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� 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:1739–1748 (2007)
Variable Expressivity in Patau Syndrome isNot All Related to Trisomy 13 Mosaicism
Hui-Fang Hsu1 and Jia-Woei Hou1,2*1Department of Pediatrics, Chang Gung Children’s Hospital, Taoyuan, Taiwan
2Chang Gung Institute of Technology, Taoyuan, Taiwan
Received 17 April 2006; Accepted 13 March 2007
Patau syndrome (trisomy 13) is very rare in live-born babies.Individuals with this chromosomal syndrome have a shortlifespan and are rarely seen beyond infancy. This study isaimed at the clinical spectrum, natural history, and survival ofpatients with trisomy 13. We reviewed the detailed data of 13Patau syndrome live-born babies. Among them two indivi-duals were delivered from continuation of pregnancy evenafter prenatal diagnosis. The remaining 11 patients wereborn to younger mothers who did not undergo amniocent-esis because no major anomalies except for cleft lip/palatewere found on prenatal sonograms. The common features ofPatau syndrome including the clinical triad (microphthalmia,cleft lip/palate, and polydactyly) and non-cyanotic heartdefects were always found in our series. However, certainserious central defects (holoprosencephaly, omphalocele,and single umbilical artery), which are easily recognizedfrom prenatal sonogram, occurred less frequently than thosestated in the literature. The median survival time was 95 days
and was longer than that previously reported. There weretwo infants with trisomic mosaicism with different outcomesin both clinical spectrum and survival. Otherwise, we alsofound the increased recurrence risks of aneuploidy in twoindividuals, and the longest survivor (84 months) of non-mosaic trisomy 13 in Taiwan. We thus suggest that long-term survival in our series is strongly correlated withdifferent expressivity after prenatal selection, in additionto cytogenetic mosaicism. Less associated anomalies suchas polyhydramnios, oligohydramnios, intrauterine growthretardation, single umbilical artery, eye defects, holoprosen-cephaly, omphalocele, and polycystic kidney may contributeto their clinical courses. � 2007 Wiley-Liss, Inc.
Key words: Patau syndrome; trisomy 13; recurrent aneu-ploidy; mosaicism; long-term survival
How to cite this article: Hsu H-F, Hou J-W. 2007. Variable expressivity in Patau syndrome is not allrelated to trisomy 13 mosaicism. Am J Med Genet Part A 143A:1739–1748.
INTRODUCTION
Patau syndrome (trisomy 13 syndrome) is the thirdmost common autosomal chromosome trisomy[Spencer et al., 2000; Rasmussen et al., 2003; Duarteet al., 2004]. One out of every 5,000 newborns hastrisomy 13 [Tongsong et al., 2002; Chen et al., 2004;Duarte et al., 2004; Rios et al., 2004]. It is estimatedthat the frequency of trisomy 13 is 100 times higher inspontaneous abortions than in live births [Zoll et al.,1993; Parker et al., 2003; Rios et al., 2004]. From theliterature, only a small number of these childrensurvive the first year of life and even fewer cases arereported to live longer. Race and gender seem toaffect survival, with girls and blacks showing highermedian age at death [Baty et al., 1994a; Rasmussenet al., 2003]. As with Down syndrome, risk of thistrisomy increases with advanced maternal age. Anestimated incidence of 10–25% of all humanpregnancies are aneuploid as a result of errors duringfemale meiosis, and aging oocytes lead to increased
levels of meiotic non-disjunction [Chen et al., 2004;Rios et al., 2004].
Patau syndrome is a multiple malformation syn-drome and includes anomalies of the central nervoussystem (CNS), cardiac, and circulatory system, andthe urogenital system. It is characterized by thefollowing triad: microphthalmia or anophthalmia,cleft lip and palate, and postaxial polydactyly. Butthese three cardinal features have only 60–70%occurrence rate in this syndrome [Duarte et al., 2004;Carey, 2005]. The diagnosis of Patau syndrome canbe confirmed antenatally or after delivery by cyto-genetics. We have collected and compared the clini-cal manifestations of 13 Patau syndrome live-born
*Correspondence to: Dr. Jia-Woei Hou, Department of PediatricsChang Gung Children’s Hospital, 5 Fu-Shin Street, Taoyuan 333,Taiwan—Republic of China. E-mail: [email protected]
DOI 10.1002/ajmg.a.31835
infants in Taiwan, evaluated the possible factors oflonger survival, and reviewed the literature.
PATIENTS AND METHODS
We collected the medical records of 13 patients ofPatau syndrome that had occurred over 14 years(1993–2006) in Chang Gung Children’s Hospital,Taiwan, a tertiary referral center. The diagnosis ofPatau syndrome was based on prenatal or postnatalchromosome studies. In this hospital, the amnio-centeses are performed on about 34% of pregnantwomen, and nearly 1.8% of these amniocytekaryotyping reports are trisomy 13. Almost allprenatally diagnosed trisomy 13 fetuses succumbedto elective termination. The live-born babiesincluded seven females and six males. Five werepremature babies (gestational age between 32 and36 weeks). The fathers’ median age was 35 years(26–43 years) and the mothers’ was 31 years (23–35 years). Prenatal ultrasound examinations foundminor or major fetal anomalies in five fetuses. Twofamilies had received antenatal diagnostic amnio-centesis. One mother (Patient 6) was of an advancedmaternal age (her first pregnancy also produced anabnormal fetus with trisomy 21) and underwentamniocentesis. The other parents (Patient 2) hadpreviously had an abnormal fetus (anencephaly) andreceived in vitro fertilization resulting in twins.Trisomy 13 fetuses were found in these two couples.One couple continued the pregnancy due toreligious beliefs and the other couple’s decisionwas associated with having twins of normal andtrisomic fetuses. All patients received brain imagestudy, heart and renal sonograms, and ophthalmo-logical consultation for the multiple anomalies afteradmission. The clinical manifestations and relatedprenatal or family history are shown in Table I.
RESULTS
Structural Defects
Two babies had intrauterine growth retardation,four were small for their gestational age, and onlyone had oligohydramnios. All 13 individuals hadrocker-bottom feet and clenched hands. This syn-drome has the triad: microphthalmia or anophthal-mia, cleft lip and palate, and postaxial polydactyly.Six babies (46%) had ocular defects, 10 babies (77%)had cleft lip and/or cleft palate, and polydactylywas found in eight babies (61%). The common heartdefects were shunt lesions, including patentductus arteriosus (12 cases, 92%), atrial septal defect(11 cases, 85%), and ventricular septal defect (sixcases, 46%). Non-cyanotic heart defects accountedfor 77% of these patients. Further, there were threeindividuals with complex congenital heart defects(tetralogy of Fallot and transposition of the great
arteries). Brain anomalies were found in 10 patients(76%), corpus callosum anomaly, and ventriculome-galy being the most common (seven and nine cases,respectively). Neural tube defects occurred in twoinfants (15%) and hydrocephalus occurred in one(7%). Almost half of the patients had seizuredisorders. Holoprosencephaly, omphalocele, andsingle umbilical artery, the common central defectsin Patau syndrome, each occurred in just one babyin our series (Patient 6, Patient 9, and Patient 7,respectively, accounting for 7%). Alimentary tractdefects were found in four individuals (30%). Renalinvolvement was found in 11 infants (85%). Hydro-nephrosis was the most common, while polycystickidney occurred in only one patient (7%). Fifty-threepercent of the patients (seven cases) had additionalskeletal defects other than limbs, and almost one-third (five cases, 38%) had scalp defects. Ear andgenital organ anomalies were always found in thesebabies.
Recurrent Aneuploidy
Two mothers had also had another trisomic fetus(trisomy 21). The first pregnancy of Patient 6’smother resulted in a trisomy 21. Patient 11’s motherhad trisomy 21 in her next pregnancy. Both of thesetrisomic fetuses died in utero in the first trimester.
Cytogenetics
All the patients, except two, were full trisomy 13.These two individuals were mosaic. The cytogeneticstudy of Patient 3 was performed at anothermedical center and the lymphocyte karyotyping ofPatient 9 showed 47, XY, þ13/46, XY in the ratio of13:9; thus 60% of the cells were trisomic. The formersurvived more than 19 months and the latter died at2 months 20 days.
Cause of Death
With the exception of two, the remaining babiesstudied died in their first year of life. Three patientsdieddue to sepsis shortly after emergency surgery fortheir major defects (Patient 4 had menigomyelocelewith cerebrospinal fluid leakage; the others, Patients5 and 9, had alimentary tract defects and pneumo-peritoneum). The two prenatally diagnosed patientsreceived less invasive care; one died due to apnea(Patient 2) and the other due to congestive heartfailure resulting from a shunt lesion (Patient 6, theonly infant with holoprosencephaly, also died from aheart lesion). The remaining infants were ventilatordependent and their families decided to receive non-invasive management following the confirmeddiagnosis. Four infants (Patients 1, 7, 8, and 13)expired within several hours or days after ventilatorwithdrawal due to cyanotic episodes; and the other
1740 HSU AND HOU
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
TABLE
I.Clinic
alM
anifest
atio
ns
ofPat
auSy
ndro
me
Pat
ients
Pat
ients
12
34
56
78
910
11
12
13
Sex
FF
FF
FF
FM
MM
MM
MY
ear
ofbirth
1994
1995
1996
1999
2000
2002
2004
1993
1999
1999
2000
2000
2001
Fat
her’s
age
(year
s)28
39
32
36
43
36
35
26
35
34
35
34
35
Moth
er’s
age
(year
s)23
34
26
31
32
35
31
26
33
31
31
29
28
Pre
gnan
cyhis
tory
NM
IVF,E
AN
MB
EA
AE
NM
CD
,E
EO
ligohydra
mnio
s�
��
��
��
��
��
�þ
Intrau
terine
gro
wth
reta
rdat
ion
�þ
��
��
��
��
��
þN
eonat
alas
phyxia
NM
þN
Mþ
NM
þþ
þþ
þþ
��
Birth GA
(weeks)
FT
35
40
38
38
38
32
37
34
39
37
33
36
Wei
ght(g
)3,1
45
1,5
00
3,2
50
2,4
00
2,6
00
2,6
10
1,5
00
2,2
00
2,4
44
3,7
47
2,8
70
1,6
40
1,9
50
Smal
lfo
rgest
atio
nal
age
�þ
�þ
��
�þ
��
��
þApgar
score
NM
4!
9N
MN
MN
M4!
75!
86!
86!
8N
MN
M9!
10
8!
10
Deliver
yC/S
C/S
NSD
NSD
C/S
NSD
C/S
NSD
NSD
NSD
NSD
NSD
C/S
Fam
ily
His
tory
WN
LTw
in,B
rain
(K)
WN
LW
NL
WN
L47,XX,þ
21
(G)
CH
D(H
)CL/
CP
(I)
WN
LW
NL
47,XX
,þ
21
(G)
WN
LW
NL
Seiz
ure
sþ
NM
�þ
NM
NM
þN
MN
Mþ
þþ
NM
Bra
in Mic
roce
phal
y�
þ�
þþ
þþ
þ�
þ�
�þ
Holo
pro
sence
phal
y�
��
��
þ�
��
��
��
Corp
us
callosu
man
om
aly
þ�
�þ
þþ
�þ
�þ
�þ
�Ventric
ulo
megal
yþ
��
þ�
þþ
þþ
þþ
þ�
Hydro
cephal
us
��
�þ
��
��
��
��
�M
enin
goce
le�
��
��
��
�þ
��
��
Men
ingom
yelo
cele
��
�þ
��
��
��
��
�H
ead
and
Fac
eSc
alp
defe
ct�
þ�
þ�
��
þþ
þ�
��
Slopin
gfo
rehead
þþ
NM
NM
NM
þ�
�N
Mþ
�N
MN
MFro
nta
lboss
ing
��
��
��
þ�
��
þ�
�Bro
ad,flat
nose
NM
þþ
þþ
NM
þþ
NM
þþ
NM
þH
ypertelo
rism
��
�þ
��
þ�
�þ
��
�H
ypote
lorism
�þ
þ�
�þ
��
��
�þ
þM
id-fac
ehypopla
sia
þþ
þ�
�þ
��
��
�þ
þM
icro
gan
thia
þN
MN
MN
MN
Mþ
þN
MN
Mþ
NM
NM
NM
Abse
ntphiltrum
þN
Mþ
NM
þþ
þþ
NM
þN
Mþ
þEyes
NM
Mic
rophth
alm
ia�
��
��
�þ
þ�
��
�þ
Colo
bom
ata
�þ
��
��
�þ
��
��
�Cat
arac
ts�
��
��
�þ
þ�
��
þ�
Gla
uco
ma
��
��
��
��
��
�þ
�O
ptica
ldis
can
om
aly
�þ
��
��
þ�
��
þ�
�Ear
s Low
setear
sþ
þþ
þþ
NM
�þ
þþ
NM
NM
NM
Pre
auricu
lar
tags
orpits
��
��
��
��
��
�þ
�Abnorm
alau
ricl
es
þ�
��
þþ
þ�
þ�
þ�
�M
outh
and
lary
nx
Cle
ftlip/c
left
pal
ate
þ/þ
�/þ
þ/þ
�/þ
þ/þ
þ/þ
�/�
þ/þ
�/�
þ/þ
�/�
þ/þ
þ/þ
Hig
har
ched
pal
ate
��
��
��
þ�
þ�
þ�
�N
ola
bia
frenulu
m�
��
�þ
��
��
��
��
Nat
alte
eth
þ�
��
þ�
��
��
þ�
�
(Con
tinued
)
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
TABLE
I.(Con
tinued
)
Pat
ients
12
34
56
78
910
11
12
13
Rete
ntion
cyst
��
��
��
��
�þ
��
�Thyro
glo
ssal
cyst
��
��
��
��
�þ
��
�La
ryngeal
web
��
��
��
��
��
þ�
�Bro
nch
us
anom
aly
��
��
��
þ�
��
��
�W
eb
orsh
ort
neck
NM
þN
MN
MN
Mþ
þþ
NM
þN
MN
M�
Chest
wal
lan
om
aly
��
��
��
��
þ�
��
þN
ipple
anom
aly
��
��
��
��
þ�
��
þH
ear
tAtria
lse
pta
ldefe
ctþ
þþ
þþ
�þ
þ�
þþ
þþ
Pat
entduct
us
arte
riosu
sþ
þþ
�þ
þþ
þþ
þþ
þþ
Ventric
ula
rse
pta
ldefe
ct�
�þ
�þ
þþ
�þ
��
�þ
Tetral
ogy
ofFal
lot
��
��
��
þ�
þ�
��
�Tra
nsp
osi
tion
ofgre
atar
teries
��
��
��
��
��
��
þPulm
onar
yar
tery
hypopla
sia
��
��
��
þ�
þ�
��
þConfluentpulm
onar
yar
tery
��
��
��
þ�
þ�
��
�D
extroca
rdia
þ�
��
��
��
��
��
�Bow
elan
om
aly
��
�þ
þ�
��
þþ
��
�Im
perf
ora
tean
us
��
��
��
��
þ�
��
�M
eck
eldiv
erticu
lum
��
��
þ�
��
��
��
�O
mphal
oce
le�
��
��
��
�þ
��
��
Um
bilic
alco
rdan
om
aly
��
��
��
þ�
��
��
�Renal
mal
form
atio
nþ
�þ
þþ
þ�
þþ
þþ
þþ
Poly
cyst
ickid
ney
��
�þ
��
��
��
��
�G
enital
anom
aly
NM
NM
NM
NM
þN
Mþ
þþ
þþ
þþ
Skele
talan
om
aly
Poly
dac
tyly
offingers
þþ
�þ
��
þþ
��
þþ
�Poly
dac
tyly
ofto
es
þþ
��
��
þ�
þ�
þþ
�Cle
nch
ed
han
ds
þþ
þþ
þþ
þþ
þþ
þþ
þRock
er-
bottom
feet
þþ
þþ
þþ
þþ
þþ
þþ
þJo
intco
ntrac
ture
NM
NM
þN
MN
MN
Mþ
NM
NM
�þ
NM
NM
Vertebra
ean
om
aly
��
�þ
��
��
þþ
��
þRib
anom
aly
þ�
��
��
þ�
þ�
þ�
þN
ailan
om
aly
þ�
��
�þ
��
��
þ�
�Chro
moso
me
report
47,þ
13
L(þ
)A(þ
)L(
m)
L(þ
)L(þ
)A(þ
)L(þ
)L(þ
)L(
m)
L(þ
)L(þ
)L(þ
)L(þ
)Age
atdeat
h(m
onth
s–day
s)3–4
0–11
>19–0
7–1
2–22
1–4
3–10
1–7
2–20
Alive
for
7year
s4–0
6–0
0–10
þ,S
ym
pto
mpre
sent;�
,sym
pto
mnotp
rese
nt;
A(þ
),am
nio
cyte
—fu
lltris
om
y13;A
,dru
gexposu
re(C
hin
ese
herb
aldru
gorm
edic
inesfo
rco
mm
on
cold
);B,t
raffi
cac
cidenta
tfirs
ttrim
est
er;
C,m
atern
alvar
icella
at36
weeksof
gest
atio
n;C
/S,c
esa
rean
sect
ion;D
,pre
gnan
cyin
duce
dhypertensi
on;E
,abnorm
alpre
nat
alfe
tale
xam
inat
ion;F
,fem
ale;F
T,f
ull
term
;G,a
noth
erab
norm
alpre
gnan
cy(f
etu
sw
ith
tris
om
y21-D
ow
nsy
ndro
me);
GA,g
est
atio
nal
age;H
,fa
mily
his
tory
ofco
ngenital
hear
tdefe
ct;I,
fam
ily
his
tory
ofcl
eft
lip
and
cleft
pal
ate;IV
F,in
vitro
fertiliz
atio
n;K
,th
isbab
y(p
atie
nt2)w
astw
inA
from
invitro
fertiliz
atio
nan
dherm
oth
erhad
anan
ence
phal
yfe
tus
pre
gnan
cybefo
re;L(þ
),ly
mphocy
tes—
full
tris
om
y13;L(
m),
lym
phocy
tes—
mosa
ictris
om
y13;M
,m
ale;N
M,notm
entioned;N
SD,vag
inal
delivery
;W
NL,
fam
ily
his
tory
isw
ithin
norm
alra
nge.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
two individuals (Patients 11 and 12) died severalmonths later at a local respiratory care center. Ofthese six patients, two had cyanotic heart defects(Patients 7 and 13) and three had corpus callosumanomalies (Patients 1, 8, and 12), although thesestructural anomalies may not have been the majorcauses of death. The median survival time was95 days.
Long Survival
The first surviving baby had mosaic trisomy13 (Patient 3) with non-cyanotic heart defects,hydronephrosis, and corrected cleft lip/palate. Shehad a normal prenatal examination, no intrauterinegrowth retardation, and was born at term. She alsohad developmental delay and was lost to follow upafter the age of 1 year 7 months. Patient 10 is a 7-year-old boy with non-mosaic trisomy 13. This is thelongest survival (84 months) report of full trisomy 13in Taiwan. He had normal prenatal history andaverage weight and age at birth. Perinatal asphyxiaoccurred at birth and resuscitation was doneimmediately. He had a cleft lip and palate, thyr-oglossal cyst, scalp defect, dysgenesis of corpuscallosum, atrial septal defect, patent ductus arterio-sus, and penis dysgenesis. This boy developedseizures when he was 3 years old. He wasventilator-dependent in early infancy, then hadrecurrent apnea or pulmonary infection with respira-tory failure in childhood, and underwent a tracheost-omy at the age of 4 years. He also underwent cleft lip/palate repair at the age of 4 years. At the age of 5 years4 months, he had microcephaly (head circumference48 cm, below 3rd centile), growth deficiency (weight16 kg, below 3rd centile; height 108 cm, about10th centile), contractures of the lower limbs anddystrophy of the leg muscles. Contracted upperlimbs and clenched hands were noted at birth andresolved spontaneously later. This child was able tohold objects and take them to his mouth; visualcontactwas rare andaccidental; spontaneous smilingoccurred during caressing but was independent ofwhether the person caressing him was known or not.He was not able to sit, stand, follow commands orbabble a few words. He has been admitted to ourhospital frequently due to recurrent infections(pneumonia, urinary tract infection, and centralvenous line infection). He was no longer livingwith his family andwas cared for in a local respiratorycare center.
DISCUSSION
Patau syndrome is a serious disorder associatedwith high rates of spontaneous abortion and pooroutcomes of surviving infants. It is assumed that if alltrisomy 13 fetuses identified antenatally survived tothe third trimester, then the incidence at birth would
be 1 in 5,886 (95% confidence interval, 1 in 4,383 and1 in 8,101) [Parker et al., 2003]. However, only 18% oftrisomy 13 cases are live-born; 7% are stillborn, 7%are miscarried, and the remainder are terminatedafter prenatal diagnosis [Parker et al., 2003]. Thecytogenetically confirmed trisomy 13 live-bornbabies were 1 in 14,700 in the United States between1968 and 1999 [Rasmussen et al., 2003]. Thesetwo frequency figures differ due to the exclusion offetus loss resulting from spontaneous abortionor pregnancy termination in the latter study. Newdevelopments in prenatal diagnosis programs havecontributed to the decrease in birth-prevalence ofthis chromosome condition [Gessner, 2003; Parkeret al., 2003; Rasmussen et al., 2003; Carey, 2005].
Prenatal Diagnosis in Pregnancy
In Taiwan, the present prenatal screening fortrisomy 13 consists of considering advanced mater-nal age, ultrasound evaluation and amniocentesisconfirmation. The triple screen (alpha-fetoprotein,total beta-human chorionic gonadotrophin, andestriol) and fetal nuchal translucency, originally usedforDown syndromedetection [Gessner, 2003; Parkeret al., 2003; Rios et al., 2004], have also aidedscreening. Almost two-thirds of all cases are identi-fied through prenatal chromosome analysis initiatedbecause of abnormalities noted on fetal anomalyscanning in the second trimester. An additional 16%of cases are detected as a result of investigations(usually amniocentesis) initiated on the grounds ofadvancedmaternal age, whereas only 2% of cases areinitiated by the serum-screening program. Theremainders are not recognized antenatally. Some ofthem (about 14% of total cases) are identified afterdelivery, and the others (about 7%) are confirmedby culture of material produced at miscarriage[Parker et al., 2003]. Thus, the most efficient prenatalscreening for trisomy 13 is based on advancedmaternal age and second trimester ultrasound.It is not likely, using present serum screeningmethods, that we could improve detection rates forPatau syndrome [Abramsky and Chapple, 1993;Parker et al., 2003; Rios et al., 2004]. In fact, thedetection of trisomy 13 occurs via serum screeningonly by chance or if the aneuploidy is associatedwith a neural tube defect. In our series, the medianmaternal age was 31 years and only one mother hadan advanced maternal age. Other high-risk groups,including advanced maternal age, increased nuchaltranslucency thickness and abnormal serum tests,had already received elective termination after theprenatal karyotyping confirmation. Prenatal ultra-sound examination showed minor or major fetalanomalies (e.g. intrauterine growth retardation, cleftlip and palate) in three individuals, excluding twoknown trisomy 13 fetuses, did not persuade familiesto receive an amniocentesis.
PATAU SYNDROME EXPRESSIVITY 1743
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
Issues surrounding the prevalence of trisomy 13 inthe era of prenatal diagnosis and options forpregnancy termination are complex. One factormay be due to some mothers not displaying therelevant risk factors or some fetal sonographicmarkers not being identified before the secondtrimester (the latest termination point). Women aremore likely to choose an amniocentesis following anabnormal ultrasound than solely for advancedmaternal age [Gessner, 2003]. Another factor is thatabout half to two-thirds of mothers decline to havediagnostic tests (e.g. amniocentesis) or other pre-natal care performed, or do not choose to have theirpregnancies terminated [Gessner, 2003]. There are14% of couples that choose to continue with thepregnancy following chromosomal confirmation of asuspected diagnosis [Parker et al., 2003]. In thepresent series, one set of parents declined pregnancytermination due to religious beliefs, and the otherbecause of a normal finding in the other twin.
Structural Defects
The frequencies of clinical features in our seriescompared to the literature are listed in Table II. Manyof the abnormal clinical features in Patau syndromeare primary malformations of midline development.Up to 70% of infants with trisomy 13 have someform of holoprosencephaly [Rios et al., 2004]. Otherrelated midline facial defects including cyclops,synophthalmia, anophthalmia, proboscis, ceboce-phaly, and cleft lip/palate are also associatedwith themalformation of the forebrain. Another two midline
defects, include omphalocele and single umbilicalartery, both occurring in 13–28% of trisomy13 infants. These abnormalities are easily recognizedin prenatal sonography at mid pregnancy [Tongsonget al., 2002]. These significant morphological findingwerenot common inour series,we suspect, due to anartificial selection by the well-established prenataldiagnosis and subsequent termination. Cleft lipand palate was present in 77% of our patients,and polydactyly was seen in 61%. Other commondistinctive external appearances, including ocularmalformation and scalp defects, had different fre-quencies compared with the literature possibly dueto the small sample size in our series. Vital organanomalies are always seen in Patau syndrome, butmost of them are not features specific to thissyndrome. Non-fatal anomalies, such like patentductus arteriosus, atrial septal defect, hydronephro-sis, cryptorchidism, ventriculomegaly, and corpuscallosum anomaly, were frequently seen in thepresent series. Some serious malformations, such asmeningocele, meningomyelocele, hydrocephalus,and Meckel diverticulum, occurred in lower fre-quencies in our series as well as previous studies(Table II). Because this study is focused on thetrisomy 13 live births in times of widespreadintroduction of prenatal diagnosis programs, someclinical features which could be recognized at midpregnancy (i.e. polyhydramnios, oligohydramnios,intrauterine growth retardation, single umbilicalartery, eye defects, polycystic kidney, holopro-sencephaly, and omphalocele) are less seen in ourseries (Table II).
Recurrent Aneuploidy
Two individuals had a previous or subsequentsibling with a confirmed diagnosis of trisomy 21.There was no record of any patient having a siblingwith either trisomy 13 or trisomy 18, whereas oneinfant had a previous sibling with anencephaly.Similar observations have been made elsewhere[Baty et al., 1994a; Shulman et al., 1997; Arbuzovaet al., 2001; Parker et al., 2003], and Baty et al. [1994a]found the sibling recurrence risk for trisomy 18 ortrisomy 13 was 0.55%. Although, most patients oftrisomy 13 are sporadic events, Hecht et al. [1964]suggested that there was a possible predisposition toaneuploidy in a minority. If women had had aprevious trisomy 21 pregnancy, the result of amnio-centesis documented that there was a statisticallysignificant excess of 0.54% and 0.25%, comparedwith the number expected on the basis of maternalage alone, in trisomy 21 recurrence and in otheraneuploidies (XXY, þ18, 45X, þ13, XYY, XXX),respectively [Arbuzova et al., 2001].
Our study showed an apparent recurrencebetween trisomy 13 and 21. Some studies havenoted a fundamental mechanism common to
TABLE II. The Frequency of Clinical Features in Patau Syndrome
Clinical features Literature (%) Our patients
Mental retardation 100 2a
Congenital heart defects 80–84 13 (100%)Central nervous system defects 75 10 (76%)Holoprosencephaly 60–70 1 (7%)Cleft lip/cleft palate 60–80 10 (77%)Polydactyly 60–70 8 (61%)Eye defects 60–70 6 (46%)Scalp defects 44 5 (38%)Seizures 25–50 6 (46%)Kidney problems 37 11 (85%)Polycystic kidney 31 1 (7%)Genitalia abnormality 30 8 (61%)Single umbilical artery 13–28 1 (7%)Intrauterine growth retardation 27 2 (15%)Prematurity 19 5 (38%)Polyhydramnios 15–27 0 (0%)Oligohydramnios 10–13 1 (7%)Omphalocele 13 1 (7%)Meckel diverticulum 11 1 (7%)Hydrocephalus 5–7 1 (7%)Neural tube defects 3–9 2 (15%)
The frequencies are according to the literature [Rodriguez et al., 1990; Baty et al.,1994a; Tongsong et al., 2002; Rios et al., 2004; Carey, 2005].aJust two patients survived, and the mental retardation rate was 100%.
1744 HSU AND HOU
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
the occurrence of non-disjunction in these acro-centric trisomies [Ishikiriyama and Niikawa, 1984;Robinson et al., 1996]. In trisomy 13, the origin of theextra chromosome is maternal in about 90% ofpatients [Ishikiriyama and Niikawa, 1984; Robinsonet al., 1996; Rios et al., 2004].Most of the time the non-disjunction occurs in maternal first meiotic divisionand approximately 12% of cases take place inpaternal meiosis or in postzygotic mitosis [Ishikir-iyama and Niikawa, 1984; Robinson et al., 1996].Because many fetuses with trisomy 13 succumbed toelective terminations after prenatal diagnosis, therecurrent aneuploidy occurred in our series was notcorrelated with the maternal age.
Cytogenetics
Twoof our patients had trisomy13mosaicism.Onepatient, with cleft lip and palate, non-cyanotic heartdefects, hydronephrosis, and mental retardation,lived longer than 19 months, theoretically due tothe mosaicism. The other patient had omphalocele,tetralogy of Fallot, meningocele and a spinal defect,and lived for only a short time. Translocationand mosaicism occur in approximately a quarter oftrisomy 13 patients, with the respective frequenciesof 20% and 5%. Infants with mosaicism mighthave fewer phenotypic features according to thefraction and tissue distribution of the abnormal cells[Delatycki and Gardner, 1997]. Some patients did notshow typical Patau gestalt due to variability in thetissue distribution of the trisomic cells [Eiben et al.,1989; Delatycki and Gardner, 1997]. There is noclear association, however, between the level ofmosaicism, the severity of the phenotype andpotential survival at birth [Delatycki and Gardner,1997; Rasmussen et al., 2003; Chen et al., 2004; Rioset al., 2004]. Besides, trisomy mosaicism with normalmorphology also has some risk of mental anddevelopmental delay. A decrease in the percentageof abnormal cells with age was also noted in theliterature, and this might be due to a natural selectionagainst the abnormal cells [Delatycki and Gardner,1997; Chen et al., 2004].
Cause of Death
From most published reports, the cause of death inPatau syndrome disagrees with the earliest hypoth-esis, originally described by Patau et al. [1960], thatventricular septal defects are always fatal. Themajority of cardiac defects in trisomy 13 are shuntlesions and always non-fatal in infancy or earlychildhood, even without surgery [Wyllie et al., 1994;Rasmussen et al., 2003; Rios et al., 2004; Carey, 2005].The reason for death is suggested as primary apnea,regardless of the presence of a CNS abnormality[Wyllie et al., 1994; Rios et al., 2004; Carey, 2005].All except for two of our patients were ventilator-
dependent their whole life; 25% of the babies died ofsepsis and the remainder died due to recurrentcyanotic episodes. The cause of recurrent cyanosismay be a cyanotic heart defect, pulmonary hyperten-sion, congestive heart failure, aspiration pneumonia,gastro-esophageal reflux, obstructive apnea fromairway anomaly or laryngomalacia, hypoventilation,seizure disorder, primary apnea, or other cause. Thefirst surviving baby had mosaic trisomy 13 withoutsevere respiratory problems, while the other had apoor respiratory drive and underwent a trachostomyfor ventilation. There is no evidence that their deathscan be attributed to congenital heart defects (exceptfor Patient 6); however, recurrent cyanotic episodesand ventilator dependence suggest that a poorrespiratory drive from multiple causes might be fatal.Previous study has showed that the operation rate intrisomy 13 infants is about 23% [Baty et al., 1994a]. Nopatients in our series received emergency cardiacintervention for their cardiac defects, and this alsoimplies that cardiac malformation was not the causeof death. Five of our patients received surgeries,either for life threatening conditions (in threepatients), or for the improvement in medical states(cleft lip and palate, and thacheostomy in twosurviving patients).
Almost half of infants with trisomy 13 will die in thefirst month of life. The probability of survival until1 month for trisomy 13 live births is about 28%, andthere is only a 5–10%chance that theywill survive for1 year [Brewer et al., 2002; Rasmussen et al., 2003].The median and mean survival times for babies withtrisomy 13 were 2.5 and 8.5 days in the UnitedKingdombetween1997 and2001 [Parker et al., 2003].However, earlier studies showed the median survivaltime for these babies varied from 7 to 10 days during1968 to 1999 [Brewer et al., 2002; Rasmussen et al.,2003]. The median age at death significantlydecreased through the years studied, reflecting thechanges in management of affected infants in thelight of better understanding of the poor long-termprognosis [Rasmussen et al., 2003]. In our study, themedian survival time was 95 days; this may be due tothe smallness of the sample and the inclusion of twooutliers. The other reasons for this longer lifespanin our series, in comparison to the literature, areprobably attributable to the fact that a number ofcases with shorter lifespan might have diedbefore transfer or before diagnosis, and to the factthat more aggressive management (resuscitation,tracheostomy, ventilator support, and operation,etc.) for the live births in this tertiary referral centermight skew the natural course of Patau syndrome.If an infant has had a diagnosis of trisomy 13 antena-tally, the parental decision to decline any othersupport or operation for prolongation of life wouldshorten the lifespan, just like our Patients 2 and 6.Holoprosencephaly, complex heart defects, ompha-locele, single umbilical artery, microphthalmia, and
PATAU SYNDROME EXPRESSIVITY 1745
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
TABLE
III.
Maj
orM
anifest
atio
ns,
Triso
my
13
Pat
ients
ofPro
longed
Surv
ival
Tim
e
Pat
ientnum
ber
Triso
my
13
com
mon
signs
1a
2b
3c
4c
5d
6e
7f
8g
9h
Sex
FM
MF
MF
FF
MN
eonat
alas
phyxia
(þ)
þ�
�þ
NM
þN
Mþ
þReported
age
5year
s9
year
s11
year
s19
year
s22
year
s11
year
s32
year
s2
year
s4
month
s7
year
sBirth GA
Pre
term
(19%
)Term
Term
Pre
term
Term
Term
Pre
term
Pre
term
Term
Term
Wei
ght(g
)2,6
00
2,0
69
3,3
50
2,3
70
2,7
60
3,4
00
1,5
60
NM
2,6
00
3,7
47
Bra
in Mic
roce
phal
yþ
þþ
þþ
þþ
þþ
þH
olo
pro
sence
phal
yþ
(60–70%
)�
��
��
��
��
Head
/fac
eSc
alp
defe
ctþ
(44%
)N
MN
MN
MN
MN
Mþ
þ/�
þþ
Slopin
gfo
rehead
þþ
þþ
þþ
þN
Mþ
þBro
ad,flat
nose
þþ
þþ
þN
Mþ
þþ
þCle
ftlip/p
alat
eþ
(60–80%
)þ
��
��
��
�þ
Hig
hly
arch
ed
pal
ate
þ�
�þ
þþ
þN
MN
M�
Pro
trudin
glo
werlip
(þ)
NM
��
þN
Mþ
NM
NM
�Ear
s Hea
ring
loss
(þ)
NM
�þ
��
þþ
�N
MLo
w-s
etear
sþ
þþ
þþ
NM
þN
Mþ
þAbnorm
alau
ricl
es
þþ
þþ
þN
Mþ
NM
��
Eyes
Mic
rophth
alm
iaþ
(60–70%
)Su
nken
eyes
þþ
þþ
Sunken
eyes
þSu
nken
eyes
�Colo
bom
a,ca
tara
cts
þþ
þþ
þN
M�
þN
M�
Congenital
hear
tdefe
cts
þ(8
0–84%
)�
þ�
Dextroca
rdia
NM
�D
extroca
rdia
þþ
Renal
mal
form
atio
nþ
(37%
)N
Mþ
��
NM
þN
MN
Mþ
Genital
anom
aly
(þ)
(30%
)�
þþ
þþ
��
�þ
Lim
bs
Poly
dac
tyly
þ(6
0–70%
)�
þþ
þ�
��
þ�
Cle
nch
ed
han
ds
þþ
þþ
þþ
þN
M�
�Rock
er-
bottom
feet
þþ
þþ
þþ
�N
Mþ
þJo
intco
ntrac
ture
s(þ
)N
MN
Mþ
þN
Mþ
NM
NM
�K
yphosi
s,sc
oliosi
s(þ
)N
MN
MN
MN
MN
M�
NM
NM
þM
enta
lre
tard
atio
nþ
(100%
)þ
þþ
þþ
þþ
þþ
Seiz
ure
sþ
(25–50%
)þ
�þ
þN
Mþ
þþ
þFai
lure
toth
rive
þþ
þþ
þþ
þþ
þþ
Cyto
genetics
LþSk
þLþ
Sk�
?Lþ
Skþ
,m
os?
LþSk
NM
LþSk
þLþ
Skþ
,m
os?
LþSk
þLþ
Skþ
LþSk
NM
LþSk
NM
Modifi
ed
form
ofth
eta
ble
ofZoll
etal
.[1
993];
the
frequenci
es
ofcl
inic
alfe
ature
sar
eac
cord
ing
toTab
leII.
þ,sy
mpto
mpre
sent;�
,sy
mpto
mnotpre
sent;
(þ),
notobligat
ory
;G
A,gest
atio
nal
age;N
M,notm
entioned;Lþ
,ly
mphocy
tes—
full
tris
om
y13;Sk
þ/�
/mos,
tris
om
y13
insk
infibro
bla
sts
pre
sent/
notpre
sent/
mosa
ic.
aM
ankin
en
and
Sear
s[1
976].
bCow
en
etal
.[1
979].
cRedheendra
netal
.[1
981].
dSi
ngh
[1990].
eZoll
etal
.[1
993].
f Tunca
etal
.[2
001].
gD
uar
teetal
.[2
004].
hPre
sentPat
ient10.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
polydactyly were not found in the present survivingpatients (Patients 3 and 10), and both individuals haduncomplicated antenatal history and born at termwith average weight. Thus, an advanced prenataldiagnosis will lower the birth-incidence and alsochange the spectrum of features toward less severeones in live-born trisomy 13 infants, resulting in alonger median survival time [Brewer et al., 2002].
Long Survival
Ninety percent of infants died within the first year;only 5% to 10% of babies with this condition survivebeyond the first year of life, and those that do have asevere to profound developmental handicap [Batyet al., 1994b; Rasmussen et al., 2003; Chen et al., 2004;Rios et al., 2004; Carey, 2005]. Information on factorsassociated with long-term survival are limited, butseveral studies have suggested that certain cytoge-netic forms (translocations and mosaicism), beingfemale and of African decent, increase the medianage at death [Baty et al., 1994a; Rasmussen et al.,2003; Duarte et al., 2004]. There are only five isolatedcases reported of full trisomy 13 where the indivi-duals have reached their teens [Zoll et al., 1993;Tunca et al., 2001; Duarte et al., 2004], and some ofthem are listed in Table III. From the literature andour series, we have found no significant genderdifference in life span (five female and four malepatients). These patients all showed microcephaly,and serious mental retardation with or withoutseizure disorder. Released joint contractures andhypotonia, opposed to spasticity during infancy,were found in the literature [Duarte et al., 2004] and inour Patient 10. Failure to thrive was always noted inthese patients, but height might have been lessaffected in the third and fourth years of life [Batyet al., 1994a; Duarte et al., 2004; Carey, 2005], just likeour Patient 10. Other medical problems reportedinclude feeding difficulties, gastroesophageal reflux,recurrent urinary tract infections, autistic behavior,and the delay in motor milestones averaging 7–9 months [Zoll et al., 1993; Tunca et al., 2001; Duarteet al., 2004; Carey, 2005]. After physiotherapy andpsychological support, these children did achievesome skills of childhood and continued to learn [Batyet al., 1994b; Duarte et al., 2004]. Walking ability andsome toileting skills were attained in a small numberof trisomy 13 individuals [Baty et al., 1994b; Carey,2005]; and Baty et al. [1994b] stated that thedevelopmental age in the older children with trisomy13 averaged 13 months Major neural and cardiacdefects (holoprosencephaly and complex heartdefects) were not or rarely seen in these patients.Cleft lip and palate were also less seen in the longersurvivors (Table III), but occurred in the two presentsurviving patients. This may be due to the advancedmanagement in the correction of cleft lip/palate inthis hospital, and the prenatal recognition of cleft lip/
palate is not a strong indicator for amniocentesis.Data on patients with mosaic trisomy 13 suggestedthat the relativelymild clinicalmanifestations in thesepatientswere attributable to the presence of a normalcell line [Cowen et al., 1979; Singh, 1990; Zoll et al.,1993]. We suggest that non-fatal congenital anoma-lies and aggressive medical care have played animportant role in the prolonged survival of patientswith trisomy 13 based on above findings [Zoll et al.,1993; Tunca et al., 2001; Duarte et al., 2004]. But fromother studies and patients in the internationalsupport group Support Organization For Trisomy(SOFT 18, 13, and related disorders), some childrenwith trisomy 13 who are beyond the newborn periodhave not received more aggressive or extraordinarycare [Baty et al., 1994b; Carey, 2005]. Therefore, theclinical spectrum of trisomy 13 is the most importantfactor in long-term survivors.
We conclude that the long-term survival anddifferent expressivity in our series are stronglycorrelated with present prenatal screening strategiesand the ascertainment of our series. A decrease in theprevalence of live-born infants with trisomy 13 mightoccur with implementation of prenatal screeningstrategies and choice of pregnancy termination[Gessner, 2003]. However, education and counselingsystems around issues of outcome need to occurso that families are in position to make informeddecisions [Brewer et al., 2002; Rios et al., 2004]. Thecost-effectiveness of potential intervention strategiesneeds to be evaluated, particularly for women with alow risk of a trisomic pregnancy, as in the majority ofour series.
REFERENCES
Abramsky L, Chapple J. 1993. Room for improvement? Detectingautosomal trisomies without serum screening. Public Health107:349–354.
Arbuzova S, Cuckle H, Mueller R, Sehmi I. 2001. Familial Downsyndrome: Evidence supporting cytoplasmic inheritance. ClinGenet 60:456–462.
Baty BJ, Blackburn BJ, Carey JC. 1994a. Natural history of trisomy18 and trisomy 13. I. Growth, physical assessment, medicalhistories, survival, and recurrence risk. Am J Med Genet49:175–188.
Baty BJ, Jorde LB, Blackburn BJ, Carey JC. 1994b. Natural historyof trisomy 18 and trisomy 13. II. Psychomotor development.Am J Med Genet 49:189–194.
Brewer CM, Holloway SH, Stone DH, Carothers AD, FitzPatrickDR. 2002. Survival in trisomy 13 and trisomy 18 casesascertained from population based registers. J Med Genet39:e54.
Carey JC. 2005. Trisomy 18 and trisomy 13 syndromes. In: CassidySB, Allanson JE, editors. Management of Genetic Syndromes.2nd edition. New York: Wiley-Liss. p 555–568.
Chen M, Yeh GP, Shih JC, Wang BT. 2004. Trisomy 13 mosaicism:Study of serial cytogenetic changes in a case from earlypregnancy to infancy. Prenat Diagn 24:137–143.
Cowen JM, Walker S, Harris F. 1979. Trisomy 13 and extendedsurvival. J Med Genet 16:155–157.
Delatycki M, Gardner RJM. 1997. Three cases of trisomy 13mosaicism and a review of the literature. Clin Genet 51:403–407.
PATAU SYNDROME EXPRESSIVITY 1747
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
Duarte AC, Menezes AI, Devens ES, Roth JM, Garcias GL, Martino-Roth MG. 2004. Patau syndrome with a long survival. A casereport. Genet Mol Res 3:288–292.
Eiben B, Hansen S, Goebel R, Hammans W. 1989. Tissue-specific45,X0/47,XY, þ13 mosaicism in an 18-year-old woman. HumGenet 82:391–392.
Gessner BD. 2003. Reasons for trisomy 13 or 18 births despite theavailability of prenatal diagnosis and pregnancy termination.Early Hum Dev 73:53–60.
Hecht F, Bryant JS, Gruber D, Townes PL. 1964. The nonrandom-ness of chromosomal abnormalities. Association of trisomy 18and Down’s syndrome. New Engl J Med 271:1081–1086.
Ishikiriyama S, Niikawa N. 1984. Origin of extra chromosome inPatau syndrome. Hum Genet 68:266–268.
Mankinen CB, Sears JW. 1976. Trisomy 13 in a female over 5 yearsof age. J Med Genet 13:157–161.
Parker MJ, Budd JL, Draper ES, Young ID. 2003. Trisomy 13 andtrisomy 18 in a defined population: Epidemiological, geneticand prenatal observations. Prenat Diagn 23:856–860.
Patau K, Smith DW, Therman E, Inhorn SL, Wagner HP. 1960.Multiple congenital anomaly causedby an extra chromosome.Lancet 1:790–793.
Rasmussen SA, Wong L-YC, Yang Q, May KM, Friedman JM. 2003.Population-based analyses of mortality in trisomy 13 andtrisomy 18. Pediatrics 111:777–784.
Redheendran R, Neu RL, Bannerman RM. 1981. Long survival intrisomy 13 syndrome: 21 cases including prolonged survivalin two patients 11 and 19 years old. Am J Med Genet 8:167–172.
Rios A, Furdon SA, Adams D, Clark DA. 2004. Recognizing theclinical features of Trisomy 13 syndrome. Adv Neonat Care4:332–343.
Robinson WP, Bernasconi F, Dutly F, Lefort G, Romain DR,Binkert F, Schinzel AA. 1996. Molecular studies of transloca-tions and trisomy involving chromosome 13. Am J Med Genet61:158–163.
Rodriguez JI, Garcia M, Morales C, Morillo A, Delicado A. 1990.Trisomy 13 syndrome and neural tube defects. Am J MedGenet 36:513–516.
Shulman LP, Emerson DS, Phillips OP. 1997. Fetal trisomy 13distinguished by persistent fetal tachycardia. Int J GynaecolObstet 57:317–318.
Singh KST. 1990. Trisomy 13 (Patau’s syndrome): A rare case ofsurvival into adulthood. J Ment Defic Res 34:91–93.
Spencer K, Ong C, Skentou H, Liao AW, Nicolaides KH. 2000.Screening for trisomy 13 by fetal nuchal translucency andmaternal serum free beta-hCG and PAPP-A at 10–14 weeks ofgestation. Prenat Diagn 20:411–416.
Tongsong T, Sirichotiyakul S, Wanapirak C, Chanprapaph P.2002. Sonographic features of trisomy 13 at midpregnancy. IntJ Gynaecol Obstet 76:143–148.
Tunca Y, Kadandale JS, Pivnick EK. 2001. Long-term survival inPatau syndrome. Clin Dysmorphol 10:149–150.
Wyllie JP, Wright MJ, Burn J, Hunter S. 1994. Natural history ofTrisomy 13. Arch Dis Child 71:343–345.
Zoll B, Wolf J, Lensing-Hebben D, Pruggmayer M, Thorpe B.1993. Trisomy 13 (Patau syndrome) with an 11-year survival.Clin Genet 43:46–50.
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