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Made Ayu Krishna Levina, I Made Arimbawa

Department of Child Health Udayana University Medical School / Sanglah Hospital Denpasar


Mixed gonadal dysgenesis is a very rare case with genital ambiguity as a clinical manifestation.
Diagnosis of this condition is emerging due to proper gender assignment and prompt treatment to
achieve optimal physical and psychologic development. We reported a genital ambigous in a 7 month
old baby, who was referred with enlargement of clitoris, an unpalpable testis, but with a high
concentration testosteron serum level, an uterus from genitography, and a mosaic karyotype 45,X/
46,XY. The working diagnosis of this baby is mixed gonadal dysgenesis. Patients is being evaluated by
a multidisciplinary team and planned having laparoscopy. [MEDICINA 2014;45:52-57]

Keywords : mixed gonadal dysgenesis, mosaic karyotype, ambiguous genitalia


Made Ayu Krishna Levina, I Made Arimbawa

Bagian Ilmu Kesehatan Anak Fakultas Kedokteran Universitas Udayana / Rumah Sakit
Umum Pusat Sanglah, Denpasar


Mixed gonadal dysgenesis merupakan suatu penyakit yang jarang dijumpai dengan manifestasi klinis
berupa ambigus genitalia. Penegakan diagnosis terhadap kondisi ini harus segera dilakukan untuk
menentukan jenis kelamin, tata laksana tepat sedini mungkin untuk mencapai tumbuh kembang
optimal. Kami melaporkan kasus ambigus genitalia pada bayi berusia 7 bulan yang datang dengan
pembesaran klitoris, testis tidak teraba, kadar serum terstosteron tinggi, ditemukan uterus dari
hasil genitografi dan kariotipe mosaik 45,X/46,XY. Pasien didiagnosis kerja dengan mixed gonadal
dysgenesis. Saat ini pasien tetap dimonitoring oleh tim multidisiplin dan direncanakan menjalani
laparoskopi. [MEDICINA 2014;45:52-57]

Kata kunci : mixed gonadal dysgenesis, kariotipe mosaik, ambigus genitalia

INTRODUCTION gonad produces enough Mullerian unilateral gonadoblastoma and a

Inhibiting Substancies (MIS). In contralateral streak gonad were

T he syndrome of mixed
gonadal dysgenesis
most cases of partial gonadal
dysgenesis, a range of karyotypes
included in the original description
of the syndrome of MGD, most of
(MGD) is characterized by an is seen such as 45,XO/46,XY; those patients differ clinically and
unilateral testis, usually intra- 45,XY/XO; 46XX. One gonad is cytogenetically from patients with
abdominal, a streak gonad on the usually a streak, and another is a testis and probably should be
contralateral side, and persistent likely to be a fairly well-developed considered more akin to patients
Mullerian structures. It has an testis in which Leydig cells can with a syndrome of pure gonadal
extreme phenotypic variability usually be identified. In the dysgenesis, than to MGD.2,5,6 Many
postnatally that may extend from complete form of XY gonadal problems in diagnosis of and
a Turner-like syndrome to a male dysgenesis, both gonads are therapy for this condition such as
phenotypic with a penile urethra.1 streaks. 2,3 The discrepancy karyotyping in ambiguous
Mixed gonadal dysgenesis is between normal leydig cell genitalia is a widely recommended
suggested as a second common function at puberty and an procedure, as it allows early
cause of disorder of sex evidence of incomplete genital diagnosis and early application of
development (DSD) and the masculinization during fetal life an appropriate therapy. Close
incidence is approximately 1 : may possibly be explained by a follow-up for development of
10,000 of newborn. Internally, 75% delayed and asynchronous fetal gonadal tumors is mandatory in
of patients with partial XY gonadal testicular development.2,4,5 all patients with 45,X/46,XY
dysgenesis have an uterus because Although patients with an karyotype. 7 The primary aim


Mixed Gonadal Dysgenesis In A Seven Month Old Baby | Made Ayu Krishna Levina, dkk.

should be to achieve a diagnosis, medication throughout the course Laboratory investigation

sex assignment (if needed) and of gestation on the mother. The revealed a normal cell blood count,
management plan as quickly as immunization history was electrolyte, and glucose.
possible, but without rash complete according to the Testosterone concentration was 5
decisions being made.8,9 We report recommended immunization plan ng/mL (normal male at the age less
this seven months old baby who by Indonesian Pediatric Society. than 1 years old, 12-21), and it
had the classical morphology Physical examination revealed decreased with age, progesterone
features of mixed gonadal an alert child, who looked active. 17-OH serum concentration was
dysgenesis. Vital sign within normal limit. 12 ng/mL (range normal at the age
Chest examination, abdomen and less than 1 years old, 11-170 ng/
CASE ILLUSTRATION extremities also within normal mL). The chromosome analysis
R, a seven month old baby was limit. Urogenitalia examination using G-banding showed a
referred to endocrinology showed phalus measured 30 mm karyotype of 45,XO/46,XY as
outpatient Sanglah Hospitals in length with a 5-mm base, shown in Figure 2. Polymerase
clinic because of a slight without palpable testicular. chain reaction (PCR) showed the
enlargement of the clitoris. The Orifisium urethrae and introitus presence of the sex-determining
parents worried about the size of vaginae cannot be seen clearly region Y. Using technique
the clitoris. They saw there was (Figure 1). Methapase Fluorescence in situ
an enlargement of clitoris at their hybridization (FISH) analysis
child, and it looks like a small with X chromosome-specific probes
penis. They realized this (control), there was three
abnormality since 2 months ago population cell (mosaic), including
and they had already discussed 138 cell (69%) without SRY gen,
this problem to their family. They 59 cell (29.5%) with 1 SRY gen and
decided to see a pediatrician and 3 cell (1.5%) with 2 SRY gen as
then their child was referred to an shown ini Figure 3.
endocrinology outpatient clinic to Ultrasonography examination
have some examinations. While (genitography) was conducted to
waiting for the result of the evaluate the genitalia. It revealed
examination, now, their child is Figure 1. Appearance of the no abnormality of the urinary
already 7 months old, and the external genitalia. bladder (Figure 4). The contrast
parents became more confused
about the gender of their child.
She was born full term,
normal, spontaneously, and birth
weight was 2700 grams. She did
not receive any prior medications
for specific diseases. There were no
history of having profuse vomiting
after birth and hospitalized
because of this condition, there
were no hiperpigmentation on the
patient as well. From the family Figure 2. Chromosome analysis showed 45,XO/46,XY.
history, the parents were 45 years
old (father) and 42 years old
(mother) at the child birth. The
baby is the third child at this
family, with two older sisters. The
eldest one was 5 years old and the
second one was 4 years old. Both
of the sisters have normal growth
and development. Neither of the
parents or other family member Figure 3. FISH analysis. (A) One green dot showed there was one X
have any signs and symptoms of chromosome. The absence of red dot showed there were no SRY gene,
sexual organ dysfunctions nor (B) One green dot showed there was one X chromosome. Two red dot
delayed puberty before. There were showed there were two SRY gene, (C) Presence of one green dot showed
no prior history of receiving there was one X chromosome. Presence of one red dot showed there was
hormonal therapy and no one SRY gene.



1000 IU/day, revealed increasing

level of testosterone hormone from
5 ng/mL to 302 ng/mL. Based on
history taking, physical finding,
laboratory and radiology
examination, we suggested this
patient suffered from ambiguous
genitalia due to MGD with parsial
androgen insensitivity syndromme
(PAIS) and congenital adrenal
hyperplasia (CAH) as a differential
diagnosis. Laparoscopy is needed
Figure 4. Ultrasonography examination. It revealed no abnormality of
for gonadal evaluation and to
the urinary bladder.
diagnose MGD from biopsy
specimen although we strongly
study showed there was canal the cavum abdomen and also there suspected MGD in this case.
above the anal with 1 cm depth. was no contrast on vesica urinaria. Unfortunately in our region
The contrast injected into the It concluded that there was an hospital, laparascopy procedure on
canal made an oval-like shaped, uterus-like shaped (possibly a girl) child has not been conducted yet.
sized 22.03 mm x 11.98 mm, plain (Figure 5). Therefore, we recommend the
edge, sharp on the inferior. There Human chorionic gonadotro- patient to conduct laparascopy
were no contrast extravasation to pin (hCG) stimulation test using procedure in Cipto Mangunku-
sumo Hospital at Jakarta.

Gonadal dysgenesis is defined
on the basis of gonadal
morphological features as an
abnormal testis on one side and a
streak gonad on the other side. The
estimated incidence of clinically
detectable ambiguous genitalia at
birth in Germany is 2.2 per 10,000
The incomplete formation of
the male external genitalia
constitutes a defect in normal
physical sex differentiation, which
is related to the theory of hormonal
dependence of male sexual
differentiation. Gonadal dysgenesis
is caused by abnormal testicular
determination and differentiation.
It could be expected that decreased
androgen production results not
only in phenotypic disturbances
but also in changes of regulatory
mechanisms in the central
nervous system. The
determinants of gender-related
behavior patterns can be
arbitrarily subdivided into
neuroendocrine factors (principally
the effects of testosterone on the
brain) and sociocultural factors,
which include sex of rearing,
Figure 5. Contrast Study. It concluded that there was an uterus shaped- interactions with parents,
like. siblings, and peers, and the culture


Mixed Gonadal Dysgenesis In A Seven Month Old Baby | Made Ayu Krishna Levina, dkk.

to which the individual is exposed. ambiguous genitalia. a canal above the anal with 1 cm
Excessive exposure to prenatal Ultrasonography is the primary depth, oval shaped-like, sized 22.03
androgens may have a stronger modality for evaluation of the mm x 11.98 mm, concluded that
impact on some components of internal reproductive organs, there was an uterus-like shape.
psychosexual differentiation than whereas genitography and voiding Polymerase chain reaction showed
on others (i.e., gender identity).5,11 cystourethrography are used for the presence of the sex-
In our case the patient is seven evaluation of urethral and vaginal determining region Y (SRY)
month old baby, born term, risk tracts and fistulas. A gonad with sequence. Using technique
factor for disturbance sexual the morphologic appearance of a Methapase Fluorescence in situ
differentiation such as hormone testis or ovary on ultrasonography hybridization (FISH) analysis
exposure during prenatal or may prove to be a dysgenetic gonad with X chromosome-specific probes
perinatal factors and sociocultural at biopsy. At minimum, a (control), there were three
factors were no found. rudimentary uterus or fallopian population cells (mosaic), including
Mixed or partial gonadal tube can be seen on the edge with 138 cell (69%) without SRY gen,
dysgenesis (45,XO/46,XY or 46,XY) the streak gonad. On the edge with 59 cell (29.5%) with 1 SRY gen and
involves a streak gonad on one side the testis, local MIS diffusion 3 cell (1.5%) with 2 SRY gen. We
and a testis, often dysgenetic, on prevents development of a fallopian planned to perform an initial
the other side. Affected patients tube. Fluorescence in situ laparoscopic approach for gonadal
have ambiguous external genitalia hybridization as a molecular evaluation and diagnose MGD
and persistent Mullerian (female) analysis is most useful and from biopsy specimens.
duct structures. The genital informative for detecting the SRY Laparoscopy was not performed yet
phenotype is varied, ranging from sequence and localizing the signal because laparoscopic procedure on
a hypospadial penis and unilateral easily. Although several key baby has not been conducted yet
descended testis to female genitalia factors are responsible for sexual in our region hospital and also
with varying degree of virilization. differentiation and disorder of sex prepare physical and
All these patients had female development (DSD), the presence physicological factor of the patient
internal genitalia derived from of the SRY sequence often indicates and parent. Finally, according to
Mullerian structures. MGD the existence of a testicular doctor recommendation, parents
patients are shorter than component, even in a phenotypic decided to bring their child to Cipto
normal.5,8-10 In our case, on first girl, as well as the gene responsible Mangunkusumo Hospital at
addmission, the parents complain for tumor formation in a Jakarta to perform laparoscopic
about clitoris enlargement of their dysgenetic gonad map close to the procedure immediately.
daughter that realized since a Y chromosome centromere, Patients who raised as girls,
month ago. Physical examination making the Y centromeric probe streak gonads and any testicular
showed a 7 month old baby with important for evaluation of marker tissue were excised and feminizing
30 mm phalus length, unpalpable chromosomes. In addition, Yq genitoplasty were performed in
testis, and normal urine excretion. microdeletions may be associated childhood. In addition, hormone
Hormonal evaluations and with Y chromosomal instability replacement therapy was given at
imaging studies are sometimes leading to the formation of 45,XO pubertal age. In all patients raised
useful to diagnose these patients, cell lines; however, as a result, as boys, streak gonads and
but they are not always definitive. gonadal biopsy is sometimes Mullerian structures were excised
An hCG stimulation test is necessary to establish the correct and the penis reconstructed. The
required to assess Leydig cell final diagnosis and subsequent procedure of penis reconstruction
function and testosterone treatment. is complicated, consisting of
production. Assessment of Laparoscopy provides an multiple stages. It began in early
testosterone production after hCG excellent view of the childhood and, in some patients,
stimulation could be useful in such intraabdominal gonad and internal was completed at late peripubertal
patients, especially in the first year genitalia by magnification, age (from mullerian ducts removal
of life.5,12 Testosterone response maintaining a wide space, easy to plastic surgery of the urethra),
depend on the age of the patient.5 access to the pelvic cavity and hence surgical removal of the
The highest levels are observed adequate illumination, and is gonad is recommended. Patients
during the first months of life. helpful for correct diagnosis.5,8,13,14 with a 45,XO/46,XY karyotype and
Testosterone levels are determined In our patients, there were high normal testis biopsy could retain
by radioimmunoassay (RIA) before testosterone serum level hCG the testis if it is descended or can
and after stimulation. Imaging stimulation test. It means there be placed in the scrotum. These
plays an important role in depicting were gonadal function. children would then need a close
the internal organs and urogenital Ultrasonography examination follow-up of the testis by monthly
anatomy in children with (genitography) showed there was self examinations for tumor



formation. Laparoscopic neoplasia or carcinoma in situ.10 ting with a 45,X/46,Xr(Y)

management is a good approach for Sex assignment is usually difficult (p11.2; q11.23)/47,X,idid (Y)
patients with DSD, including MGD in patients with major ambiguous (p11.2),idic(Y)(p11.2) karyo-
because it enables minimally external genitalia. Careful type. Ann de Genet.
invasive surgery for children and evaluation and correct diagnosis 2001;44:5-8.
all necessary procedures, including are very important to prevent
5. Czapnik MS, Starowicz ZL,
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Zucker KJ. A psychosexual
gonadectomy for diagnosis and gonadoblastoma because 15%20%
follow-up study of patients
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with mixed or partial gonadal
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dysgenesis. J Pediatr Adolesc
a boy. It is difficult to distinguish or 2nd decade of life. That is why
Gynecol. 2007;20:333-8.
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presence of SRY on the polymerase be removed.6,8,10,15 PS, Salle JLP. Imaging of
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stimulation test. Now, we plan to We reported a 7 month old approach. RadioGraphics.
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descended and placed in the shaped-like from genitography, 46,XY mosaic karyotype, and
scrotum, so it can reach their and a mosaic karyotype 45,X/ Y chromosome microdeletions
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