mosaic trisomy 22: five new cases with variable outcomes. implications for genetic counselling and...

PRENATAL DIAGNOSISPrenat Diagn 2010; 30: 168–172.Published online 17 December 2009 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.2427

RESEARCH LETTER

Mosaic trisomy 22: five new cases with variable outcomes.Implications for genetic counselling and clinical management

Sandrine Leclercq,* Xavier Baron, Marie-Line Jacquemont, Fabrice Cuillier and Francois CartaultCentre Hospitalier Felix Guyon, Service de Genetique, Pole Femme Mere Nouveau-ne Genetique, Bellepierre, 97405 St DenisCedex

KEY WORDS: trisomy 22; mosaicism; prenatal diagnosis

Non-mosaic trisomy 22 is the second most commonaneuploidy identified in spontaneous miscarriage withan incidence of almost 2.2% (Warburton et al., 1991).Live births are rare with survival expected only dur-ing the neonatal period. On the contrary, mosaic tri-somy 22 is rare but compatible with prolonged sur-vival. To our knowledge, 19 prenatal cases and 21postnatal cases have been reported. Regarding postna-tal cases, mosaic trisomy 22 has variable clinical pre-sentations that often include growth retardation (GR),dysmorphic features (DF), mental retardation (MR),hemiatrophy, cardiac, ophthalmic, ear and limb mal-formations (Wang et al., 2007). On the contrary, twopatients were recently reported to have normal intelli-gence (Thomas et al., 2004; Florez and Lacassie, 2005).Prenatal detection of mosaic trisomy 22 in chorionic vil-lus or amniotic fluid samples may generate difficulties interms of genetic counselling and clinical management.As has been reported, heterogeneous pregnancy out-comes can range from normal to severely impaired (Hsuet al.,1997). Further investigations are usually requiredto discriminate confined placental mosaicism (CPM) andtrue foetal mosaicism. We present here five new casesof mosaic trisomy 22: four of them were prenatallydiagnosed and one at the age of four. These clini-cal observations combined with previously publisheddata help us to delineate how to manage follow-upand genetic counselling in such pregnancies with vari-able outcomes. Clinical findings of these five new casesare presented in Table 1. Cytogenetic analysis was per-formed on cultured amniocytes, blood lymphocytes orskin fibroblast using standard techniques. For case 1and 2, FISH investigation was conducted on uncul-tured tissue sample using the Di George syndrome probe(MD Di George N25, KBI 40 102, Kreatech Poseidon).In case 5, intrauterine growth retardation (IUGR) witholigoamnios was discovered at 28 weeks as a result ofpoor follow-up of pregnancy. All patients had a non-contributory family history except for case 5 who had a

*Correspondence to: Sandrine Leclercq, Centre Hospitalier FelixGuyon, Service de Genetique, Pole Femme Mere Nouveau-neGenetique, Bellepierre, 97405 St Denis Cedex.E-mail: [email protected]

mentally retarded older brother but not cytogeneticallyexplored. All parental karyotypes were found to be nor-mal. Regarding cytogenetic analysis, four cases (case 1,3, 4 and 5) were consistent with true foetal mosaicismconforming affected foetus. Confirmation studies wereperformed on foetal blood sampling or by skin biopsyafter birth. For case 2, it was not possible to discrim-inate true foetal mosaicism and CPM as intrauterinefoetal death (IUFD) occurred 1 week after amniocente-sis. Our five cases demonstrated the variable outcomesassociated with mosaic trisomy 22. A completely nor-mal outcome (case 1) occurs in one case. Karyotypingon skin showed the trisomy in 6% of the mitoses. Onthe contrary, three other cases have poor outcome, con-sidering IUFD, GR and multiple congenital anomalies(MCA) for cases 2, 4 and 5. Interestingly, true foetalmosaicism was cytogenetically established for three ofthem (case 1, 4 and 5) on skin fibroblast or foetal bloodsamples. To our knowledge, case 1 is the first reportedcase of true foetal mosaic trisomy 22 without congenitalmalformation, DF or delayed developmental milestones.Chromosomes on skin fibroblasts confirmed the diag-nosis of mosaicism: 47,XX,+22[6]/46,XX[94]. The twoprevious cases of true mosaic trisomy 22 with normalintelligence presented either minor anomalies (isolatedocular manifestations, Thomas et al, 2004) or IUGR(Florez and Lacassie, 2005). Our case remains unclearas full trisomy 22 on placenta tissue is not associatedwith IUGR and emphasizes how genetic counselling andprognosis are challenging in such pregnancies. Focus-ing on the 19 previously published prenatally cases,8 cases are true foetal mosaicism (Wang et al., 2007,3 cases—XVII-1 XVII-2 XVII-6—from Phillips et al.,1996; De Pater et al., 1997; Hsu et al., 1997; Berghellaet al., 1998; Schinzel, 1981). Three other cases refersto CPM (Balmer et al., 1999; Stioui et al., 1989; Bryanet al., 2002). We omitted eight cases which do not con-tain sufficient detail on cytogenetic confirmation stud-ies (one case from Hall et al., 2009; seven cases fromHsu et al., 1997). Reviewing clinical reports of theseeight cases of true mosaicism with information avail-able on pregnancy outcome, diagnosis of trisomy 22often follows an investigation for IUGR with six outof eight cases. IUGR is often associated with varioussonographic findings such as nuchal thickening, cardiac

Copyright 2009 John Wiley & Sons, Ltd. Received: 19 June 2009Revised: 6 November 2009

Accepted: 13 November 2009Published online: 17 December 2009

PRENATAL MANAGEMENT OF MOSAIC TRISOMY 22 169

Tabl

e1

—Fi

veca

ses

ofm

osai

cism

tris

omy

22an

dre

view

oflit

erat

ure

with

rega

rdto

preg

nanc

yca

use

and

outc

omes

Publ

ishe

dca

ses

Age

pari

tyIn

dica

tion

for

kary

otyp

ing

Ultr

asou

ndfo

llow

-up

Pren

atal

cyto

gene

ticex

plor

atio

nPr

egna

ncy

outc

ome

Post

nata

lcy

toge

netic

expl

orat

ion

Clin

ical

eval

uatio

n

Cas

e1

39A

MA

Nor

mal

AF:

47,X

X+2

2[84

]/46

,XX

[16]

[16%

]by

FISH

Bir

th(4

1w

eeks

)Sk

in:

47,X

X,+

22[6

]/46

,XX

[94]

At

birt

h:no

rmal

clin

ical

exam

inat

ion

G1

P0B

lood

:46

,XX

[100

][1

00%

]A

t4-

year

s-ol

d:no

rmal

cogn

itive

,be

havi

oura

lan

dph

ysic

alde

velo

pmen

tPl

acen

ta:

47,X

X,+

22[1

00]

[100

%]

Cas

e2

26A

UIU

GR

,33

wee

ksA

F:47

,XX

+22[

7]/4

6,X

X[4

3][1

4%]

byFI

SHIU

FD(3

4w

eeks

)Po

st-m

orte

mex

amin

atio

n:D

FG

2P1

-hy

popl

asic

ears

-pr

eaur

icul

arpi

ts

Cas

e3

44A

MA

+A

UIU

GR

,in

crea

sed

NT

,hy

drot

hora

x24

wee

ksA

F:47

,XX

,+22

[17]

/46,

XX

[49]

[26%

]M

TP

(28

wee

ks)

Post

-mor

tem

exam

inat

ion:

isol

ated

GR

G3P

2N

ucha

lth

icke

ning

Foet

albl

ood:

47,X

X,+

22[5

]/46

,XX

[109

][4

%]

Cas

e4

37.5

AU

IUG

R24

wee

ksA

F(s

ingl

ecu

lture

flask

,ps

eudo

mos

aici

sm?)

:47

,XY

,+22

[43]

[100

%]

IUFD

(33

wee

ks)

Post

-mor

tem

exam

inat

ion:

MC

A

G1P

0Fo

etal

bloo

d:47

,XY

,+22

[3]/

46,X

Y[1

8][1

4%]

GR

–M

CA

Cas

e5

37—

IUG

R,

olig

oam

nios

(28

wee

ks)

?B

irth

(29

wee

ks)

Blo

od:

46,X

XA

tbi

rth:

GR

,M

CA

,D

FG

6P5

Skin

biop

sy(4

year

s):

47,X

X,+

22[3

3]/4

6,X

X[6

7][3

3%]

Nin

em

onth

s:co

rtic

alat

roph

y

Four

year

s:G

R,

RM

Wan

g(2

007)

34A

UC

HD

/IU

GR

AF:

47,X

X,+

22[6

]/46

,XX

[11]

[35%

]B

irth

(35

wee

ks)

Blo

od:

46,X

XG

R–

DF

G3T

1A1

Hyd

roth

orax

(35

wee

ks)

tric

uspi

dre

gurg

itatio

n

Skin

:47

,XX

,+22

[16]

/46,

XX

[5]

[76%

]

-A

tria

lse

ptal

defe

ct

-Pa

tent

duct

usar

teri

osus

-H

emia

trop

hy

Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2010; 30: 168–172.DOI: 10.1002/pd

170 S. LECLERCQ ET AL.B

ergh

ella

(199

8)35

AU

Cho

roid

plex

uscy

st(1

8w

eeks

)A

F:47

,XY

,+22

[4]/

46,X

Y[1

5][2

1%]

MT

PN

otU

PDPo

st-m

orte

mex

amin

atio

nG

2P1

Blo

od:

46,X

Y[1

01]

[0%

]m

osai

cism

diff

eren

ttis

sues

bloo

d,lu

ng-

Hyp

erte

lori

sm

Foet

alsk

inbi

opsy

(20

wee

ks)

47,X

Y,+

22[7

]/46

,XY

[8]

[47%

]-

Lar

gelo

w-s

etea

rs

-B

ilate

ral

pulm

onar

ypo

lylo

bati

on-

Up

slan

ted

palp

ebra

lfis

sure

spr

opto

sis

De

Pate

r(1

997)

34A

UIU

GR

CV

S:47

,XX

,+22

[12]

[100

%]

Bir

th(3

9.6

wee

ks)

Blo

od:

46,X

XA

tbi

rth:

G3P

1C

HD

AF:

47,X

X,+

22[2

]/46

,XX

[8]

[20%

]Sk

in:

47,X

X,+

22[7

]/46

,XX

[25]

[22%

]

- GR

–D

F—

Hyp

oton

ia

37w

eeks

-V

entr

icul

arse

ptal

defe

ct-

Shor

tno

sebr

oad

nasa

lbr

idge

long

phil

trum

,m

icro

gnat

hia,

hypo

plas

icna

ils,

clin

odac

tylie

fifth

finge

rs.

Phil

lips

(199

6)43

AM

A+

AU

IUG

RC

VS

47,X

Y,+

22[1

7]/4

6,X

Y[2

3][4

2%]

MT

PFo

etal

lung

:47

,XY

,+22

[47]

[100

%]

—

G1P

010

.6w

eeks

CV

S11

wee

ksU

mbi

lical

cord

:46

,XY

[29]

AF:

46,X

Y[5

0][0

%]

Ren

alce

lls:

47,X

Y,+

22[2

]/46

,XY

[48]

[4%

]

Schi

nzel

(198

1)?

AU

IUG

R(3

2w

eeks

)A

F:47

,XX

,+22

[50]

/46,

XX

[50%

]N

eona

tal

deat

hB

lood

:47

,XX

,+22

[18]

/46,

XX

[2]

[90%

]

-D

F

Blo

od:

47,X

X,+

22[1

]/46

,XX

[26]

[4%

]-

Car

diop

athy

—M

CA

Hsu

XV

II—

1(1

997)

?A

UIU

GR

card

iopa

thy/

abno

rmal

ears

AF:

47,X

X,+

22[2

]/46

,XX

[18]

[11%

]—

Skin

:47

/46

47,X

X,+

22[9

]/46

,XX

[1]

[90%

]

-C

ardi

opat

hy—

DF

Hsu

XV

II—

2(1

997)

?A

UIU

GR

hydr

ocep

haly

AF

47,X

X,+

22/4

6,X

XN

eona

tal

deat

hSk

in47

,XX

,+22

[18]

/46,

XX

[2]

[90%

]

-G

R

-hy

droc

epha

ly

Hsu

XV

II—

6(1

997)

?—

Faci

alas

ymm

etry

47,X

X,+

22/4

6,X

XM

TP

-D

F–

GR

AM

A,

adva

nced

mat

erne

lag

e;A

F,am

niot

icflu

id;

AV

,ab

norm

alul

tras

ond;

MT

P;m

edic

alte

rmin

atio

nof

preg

nanc

y;D

F,dy

smor

phic

feat

ures

;G

R,

grow

thre

tard

atio

n;M

CA

,m

ultip

leco

ngen

ital

anom

alie

s;?,

data

not

avai

labl

e.


PRENATAL MANAGEMENT OF MOSAIC TRISOMY 22 171

defects or hydrocephaly (four out of eight cases). Sixout of eight cases were female foetus. Our experience isin agreement with this result as IUGR is noticed at 2ndor 3rd trimester for four out of five cases (case 2, 3, 4and 5), with four out of five females and is associatedin three cases of true foetal mosaicism (case 3,4 and 5)with heterogeneous congenital malformations. However,owing to the limited number of reported cases, it remainsdifficult to attribute specific sonographic features tofoetal mosaicism. However, commonly described post-natal clinical features could help clinicians to refine fur-ther ultrasound explorations. Among them, heart defectsincluding ventricular septal defect, atrial septal defect,pulmonary or aortic stenosis, hemiatrophy, craniofacialand limbs anomalies could provide further elements con-sistent with foetal involvement. In case 2, post-mortemexamination shows: proeminent forehead, small low-setand posteriorly angulated ears, bilateral epicanthal fold,short neck with redundant skin and case 4, anal atre-sia, distal caecal atresia, macro and micro kidney cysts.On the contrary, some foetal mosaicism cases presentingsubtle phenotypic characteristics (Thomas et al., 2004;Florez and Lacassie et al., 2005; our case 1) may not beidentifiable through sonographic exploration. Therefore,foetal sonography is recommended but not exclusivelyfor the evaluation of foetal mosaicism. Confirmationstudies by foetal blood sampling could be proposedbut have also limited predictive value as trisomic cellsmay be absent from haematological lines despite foetalinvolvement. There is no correlation between the numberof trisomic cells in the amniotic fluid and the pregnancyoutcome. In our observations, the percentage is includedbetween 14 and 100%. We observed IUFD in cases2 and 4. Cytogenetic confirmation of foetal mosaicismwas proven by karyotyping fibroblasts or blood. Someauthors (Berghella et al., 1998) suggest that foetal skinbiopsy may have higher diagnostic value in these cases.In French general practice, skin biopsy is proposed post-natally, but is not included in routine prenatal evaluationof foetal mosaicism as several clinical questions suchas skin sites or number of biopsies remain unsolved.Concerning post-natal follow-up of prenatally diagnosedcases, little is known as only 6 out of 11 cases wereliveborns. Most often, true foetal mosaicism seems toresult in a poor outcome (GR with DF and/or MCA:De Pater et al., 1997; Wang et al, 2007; case XVII-1from Hsu et al., 1997) while CPM to an isolated GRwith sometimes minor anomalies (Stioui et al., 1989;Balmer et al., 1999; Bryan et al., 2002). On the con-trary, we reported here two liveborn cases (cases 1 and5) displaying true mosaicism and presenting contrastedclinical findings with an unexpected normal phenotypefor case 1 and a severely impaired one for case 5. Incase 1, the clinical examination was normal without DFand/or malformations. At 4 years, the mental develop-ment was normal. In case 5 the diagnosis was postnatal.The clinical examination at 4 years showed malforma-tions with posterior cleft palate, facial and body asym-metry and left coxa valga, distal phalange agenesis ofthe left hand and foot, C2 C3 synostosis, bilateral glau-coma, ventricular septum defect and DF with sparse hair,high frontal hairline, hypertelorism, prominent forehead,

anteverted nares, long philtrum, low-set large ears, slantdown palpebral fissures. In conclusion, we emphasizethe fact that the prenatal diagnosis of mosaic trisomy22 generates difficulties in counselling and pregnancymanagement. Moreover, the rare cases published of pre-natal and postnatal diagnosis show the great variabilityof the clinical expression of such an anomaly. In thecase of abnormal ultrasound findings leading to amnio-centesis and diagnosis of mosaic trisomy 22 (with orwithout proved foetal mosaicism), prenatal managementwill be facilitated by a prognosis of IUGR and associatedmalformation. The karyotyping from chorionic villussampling or amniotic fluid is not sufficient to confirma definitive diagnosis, giving rise to difficult counsellingfor both clinicians and parents. To confirm the diagno-sis, knowing that the number of trisomic cells is verylow in lymphocytes, the karyotyping is more effectiveusing fibroblasts. There is no correlation between thepercentage of trisomic cells and intelligence. Moreover,in cases of fortuitous diagnosis of mosaic trisomy 22with normal ultrasound follow-up, genetic counsellingwill not be aided. Even if normal outcomes have beendescribed (as case 1) and are probably underestimated inliterature, the trisomic cells distribution in foetal tissuesis not predictable. Parental decision to continue preg-nancy should rely on their willingness to accept a certaindegree of risk, as normal ultrasound studies do not nec-essarily signify the absence of impaired psychomotordevelopment.

REFERENCES

Balmer D, Baumer A, Rothlisberger B, Schinzel A. 1999. Severeintra-uterine growth retardation in patient with maternal uniparentaldisomy 22 and a 22-trisomic placenta. Prenat Diagn 19:1061–1064.

Berghella V, Wapner RJ, Yang-Feng T, Mahoney MJ. 1998. Prenatalconfirmation of true fetal trisomy 22 mosaicism by fetal skinbiopsy following normal fetal blood sampling. Prenat Diagn 18:384–389.

Bryan J, Peters M, Pritchard G, Healey S, Payton D. 2002.A second case of intrauterine growth retardation and primaryhypospadias associated with trisomy 22 placenta but with biparentalinheritance of chromosome 22 in the fetus. Prenat Diagn 22:137–140.

De Pater JM, Schuring-Blom GH, van den Bogaard R, et al. 1997.Maternal uniparental dismy for chromosome 22 in a child withgeneralized mosaicism for trisomy 22. Prenat Diagn 17: 81–86.

Florez L, Lacassie Y. 2005. Mosaic trisomy 22: report of a patientwith normal intelligence. Am J Med Genet A 132: 223–225.

Hall T, Samuel M, Brain J. 2009. Mosaic trisomy 22 associated withtotal colonic aganglionosis and malrotation. J Pediatr Surg 44:e9–e11.

Hsu LY, Yu MT, Neu RL, et al. 1997. Rare trisomy mosaicismdiagnosed in amniocytes, involving an autosome other thanchromosomes 13, 18, 20 and 21: karyotype/phenotype correlations.Prenat Diagn 17: 201–242.

Phillips OP, Tharapel AT, Lerner JL, Park VM, Wachtel SS, Shul-man LP. 1996. Risk of fetal mosaicism when placental mosaicismis diagnosed by chorionic villus sampling. Am J Obstet Gynecol174: 850–855.

Schinzel A. 1981. Incomplete trisomy 22. III. Mosaic-trisomy 22 andthe problem of full trisomy 22. Hum Genet 56: 269–273.

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172 S. LECLERCQ ET AL.

Thomas S, Parker M, Tan J, Duckett D, Woodruff G. 2004. Ocularmanifestation of mosaic trisomy 22: a case report and review of theliterature. Ophthalmic Genet 25: 53–56.

Wang JC, Dang L, Mondal TK, Khan A. 2007. Prenatally diagnosedmosaic trisomy 22 in a fetus with left ventricular non-compactioncardiomyopathy. Am J Med Genet A 143: 2744–2746.

Warburton D, Byrne J, Canki N. 1991. Chromosome Anomalies andPrenatal Development: Atlas. Oxford University Press: Oxford.


mosaic trisomy 22: five new cases with variable outcomes. implications for genetic counselling and...

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