Syndromes with Cleft Lip and Cleft Palate M. MICHAEL COHEN, JR., D.M.D. Seattle, Washington 98195 A series of tables is presented as a diagnostic aid for the clinician when he confronts a patient who has a cleft lip and/or palate, together with associated anomalies. The tables provide a rapid way of sorting through the recognized syndromes with orofacial clefting in search of a possible overall diagnosis. Today, 154 such syndromes are recognized. This is more than twice as many as were known in 1971. Undoubtedly, many new syndromes with orofacial clefting will be delineated in the future. Isolated cleft lip and cleft palate are com- mon malformations. Their epidemiologic, ge- netic, and pathogenetic characteristics have been reviewed elsewhere (Burdi et al., 1972; Drillien et al., 1970; Fraser, 1970, 1971; Gor- lin et al., 1971a, 1976; Woolf, 1971). The purpose of this paper is to present a series of tables that can be used as a diagnostic aid when the clinician is confronted with a pa- tient who has a cleft and other associated anomalies. The tables provide a rapid way of sorting through the recognized syndromes with orofacial clefting in search of a possible overall diagnosis. Given the diagnosis, the tables can also be used to find the frequency of clefting in the syndrome, other features of the syndrome, and pertinent references. Frequency of Syndromes with Clefting In 1970, it was noted that less than three per cent of all cases of clefting were associated with syndromes (Fraser, 1970), although the basis for this estimate was not given. In 1971, Gorlin et al. reviewed 72 syndromes in which clefting occurred. In 1976, we discussed ap- proximately 117 syndromes with orofacial clefting (excluding lateral and oblique facial Dr. Cohen is Professor of Oral & Maxillofacial Sur- gery, School of Dentistry, and Professor of Pediatrics, School of Medicine, University of Washington, Seattle, Washington. This project was supported by U.S.P.H.S. Grant No. DE 04502-01. Modified and updated from Cohen, M. M., Jr., Dep- morphic syndromes with craniofacial manifestations, In Stewart, R. E., and Prescott, G. H., editors, Oral Facial Genetics, St. Louis: The C.V. Mosby Co., 1976. clefts and mandibular clefts) (Gorlin et al., 1976). The current paper tabulates 154 such conditions. Thus, syndrome delineationis a dynamic, ongoing process that results in rapid expansion of our knowledge. Today we are aware of more than twice as many syndromes with orofacial clefting as we were in 1971. Use of Syndromes Tables A summary of syndromes with cleft lip and cleft palate (Tables 2-7) is provided in Table 1. The total number of syndromes listed is 176. Lateral, oblique, and mandibular clefts have not been included nor has an attempt been made to include syndromes with congen- ital palatopharyngeal incompetence. Several conditions appear more than once in Tables 2 through 7. For example, the Stickler syn- drome may include cleft palate (Table 3-Syndromes with Cleft Palate) or the Ro- bin complex (Table 4-Syndromes with the Robin Complex). There are 22 such instances of duplication in Tables 2 through 7. These are subtracted from the total number of syn- dromes. Thus, we are left with 154 syndromes with clefting. However, this is an underesti- mate since some syndromes listed are etiolog- ically heterogeneous. For instance, the Larsen syndrome has autosomal recessive etiology in some families and autosomal dominant inher- itance in others. Nevertheless, in the total number of syndromes with clefting (154), the Larsen syndrome is counted only once. If we counted the conditions known to be etiologi- cally heterogeneous more than once, the total number of syndromes would be somewhat increased. 306
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Transcript
Syndromes with Cleft Lip
and Cleft Palate
M. MICHAEL COHEN, JR., D.M.D.Seattle, Washington 98195
A series of tables is presented as a diagnostic aid for the clinician when he confronts apatient who has acleft lip and/or palate, together with associated anomalies. The tablesprovide a rapid way of sorting through the recognized syndromes with orofacial clefting insearch of apossible overall diagnosis. Today, 154 such syndromes are recognized. This ismore than twice as many as were known in 1971. Undoubtedly, many new syndromeswith orofacial clefting will be delineated in the future.
Isolated cleft lip and cleft palate are com-mon malformations. Their epidemiologic, ge-netic, and pathogenetic characteristics havebeen reviewed elsewhere (Burdi et al., 1972;Drillien et al., 1970; Fraser, 1970, 1971; Gor-lin et al., 1971a, 1976; Woolf, 1971). Thepurpose of this paper is to present a series oftables that can be used as a diagnostic aidwhen the clinician is confronted with a pa-tient who has a cleft and other associatedanomalies. The tables provide a rapid way ofsorting through the recognized syndromeswith orofacial clefting in search of a possibleoverall diagnosis. Given the diagnosis, thetables can also be used to find the frequencyof clefting in the syndrome, other features ofthe syndrome, and pertinent references.
Frequency of Syndromes with CleftingIn 1970, it was noted that less than three
per cent of all cases of clefting were associatedwith syndromes (Fraser, 1970), although thebasis for this estimate was not given. In 1971,Gorlin et al. reviewed 72 syndromes in whichclefting occurred. In 1976, we discussed ap-proximately 117 syndromes with orofacialclefting (excluding lateral and oblique facial
Dr. Cohen is Professor of Oral & Maxillofacial Sur-gery, School of Dentistry, and Professor of Pediatrics,School of Medicine, University of Washington, Seattle,Washington.
This project was supported by U.S.P.H.S. Grant No.DE 04502-01.
Modified and updated from Cohen, M. M., Jr., Dep-morphic syndromes with craniofacial manifestations, InStewart, R. E., and Prescott, G. H., editors, Oral FacialGenetics, St. Louis: The C.V. Mosby Co., 1976.
clefts and mandibular clefts) (Gorlin et al.,1976). The current paper tabulates 154 suchconditions. Thus, syndrome delineationis adynamic, ongoing process that results in rapidexpansion of our knowledge. Today we areaware of more than twice as many syndromeswith orofacial clefting as we were in 1971.
Use of Syndromes TablesA summary of syndromes with cleft lip and
cleft palate (Tables 2-7) is provided in Table1. The total number of syndromes listed is176. Lateral, oblique, and mandibular cleftshavenot been included nor has anattemptbeen made to include syndromes with congen-ital palatopharyngeal incompetence. Severalconditions appear more than once in Tables2 through 7. For example, the Stickler syn-drome may include cleft palate (Table3-Syndromes with Cleft Palate) or the Ro-bin complex (Table 4-Syndromes with theRobin Complex). There are 22 such instancesof duplication in Tables 2 through 7. Theseare subtracted from the total number of syn-dromes. Thus, we are left with 154 syndromeswith clefting. However, this is an underesti-mate since some syndromes listed are etiolog-ically heterogeneous. For instance, the Larsensyndrome has autosomal recessive etiology insome families and autosomal dominant inher-itance in others. Nevertheless, in the totalnumber of syndromes with clefting (154), theLarsen syndrome is counted only once. If wecounted the conditions known to be etiologi-cally heterogeneous more than once, the totalnumber of syndromes would be somewhatincreased.
306
Table 1 also lists the syndrome breakdown
by etiology. There are a total of 79 monogenic
syndromes. There are approximately as many
autosomal recessive syndromes (39) as there
are autosomal dominant ones (35). The in-
heritance patterns of several monogenic syn-
dromes are uncertain at the present time as,
for example, in autosomal dominant vs X-
linked dominant transmission. In such in-
stances, only one mode of inheritance identi-
fies the syndrome for inclusion in Table 1,
although both possibilities are listed under
"Etiology" in the tables of specific syndromes
(Tables 2-7). There are few X-linked syn-
dromes (5) or environmentally-induced syn-
dromes (6), but there are many chromosomal
syndromes (29).
Many syndromes of unknown genesis ap-
pear in Tables 2 through 7 with a total of 40
such syndromes appearing in the summary in
Table 1. Obviously, many more syndromes of
unknown genesis occur than appear in the
tables. In order to be included in the tables as
a syndrome of unknown genesis, associated
anomalies either had to occur with some reg-
ularity or had to be especially distinctive in
combination.
Table 2 presents syndromes with cleft lip
TABLE 1. Summary of syndromes with cleft lip and
palate.
category number
Syndromes with cleft lip-palate 28Syndromes with cleft palate 77Syndromes with the Robin complex 18
Chromosomal syndromes with clefts 29Median cleft lip 7Associations with clefting 17
Total number ofsyndromes listed in tables 183Syndromes appearing in more than one -22
310 Cleft Palate Journal, October 1978, Vol. 15 No. 4
TABLE
3-Co
ntin
ued
Clef
tpa
late
/connective
tissue
dysplasiasyndrome
Clef
tpa
late
/lat
eral
syne
chia
esy
ndro
me
Clef
tpa
late
/sta
pesfixation
syn-
drom
e
Clei
docr
ania
ldysplasia
Davi
s-La
fersy
ndro
me
Diastrophicdw
arfi
sm
Donlan
synd
rome
Dubowitz
syndro
me
Eastmansy
ndro
me
Ectrodactyly-cleft
pala
tesy
n-dr
ome
Font
aine
syndrome
Gareis-Smith
synd
rome
Gord
onsy
ndro
me
Katc
her-
Hall
synd
rome
Lars
ensyndrome
Cerv
ical
fusi
ons,
down
slan
ting
palpébral
fiss
ures
,micro-
gnat
hia,
disl
ocat
edra
dial
heads,
clinodactyly,
positional
foot
deformities
'
Lateralsynechiae
Stapes
fixa
tion
,hypodontia,
skel
etal
anomalies
Largecalvaria,re
lati
vely
small
face
,wormian
bone
s,pe
r-
sist
ent
font
anel
s,supernumerary
teet
h,delayederuption
orfailure
of
eruption,
absent
or
hypoplastic
clavicles,
otherskeletal
abnormalities
'
Mental
defi
cien
cy,hypotonia,growth
deficiency,
fron
tal
boss
ing,
epicanthal
folds,
otherabnormalities
Short
stat
ure,
contractures,cl
ubfo
ot,hi
tch-
hike
r'sthumb,
cyst
icea
r,otherdefects
'
Thin
skin
,eczema,
dental
hypoplasia,
micrognathia,
growth
fail
ure,
pancreaticinsufficiency
Growth
defi
cien
cy,mildmentaldeficiency,microcephaly,
blepharophimosis,micrognathia,eczema
Horseshoe
kidn
eys,
cardiacanomalies,
severe
mental
de-
fici
ency
,neuromuscularabnormalities,malarhypoplasia,
broad
nasa
lro
ot,prominent
ears,
plagiocephaly,hypo-
dontia
Ectrodactylyandsyndactyly(handsand
feet
)
Micrognathia,
dysp
last
icears,
ectrodactylyand
syndac-
tyly
(feet),mental
defi
ciency
insome
case
s
Shortst
atur
e
Camptodactyly,clubfoot
Short
stature,
mental
defi
cien
cy
Multiple
dislocations,sk
elet
aldefects,
flat
face
Submucous
clef
tpa
late
(2/2
)
Common
2/2
Submucous
cleft
common
palate
2/2
Common
Common
Submucous
clef
t,bi
fid
uvulacommon
1/3
Common
Submucous
cleftwith
bifi
d
uvulauncommon
Common
Common
Common
Uncommon
?X-linked
orautosomal
re-
cess
ive
Autosomaldominant
Autosomal
recessive
Autosomaldominant
?Autosomal
recessive
Autosomal
recessive
?Autosomal
recessive
Autosomal
rece
ssiv
e
Autosomal
recessive
Autosomaldominant
Autosomaldominant
Dominant
(X-linked?)
Autosomaldominant
?Autosomal
rece
ssiv
e
Autosomal
recessiveandau-
tosomaldominant
type
s
Cohen,
1977
Fuhrmann
etal.,
1972
Gorlin
etal.,
1971b
Gorlin
etal
.,1976
Davisand
Lafe
r,1976
Walker
etal
.,1972
Donlan,
1977
Gorlin
etal
.,1976
Eastmanand
Bixler,1977
Opitz,
1975
Fontaine
etal
.,1974
GareisandSmith,
1971
Gordon
etal
.,1969
Katcherand
Hall,
1975
Cohen, synprRomEs
Gorlin
etal
.,1976
(continuedonnextpage)
311
TABLE
3-Continued
syndro
me
Lowry-Miller
synd
rome
Marden-Walkersy
ndro
me
Marf
ansyndrome
Mege
piph
ysea
ldw
arfi
sm
Micrognathic
dwar
fism
Mult
iple
pterygia
synd
rome
Nance-Sweeneychondrodyspla-
sia
Nage
rac
rofa
cial
dyso
stos
is
Oral
-fac
ial-
digi
talsyndrome
I
Oral
-fac
ial-
digi
talsy
ndro
meII
Otopalatodigital
synd
rome
Pala
ntsyndrome
Pena-Shokeir
synd
rome
stri
king
features
Persistent
truncus
arte
rios
us,ab
norm
alri
ghtpulmonary
arte
ry,in
trau
teri
nedeat
h
Blepharophimosis,
joint
contractures,
muscular
hypo
-to
nia,
othe
rab
norm
alit
ies
Dolichostenomelia,
arac
hnod
acty
ly,ec
topi
ale
ntis
,aortic
aneurysm
Enla
rged
join
ts,ab
brev
iate
dlo
ngbo
nes,
larg
eep
iphy
ses,
flared
metaphyses
Micromelic
dwarfism,smallmandible?
clef
tvertebrae
Multiplepterygia
Rhizomelicdwarfism,
dysp
last
icea
rs,th
ickle
athe
rysk
in,
soft
tissue
calc
ific
atio
ns
Hypoplastic
ears
,downslantingpalpebral
fiss
ures
,micro-
gnat
hia,
prea
xial
upperlimb
deficiency
Dystopia
canthorum,
hypoplastic
alar
cartilages,
mili
a,multiple
fren
ula,
late
rall
ycleftap
late
,bi
fidtongue,mal-
posed
teet
h,toothanomalies,brachydactyly,syndactyly,
clin
odac
tyly
Lobedtongue,manual
polydactyly,bilateralpolysyndac-
tyly
oftheha
lluc
es
Frontal
prominence,
ocular
hypertelorism,
broad
nasa
lro
ot,
occi
pita
lprominence,
conduction
deaf
ness
,sh
ort
terminal
phalangesand
shor
tna
ilson
fingersand
toes
,fi
fth
fing
erclinodactyly,widelyspacedcurved
toes
,dis-
loca
tion
ofthera
dial
heads,pectusexcavatum
Microcephaly,
shor
tst
atur
e,mental
deficiency,almond-
shaped
deep
-set
eyes
,bulbous
nasa
lti
p,cl
inod
acty
lyof
toes
,prominenceofanteromedial
aspectsofwrists
Prenatalon
setgrowthdeficiency,pe
rina
talde
ath,
low-
set
ears
,ocular
hypertelorism,
epicanthal
fold
s,depressed
nasal
tip,
muscular
atrophy,
arthrogryposis,
club
feet
,camptodactyly
relative
freq
uenc
yof
clef
tpalate
insyndrome
2/2
Uncommon
Veryuncommon
Common
Common
Uncommon
Common
Uncommon
Common
Clef
tpa
late
uncommon
etio
logy
Autosomal
rece
ssiv
e
Autosomal
rece
ssiv
e
Autosomaldominant
?Autosomal
recessive
Autosomal
recessive
Autosomal
rece
ssiv
e
Autosomal
rece
ssiv
e
Autosomal
rece
ssiv
e,maybe
etiologicallyhe
tero
gene
sis
X-linkeddominant,le
thal
in
themale
Autosomal
recessive
X-linked
Autosomal
rece
ssiv
e
?Autosomal
recessive
refe
renc
es
Lowryand
Miller,
1971
MardenandWalker,
1966
Gorlin
etal.,
1976
Gorlin
etal.,
1973
Maroteaux
etal.,
1970
Gorlin
etal
.,1976
NanceandSweeney,
1970
Herrmann,
1975
Gorlin
etal.,
1976
_
Gorlin
etal.,
1976
Gorlin
etal.,
1976
Palant
etal.,
1971
Pena
and
Shok
eir,
Mease
etal
.,1976
1974
;
(continuedon
nextpage)
312 Cleft Palate Journal, October 1978, Vol. 15 No. 4
TABLE
3-Continued Persistent
left
superior
vena
cava
syndro
me
Phillips-Griffiths
syndrome
Pseu
dodi
astr
ophi
cdw
arfi
sm
Rollandsy
ndro
me
Rudigersy
ndro
me
Saet
hre-
Chot
zensy
ndro
me
Sald
ino-
Noon
ansyndrome
Saysyndrome
Skeletal-apocrine-mammary
syndrome
Smith-Lemli-Opitzsyndrome
Spondyloepiphyseal
dysp
lasi
acongenita
Stic
kler
syndrome
Pers
iste
ntleft
supe
rior
vena
cava
,atrial
sept
aldefect,
club
foot
Grow
thdeficiency,
macular
colo
boma
s,hallux
valg
us,
flex
ion
defo
rmit
iesof
the
dist
alinterphalangealjo
intof
the
fift
hfi
nger
s,ot
herab
norm
alit
ies
Flat
nose
,oc
ular
hype
rtel
oris
m,mi
crog
nath
ia,
full
chee
ks,
malformed
ears
,micromelia,
tali
peseq
uino
varu
s,ex
ter-
nall
yrotated
hand
s,toean
omal
ies,
othe
rab
norm
alit
ies
Shor
tst
atur
e,sh
ortbr
oadtubularbo
neswith
meta
phys
eal
wide
ning
,acceleratedca
rpal
bone
matu
rati
on,bo
wing
oflegs,
aswe
llas
thighs
and
forearms,
shor
tbr
oad
pelv
iswith
wide
flar
edil
iacwi
ngs,
vert
ebra
lanomalies,
resp
ira-
tory
distress,mi
crog
nath
ia
Grow
thre
tard
atio
n,flexion
contractures
ofthe
hand
s,si
mian
crea
ses,
smal
lfingersand
fing
erna
ils,
uret
eral
ste-
nosi
s,co
arse
faci
es,lethal
duri
ngfi
rstye
arof
life
Craniosynostosis,
faci
alas
ymme
try,
low-set
frontal
hair
-li
ne,pt
osis
ofth
eeyelids,
deviated
nasa
lse
ptum
,va
riab
lebrachydactyly,
vari
able
cutaneous
syndactyly
especially
ofth
e2n
dan
d3rd
fing
ers.
Shor
t-li
mbed
dwarfism,po
stax
ialpolydactyly,
brac
hyda
c-ty
ly,na
rrow
thor
ax,protuberantab
dome
n,de
athin
uter
oor
shor
tly
afte
rbi
rth,
multiple
inte
rnal
malf
orma
tion
sespecially
transposition
ofthe
great
vessels,
hypo
plas
tic
lungs,
anal
atre
sia,
anomaliesof
thege
nita
lor
gans
Smal
lhe
adsi
ze,la
rgeears,sh
ortst
atur
e,tapering
fing
ers,
hypo
plas
tic
dist
alphalange
s,pr
oxim
ally
plac
edth
umbs
Ulnarray
defi
cien
cyinvo
lvin
g4than
d5th
fingers,
apo-
crin
eglan
dhypoplasia,mammary
glan
dhypoplasia,
de-
laye
dsexual
matu
rati
on
Grow
thdeficiency,
mental
deficiency,
broa
dnasal
tip,
anteverted
nost
rils
,pt
osis
ofthe
eyel
ids,
broad
alve
olar
ridg
es,
micrognathia,
hypo
spad
ias,
cryp
torc
hidi
sm,
2-3
synd
acty
lyof
feet
Disproportionate
shor
tstatureinvolvingne
ckan
dtr
unk,
myopia,
retinalde
tach
ment
Myopia,
reti
nal
deta
chme
nt,
flat
midface,
prominent
joints
with
dege
nera
tive
join
tdi
seas
e,mild
epip
hyse
aldysplasia,
over
-tub
ulat
ionof
long
bone
s,ot
herabnormal-
itie
s
Common
Appa
rent
lycommon
2/2
2/3
2/2
Rare
Uncommon
Appa
rent
lycommon
Bifi
duv
ula
(1/7)
Uncommon
Common
Common
X-linked
rece
ssiv
e
?Autosomal
rece
ssiv
e
?Autosomal
recessive
Sporadic.One
report
sug-
gest
saf
fect
edsibs.Qu
esti
on-
able
auto
soma
lre
cess
ive
Auto
soma
lre
cess
ive
Autosomaldo
mina
nt
Auto
soma
lrecessive
Autosomaldo
mina
nt
Autosomaldo
minant
vs.X-
link
eddo
mina
nt
Auto
soma
lrecessive
Autosomaldo
mina
nt
Auto
soma
ldo
mina
nt
Gorlin
etal.,
1970
Phil
lips
and
Grif
fith
s,19
69
Burg
ioet
al.,
1974
Lang
eret
al.,
1976
Rudi
ger
etal
.,1971
Pant
keet
al.,
1975
Gord
onan
dBr
own,
1976
Say
etal
.,19
75
Pallisteret
al.,
1976
Gorlin
etal.,
1976
Spra
nger
andLanger,19
70
Cohen, synDpRoOMEs
Herr
mann
andOp
itz,
1975
313
(c
onti
nued
onne
xtpa
ge)
TABLE
3-Continued
synd
rome
stri
king
feat
ures
relative
frequencyof
cleftp
alate
insy
ndro
meetiology
refe
renc
es Tr
each
erCollinssy
ndro
me
VSR
syndrome
Wsy
ndro
me
Wall
acesyndrome
Weav
er-W
illi
amssy
ndro
me
Wild
erva
ncksy
ndro
me
Environmentally-InducedSy
ndro
mes
Amin
opte
rinsy
ndro
me
Feta
lal
coho
lsy
ndro
me
Thal
idom
idesy
ndro
me
Unknown-GenesisSyndromes
Beck
with
-Wie
dema
nnsy
n-dr
ome
Char
lieM.
syndro
me
Dysp
last
iclo
w-se
tea
rs,downslanting
palp
ebra
lfissures,
micrognathia
Shor
tst
atur
e,mesomelic
shortness
ofarms,
rhiz
omel
icsh
orte
ning
oflo
wer
limb
s,sc
olio
sis,
join
tco
ntra
ctur
es,
prom
inen
tzy
goma
s,br
oadmaxillaan
dma
ndib
le
Mental
defi
cien
cy,
seizur
es,
frontalpr
omin
ence
,an
teri
orco
wlic
k,ocular
hypertelorism,
downslanting
palp
ebra
lfi
s-su
res,
strabismus,br
oad
nasal
tip,
cent
ralnotchof
uppe
rlip,
cong
enit
ally
abse
ntcentral
inci
sors
,pr
omin
entlower
faci
alheight,
cubi
tus
valgus,su
blux
atio
nat
radio-ulnar
join
ts,camptodactyly,
clinodactyly
Shortli
mbs,
deformed
ribcage,hy
droc
epha
lus,
hypo
plas
-ti
clu
ngs,
congenital
hear
tde
fect
s,ce
ntra
lnotchof
uppe
rlip
Mental
defi
cien
cy,
dimini
shed
subc
utan
eous
tissue
and
musc
lema
ss,microcephaly,hypoplastic
ears
,mi
dfac
ehy-
popl
asia
,de
epse
tey
es,smalldo
wn-t
urne
dmouth,
mal-
form
edte
eth,
long
thin
neck,ge
nera
lize
dbo
nehypoplasia,
increasedtu
bula
tion
oflo
ngbo
nes,
delayedos
seou
sma
t-ur
atio
n,do
wn-s
lopi
ngribs
,cl
inod
acty
ly
Cervical
fusi
on,deafness,ab
duce
nsparalysis
Cranial
dysplasia,
craniosynostosis,
micr
ogna
thia
,cl
ub-
foot
,hy
poda
ctyl
y
Grow
thde
fici
ency
,mental
deficiency,mi
croc
epha
ly,na
r-row
palp
ebra
lfissures,
cong
enit
alheart
defe
cts,
join
tan
omal
ies,
othe
rab
norm
alit
ies
Phoc
omel
ia,dy
spla
stic
ears
,facial
hemangioma,
atre
siaof
esophagusor
duodenum,tetralogyof
Fallot,renalag
enes
is
Macr
oglo
ssia
,om
phal
ocel
e,neonatal
hypoglycemia,
gi-
gant
ism,
othe
rab
norm
alit
ies
- Ocular
hypertelorism,
seve
nthne
rve
paralysis
inso
meca
ses,
abse
ntor
conical
incisors,va
riab
lelimb
anomalies
from
oligodactyly
tope
rome
lia
Common
Common
Common
Appa
rent
lycommon
Uncommon
Uncommon
Rare
Rare
Autosomaldo
mina
nt
Autosomaldo
mina
nt
?Autosomaldo
mina
nt
Auto
soma
lrecessive
Autosomal
rece
ssiv
e
Auto
soma
ldo
mina
nt
Aminopterin
asan
abortifa-
cien
tduring
the
firs
ttr
imes
-terof
preg
nanc
y
Chro
nic
alcoholi
smdu
ring
pregnancy
Thalidomide
duri
ngpr
eg-
nanc
y
Most
case
ssp
orad
ic,few
fa-
milial
inst
ance
s
Spor
adic
todate
Gorl
inet
al.,
1976
Herr
mann
and
Opit
z,19
77
Pallisteret
al.,
1974
Wall
ace
etal.,
1970
Weav
erandWi
llia
ms,
1977
Wild
erva
nck,
1960
Shaw
and
Steinback,
1968
Jone
set
al.,
1973
Shepard,
1976
Gorlin
etal
.,19
76
Gorl
inet
al.,
1976
(c
onti
nued
onne
xtpa
ge)
314 Lleft Palate Journal, October 1978, Vol. 15 No. 4
TABLE
3-Co
ntin
ued
Clef
tpalate/acanthosis
nigr
i-ca
nssyndrome
Coff
in-S
iris
synd
rome
Femo
ralhypoplasia-unusual
fa-
cies
synd
rome
Glos
sopa
lati
nean
kylo
sissy
n-dr
ome
Hausamsyndrome
Hosy
ndro
me
Klippel-Feil
synd
rome
Knie
stsyndrome
deLa
ngesy
ndro
me
Lowry-MacLeansy
ndro
me
Maje
wski
synd
rome
Cuti
sgy
ratu
m,acanthos
isni
gric
ans,
ocular
hypertelorism,
neonatal
teet
h,hypodontia,
bifi
dni
pple
s,hypogonadism
Coarse
faci
es,ab
sent
fift
hfingernailsan
dto
enai
ls,gr
owth
defi
cien
cy,mental
defi
cien
cy,otherab
norm
alit
ies
Upsl
anti
ngpa
lpeb
ral
fiss
ures
,shortnose
with
hypo
plas
tic
alar
cartilages,lo
ngph
iltr
um,shortor
abse
ntfe
murs
and
fibu
las,
othe
rde
fect
s
Glossopalatine
ankylosis,
micr
ogna
thia
,hypodontia,
var-
lableli
mban
omal
iesfr
omol
igod
acty
lyto
peromelia
Craniosynostosis,as
ymme
tric
craniofacies,oc
ular
prop
to-
sis,
flat
forehead,
low-set
posterior
hairline,contractures
atelbows
and
knees,
plan
tar
furr
ows,
abse
ntth
umbs
,ab
sent
midd
leph
alan
ges
(various),
imperforatean
us,sud-
den
infa
ntde
athsy
ndro
me
Micr
ogna
thia
,wormian
bones,
cong
enit
alhe
art
defect,
disl
ocat
edhi
ps,
abse
ntti
biae
,bo
wed
fibu
lae,
prea
xial
polydactyly
(feet),si
mian
crea
ses,
ulnardeviationof
fin-
gers
Bloc
kfu
sion
ofce
rvic
alvertebrae
Disproportionate
dwarfism,roun
dfa
ce,flat
midf
ace,
short
neck
,lo
rdos
is,kyphoscoliosis,
tibial
bowi
ng,
progressively
enla
rged
stif
fand
pain
fuljoints,cl
ubfe
et,se
vere
myop
ia,
retinalde
tach
ment
,ca
tara
cts,
deaf
ness
,re
curr
ent
resp
i-ra
tory
infe
ctio
ns
Microbrachycephaly,confluentey
ebro
ws,an
teve
rted
nos-
trils,
long
phil
trum
,th
inli
ps,gr
owth
defi
cien
cy,me
ntal
defi
cien
cy,li
mbanomalie
s,ot
herabnormalities
Micr
ocep
haly
,cr
anio
syno
stos
is,
seiz
ures
,prominent
beak
ednose,down-slantingpa
lpeb
ral
fiss
ures
,pr
opto
sis,
glaucoma,
delayed
dent
aldevelopment,
atri
alseptal
de-
fect
,ev
entr
atio
nof
thedi
aphr
agm,
narr
owhyperconvex
fing
erna
ils
Shortna
rrow
thor
ax,pr
eaxi
aland
postaxialpolydactyly
ofha
nds
and
feet
,sh
ort
tibias,
protuberantab
dome
n,cardiac
anom
alie
s,genital
anomalies,
medi
ancleft
lip
Very
uncommon
Common
Uncommon
2/2
Fair
lycommon
Common
Fairlycommon
Common
Spor
adic
todate
Most
case
ssp
orad
icto
date,
one
know
nin
stan
ceof
af-
fect
edsi
bs
Sporadic
todate
Allca
sessporadic
toda
te
Unknown(MZ
twin
s)
Spor
adic
todate
Almo
stal
lca
ses
sporadic,
few
fami
lial
instances
(aut
o-somal
recessive)
Almo
stal
lcasessp
orad
icto
date;onekn
own
familial
in-
stance
(aut
osom
aldo
mi-
nant?)
Most
case
ssp
orad
ic,fe
wfa
-milial
inst
ance
s
?Sp
orad
ic
Allca
sessp
orad
icto
date
Beare
etal.,
1969
Gorl
inet
al.,
1976
Daen
tlet
al.,
1976
Gorl
inet
al.,
1976
Hausam
etal.,
1977
Ho
etal
.,19
75
Gorl
inet
al.,
1976
;Gu
nder
son
etal
.,19
67
Sigg
ers
etal.,
1974
Berg
etal.,
1970
LowryandMa
cLea
n,1977
Cohen, synDpRoMEs
Spra
nger
andGr
imm,
1974
315
(c
onti
nued
onne
xtpa
ge)
316 Cleft Palate Journal, October 1978, Vol. 15 No. 4
occurrence of two or more anomalies in the
same patient on a nonrandom basis. The
etiology and the phenotypic spectrum of
anomalies are not well-defined and need fur-
ther delineation.references
Non-Specificity of Clefting
Shpr
intz
enet
al.,
1978
Wald
enet
al.,
1971
Hall
etal.,
1977
The syndromes presented in Tables 2
through 7 require several general comments.
First, syndromes are composed of a number
of malformations, each of which is individ-
ually nonspecific. Each malformation may
occur as an isolated abnormality; each may
also occur as a component part of various
syndromes. Because malformations occur
with different frequencies in different syn-
dromes, they are facultative rather than oblig-
atory, that is, they may or may not be present
in a particular instance of a syndrome in
which they are said to occur. For example,
although congenital heart defects are com-
mon in the Meckel syndrome, in some in-
stances, the heart is normal.
Pathognomonic anomalies for various mal-
a formation syndromes are either nonexistent
or very rare. Since individual malformations
are both nonspecific and facultative, the di-
agnosis of a syndrome is made from the overall
pattern of abnormalities. The more anomalies
there are in a syndrome, the easier the con-
dition is to diagnose because, even if some of
the features are not expressed, the overall
pattern is still discernible. Conversely, the
fewer abnormalities there are in a syndrome,
the more difficult the condition is to diagnose
if some of its features are not expressed. In
general, diagnosis of any syndrome in which
some of its features are not expressed is more
of a problem in a sporadic occurrence than in
a familial instance.
Tables 2 through 7 should be interpreted
in accordance with the preceding discussion.
Thus, some of the phenotypic characteristics
listed under "distinct features'" may not be
present in some cases. Furthermore, many
low-frequency anomalies that occur in various
syndromes are not listed, although they may
be found in the references for each condition.
Finally, some syndromes are incompletely de-
lineated at the present time. In these in-
stances, new findings will undoubtedly come
to light in the future.
etiology
Most
case
ssporadic;fo
urfa
-
?Sp
orad
ic.
Only
one
case
mili
alin
stan
ces
know
n.
?Sporadic
pala
tecl
eft
relative
frequencyof
clef
tpalate
insy
ndro
me
Subm
ucou
scommon
1/1
striking
feat
ures
except
skul
lbase
and
clav
icle
s,disproportionately
smal
ltr
unkan
dla
rgehead
,oc
ular
hype
rtel
oris
m,flipper-like
limb
s,po
lysy
ndac
tyly
ofha
nds,
threeblob-shapedto
eson
kidn
eys,
hypo
plas
tic
respiratory
trac
t,bicornaute
uter
us,
Hypo
toni
a,po
orfi
nemo
torcoordination,sp
ecif
iclearning
disability,ve
ntri
cula
rseptal
defe
ct,lo
ngface,
flat
mala
rregion,sy
noph
rys,
largeno
se,retruded
mandible,ov
erbi
te
each
foot
,pe
rsis
tent
left
superior
vena
cava,hypoplastic
abse
ntolfactorytr
act
and/
orpalate,ot
herab
norm
alit
ies,
deathfrom
resp
irat
ory
Shortbr
oad
ribs,mark
edunderossification
ofallbo
nes
dist
ress
Shorthumeri
andfemo
ra,long
radi
ian
dti
biae
synd
rome
Shor
tri
b-po
lydactylysy
ndro
me,
Type
III
Shprintzen
synd
rome
Walden
synd
rome
TABLE
3-Continued
Population Definition of a Syndrome
It is sometimes asked if an occasionally
observed abnormality is part of a syndrome
or not. How frequently does cleft palate, for
example, have to occur in a syndrome to be
considered a feature of that syndrome? Since
the pathogenesis of many syndromes is ob-
scure, there is no direct way of knowing.
However, by using a population definition of
a syndrome, it can be determined indirectly.
If a given abnormality occurs with greater
frequency in the syndrome population than it
does as an isolated abnormality in the general
population, it should be considered part of
the syndrome. This principle commits us to
statements such as "orofacial clefting is part
of the Down syndrome" because clefting oc-
curs three times more commonly than it does
as an isolated defect in the general population.
However, orofacial clefting is an extremely
uncommon feature of the Down syndrome.
The frequency of clefting in various syn-
dromes is not expressed as a percentage in the
tables because ascertainment biases inherent
in case reports in the literature tend to make
percentage estimates inaccurate and mislead-
ing. Generally, in all tables, frequency of cleft-
ing is listed as "common," "uncommon," or
"rare." "Common" should be interpreted to
mean that the frequency of clefting is at least
30 per cent or higher. Most frequencies listed
as "common" are considerably higher (except
in Table 5). When only a few instances of a
syndrome have been reported, a number may
be given in the frequency column. For exam-
ple, 2/5 means that clefting occurred in two
of the five reported cases. Since there are so
few cases known, it is not yet possible to
ascertain how common clefting will be in the
syndrome. '
Syndrome Delineation
To date, many anomalies reported in asso-ciation with cleft lip and cleft palate are notrecognized as constituting syndromes ofknown genesis. In epidemiologic studies ofclefting to date, the frequency with which oneor more malformations accompany clefts var-ies from eight to 50 per cent (Gorlin et al.,1976). Undoubtedly, many new syndromes ofknown genesis will be delineated from thisgroup in the future. Thus, the estimate of less
317Cohen, s¥NDROMES
than three per cent of all cases of cleftingbeing associated with "syndromes" (Fraser,1970) is too low in our opinion.The significance of syndrome delineation
cannot be overestimated. In a large study ofnewborn infants with multiple anomalies ofall kinds (malformation syndromes), only 40per cent had known, recognized entities (Mar-den et al., 1964). The other 60 per cent rep-resented provisionally-unique-pattern syn-dromes that needed to be further delineated.As an unknown syndrome becomes deline-ated, its phenotypic spectrum, its natural his-tory, and its inheritance pattern or risk ofrecurrence become known, allowing for betterpatient care and family counseling. If thephenotypic spectrum is known, the cliniciancan search for suspected defects that may notbe immediately apparent but which may pro-duce clinical problems at a later time, such asa hemivertebra in the Goldenhar syndrome.If a certain complication can occur in a givendisorder, such as a Wilms tumor in the Beck-with-Wiedemann syndrome, the clinician isforewarned to monitor the patient with intra-venous pyelograms. Finally, if the recurrencerisk is known, the parents can be counseledproperly about future pregnancies. This isespecially important if the risk is high and thedisorder is severely handicapping or disfigur-ing, has mental deficiency as one component,or has a dramatically shortened life span. Forexample, cleft palate or the Robin complex isa common feature of the Stickler syndrome,an autosomal dominant disorder with a 50per cent recurrence risk when one parent isaffected. In this condition, retinal detachmentis thought to occur in 20 per cent of reportedcases and blindness in 15 per cent (Herrmannet al., 1975). Genetic counseling is of greatimportance because the risk of developmentof serious ocular problems is high. This rela-tively common condition also illustrates theimportance of syndrome delineation becausethe entity was unknown and unrecognizedbefore 1965, although surely it existed beforethat time. Thus, the overall treatment pro-gram gains rationality if a syndrome is delin-eated. In contrast, with a provisionally-unique-pattern syndrome, the treatment pro-gram and overall management frequentlyleave something to be desired.
Other associated anomalies Gorlin et al., 1971afrequent
Shah et al, 1970;Gorlin et al., 1976
Other associated anomalies Gorlin et al., 1971afrequent
Gorlin et al., 197 1a
Gorlin et al., 1971a
Gorlin et al., 1971a
Usually occurs with absent Gorlin et al., 1971anostril on ipsilateral side
Gorlin et al., 197 1a
Gorlin et al., 197 1a
Gorlin et al., 197 1a
A major task in clinical genetics is to delin-
eate the unknown-genesis syndromes as rap-
idly as possible. Any clinician may be the first
to see and identify a patient with a new
malformation syndrome in which orofacial
clefting is a feature. As we pointed out earlier,
more than half of all malformation syndromes
are not recognized as known entities at the
present time. The discovery of a new malfor-
mation syndrome is equivalent to discovering
a new disease. Careful evaluation of the over-
all pattern of abnormalities (including minor
as well as major anomalies) is required. Pho-
tographic documentation of the clinical and
radiologic findings is essential, especially
when subtle phenotypic features defy verbal
description. A thorough study of various rel-
atives and an extended pedigree are necessary.
Ideally, the findings of such syndromes
should always be published. In practice, fa-
milial instances or two or more sporadic in-
stances of a new syndrome are usually pub-
lished. Provisionally-unique-pattern syn-
dromes are commonly filed away and not
published since their significance is uncertain.
However, the publication of a distinctive pro-
visionally-unique-pattern syndrome is like an
advertisement with a red flag; it reaches a
large audience and allows a few clinicians to
react by publishing similar cases. When this
happens, the syndrome delineation process is
underway.
Pathogenesis of Clefting
Finally, we should be careful not to confuse
the process of syndrome delineation with our
understanding or lack of understanding of a
syndrome's pathogenesis, even at the higher
stages of delineation. For example, in a syn-
drome of known genesis such as the recessively
inherited Meckel syndrome, we know nothing
about how the homozygous state of the
Meckel gene produces such diverse features as
encephalocele, polydactyly, polycystic kid-
neys, and orofacial clefting. Clearly, since so
much ettologic heterogeneity is known to occur in
human syndromes with orofacial clefting, we
should expect some pathogenetic heterogeneity in
the production of clefts as well. A great deal
about the pathogenesis of orofacial clefting
remains to be learned.
Since this manuscript went to press, Cen-
tervold (1978) has called my attention to some
new chromosomal syndromes with orofacial
clefting. Cleft palate has been observed in the
5-q-syndrome and cleft lip-palate in the 1-q-
syndrome.
Acknowledgment: I am extremely grateful to
Ms. Diane McDannald for her help with this
project.
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