American Journal of Medical Genetics 10:55-64 (1981)

De Novo Partial 2p Duplication With Postmortem Description P. L. Monteleone, J. D. Blair, E. R. Graviss, Su-chiung Chen, A. Salvador, J. A. Grzegocki, and J. A. Monteleone

DepartmentofPediatrics(P.L.M.,S.C., A.S., J.A.G.,J.A.M.), Pathology(J.D.B.),and Radiology (E. R.G.), St. Louis University School of Medicine and Cardinal Glennon Memorial Hospital for Children, St. Louis

An unbalanced karyotype most likely consisting of a partial duplication of the short arm of chromosome 2 (pl3+pter) was found in a newborn infant with intrauterine growth retardation, facial, skeletal, and cardiac abnormalities. There was no evidence of a translocation in either parent. At autopsy, striking histopathologic abnormalities were detected in the central nervous system and ovaries.

Key words: ovarian dysplasia, partial duplication 2p, fused sternum, hypoplastic pubis

INTRODUCTION

A syndrome of mental and growth retardation due to duplication of the distal half of 2p was first described by Francke and Jones [1976]. Fourteen cases of this syndrome have been reviewed by Cassidy et a1 [1977]. All 14 cases had a translocation carrier parent [Armendares and Salamanca-Gomez, 1978; Buyse et al, 1977; Bender et al, 1969; Cassidy et al, 1976; Cassidy et al, 1977; Francke and Jones, 1976; Magenis et al, 1975; Neu et al, 1979; Sekhon et al, 1978; Stoll et al, 1974; Yunis, 19781. Only one report [Neu et al, 19791 described autopsy findings in a male with partial 2p duplication.

port of autopsy findings in a female patient with this syndrome. In the family described here, no translocation carrier was identified. It is the first re-

REPORT OF PATIENT

History

The patient was a 1,900-g white female born to a 3 1 -year-old gravida 1 para 1 aborta 0 white mother and 33-year-old white father at 40 weeks’ gestation by spontaneous vaginal delivery. Pregnancy and labor were unremarkable. The patient had no spontaneous respira-

Received for publication November 1, 1980; revision received March 16, 1981.

Address all correspondence and reprint requests to P. Monteleone, MD, Cardinal Glennon Memorial Hospital for Children, 1465 South Grand Boulevard, St. Louis, MO 63104.

0148-7299/81/1001-0055$03.00 0 1981 Alan R. Liss, Inc.

56 Monteleone et al

tions at birth and was intubated. Both placenta and cord were small. Family history was negative for multiple congenital anomalies and for parental exposure to x-rays or clasto- gens. There was no consanguinity.

Physical Examination

Physical examination revealed a poorly developed infant with unusual facial appear- ance, high prominent forehead, epicanthal folds, hypertelorism with upward slant of pel- pebral fissures, maxillary hypoplasia, depressed nasal bridge, short nose with a prominent tip, anteverted nares, flat philtrum, cleft palate, micrognathia, and apparently low-set, pos- teriorly angulated ears with folded helices. (Fig. 1). Head circumference was 31 cm; crown- heel length was 34.5 cm; crown-rump length was 26.5 cm; chest circumference was 27 cm. Neck was short. Nipples were widely spaced; two accessory nipples were present in addi- tion to a pectus excavatum with a short sternum. A I-II/VI systolic murmur was heard at the left sternal border at two days. There were rocker-bottom feet, left equino-valgus de- formity, and overriding of second toe over third and an unusual gap between first and sec- ond toes. No simian creases were present, and there were two flexion creases on both fifth fingers. The patient developed seizures, sepsis and renal failure and died at 11 days.

Complementary Findings

Radiographs of the chest showed fusion of the sternal segments with anterior bow. ing and 11 pairs of ribs. The posterior portion of the ribs was thin. The lungs appeared hypoplastic with associated pneumomediastinum and bilateral pneumothoraces and the heart was displaced horizontally. A narrowed diameter of the long tubular bones was

Fig. 1. Postmortem photograph of the patient.

De Novo Partial 2p Duplication 57

more apparent distal than proximal. The pubic bones were hypoplastic but the acetabular and iliac angles were normal. Electrocardiogram showed superiorly oriented frontal QRS axis of -90" to -120" and right atrial hypertrophy. On an intravenous urogram, the kid- neys were poorly visualized.

Autopsy Findings

Autopsy revealed a high ventricular septal defect and multiple atrial septal defects in the form of fenestrations of the septum secundum, bicuspid right atrioventricular and pulmonic valves, and left ventricular dilatation. The dustus arteriosus was probe-patent. The lungs were hypoplastic and the right lung was bilobed. The ovaries were grossly hypo- plastic and there was dysplasia with marked decrease of germ cells and degeneration of few primordial follicles. The germ cells were embedded in scanty stromal tissue (Fig. 2). The infant also had cerebellar dysplasia: dysplastic gyri with heterotopic neuronal and cerebellar cortical tissue in white matter; heterotopic, poorly differentiated neurons, ma- trix cells, and immature, hyperchromatic, elongated cells resembling those of the external granular layer were present in cerebellar white matter and dentate nuclei.

Cytogenetic Findings

the patient and revealed a 46,XX,8pt karyotype in 50 metaphases. The extra material had a banding pattern similar to that of the distal short arm of chromosome 2. Her karyotype

Chromosomal analysis with GTL banding was performed on the peripheral blood of

Fig. 2. Dysplastic ovary. Note few degenerating primordial follicles and scant, slightly immature stroma. (H&E, X635).

TAB

LE I.

Dup

licat

ion

(2p)

Syn

drom

e

1 2

3 4

5 6

7 8

Ref

eren

ce

[I01

[7

1 16

1 15

1

-

Ban

ding

met

hod

Pare

ntal

tran

sloc

atio

n

Patie

nt

Sex

Ges

tatio

n B

irth

wei

ght

(gm

) B

irth

leng

th (

cm)

Age

at r

epor

t G

row

th r

etar

datio

n Ps

ycho

mot

or r

etar

datio

n C

rani

ofac

ial a

rea

Hig

h pr

omin

ent

fore

head

Fr

onta

l ups

wee

p of

hai

r H

y per

telo

rism

Ep

ican

thal

fol

ds

Max

illar

y hy

popl

asia

Sh

ort n

ose

with

pro

min

ent

Bro

ad a

lveo

lar

ridge

s/na

r-

Smal

l man

dibl

e/po

inte

d ch

in

Ptos

is

Stra

bism

us

Myo

pia

Dac

ryos

teno

sis

Hyd

roce

phal

us

Web

bing

of

neck

tip (

“pug

nos

e”)

row

pal

ate

R Q

G

G

t(2;

I 4)(

p22;

pll)

mat

t(

2;18

)(p2

3;pl

l)pa

t t(

2;7)

(p23

;q36

)mat

t(

2;3)

(p23

;p27

)mat

1 M

term

3,

200

50

7 Yr

<

3rd%

pr

ofou

nd

+ + + + + + + + + + + -

-

-

2 M

term

3,

450

52

3 m

o ..

. ..

.

+ + + - + + + + -

-

-

-

-

-

-

F 41 w

k 3,

700

53

9 m

o (4

yr)

< 3

rd%

pr

ofou

nd

+ + - + + + + + - + + + -

-

1 M

40 w

k 2,

350

46

< 3r

d%

prof

ound

8 yr

+ + + + + + + + + + + + -

-

2 F 42 w

k 2,

260

53

12 y

r < 3

rd%

pr

ofou

nd

+ + + - + + + + + - + + -

-

1 M

term

3,

525

5 Yr

<5

th%

m

arke

d

...

+ - + + + + + + + + ...

-

-

-

2 M

term

3,

465

1 Yr

<

5th%

de

laye

d

...

+ - + + + + + + + + ...

+ -

-

3 M

term

3,

125

18 y

r <5

th%

pr

ofou

nd

...

+ + + - + + + + - + ...

-

-

-

c

Skel

eton

Pe

ctus

exc

avat

um

Long

, nar

row

tru

nk

Dol

icho

sten

omel

ia

Long

fing

ers

and

toes

H

yper

exte

nsib

le f

inge

rs

Flat

fee

t W

idel

y sp

aced

toes

O

verla

ppin

g di

gits

S c

olio

sis

Sim

ian

crea

ses

Con

geni

tal h

ip d

islo

catio

n H

emiv

erte

brae

11

pai

rs o

f ri

bs

Hyp

opla

stic

pub

is

Hyp

opla

stic

kid

ney

Con

geni

tal h

eart

dis

ease

G

enita

lia

Ove

rrid

ing

(“sh

awl”

) sc

rotu

m

Hyp

opla

stic

ext

erna

l gen

italia

C

rypt

orch

idis

m

H yp

ospa

dias

A

utop

sy f

indi

ngs

Ova

rian

dysp

lasi

a C

ereb

ella

r dy

spla

sia

...

...

...

...

...

...

...

...

-

-

...

...

-

-

...

...

...

...

...

-

- ... ...

...

...

- + + + - ...

...

-

- ...

...

...

...

- ... + ..

.. ...

...

-

-

- ...

...

...

...

-

-

-

- ...

...

...

...

- + + ..

-

+ +

+ +

-

+ ..

. +

...

...

...

+ +

+

-

-

-

-

...

...

...

...

...

...

...

...

-

-

+ +

+ +

+ ..

. -

-

...

...

...

...

z s ii

(Tab

le I

con

tinue

d)

TAB

LE I

. Dup

licat

ion

(2p)

Syn

drom

e (c

ontin

ued)

Cas

e

9 10

11

12

13

14

15

Pres

ent

Ref

eren

ce

Ill

[31

191

PI

111

Ban

ding

met

hod

G

s, G

G, Q

G

G

ca

se

Pare

ntal

tran

sloc

atio

n Pa

t p2

3 or

25)

pat

mat

Pa

t t(

2;15

)(p2

1 :q2

6)

none

t(

2;7)

(p21

;q36

.3)

t(2;

6)(p

21 o

r 23

; t(

2;14

)(p2

1;q3

2)

t(2;

5)(p

23;p

W

G

Patie

nt

Sex

Ges

tatio

n B

irth

wei

ght

(gm

) B

irth

leng

th (

cm)

Age

at r

epor

t G

row

th re

tard

atio

n Ps

ycho

mot

or r

etar

datio

n C

rani

ofac

ial a

rea

Hig

h pr

omin

ent f

oreh

ead

Fron

tal u

psw

eep

of h

air

Hyp

erte

lori

sm

Epic

anth

al f

olds

M

axill

ary

hypo

plas

ia

Shor

t now

with

pro

min

ent

Bro

ad a

lveo

lar r

idge

s/na

r-

Smal

l man

dibl

e/po

inte

d ch

in

Ptos

is

Stra

bism

us

Myo

pia

Dac

ryos

teno

sis

Hyd

roce

phal

us

Web

bing

of

neck

tip (

“pug

nos

e”)

row

pal

ate

-

F term

1,

060

11 m

o m

arke

d se

vere

...

+ ...

+ - + + ...

-

-

- ...

...

-

-

-

F term

3,

100

41

16

mo

seve

re

prof

ound

-

M

term

2,

900

...

2 Yr

se

vere

pr

ofou

nd

-

M

31 w

k 1,

500

new

born

se

vere

...

...

1 M

25 w

k 1,

250

2 M

term

2,

000

4 yr

<

3rd%

pr

ofou

nd

...

-

F term

1,

900

34.5

ne

wbo

rn

<3rd

%

...

3 yr

<

3rd%

pr

ofou

nd

t ...

+ - + +

+ - + +

t ...

+

t ...

+

+ ..

. ..

. + ..

. ..

. +

...

...

...

+ ..

.

t

...

+ - +

+ ...

...

...

...

+ ...

+

+ ...

+ ..

. ..

. -

-

t

Skel

eton

Pe

ctus

exc

avat

um

Long

, nar

row

tru

nk

Dol

icho

sten

omel

ia

Long

fin

gers

and

toes

H

yper

exte

nsib

le f

inge

rs

Flat

feet

W

idel

y sp

aced

toes

O

verla

ppin

g di

gits

Sc

olio

sis

Sim

ian

crea

ses

Con

geni

tal h

ip d

islo

catio

n H

emiv

erte

brae

11

pai

rs o

f ri

bs

Hyp

opla

stic

pub

is

Hyp

opla

stic

kid

ney

Con

geni

tal h

eart

dis

ease

G

enita

lia

Ove

rrid

ing

(“sh

awl”

) sc

rotu

m

Hyp

opla

stic

ext

erna

l gen

italia

C

rypt

orch

idis

m

H yp

ospa

dias

A

utop

sy f

indi

ngs

Ova

rian

dysp

lasi

a C

ereb

ella

r dys

plas

ia

+ + ...

+ - ...

...

-

-

-

- ...

...

...

...

- ...

+ ...

...

...

...

- + ...

...

-

-

-

-

- ...

...

...

...

- ...

...

...

...

...

...

+

...

...

...

...

...

...

+ ...

...

...

...

...

...

- + - + -

-

...

...

+ + ...

...

+ - + + + - ...

...

- + -

-

-

-

...

...

+ -k ...

...

+ - + + - + ...

...

- + -

-

-

-

+ - + - + + - + -

-

-

- + + - + ...

...

...

...

...

...

...

...

...

...

a +

...

...

...

...

+ 5

’E

! i;’

...

...

Sym

bols

: +, p

rese

nt; -, n

ot p

rese

nt;.

. ., no

t kno

wn

or n

ot a

pplic

able

. $. 3

ch 3

62 Monteleone et al

Fig. 3. Karyotype of the patient.

Fig. 4. Enlarged views of chromosomes 2 and 8.

De Novo Partial 2p Duplication 63

has been interpreted as 46,XX,-8,+der(8),t(2;8)(p13 ;p23), indicating duplication of re- gion 2p13-+2pter (Figs. 3,4). Chromosomes of both parents were normal. The possibility of non-paternity was looked for and ruled out with major blood groups and chromosome heteromorphisms.

DISCUSSION

Partial duplication of the distal short arm of chromosome 2 has been reported in 14 cases. The characteristic clinical features are physical and mental retardation, unusual facial appearance with microcephaly, frontal bossing, hypertelorism, antimongoloid slant, flat nasal bridge, epicanthal folds, strabismus, myopia, ptosis, broad gums, anteverted nares, highly arched palate, long philtrum, and malformed ears. Several cases have had heart murmurs, abnormal sternal segmentation, pectus excavatum, thin posterior ribs and nar- rowed diaphyses of the long tubular bones. Several males have had a small penis and cryptorchidism. Our patient showed most of the described clinical findings. In addition, she had a cleft soft palate and hypoplastic pubic bones that have not been previously re- ported in this entity.

Neu [ 19791 reported autopsy findings on one patient who had a “double-outlet right ventricle and transposition of the great arteries, hypoplastic right ventricle, atrial septal defect, ventricular septal defect and patent ductus arteriosus.” Microscopic examina- tion of frontal lobe sections revealed heterotopias of undifferentiated neurons and stream- ing groups of matrix cells within the white matter between the floor of the ventricle and cortex of the frontal lobe. Very similar brain lesions were found in our patient. The central nervous system findings are similar to those described by Terplan [ 19661 in the cerebellum of patients with trisomy 13 and in the frontal lobe of the patient described in Neu et a1 [1979]. Thus, these dysplastic lesions are not specific for either trisomy 13 or partial du- plication of 2p. Small penis and cryptorchism have been found in male patients. There has been no previous autopsy report on female patients. The autopsy of our case demonstrated ovarian dysplasia.

The clinical findings in all patients including the present case are very similar in spite of the fact that different amounts of 2p were duplicated (Table I). The 14 previously re- ported cases had a carrier parent with translocations between 2p and chromosomes 3 , 5 , 7, 14, 15 or 18. Our patient did not have a carrier parent and thus her translocation is sporadic. The risk of recurrence is unknown, but presumed to be low.

ACKNOWLEDGMENTS

We wish to acknowledge the help of Dr. H. Chung for his review of the neuropathol- ogy findings and Dr. Rathaya Vongsnichakul for the initial postmortem report. We thank Michael Tietjens and Tanvagarn Satayaviboon for their invaluable assistance.

REFERENCES

Armendares S, Salamanca-Gomez F (1978): Partial 2p trisomy (p2l jp te r ) in two siblings of a family

Buyse M, Bull MJ, Atkins L (1977): Prenatal diagnosis of partial trisomy 2p. Am J Hum Genet 29:26A. Bender K, Reinwein H, Gorman LZ et a1 (1969): Familiare 2/C-translocation: 46,XY,t(2p-*;Cp+) und

with a 2p-*:15q+ translocation. Clin Genet 13:17-24.

46,XX,Cpf. Humangenetik 8:94-104.

64 Monteleone et al

Cassidy SB, McGee BJ, Heller RM et a1 (1976): Distal 2p trisomy (2) (p23-tter) in three members of a family with a balanced 2p-;3p' translocation. Abstracts V International Congress of Human Genetics. Mexico City, October.

J Pediatr 91(6):934-938. Cassidy SB, Heller RM, Chazen EM et a1 (1977): The chromosome 2 distal short-arm trisomy syndrome.

Francke U, Jones KL (1976): The 2p partial trisomy syndrome. Am J Dis Child 130:1244-1249. Magenis RE, Koler RD, Lovrien E et a1 (1975): Gene dosage: Evidence for assignment of erythrocyte

acid phosphatase locus to chromosome 2. Proc Natl Acad Sci USA 72:4526-4530. Neu RL, Dennis NR, Fisher JE (1979): Partial 2p trisomy in a 46,XY,der(5),t(2;5)(p23;plS)pat infant;

autopsy findings. Anna1 Gbnbt 22(1):33-34. Sekhon GS, Taysi K, Rath R (1978): Partial trisomy for the short arm of chromosome 2 due to familial

balanced translocation. Hum Genet 44:99-103. Stoll C, Messer J, Vors J (1974): Translocation t(2;14) equilibrbe chez une mere et trisomie partielle

d'une partie du bras court d'un chromosome No. 2 chez deux de ses enfants. Ann G h b t (Paris) 17: 193-196.

Terplan KL, Sandberg AA, Aceto T Jr (1966): Structural anomalies in the cerebellum in association with trisomy. JAMA 197(7):557-568.

Edited by Uta Francke