Non-contiguous finished genome sequence of Ornithobacterium ...
Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with...
9
PRENATAL DIAGNOSIS Prenat Diagn 2009; 29: 966–974. Published online 16 July 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pd.2326 Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols † Sylvie Langlois 1 *, Linlea Armstrong 1 , Kim Gall 1 , Gurdip Hulait 1 , Janet Livingston 1 , Tanya Nelson 2 , Patricia Power 1 , Denise Pugash 3 , Dawn Siciliano 1 , Michelle Steinraths 4 and Andr´ e Mattman 2 1 Medical Genetics, University of British Columbia, Vancouver, Canada 2 Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada 3 Department of Radiology and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada 4 Laboratory Medicine, Pathology and Medical Genetics, Victoria General Hospital, Victoria, Canada Objective To ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome. Methods We reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy. Results Thirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%). Conclusion The clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus. Copyright 2009 John Wiley & Sons, Ltd. KEY WORDS: X-linked ichthyosis; STS deficiency; unconjugated estriols; maternal serum screening; single gene disorders; genetic counselling INTRODUCTION It is estimated that between 1 in 2000 and 1 in 6000 men have steroid sulfatase (STS) deficiency (Ballabio and Shapiro, 2001). This results in a condition known as X- linked ichthyosis (XLI). On its own, the condition is usu- ally considered relatively benign. It is characterized by dark adherent scales of skin on the trunk, arms, and legs. Patients can also present with corneal opacities which do not affect vision. A small percentage of affected boys are born with undescended testes (Ballabio and Shapiro, 2001). In a very recent publication, Kent et al. (2008) described an association between STS deficiency and attention deficit hyperactivity disorder (ADHD). Spo- radic cases of STS deficiency with additional features due to a deletion of contiguous genes have also been reported (Ballabio et al., 1989; Bick et al. 1989; Klink et al.,1994; Muroya et al., 1996; Weiss¨ ortel R et al., *Correspondence to: Sylvie Langlois, Medical Genetics, Univer- sity of British Columbia, C234, 4500 Oak Street, Vancouver, BC, Canada V6H 3N1. E-mail: [email protected] † Presented at the 14th Meeting of the International Society of Prenatal Diagnosis, Vancouver, June 1–4, 2008. 1998; Gohlke et al., 2000). The risk of contiguous gene deletion syndrome in patients with STS deficiency has been reported to be approximately 5% (Ballabio and Shapiro, 2001) but this figure has not been derived from a prospective study of prenatally diagnosed cases. Ninety percent of cases of STS deficiency are due to a deletion of the entire STS gene whereas 10% have point mutations (Ballabio and Shapiro, 2001). In those with contiguous gene deletion syndrome, the associ- ated findings depend on the size of the deletion and whether it extends distally to include the arylsulfatase E gene (ARSE) responsible for chondrodysplasia punctata or proximally to include the KAL1 gene responsible for Kallmann syndrome. The finding of mental retardation in these reported cases with a contiguous gene deletion syn- drome and the mapping of the deletions established the presence of a locus for mental retardation between ARSE and STS. Recent studies have implicated VCXA (also known as VCX 3A) (Fukami et al., 2000; Van Esch et al., 2005; Hosomi et al., 2007). However, this has been con- tradicted by the mapping of the deletion in a large cohort of patients with isolated STS deficiency, which showed that in a significant proportion the deletion included the VCX 3A and VCX genes (Cuevas-Covarrubias and Gonzalez-Huerta, 2008). Their results, combined with Copyright 2009 John Wiley & Sons, Ltd. Received: 8 August 2008 Revised: 3 June 2009 Accepted: 3 June 2009 Published online: 16 July 2009
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Transcript of Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with...
PRENATAL DIAGNOSISPrenat Diagn 2009; 29: 966–974.Published online 16 July 2009 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.2326
Steroid sulfatase deficiency and contiguous gene deletionsyndrome amongst pregnant patients with low serumunconjugated estriols†
Sylvie Langlois1*, Linlea Armstrong1, Kim Gall1, Gurdip Hulait1, Janet Livingston1, Tanya Nelson2,Patricia Power1, Denise Pugash3, Dawn Siciliano1, Michelle Steinraths4 and Andre Mattman2
1Medical Genetics, University of British Columbia, Vancouver, Canada2Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada3Department of Radiology and Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University ofBritish Columbia, Vancouver, Canada4Laboratory Medicine, Pathology and Medical Genetics, Victoria General Hospital, Victoria, Canada
Objective To ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in BritishColumbia between August 2002 and July 2007 to determine the incidence of this condition, the clinicaland laboratory findings, and the risk of a contiguous gene deletion syndrome.
Methods We reviewed the medical records of these patients to obtain detailed information about the maternalserum screening results, family history, investigations performed, and outcome of the pregnancy.
Results Thirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimalestimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this conditionwas isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STSdeficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 outof 12 (8.3%).
Conclusion The clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STSdeficiency indicates that this is a common condition and in cases with no family history, the risk of contiguousgene deletion syndrome is significant, and warrants additional molecular genetic investigations of the motherand/or fetus. Copyright 2009 John Wiley & Sons, Ltd.
KEY WORDS: X-linked ichthyosis; STS deficiency; unconjugated estriols; maternal serum screening; single genedisorders; genetic counselling
INTRODUCTION
It is estimated that between 1 in 2000 and 1 in 6000 menhave steroid sulfatase (STS) deficiency (Ballabio andShapiro, 2001). This results in a condition known as X-linked ichthyosis (XLI). On its own, the condition is usu-ally considered relatively benign. It is characterized bydark adherent scales of skin on the trunk, arms, and legs.Patients can also present with corneal opacities which donot affect vision. A small percentage of affected boysare born with undescended testes (Ballabio and Shapiro,2001). In a very recent publication, Kent et al. (2008)described an association between STS deficiency andattention deficit hyperactivity disorder (ADHD). Spo-radic cases of STS deficiency with additional featuresdue to a deletion of contiguous genes have also beenreported (Ballabio et al., 1989; Bick et al. 1989; Klinket al.,1994; Muroya et al., 1996; Weissortel R et al.,
*Correspondence to: Sylvie Langlois, Medical Genetics, Univer-sity of British Columbia, C234, 4500 Oak Street, Vancouver, BC,Canada V6H 3N1.E-mail: [email protected]† Presented at the 14th Meeting of the International Society ofPrenatal Diagnosis, Vancouver, June 1–4, 2008.
1998; Gohlke et al., 2000). The risk of contiguous genedeletion syndrome in patients with STS deficiency hasbeen reported to be approximately 5% (Ballabio andShapiro, 2001) but this figure has not been derived froma prospective study of prenatally diagnosed cases.
Ninety percent of cases of STS deficiency are due toa deletion of the entire STS gene whereas 10% havepoint mutations (Ballabio and Shapiro, 2001). In thosewith contiguous gene deletion syndrome, the associ-ated findings depend on the size of the deletion andwhether it extends distally to include the arylsulfatase Egene (ARSE) responsible for chondrodysplasia punctataor proximally to include the KAL1 gene responsible forKallmann syndrome. The finding of mental retardation inthese reported cases with a contiguous gene deletion syn-drome and the mapping of the deletions established thepresence of a locus for mental retardation between ARSEand STS. Recent studies have implicated VCXA (alsoknown as VCX 3A) (Fukami et al., 2000; Van Esch et al.,2005; Hosomi et al., 2007). However, this has been con-tradicted by the mapping of the deletion in a large cohortof patients with isolated STS deficiency, which showedthat in a significant proportion the deletion includedthe VCX 3A and VCX genes (Cuevas-Covarrubias andGonzalez-Huerta, 2008). Their results, combined with
Copyright 2009 John Wiley & Sons, Ltd. Received: 8 August 2008Revised: 3 June 2009
Accepted: 3 June 2009Published online: 16 July 2009
STEROID SULFATASE DEFICIENCY 967
previous mapping studies, provide evidence that themental retardation seen in patients with a contiguousgene deletion is the result of a deletion of the neuroli-gin 4 gene (NLGN4X). This is further supported by thefinding of point mutations in NLGN4X in related maleswith X-linked mental retardation and autism (Laumon-nier et al., 2004) and in siblings with autism (Jamainet al., 2003). However, one family with a deletion ofSTS, VCXA and NLGN4 showed variable phenotypeamongst the three affected males (Macarov et al., 2007).
STS deficiency can be readily detected in pregnanciesusing second trimester measurements of maternal serumunconjugated estriol (uE3), which is part of the typi-cal second trimester maternal serum screening for Downsyndrome. Furthermore protocols designed to screen forSmith–Lemli–Opitz syndrome (SLOS) (Palomaki et al.,2002) are more likely to identify fetuses with STS defi-ciency than SLOS. Fifty cases of STS deficiency werediagnosed amongst the 739 women who screened posi-tive only for SLOS in a large prospective study (Craiget al., 2006). There is interest in prenatal identificationof pregnancies with STS deficiency because of the asso-ciated risk of a contiguous gene deletion syndrome.
Since August 2002, in British Columbia, prenatalscreening has been expanded to include screening forSLOS, in addition to Down syndrome, trisomy 18, andopen spina bifida. Although no case of SLOS has beendetected using the published algorithm and a risk cut-offof one in 50 (Palomaki et al., 2002), STS deficiency hasbeen diagnosed in a number of pregnancies. The aimof this study was to review all cases of prenatally diag-nosed STS deficiency diagnosed between August 2002and August 2007 in order to assess the incidence of thiscondition, its clinical and laboratory findings and theassociated risk of contiguous gene deletion syndrome.Our objective was to determine based on our findings,the most appropriate approach to arrive at a definite pre-natal diagnosis of STS deficiency, exclude a contiguousgene deletion syndrome while minimizing the need forinvasive prenatal diagnosis and its associated risks.
METHODS
In British Columbia, maternal serum screening for Downsyndrome, trisomy 18, open neural tube defect andSLOS was performed through one central laboratory inthe Children’s and Women’s Health Centre of BritishColumbia. During the study period, screening con-sisted of measuring maternal serum alpha-fetoprotein(AFP), uE3, and human chorionic gonadotrophin (hCG)between 15 weeks’ and 20 weeks 6 days’ gestation. Allthree markers were measured with the AutoDelfia auto-mated immunoassay method (Perkin Elmer, Turku, Fin-land). Pregnant patients who screen positive for SLOSare referred to the Provincial Medical Genetics Pro-gram in Vancouver for assessment and counseling aftergestational age and fetal viability are confirmed. Theprogram’s patient database was searched to ascertain allpatients referred between August 2002 and August 2007for a positive SLOS screen and for which a diagnosis of
STS deficiency was made. The medical records of thesepatients were reviewed to obtain detailed informationabout the maternal serum screen results, family history,investigations performed, and outcome of the pregnancy.
Maternal urine sterols
In the first 2 years of the study, testing of maternal urinesterols was available through a reference laboratory andwas measured as per a previously described method(Shackleton et al., 2001).
Cytogenetic analysis
Fluorescence in situ hybridization was performed onstimulated peripheral blood lymphocytes using the LSISTS Spectrum Orange/LSI CEP X Spectrum Greenprobe (previously Vysis and now Abbott Molecular Inc.,Des Plaines, IL, USA).
Molecular analysis
DNA extracted from cultured amniocytes was testedusing mulitplex PCR analysis with primers specific tothe STS locus and the DMD locus as control (Maya-Nunez et al., 1998). In cases with no amplificationproduct for the STS locus, routinely, the followingmarkers (order telomeric to centromeric) were ampli-fied by PCR to determine the extent of the dele-tion: DXS996(NLGN4), DXS6837 (NLGN4), DXS1130,DXS237, and DXS7470 (immediately telomeric toKAL1) (Jimenez Vaca et al., 2001; Boycott et al., 2003).In the case where DXS996 was shown to be deleted, fur-ther markers were analyzed: RH1702, SY748 (ARSE),DXS31, DXS1060 (see Figure 1).
Figure 1—Map of Xp22.3 with position of the markers typed andgene loci as per the UCSC March 2006 assembly
Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 966–974.DOI: 10.1002/pd
968 S. LANGLOIS ET AL.
RESULTS
Between August 2002 and August 2007, a total of90,802 prenatal screens were done in British Columbia.During this 5 year period, 30 patients who screenedpositive for SLOS were ultimately found to have a malefetus/infant with STS deficiency, giving an incidenceof this condition of approximately 1 in 1513 males. In29 cases, the finding was isolated STS deficiency. Onepatient was found to have a contiguous gene deletionsyndrome.
The clinical details of the 30 cases of prenatallydiagnosed STS deficiency are summarized in Table 1.Of these, 21 patients screened positive only for SLOS.Four patients screened positive for SLOS and trisomy18, whereas five patients screened positive for SLOSand trisomy 21. The ethnic background of the patientpopulation was comparable to the population screenedwith 60% Caucasian, 20% SouthEast Asian, 13% EastAsian, and 7% First Nations ancestry.
In this group of 30 patients, all reported uE3 levelswere below 0.25 MoM (median of 0.08 MoM with arange from undetectable uE3 level to 0.24 MoM). Mostresults were in the vicinity of the detection limit ofthe assay (0.2 nmol/L) with a median uE3 level of 0.4nmol/L (range from undetectable uE3 to 0.82 nmol/L).The range of uE3 values was substantially higher for theentire group of patients referred for a positive screen forSLOS: median uE3 level of 0.2 MoM with a range fromundetectable to 0.40 MoM. In contrast, the AFP and hCGmedian MoM values (1.04 and 0.99, respectively) werenot different in the group with a final diagnosis of STSdeficiency from those seen in unaffected pregnancies.Of note is that all patients seen during the study periodwith a uE3 less than 0.15 MoM and a normal ultrasoundindicating a male fetus had a diagnosis of STS deficiencypresenting as XLI.
Patients were seen at a gestational age ranging from16 weeks 1 day to 23 weeks 1 day. All patients had adetailed ultrasound on the day of the medical geneticsconsultation. In only two cases were abnormalities notedon the fetal ultrasound.
Case ID 12 was seen at 21 weeks’ gestation. Fetalbiometry was appropriate for gestational age and nofetal structural abnormality was noted. However, thefetus was found to have an abnormal profile withflattening of the nasal bones and mild micrognathia(Figures 2 and 3). These findings raised the possibil-ity of a contiguous gene deletion syndrome. The familyhistory was negative for XLI. An amniocentesis wasperformed for cytogenetic and molecular analysis. Inaddition, cytogenetic analysis was performed on thepatient’s blood. The patient’s karyotype was found to be46,X,del(X)(p22.31p22.33).ish del(X) (DXZ1+,STS−,DXYS129+). Although the fetal karyotype was foundto be 46,XY, molecular analysis confirmed the presenceof a contiguous deletion that included the ARSE, NLGN4,and STS genes but not KAL1. The couple opted to inter-rupt the pregnancy.
Case ID 25 was seen at 23 weeks’ gestation and theultrasound showed a fetus with normal biometry forgestational age and a unilateral cleft lip and cleft palate.
Figure 2—2D ultrasound of case ID 12
Figure 3—3D ultrasound of case ID 12
The amniotic fluid volume was normal. The patient had apositive family history of XLI making it most likely thatthe fetus had two distinct conditions. An amniocentesiswas done for cytogenetic analysis because of the fetalanomaly on ultrasound and the fetus was found to have anormal male karyotype. Postnatally the child was indeedfound to have XLI, non syndromic cleft lip and cleftpalate and to be developmentally normal.
A detailed family history was obtained in all cases.Eighteen patients were found to have a positive orsuspicious family history for XLI. In the latter group,although the diagnosis of XLI had not been previouslymade, the patients described at least one family memberwith very dry skin. In cases with a positive or suspicious
Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 966–974.DOI: 10.1002/pd
STEROID SULFATASE DEFICIENCY 969Ta
ble
1—
Bio
chem
ical
and
clin
ical
deta
ilsof
all
case
sof
XL
Idi
agno
sed
incl
udin
gon
eca
seof
cont
iguo
usge
nede
letio
nsy
ndro
me
Cas
eID
AFP
MoM
uE3
MoM
hCG
MoM
Scre
enpo
siti
vefo
rT
21
Scre
enpo
siti
vefo
rT
18G
AFa
mhx
Dia
gnos
ism
ade
byPa
tient
test
edD
eliv
ery
10.
910.
110.
99N
oN
o17
wks
5da
ysN
oM
ater
nal
urin
est
erol
profi
le;
DN
Ate
stin
gof
new
born
No
SRO
Mat
40w
eeks
,C
Sfo
rfa
ilure
topr
ogre
ss2
0.68
0.08
0.86
No
No
18w
ks2
days
No
DN
Ate
stin
gof
amni
ocyt
esY
es—
carr
ier
TA3
0.77
0.06
0.37
No
Yes
19w
ks6
days
No
DN
Ate
stin
gof
amni
ocyt
esN
oSV
Dat
40w
ks4
0.99
0.08
0.33
No
Yes
18w
ks5
days
No
DN
Ate
stin
gof
amni
ocyt
esN
oN
/A5
0.89
0.07
1.83
Yes
No
19w
ksN
oD
NA
test
ing
ofam
nioc
ytes
No
C/S
for
bree
ch6
1.04
ND
2.92
Yes
No
16w
ks1
day
No
Mat
erna
lur
ine
ster
ol;
amni
ocyt
esne
gativ
efo
rth
ede
leti
on;
diag
nosi
sco
nfirm
edcl
inic
ally
post
nata
lly
No
SVD
at42
wks
with
prol
onge
dla
bur
71.
060.
122.
51Y
esN
o17
wks
1da
yN
oD
NA
test
ing
ofam
nioc
ytes
Yes
—ca
rrie
rTA
81.
580.
060.
95N
oN
o22
wks
2da
ysN
oD
NA
test
ing
ofam
nioc
ytes
No
N/A
90.
940.
111.
03N
oN
o18
wks
No
DN
Ate
stin
gof
amni
ocyt
esN
oSV
Dat
38w
ks10
1.3
0.13
0.89
No
No
18w
ks5
days
No
FISH
anal
ysis
ofm
ater
nal
bloo
dY
es—
carr
ier
N/A
111.
020.
050.
94N
oN
o19
wks
5da
ysN
oFI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rSV
D40
wk
3d
121.
140.
061.
2N
oN
o21
wks
No
DN
Ate
stin
gof
amni
ocyt
es;
cyto
gene
tican
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rTA
131.
070.
091.
43N
oN
o20
wks
5da
ysY
esFI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rC
Sfo
rpl
acen
tapr
evia
140.
950.
030.
74N
oN
o22
wks
2da
ysY
esM
ater
nal
urin
est
erol
No
N/A
151.
10.
080.
72N
oN
o19
wks
4da
ysY
esM
ater
nal
urin
est
erol
No
N/A
161.
310.
071.
3N
oN
o22
wks
Yes
Mat
erna
lur
ine
ster
ol;
DN
Ate
stin
gof
new
born
bloo
dN
oN
/A
170.
590.
161
No
No
17w
ks1
day
Yes
Mat
erna
lur
ine
ster
olN
oSV
D40
wks
2d18
1.01
0.07
0.56
No
Yes
20w
ksY
esD
NA
test
ing
ofam
nioc
ytes
No
38w
ks5d
spon
t.la
bur,
AR
OM
,C
Sfo
rfa
ilure
topr
ogre
ssan
dfe
tal
dist
ress
192.
090.
111.
45N
oN
o16
wks
2da
ysY
esD
NA
test
ing
ofne
wbo
rnbl
ood
No
N/A
201.
490.
161.
02N
oY
es17
wks
3da
ysY
esD
NA
test
ing
ofne
wbo
rnbl
ood
No
CS
for
non
reas
suri
ngfe
tal
mon
itori
ngat
42w
ks (con
tinu
edov
erle
af)
Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 966–974.DOI: 10.1002/pd
970 S. LANGLOIS ET AL.
Tabl
e1
—(C
onti
nued
)
Cas
eID
AFP
MoM
uE3
MoM
hCG
MoM
Scre
enpo
siti
vefo
rT
21
Scre
enpo
siti
vefo
rT
18G
AFa
mhx
Dia
gnos
ism
ade
byPa
tient
test
edD
eliv
ery
210.
930.
072.
02Y
esN
o21
wks
2da
ysY
esD
NA
test
ing
ofam
nioc
ytes
;FI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rN
/A
221.
210.
240.
87N
oN
o18
wks
5da
ysY
esFI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rN
/A
231.
020.
120.
69N
oN
o22
wks
5da
ysPo
ssib
le:
mat
erna
lun
cle
dxof
psor
iasi
s
DN
Ate
stin
gof
Am
nioc
ytes
;FI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rB
orn
38w
ksC
/Sfo
rab
rupt
io
240.
80.
070.
85N
oN
o19
wks
Yes
-FI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rN
/A
250.
850.
090.
53N
oN
o23
wks
1da
ysY
esFI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rR
epea
tC
S
260.
830.
021.
97Y
esN
o19
wks
6da
ysPo
ssib
le:
brot
her
dry
skin
DN
Ate
stin
gof
amni
ocyt
es;
FISH
anal
ysis
ofm
ater
nal
bloo
d
Yes
—ca
rrie
rR
epea
tC
S
271.
170.
171.
6N
oN
o19
wks
3da
ysY
esFI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rR
epea
tC
S
280.
80.
140.
37N
oN
o18
wks
Yes
FISH
anal
ysis
ofm
ater
nal
bloo
dY
es—
carr
ier
CS
for
feta
ldi
stre
ssat
39w
eeks
291.
870.
141.
74N
oN
o18
wks
3da
ysY
esFI
SHan
alys
isof
mat
erna
lbl
ood
Yes
—ca
rrie
rSV
Dat
40w
eeks
,SR
OM
>36
h,ox
ytoc
inst
imul
atio
n30
1.15
0.24
0.68
No
No
18w
ks1
day
Yes
FISH
anal
ysis
ofm
ater
nal
bloo
dY
es—
carr
ier
N/A
GA
,ge
stat
iona
lag
e;fa
mhx
,fa
mily
hist
ory;
wks
,w
eeks
;SR
OM
,sp
onta
neou
sru
ptur
eof
mem
bran
es;
CS,
cesa
rean
sect
ion;
SVD
,sp
onta
neou
sva
gina
lde
liver
y;TA
,th
erap
eutic
abor
tion;
N/A
,no
tav
aila
ble;
ND
,no
tde
tect
able
.
Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 966–974.DOI: 10.1002/pd
STEROID SULFATASE DEFICIENCY 971
family history, the diagnosis was established by differentapproaches depending on how definite the family historywas and whether an amniocentesis was being donefor a screen positive for trisomy 18 or trisomy 21.Furthermore, in the first 2 years of the study, maternalurine sterol analysis was available. For the last threeyears, fluorescent in situ hybridization (FISH) analysisof the STS locus on maternal blood was used as analternative method to confirm the carrier status of themother. In two cases the diagnosis was made based on afamily history with DNA confirmation at birth. Maternalurine sterol analysis diagnosed four cases; FISH testingfor the STS locus in maternal blood diagnosed eightcases. DNA testing of cultured amniocytes was done inone case which also screened positive for trisomy 18. Inthree cases, both FISH testing in maternal blood andDNA testing of cultured amniocytes were done: twoof those cases screened positive for trisomy 21, whilethe third case was done as the family history was of amaternal uncle with psoriasis requiring additional testingto confirm the diagnosis of XLI.
In 12 cases the family history was negative and anamniocentesis was offered for molecular analysis. Ninepatients chose to have amniocentesis. In 8 of the 9 cases,a deletion was detected in the fetus. In seven of the eightcases, the deletion predicted a diagnosis of isolated XLI.In case ID 12, as discussed above, the fetus was found tohave a contiguous gene deletion syndrome. In one case,the fetus was negative for the deletion and the diagnosiswas made by maternal urine sterol analysis. In the threepatients who declined amniocentesis the diagnosis wasmade by maternal urine sterol in one case and by FISHtesting of maternal blood in the other two. All threepatients declined amniocentesis despite being informedof the risk of contiguous gene deletion syndrome. In allthree cases testing of the infant was done postnatallyand confirmed the diagnosis of STS deficiency. In cases
of sporadic STS deficiency diagnosed prenatally, thefrequency of contiguous gene deletion syndrome in thisstudy was 1 out of 12 (8.3%, 95% confidence interval(CI) of 0.2–38.5%).
Delivery information was available for 19 cases.Three pregnancies were terminated, one due to the find-ing of a contiguous gene deletion syndrome and twodue to the perception of the parents that the skin dis-order would have significant impact on the quality oflife of their child. Three patients had repeat cesareansections (CS), one patient had a CS for breech pre-sentation and one for placenta previa. Of the remain-ing 11 pregnancies, 4 had spontaneous vaginal deliv-eries at term. One patient went into spontaneous laborat 40 weeks but required oxytocin stimulation due toslow progression and 36 h of ruptured membranes. Onepatient had a spontaneous vaginal delivery at 42 weeksbut labor was prolonged. CSs were done in the remain-ing four patients, three at term due to fetal distress inlabor and/or failure to progress. The fourth patient wasdelivered by CS at 42 weeks due to nonreassuring fetalmonitoring.
Results of the molecular analysis of all deleted cases,analyzed either on amniocytes, cord blood, or bloodfrom an affected relative, are summarized in Table 2.Clinically all patients have isolated STS deficiencyexcept case ID 12. In 29 of the 30 patients, the cen-tromeric breakpoint was located between DXS237 andDXS7470. In only one patient was DXS237 present.The telomeric breakpoint was between DXS6837 andDXS1130 in 26 patients and between DXS1130 and STSin 3 patients. The distal breakpoint in case ID 12 wasnot defined but is telomeric to RH1702 (Figure 1).
Testing of the pregnant patients by FISH analysis wasdone in five sporadic cases. In all cases the patient wasfound to be a carrier despite the absence of a familyhistory.
Table 2—Results of molecular testing performed
Case ID RH1702 SY748 DXS31 DXS1060 DXS996 DXS6837 DXS1130 STS DXS237 DXS7470
5 + + + + + + − − + +11 + + + + + + + − − +23 + + + + + + + − − +26 + + + + + + + − − +1 + + + + + + − − − +2 + + + + + + − − − +3 + + + + + + − − − +4 + + + + + + − − − +7 + + + + + + − − − +8 + + + + + + − − − +9 + + + + + + − − − +10 + + + + + + − − − +16 + + + + + + − − − +18 + + + + + + − − − +19 + + + + + + − − − +20 + + + + + + − − − +21 + + + + + + − − − +24 + + + + + + − − − +30 + + + + + + − − − +12 − − − − − − − − − ++, presence of PCR amplification product; −, absence of PCR amplification product (locus deleted).
Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 966–974.DOI: 10.1002/pd
972 S. LANGLOIS ET AL.
DISCUSSION
Although the incidence of STS deficiency (XLI) is saidto be between one in 2000 and one in 6000 males(Ballabio and Shapiro, 2001; Ingordo et al., 2003), ourstudy indicates that in our population, STS deficiency isa common condition seen in 1 in 1513 male births as aminimal estimate. It is possible that some STS deficiencycases could have gone undetected in our screening giventhat a low uE3 level in combination with a normal orhigh hCG level, or a normal or high AFP level may havea risk of SLOS below the cut-off chosen. The higherincidence of STS deficiency in our population comparedto postnatal reports, most likely reflects the mode ofascertainment, with prenatal measurement of maternalserum uE3 allowing the diagnosis of most if not allSTS deficiency cases in the screened population. This issupported by very similar frequencies (1 in 1300 males;1 in 1500 males) being noted in two other prenatal series(Bartels et al., 1994; David et al., 1995). More recentlySchoen et al. reported on the outcome of prenatallydetected cases of low uE3 defined as less or equal to 0.15MoM and found a minimum incidence of XLI of 1 : 4289(Schoen et al., 2003). However, limited information isprovided on prenatal investigations and the postnatalfollow-up in males said to be normal at birth waslimited. Both factors would likely underestimate thenumber of STS deficiency cases. Based on all studiesreported and the various ethnic backgrounds of thepopulations tested, one can conclude that STS deficiencyis common in various ethnic populations and that givenits clinical variability there is under ascertainment inpostnatal populations. With a high incidence and theability to identify most, if not all cases, prenatally, thecondition will be detected in approximately 1 in 3000pregnancies undergoing second trimester maternal serumscreening for Down syndrome which incorporates themeasurement of uE3.
Although a recent publication (Kent et al., 2008) sug-gests an increased risk of ADHD in boys with iso-lated STS deficiency, the risk of developmental dis-ability (defined as IQ less than 70) or autism is notincreased unless the STS deficiency is part of a con-tiguous gene deletion syndrome. Although this latterassociation is well established in the literature, our studyis the first prenatal series to estimate the risk of contigu-ous gene deletion syndrome to be 8.3% in the context ofa prenatally diagnosed sporadic case of STS deficiency(n = 12). Given this risk, making a diagnosis of STSdeficiency is important and when a diagnosis is made,excluding a contiguous gene deletion syndrome is war-ranted. In the study period, amongst all cases referred fora positive screen for SLOS, excluding cases with cytoge-netic or ultrasound abnormalities, 37 patients had a uE3level less than 0.25 MoM and a male fetus. Of those, 30had STS deficiency (81%). For cases with a uE3 levelless than 0.25 MoM and normal fetal ultrasound indicat-ing male gender, obtaining a detailed family history iscrucial as establishing the diagnosis of XLI in a familymember who is otherwise developmentally normal withno evidence of Kallmann syndrome or chondrodyspla-sia punctata provides reassurance that the fetus is not at
increased risk of developmental disability or other syn-dromes. The phenotype of isolated STS deficiency in theaffected family member does predict that the affectedfetus would also have isolated STS deficiency and not acontiguous gene deletion syndrome given that the phe-notype is determined by the size of the deletion whichwould be expected to be the same in all family members.In our population, 60% of cases had a positive fam-ily history. Similar results were found in the other twoprenatal series with 60% and 66% of patients having apositive family history respectively (Bartels et al., 1994;David et al. 1995). In cases of uE3 less than 0.25 MoMwhere there is a family history, confirming the diagno-sis of STS deficiency (XLI) in the family member byeither biochemical, molecular or FISH analysis and/ordoing FISH analysis in the pregnant patient allows oneto be confident that the cause of the low uE3 is indeedfetal STS deficiency. In this instance, the patient can bereassured without invasive prenatal diagnosis. In casesof uE3 less than 0.25 MoM and a normal ultrasoundindicating male gender where there is no family history,establishing a diagnosis of STS deficiency is importantgiven its high likelihood and the associated risk of con-tiguous gene deletion syndrome. As the latter confersa risk of developmental disability, these patients shouldbe offered additional testing to establish a diagnosis ofSTS deficiency in the fetus and define the size of thedeletion in confirmed cases. During the course of ourstudy, all pregnant patients with negative family his-tory were offered amniocentesis for molecular testing.When a diagnosis of STS deficiency was confirmed bymolecular analysis, typing of multiple loci in the Xp22.3genomic region between ARSE and KAL1 allowed thesize of the deletion to be established in all patients, anda diagnosis of either isolated STS deficiency or con-tiguous gene deletion syndrome to be made. As thistesting was done on cultured amniocytes, these pregnan-cies were subjected to a small risk of procedure relatedloss. However, given that in all instances when the preg-nant mother of a sporadic case was tested she was foundto be a carrier (five out of the five sporadic cases of STSdeficiency, including the one case of contiguous genedeletion syndrome), it may be possible to arrive at adiagnosis STS deficiency in cases of maternal low uE3without a family history and determine the extent of thedeletion by FISH or molecular analysis of the pregnantpatient, avoiding the need for amniocentesis in a numberof cases. This approach is supported by a review of casesand series of XLI published in the literature to ascertainall sporadic cases where carrier testing was done in themother of the affected boy. A total of 21 mothers of spo-radic cases with proven STS deletion had been tested andin 19 cases the mother was found to be a carrier of thedeletion (Ahmed et al.,1998; Valdes-Flores et al., 2001;Toral-Lopez et al., 2008; Hosomi et al., 2008). Further-more, Toral-Lopez et al. reported on molecular analysisof families to identify the parental origin of the affectedX-chromosome in seven unrelated sporadic cases of XLI(Toral-Lopez et al., 2008). In all five informative fam-ilies, segregation analysis showed paternal transmissionof the affected X-chromosome to the XLI carrier daugh-ter. Taken together, these findings indicate that the STS
Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 966–974.DOI: 10.1002/pd
STEROID SULFATASE DEFICIENCY 973
deletion occurs more commonly in male meiosis andthat mothers of sporadic cases have a high likelihood ofbeing a carrier. FISH analysis could be used to establishthe diagnosis of STS deficiency in the pregnant patientof sporadic suspected cases based on low uE3. If thepatient is found to be a carrier, the size of the deletionwould need to be established either by additional molec-ular or cytogenetic analysis in the patient herself or ifsuch testing is not available, an amniocentesis should beoffered for DNA analysis of amniocytes.
The presence of low-copy repeat regions on eitherside of the STS gene has been shown to be respon-sible for the recurrent microdeletion (Yen et al., 1990)seen in STS deficiency, with common breakpoints beingseen in a significant proportion of patients (Saeki et al.,1998; Aviram-Goldring et al., 2000; Vaca et al., 2001;Kent et al., 2008). The deletion mapping in our patientswas consistent with results of previous studies. As inprevious studies (Aviram-Goldring et al., 2000; Vacaet al., 2001; Cuevas-Covarrubias and Gonzalez-Huerta,2008; Kent et al., 2008), we confirmed that the pres-ence of marker DXS996 in patients with STS defi-ciency is predictive of normal development. In contrast,in the literature, a number, though not all, of patientswho are deleted for DXS996 have been reported topresent with developmental delay and some meet thediagnostic criteria for autism spectrum disorder (Mac-arov et al., 2007; Kent et al., 2008). This providessupport for including DXS996, or other markers thatmap at the NLGN4 locus, in the panel of markers tobe typed in any prenatal case found to have an STSdeletion.
Pregnancies affected with STS deficiency have dimin-ished estriol biosynthesis which can be associated withdelayed onset, or prolonged labor often leading to CS.One study of perinatal complications in pregnancies withunexplained low maternal serum uE3 and male fetusespresumed to have STS deficiency found that primary C/Soccurred about twice as often as in controls (Bradleyet al., 1997). Although our study did not include a con-trol group, we did observe that in a significant proportionof pregnancies (55%) an intervention had to take placedue to either prolonged labor with failure to progress,fetal distress or post-term dates. The association betweenSTS deficiency and perinatal complications should bekept in mind when managing pregnancies diagnosedwith STS deficiency.
In summary, our study provides clinical, cytogenetic,and molecular data on a series of prenatally diagnosedcases of STS deficiency. Although this is a commoncondition, in cases with no family history, the risk ofcontiguous gene deletion syndrome is significant andwarrants additional molecular genetic investigations ofthe mother and/or fetus. Although screening for SLOSis not done in all jurisdictions providing screening forDown syndrome, pregnancies with STS deficiency canbe identified by the presence of a low maternal serumuE3 level less than 0.25 MoM. These patients should becounselled and offered appropriate testing depending ontheir family history.
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