Syndromes with Cleft Lip and Cleft Palate M. MICHAEL COHEN, JR., D.M.D. Seattle, Washington 98195

A series of tables is presented as a diagnostic aid for the clinician when he confronts a patient who has a cleft lip and/or palate, together with associated anomalies. The tables provide a rapid way of sorting through the recognized syndromes with orofacial clefting in search of a possible overall diagnosis. Today, 154 such syndromes are recognized. This is more than twice as many as were known in 1971. Undoubtedly, many new syndromes with orofacial clefting will be delineated in the future. Isolated cleft lip and cleft palate are com- clefts and mandibular clefts) (Gorlin et al., mon malformations. Their epidemiologic, ge- 1976). The current paper tabulates 154 such netic, and pathogenetic characteristics have conditions. Thus, syndrome delineation is a been reviewed elsewhere (Burdi et al., 1972; dynamic, ongoing process that results in rapid Drillien et al., 1970; Fraser, 1970, 1971; Gor- expansion of our knowledge. Today we are lin et al., 1971a, 1976; Woolf, 1971). The aware of more than twice as many syndromes purpose of this paper is to present a series of with orofacial clefting as we were in 1971. tables that can be used as a diagnostic aid when the clinician is confronted with a pa- Use of Syndromes Tables tient who has a cleft and other associated A summary of syndromes with cleft lip and anomalies. The tables provide a rapid way of cleft palate (Tables 2-7) is provided in Table sorting through the recognized syndromes 1. The total number of syndromes listed is with orofacial clefting in search of a possible 176. Lateral, oblique, and mandibular clefts overall diagnosis. Given the diagnosis, the have not been included nor has an attempt tables can also be used to find the frequency been made to include syndromes with congen- of clefting in the syndrome, other features of ital palatopharyngeal incompetence. Several the syndrome, and pertinent references. conditions appear more than once in Tables 2 through 7. For example, the Stickler syn- Frequency of Syndromes with Clefting drome may include cleft palate (Table In 1970, it was noted that less than three 3-Syndromes with Cleft Palate) or the Ro- per cent of all cases of clefting were associated bin complex (Table 4-Syndromes with the with syndromes (Fraser, 1970), although the Robin Complex). There are 22 such instances basis for this estimate was not given. In 1971, of duplication in Tables 2 through 7. These Gorlin et al. reviewed 72 syndromes in which are subtracted from the total number of syn- clefting occurred. In 1976, we discussed ap- dromes. Thus, we are left with 154 syndromes proximately 117 syndromes with orofacial with clefting. However, this is an underesti- clefting (excluding lateral and oblique facial mate since some syndromes listed are etiolog- ically heterogeneous. For instance, the Larsen syndrome has autosomal recessive etiology in Dr. Cohen is Professor of Oral & Maxillofacial Sur- gery, School of Dentistry, and Professor of Pediatrics, some families and autosomal dominant inher- School of Medicine, University of Washington, Seattle, itance in others. Nevertheless, in the total Washington. number of syndromes with clefting (154), the This project was supported by U.S.P.H.S. Grant No. Larsen syndrome is counted only once. If we DE 04502-01. Modified and updated from Cohen, M. M., Jr., Dep- counted the conditions known to be etiologi- morphic syndromes with craniofacial manifestations, In cally heterogeneous more than once, the total Stewart, R. E., and Prescott, G. H., editors, Oral Facial number of syndromes would be somewhat Genetics, St. Louis: The C.V. Mosby Co., 1976. increased. 306 Cohen, s¥NDROMES 307

Table 1 also lists the syndrome breakdown and cleft palate. As an isolated defect, cleft lip by etiology. There are a total of 79 monogenic with or without cleft palate is etiologically syndromes. There are approximately as many distinct from cleft palate (Fogh-Andersen, autosomal recessive syndromes (39) as there 1942). This distinction breaks down in some are autosomal dominant ones (35). The in- malformation syndromes. For example, in the heritance patterns of several monogenic syn- autosomal dominant van der Woude syn- dromes are uncertain at the present time as, drome in which clefts occur together with lip for example, in autosomal dominant vs X- pits, an affected individual may have cleft lip, linked dominant transmission. In such in- cleft lip and cleft palate, or cleft palate. The stances, only one mode of inheritance identi- van der Woude syndrome is found in Table fies the syndrome for inclusion in Table 1, 2. Any syndrome in which a cleft palate is although both possibilities are listed under expressed without cleft lip ever occurring, as "Etiology" in the tables of specific syndromes in the Larsen syndrome, is found in Table 3. (Tables 2-7). There are few X-linked syn- Syndromes with cleft palate are much more dromes (5) or environmentally-induced syn- common (77) than syndromes with cleft lip- dromes (6), but there are many chromosomal palate (28). syndromes (29). Table 4 presents syndromes with the Robin Many syndromes of unknown genesis ap- complex (cleft lip, micrognathia, and glossop- pear in Tables 2 through 7 with a total of 40 tosis). Once thought to constitute a specific such syndromes appearing in the summary in syndrome, the Robin complex is now known Table 1. Obviously, many more syndromes of to be nonspecific, occurring sut generis or as a unknown genesis occur than appear in the component part of various syndromes (Cohen, tables. In order to be included in the tables as 1976). a syndrome of unknown genesis, associated Table 5 presents chromosomal syndromes anomalies either had to occur with some reg- associated with cleft lip and cleft palate. The ularity or had to be especially distinctive in overwhelming majority of chromosomal syn- combination. dromes show an increase in clefting. Other Table 2 presents syndromes with cleft lip common abnormalities found in many chro- mosomal syndromes are psychomotor and TABLE 1. Summary of syndromes with cleft lip and mental retardation, growth deficiency, micro- palate. cephaly, malformed ears, congenital heart de- fects, ocular hypertelorism, micrognathia, and category number cryptorchidism (Lewandowski and Yunis, Syndromes with cleft lip-palate 28 1975). Syndromes with cleft palate 77 Syndromes with median cleft lip are pre- Syndromes with the Robin complex 18 sented in Table 6. There are three major types Chromosomal syndromes with clefts 29 of median cleft lip. The form with the worst Median cleft lip 7 Associations with clefting 17 prognosis is premaxillary agenesis which is almost always associated with alobar holopro- Total number of syndromes listed in tables 183 Syndromes appearing in more than one -22 sencephaly, amentia, seizures, apnea, and a table __ __ very early demise. A second type of median Total number of syndromes 154 cleft lip results from persistence of the infra- nasal furrow which frequently accompanies a Syndrome breakdown by etiology more generalized median facial dysrhaphia Etiology Number with ocular hypertelorism, widely spaced nos- Monogenic 79 trils, and lack of elevation of the nasal tip. A Autosomal dominant . (35) third type, a pseudomedian cleft, occurs when Autosomal recessive (39) the insertion of the maxillary labial frenum X-linked (5) pulls up the middle part of the upper lip, as Environmentally-induced 6 in oral-facial-digital syndrome I. Chromosomal _ 29 Table 7 lists the known associations of var- Unknown genesis ’ 40 ious abnormalities with cleft lip and cleft Total 154 palate. An association may be defined as the 308 Cleft Palate Journal, October 1978, Vol. 15 No. 4

1976

1969

1969

1972

1a

1966

1971a

197

1976

1970

1969

1971

1969

Armstrong,

Hayward,

Sedano,

al.,

al.,

references al.,

al.,

al.,

al.,

al.,

Wollschlaeger, 1977

et

and

and

et

et

and

et

et

et

et

and

Bixler Bowen Appelt

Gorlin Gorlin Ide

Bixler

Freire-Maia,

Cohen, Gorlin

Gorlin Opitz

Juberg

re-

au-

eti-

pre-

with

dom-

trans-

famil-

be

type

with

compat-

some

syndrome

with

dominant

limitation

few

autosomal

may

this

sex

heterogeneous

identical

rare

recessive

__

autosomal

recessive

be

pedigrees

pseudothalidomide

recessive;

male

dominant

recessive recessive

dominant dominant recessive recessive

dominant

recessive dominant

and

sporadic,

heterogeneous to

etiology

autosomal

type

consider

penetrance,

the

type

cases

common

autosomal

with

autosomal

instances,

thorities

and Autosomal

syndrome Autosomal

Autosomal

Autosomal

Autosomal Autosomal

Autosomal

duced

an

Autosomal Etiologically

inant ologically

Most

ial with ible recessive

Autosomal

dominantly

and mission

Autosomal Autosomal cleft com- of syndrome in

frequency

Common Common mon

Apparently

Common Uncommon Uncommon Common Uncommon Rare

Uncommon Uncommon Uncommon

Common page) lip-palate relative

or

ra-

syn- next

geni-

heart

anom-

genito- on

penis

short

electroen-

unilateral epibulbar

anomalies

overfolding

hypoplastic

oligodontia,

renal

nasi,

variable

adnatum

pit,

hypogonadism,

hyperpigmented

anomalies,

congenital

hair,

hair,

nose,

thumbs,

alae

enlarged

skeletal

variably

abnormal

defects,

of (continued

flat

4-5),

form,

hairline,

and/or

sparse

blond

filiforme

cysts,

and

placed

abnormalities

kidneys,

vertebral

(2-3,

ears,

tags

jaw

cardiac

crown

sparse

frontal

other

deficiency,

coloboma

toes

features

ramus,

ear

adnatum

distally

ectopic

of

feet),

tetraphocomelia,

feet,

hypertelorism,

ear,

conical

deformed

striking

mental

clinodactyly,

and

anomalies,

abnormal carcinomas,

ankyloblepharon

obstruction

and

foramina

filiforme

large

microtia,

ocular

hypospadias,

cell

deficiency

mandibular

hypoplastic

syndactyly

.

duct

(hands

of

hands

abnormalities

dysplastic

vertebral

parietal

basal

oligodontia,

mesomelia,

retardation,

hypertelorism, of

anomalies

deficiency

growth

oligodontia,

other

anomalies

helix,

Ocular

clitoris Hypertelorism, defect,

Growth cephalogram,

areas,

Enlarged Cryptophthalmos, dactyly urinary

Ankyloblepharon Ectrodactyly nasolacrimal

nipples, mental Multiple

Tetraperomelia, Macrocephaly, tal

of

Unilateral hypoplasia dermoids, alies, Hypertelorism,

Microcephaly,

dii

lip-palate

cleft

foramina syn- syn-

with dyspla-

(Golden-

parietal

syndrome syndrome syndrome

syndrome

syndrome

Syndromes

microsomia syndrome

syndrome

2.

Syndromes

syndrome syndrome

syndrome

face

syndrome)

Appelt

Bixler Bowen-Armstrong

syndrome

Clefting/ankyloblepharon drome Clefting/enlarged Cryptophthalmos

Ectrodactyly-ectodermal Freire-Maia sia-clefting

Fetal Gorlin Hypertelorism-hypospadias

har

Hemifacial drome Juberg-Hayward

TABLE

Monogenic

Cohen, s¥NDROMES 309

1968 1975b

1971 19692 1969b 1967

1968. 1975

1975 al., al.,

1976 197l1a Smith, al., 1974 1977

Cohen,

1971 et et

Hodgkin,

al., et 1975 al., al.,

al., al., al., and al., al.,

et

and et et

et et

and et et et

Hsia Rapp Hanson Zackai

Herrmann Pantke Herrmann Pilotto Gorlin Gorlin, Gorlin Bergsma, Cervenka Jones

Yong

to

in-

dominant

during

parametha-

familial

sporadic

or

date

date date

pregnancy

cases

date

recessive dominant recessive

dominat dominant dominant

to to to

known

bands

autosomal

to

all

one during

Sporadic Sporadic Sporadic

Diphenylhydantoin

? Probably ? ? pregnancy dione

date, Autosomal Almost

Autosomal Autosomal Autosomal Trimethadione stance

Autosomal Amniotic Autosomal Sporadic

cleft

Uncommon Rare Uncommon

Common

Uncommon Common Common Common Uncommon Uncommon Common

Incomplete lip

?

rib

en- ep- hy-

psy- mal-

stat-

anom-

digital

patent bridge,

cardiac fingers,

pinnae,

and limbs,

deficiency

short

anomalies,

abnormali- scoliosis, other

and

fifth

or nasal

eyebrows,

especially

iris eyelids,

limb hairline, growth

alae

other and helix,

nails

high digits

of

symmetrically

microbrachycephaly, abnormalities

lower

genitalia,

lower of

pigmentosa, facies, encephalocele,

V-shaped

anomalies

fourth

ears,

posterior of

and

other

of

microcornea, anomalies,

seizures overfolded

cartilage

low external dystrophic

deficiency anomalies

retinitis deficiency,

upper unusual

disorder,

clefts, alae, kidneys,

with neck, hair,,

delay,

amputations

ectropion

defects malformed

other

craniosynostosis,

deficiency anomalies ears

mental

mental

facial and speech

wiry

musculoskeletal short

hypoplastic hypoplastic

myopathy,

abnormalites dysostosis,

genitourinary camptodactyly

hypoplasia, mental thin low-set

polycystic

hypoplastic skeletal

vitiligo

reduction

bizarre and other nail

retardation,

digits, pterygia,

developmental

folds,

hypertelorism,

nose, retardation,

deficiency,

other

limbs,

hypoplasia limb

hypertelorism,

arteriosus, asymmetry,

hemangiomas, and constrictions poliosis, pits

mild

formed

facial

Ring Mental Microbrachycephaly, icanthal alies

defects, ductus

cephalocele, Digit

and/or

ocular

Growth chomotor Ocular Hypohidrosis,

facial Polydactyly, Dystopiacanthorum,synophrys,heterochromiairides,deaf— ness, anomalies, Popliteal

Lip ties poplastic

ure Narrow Tetraphocomelia, Mandibulofacial Undifferentiated

syndactyly enamel

II

dysplasia

syndrome

syndrome

syndrome syndrome

Syndromes

syndrome

syndrome

syndrome syndrome

syndrome

syndrome Syndromes

v syndrome

band

pEerygium Woude

2-Continued

syndrome

syndrome

trimethadione syndrome

hydantoin

der

Clefting/ectropion

Herrmann Pilotto

Fetal Fetal Wildervanck-Smith

Rapp-Hodgkin

Meckel Popliteal Pseudothalidomide

van

Waardenberg Oculo-dento-osseous

Amniotic Yong

TABLE Unknown-Genesis Environmentally-Induced

310 Cleft Palate Journal, October 1978, Vol. 15 No. 4

1974

1977

Cohen,

1972

1976

1962

1968

al.,

1973;

1971

et

Erickson,

Beals,

1974

Herrmann,

al.,

al.,

Bayer,

references

Smith, 1974

et

al.,1976

and

and

al.,

et 1975

and

and

et

et

and

Chapelle

la

1977

Aase

Abruzzo

Weleber Cohen,

Bencze Braun

Opitz Langer

de

Gorlin

Christian Erickson, X- re-

type, vs. autosomal

heterogeneous dominant

recessive dominant

dominant dominant dominant or etiology recessive recessive

recessive

recessive

dominant dominant Autosomal X-linked ? linked Autosomal

Autosomal Autosomal ? Autosomal cessive Autosomal

Autosomal

etiologically Autosomal

Autosomal

Autosomal

Autosomal fas

i

bifid palate

palate

with (2/5)

cleft

of cleft

cleft only

syndrome

uncommon

frequency

uvula page) Common

uvula Submucous Common Submucous

common Cleft

Common Common 2/2

Uncommon Common Common

relative

next on

of

at

hy-

pal-

and ver-

eyes

face,

dislo-

com-

ductus

thoracic

pretibial

flat

involving

hip

adducted

phalanges

symmetric

abnormal-

radius

clubbing

asymmetry,

midface

extension

sensorineural (continued

abnormalites,

defects

patent

hypertelorism,

bathrocephaly,

phalanges,

tibiae,

hypoteloric

other

distal

with

period

downslanting

scapulas,

facial

age valga,

forehead,

other

other

and

region, abnormalities,

minimally

limited

of

ovale,

ocular

deficiency,

(especially

double

defects,

deep-set

malformation,

arthrogryposis,

feet,

feet

genua

amblyopia

malformations

other

ears,

malar

neonatal

features phalanges femora

of

stature,

bones

scapulae,

ulna,

deafness gap

months

neuritis,

prominent

rudimentary

and

midface

flat hypoplastic

foramen

of

deficiency

dolichocephaly,

rib

other

hypertelorism,

fissures,

the

six

and

short

during

low-set

striking

lethal

kyphosis,

of ears,

curved

plexus

terminal

hands

ears,

epiphyses,

strabismus,

patent

humeri,

deformity

mental

bowing

teeth

ocular

before

microcephaly,

fibula

soft

lethal

Dandy-Walker

conduction

proptosis,

4,

short the

of

anomalies,

the posterior

palpebral

stature

and

of

winging

dwarfism,

of

large

and lethal

loss

hypertelorism,

brachial

valgus

commonly

ends,

stippled

micrognathia,

root,

defects,

hypospadias,

tract

3,

short

malformed

fissures,

asymmetry, anomalies,

lethal

triangular

2,

femora

face,

bifid commonly

nasal

elbows,

palate

Hydrocephaly,

cation,

deafness, Dissolution Craniosynostosis, pebral

Coloboma, digits Facial Urinary

fingers, syndactyly

poplasia, Flat vertebral ities,

premature with dimpling, Microcephaly,

commonly

flat

Micromelic ulna), tebral

arteriosus, Short

cataracts, monly

thumbs Recurrent

Craniosynostosis, the down-slanting

cleft

with syn-

plexus

syndrome

punctata

syndrome

syndrome

syndrome

syndrome

syndrome

Syndromes

type) syndrome syndrome

3. Syndromes

syndrome

syndrome

syndrome

Chapelle

palate/brachial

la

Aase-Smith

Abruzzo-Erickson

Acroosteolysis

Apert Braun-Bayer

Bencze

(rhizomelic

Campomelic drome Cerebrocostomandibular

de

Chondrodysplasia

neuritis

Christian Cleft

TABLE Monogenic

Cohen, synprRomEs 311

1977

1975

1971

1972

1976

1974

1972

1969

al.,

Bixler,

1971b

1976 1976

1976

Hall,

al.,

et

Smith,

Lafer,

al.,

al.,

al.,

al., al.,

and

et

al., 1977

and 1977

et

et

et

et et

1975

et

and

and

Cohen, Fuhrmann

Gorlin

Gorlin Davis

Walker Donlan, Gorlin

Eastman

Opitz,

Fontaine

Gareis Gordon Katcher

Gorlin re- au- and types autosomal

recessive recessive

recessive

or

dominant recessive

dominant recessive recessive recessive

dominant dominant

dominant recessive

(X-linked?) dominant X-linked

Autosomal Autosomal

Autosomal ?

cessive

Autosomal Autosomal ?

Autosomal

? Autosomal Autosomal Autosomal

Dominant

Autosomal Autosomal

Autosomal ? tosomal

Autosomal

bifid bifid

palate

palate

with cleft,

cleft

cleft

cleft

common

uncommon page)

(2/2)

Submucous

2/2 1/3 Common 2/2 Submucous Common

common Common

Submucous uvula

Common

Submucous

uvula

next

Common Uncommon Common Common on

de-

per-

hypo-

micro-

frontal

thumb,

syndac-

eruption

clavicles,

positional

bones,

mental

hypoplasia,

and (continued

micrognathia,

microcephaly,

fissures,

face

'

feet)

delayed

severe

malar

deficiency,

flat

'

cases

anomalies

hitch-hiker's

wormian

and

plagiocephaly,

hypoplastic

'

clinodactyly,

teeth,

eczema

or

deficiency,

palpébral

abnormalities some

face,

ectrodactyly

growth

ears,

hypoplasia,

defects,

(hands

in

skeletal

anomalies,

clubfoot,

heads,

insufficiency

other ears,

small

absent

mental

abnormalities,

dental

skeletal deficiency

radial

cardiac

folds,

hypotonia,

mild

micrognathia,

prominent

deficiency

syndactyly

downslanting

supernumerary

defects clubfoot

hypodontia,

relatively

pancreatic

dysplastic

eruption,

contractures,

abnormalities mental

root,

and

eczema,

of kidneys,

mental

other

fusions,

dislocated

dislocations,

neuromuscular

epicanthal

deficiency, deficiency,

synechiae

failure,

fixation,

fontanels,

nasal

skin,

calvaria,

ear,

stature,

skeletal stature stature,

deformities

(feet),

failure

foot

Stapes Cervical gnathia, Lateral

Mental

Large bossing,

other Short growth blepharophimosis,

sistent or cystic Growth Horseshoe ficiency,

Thin broad dontia

Ectrodactyly

Micrognathia,

tyly Short Camptodactyly, Short

Multiple

syn- syn-

tissue

synechiae

fixation

palate

dysplasia

syndrome

syndrome

syndrome

dwarfism syndrome

syndrome syndrome syndrome

3-Continued

syndrome

syndrome syndrome

palate/connective

palate/lateral

palate/stapes drome

Cleft dysplasia

syndrome Cleft Cleft

Davis-Lafer

Donlan

Diastrophic Cleidocranial Dubowitz

Eastman

drome Ectrodactyly-cleft

Fontaine

Gareis-Smith Larsen Gordon Katcher-Hall

TABLE

312 Cleft Palate Journal, October 1978, Vol. 15 No. 4 1974;

1966

1970

1971

_

1970

al.,

1976

1973

Shokeir,

1976

1976

1976 1971

1976

Walker,

1976

1975

Miller,

et

Sweeney,

references

al.,

al.,

al.,

al.,

al., al.,

al.,

al.,

and

and

et

et and

et

and

et

et et

et

et

Lowry

Marden

Gorlin

Gorlin Maroteaux

Nance

Gorlin Herrmann,

Gorlin

Gorlin

Gorlin Palant

Pena

Mease

in be may

lethal

recessive

recessive heterogenesis

recessive

etiology recessive

dominant recessive recessive recessive recessive, recessive recessive

dominant,

male

Autosomal

Autosomal

Autosomal

Autosomal

?

Autosomal Autosomal Autosomal Autosomal Autosomal

etiologically the

X-linked Autosomal X-linked

Autosomal ?

in

palate

cleft

of

uncommon

syndrome

frequency page)

uncommon

palate 2/2 next

Uncommon Common

Very Common Uncommon

Common

relative Uncommon Common

Cleft on

of

dis-

skin, toes,

mal-

short

nasal

hypo-

aortic

milia,

micro-

low-set

almond-

clubfeet,

toes,

and

epiphyses,

depressed

pulmonary

syndactyly,

polysyndac- (continued

lentis,

broad

vertebrae

tongue,

wrists

leathery

death,

fissures,

deafness,

clinodactyly

large

of

muscular

right

folds,

curved

cartilages,

fingers

cleft

bifid

thick

tip,

deficiency,

ectopia

on

bilateral

excavatum

alar

bones,

aspects

perinatal

ears,

spaced

palpebral

arthrogryposis,

aplate,

nasal

nails

brachydactyly,

abnormal

deficiency

long

features hypertelorism,

conduction

mental

mandible?

epicanthal

pectus

contractures,

cleft

widely

short

limb

polydactyly,

small hypoplastic

dysplastic

striking

bulbous

deficiency,

atrophy,

ocular

heads,

stature,

and

arachnodactyly,

death

joint

anteromedial

arteriosus,

anomalies,

downslanting

laterally

upper

of

abbreviated

eyes,

prominence,

manual short

radial

growth

hypertelorism,

ears,

tooth

abnormalities

dwarfism,

dwarfism,

clinodactyly,

muscular

the

halluces

truncus

calcifications

canthorum,

joints,

pterygia

phalanges

frenula,

preaxial

onset

prominence,

of

deep-set

intrauterine

the

tongue,

other metaphyses

teeth,

tip,

occipital

ocular

finger

prominence

of

tissue

Persistent

Blepharophimosis,

artery,

tonia, Dolichostenomelia,

Enlarged flared

aneurysm Micromelic

Multiple Rhizomelic

Hypoplastic gnathia,

soft

Dystopia multiple

posed Lobed tyly Frontal

clinodactyly

root,

terminal fifth location Microcephaly,

toes, Prenatal

shaped

nasal

ears,

camptodactyly

I

II

syndrome

syndrome

syndrome

syndrome

dysostosis

syndrome

chondrodyspla-

dwarfism

dwarfism

syndrome

syndrome syndrome

pterygia

3-Continued

syndrome

syndrome

acrofacial

Lowry-Miller

Marden-Walker

Marfan Micrognathic

Megepiphyseal

Multiple Nance-Sweeney

Nager

sia

Oral-facial-digital

Oral-facial-digital Otopalatodigital

Palant

Pena-Shokeir

TABLE

Cohen, synDpRoOMEs 313

1969

1975

1970

1976

1971

Opitz,

1976

1976

1974

1975

1970 Langer,

1976

Griffiths,

Brown,

al.,

al.,

and 1975

al.,

al.,

al.,

al.,

and

al.,

et

and et

and

et

et

et

et

et al., et

Phillips

Gorlin

Burgio

Langer

Rudiger

Pantke

Gordon Say

Pallister

Gorlin Spranger

Herrmann

X- sug-

vs.

Question-

report

recessive sibs.

recessive

recessive recessive

dominant

recessive dominant dominant dominant dominant

recessive One

recessive

dominant

affected autosomal

Autosomal

Autosomal

?

X-linked ?

Sporadic.

gests able Autosomal

Autosomal Autosomal

linked Autosomal

Autosomal

Autosomal Autosomal Autosomal

common (1/7)

common

page)

uvula next Common

Apparently 2/2 2/3

2/2 Bifid

Rare

Uncommon Apparently Uncommon

Common Common on

of

of

de-

2-3

ste-

tip,

apo-

hair-

utero

exter-

pelvis

defect,

trunk,

valgus, hands,

cheeks,

fingers,

respira-

joint

in

thumbs

variable

alveolar

especially

bowing

nasal

full

prominent abnormal-

the epiphyseal

and

brachydac-

hypoplastic

life

ureteral (continued

metaphyseal

frontal

broad

fingers,

organs

septal

abnormalities

death

of

hallux

of

malformations

broad

placed

hypoplasia,

neck

tapering

septum,

other

5th mild

broad

with

short

anomalies,

equinovarus,

year

vessels,

other

atrial

low-set

cryptorchidism,

genital

midface,

syndactyly

and

gland

nasal

maturation,

eyelids,

bones

bones,

internal

fingernails,

polydactyly,

interphalangeal

first

abdomen,

stature,

the

micrognathia,

disease,

great

4th

flat

cava,

involving

colobomas,

talipes

proximally

of

contractures

the

bone

vertebral and

long

deficiency,

forearms,

the

short

distal

of

of

anomalies, during

tubular

deviated

joint

vena

cutaneous

of

asymmetry,

mammary

postaxial multiple

and

stature

abnormalities

the

hypospadias,

carpal

ears,

toe wings,

flexion

fingers involving

macular

protuberant mental

ptosis

of

fingers.

lethal

broad anomalies

phalanges,

facial

eyelids, detachment,

micromelia,

short

birth,

iliac

hypertelorism,

other

large

thighs

variable

detachment

superior

3rd

small

hands,

short

the

dwarfism,

feet

as

micrognathia

facies,

maturation

thorax,

distal

ears, degenerative

hypoplasia,

size,

atresia,

after nostrils,

of

left

and of

deficiency

transposition

flared

accelerated

ocular

over-tubulation

retinal

deficiency,

fingers,

retardation,

deficiency,

retinal

well

deformities

micrognathia,

creases,

anal ray

2nd

with

head

rotated

stature, coarse

sexual

gland

as

wide

narrow

ptosis

nose,

distress,

fifth

shortly

the

Persistent

clubfoot Growth flexion

the

Flat malformed nally

Short line, Short-limbed tyly,

Craniosynostosis, brachydactyly, lungs,

nosis, widening, legs, tory of or especially

with

Growth simian

Small hypoplastic Ulnar layed

crine

Growth anteverted ridges, Disproportionate Myopia,

myopia,

syndactyly dysplasia, ities

joints dysplasia syndrome

dwarfism

syndrome

syndrome syndrome

superior

syndrome

left syndrome

syndrome

3-Continued syndrome

cava syndrome

Persistent vena Phillips-Griffiths

Pseudodiastrophic Rolland

Rudiger

Saethre-Chotzen Saldino-Noonan Say Skeletal-apocrine-mammary syndrome

Smith-Lemli-Opitz Spondyloepiphyseal Stickler congenita

TABLE

314 Lleft Palate Journal, October 1978, Vol. 15 No. 4

1977

1977 1968

Opitz, 1974

1970 1960

1976 1976 1976

Williams, 1973 al.,

and

al., Steinback, references

al.,

1976 al., al., et

et al.,

and

et et et and et

Herrmann Pallister

Gorlin

Wallace Shaw

Wildervanck, Shepard, Gorlin Gorlin Jones

Weaver fa-

preg-

during

trimes-

few

abortifa-

first an

during as

dominant

the

date

dominant dominant

recessive dominant sporadic, recessive

etiology

to

alcoholism

instances

pregnancy

cases

during of

Autosomal

Autosomal Autosomal ?

ter

pregnancy nancy

Autosomal Autosomal Chronic Sporadic Aminopterin Most

milial cient Autosomal Thalidomide in palate cleft

of common syndrome

frequency

page) Common

Uncommon Uncommon

Common Apparently Rare Rare Common

relative

next on

of fis-

gi-

hy-

and

nar-

mal-

mat-

joint

club- some lower upper

upper

fissures, anterior

agenesis

in of

of

atresia

hypoplas-

anomalies

rhizomelic

tissue radio-ulnar

hypoplasia,

midface

contractures, palpebral

mouth, osseous (continued

defects,

renal at notch

notch

limb prominent

mandible

arms,

bone

ears,

palpebral

paralysis

hypoglycemia,

joint

microcephaly,

of

micrognathia, heart

Fallot, prominence,

delayed

and

paralysis central

central

of

hemangioma,

variable

subcutaneous incisors,

hydrocephalus,

nerve tip,

down-turned downslanting subluxation

scoliosis,

features neonatal

bones, frontal

generalized

facial

hypoplastic

maxilla

clinodactyly

deficiency,

shortness

defects,

cage,

abducens

congenital

tetralogy nasal

downslanting central

small

incisors,

long

seventh clinodactyly

neck, ears, valgus,

rib

ribs,

striking

limbs,

broad

of

peromelia

heart

diminished seizures,

mental

craniosynostosis,

ears,

eyes,

thin broad

to absent

abnormalities

deafness, conical

fissures, hypertelorism,

mesomelic

set

lower

abnormalities

omphalocele, cubitus

long

microcephaly, or

duodenum,

dysplastic

deformed

of

low-set

zygomas,

other

or

tubulation

congenital deep

other

fusion, ocular

dysplasia,

down-sloping deficiency,

deficiency,

deficiency,

hypertelorism,

teeth,

mass, camptodactyly,

stature, height, strabismus,

absent

limbs,

oligodactyly

hypodactyly palpebral congenitally

lungs, Mental facial Dysplastic cowlick, lip,

micrognathia Short sures,

shortening prominent

foot,

Phocomelia,

joints, Cervical Cranial

formed anomalies, row gantism, lip Growth esophagus from

muscle poplasia, increased Short tic Mental Macroglossia, Ocular cases,

uration,

-

syn- Syndromes

syndrome

syndrome

Syndromes

syndrome syndrome

syndrome syndrome syndrome syndrome

Collins

syndrome 3-Continued M.

syndrome alcohol

syndrome VSR

Treacher

W

Beckwith-Wiedemann drome

Aminopterin Wildervanck Fetal Thalidomide Charlie

Wallace Weaver-Williams TABLE

Unknown-Genesis Environmentally-Induced

Cohen, synDpRoMEs 315

1974

1977

Gunderson

1977

1976

1974

Grimm,

1976

1976

1976;

1969

al.,

1970

MacLean,

1975

al.,

al.,

al.,

al.,

al.,

and

et

al.,

al.,

et

et

et

et

et

and

et

1967

al.,

et

et

al.,

Beare

Gorlin Daentl

Hausam

Gorlin

Ho

et Siggers

Gorlin

Berg

Lowry

Spranger

to af- fa-

in-

date, of

(auto- domi- few

date to

date sporadic, to

to familial

sporadic

twins) instance cases

date instances

date

date sporadic sporadic,

cases (MZ to

known

to to sporadic

sporadic (autosomal all

all sibs recessive)

instances cases cases

one known familial cases

cases Sporadic

Sporadic

Most

fected

Sporadic one

Unknown All Sporadic few

somal Almost date; nant?)

Almost Most milial stance ?

All

common common

uncommon page)

Very Common Uncommon 2/2

Fairly Common Fairly

Common

next on

lip

de-

fin-

and

var-

sud- nos-

short

respi-

of

defect,

growth

mental

propto-

thumbs, preaxial

myopia,

cleft

proptosis,

anus,

septal

abdomen,

prominent

femurs

hypoplastic

polydactyly

contractures

heart hyperconvex

progressively (continued

hypertelorism, midface,

ocular

hypogonadism

peromelia

severe

anteverted

toenails,

recurrent

absent

atrial

deviation

with

hypodontia,

fibulae,

median

to

flat

absent fissures,

deficiency,

and

narrow

ocular

abnormalities

or

nose

hairline,

seizures,

bowing,

postaxial

imperforate

ulnar

nipples,

face,

protuberant

abnormalities

clubfeet,

congenital

bowed

furrows,

eyebrows,

deafness,

and

growth

short

other

short

craniofacies,

tibial

bifid

palpebral

anomalies,

round

other

oligodactyly

development,

tibias,

creases,

nigricans,

posterior

fingernails

joints,

lips,

micrognathia,

bones,

(various),

tibiae,

diaphragm,

vertebrae

plantar

fissures, preaxial

confluent

from

fifth

cataracts,

thin

short

philtrum,

genital

the

dental

deficiency,

simian

painful

low-set

asymmetric

syndrome dwarfism,

absent

of

craniosynostosis,

anomalies,

knees,

hypodontia,

acanthosis

cervical

ankylosis, wormian

long

feet,

phalanges

kyphoscoliosis,

absent thorax,

defects

and

down-slanting

of

(feet),

palpebral

mental

and hips,

death

limb

delayed

anomalies

philtrum,

and

teeth,

stiff

anomalies,

forehead,

other

nose,

facies, detachment,

middle

infections

fusion

narrow

gyratum,

lordosis,

limb

long

eventration

cartilages,

infant

flat

elbows

hands

neonatal

Cutis

fibulas,

Coarse deficiency, Upslanting alar

lable

Glossopalatine at absent den

Craniosynostosis, sis, Micrognathia,

dislocated polydactyly gers Block

Disproportionate neck, trils,

enlarged retinal ratory Microbrachycephaly,

deficiency, fect,

Microcephaly, beaked glaucoma, fingernails Short

of

cardiac

fa- syn- nigri-

unusual

syndrome ankylosis syndrome syndrome syndrome syndrome syndrome

hypoplasia-

3-Continued

syndrome palate/acanthosis syndrome

syndrome

syndrome Lange Cleft cans Coffin-Siris

Femoral cies drome Hausam

Glossopalatine Ho Klippel-Feil

Kniest de

Lowry-MacLean Majewski

TABLE

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

1978 etiology and the phenotypic spectrum of 1971

al., anomalies are not well-defined and need fur- 1977 et al., references ther delineation. et al.,

et Non-Specificity of Clefting Hall Shprintzen Walden The syndromes presented in Tables 2 through 7 require several general comments. fa-

case First, syndromes are composed of a number

four of malformations, each of which is individ- one ually nonspecific. Each malformation may

Only occur as an isolated abnormality; each may etiology

sporadic; also occur as a component part of various instances

cases syndromes. Because malformations occur

Sporadic. with different frequencies in different syn-

Sporadic

?

known. ? milial Most dromes, they are facultative rather than oblig-

in atory, that is, they may or may not be present in a particular instance of a syndrome in palate

palate which they are said to occur. For example, cleft

of although congenital heart defects are com- cleft

mon in the Meckel syndrome, in some in- syndrome stances, the heart is normal. frequency Pathognomonic anomalies for various mal-

1/1 a formation syndromes are either nonexistent Submucous

common relative or very rare. Since individual malformations

on are both nonspecific and facultative, the di-

small

bones

malar

uterus,

toes agnosis of a syndrome is made from the overall

overbite

learning all

flat pattern of abnormalities. The more anomalies

flipper-like

respiratory hypoplastic of there are in a syndrome, the easier the con-

tibiae

face,

specific from

cava, dition is to diagnose because, even if some of

bicornaute

mandible, blob-shaped and

long the features are not expressed, the overall

death

vena

tract, disproportionately

radii pattern is still discernible. Conversely, the

three

hypertelorism,

retruded defect,

features fewer abnormalities there are in a syndrome,

coordination, underossification

long superior

hands, the more difficult the condition is to diagnose

nose,

ocular

clavicles,

septal

striking

of

respiratory left

motor if some of its features are not expressed. In

abnormalities,

marked femora,

large and

head, general, diagnosis of any syndrome in which

fine

tract other

and some of its features are not expressed is more

ribs,

base

poor

large persistent

ventricular of a problem in a sporadic occurrence than in

hypoplastic

palate,

synophrys,

skull

olfactory

polysyndactyly

and broad

humeri a familial instance. foot,

Tables 2 through 7 should be interpreted

Hypotonia,

limbs, trunk Short

region,

disability,

kidneys, Short absent

except and/or distress each 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

syndrome, low-frequency anomalies that occur in various syndromes are not listed, although they may

be found in the references for each condition. syndrome

syndrome Finally, some syndromes are incompletely de-

syndrome

3-Continued III rib-polydactyly lineated at the present time. In these in-

stances, new findings will undoubtedly come

Type

Shprintzen Short Walden

TABLE to light in the future. Cohen, s¥NDROMES 317

Population Definition of a Syndrome than three per cent of all cases of clefting It is sometimes asked if an occasionally being associated with "syndromes" (Fraser, 1970) is too low in our opinion. observed abnormality is part of a syndrome The significance of syndrome delineation or not. How frequently does cleft palate, for cannot be overestimated. In a large study of example, have to occur in a syndrome to be newborn infants with multiple anomalies of considered a feature of that syndrome? Since all kinds (malformation syndromes), only 40 the pathogenesis of many syndromes is ob- per cent had known, recognized entities (Mar- scure, there is no direct way of knowing. den et al., 1964). The other 60 per cent rep- However, by using a population definition of resented provisionally-unique-pattern syn- a syndrome, it can be determined indirectly. dromes that needed to be further delineated. If a given abnormality occurs with greater frequency in the syndrome population than it As an unknown syndrome becomes deline- ated, its phenotypic spectrum, its natural his- does as an isolated abnormality in the general tory, and its inheritance pattern or risk of population, it should be considered part of recurrence become known, allowing for better the syndrome. This principle commits us to patient care and family counseling. If the statements such as "orofacial clefting is part phenotypic spectrum is known, the clinician of the Down syndrome" because clefting oc- can search for suspected defects that may not curs three times more commonly than it does be immediately apparent but which may pro- as an isolated defect in the general population. duce clinical problems at a later time, such as However, orofacial clefting is an extremely a hemivertebra in the Goldenhar syndrome. uncommon feature of the Down syndrome. If a certain complication can occur in a given The frequency of clefting in various syn- disorder, such as a Wilms tumor in the Beck- dromes is not expressed as a percentage in the with-Wiedemann syndrome, the clinician is tables because ascertainment biases inherent forewarned to monitor the patient with intra- in case reports in the literature tend to make venous pyelograms. Finally, if the recurrence percentage estimates inaccurate and mislead- risk is known, the parents can be counseled ing. Generally, in all tables, frequency of cleft- properly about future pregnancies. This is ing is listed as "common," "uncommon," or especially important if the risk is high and the "rare." "Common" should be interpreted to disorder is severely handicapping or disfigur- mean that the frequency of clefting is at least ing, has mental deficiency as one component, 30 per cent or higher. Most frequencies listed or has a dramatically shortened life span. For as "common" are considerably higher (except example, cleft palate or the Robin complex is in Table 5). When only a few instances of a a common feature of the Stickler syndrome, syndrome have been reported, a number may an autosomal dominant disorder with a 50 be given in the frequency column. For exam- per cent recurrence risk when one parent is ple, 2/5 means that clefting occurred in two affected. In this condition, retinal detachment of the five reported cases. Since there are so is thought to occur in 20 per cent of reported few cases known, it is not yet possible to cases and blindness in 15 per cent (Herrmann ascertain how common clefting will be in the et al., 1975). Genetic counseling is of great syndrome. ' importance because the risk of development Syndrome Delineation of serious ocular problems is high. This rela- To date, many anomalies reported in asso- tively common condition also illustrates the ciation with cleft lip and cleft palate are not importance of syndrome delineation because recognized as constituting syndromes of the entity was unknown and unrecognized known genesis. In epidemiologic studies of before 1965, although surely it existed before clefting to date, the frequency with which one that time. Thus, the overall treatment pro- or more malformations accompany clefts var- gram gains rationality if a syndrome is delin- ies from eight to 50 per cent (Gorlin et al., eated. In contrast, with a provisionally- 1976). Undoubtedly, many new syndromes of unique-pattern syndrome, the treatment pro- known genesis will be delineated from this gram and overall management frequently group in the future. Thus, the estimate of less leave something to be desired.

318 Cleft Palate Journal, October 1978, Vol. 15 No. 4

1974

1974

1975

19752;

1975°

Spranger

1975

1972

1971

1970°

Aal..,

1970.

Smith,

Smith,

Herrmann,

1972;

Laurent,

Grossman,

et

reference

al.,

al.,

al.,

1977

and

and

et

and

and

1975

et

and

Langer,

Donlan,

Langer

Hanson

Herrmann Storer

Coheffet and Aurias

Walker

Hanson

Holthusen,

Gorlin

Opitz,

of

few

type,

arm

distal

long

11

recessive

dominant

heterogeneous

the

recessive

recessive recessive

dominant

the dominant

dominant sporadic,

etiology

recessive

for

of

instances

cases

Autosomal

Autosomal

?

chromosome segment familial Autosomal Most

Autosomal

? etiologically Autosomal Autosomal Trisomy

Autosomal X-linked

Autosomal

given

in

cleft

cleft

cleft

cleft

Robin

common

known

palate

complex

most

isolated

isolated

isolated

common;

(2/2)

least

isolated

cases

cleft

condition

(1/2)

Robin

most

of

uncommon common common

common

few

palate

page)

Too

Cleft complex

palate Micrognathia

palate

glossoptosis Uncommon, palate

palate Uncommon, Common; Common Common common; second

?

Uncommon,

Uncommon Common

next

frequency

on

'

trunk,

beaked

chest,

various

renal

pretibial

thoracic defect,

and

face,

(continued

neonatal

epiphyseal

prominent

abnormalities

narrow

micropenis,

neck

other

other

tibias, septal

defect, cataracts,

micrognathia, mild

hitch-hiker's

scapulas,

and

neck,

other

tract, wrinkled

atrial

heart

bones,

midface,

defects,

defects

involving

foot,

wasting,

disease,

short flat

features

long

femurs cava,

visceromegaly,

gap of

clubfoot, urinary insufficiency

hypoplasia,

other

anosmia

of

of

hypoplastic ears,

defects

rib

of

joint stature

vena

congenital

hypertonia, muscle

striking clubfoot dental

complex

other

short

bowing

limb

deformity

detachment, detachment

pancreatic

gigantism,

synostosis,

posterior

nipples, omphalocele, contractures, ear,

superior malformed

Robin

degenerative

dysplasia, progressive

eczema,

valgus

overtubulation

left

hypertelorism,

defects,

malformations

retinal retinal cystic

failure, spaced equinovarus

the

stature,

with hypotonia, abnormalities

skin,

low-set face,

with

hypoglycemia, Macroglossia,

growth

dimpling,

vertebral Persistent nose,

dysplasia,

Disporportionate Microcephaly, Radiohumeral Flat Short thumb, myopia, widely

abnormalities

abnormalities Axial Myotonia, Thin Myopia, talipes agenesis, acetabular

other joints

associated

vena

(severe

dysplasia

synostosis

superior

syndrome dwarfism

Conditions

condition

dystrophy left Syndromes

11q syndrome syndrome

4.

Syndromes

syndrome

Donlan Persistent

Spondyloepiphyseal Diastrophic Stickler

syndrome

Campomelic Myotonic Radiohumeral Cerebrocostomandibular Trisomy Beckwith-Wiedemann congenita

syndrome

congenital) cava syndrome Chromosomal

TABLE Monogenic

TABLE 4-Continued

T eratogenically-Induced Syndromes Fetal alcohol syndrome Growth deficiency, mental deficiency, microcephaly, Uncommon Chronic alcoholism during Jones et al., 1973 narrow palpebral fissures, congenital heart defects, joint pregnancy - anomalies, other abnormalities Fetal hydantoin syndrome Digit and nail hypoplasia, unusual faces, growth and Uncommon, cleft lip and Diphenylhydantoin during Hanson and Smith, 1975b psychomotor retardation, other anomalies palate also observed pregnancy Fetal trimethadione syndrome Mental deficiency, speech disorders, V-shaped eyebrows, Uncommon, cleft lip and Trimethadione during Zackai et al., 1975 epicanthus, low-set posteriorly rotated ears with palate also observed pregnancy overfolded helix, cardiac anomalies, irregular teeth, other defects

Unknown-Genesis Syndromes Femoral dysgenesis-unusual Upslanting palpebral fissures, short nose with Micrognathia and cleft Sporadic, cause unknown Daent! et al., 1975 facies syndrome hypoplastic alar cartilages, long philtrum, short or palate common, absent femurs and fibulas, other defects glossoptosis uncommon

Martsolf syndrome Square forehead, abnormal ears, wide-set eyes, small ? Too few cases known Sporadic, cause unknown Martsolf et al., 1977 mouth, mild neck webbing, short neck, rhizomelic brachymelia, broad thumb, short index finger, broad halluces with valgus deformity, postaxial hexadactyly of the feet, skeletal abnormalities

Robin-accessory metacarpal Bilateral accessory metacarpal of index finger with ? Too few cases known Sporadic, one instance of Holthusen, 1972; Gewitz et syndrome clinodactyly, pectus carinatum affected sibs al., 1978

Robin-amelia syndrome Amelia ? Too few cases known Sporadic, cause unknown Holthusen, 1972 Cohen, synpromes 319

320 Cleft Palate Journal, October 1978, Vol. 15 No. 4

1975

1974

1974

1978

1974

1976

1975

Kobayashi,

al.,

1974 1975

references

al.,

1971 1971

Hoehn,

1977

al.,

et

1973

Behi,

et

al.,

and

Sanchez,

et

al., al.,

and

al.,

al.,

et

and

et et

et

et

and

Kempen,

Sanchez McPherson Harris Nakogome Yunis

Sedano Ballesta Bartoshesky, Vogel

Norwood Sedano Van

Allderdice *

H +

uvula bifid*

+1 +? +? +? +2 +?

+?

palate cleft**

+1

+? lip +?

+?

Cl€fl**

hy-

the

mi-

eye-

early

short

neck;

folds,

tissue

recto-

at

simple

hyper-

defect,

growth

skeletal

nostrils,

|

page) skin

palpebral

soft

strabismus,

short

arched

bridge,

heart

equinovarus,

ears,

lax

downslanting

ocular

atresia,

dimple,

micrognathia,

frequent

developmental

next

myopia,

small

epicanthic

extension

face,

nasal

deficiency,

anal

on

fingers,

anteverted

nose,

fissures,

head,

of

cryptorchidism,

tip,

talipes

low-set

thrive,

flat

relatively

phenotype

stature;

congenital

nose,

to

I)

small

varus,

fontanel,

small

rounded

micrognathia;

mental

function

preauricular

defects,

ears,

hypertelorism,

hernia,

pes

short

bulbous

palpebral

joints,

short

ears,

flat

limitation

(part

hypertelorism,

(continued

failure

ears;

fingers,

overlapping

renal

malformed

phenotype

heart

delineated

anterior

with

fissures,

ocular

hypotonia,

pointed

toes,

fissures,

ocular

dimple,

umbilical

wide

tapered

'

nose face,

reduced

micrognathia, tongue,

malformed

or

equinovarus;

anomalies

malformed

micrognathia,

downslanting

great

delineated

microcephaly,

congenital

features

long

hair, hyperextensible

seizures,

sacral

palpebral

mild

large

round

incompletely

palpebral

forehead,

superiorly

cryptorchidism,

ears,

and

defect

furrows,

talipes

tags,

low-set

fuzzy

palatal

ears,

striking prominent

bossing,

nose,

high

defects,

heart

skin

omphalocele

and

retardation,

plantar

incompletely large,

thumbs

retardation,

microphthalmia,

anomalies,

upslanting

small

micrognathia,

anomalies,

low-set

frontal

micrognathia,

downslanting

anal

malformed

toes

dysplasia;

bossing,

microcephaly,

cardiac

deep

lobe,

deficiency,

hypertelorism,

clefts

sacrum

ears,

folds;

and lip

renal

ears,

placed

congenital

fissures,

labia,

variable

the mouth,

low-set

nose, lung

brachycephaly,

frontal

with

glabella,

at

ocular

infancy,

thymus

psychomotor

mental

low-set

hypotonia,

micrognathia,

psychomotor

neck,

strabismus,

fingers

defect;

other

defects,

hypertelorism,

anomalies

epicanthic

absent

and

palpebral

prominent

short

prominent

proximally

absent

during

displaced

forehead,

camptodactyly,

broad

heart

weight,

bridge,

heart

dimpling

fissures,

downturned

or

forehead,

prominent

ocular

syndromes

cry

deficiency,

deficiency,

deficiency,

fistula, nose,

ears,

skeletal

hypertelorism,

growth

narrow

neck,

mouth,

birth

nasal

Microcephaly;

fissures, delay.

vaginal Low

nystagmus, congenital

philtrum,

telorism,

Prominent Growth Mental

brows, deficiency

Severe

involuted

Craniosynostosis, Ocular Microbrachycephaly,

cupped

palpebral

short anomalies syndactyly,

pospadias,

demise

low

large Distorted Cat-like Beaked

elbows, congenital crognathia, Mental

Chromosomal

5.

+

+ + +

+

+

karyotype* 1q 7q

6q- 7q-

3p 3P—3q+ 5p-

4p-

10q

11p

10p TABLE

Cohen, s¥NDROMES 321

al.,

et

1973

Lazjuk.

al.,

and

et Lejeune

1975

Lurie

1974

1972;

Muldal

1969;

1971

Yunis, 1972;

Laurent,

Lazjuk,

al.,

al.,

and

1969 1969

and

et

and

et Grouchy,

1972 1968

Lurie

Smith, de

Escobar Short

Smith, Orbeli Aurlas

+I

++ ins

both

with

mal-

heart

renal

nasal

heart

severe

micro-

imper- growth

or

defects,

defects,

page)

flat

prominent

coloboma,

heart

next heart

iris

demise,

eyes, thumbs,

segment

congenital

microphthalmia,

congenital

on micropenis,

syndromes

micrognathia,

early

microphthalmia,

micrognathia, hypertelorism,

13

holoprosencephaly

deep-set

congenital

whorls,

congenital

nose,

to

ears,

nipples,

clubfoot,

microphthalmia,

deficiency,

hypoplastic

ocular creases,

chromosome

(continued

deficiency,

digital

delineated microphthalmia), or

chromosomal

fingers,

defects

beaked

spaced

features

mental

hypoplasia, ptosis,

chromosome

simian

polydactyly,

nose,

malformed

dysplasia,

mental heart

of

large flat

common

increased cryptorchidism

widely folds,

.

micrognathia, microcephaly,

arm

midface

low-set

defects, face, chromosome

incompletely

severe

overlapping Turner-like

most is

of

ears, chest, long

or

congenital

fingers, acetabular

clinodactyly,

scalp

trigonocephaly,

from seizures,

the

epicanthic

episodes,

wrinkled diameter, deficiency,

of

hypotelorism, ears,

deletion

micrognathia,

narrow syndrome

or

tapering

malformed thrive,

part hypertonicity,

syndromes

thrive,

ears,

apneic

ocular

phenotype

mental

to

neck,

since

to

bifrontal

low-set

hemangioma,

cryptochidism, malformations,

trisomy

hypertonia,

mouth, short proximal

=

holoprosencephaly,

seizures, failure

variable

failure

narrow

deficiency,

tract

(including

limb

malformed

unknown no.

the glabellar

chromosomal

ears,

anomalies or

letter

retinoblastoma,

lobar

neck,

microcephaly,

retardation, for hypospadias,

or

date

ears,

mental

occiput,

carp-shaped

urinary

to

short

deficiency, no.

deficiency,

low-set

genital

low-set

anomalies frequency

anus,

hypotonia,

stature, dysmorphia

trisomy

dysmorphia

demise chromosome arm

well-known coloboma,

arm

=

Short

antihelix, defects

facial

Prominent gnathia,

forate

Psychomotor Mental Mental deficiency, bridge,

genital

iris formed early

malformed reported facial Holoprosencephaly, Microcephaly,

Axial coloboma agenesis, defects,

relative 22

more partial following short long

= not

(>15%) but p=

q= or +,

+"= through

13q 1

Boldface

5-Continued

uncommon

common

reported

rare absent

+ +"

+

= = Nos.

% *

18q- += +=

% t+

18p-

14q 13g 11q 13q-

18+

13+ +?=

+ Key

TABLE

322 Cleft Palate Journal, October 1978, Vol. 15 No. 4

1975

1971

Coco, 1973

references

and

1972

1976 1976

1976 1976

Cohen,

al.,

al.,

al., al., al., al.,

et

et

and

et et et et

DeCicco Penchaszadeh

Cohen Buhler

Gorlin Gorlin Gorlin Gorlin uvula bifid** *

A +1 +? palate Clefl*

+ lip

++ Clefi**

of

and syn-

folds, fourth

ocular down- anom- low-set

skeletal defects,

fissures, webbed

cardiac, iris auditory dentition, finger-like synostosis,

microceph-

renal short large clinodactyly,

syndactyly heart taurodontism, fissures, fistula, hyperflexibility,

stenosis, nipples, epicanthic external palpebral delayed

fingers,

aorta, micrognathia, skin,

tissue valgus, microcephaly, radioulnar

spots, the large

pyloric ears, soft neck,

palpebral congenital musculature,

neck

of microphthalmia, slender hypotonia, micrognathia,

ears, cubitus rectovagmal

brachydactyly, widely-spaced

hernia, low-set long bridge, downslanting deficiency, Brushfield

posterior clubfoot, posterior upslanting low-set defects,

atresia, coarctation on disease, philtrum, nasal

cryptorchldlsm

breasts, asymmetry, inguinal growth fissures, choroid, underdeveloped cryptochidism heart skin anal

flat creases,

long

and

anomalous micrognathia, strabismus, testes,

features infancy, and redundant hypotonia,

prominent nevi pits, loose fingers folds,

nose, ears, iris

pits, simian

periodontal vagina

or hypotonia, palpebral small root, striking neck, of hypotonia, congenital fifth

hypertonia, during dislocation, and tags of cryptorchidism, tongue, beaked hip deficiency, nasal

short

fingers,

hypertelorism, pigmented

loops, infantile tags

epicanthic prominent long

upslanting deficiency, anomalies deficiency, micropenis, broad folds, deficiency, colomboma

mental malocclusion, fourth ulnar

defects,

ocular

lymphedema multiple protruding

clinodactyly preauricular agenesis, valga hypospadias,

deficiency

and

hairline,

mental mild midface, heart severe hypotonia, mental skeletal fissures, mental ears,

preauricular nails, toes, asymmetry, flat increased genua

epicanthic third

and ovarian anomalies, and mental

retardation, peripheral prognathism, ears,

third

the posterior

congenital deficiency,

palpebral colobomas,

deficiency, of deficiency,

valgus, anomalies creases, and micrognathia, tooth

hypertelorism, low

malformed stature,

stature, hypoplastic microcephaly, craniofacial thumbs, malformed mandibular

aly,

alies, metacarpals, neck,

genitourinary, Short Brachycephaly, Psychomotor Psychomotor Mental Mild

hypertelorism,

minor dactyly

cubitus genital short

anomalies Growth slanting Growth

small second choroid simian

canals, ocular

5-Continued + karyotype*

'

22q-

22+ 21q- 22q

21+ X0 XXXXY

T'riploidy TABLE

Cohen, synprRomEs 323

press

in

1974

1974

1970

1976

1976

1976

al.,

Hohl,

references

al.,;

al.,

al., et

al.,

al.,

et

et

et

et and

et

Gorlin Spranger

Gorlin

Cohen Pallister

Gorlin

Wallace

in

18p-

few

date

autosomal

lethal

syndrome,

probably

to

chromosomal

markedly

heterogeneous

dominant

heterogeneous

Meckel

etiology

syndrome,

sporadic,. recessive

recessive

other

recessive,

with

dominant,

sporadic

13

expressivity)

instances,

cases

male

cases

Autosomal

Most familial

(trisomy

etiologically the

All

X-linked Etiologically

dominant variable karyotype, aberrations, Autosomal ?

autosomal

Autosomal

of

in

lip

cleft

frequency

condition

median

Uncommon

relative Common

Common

Common Common

?

Common

.

of

the

lip

other

of

upper

central

cardiac

of

seizures,

milia,

anterior

hypoplastic upper

valgus,

palate,

cranium

of

polydactyly absent

palpebral

other

tongue,

notch

elevation

abdomen,

of

amentia,

cubitus

notch

bifid

cartilages,

and/or

distress

anterior

lack

bilateral central

nostrils,

prominence,

postaxial

lip

alar

hypotelorism,

brachydactyly,

of

camptodactyly,

tip,

hydrocephalus,

congenitally height,

palate,

peak,

central

and

downslanting

cleft

features

protuberant

nostrils,

frontal

ocular

respiratory

nasal

cleft

cage,

joints,

facial

abnormalities,

palate,

polydactyly,

defects,

striking

rib

widow's

anomalies,

colobomas

hypoplastic

preaxial

tibias,

nose,

from

broad

other

lower

or cleft

wide-set

seizures,

anomalies,

halluces

laterally

flat heart

demise

tooth

short

of

hypertelorism,

manual

death radioulnar

thorax,

lip,

:

deformed

at

clinodactyly

genital

feet,

teeth,

notching

canthorum,

palate

frenula,

occultum,

ocular

cleft prominent

strabismus,

deficiency,

hypertelorism,

submucous

neonatal

lip

tongue,

and

congenital

narrow

limbs,

tip,

cleft

and

cleft

nasal abnormalities

Ocular bifidum Short abnormalities,

multiple hands anomalies, Dystopia Lobed Median

polysyndactyly

syndactyly, apnea, holoprosencephaly, Mental

malposed cowlick, fissures, incisors,

lip Short lungs, and

subluxation clinodactyly

median

I II

with

syndrome

syndrome

conditions

Conditions

agenesis

-

dysplasia

6.

syndrome

syndrome

syndrome

Frontonasal

TABLE

Majewski Premaxillary

Oral-facial-digital

Oral-facial-digital

W

Wallace

324 Cleft Palate Journal, October 1978, Vol. 15 No. 4

TABLE 7. Association of clefts with other abnormalities

type of cleft association comment references

Cleft lip or cleft palate Thoracopagus twins Gorlin et al., 197 1a or both

Cleft palate Oral duplication Gorlin et al., 1971a

Cleft lip or cleft palate Anencephaly Gorlin et al., 197 1a or both

Cleft palate Congenital oral teratoma Cleft palate probably secondary Gorlin et al., 197 1a to teratoma

Cleft lip or cleft palate Nasal glioma or meningoencephalocele Cleft palate probably secondary Gorlin et al., 197 1a or both to glioma or meningoencephalocele

Cleft lip or cleft palate Congenital neuroblastoma Other associated anomalies Gorlin et al., 1971a or both frequent

Cleft lip or cleft palate Congenital cardiovascular defects (ASD, Shah et al, 1970; or both or Robin VSD, PDA, pulmonary valvular atresia, Gorlin et al., 1976 complex tetralogy of Fallot, tricuspid stenosis, coarctation of the aorta, biventricular aorta, cor triloculare, dextrocardia)

Cleft lip or cleft palate Forearm bone aplasia Other associated anomalies Gorlin et al., 1971a or both frequent

Cleft lip-cleft palate Sacral agenesis Gorlin et al., 197 1a

Cleft lip-cleft palate Cleft larynx Gorlin et al., 1971a

Cleft lip-cleft palate Laryngeal web Gorlin et al., 1971a

Cleft lip-cleft palate Lateral proboscis Usually occurs with absent Gorlin et al., 1971a nostril on ipsilateral side

Cleft palate Persistent buccopharyngeal membrane Gorlin et al., 197 1a

Cleft palate Aniridia Gorlin et al., 197 1a

Cleft palate Aplas.ia of trochlea Gorlin et al., 197 1a

A major task in clinical genetics is to delin- Ideally, the findings of such syndromes eate the unknown-genesis syndromes as rap- should always be published. In practice, fa- idly as possible. Any clinician may be the first milial instances or two or more sporadic in- to see and identify a patient with a new stances of a new syndrome are usually pub- malformation syndrome in which orofacial lished. Provisionally-unique-pattern syn- clefting is a feature. As we pointed out earlier, dromes are commonly filed away and not more than half of all malformation syndromes published since their significance is uncertain. are not recognized as known entities at the However, the publication of a distinctive pro- present time. The discovery of a new malfor- visionally-unique-pattern syndrome is like an mation syndrome is equivalent to discovering advertisement with a red flag; it reaches a a new disease. Careful evaluation of the over- large audience and allows a few clinicians to all pattern of abnormalities (including minor react by publishing similar cases. When this as well as major anomalies) is required. Pho- happens, the syndrome delineation process is tographic documentation of the clinical and underway. radiologic findings is essential, especially Pathogenesis of Clefting when subtle phenotypic features defy verbal description. A thorough study of various rel- Finally, we should be careful not to confuse atives and an extended pedigree are necessary. the process of syndrome delineation with our Cohen, s¥NDROMES 325

understanding or lack of understanding of a SmITH, G. F., The deLange Syndrome. New York: Perga- mon Press, 1970. > syndrome's pathogenesis, even at the higher Brrosma, D., Case report 28, Syndrome Ident., 3 (1), 7, stages of delineation. For example, in a syn- 1975. drome of known genesis such as the recessively BixieEr, D., CuristIAN, J. C., and GoRLIN, R. J., Hyper- inherited Meckel syndrome, we know nothing telorism, microtia and facial clefting: A newly de- about how the homozygous state of the scribed inherited syndrome, Birth Defects, 5, 77-81, 1969. Meckel gene produces such diverse features as Bixier, D., Spivack, J., BEnnEtTt, J., and J. encephalocele, polydactyly, polycystic kid- C., The ectrodactyly-ectodermal dysplasia-clefting neys, and orofacial clefting. Clearly, since so (EEC) syndrome, C/in. Genet., 3, 43-51, 1971. much ettologic heterogeneity is known to occur in Bowen, P., and Armstrong, H. B., Ectodermal dysplasia, human syndromes with orofacial clefting, we mental retardation, cleft lip/palate and other anoma- lies in three sibs, Clin. Genet., 9, 35-42, 1976. should expect some pathogenetic heterogeneity in Braun, F. C., Jr., and BayEr, J. F., Familial nephrosis the production of clefts as well. A great deal associated with deafness and congenital urinary tract about the pathogenesis of orofacial clefting anomalies in siblings, J. Pediatr., 60, 33-41, 1962. remains to be learned. BunieEr, E. M., MenxEes, K., Muruer, H., and STALDER, G. R., Cat-eye syndrome, a partial trisomy 22, Human- Since this manuscript went to press, Cen- genetik, 15, 150-172, 1972. tervold (1978) has called my attention to some Burp1, A., FEmncourp, M., Larsson, K. S., Leck, I., Zm- new chromosomal syndromes with orofacial MERMAN, E. F., and FrRrasER, E. C., Etiology and path- clefting. Cleft palate has been observed in the ogenesis of congenital cleft lip and cleft palate, an 5-q-syndrome and cleft lip-palate in the 1-q- NIDR state-of-the-art report, Teratology, 6, 255, 1972. Burcto, G. R., BEiront, C., and BELurFr1, G., Nanisme syndrome. pseudodiastrophique. Etude de deux soeurs nouveau- Acknowledgment: I am extremely grateful to nées, Arch. Fr. Pediatr., 31, 681-696, 1974. Ms. Diane McDannald for her help with this CENTERVOLD, W. R., personal communication, 1978 project. CERVENKA, J., GoRLIN, R. J., and AnipeErson, V. E., The syndrome of pits of the lower lip and cleft lip and/or palate, genetic considerations, Am. J. Hum. Genet., 19, References 416-432, 1967. AasE, J. M., and Smit, D. W., Dysmorphogenesis of CiHrRrIsTIAN, J. C., AnprEws, P. A., ConEarLy, P. M., and joints, brain and palate: A new dominantly inherited MuruerR, J., The adducted thumbs syndrome, (/m. syndrome, J. Pediatr., 73, 606-609, 1968 Genet., 2, 95-103, 1971. ABrUZzzOo, M. A., and Erickson, R. P., A new syndrome M. M., Jr., Goruim, R. J., FEmmcorp, M., and of cleft palate associated with iris coloboma, hypo- TEN R. W., The Beckwith-Wiedemann syn- spadias, deafness, short stature, and radial synostosis, drome-Seven new cases, Am. J. Dis. Child., 122, J. Med. Genet., 14, 76-80, 1977. 515-519, 1971. ALLDERDICE, P. W., Brownr, N., and MURPHY D. P., ConEn, M. M., Jr., An etiologic and nosologic overview Chromosome 3 duplication q21—)qter syndrome in of craniosynostosis syndromes, Birtk Defects, 11(2), children of carriers of a pericentric inversion inv(3) 137-189, 1975. (p25q21), Am. J. Hum. Genet., 27, 699-718, 1975. CoxEn, M. M., Jr., The Robin anomalad-its nonspec- AppELt, H., GERKEN, J., and Lenz, W., Tetraphokomelie ificity and associated syndromes, /. Oral Surg., 34, 587, mit Lippen-Kiefer-Gaumenspathe und clitorishyper- 1976. trophic-ein syndrome, Paediat, Paedol., 2, 119-124, CoxEn, M. M., Jr., personal observation, 1977. 1966. Coxrn, M. M., Sr., and Conrn, M. M., Jr., The oral Aurias, A., and Laurent, C., Trisomie 11q. Individuali- manifestation of trisomy G:; (Down syndrome), Birth zation d'un nouveau syndrome, Ann. Genet., 18, Defects, 7(7), 241-251, 1971. 189-191, 1975. Conxrn, M. M., Jr., and Hox, T. H., Etiologic hetero- BaruEsTA, F., and Brx1, L., Trisomie partielle pom la geneity in the holoprosencephalic disorders, in Devel- partue distate du bras court due chromosome 3, Ann. opment of the Basicranium, J. F. Bosma, Ed., DHEW Genet., 17, 287-290, 1974. Publication No. (NIH) 76-989, Bethesda, 1976, pp. BartosnmEsky, L., Lewis, M. B., and PasHmavyan, H. M 383-399. Developmental abnormalltles assoaated with long arm DarntL, D. L., Situ, D. W., Scott, C. I., Harr, B. D., deletion of chromosome No. 6, Clin. Genet., 13, 68-71, and Goopinc, C. A., Femoral hypoplasia-unusual 1978. facies syndrome, J. Pediatr., 86, 107-111, 1975. Brare, J. M., Dopcr, J. A., and Nevin, N. C., Cutis Davis, J. G., and Larer, C., A possible new mental gyratum, acanthosis nigricans, and other congenital retardation syndrome, Birth Defects, 12(5), 235-238, anomalies-A new syndrome, Br. ]. Dermatol., 81, 1976. 241-247, 1969. DeCicco, F., STEELE, M. W., and Pan, S., Monosomy of BrenczE, J., ScHnITzLER, A., and WarawskaA, J., Domi- chromosome No. 22: A case report, j Pediatr., 83, nant inheritance of hemifacial hyperplasia associated 836-838, 1973. with strabismus, Oral Surg, 35, 489-500, 1973. Dr GroucHy, J., The 18p-, 18q-, and 18r syndromes, Brerc, J. M., McCrEary, B. D., RipueEr, M. A. C., and Birth Defects, 5(5), 74-87, 1969. 326 Cleft Palate Journal, October 1978, Vol. 15 No. 4 Dr ca CHaAPELLE, A., MarotEaux, P., Haru, N., and Gorin, R. J., Scmrorr, R. A., and Parareurua, M. M., GranrotTx, G., Une rare dysplasie osseuse léethale de Cleft palate, stapes fixation and oligodontia-A new transmission recessive autosomique, Arch. Fr. Pediatr., autosomal recessively inherited syndrome, Birth Defects, 29, 759-770, 1972. 7(7), 87-88, 19716. Donran, M. A., Growth failure, cleft palate, ectodermal GorLin, R. J., and SEpano, H. O., Multiple nevoid basal dysplasia, and apparent pancreatic insufficiency-? a cell carcinoma syndrome, Handbook Clin. Neurol., 14, new syndrome. Birth Defects, 13(3B), 230-231, 1977. 455-473, 1972. DrirriEn, C. M., Incram, T. T., and Wiikinson, E. M., GorRrLIN, R. J., AupER, R., and LancER, L., Megepiphyseal The Causes And Natural History Of Cleft Lip And Palate. dwarfism, J. Pediatr., 83, 633-635, 1973. Edinburgh: E & S Livingstone, 1966. Gorm, R. J., Pinpsorce, J. J., and ConEn, M. M., Jr., EAstTMAN, J. R., and BixuEr, D., Facio-cardio-renal syn- Syndromes Of The Head And Neck, edition 2. New York: drome: a newly delineated recessive disorder, C/zn. McGraw-Hill Company, 1976. Genet., 11, 424-430, 1977. Gunperson, C. H., GrEEnsPaAN, R. J., Graser, G. H., and ERIKSON A., Hereditary syndrome consisting of recurrent Luss, H. A., The Klippel-Feil syndrome: Genetic and attacks resemblmg brachial plexus neuritis, special fa- clinical re-evaluation of cervical fusion, Medicine, 46, cial features and cleft palate, Acta Paediatr. Scand., 63, 491-512, 1967. 885-888, 1974. Harr, J., Pirprorn, M., Karp, L,; Hickox, D., and EscoBAR, J. I., and Yunis, J. J., Trisomy for the proximal WiraEnsTEIN, L., A new short-rib polydactyly syn- segment of the long arm of chromosome 13, Am. J. Dis. drome, Birth Defects, 13(3B), 242-243, 1977. Child., 128, 221-222, 1974. Hanson, J. W., and Smit, D. W., U-shaped palatal Focm-AnpERSEN, P., Inheritance Of Harelip And Cleft Palate. defect in the Robin anomalid: Developmental and Copenhagen: Busck, 1942. clinical relevance, J. Pediatr., 87, 30-33, 1975a. FoxntTamE, G., Farriaux, J. P., DeratTTrRE, P., GIDLECKI, Hanson, J. W., and SmittH, D. W., The fetal hydantoin Z., Pourarp, B., DuriEux, G., and PiQqguEt, J. J., Une syndrome, J. Pediatr., 87, 285-290, 1975b. observation familiale du syndrome ectrodactylie et dy- Harris, E. L., WarpnER, R. S., and Parmer, C. G., 7q sostose mandibulo-faciale, J. Génét. Hum., 22, 289-307, deletion syndrome, Birth Defects, 13(3B), 244, 1977. 1974. Hausam, T. J., Wraver, D. D., and Prescott, G. H., FrasER, F. C., The genetics of cleft lip and cleft palate, The occurrence of an Apert-like syndrome and the Am. J. Hum. Genet., 22, 336-352, 1970. VATER association in twins, Birth Defects, 13(3C), 239, FrRrasER, F. C., Etiology of cleft lip and palate, in Cleft Lip 1977. And Palate, edited by Grabb W. C., Rosenstein S. W., HERRMANN, J., personal communication, 1975. and Bzoch K. R. Boston: Little, Brown, and Company, HrErrmann, J. and OpITz, J. M., The Stickler syndrome 54-65, 1971. (hereditary arthoophthalmopathy), Birth Defects, 11(2), FrEirE-MAia, N., A newly recognized genetic syndrome 76-103, 1975. of tetramelic deficiencies, ectodermal dysplasia, de- HErmannNn, J., and OritTz, J. M., The VSR syndrome, formed ears, and other abnormalities, 4m. J. Hum. Birth Defects, 13(3C), 69-84, 1977. Genet., 22, 370-377, 1970. Herrmann, J., FEmcorp, M., TurFL1, G. A., and OPITz, FunurmaAnn, W., Kock, F., and ScnwEckENDIEK, W., Au- J. M., A familial dysmorphogenic syndrome of limb tosomal dominante Vererbung von Gaumenspalte und deformities, characteristic facial appearance and asso- Synechien zwischen Gauman und Mundboden oder ciated anomalies: The "Pseudothalidomide" or "SC- Zunge, Humangenetik, 14, 196-203, 1972. Syndrome," Birth Defects, 5(3), 81-89, 19692. GareEs, F. J., and Smit, D. W., Diminished stature- Herrmann, J., ParuistER, P. D., and Opitz, J. M., Cra- defective palate syndrome: a dominantly inherited niosynostosis and cranlosynostos1s syndromes Rocky Mt. disorder, J. Pediatr., 79, 470-472, 1971. Med. J., 66, 45-56, 1969b. GrEwIitTz, M., DinwipoiE, R., T., E., aAnp Hrrrmann, J., France, T. D., and Opitz, J. M., The _ C. O., Cleft palate and accessory metacarpal Stickler syndrome, Birth Defects, 11(6), 203-204, 1975. of index finger syndrome: possible familial occurrence. Ho, C. K., Kaurman, R. L., and McAustER, W. A., J. Med. Genet., 15, 162-164, 1978. Congenital malformations-cleft palate, congenital Gorpon, H., Davies, D., and Berman, M., Camptodac- heart disease, absent tibiae and polydactyly, Am. J. tyly, cleft palate, and clubfoot-A syndrome showing Dis. Child., 129, 714-1716, 1975. the autosomal-dominant pattern of inheritance, /. HortHuUsEN, W., The Pierre Robin syndrome: unusual Med. Genet., 6, 266-274, 1969. associated developmental defects, Ann. Radiol., 15, Gorpon, I. R., and Brown, N. J., The syndrome of 253-262, 1972. _ micromelic dwarfism and multiple anomalies, 4nz. Hsia, Y. E., Bratu, M., and HErBoLTt, A., Genetics of the Radiol., 19, 161-165, 1976. Meckel syndrome (dysencephalia splanchnocystica), Goruin, R. J., SEpano, H. O., and CirrvEnK®a, J., Poplit- Pediatrics, 48, 237-241, 1971. eal pterygium syndrome, Pediatrics, 41, 503-509, 1968. Ipr, C. H., and WorrscnxrararErR, P. B., Multiple congen- Gorm, R. J. CrrvEnka, J., and Anerson, R. C., Ro- ital abnormalities associated with cryptophthalmia, bin's syndrome. A probably x-linked recessive sub- Arch. Ophthalmol., 81,.638-644, 1969. variety exhibiting persistence of left superior vena cava Jones, K. L., Smit, D. W., UrretranDp, C. N., and and atrial septal defect, Am. J. Dis. Child. 119, 176-181, StrEssoutH, P., Pattern of malformation in offspring 1970. of chronic alcoholic mothers, Lancet 1, 1267-1271, 1973. Gorm, R. J., CrrvEenka, J., and Pruzansky, S., Facial Jongs, K. L., Suirtn, D. W., Harr, B. D., Hart, J. G., clefting and its syndromes, Birtk Defects, 7(7), 3-49, Emsin, A. J., Massoubp, H., and Gorsus, M. S., A 1971a. pattern of craniofacial and limb defects secondary to Cohen, syNDROMES 327

aberrant tissue bands. J. Pediatr., 84, 90-95, 1974. BBB syndrome-Familial telecanthus with associated JuseErc, R. C., and Haywarp, J. R., A new familial congenital anomalies, Birth Defects, 5(2), 86-94, 1969. syndrome of oral, cranial, and digital anomalies, /. D. J., Lurie, I. W., and GorosnEnko, J. L., The Pediatr., 74, 755-1762, 1969. syndrome associated with the partial D-monosomy. KatcHrrRr, M., and Harz, J. G., personal communication, Case report and review, Humangenetik, 13, 296-308, 1975. 1971. LancEr, L. O., Jr., and HERRMANN, J., The cerebro- ParaAnt, D. I., FEincorp, M., and Berkman, M. D., costomandibular syndrome, Birtk Defects, 10(7), Unusual facies, cleft palate, mental retardation and 167-170, 1974. limb abnormalities in siblings-a new syndrome, J. LancrrRr, L. O., JR., GoNnzALEz-Ramos, M., H., and Pediatr., 78, 686-689, 1971. Espiritu, C. E., A severe infantile micromelic chon- ParustER, P. D., HERRMANN, J., SprancER, J. W., GoRLIN, drodysplasia which resembles Kniest disease, Eur. /. R. J., Lancer, L. O., and Oritz, J. M., The W syn- Pediatr., 123, 29-38, 1976. drome, Birth Defects, 10(7), 51-60, 1974. LeEjrEunE, J., M-O, BrErorr, R., ABoNYI, D., ParristER, P. D., Herrmann, J., and OPiTz, J. M., Studies Dutrirraux, B., and See, G., Trisome C partielle par of malformation syndromes in man. XXXKXII: Pleio- translocation familiale t(Cq+;Cq-), Ann. Geénét., 11, tropic dominant mutation affecting skeletal and apo- 171-175, 1968. crine-mammary development, Birth Defects, 12(5), LeEwanpowsKkI, R. C., Jr., and Yunis, J. J., New chro- 247-254, 1976. mosomal syndromes, Am. J. Dis. Child. 129, 515-529, O. A., and Conen, M. M., Jr., The Waarden- 1975. burg syndrome, Birth Defects. 7(7), 147-152, 1971. Lowry, R. B., and Mirirr®, J. R., Cleft palate and PantkE, O. A., Conrn, M. M., Jr., Wirkor, C., FEmmnNcorp, congenital heart disease, Lancet, 1, 1302-1303, 1971. M., ScHaumann, B., Pantkr®, H. C., and Gor1m, R. J., Lowry, R. B., and MacLean, J. R., Syndrome of mental The Saethre-Chotzen syndrome, Birth Defects, 11(2), retardation, cleft palate, eventration of diaphragm, 190-225, 1975. ” congenital heart defect, glaucoma, growth failure, and Pena, S. D. J., and SmoxrEir, M. H. K., Syndrome of craniosynostosis, Birth Defects, 13(3B), 203-210, 1977. camptodactyly, multiple ankyloses, facial anomalies, Lurg, I. W., and LazjuK, G. I., Partial monosomies 18. and pulmonary hypoplasia: A lethal condition, J. Pe- Review of cytogenetical and phenotypical variants, diatr., 85, 373-375, 1974. Humangenetik, 15, 203-222, 1972. PencHaszapex, V. B., and Coco, R., Trisomy 22. Two Marpen, P. M., Suirtu, D. W., and McDonarp, M. J., new cases and delineation of the phenotype, J. Med. Congenital anomalies in the newborn infant, including Genet., 12, 193-199, 1975. minor variation, /. Pediat., 64, 358-371, 1964. PHiruips, C. I., and Grirrityus, D. L., Macular coloboma Marpen, P. M., and WALKER, W. A., A new generalized and skeletal abnormality, Br. J. Ophthalmol., 53, connective tissue syndrome, Am. J. Dis. Child., 112, 346-349, 1969. 225-228, 1966. PitoTro, R. F., MarcarLro, F. A., and OPtTz, J. M., Study MarotEaAuUx, P., Roux, C., and FruvcHtTER, Z., Le nanisme of a child with an "idiopathic' micrognathe, Presse Méd., 78, 2371-2374, 1970. retardation syndrome, Birth Defects, 11(2), 51-53, 1975. Martsour, J. T., Rerp, M. H., and HuntERr, A. G. W., RAPP, R. S., and Hopoxin, W. E., Anhidrotic ectodermal Case report #56: Skeletal dysplasia, Robin anomalad, dysplasia: Autosomal dominant inheritance with pal- and polydactyly, Syndrome Identification, 5(1), 14-18, ate and lip anomalies, /. Med. Genet., 5, 269-272, 1968. 1977. ~ RupicErR®, R. A., Scnmipt; W., LoosE, D. A., and Pas- McPurErson, E., Hart, J. G., and Hickman, R., Chro- SARGE, E., Severe developmental failure with coarse mosome 7 short arm deletion and craniosynostosis. A facial features, distal limb hypoplasia, thickened pal- 7p- syndrome, Humangenetik, 35, 117-123, 1976. mar creases, bifid uvula and ureteral stenosis: a previ- MrasE, A. D., YEatman, G. W., PETTETT, G., and MErR- ously unidentified familial disorder with lethal out- ENSTEIN, G. B., A syndrome of ankylosis, facial anom- come, /. Pediatr., 79, 977-981, 1971. alies and pulmonary hypoplasia secondary to fetal SancHEz, O., Yunis, J. J., and Escomar, J. I., Partial neuromuscular dysfunction, Birtk Defects, 12(5), trisomy 11 in a child resulting from a complex maternal 193-200, 1976. rearrangement of chromosomes 11, 12 & 13, Humange- MurpaL, S., Enock, B. A., AnmrEDp, A., and Harris, R., netik, 22, 59-65, 1974. Partial trisomy 14q- and pseudoxanthoma elasticum, SeEpano, H. O., Look, R. A., CartER, C., and ConEn, M. Clin. Genet. 4, 480-489, 1973. M., Jr., B group short-arm deletion syndromes, Birth NaxracomE, Y., and KosavasH1, H., Trisomy of the short Defects, 7(7), 89-97, 1971. arm of chromosome 10, J. Med. Genet., 12, 412-414, Say, B., Barger, D. H., and Hosss, J., A new dominantly 1975. inherited syndrome of cleft palate, Humangenetik, 26, Nance, W. E., and SweEnEy, A., A recessively inherited 267-269, 1975. : chondrodysplasia, Birth Defects, 6(4), 25-27, 1970. Snax, C. V. S., and Harris, W. S., Cardiac Norwoon, T. H., and Hoenn, H., Trisomy of the long malformations with facial clefts; with observations on arm of human chromosome 1, Humangenetik, 25, 79-82, the Pierre Robin syndrome, Am J. Dis. Child., 119, 1974. 238-244, 1970. : OPITZ, J. M., personal communication, 1975. SHaw, E. B., and StEmmNBAcKH, H. L., Aminopterin-induced OriTz, J. M., FEmcorp, M., Burr, M. J., and SprancrEr, fetal malformation, Am. J. Dis. Child., 115, 477-482, J. W., The campomelic syndrome-comments, Birtk 1968. Defects, 10(9), 97-99, 1974. SHEPARD, T. H., Catalog of Teratogenic Agents. Baltimore: Opitz, J. M., SummIrTT, R. L., and Suit, D. W., The Johns Hopkins University Press. Second Edition. 328 Cleft Palate Journal, October 1978, Vol. 15 No. 4 218-220, 1976. WarpEn, R. H., Logosso, R. D., and BRENNAN, L., Pierre Snort, E. M., Sormarr®r, G. B., and BrEo, W. R., A case Robin syndrome in association with combined congen- of partial 14 trisomy 47,XY,(14q-)+ and transloca- ital lengthening and shortening of the long tion t(Op+;14p-) in mother and brother, J. Med. bones-Case report, Plast. Reconstr Surg., 48, 80-82, - Genet., 9, 367-373, 1972. 1971. SmprintzEn, R. J., GorpBErc, R. B., Lewin, M. L., WarkrErR, B. A., Scott, C. I., Harr, J. G., Murpock, J. Spot:, E. J., Berkman, M. D., ArGaMaso, R. V., and L., and McKusick, V. A., Diastrophic dwarfism, Med- Young, D., A new syndrome involving cleft palate, icine, 51, 41-59, 1972. cardiac anomalies, typical facies, and learning disabil- Warraer, D. C., Exton, L. A., Prircnarp, D. A., Leunc, ities: velo-cardio-facial syndrome, Cleft Palate J., 15, Y., and CooKrE, R. A., Severe achondroplasia. Dem- 56-62, 1978. onstration of probable heterogeneity within this clini- SicerErs, D. C., D. L.., Dorst, J. P., Doty, S. B., cal syndrome, J. Med. Genet., 7, 22-26, 1970. B. R., HoruistER, D. W., SirBERBERCG, R., WravEr, D. D., and Wirumams, C. P., A syndrome of CranurEy, R. E., Kaurman, R. L., and V. microcephaly, mental retardation, unusual facies, cleft A., The Kniest syndrome, Birth Defects, 10(9), 193-208, palate, and weight deficiency, Birth Defects, 13(3C), 1974, and 10, 432-442, 1974. 69-84, 1977. Smit, D. W., The 18 trisomy and the 13 trisomy syn- WrrrEBER, R. G., and BrEars, R. K., The Hajdu-Cheney dromes, Birth Defects, 5(5), 67-71, 1969. syndrome, J. Pediatr., 88, 243-249, 1976. SPRANGER, J. W., and LanoEr, L. O., Jr., Spondyloepi- WILDERVANCK, L. S., Een cervico-ocular-acusticussynd- physeal dysplasia congenita, Radiology, 94, 313-322, room, Ned. Tijdschr. Geneeskd., 104, 2600-2605, 1960. 1970. Woorr, C. M., Congenital cleft lip, J. Med. Genet., 8, SprANGER, J., and Grimm, B., Short rib-polydactyly 65-83, 1971. - (SRP) syndromes, typus Majewski and Saldino- Yonc, L., Lowry, R. B., and Jan, J. E., Syndrome of Noonan, Z. Kinderheilkd., 116, 73-94, 1974. myopathy, short stature, seizures, retinitis pigmentosa, - StorER, J., and Grossman, H., The campomelic syn- and cleft lip, Birth Defects,. 13(3B), 230-231, 1977. drome, Radiology, 111, 673-681, 1974. Yunis, J. J., and SancnEz, O., A new syndrome resulting Van KrmprEn, C., A patient with congenital anomalies from partial trisomy for the distal third of the long arm and deletion of the long arm of chromosome 4 of chromosome 10, J. Pediatr., 84, 567-570, 1974. [46,XY,del(4)(q31)], J. Med. Genet., 12, 204-212, 1975. ZaAackA, E. J., Meruinan, W. J., NemperER, B., and Han- Vocrt, W., SiEBERS, J. W., and ReimwEin, H., Partial son, J. W., Trimethadione teratogenic syndrome, J. trisomy 7q, Ann. Genet., 16, 227-230, 1973. Pediatr., 87, 280-284, 1975. ‘