence to suppon the inclusion of rnicrognathia and midface

prominence as çkeletal craniofacial features associated with Mobius syndrome. The overall

findings can be observed on the mean facial diayrams of the primary sample superimposed

on the control group. (Figure 10 a. b. c).

Secondarv Sample

Due to the srnall sample size of the secondary sample with trigeminal nerve involvement

(muscles of mastication), statistical analysis was not possible. Individuals with Mobius

syndrome in the secondary sample can be described as having a craniofacial morphology

which was extreme with respect to the vertical pattern of growth, amount of clockwise

rotation of the mandible and anterior openbite.

The lack of functioning muscles of mastication and the effects on the craniofacial

morphology may be comparable to that seen in congenital muscular dystrophy. myotonic

dystroph y, Duchenne muscular dystrophy and Facioscapulohumeral muscular dystrophv

where an extreme vertical pattern of growth and anterior openbites have also been observed

and have been attributed to the lack of functioning of the muscles of mastication (Hanson et

al. 1971, Kreiborg et al. 1978, Kiliaridis et ai. 1989. Eckardt & Harzer 1996). These findings

suggest that the lack of function of the muscles of mastication is more likely to affect the

craniofacial skeletal rnorphology than the lack of function of the muscles of facial

expression. It should be kept in mind that the paralysis of the facial and rnasticatory

musculature is progressive in these conditions whereas the paralysis is non-progressive in

Mobius syndrome.

Unlike the primary sample. a substantially larger difference was observed between the

Harvold rna~illary and mandibular unit length difference. This could be attributed to both the

srnalier maxillary length or the larger mandibular lensth observed. The mandibular length

was very large as compared to the control group and the primary sample. Class I I I

malocclusions have been previously reponed by Thomas 1898. Briggs 1965. and Chester &

Zuker 1992. but the extent of the trigeminal nerve involvement was not reported. Unlike the

primary sample, whose mean overbite was identical to the normal controls. the secondary

sample exhibited large openbites similar to Rizos et al.'s (1998) case report.

Smmarv o f S t ? ~ ~ o ~ ' m + y hhmple

The secondary group had a more extreme pattern of vertical growth of the face, a retmded

mauilla. larger mandibular lengths and anterior openbites (Figure 1 1. 12). Further controlled

studies with a larger sample size are indicated in order to determine the significant difference

between individuals with Mobius syndrome with and with out trigeminal nerve involvement.

Obtaining an adequate sample size may be difficult given thal trigeminal nerve involvement

occurs in approximately 6%- 8% of individuals with Mobius syndrome (Engler et al. 1979.

Carr et al. 1997). The overall findings can be observed on the mean facial diagrams of the

secondary sample superimposed on the control group (Figure 13 a. b. c).

Figure 10a: Mean latenl ccphalometric tracings: p r i m w sample supcrimposed on control group at Ba-Na.

Control group Primav saniple (C.N. VI1)-------

Figure lob: Mean lateral cephalometric tncings: pnm- sample superimposed on control group at ANS-PNS.

Convol group Prima- samp le (C. N. VI 1 )----------------

Figure ~ O C : blran Iritcnl ccphalomrtric tncings; prim- samplr: superimposrd on control group on mandibular plane.

Conuol group Prin i rc sriniplc (C. N. VI1 1--------------

Figure I l : Lateral cephalometric radiographs- priman, sarnple.

Figure 12: Laterd cephalometric radiographs- second- sampie demonstrating vertical pattern of growh. Iarge mmdibular length and antcrior opeubite.

Figure 13a: Mean lateral cephalomçtric tracings: seconduy sample superirnposcd on control group at Ba-Na.

Controi group Seconda? sarnpk ( C . N V)---------

Figure 13b: Mean latcnl cephalornetnc tncings: second.. sample superimposed on control group at ANS-PNS.

Conrrol group Sccondan srtniplc (C. N. V)------

Figure 13c: Mcm latrnl ccphaiomctric tncings: second-. smple stipenmposcd on control group on mandibulx plme.

ConuoI g o u p Sccondan srmipic (C. N. V)------------

CONCLUSIONS

The purpose of the study was to determine the craniofacial skeletal rnorpholo~y associated

with Mobius syndrome. Anecdotal descriptions of the soft tissue of the face and three case

reports which included lateral cephalometric findings have been reported in the literature. but

cephalometric studies looking at the craniofacial skeletal morphology are absent. The present

study is the only one which has used cephalometric radiographs to objectively examine the

craniofacial morphology associated with ;\lob ius syndrome versus normal controls. The

finding of this study indicated the following:

I The craniofacial skeletal morphology associated with Mdbius syndrome. without trigeminal

nerve involvement. was significantly different (p< 0.05) for 10 of the 30 measured variables.

However. individuais with Mobius syndrome may have a smaller craniofacial complex given

the significantly smaller (p ~ 0 . 0 1 ) cranial base lenpth (Na-Ba). When the 8 linear

measurements were size adjusted to the cranial base length. the Mobius group was

comparable to the control group. Even without size adjustment. the size of the maxilia and

mandible were within the range of normal Harvold mean values. Thus, this study refutes the

daims of a midface prominence and a rnicrognathic mandible being associated with Mobius

syndrome and indicates that. except for overall size of the craniofacial complex, there is little

di fference in the s keletal cranio hciai rnorp hology.

2. The small sample of individuals with Mobius syndrome, with trigeminal nerve involvement,

had an extreme pattern of vertical growth with clockwise rotation of the mandible, an

anterior openbite and overeruption of the rnaxillary and rnandibular molars. A smaller

rnaxillary length with a laqer mandibular length was also observed.

FURTHER RESEARCH

Reanimation surgery is ideally performed at an earlier age for psychosocial and speech

concems. Whether gracilis muscle transfer resul ts in a more favorable pattern of facial

growth and development has not been established. This study suggests that the craniofacial

cornplex is less affected when the trigeminal nerve, and hence the muscles of mastication,

are not involved. Early surgical intervention may be more critical with those individuals with

trigem inal nerve invo lvement where the cran io facial skeletal morphology seems to be more

severeiy altered. Longitudinal studies. to determine the long-term facial growth and

development of individuals with Mdbius svndrome who have undergone gracilis muscle

transfer at various ages. are currently undenvay at The Hospital for Sick Children.

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Operational Definitions

Operational Definitions

Cephalometric iMeasurements

Sella Nasion to Point A (SN;\): thc anglc cstriblishcd b'. the lincs connccting thc thrcc points. Sclla Tursica Nasion and Point A

Sella Nasion to Point B (SNB): the anglc cstablished by the lines connecting the thrce points. Sclla Tursica Nasion and Point B

Point A to Point B difference (ANB): thc anglc cstablishcd by the lincs connçcting the thrcc points. Point A. Nasion and Point B

Basion Nasion ta Point .A (Ba-Na-A point): thc anglc cstablished b!* the lines connecting the thrcî points. Basion. Nasion and Point A

Maxillary Length (Max length): the distmcç in mm from the rnost posterior-supcrior point on the hcad of the condyle (Co) to Subnaale

blandibular Length (%land length): the distancc in mm frorn the most posterior-superior point on the hccid of tlic coiid!ltt (Co) to Cinathion

Unit length Differences (Max-Mand diff): martdibular unit lrngth minus rnaxillary unit length

Basion to Posterior llasal Spine (Ba-PNS): the distance in mm from Biision to Postcnor Nasal Spinc

Posterior Nasal Spine to Point A (PNS-A point): the distaiicc in mm from thc Posterior Nasal Spinc to Point A

Basion to Point A (Ba-A point): thc distai~cc in mm from Basion to Point .A

1 1 . Condylion to Gonion (Co-Go): thc distance in mm from the most posterior-superior point on the head of the condyle (Co) to the angle of the mmdiblc

17. Conion to Gnathion (Co-Gn): the distance in mm from the angle of the rnandibls to the most inferior and mterior point on the chin (Gn)

13. Conial angle: the angle cstablished by the lines connecting the three points Condylion. Gonion. and Gnathion

14. Nasion to Menton (Na-Me): the distance in mm from Nasion to Menton

15. Upper Face Height (UFH): the distance in mm fiom Nasion to Subnzale*

16. Lower Anterior Face Height (LFH): the distance in mm from Subnasale' to Menton

17. Face Height Ratio (FHR): the ntio dçtermined by the equation URVLFH

18. Basion Nasion to Condylion Gnathion (Ba-Na to Co-Gn): the angle establishcd by the lines Basion to Nasion. and Condylion to Gnathion

19. Upper Incisor to Nasal Floor (U1 to NF): the posterior-superior anglc formed by thc intenection of the lines dnwn through thc long avis of the most prominent niauillary incisor to the line n-hich conncct ANS to PNS

20. Upper lncisor to Nasal Floor, height (U1 to NF): the mm distance drawn bctwen the tip of the ixisal edge of the most prominent r n u i l l q 8 incisor perpendicular to the line which connects ANS to PNS

21. Lower lncisor to Mandibular Plane (dl ( L l to MP): the postcrior-superior angle formed b!. the intersection of the lines d m v n through the long %vis of thc most prominent rnuidibulor incisor to thc mandibular plant:

22. Lower lncisor to ~Mantiibular Plane, height ( L l to MP): the mm distance d r w n bctnwn the tip of the incisai edge of the most prominent mandibular incisor pcrpcndiculrir to the mandibulx plant:

23. Lower incisor and Menton to Nasion and Menton Ratio (Li Me: Na Me): thc ratio dcttlnnined by the equation L 1 -Me/Na-Mc

24. Interincisal angle: the angle formed by the intenection of the lines dnwn through the long mis of the rna~illary and mandibular centrai incisors

25. Overjet: th6 horizontai distance in nim from dic incisd edgc of thc most prominent m a ~ i l l q incisor to the incisril cdge ofthe most prominent mmdibular incisor

26. Overbite: thc venicd distuicc in mm from the incisd edge of the most prominent n~a..illary incisor to the incisa1 edge of the most prominent mandibulm incisor

27. Upper Molar to Nasal Floor, height (U6 to NF): the mm distance drawn betwcen the tip of the incisal cdge of the mwill- fint rnolar psrprndicular to the line which connects ANS to PNS

28. Lower Molar to iMandibular Plane, height (L6 to IMP): the mm distance drawn behvecn the tip of the incisal rdge of the mandibular first molsr perpendicular to the mmdibular plane

29. Basion to Nasion (Ba-Na): the distancc in mm from Basion to Nasion

30. Basion to Sella to Nasion (Ba-SNI): the mgle rstablished by the lines connecting the three points. Basion. Sella and Nasion

APPENDIX B

Raw Data: Primary Sample

---- -- y]. 1 7 t =r\ -3. t. F ~ F ~ . iq~m sl - 3 7 3 =\ in ~n e t x. ln I? C I C = fi r- + pi fi 3 r- a =c F. w, * lh th & w 1 - ~ x + & I ~ , s FI + , - p # + C I - I A ; C - E r ? r - ~ ~ c f . ~ t 5 m C I X 3 # m e c r i - c.I

_ *- -.- - ..-_ .-_- _-.-.-. - - . .-* ---. *__IC ------- ~ ~ ~ 3 ~ 3 . 3 , 3 , x ~ . = , ~ X . ~ - 3 - c . N . ~ 3 . - , m X \ = N ; . 3 =\ = - $ = i n r-- 45 =.\ \1 = -r 3 f \ = X & yz p J ' - , - & 6 pli ?\ + e l e - N r r ~ x i C , ~ 2 = m

c. r - 2 = ? m . = P I

Raw Data: Secondary Sample

Raw Data: Control for Primary Sample

1 , 8

, . 1 ; . l ' 1 i , ' ; , , , ' 1

I l t j : ! . , : ! ! : . I b < - 0 1 ' 1 ! ! - , j j - o n j v l m t v i ~ i - ~ , ~ l ~ , ~ ~ ~ t ~ , t n ~ ~ m m m a i a ~ m l m , r n 4 s 3 ~ i m ri a l ~ i & ~ i i i i i i ~ l a ~ N I - ! ~ , , U ! D I - ! n i n T 1 + ! n / r n l ~ I ~ i - i q , a , , - , - I ; c ~ ~ ~ = j c ( o , n 1 n y n i m I n m - , - I :

APPENDIX E

Raw Data: Control for Secondary Sample

c l -

1 , : l :

I I ,

Cephalometric Tracings: Prirnary Sample

j * b . (M)

d . d . (H)

e . s . (U)

m . r . (F)

k. j . (F) t. W. (F)

b . v . (F) t * h . (F)

r. c . (n) r . k. (H)

r. S . (H) a . d . (H)

j . d. (F) c . m. (M)

a. h. (F) b. h. (F) k . h. (F)

S . III. (F)

Cephalometric Tracings: Secondary Sample

b . m. (M) 8y Om

h . m . (F) 16y 7m

W . m. (H) 14y I 1 m

j . b . (H) 16y I l m

APPENDIX H

Statistical Data

n1mr wmrr re l l aa l l i t y :

r r l l ~ O ~ 1 1 r v : u & n QI -WU€- SI 168 wf EMS EW EUS üW $(d JDF K hifT* s inglr scorr k scores

w - wr use n*5 EMS r w sra

XOllf 0.14545 34S.375 0. l4S45 O.Il345 10 345.175

S t a t l S t i C V a lue C Hum Of Oen OF P r F

w i l k s ' Cauwia 0.31614373 0.9602 60 74 0.5620 P i l l a i ' s Trace 0.67497443 0,9851 60 76 0.5205 n o t e l l i q - l a i l e y Trace 1 .5585(U195 0.9352 60 72 0.6035 Roy's Gre l tes t R w t 0.83r93049 1.0531) 30 33 0.4348

Manava Test C r l t e r l a and F Aqproximations f o r t n t nypotnesis o t na O v e r a l l FSiEWGROUP E l l c c t tl - Type III SS4CP U a t r i r f o r AGE'CRUJP E = E r r o r SSdCP Matr i x

V i l k s ' L a r W I 0.29976801 1.0193 60 74 0.4657 P i l a i ' s Trace 0,18S23211 i.oaS9 60 76 0.4867 HoteLling-Lawiey Trace 1.7 la76866 1.0333 60 72 0.4476 Roy's Gfeatest Roat 1.20780521 1 -5299 30 38 0.1073

Manova Test C r i t e r i a ancl Exact F S t a t i ~ t l c l f o r th. Hypothesis o t no O v e r i l i SUgGROUP E l l e e t n = T y p e I I I SSICP utri1 l o r SEX.GAOUP E = E r m r SSCP U a t r f x

s t a t u t i c value F N u i OC Dan OF Pr * F

N i l k a ' U- 0.54432318 1.032s M 37 0 .498 P i l l a i ' s Tncr O -45567W 1. Ws 30 37 0 . 4 ~ Hot r l l i ng -LawleyTrace 0.û3714389 t.0325 30 37 0.4588 Roy's C n a t i s t R o o t 0.ô3714309 1.0325 30 37 0.4508

uanova Test t r i t e r l a and F Approxiriatiocis f o r the Hypotnasis or no O v e r a l l SE Er tec t H = Type III SSKCP Y l t r l x f o r AGE E = E r r o r SSaCP Y I t r i x

S t a t i s t i c Value F W D F DcnW P r . F

Wi lk r ' C a i W i 0.07227800 5.3542 60 74 0.0001. P i l l a i ' s Trace 1 .35424065 2 .ô564 60 76 0.0001 ~ o t e l i i n g - L n l e y T n c c 6.93428416 4.1606 60 72 0.0001 uoybs Gr ta tes t uoot s . s 4 i o ~ r i s 7 . 5 2 s 30 3a 0 ~ 1

UanoVa Test C r l t e r i a and Exact F S t a t i s t i c s f o r tri. t t ypo tn ts is o f no Overa l l SEX E f f e c t N - Type 1x1 SSaCP U a t r i x f o r SU E - Error SSICP U a t r i x

Sta t l s t i c V a l w F N u i O f Oen OF P r f

WiLks' L a M a 0.28711867 1.0622 30 37 0.0007 P i l l a i ' s Tnce 0.71289133 3.0622 30 37 O.Oû07 & t e l L i n g - L a r i e y t r a c e 2.482WM2 3.0622 30 37 O-aOO7 Roy's t r i a t e s t Raat 2.482ô8042 3 -0622 30 37 0.0007

Manova Test C r i t e r r a ana Exact F S t a t f s t i c s f o r t t m n y p i t l u s i s o f no Overa l l QlW E r f e c t M = Type III SSICP Y i t r i x f o r GROUP E = E r r o r SSLCP Y a t r i x

r i u s * u a d a 0.~59026s1 3.5281 3(] 37 0 . ~ ~ 2 P i l l a i ' s T n c e 0~74091349 3.5201 30 37 0.0002 m t e l l i n g - L a w l e y T n c r 2.56060976 3.5281 M 37 o.am2 Roy's Grra tes t Root 2.86060876 3.5211 30 37 0.0002

C.V.

¶y# I I I Sf

OF sui o r =u&rrr w r n Square F v a l u e P r F

Error 66 182.95154533 i3.37M15629

Corrrctra t o t a l I 7 i021.628333;2

Crror 66

W l n Square

Source D Su o f Squares man Squarr F Valu. P r F

91. 1-27 8.28256930 o . a . m t

657.21017619 9.9973449

7 ~ 8 . 3 l W 6

C.V. R a a t USE B r u Mean

4 .-285 3,15558702 63.23461530

E r r o r 66

Corrrcrea t o t a l 77

Source a 1- t t i s

Errar 66 1699.61016667 25.15166919

OF type I l l SS wrn Squrrr F V a l w Pr J f

(i.ntral Cirurr w r k s Proceaur i

Dr S u . o ï Squrris urrn Squrrt V a l w Pr b F

Sm a f Squirtr Win Square F Valui pr . f

C.V. b a t USE Win

f r r o r 66 1046.07739286 15 ai996050

ucrn S e ~ r r + F vil-r P r . F

R-Squrrr C.V. A O û t USE uwan

tne S& Systrm 14:22 uonoay. &ri1 26, 1999 218

t r r o r 66

C.V. fbot rSL W W8n

30M. I W 3 3 3

C.V.

Source Of

Errar 66

Correctba total 17

S u of Sqrurtr w r n Square C V a l r I r a f

1107 .X32Si57 160.66SJ#771 10.03 0.aoo1

662.%04$230 10.03009716

1769.O.37l795

C.V. Amr USE Wn W i n

6.1 ts42 3.16~5353 51.30197436

L r r o r 66

Source Of

e 2 SEI 1

-*SEI 2 QwM 1

&€-a- 2 s x - m 1

r Q * s € x - ~ 2

w r n Square i vrluc P r rn f

33.3207703t 1.86 0.6612

lt.9l126245

Corrmct.0 Tota l 77 154d.671?9(l7

R - W r 8 C.V.

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C.V. aAQt USE LI- vrrn

Tw 111 ES Wan Sqwrr F v a l u Pr F

Source OC

Crmr a

Source 0Ç L m o ï Squares w r n Spurr. F V a t w P r r F

corrtctra T o t a l 71 i 410 .02615~5

Source

Corrrcrro focal 77

r y p . I t t SS

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1 .owoo 2.00Qd0 1 .O0000 2.- 1 .aam 2.-

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1

2.00000 1.00000 2.00#10 1 .O0400 2.-

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1 - 00000 1.0060a 2 .aaaoo 2.W000

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1 .ooQoa 1 .Q0000 2 .am00 2 .omlm

12.4~000 87.263335 as. 1- 13. OSOûOO 96.52SOOa 95.61a000 87.b00000 9 1 .98XlS 96.910000

1 0 1 . 3 7 ~ 87.240004 92.)00000

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21.76b6667

27.9666667 21.1114206

26.366666 1 32. r2-

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