Cohen,s¥NDROMES 307
Transcript of Cohen,s¥NDROMES 307
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
table __ __
Total number of syndromes 154
Syndrome breakdown by etiology
Etiology Number
Monogenic 79Autosomal dominant . (35)Autosomal recessive (39)X-linked (5)
Environmentally-induced 6
Chromosomal _ 29Unknown genesis ’ 40
Total 154
307Cohen, s¥NDROMES
and cleft palate. As an isolated defect, cleft lip
with or without cleft palate is etiologically
distinct from cleft palate (Fogh-Andersen,
1942). This distinction breaks down in some
malformation syndromes. For example, in the
autosomal dominant van der Woude syn-
drome in which clefts occur together with lip
pits, an affected individual may have cleft lip,
cleft lip and cleft palate, or cleft palate. The
van der Woude syndrome is found in Table
2. Any syndrome in which a cleft palate is
expressed without cleft lip ever occurring, as
in the Larsen syndrome, is found in Table 3.
Syndromes with cleft palate are much more
common (77) than syndromes with cleft lip-
palate (28).
Table 4 presents syndromes with the Robin
complex (cleft lip, micrognathia, and glossop-
tosis). Once thought to constitute a specific
syndrome, the Robin complex is now known
to be nonspecific, occurring sut generis or as a
component part of various syndromes (Cohen,
1976).
Table 5 presents chromosomal syndromes
associated with cleft lip and cleft palate. The
overwhelming majority of chromosomal syn-
dromes show an increase in clefting. Other
common abnormalities found in many chro-
mosomal syndromes are psychomotor and
mental retardation, growth deficiency, micro-
cephaly, malformed ears, congenital heart de-
fects, ocular hypertelorism, micrognathia, and
cryptorchidism (Lewandowski and Yunis,
1975).
Syndromes with median cleft lip are pre-
sented in Table 6. There are three major types
of median cleft lip. The form with the worst
prognosis is premaxillary agenesis which is
almost always associated with alobar holopro-
sencephaly, amentia, seizures, apnea, and a
very early demise. A second type of median
cleft lip results from persistence of the infra-
nasal furrow which frequently accompanies a
more generalized median facial dysrhaphia
with ocular hypertelorism, widely spaced nos-
trils, and lack of elevation of the nasal tip. A
third type, a pseudomedian cleft, occurs when
the insertion of the maxillary labial frenum
pulls up the middle part of the upper lip, as
in oral-facial-digital syndrome I.
Table 7 lists the known associations of var-
ious abnormalities with cleft lip and cleft
palate. An association may be defined as the
TABLE
2.Syndromeswi
thcl
eftli
p-pa
late
synd
rome
stri
king
feat
ures
rela
tivefrequencyof
clef
tlip-palate
insy
ndro
meet
iolo
gyre
fere
nces MonogenicSyndromes
Appe
ltsy
ndro
me
Bixler
synd
rome
Bowe
n-Ar
mstr
ongsyndrome
Clef
ting
/ank
yloble
phar
onsy
n-dr
ome
Clefting/enlarged
pari
etal
fora
mina
synd
rome
Cryptophthalmo
ssyndrome
Ectr
odac
tyly
-ect
oder
maldy
spla
-si
a-cl
efti
ngsynd
rome
Frei
re-M
aiasy
ndro
me
Feta
lface
syndro
me
Gorl
insyndrome
Hemifacialmicrosomia(Golden-
harsyndrome)
Hypertelorism-hypospadiassy
n-
drome
Juberg-Haywardsyndrome
Ocular
hypertelor
ism,
tetraphocomelia,
enlarged
penis
or
clit
oris
Hypertelorism,
micr
otia
,ectopic
kidn
eys,
congenital
hear
tdefect,growth
defi
cien
cy
Growth
reta
rdat
ion,
mental
defi
cien
cy,abnormal
elec
troe
n-cephalogram,syndactylyofto
es(2
-3,4-
5),hyperpigmented
area
s,ol
igod
onti
a,ankyloblepharon
fili
form
eadnatum
Ankyloblepharonfiliformeadnatum
Enlarged
parietal
foramina
Cryp
toph
thal
mos,
abnormal
fron
tal
hair
line
,va
riab
lesy
n-da
ctyl
yof
hand
sand
feet
,coloboma
ofalae
nasi
,genito-
urinaryan
omal
ies
Ectr
odac
tyly
(han
dsand
feet
),sp
arse
blondha
ir,oligodontia,
naso
lacr
imal
duct
obst
ruct
ion
Tetr
aper
omel
ia,la
rgede
form
edea
rs,sp
arse
hair,hypoplastic
nipp
les,
olig
odon
tia,
coni
cal
crown
form
,hypogonadism,
ment
aldeficiency
Macr
ocep
haly
,oc
ular
hypertelorism,
flat
nose
,ov
erfo
ldin
gof
heli
x,me
some
lia,
clin
odac
tyly
,ve
rteb
ralan
omal
ies,
geni-
talan
omal
ies
.
Mult
iple
basa
lce
llca
rcin
omas
,jaw
cyst
s,sk
elet
alan
omal
ies
Unil
ater
aldy
spla
stic
ear,
ear
tags
and/
orpi
t,un
ilat
eral
hypo
plas
iaof
mand
ibul
arramus,
and
vari
ably
epib
ulba
rde
rmoi
ds,
vert
ebra
lan
omal
ies,
cardiac
defects,
rena
lanom-
alie
s,ot
herabnormalities
Hype
rtel
oris
m,hy
posp
adia
s,ot
herab
norm
alit
ies
Microcephaly,hypoplastic
dist
ally
plac
edthumbs,
shor
tra
-dii
Common
Common
Apparently
com-
mon
Common
Uncommon
Uncommon
Common
Uncommon
Rare
Uncommon
Uncommon
Uncommon
Common
Autosomal
rece
ssiv
e;some
au-
thoritiesco
nsid
erth
issyndrome
and
the
pseudothalidomide
syndrome
tobe
identical
Autosomal
recessive
Autosomal
recessive
Autosomaldominant
Autosomaldominant
Autosomal
recessive
Autosomal
dominant
with
re-
duced
penetrance,may
beeti-
olog
ical
lyheterogeneous
with
anautosomal
recessivetype
Autosomal
recessive
Etio
logi
call
y__he
tero
gene
ous
with
common
auto
soma
ldom-
inanttype
and
rare
autosomal
rece
ssiv
etype
Autosomaldominant
Most
case
ssp
orad
ic,fe
wfamil-
ialinstances,
pedi
gree
sco
mpat
-ible
with
autosomaldominant
andautosomal
recessive
tran
s-mi
ssio
n
Autosomaldominantwith
pre-
domi
nant
lymalese
xlimitation
Autosomal
rece
ssiv
e
Appelt
etal.,
1966
Bixl
eret
al.,
1969
BowenandArmstrong,
1976
Gorlin
etal
.,19
71a
Gorlin
etal.,
1971a
IdeandWollschlaeger,
1969
Bixl
eret
al.,
1971
Frei
re-M
aia,
1970
Cohe
n,19
77
Gorl
inandSe
dano
,1972
Gorl
inet
al.,
1976
Opitz
etal.,
1969
Jube
rgandHayward,
1969
(continuedonnextpage)
308 Cleft Palate Journal, October 1978, Vol. 15 No. 4
TABLE
2-Continued
Meckel
syndrome
Ocul
o-de
nto-
osse
ousdy
spla
sia
PoplitealpEerygiumsyndrome
v
Pseudothalidomidesyndrome
Rapp-Hodgkinsyndrome
vanderWoudesyndrome
Waardenbergsyndrome
Envi
ronm
enta
lly-
Indu
cedSyndromes
Amnioticbandsyndrome
Feta
lhydantoinsyndrome
Feta
ltrimethadionesyndrome
Unknown-GenesisSy
ndro
mes
Clefting/ectropionsyndrome
Herrmannsyndrome
II
Pilo
ttosyndrome
Wildervanck-Smithsyndrome
Yongsyndrome
Polydactyly,
polycystic
kidn
eys,
encephalocele,
cardiac
anomalies,otherabnormalites
Narrow
nose,hypoplastic
alae,microcornea,
iris
anomalies,
syndactylyand
camptodactyly
offourth
and
fift
hfi
nger
s,
enamelhypoplasia
Popl
itea
lpterygia,musculoskeletalanomalies
especially
hy-
popl
asti
cdi
gits
,genitourinaryanomalies,otherabnormali-
ties
Tetraphocomelia,hypoplastic
cart
ilag
eofal
aeand
pinnae,
faci
alhemangiomas,mental
defi
cien
cy
Hypohidrosis,th
inwiry
hair,,dystrophic
nail
s
Lip
pits
Dystopiacanthorum,synophrys,heterochromiairides,deaf—
ness
,po
lios
is,vi
tiligo
Ring
cons
tric
tion
sand
amputations
of
digi
tsor
limbs,
en-
ceph
aloc
ele,
bizarre
faci
alcl
efts
,otherabnormalities
Digi
tand
nail
hypoplasia,unusual
faci
es,growthand
psy-
chomotorre
tard
atio
n,otheranomalies
Mental
defi
cien
cy,speech
diso
rder
,V-shapedeyebrows,ep
-
ican
thal
fold
s,low-setea
rswithoverfoldedhelix,
otheranom-
alie
s
Ocular
hypertelorism,
ectropion
of
lower
eyel
ids,
digi
tal
and/orlimbreductionde
fect
s
Microbrachycephaly,
cran
iosy
nost
osis
,symmetrically
mal-
formed
limb
s,mental
defi
cien
cy
Growthretardation,
mentalde
fici
ency
,microbrachycephaly,
ocular
hypertelorism,
malformed
ears,
high
nasa
lbr
idge
,
faci
alasymmetry,
shor
tneck,low
posterior
hair
line
,patent
ductusar
teri
osus
,hypoplasticex
tern
alge
nita
lia,
scol
iosi
s,ri
b
defects,
otherskelet
alanomalies
Mandibulofacial
dyso
stos
is,upperandlowerlimbdeficiency
Undifferentiatedmyopathy,
reti
niti
spigmentosa,short
stat
-
uremilddevelopmental
delay,
seiz
ures
Common
Rare
Common
Uncommon
Common
Common
Uncommon
Uncommon
Uncommon
Uncommon
Common
Incomplete
clef
t
lip
?
Autosomal
recessive
Autosomaldominant
Probablyautosomaldominant
Autosomal
rece
ssiv
e
Autosomaldominant
Autosomaldominat
Autosomaldominant
Amnioticbands
Diphenylhydantoinduring
pregnancy
Trimethadione
orparametha-
dioneduringpregnancy
Almost
all
cases
sporadic
to
date
,one
known
fami
lial
in-
stance
?Sporadic
todate
?Sporadic
todate
?Sporadic
todate
Sporadic
todate
Hsia
etal.,
1971
Gorlin
etal.,
1976
Gorlin,
etal
.,1968.
Herrmann
etal
.,19692
RappandHodgkin,
1968
Cervenka
etal.,
1967
PantkeandCohen,
1971
Jones
etal
.,1974
HansonandSmith,
1975b
Zackai
etal.,
1975
Gorlin
etal.,
197l
1a
Herrmann
etal.,
1969b
Pilo
tto
etal
.,1975
Cohen, s¥NDROMES
Bergsma,
1975
Yong
etal.,
1977
309
TABLE
3.Syndromeswi
thcl
eftpa
late
syndro
me
Mono
geni
cSyndromes
Aase
-Smi
thsy
ndro
me
Abru
zzo-
Eric
kson
synd
rome
Acroosteolysis
synd
rome
Aper
tsyndrome
Bencze
syndrome
Braun-Bayersy
ndro
me
Campomelic
synd
rome
Cere
broc
osto
mand
ibul
arsy
n-dr
ome
dela
Chap
elle
synd
rome
Chon
drod
yspl
asia
punc
tata
(rhizomelictype
)
Christiansyndro
me
Clef
tpalate/brach
ialpl
exus
neur
itis
synd
rome
striking
feat
ures
Hydr
ocep
haly
,Da
ndy-
Walk
ermalformation,
hip
dislo-
cation,malformed
ears,ot
hermalformations
Colo
boma
,la
rgesoft
ears
,flat
mala
rregion,sensorineural
deafness,hy
posp
adia
s,sh
ortst
atur
e,ot
herdefects
Dissolution
ofthe
terminal
phal
ange
swith
clubbing
offi
nger
s,sh
ort
staturekyphosis,ge
nua
valg
a,midfacehy-
poplasia,
micr
ogna
thia
,do
lich
ocep
haly
,ba
thro
ceph
aly,
premature
loss
ofte
eth
Craniosynostosis,oc
ular
hypertelorism,
down
slan
ting
pal-
pebral
fiss
ures
,proptosis,
midface
defi
cien
cy,symmetric
synd
acty
lyof
theha
nds
and
feet
minimally
involving
digi
ts2,
3,an
d4,
ment
aldeficiency
Faci
alasymmetry,
strabismus,amblyopia
Urin
ary
trac
tan
omal
ies,
rudimentary
dist
alphalanges
with
bifi
den
ds,co
nducti
ondeafness
Flat
face
,hypertelorism,
hypoplastic
scap
ulas
,th
orac
icvertebral
defe
cts,
bowi
ngof
femo
raand
tibiae,
pretibial
dimp
ling
,va
lgus
deformity
offe
et,other
abnormalites,
comm
only
lethal
before
sixmo
nths
ofage
Micr
ocep
haly
,posterior
ribgap
defe
cts,
othe
rabnormal-
itie
s,commonly
leth
aldu
ring
neon
atal
peri
od
Micromelic
dwarfism,
low-
set
ears
,ocular
hypertelorism,
flat
nasa
lro
ot,sh
ortcurved
bone
s(especiallyra
dius
and
ulna
),triangular
fibu
laan
dul
na,do
uble
phalanges,
ver-
tebr
alanomalies,
pate
ntforamen
oval
e,patent
duct
usar
teri
osus
,commonly
leth
al
Shortfe
mora
andhu
meri
,prominent
forehead,
flat
face,
cataracts,
stip
pled
epip
hyse
s,ot
her
abnormalities,
com-
monl
ylethal
Craniosynostosis,microcephaly,arthrogryposis,ad
duct
edthumbs
Recu
rren
tbr
achi
alpl
exus
neur
itis
,li
mite
dextension
atthe
elbows,wi
ngin
gof
the
scapulae,
facial
asym
metr
y,down-slantingpa
lpeb
ral
fiss
ures
,de
ep-s
ethy
pote
lori
cey
es
rela
tive
frequencyof
cleft p
alate
isy
ndro
me
fas
Common
Subm
ucou
scl
eftwith
bifi
duv
ulauncommon
Common
Subm
ucou
scl
eft
pala
tecommon
Clef
tuv
ulaon
ly(2
/5)
Common
Common
2/2
Uncommon
Common
Common
etiology
?Autosomaldo
mina
nt
Autosomaldo
mina
ntvs.X-
linked
domi
nant
Autosomaldo
mina
nt
Auto
soma
ldo
mina
nt
Auto
soma
ldo
mina
nt
?X-
link
edor
auto
soma
lre
-ce
ssiv
e
Autosomal
rece
ssiv
ety
pe,
etiologically
heterogeneous
Auto
soma
lre
cess
ive
Auto
soma
lrecessive
Autosomal
rece
ssiv
e
Autosomal
rece
ssiv
e
Auto
soma
ldo
mina
nt
refe
renc
es
Aase
andSm
ith,
1968
Abruzzoand
Erickson,
1977
Wele
berand
Beal
s,1976
Cohen,
1975
Benc
zeet
al.,
1973
;Co
hen,
1977
Brau
nand
Bayer,
1962
Opit
zet
al.,
1974
Lang
erandHe
rrma
nn,
1974
dela
Chapelle
etal.,
1972
Gorlin
etal
.,19
76
Christian
etal.,
1971
Eric
kson
,1974
(c
onti
nued
onne
xtpa
ge)
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.
TABLE
4.Co
ndit
ions
associated
with
theRobincomplex
318
frequencyof
Robincomplex
ingi
ven
condition
stri
king
feat
ures
condition
etiology
reference Mo
noge
nicSyndromes
Beck
with
-Wie
dema
nnsyndrome
Campomelic
synd
rome
Cere
broc
osto
mand
ibul
arsy
ndro
me
Diastrophicdw
arfi
sm
Donl
ansyndrome
Myot
onic
dystroph
y(s
ever
econgenital)
Persistent
left
superior
vena
cava
synd
rome
Radi
ohum
eral
syno
stos
issy
ndro
me
Spondyloepiphyseal
dysplasia
congenita
Stic
kler
synd
rome
Chro
moso
malSy
ndro
mes
Tris
omy
11q
Macroglossia,om
phal
ocele,
visceromegaly,
neon
atal
hypo
glyc
emia
,gigantism,
otherde
fect
s
Flat
face,hypertelorism,
hypo
plas
ticscapulas,th
orac
icve
rteb
ral
defe
cts,
bowi
ngof
femurs
and
tibi
as,pr
etib
ial
dimpling,valgus
defo
rmit
yof
foot,ot
herabnormalities
Micr
ocep
haly
,posteriorribga
pde
fect
s,ot
her
abno
rmal
itie
s
Short
stature,
cont
ract
ures
,cl
ubfo
ot,hitch-hiker's
thumb,
cystic
ear,
othe
rdefects
Thin
skin,ec
zema
,de
ntal
hypoplasia,mi
crog
nath
ia,
grow
thfa
ilur
e,pa
ncre
atic
insufficiency
Myot
onia
,pr
ogre
ssiv
emu
scle
wast
ing,
cataracts,
various
othe
rab
norm
alit
ies
Persistent
left
supe
rior
vena
cava,
atrial
septal
defect,
talipeseq
uino
varu
s
Radiohumeral
syno
stos
is,an
osmi
a
Disp
orpo
rtio
nate
shor
tst
atur
einvolvingne
ckan
dtr
unk,
myopia,
retinalde
tach
ment
'
Myop
ia,
reti
nalde
tach
ment
,fl
atmidface,
prom
inen
tjo
ints
with
dege
nera
tive
join
tdi
seas
e,mild
epip
hyse
aldysplasia,
overtubulation
oflong
bone
s,ot
her
abno
rmal
itie
s
Axia
lhypotonia,
limb
hypertonia,wr
inkl
edfa
ce,be
aked
nose,lo
w-se
tmalformed
ears
,sh
ortneck,na
rrow
ches
t,wi
dely
spac
edni
pple
s,co
ngen
ital
heart
defe
ct,re
nal
agenesis,malformationsof
urinary
trac
t,micropenis,
acet
abul
ardysplasia,
clubfoot
Uncommon,
isol
ated
clef
tpa
late
uncommon
Common
Common
Uncommon,
isol
ated
clef
tpa
latecommon
Cleftpalate
(2/2
)Robin
complex
(1/2)
Uncommon
Common
?Toofewca
sesknown
Uncommon,
isol
ated
clef
tpalatecommon
Common;
isol
ated
clef
tpa
latecommon
Micrognathia
most
common;
clef
tpalate
second
most
common;
glossoptosis
leas
tcommon
Most
case
ssporadic,few
fami
lial
instances
Autosomal
recessivetype,
etiologicallyheterogeneous
Autosomal
recessive
Autosomal
recessive
?Autosomal
recessive
Autosomaldominant
X-li
nked
recessive
?Autosomaldominant
Autosomaldominant
Autosomaldominant
Trisomy
forth
edi
stal
segmentof
thelo
ngarmof
chromosome
11
Cohe
ffet
al.,
1971
Stor
erandGr
ossm
an,
1974
Langer
andHerrmann,
1974
HansonandSm
ith,
19752;
Walker
etal
.,19
72
Donlan,
1977
Opitz,
1975
Gorl
inet
al.,
1970
°
HansonandSm
ith,
1975°
Holt
huse
n,19
72;Sp
rang
erandLa
nger
,1970.
Herrmann
etAa
l..,
1975
AuriasandLaurent,
1975
(continuedonnextpage)
Cleft Palate Journal, October 1978, Vol. 15 No. 4
TABLE
4-Co
ntin
ued
Teratogenically-Induced
Syndromes
Feta
lal
coho
lsynd
rome
Feta
lhydantoinsy
ndro
me
Feta
ltrimethadionesy
ndro
me
Unknown-GenesisSyndromes
Femo
raldy
sgen
esis
-unu
sual
faci
essy
ndro
me
Mart
solf
synd
rome
Robi
n-ac
cess
oryme
taca
rpal
synd
rome
Robi
n-am
elia
synd
rome
Growth
deficiency,mental
defi
cien
cy,microcephaly,
narrow
palpebral
fissures,congenital
heart
defects,
joint
anomalies,
otherabnormalities
Digitand
nail
hypoplasia,un
usua
lfa
ces,
growth
and
psychomotorretardation,
otheranomalies
Mental
deficiency,speech
disorders,
V-shaped
eyebrows,
epicanthus,low-setpo
ster
iorl
yrotatedears
with
overfolded
heli
x,cardiacanomalies,
irregularte
eth,
otherdefects
Upsl
anti
ngpalpebral
fissures,shortnose
with
hypo
plas
tical
arcartilages,long
philtrum,sh
ortor
abse
ntfemurs
and
fibu
las,
otherde
fect
s
Squa
reforehead,abnormal
ears
,wi
de-s
etey
es,sm
all
mouth,
mild
neck
webb
ing,
shor
tne
ck,rh
izom
elic
brachymelia,
broa
dthumb,
shor
tin
dex
fing
er,br
oad
hall
uces
with
valg
usde
form
ity,
postaxialhe
xada
ctyl
yof
the
feet,skeletal
abnormalities
Bila
tera
laccessoryme
taca
rpal
ofin
dexfi
nger
with
clinodactyly,pe
ctus
carinatum
Amel
ia
Uncommon
Uncommon,
clef
tli
pand
pala
teal
soob
serv
ed
Uncommon,
clef
tlipan
dpa
late
also
observed
Micrognathia
and
clef
tpa
late
common,
glos
sopt
osisuncommon
?Toofewca
seskn
own
?To
ofewca
sesknown
?Toofewca
seskn
own
Chronicalcoholi
smdu
ring
pregnancy
-
Diphenylhydantoindu
ring
pregnancy
Trimethadionedu
ring
pregnancy
Sporadic,causeunknown
Sporadic,ca
useunknown
Sporadic,on
einstance
ofaf
fect
edsi
bs
Spor
adic
,causeunknown
Jone
set
al.,
1973
Hans
onandSm
ith,
1975
b
Zack
aiet
al.,
1975
Daen
t!et
al.,
1975
Mart
solf
etal.,
1977
Holt
huse
n,19
72;Ge
witz
etal.,
1978
Holthusen,
1972
Cohen, synpromes 319
TABLE
5.Chromosomalsy
ndro
meswi
thcl
eftsand
palatalan
omal
ies
(part
I)
kary
otyp
e*
1q+
3p+
3P—3q+
4p-
5p-
6q-
7q+
7q-
10p+
10q+
11p+
stri
king
features
Beaked
nose,prominent
ears,micrognathia,longtapered
fingers,congenital
heart
defect,
involutedorabsentthymus
Microbrachycephaly,
frontalbossing,highforehead,ocularhypertelorism,ep
ican
thic
fold
s,largemo
uth,
shor
tne
ck,congenital
hear
tdefect
Distortedforehead,low-setea
rs,up
slan
ting
palpebral
fissures,sh
ortnose,anteverted
nostrils,
low
nasal
brid
ge,
micrognathia,
omphalocele
orumbilical
hernia,
tali
pes
equinovarus,
cong
enit
alheart
defects,
rena
lanomalies,
cryptorchidism,
failure
toth
rive
,fr
eque
ntea
rly
demi
se'
Seve
regr
owth
andpsychomotor
reta
rdat
ion,
seiz
ures
,hypotonia,
smal
lhead,oc
ular
hyper-
telo
rism
,prominent
glabella,do
wnsl
anti
ngpa
lpeb
ral
fiss
ures
,pr
eaur
icul
ardi
mple
,short
phil
trum
,downturnedmo
uth,
micrognathia,
cong
enit
alheart
defects,
cryp
torc
hidi
sm,hy-
posp
adia
s,di
mpli
ngat
thesacrum
|
Mental
defi
cien
cy,
ocul
arhypertelorism,
supe
rior
lypointed
ears
,fl
atna
sal
bridge,
mi-
crog
nath
ia,
displaced
nose,
card
iac
defe
cts,
sacr
aldimple,
limi
tati
onof
extension
atthe
elbo
ws,
skel
etal
anom
alie
s
Cat-like
crydu
ring
infa
ncy,
micr
ocep
haly
,round
face
,ocular
hypertelorism,
down
slan
ting
palp
ebra
lfissures,strabismus,
low-
set
ears
,mild
micr
ogna
thia
,me
ntal
defi
cien
cy,gr
owth
defi
cien
cy
Micr
ocep
haly
;ep
ican
thic
folds;
larg
e,lo
w-se
tmalformed
ears
;mi
crog
nath
ia;
shor
tneck;
cong
enit
alheart
defect;
lip
dysp
lasi
a;talipes
equinovarus;
shor
tstature;
deve
lopm
enta
lde
lay.
Craniosynostosis,ot
herva
riab
leanomalies,
inco
mple
tely
deli
neat
edphenotype
Low
birth
weig
ht,mental
defi
cien
cy,
fuzzy
hair
,wi
dean
teri
orfo
ntan
el,
small
palpebral
fiss
ures
,oc
ular
hypertelorism,
smal
lnose
,la
rge
tong
ue,malformed
low-
set
ears
,sk
elet
alan
omal
ies
Prominent
forehead,
brachycephaly,
prominent
nose
with
bulbous
tip,
myopia,
simp
lecupped
ears
,pr
omin
ent
labi
a,an
alsk
inta
gs,hyperextensiblejo
ints
,re
lati
vely
laxskin
Ocular
hypertelorism,
low-setmalformed
ears
,micrognathia,pe
sva
rus,
anal
atre
sia,
rect
o-va
gina
lfistula,
abse
ntlu
nglo
be,incompletely
deli
neat
edph
enot
ype
Growth
defi
cien
cy,ps
ycho
moto
rre
tard
atio
n,microcephaly,
flat
rounded
face
,ar
ched
eye-
brow
s,na
rrow
palp
ebra
lfissures,mi
crop
htha
lmia
,malformed
ears
,sm
allno
se,mi
crog
nath
ia,
shor
tne
ck,
prox
imal
lyplaced
thumbs
and
grea
tto
es,
overlapping
fingers,
soft
tiss
uesy
ndac
tyly
,camptodactyly,
deep
plan
tarfu
rrow
s,reduced
rena
lfunction
Mental
defi
cien
cy,hy
poto
nia,
fron
tal
boss
ing,
down
slan
ting
palpebral
fiss
ures
,strabismus,
nyst
agmu
s,br
oad
fingersand
toes
Cl€fl**
lip
+?
+?
+?
+1
cleft**
palate
+2
+?
+?
+1 +?
+?
+?
bifid**
uvula
H +
references
NorwoodandHoehn,
1974
Ballestaand
Behi,1974
Allderdice
et
al.,1975
Sedano
et
al.,1971
VanKempen,
1975
Sedano
et
al.,1971
Bartoshesky,
et
al.,1978
McPherson
et
al.,1976
Vogel
et
al.,1973
Harris
et
al.,1977
NakogomeandKobayashi,
1975
YunisandSanchez,
1974
Sanchez
et
al.,1974
(continuedonnextpage)
320 Cleft Palate Journal, October 1978, Vol. 15 No. 4
TABLE
5-Continued
11q+
13+
13g+"
13q-
14q+
18+
18p-
18q-
Axia
lhy
poto
nia,
limb
hype
rton
ia,
wrin
kled
face
,largebe
aked
nose
,micrognathia,
mal-
formed
low-
set
ears,
shor
tneck,na
rrow
ches
t,wi
dely
spac
edni
pple
s,micropenis,
renal
agenesis,
urin
ary
trac
tmalformations,
acet
abul
ardy
spla
sia,
clubfoot,
cong
enit
alheart
defects,
genitalan
omal
ies
Holo
pros
ence
phal
y,se
izur
es,ap
neic
epis
odes,se
vere
mental
defi
cien
cy,ea
rlydemise,severe
faci
aldysmorphia
(including
ocular
hypo
telo
rism
,fl
atno
se,microphthalmia),
irisco
lobo
ma,
malformed
ears,glabellarhe
mang
ioma
,sc
alp
defe
cts,
poly
dact
yly,
congenital
hear
tde
fect
s,genitalan
omal
ies
Psyc
homo
tor
retardation,
low-
set
ears
,cl
inod
acty
ly,
simi
ancr
ease
s,mi
crop
htha
lmia
,in
sco
lobo
ma
Microcephaly,lo
barho
lopr
osen
ceph
aly,
trig
onoc
epha
ly,me
ntal
defi
cien
cy,mi
crop
htha
lmia
,ir
isco
lobo
ma,
retinoblastoma,malformed
ears,micrognathia,
hypo
plas
ticth
umbs
,im
per-
forate
anus
,hy
posp
adia
s,cryptochidism,
cong
enit
alheart
defe
cts
Ment
alde
fici
ency
,failure
toth
rive
,seizures,
micr
ocep
haly
,mi
crop
htha
lmia
,fl
atnasal
bridge,lo
w-se
tor
malf
orme
dea
rs,micrognathia,cryptorchidism
Prominentoc
cipu
t,na
rrow
bifr
onta
ldi
ameter,lo
w-se
tmalformed
ears
,micrognathia,gr
owth
defi
cien
cy,me
ntal
defi
cien
cy,
hypertonicity,
over
lapp
ing
fingers,
cong
enit
alhe
art
defe
cts,
earl
yde
mise
Mental
defi
cien
cy,
failure
tothrive,ep
icanthic
fold
s,pt
osis
,oc
ular
hypertelorism,
micr
o-gn
athi
a,sh
ortneck,va
riab
lephenotypefr
omTurner-likefe
atur
esto
holoprosencephalywith
facial
dysmorphia
Shor
tstature,
micr
ocep
haly
,me
ntal
defi
cien
cy,midfacehypoplasia,de
ep-s
etey
es,prominent
anti
heli
x,ca
rp-s
hape
dmo
uth,
tape
ring
fing
ers,
increased
digi
talwh
orls
,co
ngen
ital
hear
tdefects
++
+I
Aurlas
andLa
uren
t,1975
Smith,
1969
Esco
barandYu
nis,
1974
Orbe
liet
al.,
1971
Shor
tet
al.,
1972
;Mu
ldal
etal.,
1973
Smith,
1969
deGrouchy,
1969
;Lu
rie
and
Lazjuk.
1972
Luri
ean
dLa
zjuk
,19
72;Lejeune
etal.,
1968
Key *No
s.1through22
=chromosome
no.
p=
q=
+,
13q+"=
Boldface=
shortarm
longarm
.
followingno
.or
letter=
trisomyor
dele
tion
ofchromosomeor
chromosomesegment
partialtrisomy
fortheproximalpa
rtofthelongarm
ofchromosome
13
morewell-knownchromosomalsyndromesormostcommonchromosomalsyndromesor
both
%%
t+=
rare
+?=
reportedbut
rela
tive
frequencyunknown
sinc
esyndrome
isincompletelydelineated
+=
uncommon
++=
common
(>15%)
=absentornotreportedto
date
(continuedonnextpage)
Cohen, s¥NDROMES 321
TABLE
5-Co
ntin
ued
'karyotype*
21+
21q-
22+
22q+
22q-
X0
XXXXY
T'riploidy
striking
features
Brachycephaly,
flat
midf
ace,
upslanting
palpebral
fiss
ures
,Br
ushf
ield
spot
s,ep
ican
thic
folds,
smal
lma
lfor
med
ears,protruding
tong
ue,
loos
esk
inon
posteriorne
ck,de
laye
dde
ntit
ion,
minor
toot
han
omal
ies,
malocclusion,
periodontal
dise
ase,
brachydactyly,
clinodactyly,
simi
ancr
ease
s,increasedulnar
loop
s,co
ngen
ital
heart
defe
cts,
hypotonia,
hyperflexibility,
shor
tst
atur
e,mental
defi
cien
cy
Psyc
homo
torand
ment
aldeficiency,hypertonia,gr
owth
defi
cien
cy,microcephaly,do
wn-
slan
ting
palp
ebra
lfi
ssur
es,br
oadnasal
root
,pr
omin
ent
low-
set
ears
,la
rgeex
tern
alauditory
cana
ls,micrognathia,hy
posp
adia
s,crypto
rchi
dism
,in
guin
alhernia,pyloricst
enos
is,sk
elet
alan
omal
ies
Grow
thde
fici
ency
,mental
defi
cien
cy,hypo
toni
a,underdeveloped
musc
ulat
ure,
microceph-
aly,
cran
iofa
cial
asymmetry,
long
beaked
nose
,lo
ngphiltrum,micrognathia,
large
low-
set
malformed
ears
,preauricular
tags
and
pits,
stra
bism
us,
long
slen
der
fingers,
finger-like
thum
bs,co
ngen
ital
heart
defects,
hip
disl
ocat
ion,
cryptochidism
Psychomotor
reta
rdat
ion,
colomboma
ofir
isan
dch
oroi
d,do
wnsl
anti
ngpalpebral
fiss
ures
,ocular
hypertelorism,
preauricular
tags
orpits,anal
atre
sia,
rectovagmal
fist
ula,
cardiac,
geni
tour
inar
y,and
skel
etal
anom
alie
s
Mental
defi
cien
cy,hy
poto
nia,
epic
anth
icfo
lds,
flat
nasa
lbr
idge
,soft
tiss
uesy
ndac
tyly
ofse
cond
and
thir
dto
es,cl
inod
acty
lyof
fift
hfi
nger
s
Short
stature,
ovar
ian
agen
esis
,in
fant
ilevagina
and
breasts,
widely-spacednipples,
webbed
neck
,lo
wpo
ster
ior
hair
line
,prominent
ears
,micrognathia,
cubi
tus
valg
us,
shor
tfo
urth
metacarpals,
peri
pher
allymphedemaduring
infa
ncy,
coar
ctat
ionof
theaorta,
rena
lanom-
alie
s,hypoplastic
nails,
mult
iple
pigmented
nevi
Mildmicrocephaly,se
vere
ment
alde
fici
ency
,hy
poto
nia,
upsl
anti
ngpalpebral
fiss
ures
,oc
ular
hypertelorism,
epic
anth
icfo
lds,
shor
tneck,redundant
posteriorneck
skin,taurodontism,
mand
ibul
arpr
ogna
this
m,micropenis,
smal
ltestes,cr
ypto
rchl
dlsm
radi
ouln
arsy
nost
osis
,cubitusva
lgus
,genuava
lga
Growth
defi
cien
cy,
mental
defi
cien
cy,
hypotonia,
asymmetry,
micr
opht
halm
ia,
iris
and
chor
oidco
lobo
mas,
mild
ocular
hypertelorism,
anomalous
low-set
ears
,micrognathia,
syn-
dactylyof
the
thir
dand
fourth
fing
ers,
simian
creases,
club
foot
,congenital
heart
defe
cts,
genitalan
omal
ies
Clefi**
lip
+
++
Clefl**
palate
A +?
+1
bifid**
uvula
references
CohenandCohen,
1971
Gorlin
et
al.,1976
PenchaszadehandCoco,
1975
Buhler
et
al.,1972
DeCicco
et
al.,1973
Gorlin
et
al.,1976
Gorlin
et
al.,1976
Gorlin
et
al.,1976
322 Cleft Palate Journal, October 1978, Vol. 15 No. 4
TABLE
6.Co
ndit
ions
with
median
clef
tli
p
-relative
freq
uenc
yof
cond
itio
nsstriking
feat
ures
median
clef
tlip
inetiology
refe
renc
esco
ndit
ion Frontonasal
dysplasia
Ocular
hypertelorism,
widow'spe
ak,an
teri
orcr
aniu
mUncommon
Most
casessp
orad
ic,.
few
Gorl
inet
al.,
1976
bifi
dumoccultum,wi
de-s
etno
stri
ls,la
ckof
elevationof
the
fami
lial
instances,
prob
ably
nasa
lti
p,no
tchi
ngor
colobomasof
nost
rils
,ot
her
.et
iolo
gica
llyheterogeneous
abnormalities
Majewskisyndrome
Shortnarrowth
orax
,pr
eaxi
aland
post
axia
lpolydactylyof
Common
Allcasessporadicto
date
Spranger
etal
.,1974
handsand
feet
,sh
ort
tibi
as,protuberantabdomen,cardiac
anomalies,
genitalanomalies,
cleft
lipand/orpalate,other
abnormalities,
deathfrom
respiratory
dist
ress
Oral
-fac
ial-
digi
talsyndrome
IDystopiacanthorum,hypoplastical
arcartilages,mi
lia,
Common
X-linkeddominant,
leth
alin
Gorlin
etal.,
1976
multiple
fren
ula,
laterally
clef
tpalate,bi
fidtongue,
themale
malposed
teet
h,toothanomalies,brachydactyly,
synd
acty
ly,cl
inod
acty
ly
Oral
-fac
ial-
digi
talsyndrome
IILobedtongue,manual
polydactyly,
bilateral
Common
Autosomal
rece
ssiv
eGorlin
etal.,
1976
polysyndactylyofha
lluc
es
Premaxillaryag
enes
isMedian
cleft
lip,
flat
nose
,ocularhypotelorism,
Common
Etiologicallyheterogeneous
CohenandHohl,
inpr
ess
holoprosencephaly,otherabnormalities,amentia,
seiz
ures
,(t
riso
my13
syndrome,
18p-
apnea,neonataldemise
karyotype,otherchromosomal
aber
rati
ons,
Meckelsyndrome,
autosomal
rece
ssiv
e,autosomal
dominantwithmarkedly
variable
expressivity)
Wsyndrome
Mental
defi
cien
cy,seizures,frontalprominence,an
teri
or?
?Autosomaldominant
Pall
iste
ret
al.,;1974
cowl
ick,
ocularhypertelorism,downslantingpalpebral
fiss
ures
,strabismus,broadnasal
tip,
cent
ralnotchofupper
lipandsubmucous
cleftpa
late
,co
ngen
ital
lyabsentcentral
incisors,prominentlower
faci
alhe
ight
,cubitusva
lgus
,
subluxation
atradioulnarjo
ints
,camptodactyly,
clin
odac
tyly
:
Wallacesyndrome
Shortli
mbs,
deformed
ribca
ge,hydrocephalus,hypoplastic
Common
Autosomal
rece
ssiv
eWallace
etal.,
1970
lung
s,congenitalheart
defe
cts,
cent
ralnotchofupper
lip
and
cleftpalate
Cohen, synprRomEs
323
324
TABLE 7. Association of clefts with other abnormalities
Cleft Palate Journal, October 1978, Vol. 15 No. 4
type ofcleft association comment references
Cleft lip or cleft palate Thoracopagus twins Gorlin et al., 197 1aor both
Cleft palate Oral duplication
Cleft lip or cleft palateor both
Anencephaly
Cleft palate Congenital oral teratoma
Cleft lip or cleft palateor both
Cleft lip or cleft palateor both
Congenital neuroblastoma
Cleft lip or cleft palateor both or Robincomplex tetralogy of Fallot, tricuspid stenosis,
coarctation of the aorta, biventricularaorta, cor triloculare, dextrocardia)
Cleft lip or cleft palateor both
Forearm bone aplasia
Cleft lip-cleft palate Sacral agenesis
Cleft lip-cleft palate Cleft larynx
Cleft lip-cleft palate Laryngeal web
Cleft lip-cleft palate Lateral proboscis
Cleft palate
Cleft palate Aniridia
Cleft palate Aplas.ia of trochlea
Nasal glioma or meningoencephalocele
Congenital cardiovascular defects (ASD,VSD, PDA, pulmonary valvular atresia,
Persistent buccopharyngeal membrane
Gorlin et al., 1971a
Gorlin et al., 197 1a
Cleft palate probably secondary Gorlin et al., 197 1ato teratoma
Cleft palate probably secondaryto glioma ormeningoencephalocele
Gorlin et al., 197 1a
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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