Familial and genetic associations in Worster-Drought syndrome and perisylvian disorders

� 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:35–42 (2008)

Familial and Genetic Associations in Worster-DroughtSyndrome and Perisylvian Disorders

Maria Clark1,2 and Brian G.R. Neville1,2*1Neurosciences Unit, University College London, Institute of Child Health, London, UK

2Great Ormond Street Hospital for Children NHS Trust, London, UK

Received 26 June 2006; Accepted 19 July 2007

Worster-Drought syndrome (WDS) is a distinct clinicalphenotype, comprising a congenital pseudobulbar palsyusually in association with a mild tetraplegia and oftenadditional impairments. The phenotype is identical to thatdescribed in congenital bilateral perisylvian polymicrogyriasyndrome (CBPS) and appears to have several differentcauses and a significant familial incidence. This study drawsfrom a database of children with WDS phenotype orperisylvian polymicrogyria, held at a tertiary center. The

findings suggest that genetic factors are important for asignificant proportion of children and points to considerablegenetic heterogeneity. There are grounds for consideringWDS and perisylvian polymicrogyria as a spectrum ofperisylvian malfunction. � 2007 Wiley-Liss, Inc.

Key words: Worster-Drought syndrome; congenital bilat-eral perisylvian polymicrogyria syndrome

How to cite this article: Clark M, Neville BGR. 2008. Familial and genetic associations in Worster-Droughtsyndrome and perisylvian disorders. Am J Med Genet Part A 146A:35–42.

INTRODUCTION

Worster-Drought syndrome (WDS) consists of acongenital pseudobulbar palsy and is usually asso-ciated with additional impairments suggesting cort-ical involvement (mild spastic tetraplegia, learningimpairment, behavioral problems, and epilepsy) andoccasionally congenital contractures. Congenitalbilateral perisylvian syndrome (CBPS) is character-ized by bilateral perisylvian polymicrogyria onimaging [Kuznieckyet al., 1993],with clinical featuresincluding pseudobulbar palsy, learning impairment,epilepsy, congenital contractures, and mild spastictetraplegia.

We have previously proposed a WDS spectrum[Clark et al., 2000] that includes CBPS, speculatingthat it may be due to malformation of the perisylvianregion due to various perinatal or congenital causes,whether demonstrable on imaging (e.g., CBPS), orfunctional and not visible with current imagingtechniques. Support for a WDS or perisylvianspectrum comes from the observation of consider-able overlap in phenotype between WDS and CBPSand the fact that around 15% of children with WDShave perisylvian abnormalities on neuroimaging[Clark et al., 2000]. Furthermore families with theWDS phenotype may be discordant for perisylvianabnormalities on imaging (Table I, Family 8), andthere are individuals with unilateral perisylvianpolymicrogyria who functionally have impairments(e.g., pseudobulbar palsy, tetraplegia, learning

difficulties) that infer bilateral difficulties. This articledescribes familial and genetic aspects of theseconditions, and supports a spectrum of perisylvianabnormalities.

METHODS

The tertiary center has a special interest inWDSandperisylvian polymicrogyria and has established adatabase of these children. There are currentlyaround 170 children on the database, including 33with bilateral and 20 with unilateral perisylvianpolymicrogyria.

WDS phenotype was ascertained by a seniorpediatric neurologist (BN) and is defined as affectingmore than one bulbar modality (e.g., dribbling,feeding, swallowing, speech) with upper motorneuron bulbar signs on examination. The relativeselectivity of the bulbar impairments (e.g., of speechas compared to understanding) cannot always bedocumented under 2 years, and our practice is tosuspect WDS under 2 years but to be more definitiveabout diagnosis between 2 and 4 years of age.

*Correspondence to: Brian G.R. Neville, The Wolfson Centre,Mecklenburgh Square, London WC1N 2AP, UK.E-mail: [email protected]

DOI 10.1002/ajmg.a.32015

TABLE

I.Fam

ilia

lW

DS

and

Perisy

lvia

nPoly

mic

rogyria

Fam

ily

Pat

ient

WD

SCongenital

feat

ure

sPyr

Epil

IQN

.psy

Oth

er

MRI

1M

IP

Sim

ple

upperlip,bilat

talipes,

inguin

alhern

iaP

PSL

DASD

,AD

HD

—Bro

ther

PSi

mple

upperlip,in

guin

alhern

iaP

PM

LDASD

,AD

HD

N2

MI

PH

igh

nas

albridgeþ

fore

head

,sm

allear

s(o

verfold

ed

helice

s)cl

inodac

tyly

PP

SLD

ASD

,hypera

ctiv

eN

Sist

er

PSm

allear

s,righttran

svers

epal

mar

creas

e,

inverted

nip

ple

s,co

arse

faci

es

PP

SLD

Hyp

era

ctiv

eN

3M

IP

Left

voca

lco

rdpal

syP

AM

LDN

NBro

ther

PN

o—

AN

AD

HD

—4

MI(t

win

)P

No

—A

——

—M

I(t

win

)P

No

—A

——

—5

MI

PArthro

gry

posi

s(n

euro

genic

EM

G)

PP

MLD

NPar

ents

firs

tco

usi

ns

CBPS

Sist

er

PN

oP

AN

NCBPS

6FI(t

win

)P

No

PA

——

—Tw

insi

ster

PN

oP

A—

——

7M

IA

Neuro

fibro

mat

osi

sty

pe

1P

PM

LDAD

HD

Par

ents

hav

enorm

alM

RI

Rig

htPP

Bro

ther

AN

oP

AN

NRig

htPP

8M

IP

No

PA

NSh

ort

atte

ntion

Pat

ern

alau

nthad

epilepsy

and

son

with

SLD

NSo

nP

No

PA

NAD

HD

CBPS

9M

oth

er

PN

oce

ntral

philtrum

,fa

cial

dim

ple

s—

AN

NBro

theran

dhis

son

had

speec

hdela

yN

Fat

her

?—

—A

——

Speech

,fe

edin

gdifficu

ltie

sin

fath

er,

his

bro

ther

and

son

and

sist

er

and

son

—

FI

PJa

wco

ntrac

ture

PA

NN

NBro

ther

PN

oP

AM

LDAD

HD

NBro

ther(t

win

)P

No

PA

MLD

AD

HD

,au

tist

ictrai

tsN

Bro

ther(t

win

)P

No

PP

MLD

AD

HD

,au

tist

ictrai

tsN

Sist

er

PN

oP

AM

LD—

—10

Moth

er

PN

oP

AN

N—

MI

PN

oP

PN

Hyp

era

ctiv

eN

11

Moth

er

PN

o—

AN

N—

MI

PN

oP

AN

Hyp

era

ctiv

e—

12

Fat

her

?N

o—

AM

LDN

Speech

dela

y—

MI

PRig

htm

icro

phth

alm

us

AA

NH

ypera

ctiv

eRig

htPP

13

FI

PD

ouble

outleture

thra

PP

SLD

Hypera

ctiv

e,

CBPS

Mat

boy

cousi

nP

No

PP

MLD

—CBPS

14

MI

PM

icro

gnat

hia

PA

NN

Poly

hydra

mnio

sN

Pat

.uncl

e?

——

AN

ND

ysp

hag

ia,poly

hydra

mnio

s—

15

MI

PN

oP

AM

LDN

—Pat

boy

cousi

nP

——

A—

NG

ross

moto

rdela

y—

16

MI

ABilat

talipes

(neuro

genic

EM

G)

AP

NH

ypera

ctiv

eBilat

weak

nes

sþ

was

ting

belo

wknee

Mat

gt-au

ntþ

dau

ghte

rhav

eta

lipes

CBPS

17

FI

ABilat

talipes

AP

NN

Eig

htin

div

idual

sover4

genera

tions

ofm

atern

alfa

mily

had

epilepsy

Left

PP

18

MI

PN

oP

AN

NM

oth

er’s

thre

esi

sters

eac

hhav

eso

nw

ith

sam

epro

file

N

19

MI

PN

o?

PM

LDAutist

ictrai

tsBro

theran

dm

oth

er’s

sist

er’s

son

also

hav

eLK

San

dASD

CBPS

MI,

mal

ein

dex;F

I,fe

mal

ein

dex;P

,pre

sent;

A,a

bse

nt;

?,uncl

ear

;N,n

orm

al;—

,dat

anota

vai

lable

;WD

S,co

ngenital

pse

udobulb

arpal

sy;P

yr,

pyra

mid

alsi

gns;

Epil,e

pilepsy

;IQ

,inte

llig

ence

quotient;

MLD

,IQ

50–70;S

LD,I

Q<

50;N

.psy

,neuro

psy

chia

tric

difficu

ltie

s;AD

HD

,at

tention

defici

thypera

ctiv

ity

dis

ord

er;

ASD

,au

tist

icsp

ect

rum

dis

ord

er;

CBPS,

congenital

bilat

era

lperisy

lvia

npoly

mic

rogyria;

PP,perisy

lvia

npoly

mic

rogyria.

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

Perisylvian polymicrogyria was diagnosed on MRIscan by experienced pediatric neuroradiologists.

RESULTS

Familial WDS and Perisylvian Polymicrogyria

There are 19 multiplex families with 15 (1–6, 8–15,18) havingWDSphenotype. In two families, the childhas CBPS without bulbar features (16, 17) and afamily history suggestive of affected relatives.Another child (19) has CBPS and bulbar symptomsthat are seizure-related. Two brothers (7) both haveright-sided polymicrogyria that is widespread in onecase (who also has neurofibromatosis 1) and largelyconfined to the perisylvian region in the other;neither have bulbar symptoms (see Table I).

There are seven sibships (1–7) with no otherclinically affected familymember, including two twinpairs. For these, there is a male to female ratio of 10:4.For four of these sibships (1, 3, 4, 7) there are twoaffected brothers as the only affected individuals(compatible with either autosomal recessive orX-linked inheritance). In another family (5:brother and sister born to first cousin parents) bothchildren have a WDS phenotype with CBPS on MRI,but the boy is clinically more severely affected witharythrogryposis multiplex, bilateral talipes and EMGevidence of anterior horn cell disease. This could stillbe compatible with either autosomal recessive orX-linked inheritance (with the sister as a manifestcarrier). There is also a set of female twins (6) and abrother–sister pair (2) which would both fit withautosomal recessive pattern of inheritance.

There are 10 families (8–17) in which both sexesare affected in more than one generation and there ismale-to-male transmission, although there remains amale preponderance (16 male:7 female). Thispattern is suggestive of autosomal dominant withincomplete penetrance. However for two motherson dyads (10, 11), the mother has mild featureswhich could be compatible with X-linked inher-itance, with the mother a manifesting carrier. In fiveof these families (8–12) parent and child both havethe WDS phenotype, in each case the parent beingless severely affected, usually either with a sugges-tive history or soft neurological signs. In one family(8) the father was diagnosed with WDS as a child(with normal imaging) and his son is more severelyaffected with CBPS. One family (9) has multiplemembers with speech and learning disability.

For the other five families (13–17), affectedindividuals are more distantly related, includingthree with WDS features (including cousins whoboth have CBPS). One child (16) has CBPS withoutbulbar symptoms and bilateral talipes which is alsofound in distant relatives. Another child (17) hasunilateral perisylvian polymicrogyria and bilateraltalipes and a strong family history of seizures,

although other family members have not hadimaging.

For two families (18, 19), there is a strong pattern ofmale relatives being affected through the female linewith no male-to-male transmission, suggestive of anX-linked recessive disorder.

Across all of the described groups, there areexamples of variable expression within a kindred,both in severity of bulbar features, and presence ofadditional impairments. This variation may reflectthe impact of other key etiological factors on agenetically vulnerable individual.

Sporadic WDS Phenotype WithAdditional Features

Sixty percent of the patients had karyotype analysiswhich revealed four with abnormalities (A, B, C, D),none of which have previously been reported withWDS phenotype. In three children the phenotypewas due to 22q11 deletion and a small numberof other children have other features suggestive ofsyndromes (Tables II and III).

Twin data (Tables I and III) revealed three sets oftwins (two male twin pairs 4, 9: one female twinpair 6) in which both children are affected, althoughthey are not generally concordant for severity. In fourother sets of twins (R, S, T, U), only one twin of thepair is affected. There are also three children (V, W,X) thought to be a surviving twin following earlyin-utero loss of a fetus. Two of these children (V, W)have CBPS, and the third (X) has the WDSphenotype, with troublesome seizures and periodsof subclinical status associated with regression.

DISCUSSION

Familial Cases

Dr. Worster-Drought originally described 82 casesof WDS including seven families who contributed 17of the cases [Worster-Drought, 1956]. These familiesconsisted of two sisters (adults) and the daughter ofone of the sisters; father, son and daughter; motherand son; two brother and sister dyads; twin brothers;two brothers and a cousin. This last family wasfurther described [Patton et al., 1986] with a fourthaffected male member. Despite all affected membersbeing male, there was observed transmissionthrough unaffected males to their male offspring,making X-linkage unlikely, and autosomal dominantinheritance with variable penetrance and expressiv-ity was proposed. A further review of 200 cases ofWDS [Worster-Drought, 1974] noted 12 familialcases, including three pairs of twins and five adultswho were relatives of children with the disorder. Ourprevious study of 47 cases [Clark et al., 2000] foundsix children with a family history of WDS. There havebeen no molecular genetic studies to date.

GENETICS OF WORSTER-DROUGHT SYNDROME 37


TABLE

II.

WD

SPhenoty

pe

With

Additio

nal

Feat

ure

s

Cas

eAdditio

nal

asso

ciat

ion

Congenital

feat

ure

sPyr

Epil

IQN

.psy

MRI

A,G

irl

Par

tial

monoso

my

10q

var

icella

inear

lypre

gnan

cyLo

ng

nar

row

face

,hypertelo

rism

,bro

adnas

albridge,fe

ature

less

philtrum

,th

inupperlip,sh

ort

neck

PP

SLD

NN

B,Boy

Fra

gile

site

long

arm

chro

moso

me

2Rett

feat

ure

s:decr

eas

ing

head

centile

from

50th

at1

tounder3rd

at6

year

s;sc

oliosi

sin

teens

Ocu

lom

oto

rap

raxia

,H

irsc

hpru

ng

dis

eas

eP

AM

LDN

CT

norm

al

C,Boy

Chro

moso

me

7q32-3

4dele

tion

Colo

bom

aofin

ferior

rightfu

ndus,

cupped

dis

cs,ab

sentele

vat

ion

righteye,right

undesc

ended

test

is

PP

SLD

AD

HD

,ASD

—

D,Boy

Mosa

ictris

om

y9

Undesc

ended

test

es,

rightin

guin

alhern

ia,

smal

lpenis

,le

ftre

nal

duple

xP

ASL

D—

Cere

bra

lat

rophy

E,Boy

22q11

dele

tion

Thic

kao

rtic

cusp

s,sh

ort

stat

ure

AP

MLD

N—

F,Boy

22q11

dele

tion

Bilat

era

lta

lipes,

bilat

era

lin

guin

alhern

iae

PP

SLD

AD

HD

Rig

htPP

G,G

irl

22q11

dele

tion:m

oth

er,

fath

eran

dtw

osi

sters

allhav

ese

vere

speec

hpro

ble

ms,

dia

gnose

din

itia

lly

asW

DS:

moth

eran

dold

ersi

sterhav

e22q11

dele

tion

No

—A

MLD

N—

H,G

irl

Rett

feat

ure

s:fr

equenthyperv

entila

tion

with

resp

irat

ory

pau

ses

causi

ng

synco

pe:lo

sthan

dfu

nct

ion:grinds

teeth

No

PP

SLD

NRig

htPP

I,G

irl

PV

ble

ed

at17

weeks

gest

atio

nRett

feat

ure

s:lo

sthan

dfu

nct

ion

afte

r3

year

s:st

ere

oty

pic

han

dm

ove

ments

:unst

ead

ygai

t;grinds

teeth

No

PP

SLD

AD

HD

N

J,G

irl

Mat

ern

alsi

nusi

tis(a

ntibio

tics

)at

3m

gest

atio

nRett

feat

ure

s:decr

eas

ing

head

centile

from

50th

centile

at1

tounder

3rd

centile

at5

year

s.M

usc

ledis

eas

e:m

yopat

hic

EM

G

Wid

eepic

anth

icfo

lds,

hypertelo

rism

,flat

occ

iput,

weak

nes

s,pto

sis,

ocu

lom

oto

rap

raxia

PP

SLD

NCBPS

K,Boy

Musc

ledis

eas

e:in

creas

ed

ech

oon

musc

leultra

sound,

bio

psy

norm

al,poss

ible

congen

ital

musc

ula

rdyst

rophy

Smal

lau

ditory

meat

us,

long

face

,su

bm

uco

salcl

eft;ar

yth

rogry

posi

s(f

eet,

han

ds,

elb

ow

s,knees)

;m

arked

dis

talw

eak

nes

s

PP

MLD

AD

HD

CBPS

L,Boy

Musc

ledis

eas

e:W

eak

nes

soffa

ce,pal

ate,

tongue,

neck

flexors

,an

dlim

bgirdle

;hip

contrac

ture

s;CK

and

musc

lebio

psy

norm

al;dia

gnose

dat

4year

sw

ith

congen

ital

myopat

hy.G

aitdete

riora

tion

at7

year

s,CBPS

identified

Fac

ially

like

VCF

(22q11

dele

tion

negat

ive)

PP

MLD

NCBPS

M,Boy

Mar

cus-

Gunn

phenom

enon

No

PA

NN

—N

,Boy

First

cousi

npar

ents

Optic

nerv

ehypopla

sia

Low

ante

riorhai

rline,upsl

anting

pal

pebra

lfiss

ure

s,m

icro

gnat

hia

,dis

tal

inte

rphal

angeal

contrac

ture

s,pal

mar

/pla

nta

rkera

toderm

a,pse

udocl

ubbin

goffingers

/toes

PP

SLD

—CBPS

(cobble

stone)

O,Boy

Septo

-optic

dysp

lasi

a:no

feedin

gor

speec

hdifficu

ltie

sLe

ftoptic

nerv

ehypopla

sia

No

endocr

ine

abnorm

alitie

sP

AN

NCBPS,

abse

ntse

ptu

mpelluci

dum

,sm

all

pituitar

y,le

ftoptic

nerv

ehypopla

sia

P,Boy

Mat

ern

alvar

icella

at8

weeks

gest

atio

nRig

htoptic

nerv

eco

lobom

aan

dbilat

era

lch

oriore

tinal

scar

sco

nsi

stentw

ith

var

icella

PP

MLD

NCBPS,

som

ew

hite

mat

tersi

gnal

abnorm

ality

Q,Boy

Mat

ern

alvar

icella

week

befo

redeliver

y,

neonat

alch

ickenpox

No

PP

SLD

ASD

Scat

tere

dw

hite

mat

terle

sions

P,p

rese

nt;

A,a

bse

nt;

N,n

orm

al;—

,dat

anotav

aila

ble

;Pyr,

pyra

mid

alsi

gns;

Epil,e

pilepsy

;IQ

,inte

llig

ence

quotient;

MLD

,IQ

50-7

0;S

LD,I

Q<

50;N

.psy

,neuro

psy

chia

tric

difficu

ltie

s;AD

HD

,attention

defici

thypera

ctiv

ity

dis

ord

er;

ASD

,au

tist

icsp

ect

rum

dis

ord

er;

CBPS,

congenital

bilat

era

lperisy

lvia

npoly

mic

rogyria;

PP,perisy

lvia

npoly

mic

rogyria.


Bilateral perisylvian polymicrogyria has beenextensively studied and several inheritance patternssuggested including X-linked dominant, X-linkedrecessive, autosomal dominant with reduced pene-trance and autosomal recessive [Guerreiro et al.,2000; Guerrini and Carrozzo, 2001; Villard et al.,2002]. In linkage analysis of five families withmultiple affected members (following an X-linkedinheritance pattern but with considerable structuraland phenotypic inter- and intra-familial variation),a locus for bilateral perisylvian polymicrogyriamapped to Xq28 [Villard et al., 2002]. Recently amutation in the Xq22 gene, SRPX2 [Roll et al., 2006],has been described in a male with CBPS and rolandicseizures and his female relatives, some of whom hadmild mental retardation, and a separate mutation inthe SRPX2 gene has been associated with rolandicseizures, oral and speech dyspraxia and mentalretardation without imaging changes in a differentfamily, emphasizing an important role for geneticfactors in development of perisylvian structure andfunction. In a few families unilateral and bilateralperisylvian polymicrogyria co-exist, implying asingle genetic abnormality could be responsible forboth [Bartolomei et al., 1999; Guerreiro et al., 2000].Thus these observations confirm significant geneticheterogeneity both in cause and expression.

In our experience familial WDS is equally likelywith or without imaging changes (of the 19 multiplexfamilies, six have normal scans, seven have peri-sylvian abnormalities, one family is known to bediscordant for scan findings and five are unscanned).There is not always a clear relationship betweenperisylvian structural changes and clinical pheno-type. Some family members of patients with provenCBPS have bulbar features despite normal MRIfindings [Guerreiro et al., 2000]. Conversely weknow three children with CBPS (symmetrical intwo cases) who have no bulbar symptoms, anotherwho acquired pseudobulbar palsy at 2 years with the

onset of seizures and further children with CBPSwhose bulbar symptoms vary with seizure activity.There are also reports of unilateral perisylvianpolymicrogyria with functionally bilateral deficitssuch as pseudobulbar palsy, particularly with theonset of seizures [Vaquerizo and Diaz-Garcia, 1997]and we know of at least eight children with unilateralperisylvian lesions who have had a pseudobulbarpalsy from birth and hence functionally have abilateral perisylvian lesion which predated anyseizures.

Thus it seems likely there is a spectrum ofperisylvian disorders, some with manifest polymi-crogyria visible on MRI, and others with subtlecortical disorganization that impairs function yet isnot detectable with current imaging techniques.Additionally, as with other congenital lesions, thereis a phenotypic spectrum that may not correlateclosely with imaging findings.

Sporadic Cases

We have observed a number of children whoappear to have WDS as one part of a more complexcondition (Table II) which may or may not have agenetic basis. This emphasizes the heterogeneity,but may also give insight into factors influencingperisylvian development and function. The chromo-somal abnormalities (Table II) in our series were notknown to be associated with pseudobulbar palsy orpolymicrogyria, although it seems likely they werecausal. 22q11 deletion syndrome has been associ-ated with both unilateral and bilateral polymicrogy-ria including familial discordance for imagingchanges [Bingham et al., 1997; Bingham et al.,1998; Worthington et al., 2000; Ghariani et al.,2002]. At present it is unclear whether the primarygenetic defect in 22q11 deletion is causal or whetherthe polymicrogyria is secondary to vascular abnor-malities associated with the syndrome. However, a

TABLE III. WDS Phenotype in Twins (See Also Table I, Families 4, 6, 9)

Child WDS Pyr Epil IQ N.Psy Other MRI

R, Girl P P A N ADHD Non-identical twin sister is normal NS, Girl P P A N N P.V. bleed at 14 weeks gestation. IUGR. Twin

sister is normal—

T, Boy P P P MLD ADHD Premature (30 wks). Twin sister is normal. Mother’s brother,father and uncle had unexplained ‘‘blackouts’’ in childhood

Right PP

U, Boy P P A MLD N Eye movement disorder, microcephaly, growth hormone deficiency.Twin brother is normal

Cerebral atrophy

V, Boy P A A SLD N Ultrasound suggested aborted twin at 8/40, associated withheavy bleeding P.V.

CBPS

W, Boy P P P MLD ASD Difficulty with upward gaze. Aborted twin at 11/40, empty2nd gestational sac found

CBPS

X, Girl P P P SLD ADHD Unusual facial dimples, jaw contracture, difficulty withupward gaze. Hyperemesis, hypertension in early pregnancy.Empty sac at delivery suggesting aborted twin

N

P, present; A, absent; N, normal; —, data not available; WDS, congenital pseudobulbar palsy; Pyr, pyramidal signs; Epil, epilepsy; IQ, intelligence quotient; MLD, IQ50–70; SLD, IQ< 50; N.psy, neuropsychiatric difficulties; ADHD, attention deficit hyperactivity disorder; ASD, autistic spectrum disorder; CBPS, congenital bilateralperisylvian polymicrogyria; PP, perisylvian polymicrogyria.



recent multicenter study [Robin et al., 2006] con-firmed a predilection for the perisylvian regionand reported frequent asymmetry with right-sidedpreponderance, suggesting an important vascularcontribution. There is often overlap in neurodeve-lopmental features of 22q11deletion andWDS (threechildren in this series had 22q11 deletion; E, F, G),and common basis for this in abnormal developmentof the operculum may exist. Another boy (L) withCBPS has facial features of the 22q11 deletion, butdoes not have the genetic abnormality on specifictesting.

CBPS has been reported in patients with mutationsin theMECP2geneonXq28 [Geerdinket al., 2002], cf.the locus for X-linked bilateral perisylvian polymi-crogyria maps to Xq28. Several children (B, H, I, J)with WDS phenotype have features reminiscent ofRett syndrome including episodic hyperventilation,hand mannerisms and two children (one with CBPS)with decreasing head circumference centile.

Both CBPS and WDS have shown a significantassociation with congenital limb contractures (chil-dren 1, 5, 16, 17, F, K). Some of our cases haveevidence of anterior horn cell disease [Clark et al.,2006] in addition to pseudobulbar palsy or perisyl-vian polymicrogyria suggesting both cortical andanterior horn cell lesions, although causal mecha-nism is unclear.

Three sporadic cases of children with WDSphenotype and CBPS, have additional muscledisorders including one (K) with probable congen-ital muscular dystrophy (known association withpolymicrogyria) and two ( J, L) with an undefinedcongenital myopathy (not normally associated withbrain abnormalities).

Some children with WDS have structural eyeabnormalities including coloboma (C, P), micro-phthalmia (12) and optic nerve hypoplasia (N, O).One child (O) has absent septum pellucidum withperisylvian polymicrogyria, which has previouslybeendescribed [Siejka et al., 1989; Sejima et al., 2001].At least six children (B, C, J, U, W, X) have an eyemovement disorder (documented supranuclear inthree cases). Other cases gave a history of suggestiveof oculomotor apraxia as a young child thatimproved spontaneously. A report of five sporadicpatients with bulbar incoordination, jaw ankylosisand oculomotor apraxia with normal MRI scans, withone autopsy showing normal cerebral hemispheresbut neuronal depletion in cranial nerve nuclei, isprobably describing a closely related condition [Roiget al., 2003].

Etiological Factors and Causal Pathways

Polymicrogyria appears to be the endpoint ofdifferent etiological processes affecting corticaldevelopment and by extrapolation we suggest thatthese mechanisms may also cause functional peri-

sylvian impairments (manifest as WDS) withoutimaging changes. The occurrence of familial casesand association with chromosomal abnormalitiesindicate a genetic element, but there are other well-recognized associations such as fetal cerebral ische-mia in early gestation when the perisylvian regionsare vulnerable to hypoperfusion. Thus CBPS hasbeen reported following twin–twin transfusion[Lenti and Triulzi, 1996], intrauterine death of a co-twin [Baker et al., 1996; Van Bogaert et al., 1996] andin association with congenital constriction bandsyndrome [Yamanouchi et al., 2002]. Similarly ourtwin data supports both genetic (4, 6, 9) andcirculatory (R to X) etiologies.

It may be that genetic and vascular risk factors areboth important. Early fetal loss is not unusual in twinpregnancies, and yet is not usually associated withWDS phenotype or CBPS in the survivor. Wherethere are CNS lesions, they are often disseminatedand associated with multiple visceral infarcts. There-fore perhaps a genetic predisposition to operculardamage is also needed.

Intrauterine infectionhas also been associatedwithpolymicrogyria [Barkovich and Lindan, 1994] thoughnot specifically with perisylvian lesions. Threechildren (A, P, Q) were exposed to chickenpox inpregnancy (first trimester in two cases, third trimesterin one case). In both early cases, the child had CBPS,but not the more common features of congenitalvaricella (such as circatricial skin lesions or bonehypoplasia), and in the late case, more widespreadwhite matter lesions were found; varicella was likelyto be the cause in these cases.

CONCLUSION

In WDS and CBPS there is strong evidence for agenetic mechanism in a significant number ofpatients. Even in sporadic cases where otherpathological mechanisms appear to act, geneticpredisposition may still play an important role, orthere may be a genetic basis through new mutations.

On the evidence to date, it would seem thatperisylvian disorders would be best served byconsidering WDS and CBPS together. In the former,the population is identified by careful history andexamination for phenotype, in the latter structuralchanges on neuroimaging are used as a marker. Bothroutes have their weaknesses. The former is open toobserver bias, the latter is limited by the sophisti-cation of current imaging techniques and is unable toexplain outliers, such as individuals with unilateralperisylvian lesions (and yet bilateral impairments) orkindreds where affected individuals are discordantfor imaging changes. Both are only a proxy forperisylvian function.

The clustering of cases within our area of clinicalactivity in the UK suggests that WDS is an under-recognized condition in the community. It is also

40 CLARK AND NEVILLE


currently poorly understood in terms of etiology.This paper sets out clear evidence of genetic etiologyfor some families and we hope that future research(involving families identified by both phenotype andneuroimaging) will identify the responsible genesand further our understanding of neuromigrationand the perisylvian region.

In summary in this series of children with Worster-Drought phenotype and congenital perisylvianpolymicrogyria, familial occurrence is equally com-mon in those with and without scan findings of CBPSand is at a level of about 15%. Familial occurrence isparticularly helpful in delineating common bilateralphenotypes with children who are non-concordantfor CBPS and with unilateral perisylvian polymicro-gyria. There is evidence of considerable geneticheterogeneity as well as vascular, infective andepileptic mechanisms being involved in perisylviandamage and dysfunction. The effect of epilepsy onphenotype is an interesting and relatively unex-plored area. It is clear that in unilateral MRI disease,seizure activity can involve the contralateral homo-logous area and produce a bilateral motor disorder.Recognizing that in some families there may beindividuals with unilateral and bilateral MRI involve-ment but a bilateral phenotype, we have argued thatit is more likely that uneven timing of the geneticeffect may cause unilateral polymicrogyria but acontralateral abnormality, not currently identified onroutine MRI but with a reduced threshold forepilepsy. The extent of the epileptic encephalopathyin the phenotype has not therefore been explored indetail.

ACKNOWLEDGMENTS

The parent support group has been a significantsource of information and encouragement. GreatOrmond Street Hospital for Children NHS Trustreceives R and D funding from the NHS Executive.The views expressed in this publication are those ofthe authors.

REFERENCES

Baker EM, Ghazavi Khorasgani M, Gardner-Medwin D, GholkarA, Griffiths PD. 1996. Arthrogryposis multiplex congenita andbilateral parietal polymicrogyria in association with theintrauterine death of a twin. Neuropediatrics 27:54–56.

Barkovich AJ, Lindan CE. 1994. Congenital cytomegalovirusinfection of the brain: Imaging analysis and embryologicconsiderations. Am J Neuroradiol 15:703–715.

Bartolomei F, Gavaret M, Dravet C, Guerrini R. 1999. Familialepilepsy with unilateral and bilateral malformations of corticaldevelopment. Epilepsia 40:47–51.

Bingham PM, Zimmerman RA, McDonald-McGinn D, Driscoll D,Emanuel BS, Zackai E. 1997. Enlarged Sylvian fissures ininfants with interstitial deletion of chromosome 22q11. Am JMed Genet 74:538–543.

Bingham PM, Lynch D, McDonald-McGinn D, Zackai E. 1998.Polymicrogyria in chromosome 22 deletion syndrome.Neurology 51:1500–1502.

Clark M, Carr L, Reilly S, Neville BGR. 2000. Worster-Droughtsyndrome, a mild tetraplegic perisylvian cerebral palsy. Brain123:2160–2170.

Clark M, Pitt M, Neville BGR. 2006. Lower motor neuroneinvolvement in perisylvian polymicrogyria. Dev Med ChildNeurol 48:842–846.

Geerdink N, Rotteveel JJ, Lammens M, Sistermans EA, HeikensGT, Gabreels FJ, Mullaart RA, Hamel BC. 2002. MECP2mutation in a boy with severe neonatal encephalopathy:Clinical, neuropathological and molecular findings. Neuro-pediatrics 33:33–36.

Ghariani S, Dahan K, Saint-Martin C, Kadhim H, Morsomme F,Moniotte S, Verellen-Dumoulin C, Sebire G. 2002. Polymicro-gyria in chromosome 22q11 deletion syndrome. Eur J PediatrNeurol 6:73–77.

GuerreiroMM,Andermann E,Guerrini R,DobynsWB,KuznieckyR, Silver K, Van Bogaert P, Gillain C, David P, Ambrosetto G,Rosati A, Bartolomei F, Parmeggiani A, Paetau R, Salonen O,Ignatius J, Borgatti R, Zucca C, Bastos AC, Palmini A,Fernandes W, Montenegro MA, Cendes F, Andermann F.2000. Familial perisylvian polymicrogyria: A new familialsyndrome of cortical maldevelopment. Ann Neurol 48:39–48.

Guerrini R, Carrozzo R. 2001. Epileptgenic brain malformations:Clinical presentation, malformative patterns and indicationsfor genetic testing. Seizure 10:532–543.

Kuzniecky R, Andemann F, Guerrini R. 1993. Congenital bilateralperisylvian syndrome: Study of 31 patients. Lancet 341:608–612.

Lenti C, Triulzi F. 1996. Discordant clinical and neuroradiologicalfeatures of congenital bilateral perisylvian syndrome inmonozygotic female twins. Ital J Neurol Sci 17:287–290.

Patton MA, Baraitser M, Brett EM. 1986. A family with congenitalsuprabulbar paresis (Worster-Drought syndrome). Clin Genet29:147–150.

Robin NH, Taylor CJ, McDonald-McGinn DM, Zackai EH,Bingham P, Collins KJ, Earl D, Gill D, Granata T, Guerrini R,Katz N, Kimonis V, Lin JP, Lynch DR, Mohammed S, MasseyRF, McDonald M, Rogers RC, Splitt M, Stevens C, TischkowitzMD, Stoodley N, Leventer RJ, Pilz DT, Dobyns WB. 2006.Polymicrogyria and Deletion 22q11. 2 Syndrome. Am J MedGenet Part A 140A:2416–2425.

Roig M, Gratacos M, Vazquez E, Del-Toro M, Foguet A, Ferrer I,Macaya A. 2003. Brainstem dysgenesis: Report of five patientswith congenital hypotonia, multiple cranial nerve involve-ment, and ocular motor apraxia. Dev Med Child Neurol45:489–493.

Roll P, Rudolf G, Pereira S, Royer B, Scheffer I, Massacrier A,Valenti MP, Roeckel-Trevisiol N, Jamili S, Beclin C, SeegmullerC, Metz-Lutz MN, Lemainque A, Delepine M, Caloustian C, deSaint Martin A, Bruneau N, Depetris D, Mattei MG, Flori E,Robaglia-Schlupp A, Levy N, Neubauer BA, Ravid R,Marescaux C, Berkovic S, Hirsch E, Lathrop M, Cau P,Szepetowski P. 2006. SRPX2 mutations in disorders oflanguage cortex and cognition. Human Mol Genet 15:1195–1207.

Sejima H, Takusa Y, Kimura M, Tamaoki Y, Kishi K, Yamaguchi S.2001. A variant case of congenital bilateral perisylviansyndrome with asymmetric findings on neuroimaging andseptum pellucidum defect. Brain Dev 23:131–134.

Siejka S, Strefling AM, Urich H. 1989. Absence of Septumpellucidum and polymicrogyria: A forme fruste of theporencephalic syndrome. Clin Neuropathol 8:174–178.

Van Bogaert P, Donner C, David P, Rodesch F, Avni EF,Szliwowski HB. 1996. Congenital bilateral perisylvian syn-drome in a monozygotic twin with intra-uterine death of theco-twin. Dev Med Child Neurol 38:166–171.



Vaquerizo J, Diaz-Garcia C. 1997. State of bilateral operculardisorder and pseudobulbar paralysis of late onset in unilateralperisylvian dysplasia. Rev Neurol 25:1934–1936.

Villard L, Nguyen K, Cardoso C, Martin CL, Weiss AM, Sifry-PlattM, Grix AW, Graham JM Jr, Winter RM, Leventer RJ, DobynsWB. 2002. A locus for bilateral perisylvian polymicrogyriamaps to Xq28. Am J Hum Genet 70:1003–1008.

Worster-Drought C. 1956. Congenital suprabulbar paresis. JLaryngol Otol 70:453.

Worster-Drought C. 1974. Congenital suprabulbar paresis. DevMed Child Neurol 16:25.

Worthington S, Turner A, Elber J, Andrews PI. 2000. 22q11deletion and polymicrogyria—cause or coincidence? ClinDysmorphol 9:193–197.

Yamanouchi H, Imataka G, Hagiwara Y, Nakagawa E, Eguchi M.2002. Congenital bilateral perisylvian syndrome associatedwith congenital constriction band syndrome. J Child Neurol17:448–450.

42 CLARK AND NEVILLE


Documents

Familial and genetic associations in Worster-Drought syndrome and perisylvian disorders