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/r. GTIIIITIC SllilDY OF C.LEFT LlP AND CLEFT PAI.ATE
AticiiLAr.TD I 960-1 976
' C'URIL iAl.tUS CiI,|lPi'tAI!
-
A theeis suburittecl iir fulfilrnerr! cf
Ehe requirenents for the ciegree of Doctor: of Fhl-losr:phy i.n Coumunity Health,
rJa lve'r s i. ty o f Aucklan.j , l 98L
UniversitY of Auckland Libratf,
pHii-sotrt LIBRARY SCHOOL OF M-:DtClNE
*t;a-"^D'
AucKLAND'l['esis
V\4
C
4Gb
11\ b\1(,oo6s
\oiot
To those of our childrcn chus affl-icteC
'crl.pp1ings visLieC uPon us bY rraturs ln her nadcaP noods;
gaoes of bll.nCnran's buff anong
the genes, a1.1 uP and doq"n the double spiral sta-irca-ce.'
Frank Sargeson
ACKNOT^ILEDGEIIEiIf S
The study reported ln thls thesls woul.d not hal'e been posslble wlthout the cooperatl-on and assl-stance of a large number of people.
Unfortunately, I cannot thank then all by name.
Flrstly, thanks are due to the l-ar:ge nunrber of patients and
thel.r relatives wtro so readily gave !.nformation about themselves and theit fanll-Lea. A study of thJ.s klnrl would not have been
posslble wlthout thelr actlve cooperatlon.
Ttre prLneipal stftnulus and encouragement to undertake this
work came fron Profesaor A l,t O Veale, and I am indebted to hlur for
contlnued advlee and support over a long perLod. Dr A J Lee frou the Department of Mathematlcs at d,uckland llnlverstty provided
statLstlcal advlce and encouragement.
Ttre staff of the Plastlc Surgleal Unit at Mlddlernore llospltal
gave of thelr enthusiasm and actLvely helped in data collection and verlfLcatlon. In partLcular, Professor !l M Uanchester and llr J H Wllllarns were chlefly responslble for the lnltlatloa of thl-s work and have uaLntalned au actLve lnterest throughout.
I an lndebted to tyn Avery for her cheerful aod conpetent ass!.stance ln the farnlly l-nternrlens and for data entry onto the Department of Comraunity Heal.th PDPll/4O.
I had extensl-ve assLstance tn the data manageinent and
statlstLcal analysLs fror, Mr J Upsdell and Mr ? MullLas of the-
Department of Communtty lleal-th nt the School of Medl-cine.
I have been fortuoate to have the assistance of Ehree
computLng faetll-tles - the 86700 of the Universlty of lurcklandr the PDPII ln the School of lledicl-ne, and the syeten in the WeJ-!.lngtoa
{it
Cllnical Sehool. I thank the staff for thelr heip in proeesslng the
large body of datsr I accumulated"
Comprrter progEarns for the segregation analyses were very
kindly supplled by the Populetion Genetics Laboratory aE the Ilnlverel-ty of ltawalL, to vtrom I extend rny thanks. I would also
llke to thank Dr JJ Kidd of Yale lJnlversity whp was klnd enough to sead oe copLes of hls progranrmes HSTSEX and MFSEX, whLch were also used ln thls work.
I would lLke to thank the staff of Statlstlcs, who helped f111 Ln a f statLstlcs for thls country.
i{evr Zealand Department
ln the publlshed vltal of the
elr gaps
FlnancLal support for thls work was provided by the lriedlcal Research Council of New Zealand through the genetlcs prograume
grant to Professor A lI O Veale. The author was fLoanced through
thLs grant aa a Research fel.Low Lu the Unlver:eity of Auckla.od and
conpleted the aoalysig whLle hot-dlng a TralnLng Fellotushl-p frorn the Uedleal Research Couael-l.
I am also grateful to the Crl-ppled GtrllCreo's Society for
making a grant tosards the costs of collectlng and processlng Ene
data.
1v
1'SSTRACI
A study of eleft J-ip and cleft palate wa.s carried out in order
to determlne wtrether or not any dlfferences io incl-dence betweerr Buropeans and Poiyneslans lrere accompanted by differeneeg ln recurrence rLsks, and to test the genetlc hypotheses currently favoured as explanatlons of fanll.l-al agggregatLon of these disorders.
An lncl-dence study vas uirclertaken on all llve births ln the
Anckland urban area for the years 1960 to L976. !'anlly lnfornation
was obt.al.ned from these probands and frcm other affected persoD.s or thelr close relatl-r'es, by lutervlew at the cleft palaie clinlc at
Ml-ddLenore llospltal.
Tlre ascertalnment probablllty for cleft 1ip and cleft palate
probands vras about 957 and was not correlated rl-ith any of the
dernographlc eharacterlstl-cs rneasured on the probands. After correctlon for ascertalnnent, the incldence of cleft palate ln
ldaorLs was estimated to be 1.867/f000 1lve bl-rths. For Europeanu
the estimate was 0.6431L000. The correspouding flgures for c16ft ltp rrlth or wlthout cleft palate were 0.397/f000 and I.195/1000.
Ite sex ratlo for cleft palate was 0.485 wlth heterogenelty beEween
thc raees. For cleft ltp the sax re.tlo vras 0.649 overall, Ttrere
rtere no secular or seasonal trends tu ttre lncldence of faclaL
clefts and no stgnLfLcant effects of maternal age, ot paternal- age.
The nean blrth rank for probaods wi';h cleft llp wlth or wLthout cleft paLate was higher than expected. For probands wlth cleft palater Trean blrth rank vas not sLgnLflcantly elevated. The pettern of adCtttooal nalfonnatlons in these probands vas slmllar to Lhose
reported ln sioilar studles frosr other cenfres.
the recurrence rlsk for cleft patate ';ae 1.BZ sverall.
Although Lt $as s11ght3-y hlgher lrr poiynesian fanLlles than l-n
European farnillesl the dlffe.rence tras nor,rhere near Etatlstlcal slgrrlficanceo For cleft 1tp the recurreoce rLsk was 2,62 overall.
wl-th the rlsk being sllghtly htgher tn poLynes,r.an far,rLJ.ies, but agaln not slgnt.flcantly htgher than Ln European fanllLes. usLng
current analytlcal techniques, no dlscrlnLnatlon was poselble betseen a generallzed slngte autosomal_ locus rnodel and a
multLfactoriar threshold rnodel, A consLderatioa of the paraneter estlmates for both models suggests that the nul-ttfactorial
thresho.ld model le the more approprLate one Eo use for the
calculation of recurrence risks i.r cornpll-eatecl faintly sltuaLlons.
It le concluded that furcher fanily studies of thls nature vor-ild no longer be warranted unless hypothr--ses can reallsti,:ally be
tested ou the samples aval-lable. Eowever, incl.dence studles in speeiar populatlons w:'-11- rcmal.n Lmportant for hypothesls testing.
Followtng on the work usl-ng anlmal models, a study of fece shape
wlthk^ auc among races ln New zealand nay provLde clues to the
aetlology of faclal clefts, partlcularly lsoleted cleft palate. rt wtLl be lmportant to follow changes in incLrlence over tlnne and
di.cewe: vhat effects lntermarrlage and cultural changes rnLght have
on the incidence of faclal clefts.
vi
TASTE 0r .CQM.lslfts
PaEe
1. INlSOIlItCf,ION " . . t i .. . r . l . . | . . . . e t . t I t
2' METEODS OF 4SIAIT.'16IS
Aseertalnment and lng{il€nge . . . .. r . o . . r . .r . AaatryeLa of eegregatton patterss
(f) Prl.or to the advent of eouputerg o r t o r . (11) The couputef age . . . . r' r r . . | . . (lff) ffil!.ttfactorlsl. threshold Eodqls . | . . . . (tv) Irlaxlmuq ttkellhood eetfunatlon of parmeters
of rhe multlfactof,lel threehold uodeL . 32
(v) Slngle alrtosongl loctra mtdela .' . . - r . 35 (vi) Illff,ereurlatlng bet'teen genet1c modella . . . 36
(vltl Othet epproaches to the analysls
of fa,m.llydata ., r . . . . | . t . . r 43
3. LITERATURE SIJR1TEY
Ilne eubrXrology of the uppar -ltp and palate . . . . r r tts Eptdwtologleal g'tudi,eg . . r . . . . r t . r r r .' 48 Incldence r. o .. | .. r... I t )... . 50 Se,agonal gffgotg . . . r . .,. . r .' . . . . t 56
$ldeof tlnilaterralcletsof theltp. i. t. t, r.. 57
Sexratlo ... ). r... I r.. o... 57 As9o'c{atedpalfo,fqatLgtls r r.. r ... r. t.. 60 ldatefaal ager peteraal ege, and blrth f,alrk r r r :r r . 64 Other epl-denLologl,cal oonslderations t ! . . ., r . . . 68 rg.-currmc€r.iskS. r t.. r. t.-. r r. i. r'ro o': o 71 ' Gengtichypotheees o... r,. r ! I. I. 80
16
23 25
vx.t
Paee
4. EPII}E}{IOLOCICAL RESIJTTS
th,€ preaent study
Gleft palate
raa!atrlaa3aaar'aaat
Aseertalnnent aad Liteldence . . . ., ., . . r . | 88
$ex tatlo . . r o . . . . r ... r .r. .. o r . . . . 98
SgagooalLtf t r . . . | . . . . r I r r . . . IOO
Seculat treads o r . . . r . . . r, t05
Addlftonalmalforriatf.ona ...,. r. ! r r r.. 1O7
Blrthrank o.. o... I t o r r.. r. o I r. 107
lIaternal age o r . r | . . a . . . o . o . 1tr0
. Pate-r,aal age . . . r . r t . ! ! . . . 111 Oleft 1lp vlth or rrltlrcut cleft pdlate
Ascertafument and ltrcldeoce' . . . . | . . o . . I i13 SgXratLo o o r r.. r... o.... I o 118
SeasonaLity . . . r . . . I o r,f . . e . . . . 12f Sgeular trgad$, | . r . . r | | . . I r . | | . . . 125
Addlttrooalnalformatlone ... r. a. . !27 . Bltthral,k ... r r... r.. r.. r. r. L27
I{atgrnal age | . . . r e . . . r . . e . 130 Fatetnal age . . . r . . . I o . . . r . . .. . . . 131 g3
vl11
Page
5. FAI.TILY STI'DIES
DLagnoels 8Ed racg r t . . . . r . o . .r | . . . . r . r 132
O'thervarlabtreg rj | . r.'. . . I r r. . . . o . 136
Probabtllty of aseeftainneat . .
.. . r . .' . . . 139 B'anllyiata ..., o..1i r..'...'... r.... L42
€enetlc dnalyse's
(1) Slapleflod€ls r.. r...r.... r o... 15&
(Il) lrfrrltl,fac.torlal thresbold models ., . ] . . . 1,55
(111) illlsou'e Betludg . .' . . . . .' I o' . ) f56
(fv) Ttrernethodof RLddandSp,ence.. '... r ' 163 ' (v) Gomplex eegregatlon analysia . . . r 168 (vl) Thenlxedootlel .. e r r r G.... o.. o t1h 6.IIISCUSSION. . . I r r . | . . r . . . . .. r . r r I r . 181
lte{naldenceof f;ac.Lalaleft,s r r '... r... l8l Sgxratio . .r. . .. r r . ..r .. r o. I r, . r 185 Seaeocal.lty . . . . r . . . t . r . . I r r . . r . . . 186 Sgculartrggda... r r r t.... t 186 Add{tlonalualforoatloue r '.. | | o r.. | ' r.... L87
Stde of unilateral clefts of the ltp . . . .. o . tr87 Btrtb rank, uateraal age, end paterual age . . o . 1S8 Otherepldenlologl.calconslderatlons r.... '. ! r. 188
ix
Page
6. DLSCUS$ION (continued)
Fanllygtudies. r r r. + 1.... r. r r r. r r r. 189 Sarple slze . o . i . . . o . . r o . r . . . o l9l"
RgcurreneerLska.. r. r.... r... o... 193 lfulttfactorlal threahold models ..r . .r. . f. . . r . . I95 tlouogenLcnodela r r I O.. r... ? r. r. .. 197 Achoi.ceof nodels. .... r.. I r r. r.... r r [99 ItntnaL BtudleS r . . . r r . . r . r . G r o . r t . . . 201, Face ahepe and dermatoglyphtce of qar . r . . . | 203
Goucluslon9 . r o ! . I o . . . ! | | . t t. | . t . | . 205 7. BIBLI'OGRA}IilT . . t r r | . . . t . . . r . t . I . 208
x
I,IST OF TABLES
page
I. IncLdence of cleft !.ip/pai-ate per 1000 populatlon . . . . 54 II. Slde of unllaEeral cleft o . . . o . .' .' o "' 55 .III..Sexratlo lnGL/P . . . | . . . .'' I 59 LV. ReCurfence Ln elbllngS Of probandS '. . .'r . . . 75 V. Recurretrce io offsprlng of probands . . . t r . . . .'' 75 VL Recurrence ln other relattves of probande . . . o . . . . 76 VLI. Distribut.lon of the number of ascertaLnments
per proband for cleft palate . .' .'' I |'''' 93 VIII. Ttre dlstrlbutlon of the number of aecertalnments
'bysourceforcleftPalate . I o ' r ' t I r ' ' r ' 95
IX. PartLal regression coeffLelents for multiple regreeslon
of number8 of ascertaftrnents of cleft palate
probandsondemographlcvarlablee ' ' ' t ' ' | ' ' ' 99 X. Seasonal effects - numbers ascertaltred by month
by race. Cleft palate . . . . t .''''''''' t 101 XI. Seasonal effects - uumbers ascertained by month
'by sex. Cleft Palate . . . I'' t'' I'''' 102 XII. Edwarde test fof seasouallty . . .'''''' o''. |' 104 XIII. Cleftpalateblrthstryyear... o. ' ' ' ' ' ' ' ' t f06 XIV. ltalforrnatlonsamongprobandswlthCP. ' ' t c ' ' ' ' | 108
XV. Dlstrlbutlon of the ntrnber of ascertainments
per proband for cleft ltp (Palate)'' o''' t !' 116 XW. DLstrlbutlon of ascertalnments by souree
'Gleft llp (palate) . o | ' r i ' ' ' ' ' ' ' ' ' ' ' 117
xl
Fage
XVII. Partlal regresslon coefflcients for nulttple regresslon
of ascertainment of c]-eft lip (palate)
probands ou demographJ.c varlables . . . 119 XVIII. Seasonal effects. Nurnber vl-th CL ascertained by month L22 XIX. Seasonal effects. lfrrmber v'tth CLP ascertalned by month L23 XX. Seasonal cffeets. Number wtth CL(P)
ascertalned by month and by 8€x r . . . . | . . . t . L24 XXI. Cleft 1ip (Palate) blrths by year . . . L26 XXII. Cteftllpand/orpalatebirthsbyyear ... r o... L28 XEII. Halfonnatlons in CL(P) probands . . r . . . o . . . . L29
XXIV, Xhe dlstrlbutLon of slbship size by the number
affected. All Pol;'nesl-ans. Cleft pal.ate . . . o . 143
XK\l. ltre dlstrlbutlon of eibshlp stze by the number
affected. Otlrer races. Cleft palate . . . L44
gW. Ttre distrLbutlon of the number affected by tire class
of relatl.ve. Cleft palate . . . .''' f45 XXVII. ltre dlstrlbutlon of sibslrip slze by the number
affected. A11 Polynes.Lans. Cleft llp wtth/without
clgft palate . . . I .'''''' t' L4?
XX\[II. Ttre distrlbutlon of sLbshl-p slze by the number
affected. Otlter races. Cleft llp wtth/rrithcut
cleftpalate ... o r... " " o " 148
XXIX. Ihe dlstribution of the number affected by the class
of relatlve. Cleft l-tp with/rrlthout cleft palate ' . '150 EX. The dlstributlon of slbshlp size by the number
affected. A1I races coublned' t . o .' . t t' I t l5l
xtl
page
XXXI. Estlmates of heritabiltty. A1!- PolynesLans i . . r . . L57 XXXII. Estimates of herltabi..llty. Other races . o . . . f58
XXlnII. EstLmates of heritabillty. A11 race-s conblned . . ' . 159
XXXIV. Est,lmates of penetrance parametets from
l-ncl-dence data. Cleft palate ... . .,r I o . . . 161
XKX\|. Estlmates of penetrance parameters from
Lncidence data. Cleft llp (palate) a O .' . . . ., L62 LE(VI. EstLmates of herltablltty . . . | 164 ntXVII. Obeerved and expected Lncldences {n relatlves
ofprobandswlthcieftpalate '. .. r.. o. 166
XK)CVIII. Observed and expected lncldences ln relatives
of probands *ltth cleft llp (palate) . . . . o . . r . 167
)CK)GX. Parameter estinates un,ler the SML nodel . . . i6g XL. Parameter estimates for the two allele, slngle locus
model. Cleft palat€ . . . t . . t . t o . . 172
)OI. Paraneter estLuates for the two allelen single loctrs
model. Cleft llp (palate)' . . . t . . . o .' L73
XLII. srr table for represent3tlve genetic nodels.
Clgft palate . . . t''' t 175 XLIII. srr table for representatLve genetlc uodels.
Cleft 1lp (palate) . . o . . . . c r . . . t'' L76 F,IV. Parameter estlnates under the sllxed model of
Vorton and Macleaa. Cleft Palate . r . . . | . 179
XLV. Parameter estlmates under the ml-xed roodel of
llorton and }traclean. Cl-eft lip (palate) . . . .' 180
)CLVI. lhe distrLbutLon of ascertainments among sourcea . . . 184
xili
