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Prenatal Diagnosis of Sex Differentiation Disorders: The Role of Fetal Ultrasound

Article  in  Journal of Clinical Endocrinology & Metabolism · November 2002

DOI: 10.1210/jc.2001-011034 · Source: PubMed

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Prenatal Diagnosis of Sex Differentiation Disorders:
The Role of Fetal Ultrasound
ORIT PINHAS-HAMIEL, YARON ZALEL, ERIC SMITH, RAM MAZKERETH, AYALA AVIRAM,
SHLOMO LIPITZ, AND REUVEN ACHIRON
Pediatric Endocrinology and Neonatology Unit (O.P.-H., R.M.) and Prenatal Ultrasound Unit (Y.Z., A.A., S.L., R.A.), Sheba
Medical Center, Ramat-Gan 52621, Israel; and Division of Endocrinology and Metabolism, University of Cincinnati College
of Medicine (E.S.), Cincinnati, Ohio 45267
We describe our experience with prenatal diagnosis of sex dif-
ferentiation disorders, with focus on the role of ultrasound scans
for coherent assessment of prenatal diagnosis. Over a 5-yr pe-
riod all cases suspected of sexual ambiguity based on abnormal
ultrasonographic scans (US) or US/genotype US discrepancy
were evaluated prenatally by three modalities: 1) repeated fetal
US; 2) genetic studies, primarily karyotype and fluorescence in
situ hybridization analysis of sex-determining region on the Y
gene (SRY); and 3) hormonal assays of amniotic fluid.
Of approximately 10,000 gestations, 16 fetuses underwent
prenatal evaluation. Twelve were referred because of an ab-
normal US and 4 because of genotype-phenotype discrepancy.
Five fetuses were diagnosed with female pseudohermaphro-
ditism (21-hydroxylase deficiency in 3 and urorectal septum
malformation sequence in 2). Four fetuses were diagnosed
with male pseudohermaphroditism (1 with steroid sulfatase
deficiency, 1 with presumed camptomelic dysplasia, and 2
undetermined). Five cases had chromosomal abnormalities,
W ITH THE RECENT advances in prenatal diagnosis,
particularly, prenatal ultrasound (US) techniques, a
variety of fetal genitalia abnormalities can be detected as
early as 13–16 wk of pregnancy (1, 2). At the same time, the
widespread use of genetic amniocentesis has resulted in an
increased number of mismatches between the chromosome
analysis, often performed routinely for reasons not primarily
related to gender issues, and the genital anatomy on US
(phenotype-genotype discrepancies) (3). Endocrinologists
may be more often consulted for prenatal workup of ambi-
guity. The current literature, however, focuses largely on
postnatal evaluation, and only limited guidelines on in utero
investigation are available (4). The recent identification of
many of the genes involved in sex differentiation and the
newly developed ability to measure key mediating hor-
mones have made it possible for multidisciplinary teams to
conduct a carefully planned prenatal evaluation and provide
informed parental counseling. We describe our experience
with prenatal diagnosis of sex differentiation disorders in 16
cases.
Abbreviations: CAH, Congenital adrenal hyperplasia; FISH, fluores-
cence in situ hybridization; FUE, fetal ultrasound examination; GE, ge-
netic examination; HE, hormonal examination; 21-OHD, 21-hydroxylase
deficiency; 17-OHP, 17-hydroxyprogesterone; SRY, sex-determining re-
gion on the Y gene; US, ultrasound.
4547
The Journal of Clinical Endocrinology & Metabolism 87(10):4547– 4553
Copyright © 2002 by The Endocrine Society
doi: 10.1210/jc.2002-011034
and 2 had 46,XXⴙSRY sex reversal. In all genetic females the
uterus was observed on US. In 11 cases initial US scan was
performed at 13–15 wk; in 7 of 11, although the initial scan was
normal, a repeated scan later in gestation revealed an
abnormality.
Repeated US scans performed at 13–15 and 22–24 wk ges-
tation are a helpful tool in prenatal diagnosis of sex differen-
tiation disorders. Our data suggest that both size and struc-
ture anomalies of the reproductive structures may evolve
throughout pregnancy, and that they represent a develop-
mental biological process rather than a single nonprogressive
pathological event. US scan after approximately 19 wk en-
ables detection of the uterus and provides pivotal information
in cases of ambiguity. If the uterus appears normal, the most
likely diagnosis is a virilized karyotypic female. Prenatal di-
agnosis allows for early parental counseling and anticipation
of medical management postnatally. (J Clin Endocrinol Metab
87: 4547– 4553, 2002)
Subjects and Methods
In Israel, the national health insurance system provides funding for
at least one ultrasonographic scan, usually at midgestation, for every
pregnant woman. In addition, early transvaginal sonography, initially
performed primarily in high risk cases, is being performed in an in-
creasing number of low risk patients on a voluntary basis. An additional
US examination is usually performed during the third trimester for
evaluation of fetal growth and well-being.
The prenatal diagnostic US unit of Sheba Medical Center in Israel per-
forms routine fetal evaluations and serves as a tertiary center for antenatal
counseling. From 1996 to 2000, about 10,000 pregnant women underwent
routine fetal evaluation at the unit. In this study we prospectively followed
those pregnancies that met one of the following criteria: 1) ambiguous
findings on early US performed at 12–15 wk, 2) ambiguous findings on
midgestation US after a normal early US, 3) ambiguous findings on routine
midgestation US, or 4) discrepant US/genotype.
Because blood and amniotic fluid analyses are routinely required to
determine the nature of these ambiguities independent of any prospec-
tive study, no specific informed consent was considered necessary by
our institutional ethics committee. All pregnant women enrolled in the
study had already signed an informed consent for both the US scans and
the amniocentesis. The Sheba Medical Center Termination of Pregnancy
Committee, which is subject to the Israeli civil law, approved all abor-
tions. A single observer (R.A.) scanned all the cases, and a multidisci-
plinary team consisting of an obstetrician, geneticist, pediatric endocri-
nologist, neonatologist, and pediatric surgeon assessed the results.
Prenatal evaluation of the fetuses suspected of having genital malde-
velopment or sex discordance consisted of three modalities:
1. Fetal US examination (FUE)
A detailed evaluation of the fetal reproductive structures, including
the pelvic organs, was performed, in addition to a systemic examination
4548 J Clin Endocrinol Metab, October 2002, 87(10):4547– 4553
to rule out associated somatic anomalies. In 46,XX fetuses, the FUE
included a demonstration of the labia and clitoris and, after 19 wk
gestation, the uterus (5). The fetal uterus can be demonstrated on lower
pelvic transverse scan as an echogenic mass between two anechoic
structures, the bladder anteriorly and the rectum posteriorly, and its
diameters can be correlated with gestational age (Fig. 1). In 46,XY fe-
tuses, penile length and scrotal dimensions were correlated with ges-
tational age (6). After 25 wk gestation an attempt was made to document
testicular descent (7).
The initial US determination of fetal genitalia was based on the
transvaginal examination performed between 13 and 15 wk gestation.
As early as 10 –11 wk gestation, the phallic structure can be visualized
on midline sagittal view (6). The structurally normal penis has an up-
ward projection, and the clitoris has a downward orientation (sagittal
sign; Fig. 2) (8). As pregnancy progresses, penile size becomes measur-
able in terms of normal range, and the scrotum can be identified as a
distinct structure (6). By 15 wk gestation the female labia may be visu-
alized on angled coronal axial view as multiple parallel linear echo
patterns. These later become more prominent, and the labia can be
readily distinguished from the scrotum by the midline cleft separating
the labial folds (9). Thus, determination of gender requires unequivocal
visualization of the labia and clitoris or the penis and scrotum beyond
16 wk.
2. Genetic examination (GE)
GE was performed by chorionic villous biopsy, amniocentesis, or
umbilical cord sampling. No side-effects related to the invasive proce-
dures were detected. Genetic studies included chromosomal analysis
and fluorescence in situ hybridization (FISH) for the SRY gene. FISH
was performed according to Vysis (Naperville, IL) protocols for direct-
labeled probes: LSI SRY (Yp11.3) Spectrum Orange/CEP X Spectrum
Green, CEP Y (␣ Satellite) Spectrum Orange, and CEP Y Sat III: Spectrum
Orange (10).
3. Hormonal examination (HE)
At amniocentesis, 20 ml amniotic fluid were obtained for possible
hormonal assays. Hormonal assays consisted of the critical sample mea-
surements of steroid hormone metabolites in amniotic fluid (17-
hydroxyprogesterone, testosterone, androstenedione, 11-deoxycortisol,
and 7-dehydrocholesterol/cholesterol) and in maternal serum (estriol);
17-hydroxyprogesterone, testosterone, and androstenedione were mea-
sured by RIA (CIS Biointernational, Schering AG, Berlin, Germany), and
7-dehydrocholesterol and cholesterol were measured by GC-MS at the
FIG. 1. The fetal uterus (*) can be demonstrated
on lower pelvic transverse scan as an echogenic
mass between the bladder (B) anteriorly and the
rectum (R) posteriorly.
Pinhas-Hamiel et al. • Prenatal Diagnosis of Ambiguous Genitalia
Biochemistry and Endocrinology and Metabolism Unit, University Col-
lege London (London, UK). The maternal serum estriol level was mea-
sured by fluoroimmunoassay (AutoDELFIA Perkin/Elmer, Life Sci-
ences, Wallac, Inc., Turku, Finland).
Results
During the 5-yr study period, 16 cases of ambiguous gen-
italia or genotype-phenotype discrepancy (Table 1) were
evaluated from the pool of approximately 10,000 pregnan-
cies. These cases do not represent the true incidence of sex
disorders, as our center serves as a tertiary referral facility.
Twelve patients were identified by routine US screening, and
4 patients were evaluated because of a discordance between
the karyotype and the observed prenatal phenotype. In 5 of
16 cases, the initial sonographic examination was performed
in the second trimester. In 3 of the remaining 11 cases, both
initial and repeated scans were normal, and in one case initial
US at 13 wk gestation revealed abnormality (enlarge rectum).
In 7 of 11 cases, the initial scan at 13 wk gestation was normal,
and only a repeated scan later in gestation revealed an ab-
normality. The clinical data of these cases are described in
detail below.
Five fetuses (cases 1–5) were identified as having female
pseudohermaphroditism (46,XX genotype, normal Mulle-
rian duct structures, and masculinized external genitalia).
Interestingly, in all five cases in which the first step of in-
vestigation (FUE) demonstrated a uterine structure, the next
step (GE) yielded a 46,XX karyotype. In three cases (no. 1–3)
the diagnosis was 21-hydroxylase deficiency (21-OHD; Table
1). The US examination at 22–24 wk revealed an enlarged
clitoris with fused prominent labia (Fig. 3). In all three cases,
a normal uterus with measurements within the normal ref-
erence range was demonstrated, suggesting female viriliza-
tion. In case 1, in utero evaluation revealed an amniotic fluid
17-hydroxyprogesterone (17-OHP) level of 51 ng/ml (nor-
mal range, 1.8 –26.9), suggesting 21-OHD; in the other two
cases the parents declined in utero investigation. Postnatally,
Pinhas-Hamiel et al. • Prenatal Diagnosis of Ambiguous Genitalia
FIG. 2. A, Typical downward inclination of the
female clitoris in sagittal section (perpendicular
arrowhead). B, Typical male genitalia with the
phallus pointing upward (horizontal arrow-
head).
17-OHP levels were elevated in all three cases. In no case was
there a family history of the disorder.
In two cases (no. 4 and 5) the diagnosis was urorectal
septum malformation sequence (Table 1). In case 4 the first
screening US showed normal female genitalia with dilated
rectum, a potential early sign of a cloacal anomaly. In case 5
the initial scan showed a phallus-like structure of the external
genitalia (Fig. 4). In both cases the diagnosis was established
only during midgestation by the demonstration of an en-
larged pseudophallus structure and ambiguous external
genitalia. The clinical details of both of these rare cases have
been described previously (11).
In four fetuses (cases 6 –9) the diagnosis was male
pseudohermaphroditism (46,XY genotype with incom-
pletely masculinized external genitalia and no detectable
Mullerian duct structures). In cases 6 and 7 the initial US scan
at 13 wk gestation revealed an upward position of the ex-
ternal genitalia, suggesting a male phenotype, but routine
subsequent scan showed severe micropenis. In both cases the
pregnancy was terminated at wk 23; postnatal examination
confirmed the prenatal findings (Fig. 5). The structure of the
penis was normal, but the size was extremely small, consis-
tent with the diagnosis of micropenis; the internal reproduc-
tive structures were not examined because parents declined
investigation.
In case 8 the initial scan at 15 wk gestation showed a
normal penis, but routine triple hormonal test performed at
midgestation yielded an undetectable maternal serum estriol
level (normal, ⬎0.2 ng/ml), and subsequent routine US ex-
amination demonstrated micropenis. Further HE evaluation
revealed that the ratio of 7-dehydrocholesterol to cholesterol
was 9.19 ⫻ 10⫺4 (negative control, 8.69 ⫻ 10⫺4), excluding
7-dehydrocholesterol reductase deficiency (Smith-Lemli-
Opitz syndrome) and suggesting steroid sulfatase deficiency.
The diagnosis was confirmed postnatally by the presence of
dark scaly skin and mild corneal opacities.
In case 9, in addition to micropenis, short bones with arrest
J Clin Endocrinol Metab, October 2002, 87(10):4547– 4553 4549
of bone growth between 23 and 28 wk gestation strongly
suggested the lethal disorder camptomelic dysplasia. The
pregnancy was terminated without any further diagnostic
testing.
In one case (no. 10) autosomal chromosome abnormalities
were found. Initial US scan at 22 wk gestation revealed mi-
cropenis with other anomalies, including dextrocardia. On
GE, trisomy 13 was demonstrated. The pregnancy was
terminated.
In four cases (no. 11–14) sex chromosome abnormalities
were identified. In two of them (no. 11 and 12) only the
repeated US examination at midgestation demonstrated am-
biguity. In case 11 transvaginal scan at 14 wk showed normal
female external genitalia according to the sagittal sign. How-
ever, as gestation proceeded the clitoris enlarged, the major
labia fused, and the uterus was not visualized. At 27 wk
gestation amniotic fluid culture showed a 46,XX/XY geno-
type. In case 12 the US scan at 14 wk was interpreted as
normal male. At 22 wk a repeated US scan revealed bifid
scrotum and hypospadias. GE demonstrated 46,XX/45,XO,
compatible with the diagnosis of gonadal dysgenesis; it also
proved to be positive for SRY.
The other two cases (no. 13 and 14) were referred because
of genotype-phenotype discordance. In case 13 US scan
showed a normal male, but routine amniocentesis revealed
46,XX/45,XO. Therefore, FISH analysis was performed, and
it was positive for SRY. In case 14, despite the normal ap-
pearance of male genitalia on US, amniocentesis revealed a
46,XY/48,XXYY karyotype.
In two cases (no. 15 and 16) there were normal male gen-
italia and a normal female karyotype, consistent with the
diagnosis of sex reversal. In both, FISH examination con-
firmed the presence of SRY.
Of 10,000 US scans, about 60% were performed in the first
trimester (6000 scans). In 8 cases, gender could not be de-
termined in the first trimester (0.13%). In these cases an
additional scan was performed in the second trimester. In 5
4550 J Clin Endocrinol Metab, October 2002, 87(10):4547– 4553 Pinhas-Hamiel et al. • Prenatal Diagnosis of Ambiguous Genitalia

TABLE 1. Prenatal diagnosis of ambiguous genitalia: US and clinical data

US findings
Case GA Hormonal
Classification Uterus Karyotype Fetal diagnosis Neonatal diagnosis
no. (wk) tests
present
Female 1 13 Normal female Yes 46XX Elevated CAH Ambiguous genitalia,
pseudoher- 17-OHP Female pseudoher- 21-hydroxylase
maphrodism 24 Caudal phallus, maphroditism deficiency
clitoromegaly,
fused labia
2 22 Normal female, Yes 46XX Not done CAH Ambiguous genitalia,
fused labia Female pseudoher- 21-hydroxylase
maphroditism deficiency
3 24 Normal female, Yes 46XX Not done CAH Ambiguous genitalia
clitoromegaly Female pseudoher- 21-hydroxylase
maphroditism deficiency
4 13 Normal female, Yes 46XX Normal URSMS URSMS anal atresia,
enlarged 17-OHP vesico-rectal
rectum fistula
27 Pseudo phallus,
enterolithiasis
5 24 Pseudo phallus Yes 46XX Normal URSMS URSMS-EX
17-OHP
Male pseudoher- 6 13 Normal male No 46XY Not done Male pseudoher- TOP
maphrodism 22 Micropenis maphroditism
(3 mm ⬍ 2 SD)
7 13 Normal male No 46XY Not done Severe micropenis TOP
23 Severe micro-
penia
8 15 Normal male No 46XY Low Probable STS STS
22 Micropenis maternal
(4 mm ⬍ 2 SD) E3
9 14 Normal male No 46XY Not done Probable camptomelic TOP
23 Micropenis dysplasia
28 Short bones
Autosomal 10 22 Micropenis, No 47XY⫹13 Not done Trisomy 13 TOP
chromosome dextrocardia
abnormalities 11 13 Normal female No 46XX/XY Not done Ambiguous genitalia
24 Fused labia,
clitoromegaly
12 14 Normal male No 46XX/,45XO Not done Mixed gonadal
⫹SRY dysgensis,
22 Bifid scrotum,
ambiguous geni-
hypospadias
talia
13 14 Normal male No 46XX/,45XO Not done 46XX male TOP
23 Normal male ⫹SRY
14 22 Normal male No 46XX/48XX Not done Normal genitalia
YY
Sex reversal 15 14 Normal male No 46XX,⫹SRY Not done 46XX male Normal genitalia
22 Normal male, cleft
lip
16 14 Normal male No 46XX,⫹SRY Not done 46XX male Normal genitalia
22 Normal male
GA, Gestational age; URSMS, urorectal septum malformation sequence; EX, exitus; TOP, termination of pregnancy; STS, steroid sulfatase
deficiency.

cases gender was determined clearly, whereas in 3 the di- Discussion

agnosis remained questionable. GE revealed 46,XY with pos-
itive SRY in all of these cases. Postnatally, 1 was found to
have chordee, and 2 had normal male genitalia with penile
length in the third percentile. When 2 sequential US scans
were determined to be normal, there was no case of postnatal
ambiguity (no false positive).
In our cohort, in 7 of 11 cases the first US scan performed at
13–15 wk of pregnancy was determined to be normal; however,
a repeated scan at 22 wk was abnormal. Seven of 6000 is an
estimated false negative rate of 0.12% in the first trimester.
Thanks to increased sensitivity of current US technology
combined with greater operator expertise, gender can be
confidently established from the early stages of gestation on
the basis of well defined anatomical images (12). In our study
group 12 cases were evaluated because of ambiguous gen-
italia demonstrated on US, and 4 were evaluated because of
a discordance between the karyotype and the observed pre-
natal phenotype. In 11 cases US scan was performed at 13–15
wk; in 7 of 11 the initial scan was normal, and only a repeated
Pinhas-Hamiel et al. • Prenatal Diagnosis of Ambiguous Genitalia J Clin Endocrinol Metab, October 2002, 87(10):4547– 4553 4551

FIG. 3. Female pseudohermaphroditism with normal uterus. A, Sonographic view of the external genitalia; note the enlarged clitoris (C) with
fused prominent labia (L). B, The corresponding postnatal disposition verifying enlarged clitoris and fused labia.

FIG. 4. Female pseudohermaphroditism, urorectal septum malformation sequence. A, Ultrasonic view of the fetal external genitalia. B, Note
the similarity to the postnatal view (P). P, Phallus-like structure; arrow, urine orifice. [Reproduced with permission from R. Achiron et al.:
Ultrasound Obstet Gynecol 16:571–574, 2000 (11). ©International Society of Ultrasound in Obstetrics and Gynecology.]

scan later in gestation revealed an abnormality. Therefore, a An abnormal scan after an earlier normal one may be
single screening US performed at 13–15 wk is not sufficiently explained by limited resolution related to the instrumenta-
sensitive or specific. tion, fetal size and position, or a progression in maldevel-
4552 J Clin Endocrinol Metab, October 2002, 87(10):4547– 4553
FIG. 5. Male pseudohermaphroditism. A, An axial sonographic view through fetal external genitalia demonstrating normal size scrotum
(S) with almost invisible penis. B, Postabortion disposition, confirming severe micropenis.
opment. Our understanding of the in utero evolution of an
unexpected fetal phenotype is still fragmentary. To date, in
utero developmental studies have been largely limited to
spontaneous abortions and post facto evaluations of patho-
logical cases. It is generally accepted that there is a critical
period of 8 –12 wk gestation for normal sexual development.
However, insufficient attention has been directed to the pos-
sible secondary effects of aberrant processes. The secondary
growth of the penis is poorly understood, but factors other
than androgens are involved. For example, GH deficiency is
well known to cause micropenis in an otherwise normally
formed structure (13). Also, case 9, suspicious for a Sox9
defect, could represent a defect at the phase of penile growth
unrelated to androgens. It is possible that micropenis may
involve a degree of atrophy after the initial normal devel-
opment of the phallus. Indeed, in our series all 4 cases of male
pseudohermaphroditism had normal initial US scan, and
only a repeated scan showed abnormality. Our findings of
normal scan at 13–15 wk, followed subsequently by an ab-
normal one, suggest that anomalies in both size and structure
of the reproductive organs may evolve after the critical dif-
ferentiation period of 8 –12 wk gestation. Indeed, abnormal
growth of fetal organs represents a developmental biological
process rather than a single nonprogressive pathological
event (14).
In a newborn with ambiguous genitalia the direction of
diagnostic testing is determined by the presence or absence
of palpable gonads. By contrast, prenatally the testicular
status is not a reliable measure of pathology, as up to 2% of
normal males present with undescended testes at birth.
However, FUE after approximately 19 wk provides an im-
mediate image of the internal reproductive structures. In
particular, detection of the uterus provides pivotal information.
If the uterus appears normal in a prenatal scan of ambig-
uous genitalia, the most likely diagnosis is a virilized karyo-
typic female. If GE reveals 46,XX with negative SRY, the
diagnosis can be reasonably narrowed to virilized genetic
female. Once a probable diagnosis of female pseudoher-
maphroditism is established, maternal virilization secondary
to iatrogenic androgens, tumor, or fetal aromatase deficiency
Pinhas-Hamiel et al. • Prenatal Diagnosis of Ambiguous Genitalia
(15) should be excluded. In none of our cases could maternal
virilization be identified.
In a genetic female with normal uterus and ambiguity, HE
of amniotic fluid levels of 17-OHP, androstenedione, and
testosterone to pinpoint the specific inborn error of steroi-
dogenesis is optional. The most common cause of female
pseudohermaphroditism is congenital adrenal hyperplasia
(CAH), and in most ethnic groups 95% of all cases of CAH
are due to a deficiency of the p450 21-hydroxylase enzyme;
11␤-hydroxylase and 3␤-hydroxysteroid dehydrogenase de-
ficiencies are rare (16). Although the prenatal detection of
both 21-hydroxylase and 11␤-hydroxylase deficiencies has
been reported (17, 18), the diagnosis of CAH can be estab-
lished postpartum with anticipation of appropriate medical
management. In our study there were three cases of ambig-
uous genitalia with normal uterus on US in which the di-
agnosis was female pseudohermaphroditism secondary to
21-OHD. All were index cases, so the diagnosis was estab-
lished late in gestation, beyond the window of time during
which therapy is effective in preventing sexual ambiguity.
Only the family in case 1 opted for HE, but all three cases
were managed satisfactorily after birth. The prenatal diag-
nosis alerted the medical team to avoid electrolyte deterio-
ration after delivery and allowed for the provision of antic-
ipatory guidance to the parents. With respect to the urorectal
septum malformation sequence cases, the FUE step enabled
early identification and early interaction between the mul-
tidisciplinary experts, particularly the urologist and pediat-
ric surgeon, promoting better parental counseling.
The combination of 46,XY, genital ambiguity, and pres-
ence of a uterus on US may suggest aberrant SRY expression
(19) or Mullerian inhibitory substance (MIS) and MIS recep-
tor abnormalities (20). Although our series did not include
such cases, these disorders should be considered in the dif-
ferential diagnosis.
Fetal genital ambiguity with the absence of a uterus on
FUE suggests an undervirilized male. If the karyotype is
46,XY and there are other somatic abnormalities and/or au-
tosomal chromosome abnormalities, the differential diagno-
sis depends on defining these associated defects. As dem-
Pinhas-Hamiel et al. • Prenatal Diagnosis of Ambiguous Genitalia
onstrated in case 9, US examination was able to detect, in
addition to the genital ambiguity, severely shortened bones
characteristic of SOX9/camptomelic dysplasia gene defects.
This condition usually leads to death in the neonatal period
due to respiratory distress. The presumptive prenatal diag-
nosis enabled informed genetic counseling with a disposition
satisfactory to the family. This was also true in case 10 in-
volving autosomal trisomy 13, a well known lethal genetic
syndrome associated with ambiguous genitalia.
Similar to that during the newborn period, diagnosis of
cases of undermasculinization with XY genotype is a par-
ticular challenge, further complicated prenatally by the nar-
row window of time available. In two cases of our series no
definite diagnosis was established. Possible conditions with
this presentation include Star (congenital lipoid adrenal hy-
perplasia) gene defects, 17␤-hydroxysteroid deficiency, and
androgen resistance secondary to androgen receptor defects.
Our series revealed high frequency of sex chromosome
aneuploidy and SRY gene translocations. There were 2 cases
of 46,XX karyotype with positive SRY. The estimated re-
ported incidence of 46,XX males is about 1 in 20,000 (21),
which is lower than that in our study. It is possible that these
cases are missed in the newborn period if there is no ambi-
guity. The widespread use of routine US examination and
amniocentesis may establish a more accurate incidence in the
near future. We had 2 cases of mosaic gonadal dysgenesis with
46,XX/45,XO and positive SRY, demonstrating the critical im-
portance of SRY testing in establishing the diagnosis. Fetuses
with these chromosomal characteristics may manifest a diverse
genital phenotype (22). In our study 1 fetus had normal male
genitalia, and the other had severely ambiguous genitalia. In 2
other cases we found mosaic 46,XX/XY and 48,XXYY/46,XX. In
the fetuses that were carried to term, the early detection was
very helpful for anticipatory guidance regarding future fertility
and increased risk of gonadal tumors (23).
In conclusion, prenatal diagnostic work-up is feasible
when abnormalities of the fetal genitalia are suspected or
genotype-phenotype discrepancies are detected. US exami-
nations performed at 13–14 wk are not good predictors of
subsequent normality. Cases need to be examined longitu-
dinally, as sex differentiation disorders may also evolve dur-
ing the second trimester. After 19 wk the uterus has an
important role in the prenatal evaluation. Early diagnosis
allows for parental counseling and alerting the medical team.
Acknowledgments
We thank Mrs. Gloria Ganzack for her excellent editorial help.
Received June 28, 2002. Accepted July 19, 2002.
View publication stats
J Clin Endocrinol Metab, October 2002, 87(10):4547– 4553 4553
Address all correspondence and requests for reprints to: Orit Pinhas-
Hamiel, M.D., Pediatric Endocrinology, Sheba Medical Center, Ramat-
Gan, 52621, Israel. E-mail: hamiels@netvision.net.il.
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