PRENATAL DIAGNOSIS, VOL. 10,279-288 (1 990)

PRENATAL ULTRASONOGRAPHIC DIAGNOSIS

MALFORMATIONS OF RADIAL-RAY REDUCTION

JOZIEN T. J . BRONS*, HANS J. VAN DER HARTEN?, HERMAN P. VAN GEIJN’, JURI w. WLADIMIROFF~, MARTINUS F. NIERMEIJER~, DICK LINDHOUT~, PATRICIA A. STUART$, CHRIS J. L. M. MEIJERS AND NICO F.TII. ARTS*

Departments of Obstetrics and Gynecology*, and Pathology?, Free University Hospital. Amsterdam: Departments of Obstetrics and Gynecology f , and Clinical Genetics& University Hospital Dijkzigt.

Rotterdam , The Netherlands

SUMMARY Radial-ray reduction malformations (RRRMs) may occur isolated or in association with other anomalies. The data of seven fetuses born with RRRMs were collected. Six fetuses had associated lethal abnormalities of the central nervous system, urogenital system, and/or heart, detected by ultrasound. In five cases, it was possible to establish the precise diag- nosis, enabling an informed prognosis and subsequent genetic counselling. The diagnoses were: Edwards syndrome (n= 3), VACTERL association (n= l), and Poland-Moebius- like complex (n = 1). In two cases, a complete diagnosis was not possible because of inade- quate evaluation of these fetuses before and/or after birth. A proposal is given for the diagnostic approach for infants with RRRMs detected in the antenatal period by means of ultrasonography.

KE’I WORDS Ultrasonography Skeletal dysostosis Radial hypoplasia Radial aplasia Congenital limb defect

INTRODUCTION

Radial aplasia or hypoplasia may occur in isolation or in association with other anomalies. The incidence among live births has been estimated at 1:30 000 (Sofer et al., 1983). In addition to the absence or hypoplasia of the radius, there is often absence or hypoplasia of the scaphoid, trapezium, first metacarpal, and thumb. This condition, called ‘radial-ray reduction malformations’ (RRRMs), may either arise from chromosomal aberrations (Bofinger et al., 1973), or environmental insults (Lindhout, 1985; Pauli and Feldman, 1986), or be part of genetic (Brons et al., 1988a; Filkins and Russo, 1984; Glanz and Clarke Fraser, 1982; Hermann et al., 1975; Lee and Kenny, 1967; Majoor-Krakauer et al., 1987; Muis et d. 1986; Riimke et a/., 1987) or non-genetic (Czeizel and Ludanyi, 1985; Lindhout et al., 1988) syndromes with multiple organ involvement (Table 1).

Prenatal ultrasound scanning offers the possibility of detection of these skeletal malformations in the second and third trimesters of pregnancy (Brons et al., 1988a; Filkins and Russo, 1984; Lindhout et al., 1988). This paper presents data from seven infants with RRRMs born between 1984 and 1988 in the University Hospitals of

Addressee for correspondence: J. T. J. Brons, Department of Obstetrics and Gynecology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.

01 97-385 1/90/050279-10$05.00 0 1990 by John Wiley & Sons, Ltd.

Received 25 August 1989 Accepted 5 January 1990

Tabl

e I.

Diff

eren

tial d

iagn

osis

in th

e ca

se o

f rad

ial-r

ay r

educ

tion

mal

form

atio

ns (

RR

RM

s)

Inhe

ritan

ce

Con

ditio

n A

nom

alie

s

VA

CTE

RL

asso

ciat

ion

(1 3)

Chr

omos

omal

abe

rrat

ions

(T

risom

y 18

, mos

aic t

risom

y 18

, tris

omy

13) (

2)

Thal

idom

ide

Val

proi

c aci

d (3

)

Alc

ohol

(4)

Tera

toge

nic

embr

yopa

thy

Fanc

oni’s

anae

mia

(5)

Trom

bocy

tope

nia-

Abs

ent-

Hol

t-O

ram

synd

rom

e (7)

radi

us sy

ndro

me

(TA

R) (

6)

Acr

o-re

nal s

yndr

ome

(1)

Cor

nelia

de

Lang

e syn

drom

e (8

)

Acr

o-fa

cial

dys

osto

sis (

type

Aas

e syn

drom

e (1

0)

Nag

er) (

9)

Pola

nd-M

oebi

us s

yndr

ome

Rob

ert’s

synd

rom

e (1

I)

(14)

Seck

el sy

ndro

me

(1 2)

-

Ver

tebr

al, A

nal,

Car

diac

anom

alie

s -

Trac

heo-

Esop

hage

al fi

stul

a, R

enal

and

Lim

b de

fect

s (R

RR

Ms)

La

rge

rang

e of

pos

sibl

e def

ects

: abd

omin

al w

all,

the

hear

t, ki

dney

s, ce

ntra

l ner

vous

syst

em, a

nd li

mbs

(R

RR

Ms)

Var

iabl

e R

RR

Ms,

som

etim

es co

mpl

ete

amel

ia

Spin

a bi

fida,

ver

tebr

al d

efec

ts, d

efor

miti

es an

d fu

sion

of

ribs,

card

iac

defe

cts,

hyp

ospa

dia,

RR

RM

s

Panc

ytop

enia

, mic

roce

phal

y, le

ukae

mia

, der

mal

pi

gmen

tatio

n, v

aria

ble

RR

RM

s, en

hanc

ed

chro

mos

omal

bre

akag

e Th

rom

bocy

tope

nia,

RR

RM

s

Car

diac

abn

orm

aliti

es, v

aria

ble

RR

RM

s or o

ther

lim

b

Ren

al a

nom

alie

s, ex

tern

al e

ar d

efor

miti

es, R

RR

Ms

Shor

t sta

ture

, mic

roce

phal

y, ch

arac

teris

tic fa

cies

, R

RR

Ms

Mic

rogn

athi

a, d

eafn

ess,

colo

bom

ata

of lo

wer

eyel

ids,

RR

RM

s

Hyp

opla

stic

ana

emia

, cle

ft lip

lpal

ate,

bip

hala

ngea

l th

umb,

RR

RM

s

Var

ying

deg

rees

of a

nter

ior c

hest

wal

l and

pos

terio

r sh

ould

er g

irdle

abno

rmal

ities

, syn

dact

yly,

RR

RM

s C

left

lip a

nd/o

r pal

ate,

car

diac

def

ects

, tet

raph

ocom

elia

defe

cts

Mic

roce

phal

y, p

rom

inen

t nos

e, sh

ort s

tatu

re, m

enta

l re

tard

atio

n, R

RR

Ms

Mul

tifac

toria

l or s

pora

dic

I4

Whe

n ch

rom

osom

es o

f par

ents

ar

e no

rmal

: low

risk

AR

c 9

AR

?

r: A

D (w

ith v

aria

ble e

xpre

ssio

n)

z

AD

or s

ex-li

nked

dom

inan

t b

?

M

inor

chr

omos

omal

del

etio

n?

AD

(with

var

iabl

e ex

pres

sion

)

W

Cn m

Y

mul

tifac

toria

l?

AR

Mul

tifac

toria

l, pr

obab

ly n

on-

AR

; pre

mat

ure

cent

rom

ere

AR

gene

tic

split

ting

AR

=A

utos

oma1

rece

ssiv

e: A

D =

auto

som

al d

omin

ant.

RADIAL-RAY REDUCTION MALFORMATIONS 28 1

Amsterdam and Rotterdam. The study emphasizes the importance of the ultra- sonographic evaluation of the fetal radius and thumb, and the posture of the hands as part of a stage 11 ultrasound examination. Guidelines are given for a diagnostic approach, before and after birth, towards the infant with RRRMs.

PATIENTS AND METHODS

The seven fetuses described in this paper underwent a stage I1 ultrasound examin- ation either at the Dijkzigt University Hospital (Rotterdam) or at the Free Univer- sity Hospital (Amsterdam) between 1984 and 1988. In these centres, a stage IT ull rasound examination, i.e., a complete and systematic ultrasound !scan of the uterus, placenta, amniotic fluid, and fetal anatomy, is only performed when indi- cated by family history or a previous child with congenital anomalies, obstetric complications, exposure to known or potential teratogens, or fetal anomalies sus- pected during a stage I ultrasound examination (i.e., a routine scan). From cases with multiple malformations, seven appeared to have significant radial-ray defects either noted at prenatal sonography or at post-mortem analysis of the fetus.

Prenatal diagnosis of radial-ray hypoplasia was based on the ultrasound findings of severe shortening or absence of the radius, absence of the thumb, and abnormal posture of the hand (i.e., radial club-hand, Figure 1). In addition to the ultrasound records, data on karyotyping, autopsy, post-mortem radiography, and genetic counselling were collected.

RESULTS

The seven case reports are summarized in Table 2. Reasons for scanning were: fetal cardiac arrhythmia (cases 1 and 6), a uterus large for dates (cases 2 and 3) or small for dates (cases 4 and 5), and maternal use of phenobarbital (case 7). Amniotic fluid volume was abnormal in six of the cases. Ultrasound revealed polyhydramnios in cases 1,2,3, and 6, and oligohydramnios in cases 4 and 5.

In cases 1, 2, 3, 6, and 7, the existence of radial aplasia was discovered by ultra- sound at 24, 22, 37. 32, and 16 weeks of gestation, respectively. In all five cases, a club-hand was clearly visible during prolonged ultrasound observation. In case No. 1, the metacarpal bone I1 was almost parallel to the ulna because of the sl rong ulnar deviation of the hand, and erroneously thought to be due to a hypoplastic radius of 0.8 cm. Post-mortem radiography, however, showed bilateral radial aplasia. In Figure 1, an ultrasonogram, body photograph, and radiogram of case No. 2 is presented.

[n cases 4 and 5, RRRMs had not been detected prenatally. In both cases, severe oligohydramnios would have influenced adequate visualization of the skeletal structures.

Six cases had associated abnormalities of the central nervous system, digestive tract, abdominal wall, kidneys, or heart, and all infants died before or shortly after birth. In case 7, the RRRMs were the only abnormalities detected prmatally by ultrasound. After amniocentesis, a normal karyogram was found, and no spon- taneous or clastogen-induced chromosomal instability was found, which excluded the diagnosis of Fanconi’s anaemia. The baby was born at term by Caesarean

282 J. T. J. BRONS ET AL.

Figure 1. Ultrasonogram, phenotype, and radiogram ofcase No. 2, showing radial aplasia and aplasia of the first metacarpal and thumb, causing a bilateral club-hand. The fetus was affected by the Edwards

syndrome (trisomy 18)

section because of fetal distress during labour. After additional diagnostic studies, the final diagnosis was Poland-Moebius-like complex (Lindhout et al., 1988; Table 1). The child is developing, well.

Amniocentesis was also perfoirmed in cases 1,2, and 3, and all three fetuses were affected by the Edwards syndroine (trisomy 18). In the first two cases, the parents elected termination of the pregnancy. In cases 4, 5, and 6, no amniocentesis was performed because of severe oligohydramnios or refusal by the parents. In case 4, a normal karyogram was revealed by a fibroblast culture after birth. After additional diagnostic studies, the final diagnosis was VACTERL association (Czeizel and

RADIAL-RAY REDUCTION MALFORMATIONS 283

Lunanyi, 1985; Table 1). In cases 5 and 6, fibroblast cultures after birth failed to grow. As a result, only a differential diagnosis was possible in these cases.

DISCUSSION

The prenatal diagnosis of skeletal abnormalities is a rapidly growing lield (Brons ef al., 1988a, b; Filkins, 1982; Lindhout et al., 1988). This study deimonstrates the value of radial and ulnar measurements and evaluation of the po:jture of the hands in every stage I1 ultrasound examination. The detection of RR.RMs leads to an important differential diagnosis; Table 1 summarizes the most important conditions associated with RRRMs.

Our experience indicates that there are several explanations for the ulna and radius not being measured in every case. Firstly, in the ultrasonographic evaluation of the fetal limb bones, the ulna and radius are themost difficult to measure. Because of pronation and supination, the ulna and radius are seldom visualized parallel in the second and third trimesters of pregnancy; parts of the ulna and radius are often projected on top of each other (Brons et al., 1988b). This scanning eiiror can be prevented by careful transverse scanning in addition to longitudinal visualization. In pregnancies at risk, the best time for visualization and separate measurements of the radius and ulna appears to be at 13-16 weeks of gestation. Most cases, however, are incidental and will present later in gestation for ultrasonographic evaluation, when obstetrical complications lead to a stage I1 ultrasound examina.tion (cases

Another problem arises from an abnormal amount of amniotic fluid. Both poly- hydramnios and oligohydramnios can complicate visualization of thle ulna and radius. In the case of severe polyhydramnios, this is caused by the increased distance between the probe and the fetus. In the case of oligohydramnios, the ulna and radius are difficult to distinguish because they are situated close to the fetal body and uterine wall, Since oligohydramnios may severely impede fetal visualization (cases 4 and 9, the creation of an artificial fluid compartment by installation of a.n amniotic fluid substitute ‘Normofundin sk’ (Gembruch and Hansmann, 1988) should be considered.

4nother reason for the failure to detect RRRMs may be that no visualization of the ulna and radius is attempted after finding severe defects of the heart, central nervous system, kidneys, or abdominal wall. When radial abnormalities are detected, however, this will extend the scope of an important differential diagnosis (Table I). This can have profound implications for the diagnostic approach and clinical management before and after birth. In the case of severe multiple mal- formations, dubious obstetrical intervention, such as the Caesarean section in case 4, inay be prevented.

In Table 3, a proposal is given for a diagnostic approach in a case of RRRM. Before birth, careful ultrasound evaluation of all fetal limbs (length, shape, echo density) should be performed, including the position of the hands and feet and the number of digits. The pattern of associated abnormalities may give important diagnostic clues, such as microcephaly (chromosomal disorders, Seckel syndrome, Fanconi’s anaemia), cardiac defects (chromosomal disorders, VACTE.RL associ- ation, Holt-Oram syndrome, Roberts syndrome), renal defects (chromosomal

1-6).

Tabl

e 2.

Dat

a of

seve

n fe

tuse

s bo

rn w

ith ra

dial

-ray

redu

ctio

n m

alfo

rmat

ions

(RR

RM

s)

Ges

t. A

nten

atal

ultr

asou

nd f

indi

ngs

age

at

Cas

e A

ge

diag

n.

Rea

son

AF

St

ruct

ural

A

dditi

onal

fin

ding

s Fi

nal

No.

(y

ears

) (w

eeks

) fo

r sca

n vo

lum

e ab

norm

aliti

es

Am

nioc

ente

sis

Cou

rse

afte

r birt

h di

agno

sis

I 25

24

Fe

tal c

ardi

ac

arrh

ythm

ia

(ect

opic

s)

2 40

22

U

teru

s lar

ge fo

r da

tes

3 40

37

U

teru

s lar

ge fo

r da

tes

f R

adia

l hyp

opla

sia,

47

XY

, + I8

cl

ub-h

ands

, VSD

A

FP: N

T R

adia

l apl

asia

, clu

b-

47X

Y,+

18

hand

s, n

o th

umbs

A

FP: f

(F

igur

e I)

, hy

droc

epha

lus

t R

adia

l clu

b-ha

nds,

47

XY

,+ 1

8 hy

dron

ephr

osis

, A

FP:

meg

acys

tis,

omph

aloc

ele,

ASD

, and

V

SD

TO

P at

26

($52

4 9)

w

eeks

R

adia

l apl

asia

, abs

ent r

ight

Tr

isom

y 18

th

umb.

Oes

opha

geal

atr

esia

w

ith T

E-fis

tula

, aor

tic ar

ch

hypo

plas

ia, c

lub-

foot

left

Tris

omy

18

TO

P at

24

wee

ks

($48

8 8)

TE

-fis

tula

, hor

se-s

hoe

Oes

opha

geal

atre

sia

with

kidn

ey, a

ortic

arch

h y

popl

asia

Birt

h at

38

Clu

b-fo

ot r

ight

w

eeks

; die

d sh

ortly

afte

r bi

rth

(314

85 9)

Tris

omy

18

4 24

36

5 35

27

6 28

32

7 24

16

Ute

rus

smal

l for

da

tes

Ute

rus s

mal

l for

da

tes

Feta

l car

diac

ar

rhyt

hmia

(e

ctop

ics)

Mat

erna

l dru

g ex

posu

re

(phe

noba

rbita

l)

Inad

equa

te s

cann

ing

Not

pos

sibl

e bec

ause

be

caus

e of

of o

ligoh

ydra

mni

os

olig

ohyd

ram

nios

and

se

vere

mat

erna

l obe

sity

Inad

equa

te s

can-

N

ot p

erfo

rmed

olig

ohyd

ram

nios

. ol

igoh

y dra

mni

os

Mul

ticys

tic k

idne

ys,

mar

gina

l bla

dder

filli

ng

Rad

ial c

lub-

hand

s,

Ref

used

by p

aren

ts

hydr

ocep

halu

s, s

pina

bi

fida,

om

phal

ocel

e

ning

bec

ause

of

beca

use o

f

Left

side

: rad

ial a

plas

ia,

46X

X, n

orm

al

ulna

r hyp

opla

sia

and

AF

P N

cl

ub-h

and

Cae

sare

an

sect

ion

at 3

6 w

eeks

; die

d 40

min

afte

r bi

rth

($2

100 g

)

IU d

eath

at 4

0 w

eeks

($

1950

B)

Birt

h at

33

wee

ks; d

ied

shor

tly a

fter

bi

rth

($84

5 9)

Cae

sare

an

sect

ion

at 4

0 w

eeks

(9

2570

g)

Apl

asia

radi

us a

nd th

umbs

. oe

soph

agea

l atre

sia

with

TE

- fis

tula

, abs

ent l

eft k

idne

y,

VSD

, ASD

, ana

l atre

sia,

fib

robl

astic

cultu

re: 4

6XY

no

rmal

Apl

asia

radi

us a

nd th

umbs

, sp

ina

bifid

a, V

SD.

Fibr

obla

st c

ultu

re fa

iled

to

grow

Apl

asia

left

radi

us a

nd

thum

b, o

esop

hage

al at

resi

a,

hors

esho

e ki

dney

, myx

oma

umbi

lical

cord

. Fib

robl

ast

cultu

re fa

iled

to g

row

Left

side

: hyp

opla

sia

pect

oral

is m

ajor

and

thum

b cl

inod

acty

ly.

Ble

phar

ophi

mos

is le

ft ey

e,

mic

rogn

athi

a

VA

CTE

RL

asso

ciat

ion

No

defin

ite

diag

nosi

s

No

defin

ite

diag

nosi

s

Pola

nd-

Moe

bius

-like

co

mpl

ex

=inc

reas

ed; 1

=dec

reas

ed; N

= no

rmal

; AF

= am

niot

ic fl

uid;

AFP

=alp

ha-f

etop

rote

in; T

OP=

term

inat

ion

of p

regn

ancy

; VSD

=ven

tric

ular

sep

tal d

efec

t; ASD

=at

rial

sep

tal

defe

ct; T

E =

trac

heo-

esop

hage

al.

286 J. T. J. BRONS ETAL.

Table 3. Prenatal and postnatal evaluation of the fetus with radial-ray reduction malformations (RRRMs)

Before birth Ultrasonographic evaluation of all fetal limbs: length and shape of femur, tibia, fibula,

humerus, ulna, radius, hands, and feet (number of digits, posture) Ultrasonographic evaluation of amniotic fluid, fetal growth parameters (circumference of

head, thorax, and abdomen), ancd fetal anatomy (central nervous system, heart, kidneys, bladder, abdominal wall, mouth, etc.)

Family history for abnormalities, consanguinity History of teratogens (drugs, alcohol, radiation, etc.) Amniocentesis or transabdominal CVS (karyotyping, study of chromosome breakage, when

If possible: fetal blood sampling by ultrasound-guided cordocentesis (chromosome study, indicated; AFP assay)

haematologic evaluation)

After birth Post-mortem radiography Chromosome studies (in lymphocytes, in fibroblasts) Haematologic evaluation Complete autopsy Genetic counselling ~

AFP = Alpha-fetoprotein; CVS =chorion villus sampling.

disorders, VACTERL association, acro-renal syndrome), vertebral defects (VACTERL association), and severe growth retardation (chromosomal disorders, Seckel syndrome) (Table 1). Also, the family history, pregnancy history, and teratogenic factors such as drug or alcohol exposure should receive attention.

Cytogenetic evaluation before birth is strongly recommended, not only to determine the prognosis of the fetus and subsequent obstetrical management, but also to guarantee karyotyping. Especially in fetuses with multiple abnormalities, there is a high risk of spontaneous intrauterine death (case 5 ) or death during delivery. Post-mortem changes often make it impossible to culture fetal cells success- fully; in cases 5 and 6 fibroblast cultures after birth failed to grow. As a result, we may have missed a final diagnosis in these two cases. This lack of information on the chromosomal pattern makes it difficult to determine the recurrence risk and the most appropriate method for prenatal diagnosis in subsequent pregnancies. Amniocentesis may be difficult in the case of severe oligohydramnios (cases 4 and 5) . Gembruch and Hansmann (1988) found that re-aspiration of artificially installed amniotic fluid permits determination of the fetal karyotype. Other possibilities in these situations are the techniques for rapid karyotyping, i.e., ultrasound-guided choriocentesis or cordocentesis.

If termination of pregnancy is chosen, skeletal X-rays should be obtained after birth, with details of extremities and antero-posterior and lateral views of the vertebral column and skull. Specimens for cell culture and cytogenetic studies must be obtained (blood, skin, ocular lens). Finally, a complete autopsy with gross photography and histology of all organs should be carried out.

In pregnancies monitored because of a recurrence risk of any of the RRRM- related syndromes, preceding genetic counselling is advisable to establish the risk of

RADIAL-RAY REDUCTION MALFORMATIONS 287

recurrence, the degree of variability of the syndrome, and the resulting options for prenatal diagnosis. Whenever skeletal defects are a varying manifestation of the disorder (such as the Holt-Oram syndrome and Fanconi’s anaemia), ultrasound examination of the fetal skeleton alone will be insufficient to rule out recurrence in a subsequent pregnancy. The results of specific additional tests (such as fetal cardiography in the Holt-Oram syndrome, examination of the chromosome stability in Fanconi’s anaemia, or centromere splitting in Robert’s syndrome) are needed for exclusion of a recurrence. Parents need to be informed on both the options and the limitations of the tests available. The challenge of this field of ‘fetal dysmorphology’ is the combination of expertise of clinical genetics, fetal and pediatric pathology, and advanced fetal ultrasonographic imaging. The obstetrician requires full and adequate information from these disciplines to develop prenatal ultrasonography into a reliable tool in pregnancies with increased genetic risks.

ACKNOWLEDGEMENTS

The authors wish to thank the clinicians and pathologists who referred radiographs and autopsy material for consultation, and the Departments of Clinical Genetics of the University Hospital Dijkzigt in Rotterdam and the Free University Hospital in Amsterdam for the karyotyping and cytogenetic studies. We also thank Frans J. A. Copray, M.D. and Clive Pollard for help in the preparation of this manuscript.

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Filkins, K., Russo, J. (1 984). Prenatal diagnosis of thrombocytopenia absent radius syndrome using ultrasound and fetoscopy, Prenat. Diagn. 4, 139-142.

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