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)


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


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)


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)


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


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



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


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


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


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



Congenital neuroblastoma

Cleft lip or cleft palateor both or Robincomplex tetralogy of Fallot, tricuspid stenosis,

coarctation of the aorta, biventricularaorta, cor triloculare, dextrocardia)


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


Other associated anomalies Gorlin et al., 1971afrequent

Shah et al, 1970;Gorlin et al., 1976

Other associated anomalies Gorlin et al., 1971afrequent




Usually occurs with absent Gorlin et al., 1971anostril on ipsilateral side




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.

References

AasE, J. M., and Smit, D. W., Dysmorphogenesis ofjoints, brain and palate: A new dominantly inheritedsyndrome, J. Pediatr., 73, 606-609, 1968

ABrUZzzOo, M. A., and Erickson, R. P., A new syndromeof cleft palate associated with iris coloboma, hypo-spadias, deafness, short stature, and radial synostosis,J. Med. Genet., 14, 76-80, 1977.

ALLDERDICE, P. W., Brownr, N., and MURPHY D. P.,

Chromosome 3 duplication q21—)qter syndrome inchildren of carriers of a pericentric inversion inv(3)(p25q21), Am. J. Hum. Genet., 27, 699-718, 1975.

AppELt, H., GERKEN, J., and Lenz, W., Tetraphokomeliemit Lippen-Kiefer-Gaumenspathe und clitorishyper-trophic-ein syndrome, Paediat, Paedol., 2, 119-124,1966.

Aurias, A., and Laurent, C., Trisomie 11q. Individuali-zation d'un nouveau syndrome, Ann. Genet., 18,189-191, 1975.

BaruEsTA, F., and Brx1, L., Trisomie partielle pom lapartue distate du bras court due chromosome 3, Ann.Genet., 17, 287-290, 1974.

BartosnmEsky, L., Lewis, M. B., and PasHmavyan, H. MDevelopmental abnormalltles assoaated with long arm

deletion of chromosome No. 6, Clin. Genet., 13, 68-71,

1978.

Brare, J. M., Dopcr, J. A., and Nevin, N. C., Cutis

gyratum, acanthosis nigricans, and other congenital

anomalies-A new syndrome, Br. ]. Dermatol., 81,

241-247, 1969.

BrenczE, J., ScHnITzLER, A., and WarawskaA, J., Domi-

nant inheritance of hemifacial hyperplasia associated

with strabismus, Oral Surg, 35, 489-500, 1973.

Brerc, J. M., McCrEary, B. D., RipueEr, M. A. C., and

325

SmITH, G. F., The deLange Syndrome. New York: Perga-mon Press, 1970. >

Brrosma, D., Case report 28, Syndrome Ident.,1975.

BixieEr, D., CuristIAN, J. C., and GoRLIN, R. J., Hyper-telorism, microtia and facial clefting: A newly de-scribed inherited syndrome, Birth Defects, 5, 77-81,1969.

Bixier, D., Spivack, J., BEnnEtTt, J., and J.C., The ectrodactyly-ectodermal dysplasia-clefting(EEC) syndrome, C/in. Genet., 3, 43-51, 1971.

Bowen, P., and Armstrong, H. B., Ectodermal dysplasia,mental retardation, cleft lip/palate and other anoma-lies in three sibs, Clin. Genet., 9, 35-42, 1976.

Braun, F. C., Jr., and BayEr, J. F., Familial nephrosisassociated with deafness and congenital urinary tractanomalies in siblings, J. Pediatr., 60, 33-41, 1962.

BunieEr, E. M., MenxEes, K., Muruer, H., and STALDER,G. R., Cat-eye syndrome, a partial trisomy 22, Human-genetik, 15, 150-172, 1972.

Burp1, A., FEmncourp, M., Larsson, K. S., Leck, I., Zm-MERMAN, E. F., and FrRrasER, E. C., Etiology and path-ogenesis of congenital cleft lip and cleft palate, anNIDR state-of-the-art report, Teratology, 6, 255, 1972.

Burcto, G. R., BEiront, C., and BELurFr1, G., Nanismepseudodiastrophique. Etude de deux soeurs nouveau-nées, Arch. Fr. Pediatr., 31, 681-696, 1974.

CENTERVOLD, W. R., personal communication, 1978CERVENKA, J., GoRLIN, R. J., and AnipeErson, V. E., Thesyndrome of pits of the lower lip and cleft lip and/orpalate, genetic considerations, Am. J. Hum. Genet., 19,416-432, 1967.

CiHrRrIsTIAN, J. C., AnprEws, P. A., ConEarLy, P. M., andMuruerR, J., The adducted thumbs syndrome, (/m.Genet., 2, 95-103, 1971.

M. M., Jr., Goruim, R. J., FEmmcorp, M., andTEN R. W., The Beckwith-Wiedemann syn-drome-Seven new cases, Am. J. Dis. Child., 122,515-519, 1971.

ConEn, M. M., Jr., An etiologic and nosologic overviewof craniosynostosis syndromes, Birtk Defects, 11(2),137-189, 1975.

CoxEn, M. M., Jr., The Robin anomalad-its nonspec-ificity and associated syndromes, /. Oral Surg., 34, 587,1976.

CoxEn, M. M., Jr., personal observation, 1977.Coxrn, M. M., Sr., and Conrn, M. M., Jr., The oral

manifestation of trisomy G:; (Down syndrome), BirthDefects, 7(7), 241-251, 1971.

Conxrn, M. M., Jr., and Hox, T. H., Etiologic hetero-geneity in the holoprosencephalic disorders, in Devel-opment of the Basicranium, J. F. Bosma, Ed., DHEWPublication No. (NIH) 76-989, Bethesda, 1976, pp.383-399.

DarntL, D. L., Situ, D. W., Scott, C. I., Harr, B. D.,and Goopinc, C. A., Femoral hypoplasia-unusualfacies syndrome, J. Pediatr., 86, 107-111, 1975.

Davis, J. G., and Larer, C., A possible new mentalretardation syndrome, Birth Defects, 12(5), 235-238,1976.

DeCicco, F., STEELE, M. W., and Pan, S., Monosomy ofchromosome No. 22: A case report, j Pediatr., 83,836-838, 1973.

Dr GroucHy, J., The 18p-, 18q-, and 18r syndromes,Birth Defects, 5(5), 74-87, 1969.

Cohen, s¥NDROMES

3 (1), 7,

326

Dr ca CHaAPELLE, A., MarotEaux, P., Haru, N., andGranrotTx, G., Une rare dysplasie osseuse léethale detransmission recessive autosomique, Arch. Fr. Pediatr.,29, 759-770, 1972.

Donran, M. A., Growth failure, cleft palate, ectodermaldysplasia, and apparent pancreatic insufficiency-? anew syndrome. Birth Defects, 13(3B), 230-231, 1977.

DrirriEn, C. M., Incram, T. T., and Wiikinson, E. M.,The Causes And Natural History Of Cleft Lip And Palate.Edinburgh: E & S Livingstone, 1966.

EAstTMAN, J. R., and BixuEr, D., Facio-cardio-renal syn-drome: a newly delineated recessive disorder, C/zn.Genet., 11, 424-430, 1977.

ERIKSON A., Hereditary syndrome consisting of recurrentattacks resemblmg brachial plexus neuritis, special fa-cial features and cleft palate, Acta Paediatr. Scand., 63,885-888, 1974.

EscoBAR, J. I., and Yunis, J. J., Trisomy for the proximalsegment of the long arm of chromosome 13, Am. J. Dis.Child., 128, 221-222, 1974.

Focm-AnpERSEN, P., Inheritance OfHarelip And Cleft Palate.Copenhagen: Busck, 1942.

FoxntTamE, G., Farriaux, J. P., DeratTTrRE, P., GIDLECKI,Z., Pourarp, B., DuriEux, G., and PiQqguEt, J. J., Uneobservation familiale du syndrome ectrodactylie et dy-sostose mandibulo-faciale, J. Génét. Hum., 22, 289-307,1974.

FrasER, F. C., The genetics of cleft lip and cleft palate,Am. J. Hum. Genet., 22, 336-352, 1970.

FrRrasER, F. C., Etiology of cleft lip and palate, in Cleft LipAnd Palate, edited by Grabb W. C., Rosenstein S. W.,and Bzoch K. R. Boston: Little, Brown, and Company,54-65, 1971.

FrEirE-MAia, N., A newly recognized genetic syndromeof tetramelic deficiencies, ectodermal dysplasia, de-formed ears, and other abnormalities, 4m. J. Hum.Genet., 22, 370-377, 1970.

FunurmaAnn, W., Kock, F., and ScnwEckENDIEK, W., Au-tosomal dominante Vererbung von Gaumenspalte undSynechien zwischen Gauman und Mundboden oderZunge, Humangenetik, 14, 196-203, 1972.

GareEs, F. J., and Smit, D. W., Diminished stature-defective palate syndrome: a dominantly inheriteddisorder, J. Pediatr., 79, 470-472, 1971.

GrEwIitTz, M., DinwipoiE, R., T., E., aAnp_ C. O., Cleft palate and accessory metacarpalof index finger syndrome: possible familial occurrence.J. Med. Genet., 15, 162-164, 1978.

Gorpon, H., Davies, D., and Berman, M., Camptodac-tyly, cleft palate, and clubfoot-A syndrome showingthe autosomal-dominant pattern of inheritance, /.Med. Genet., 6, 266-274, 1969.

Gorpon, I. R., and Brown, N. J., The syndrome ofmicromelic dwarfism and multiple anomalies, 4nz.Radiol., 19, 161-165, 1976.

Goruin, R. J., SEpano, H. O., and CirrvEnK®a, J., Poplit-eal pterygium syndrome, Pediatrics, 41, 503-509, 1968.

Gorm, R. J. CrrvEnka, J., and Anerson, R. C., Ro-bin's syndrome. A probably x-linked recessive sub-variety exhibiting persistence of left superior vena cavaand atrial septal defect, Am. J. Dis. Child. 119, 176-181,1970.

Gorm, R. J., CrrvEenka, J., and Pruzansky, S., Facialclefting and its syndromes, Birtk Defects, 7(7), 3-49,1971a.


Gorin, R. J., Scmrorr, R. A., and Parareurua, M. M.,Cleft palate, stapes fixation and oligodontia-A newautosomal recessively inherited syndrome, Birth Defects,7(7), 87-88, 19716.

GorLin, R. J., and SEpano, H. O., Multiple nevoid basalcell carcinoma syndrome, Handbook Clin. Neurol., 14,455-473, 1972.

GorRrLIN, R. J., AupER, R., and LancER, L., Megepiphysealdwarfism, J. Pediatr., 83, 633-635, 1973.

Gorm, R. J., Pinpsorce, J. J., and ConEn, M. M., Jr.,Syndromes Of The Head And Neck, edition 2. New York:McGraw-Hill Company, 1976.

Gunperson, C. H., GrEEnsPaAN, R. J., Graser, G. H., andLuss, H. A., The Klippel-Feil syndrome: Genetic andclinical re-evaluation of cervical fusion, Medicine, 46,491-512, 1967.

Harr, J., Pirprorn, M., Karp, L,; Hickox, D., andWiraEnsTEIN, L., A new short-rib polydactyly syn-drome, Birth Defects, 13(3B), 242-243, 1977.

Hanson, J. W., and Smit, D. W., U-shaped palataldefect in the Robin anomalid: Developmental andclinical relevance, J. Pediatr., 87, 30-33, 1975a.

Hanson, J. W., and SmittH, D. W., The fetal hydantoinsyndrome, J. Pediatr., 87, 285-290, 1975b.

Harris, E. L., WarpnER, R. S., and Parmer, C. G., 7qdeletion syndrome, Birth Defects, 13(3B), 244, 1977.

Hausam, T. J., Wraver, D. D., and Prescott, G. H.,The occurrence of an Apert-like syndrome and theVATER association in twins, Birth Defects, 13(3C), 239,1977.

HERRMANN, J., personal communication, 1975.HrErrmann, J. and OpITz, J. M., The Stickler syndrome

(hereditary arthoophthalmopathy), Birth Defects, 11(2),76-103, 1975.

HErmannNn, J., and OritTz, J. M., The VSR syndrome,Birth Defects, 13(3C), 69-84, 1977.

Herrmann, J., FEmcorp, M., TurFL1, G. A., and OPITz,J. M., A familial dysmorphogenic syndrome of limbdeformities, characteristic facial appearance and asso-ciated anomalies: The "Pseudothalidomide" or "SC-Syndrome," Birth Defects, 5(3), 81-89, 19692.

Herrmann, J., ParuistER, P. D., and Opitz, J. M., Cra-niosynostosis and cranlosynostos1s syndromes Rocky Mt.

Med. J., 66, 45-56, 1969b.

Hrrrmann, J., France, T. D., and Opitz, J. M., The

Stickler syndrome, Birth Defects, 11(6), 203-204, 1975.

Ho, C. K., Kaurman, R. L., and McAustER, W. A.,

Congenital malformations-cleft palate, congenital

heart disease, absent tibiae and polydactyly, Am. J.

Dis. Child., 129, 714-1716, 1975.

HortHuUsEN, W., The Pierre Robin syndrome: unusual

associated developmental defects, Ann. Radiol., 15,

253-262, 1972. _Hsia, Y. E., Bratu, M., and HErBoLTt, A., Genetics of the

Meckel syndrome (dysencephalia splanchnocystica),Pediatrics, 48, 237-241, 1971.

Ipr, C. H., and WorrscnxrararErR, P. B., Multiple congen-ital abnormalities associated with cryptophthalmia,Arch. Ophthalmol., 81,.638-644, 1969.

Jones, K. L., Smit, D. W., UrretranDp, C. N., andStrEssoutH, P., Pattern of malformation in offspringof chronic alcoholic mothers, Lancet 1, 1267-1271, 1973.

Jongs, K. L., Suirtn, D. W., Harr, B. D., Hart, J. G.,Emsin, A. J., Massoubp, H., and Gorsus, M. S., Apattern of craniofacial and limb defects secondary to

aberrant tissue bands. J. Pediatr., 84, 90-95, 1974.JuseErc, R. C., and Haywarp, J. R., A new familial

syndrome of oral, cranial, and digital anomalies, /.Pediatr., 74, 755-1762, 1969.

KatcHrrRr, M., and Harz, J. G., personal communication,1975.

LancEr, L. O., Jr., and HERRMANN, J., The cerebro-costomandibular syndrome, Birtk Defects, 10(7),167-170, 1974.

LancrrRr, L. O., JR., GoNnzALEz-Ramos, M., H., andEspiritu, C. E., A severe infantile micromelic chon-drodysplasia which resembles Kniest disease, Eur. /.Pediatr., 123, 29-38, 1976.

LeEjrEunE, J., M-O, BrErorr, R., ABoNYI, D.,Dutrirraux, B., and See, G., Trisome C partielle partranslocation familiale t(Cq+;Cq-), Ann. Geénét., 11,171-175, 1968.

LeEwanpowsKkI, R. C., Jr., and Yunis, J. J., New chro-mosomal syndromes, Am. J. Dis. Child. 129, 515-529,1975.

Lowry, R. B., and Mirirr®, J. R., Cleft palate andcongenital heart disease, Lancet, 1, 1302-1303, 1971.

Lowry, R. B., and MacLean, J. R., Syndrome of mentalretardation, cleft palate, eventration of diaphragm,congenital heart defect, glaucoma, growth failure, andcraniosynostosis, Birth Defects, 13(3B), 203-210, 1977.

Lurg, I. W., and LazjuK, G. I., Partial monosomies 18.Review of cytogenetical and phenotypical variants,Humangenetik, 15, 203-222, 1972.

Marpen, P. M., Suirtu, D. W., and McDonarp, M. J.,Congenital anomalies in the newborn infant, includingminor variation, /. Pediat., 64, 358-371, 1964.

Marpen, P. M., and WALKER, W. A., A new generalizedconnective tissue syndrome, Am. J. Dis. Child., 112,225-228, 1966.

MarotEaAuUx, P., Roux, C., and FruvcHtTER, Z., Le nanismemicrognathe, Presse Méd., 78, 2371-2374, 1970.

Martsour, J. T., Rerp, M. H., and HuntERr, A. G. W.,Case report #56: Skeletal dysplasia, Robin anomalad,and polydactyly, Syndrome Identification, 5(1), 14-18,1977. ~

McPurErson, E., Hart, J. G., and Hickman, R., Chro-mosome 7 short arm deletion and craniosynostosis. A7p- syndrome, Humangenetik, 35, 117-123, 1976.

MrasE, A. D., YEatman, G. W., PETTETT, G., and MErR-ENSTEIN, G. B., A syndrome of ankylosis, facial anom-alies and pulmonary hypoplasia secondary to fetalneuromuscular dysfunction, Birtk Defects, 12(5),193-200, 1976.

MurpaL, S., Enock, B. A., AnmrEDp, A., and Harris, R.,Partial trisomy 14q- and pseudoxanthoma elasticum,Clin. Genet. 4, 480-489, 1973.

NaxracomE, Y., and KosavasH1, H., Trisomy of the shortarm of chromosome 10, J. Med. Genet., 12, 412-414,1975.

Nance, W. E., and SweEnEy, A., A recessively inheritedchondrodysplasia, Birth Defects, 6(4), 25-27, 1970.

Norwoon, T. H., and Hoenn, H., Trisomy of the longarm of human chromosome 1, Humangenetik, 25, 79-82,1974.

OPITZ, J. M., personal communication, 1975.OriTz, J. M., FEmcorp, M., Burr, M. J., and SprancrEr,

J. W., The campomelic syndrome-comments, BirtkDefects, 10(9), 97-99, 1974.

Opitz, J. M., SummIrTT, R. L., and Suit, D. W., The

Cohen, syNDROMES 327

BBB syndrome-Familial telecanthus with associatedcongenital anomalies, Birth Defects, 5(2), 86-94, 1969.

D. J., Lurie, I. W., and GorosnEnko, J. L., Thesyndrome associated with the partial D-monosomy.Case report and review, Humangenetik, 13, 296-308,1971.

ParaAnt, D. I., FEincorp, M., and Berkman, M. D.,Unusual facies, cleft palate, mental retardation andlimb abnormalities in siblings-a new syndrome, J.Pediatr., 78, 686-689, 1971.

ParustER, P. D., HERRMANN, J., SprancER, J. W., GoRLIN,R. J., Lancer, L. O., and Oritz, J. M., The W syn-drome, Birth Defects, 10(7), 51-60, 1974.

ParristER, P. D., Herrmann, J., and OPiTz, J. M., Studiesof malformation syndromes in man. XXXKXII: Pleio-tropic dominant mutation affecting skeletal and apo-crine-mammary development, Birth Defects, 12(5),247-254, 1976.

O. A., and Conen, M. M., Jr., The Waarden-burg syndrome, Birth Defects. 7(7), 147-152, 1971.

PantkE, O. A., Conrn, M. M., Jr., Wirkor, C., FEmmnNcorp,M., ScHaumann, B., Pantkr®, H. C., and Gor1m, R. J.,The Saethre-Chotzen syndrome, Birth Defects, 11(2),190-225, 1975. ”

Pena, S. D. J., and SmoxrEir, M. H. K., Syndrome of

camptodactyly, multiple ankyloses, facial anomalies,

and pulmonary hypoplasia: A lethal condition, J. Pe-

diatr., 85, 373-375, 1974.

PencHaszapex, V. B., and Coco, R., Trisomy 22. Two

new cases and delineation of the phenotype, J. Med.

Genet., 12, 193-199, 1975.

PHiruips, C. I., and Grirrityus, D. L., Macular coloboma

and skeletal abnormality, Br. J. Ophthalmol., 53,346-349, 1969.

PitoTro, R. F., MarcarLro, F. A., and OPtTz, J. M., Study

of a child with an "idiopathic'

retardation syndrome, Birth Defects, 11(2), 51-53, 1975.

RAPP, R. S., and Hopoxin, W. E., Anhidrotic ectodermal

dysplasia: Autosomal dominant inheritance with pal-

ate and lip anomalies, /. Med. Genet., 5, 269-272, 1968.

RupicErR®, R. A., Scnmipt; W., LoosE, D. A., and Pas-

SARGE, E., Severe developmental failure with coarse

facial features, distal limb hypoplasia, thickened pal-

mar creases, bifid uvulaand ureteral stenosis: a previ-

ously unidentified familial disorder with lethal out-

come, /. Pediatr., 79, 977-981, 1971.

SancHEz, O., Yunis, J. J., and Escomar, J. I., Partial

trisomy 11 in a child resulting from a complex maternal

rearrangement of chromosomes 11, 12 & 13, Humange-

netik, 22, 59-65, 1974.

SeEpano, H. O., Look, R. A., CartER, C., and ConEn, M.

M., Jr., B group short-arm deletion syndromes, Birth

Defects, 7(7), 89-97, 1971.

Say, B., Barger, D. H., and Hosss, J., A new dominantly

inherited syndrome of cleft palate, Humangenetik, 26,

267-269, 1975. :

Snax, C. V. S., and Harris, W. S., Cardiac

malformations with facial clefts; with observations on

the Pierre Robin syndrome, Am J. Dis. Child., 119,

238-244, 1970. :

SHaw, E. B., and StEmmNBAcKH, H. L., Aminopterin-induced

fetal malformation, Am. J. Dis. Child., 115, 477-482,

1968.

SHEPARD, T. H., Catalog of Teratogenic Agents. Baltimore:

Johns Hopkins University Press. Second Edition.

328

218-220, 1976.Snort, E. M., Sormarr®r, G. B., and BrEo, W. R., A case

of partial 14 trisomy 47,XY,(14q-)+ and transloca-tion t(Op+;14p-) in mother and brother, J. Med.Genet., 9, 367-373, 1972.

SmprintzEn, R. J., GorpBErc, R. B., Lewin, M. L.,Spot:, E. J., Berkman, M. D., ArGaMaso, R. V., andYoung, D., A new syndrome involving cleft palate,cardiac anomalies, typical facies, and learning disabil-ities: velo-cardio-facial syndrome, Cleft Palate J., 15,56-62, 1978.

SicerErs, D. C., D. L.., Dorst, J. P., Doty, S. B.,B. R., HoruistER, D. W., SirBERBERCG, R.,

CranurEy, R. E., Kaurman, R. L., and V.A., The Kniest syndrome, Birth Defects, 10(9), 193-208,1974, and 10, 432-442, 1974.

Smit, D. W., The 18 trisomy and the 13 trisomy syn-dromes, Birth Defects, 5(5), 67-71, 1969.

SPRANGER, J. W., and LanoEr, L. O., Jr., Spondyloepi-physeal dysplasia congenita, Radiology, 94, 313-322,1970.

SprANGER, J., and Grimm, B., Short rib-polydactyly(SRP) syndromes, typus Majewski and Saldino-Noonan, Z. Kinderheilkd., 116, 73-94, 1974.

StorER, J., and Grossman, H., The campomelic syn-drome, Radiology, 111, 673-681, 1974.

Van KrmprEn, C., A patient with congenital anomaliesand deletion of the long arm of chromosome 4[46,XY,del(4)(q31)], J. Med. Genet., 12, 204-212, 1975.

Vocrt, W., SiEBERS, J. W., and ReimwEin, H., Partialtrisomy 7q, Ann. Genet., 16, 227-230, 1973.


WarpEn, R. H., Logosso, R. D., and BRENNAN, L., PierreRobin syndrome in association with combined congen-ital lengthening and shortening of the longbones-Case report, Plast. Reconstr Surg., 48, 80-82, -1971.

WarkrErR, B. A., Scott, C. I., Harr, J. G., Murpock, J.L., and McKusick, V. A., Diastrophic dwarfism, Med-icine, 51, 41-59, 1972.

Warraer, D. C., Exton, L. A., Prircnarp, D. A., Leunc,Y., and CooKrE, R. A., Severe achondroplasia. Dem-onstration of probable heterogeneity within this clini-cal syndrome, J. Med. Genet., 7, 22-26, 1970.

WravEr, D. D., and Wirumams, C. P., A syndrome ofmicrocephaly, mental retardation, unusual facies, cleftpalate, and weight deficiency, Birth Defects, 13(3C),69-84, 1977.

WrrrEBER, R. G., and BrEars, R. K., The Hajdu-Cheneysyndrome, J. Pediatr., 88, 243-249, 1976.

WILDERVANCK, L. S., Een cervico-ocular-acusticussynd-room, Ned. Tijdschr. Geneeskd., 104, 2600-2605, 1960.

Woorr, C. M., Congenital cleft lip, J. Med. Genet., 8,65-83, 1971. -

Yonc, L., Lowry, R. B., and Jan, J. E., Syndrome ofmyopathy, short stature, seizures, retinitis pigmentosa, -and cleft lip, Birth Defects,.13(3B), 230-231, 1977.

Yunis, J. J., and SancnEz, O., A new syndrome resultingfrom partial trisomy for the distal third of the long armof chromosome 10, J. Pediatr., 84, 567-570, 1974.

ZaAackA, E. J., Meruinan, W. J., NemperER, B., and Han-son, J. W., Trimethadione teratogenic syndrome, J.Pediatr., 87, 280-284, 1975. ‘

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