9985 PROBLEM LIST 13yo girl with Hisutism Amenorrhae Increased testosterone level Streaky gonad Pelvic mass Left salpingo oophorectomy Gonadoblastoma ID: 933733
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Slide1
IN THE NAME OF GOD
GRAND ROUND
99.8.5
Slide2PROBLEM LIST
13y/o girl with:
Hisutism
Amenorrhae
Increased testosterone level
Streaky gonad
Pelvic mass
Left
salpingo
-oophorectomy
Gonadoblastoma
with multifocal overgrowth by
dysgerminoma
Karyotype
: pure 46XY
Slide3AGENDA
Differential diagnoses in my patient
Unusual
manifestation in
Swyer
patient
Diagnosis,
treatment and follow-up
of
gonadal malignancy in
Swyer
patient
Pregnancy
in
Swyer
syndrome
Mobidity
in
Swyer
syndrome
Embryonic cause and genes involved in
Swyer
syndrome
Slide4DDX
Gonadal
dysgenesis
– complete and partial
forms
Gonadal
dysgenesis
associated with
syndromic
phenotype
Late onset CAH
5α-
Reductase
type 2
deficiency
Androgen insensitivity
syndrome complete
androgen insensitivity syndrome (CAIS
)
Mixed gonadal
dysgenesis
Ovotesticular
46,XY
DSD
Mullerian
dysfunctional persistence
syndrome
Virilising
ovarian or adrenal
neoplasm
PCOS
Slide52014 Wolters Kluwer Health
Slide6Disorders of sex development (DSDs
):
are congenital conditions
characterised
by
discordanse
:
chromosomal
gonadal
anatomical
Slide72015 German Gynecological Education and Research Foundation
46,XY gonadal
dysgenesis
:
first described in 1959 by
Swyer
Characterized
by a
female
phenotype
Swyer
syndrome
Which
is a rare cause of DSD with an
incidence of 1:80,000
Normal
to tall
stature
Bilateral
dysgenetic
gonads
Sexual
infantilism with
primary
amenorrhea
Absent
breast
development
And
a
46,XY
( karyotype an
adequate karyotype is, of course, essential for correct
diagnosis)
Slide82015German Gynecological Education and Research Foundation
The internal structures are female with bilateral
fallopian tubes
a
uterus
and a
vagina
Axillary
and pelvic hair was
sparse
in all the
girls
V
agina
was well
canalized
Poor
development of secondary sexual
characters
Hypergonadotropic
hypogonadism
Bilateral ovaries were either not visualized or
streak gonads
Slide92014 Wolters Kluwer Health
Analysis
of
30 metaphase cells
, which will identify at least 10%
mosaicism
with 95%
confidenc
(
FISH
) should be performed to achieve greater sensitivity for detection of an occult
mosaic
Rarely, there may be an overlap between
non mosaic
Swyer
syndrome (46,XY) with the very rare 46,XX/46,XY
mosaicism
who usually retain more gonadal function and are
virilized
Similarly, 45,X/46,XY
mosaicism
span a spectrum with clear features of Turner syndrome or notable
virilization
Slide10Gonadal
dysgenesis
with no family history, so the value of
routine screening
of this phenotype
is uncertain
The
overall pattern
seen in patients with
Swyer
syndrome is that of
low androgens and androgen precursors
Elevated
gonadotrophins
low or undetectable AMH and cytogenetic analysis will reveal a
nonmosaic
46,XY karyotype
Adrenal function is usually normal unless the underlying defect is in SF-1 or related adrenal or gonadal factors
Slide11RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology
Usually
first becomes apparent in
adolescence
with delayed puberty and
amenorrhoea
gonads
have no hormonal or reproductive
potential
The median delay between diagnosis and
gonadectomy
was
1 year
(range 0.12–14 years), and the median age at
gonadectomy
was 18 years (range 9–33 years)
A
high incidence of
gonadoblastoma
and germ cell malignancies has been reported,
gonadectomy
once the diagnosis is
made
Management of
Swyer
syndrome
is
induction of puberty with estrogen to develop secondary sexual characteristics and
long-term combined replacement therapy with estrogen and
progesterone
We
therefore set out to document the long-term outcome of this syndrome in adults with
particular reference
to the estrogen-sensitive endpoints,
bone density and uterine
size
Slide12RCOG 2008 BJOG An International Journal of Obstetrics and GynaecologyJ Turk Ger
Gynecol
Assoc
2015
Early diagnosis of
Swyer
syndrome in childhood is only possible if a karyotype is carried out for other
reasons
Familial
screening
following the diagnosis of a
sibling
with the condition. Familial cases of
Swyer
syndrome have indeed been
described
The
histology report was available in 22 cases
.
Of those, seven women (32%) were diagnosed with
dysgerminoma
and three (14%) with
gonadoblastoma
. The remaining 12 cases (54%) had streak gonads. The median age at diagnosis of
dysgerminoma
was 17 years and ranged between 10 and 31 years.
Slide13Early diagnosis is likely to be of crucial importance for a number of
reasons:
First
, the risk of
gonadal
malignancy
Second
, the early institution of estrogen therapy for
induction of puberty
Third
, to allow for adequate hormone replacement to improve
bone mineral
density
The development of secondary sexual characteristics and pregnancy can be achieved through HRT and assisted reproductive techniques
RCOG
2008 BJOG An International Journal of Obstetrics and
Gynaecology
Slide142019 North American Society for Pediatric and Adolescent Gynecology
A 17-year-old girl presented
with:
Primary amenorrhea
She started having breast and pubic hair development at ages 12 and
13
She
denied any history of pubertal induction or hormone replacement therapy
.
Her
weight was 70.2 kg; height was 170.5 cm, and body mass index was 24.2.
She
had
Tanner stage 5 breast
and
pubic hair development
.
Perineal
inspection revealed normally developed labia
majora
,
minora
, clitoris with normal opening of the urethra, and vagina
Slide152019 North American Society for Pediatric and Adolescent Gynecology
Transabdominal
ultrasound showed normally developed uterus (
54*39*27
mm) and bilateral ovoid
hypoechoic
structures (right:
33*17*22
mm, and left:
28*12*18
) suggestive of
gonads
Normal
levels of
estradiol (27
pg
/mL)
and slightly elevated testosterone level (0.97
ng
/mL) and, high follicle-stimulating hormone (60 IU/mL) and luteinizing hormone (34 IU/mL) levels
.
Chromosome analysis was performed because of the diagnosis of
hypergonadotropic
hypogonadism
(46XY)
Laparoscopic bilateral
gonadectomy
Histopathologic
examination revealed
gonadoblastoma
with focal malignant
dysgerminoma
Slide162019 North American Society for Pediatric and Adolescent Gynecology
In the presence of
breast development
and
menstrual bleeding
in this condition, a history of pubertal induction and exogenous hormone use should be primarily excluded with a detailed
history
However,
spontaneous breast development and even spontaneous menarche
characterized by some episodes of menstrual bleeding were reported in only a few cases of
Swyer
syndrome in the
literature
It
has been suggested that
gonadoblastoma
can
produce gonadal steroids such estrogen and testosterone
and leads to pubertal development in these
cases
Spontaneous breast development suggests the presence of an
oestrogen
-secreting
tumour
(
gonadoblastomas
).
Slide1746, XY complete gonadal dysgenesis with pubertal virilisation due to dysgerminoma
/
gonadoblastoma
BMJ Case Rep: first published
on
7 July 2020
A 16-year-old
girl
, presented
with:
Progressive
virilisation
since the age of 12
years
Increased
growth of dark, terminal hair initially over
face
and
body
: chest, arms, legs, abdomen and
back
Increased
clitoral size
and heaviness of
voice
Poor
breast
development
Did
not attain
menarche
Medical
history and family history were
unremarkable
She
denied exposure to exogenous androgen
supplements
Slide18BMJ Case Rep: first published on 7 July 2020
S
evere
generalised
hirsutism
with modified
Ferriman-Gallwey
score of
36/36
Acneiform
eruptions
Increased
muscle bulk and low pitch
voice
Breast
development was absent (Tanner stage B1
)
Pubic
hair development
to
Tanner stage
5
Genital
examination revealed
clitoromegaly
with clitoral length of 25mm and width of 12mm
Posterior
labial fusion was absent and three separate openings could be
visualised
in the perineum: vaginal, urethral and
anal
Serum
testosterone of 24.9nmol/L
(N: 0.28–1.67nmol/L
)
Slide19BMJ Case Rep: first published on 7 July 2020
LH
of
1.0 IU/L
(N: 2.4–12.6IU/L)
FSH of 0.9 IU
/L
(N:
3.5–12.5IU/L)
Serum
17
β-
estradiol was also low at
21.3
pmol
/L
Her
thyroid function tests, serum 8 am cortisol, serum
prolactin,
(DHEAS) and
(
IGF-1) were
normal
We proceeded with abdominal and pelvic imaging to exclude a neoplastic
virilising
mass
lesion
Ultrasonography revealed the presence of
hypoplastic
uterus and a
large mass lesion with variable echogenicity and internal vascularity in the left iliac
region
ovaries
could not be
visualized
MRI and CT scan
were
performed next to confirm the
findings
MRI revealed the presence of a large
multilobulated
heterogeneously T2
hyperintense
mass (with multiple
hypointense
areas) of size 8.3×7.5×4.3cm in the left iliac fossa
Slide20BMJ Case Rep: first published on 7 July 2020
Patient
laparotomy—the
surgeon identified a streak gonad on the right side and a
large mass lesion on the left
side
On postoperative day 2, serum testosterone
0.76nmol/L LH
and FSH increased to 9.97IU/L and
35.44IU/L
Pathological the
left gonadal
tumour
measured 9.5×7.0×4.0cm. It was encapsulated, greyish white in
colour
, and showed multiple foci of
calcification
The examined sections showed features of
dysgerminoma
and the
tumour
cells were
immunopositive
for CD117 and
SALL4
Slide21BMJ Case Rep: first published on 7 July 2020
At a follow-up visit 4 months
later
the
patient reported no recurrence of
symptoms
Serum
testosterone declined to
0.55nmol/L
Serum
FSH increased to
137 IU/L
She
was started on pubertal induction with estradiol
valerate
0.5mg/day, with plan for gradual dose
uptitration
and eventual addition of progesterone for withdrawal bleeding
.
However
,
secretion of high level of androgens by
gonadoblastoma
could have resulted in suppression of gonadotropins in this case
Slide22Tumors of dysgenetic gonads in Swyer syndrome 2007 Elsevier Inc. All rights reserved.
Slide23Slide24Slide25Slide26Wisniewski et al 46,XY DSD Management Endocrine Reviews, December 2019,
Gonadal tumors such as
germ cell tumors
result
from fetal germ cells and are divided into two groups, seminoma (
seminoma
/
dysgerminoma
) and
nonseminoma
(
embryonal
carcinoma, yolk sac tumor,
choriocarcinoma
, and
teratoma
)
tumors
Among GCTs, germ cell
neoplasia
in situ and
gonadoblastoma
are
the most common
noninvasive benign tumors
that lead to the development of invasive GCTs.
not
every case will progress to GB
Identified
risk factors for GCT development include the presence of Y
chromosome
GCT
risk
in,XY
DSD is mainly
related to etiology
. GCT risk is
higher
in
conditions associated with
gonadal
dysgenesis
compared with disorders of androgen synthesis or action
Slide272014 Wolters Kluwer Health
Given
the incidence of
gonadoblastoma
and high risk of progression to
malignancy
Gonadal
biopsy has no role
and patients should proceed
straight to bilateral
gonadectomy
at the time of diagnosis
of
Swyer
syndrome
ultrasonography, MRI or
laparoscopy
Slide28World Journal of Surgical Oncology 2007
About
65%
of
dysgerminomas
are
stage I
at
diagnosis
About
85–90%
of stage I tumors are confined to
one
ovary
10–15% is
bilateral
Dysgerminoma
is the only germ cell malignancy that has this significant rate of
bilaterality
Other
germ cell tumors being rarely bilateral
Slide29World Journal of Surgical Oncology 2007
The treatment of patient with
early
disgerminoma
is
primarily
surgical
Including
resection of the primary lesion and proper
surgical
staging
Chemotherapy
and/or radiation
are administered to patients with
metastatic
disease
In patients whose contra lateral ovary has been preserved, disease can develop in
5% to 10%
of the retained gonads
over the next 2
years
Pathologic evaluation the mass to be a
dysgerminoma
and
gonadoblastoma
with the following
marker profile
:
CD117
, CEA,
Desmin
, GFAP, PLAP, S-100 ,CK mixed,
HCG
,AFP and LDH
Slide30pol J Pathol 2016
An
eighteen-year-old
woman
Primary amenorrhea
Excessive
pubic hair and clitoral
hypertrophy
(
FSH) 90
mIU
/ml (normal range 3.5-12.5
mIU
/ml
)
Estradiol
level below 10
pmol
/l (normal range 46-607
pmol
/l
)
Ultrasound
and (CT
)
showed
the uterus of a normal size and shape, a normal size of the vagina but lack of
ovaries
Streaks of connective tissues were present in the place of
gonads
XY karyotype
Slide31Three
years
later
Severe
pain in the lumbar
region
CT
of the abdomen and pelvis
showed
a solid, highly vascularized tumor with a diameter of about 15 cm (14.5 cm × 8.5 cm × 18.5 cm
)
Para-aortic
lymph nodes and dilated
pyelocalyceal
systems
The
patient reported to the hospital after 3 months and 4 cycles of chemotherapy consisting of
bleomycin
,
etoposide
, and
cisplatin
were introduced.
Slide32Chinese Medical Journal ¦ August 5, 2017
Ten days postoperatively, the HCG and LDH levels were
normal
Four cycles of BEP chemotherapy were completed with no evidence of tumor recurrence after 3
years
A resection of the gonads should be performed as soon as possible before
metastasis
Postoperative
BEP chemotherapy is effective auxiliary
therapy
A normal‑appearing
uterus and cervix can be
preserved
The
prognoses for these pregnancies is similar to the prognoses for the pregnancies of 46,XX patients with ovarian failure
Slide33A Case of Swyer Syndrome Associated with Advanced Gonadal Dysgerminoma Involving Long Survival
2015
S. Karger AG, Basel
Adjuvant chemotherapy is particularly necessary in the most advanced stages of
disease
Dysgerminomas
are
highly sensitive to
chemotherapy
The
use of
chemotherapy
in advanced
tumors
has been associated with a remarkable increase in patient survival, particularly following the introduction of
platinum-based
regimens
Survival
rates are largely dependent on
tumor
stage
In
particular,
survival
rates are lower among patients with more advanced tumors (stages 2–4; 53.9%) than among patients with
stage 1 tumors (96.9
%)
The accurate and early diagnosis of these abnormalities would allow for conservative treatment
case report describes a patient with
Swyer
syndrome associated with
stage 3 gonadal
dysgerminoma
who has
survived for 23 years
Slide342008 American Society for Reproductive Medicine, Published by Elsevier Inc.
A 21-year-old Hispanic
female
Primary
amenorrhea
Phenotypic
female
Measuring
170 cm in
height
Weighing
72.1 kg
Tanner
stage I breast
development
Tanner
stage II pubic
hair
Normal
vagina and
cervix
No
apparent somatic
abnormalities
And
no clitoral enlargement or other evidence of
virilization
(
FSH) level was 56.3
mIU
/ml
(
LH) level was 33.0
mIU
/mL
Prolactin
level was 21
ng
/mL
Total
testosterone level was 24
ng
/
dL
Karyotype 46,XY
Slide352008 American Society for Reproductive Medicine, Published by Elsevier Inc
Laparoscopic surgery
bilateral
streak gonads, which were excised
.
Pathologic
only
fibrous tissue containing ovarian
stroma
and surface epithelium
.
After surgery, the patient received exogenous hormone replacement
progesterone
to the treatment regimen after the first episode of menstrual bleeding
.
Six years after her initial presentation,
patient
and her husband expressed interest in pursuing pregnancy using oocytes
donated
cesarean
delivery of a normal female infant weighing 3617 grams with Apgar scores of
9
However, fewer than
12 successful pregnancies in patients with
Swyer
syndrome
have been described in the
literature
Android
shape
pelvis
may
predispose them to abnormalities of labor,
high
prevalence of cesarean delivery remains
unclear
Pregnancy
is possible via ova donation, and
outcomes
are similar to women with 46,XX ovarian failure.
Slide36BJOG An International Journal of Obstetrics & Gynaecology · June 2008
Slide37AGENDA
Differential diagnoses in my patient
Unusual sing and symptoms in
swyer
patient
Diagnosis , treatment and follow-up in gonadal malignancy in
swyer
patient
Pregnancy in
swyer
syndrome
Mobidity
in
swyer
syndrome
Embryonic cause and genes involved in
swyer
syndrome
Slide38There are many reasons why people with
XY
DSD may present high morbidity
Including
hypogonadism
, irregular sex hormone replacement, genital surgery, and
gonadectomy
Reduced
bone mineral density (
BMD) XY
DSD with partial
virilization
due to gonadal
dysgenesis
have a normal BMD
Increased prevalence of:
Obesity, insulin resistance,
lipid abnormalities
,
and
metabolic syndrome
Ischemic heart disease
, arteriosclerosis, hypertension, and cerebrovascular disease
Gonadal cancer
cardiovascular morbidity, impaired glucose tolerance, and
osteoporosis
complete gonadal
dysgenesis
are more likely to report
major depressive
episodes, somatization, antisocial personality, and obsessive-compulsive disorders
Slide39AGENDA
Differential diagnoses in my patient
Unusual sing and symptoms in
swyer
patient
Diagnosis , treatment and follow-up in gonadal malignancy in
swyer
patient
Pregnancy in
swyer
syndrome
Mobidity
in
swyer
syndrome
Embryonic
cause and genes involved in
swyer
syndrome
Slide40a clinical guideline. Fertil Steril 2010
Slide41Caused
by an error in sex determination during the course of
embryogenesis
Incomplete
masculinization due to
deficiencies
in the production of
testosterone
and
Müllerian
-inhibiting
factors
This
may be
related to abnormalities in the expression of SRY, SOX9, SF1,
DAX1 or NROB1, WNT4 and
other genes
located on
the Y chromosome
The SRY gene is deleted in approximately 10–15% of patients with
Swyer
syndrome and mutated in an additional 10– 15% of
Swyer
syndrome
patients
20% of 46 XY pure gonad
dysgenesia
are explained by a mutation or a deletion in
SRY
In 80%, SRY is apparently normal
Slide42Thank you for your attention
Slide432014 Wolters Kluwer Health
Slide44Chinese Medical Journal ¦ August 5, 2017