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Journal of Islamabad Medical & Dental College (JIMDC);2012(4):196-199
Case Report
45 XO/46 XY Male with Deletion of Long Arm of Y
chromosome: A Rare Cause for Ambiguous Gender
Aftab Ahmad Khan1, Naghmi Asif2, Farhat Khursheed3 and Rizwan Uppal 4
1 Consultant Hematologist, Islamabad Diagnostic Centre, Islamabad
Professor, Islamabad Medical & Dental College/Hematologist Islamabad Diagnostic Centre
3 Microbiologist, Islamabad Diagnostic Centre, Islamabad
4Assistant Professor, Department of Medicine, Al-Nafees Medical College, Islamabad
2Assistant
Abstract
Disorders of sex development are among the most complex
conditions for which many a time no definitive cause can be
found. The birth of a child with ambiguous genitalia
represents a big challenge and a multidisciplinary team is
required for the diagnosis and management of these
patients. We present a case of a 5 year old child whose
external genitalia were not well formed and he presented
with undescended testes. His ultrasound showed presence
of both testes in deep inguinal ring and small left sided
uterus. Developmentally and intellectually the child seemed
fine for his age. He was initially brought up as a girl but was
upset and felt himself misfit and when he was dressed and
made to play with boys his personality changed altogether
and he became a lively cheerful child. He was referred for
cytogenetic studies and showed 45XO karyotype in 90%
metaphases and 46, Xdel(Yq) in 10% metaphases with a
small Y chromosome having a significantly deleted q arm.
Key words:
Ambiguous Gender, Mosaicism, 45XO,
Deletion, Gonadal Dysgenesis, Y Chromosome
Introduction
Disorders of sexual development are heterogeneous group of
disorders of sex determination and differentiation. The term
mixed gonadal dysgenesis is sometimes used for this group.
‘Gonadal dysgenesis’ means inadequate development of the
gonads also known as Disorders of Sex Development. These
are among the most complex conditions encountered by the
clinician and in many patients no definitive cause for the
disorder can be found. Therefore the birth of a child with
ambiguous genitalia still represents vast challenge.1 Normal
human beings has 46 chromosomes (in 23 pairs, 22
autosomes and 2 sex chromosomes). Females have two X
chromosomes and males have an X and a Y chromosome in
their cells to give them normal gender differentiation. This
results in 46, XX karyotype in females and 46, XY
karyotype in males. However people with 45, XO/46, XY
mosaicism have two different types of cell. One type
contains a single X chromosome .The other type contains an
X and a Y chromosome. Some of the people with 45, X/46,
XY karyotype have a variant form of Y chromosome with
an unusual structure. The condition has different
presentations. Some are female and have a form of Turner
syndrome - that is, they are more like girls born with a 45, X
genetic constitution. Some are apparently normal males and
go unnoticed until puberty or later. Sometimes these
individuals are born with ambiguous external genitalia that
show incomplete development towards any side.
Most children with 45,X/46,XY are apparently healthy,
normal-appearing boys. Many of these boys commonly have
no risks or problems from their genetic constitution. Of the
normal appearing males, most will have two normally
functioning testes. But one quarter to one third of them will
not. One testis or both may be non-functioning, or one may
contain mostly fibrous tissue with a small amount of
testicular cells, or on one side there may be a nonfunctioning complete gonadal streak. In 45,X/46,XY the
sexual differentiation into male is incomplete -mildly,
moderately, or severely.
Some people with a 45,X/46,XY karyotype have reduced
fertility and some are infertile. No judgement can be made
about fertility until well after puberty in the apparently
normal males. Some of the male patients diagnosed initially
as 45,X later have proved to have a structurally aberrant Y
chromosome . Others have been found to be mosaic for a
cell line bearing a normal or abnormal Y chromosome.
About half of people with 45,X/46,XY have a structurally
abnormal Y chromosome. In some of these cases, excess
euchromatic material on an autosome has been found and
interpreted as evidence of Y chromosome/autosome
translocation.2 Part of the Y chromosome can be missing
and there can be an extra copy of another part.
Underlying the female: male difference is the presence or
absence on the Y chromosome and more of the SRY gene.
The SRY gene determines whether an individual baby will
become male or female, with testes to develop in the first
place, and they then produce the hormone testosterone. If
too small a number of gonadal cells have the SRY gene, this
results in the development of dysgenetic gonads. Overall,
the effects are generally unpredictable, regardless of the
form of the Y chromosome. The effects are believed to
depend on multiple factors: the instability of the abnormal Y
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Journal of Islamabad Medical & Dental College (JIMDC);2012(4):196-199
pelvis was advised. This was done to confirm the genetic
makeup, hormonal status and internal genitalia of the child.
Ultrasound findings suggested presence of small testicles
under deep inguinal ring on each side. In addition, presence
of a thin small uterus deviated towards the left side,
suggested the possibility of unilateral uterine development
(i.e. uterus unicornis unicollis). Chromosomal studies were
performed on peripheral blood. Culture was established in
PB Max medium and peripheral blood lymphocytes were
stimulated with PHA (Phytohaemagglutinin) to undergo
mitosis. Colcemid was used to arrest chromosomes in
metaphase stage and then harvesting was done as per
standard protocols. Twenty metaphases were analyzed after
Geimsa- Trypsin banding. The results of chromosomal
studies were very interesting as 90% of metaphases revealed
45 XO Karyotype with absence of Y chromosome. Only
10% metaphases revealed 46XY karyotype and that too with
a significantly small Y chromosome (with a deleted “q”
arm) as compared to a normal Y chromosome.
chromosome, leading to a higher proportion of 45,X cells,
the level of mosaicism in the gonads and other tissues, the
45,X cell line, the extent of the missing parts of the Y
chromosome and to a lesser extent the extra parts. In
particular, the presence or absence of the sex-determining
SRY region is a key determinant. Not uncommonly there are
more than two cell lines and this complicates the picture.
Ambiguous genitalia are more common when the breakpoint
is in the short arm. The ability to diagnose these conditions
has advanced rapidly in recent years.3 A highly specialized
team of physicians, surgeons and experts of psychosocial
care is needed to counsel parents and patients accordingly.
We present a case of a 5 year old child who was born with
ambiguous genitalia and was referred to us for cytogenetic
studies.
Case Report
In a far of village of Afghanistan a child was born to a
couple about five years back. The child was the product of
nonconsanguinous marriage, had four siblings and all were
normal. There was difficulty in ascertaining the gender of
the baby as external genitalia were not well formed. Since
phallus was not properly recognizable and labio-scrotal
appearance and urethral opening was such that the parents
considered the baby as female and dressed her as such. As
the baby grew she became withdrawn and would not talk
much. The child obviously appeared misfit amongst the girls
and would not participate in girlish games. The situation
made her aloof and depressed. The parents noticed it and
sought consultation of pediatrician who noticing the
ambiguity in gender differentiation referred the patient to a
Urologist in Islamabad. Considering it as a case of gender
ambiguity with presentation of hypospadias, chromosomal
analysis, hormonal profile and ultrasound abdomen and
Discussion
Here we see that even if only 10% metaphases revealed a
small deleted Y chromosome, while in 90% metaphases no
Y chromosome was detected, it was still enough to cause
formation of testes and male type differentiation. Initially
the affected child was brought up as a girl but remained
depressed and aloof amongst girls. Later when the child was
dressed as males and made to play with boys, he became
active and more playful and started participating
enthusiastically in all such activities that boys older than
him would do. His whole personality transformed and he
became a happy child in place of that misfit, withdrawn and
aloof kid. No doubt, “Birds of feather flock together”
Normal
Male
Karyogram
Normal Female Karyogram
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Journal of Islamabad Medical & Dental College (JIMDC);2012(4):196-199
Karyotype of the patient- 45,XO
As mentioned previously the clinical features of XO/XY
“Mosaic intersex syndrome (MIS)” vary widely. Majority
are females with some degree of masculinization depending
upon the variable activity of the Y chromosome. Some cases
of MIS are phenotypically male and show variable features.
Some are true hermaphrodites with ovo-testis, some have
gonadal dysgenesis (streak gonads), some are male pseudohermaphrodites with testicular tubular structures on both
sides while some have only one gonad.
Our case shows bilateral undescended testis (in deep
inguinal ring) even though 90% metaphases showed 45,XO
karyotype and only 10% of metaphases showed 46, X
del(Yq) karyotype with a small Y chromosome having a
truncated long (q) arm. It may be presumed that the
testicular structures are determined by the presence of Y
chromosome and the degree of intrauterine masculinization
follows from degree of development of fetal testis. Later
pubertal virilization depends upon the presence of adult type
leydig cells. Deletion of long arm of Y chromosome may be
associated with certain developmental problems e. g short
stature. Some may also have ambiguous geniltalia or undescended testis and some may be apparently normal and
referred for infertility due to azoospermia.4 These features
are however not simply correlated to the size of deletion.
In our case external genitalia were not well formed and he
had un-descended testes and thin small unicornuate uterus.
He had Y chromosome in only 10% of cells and that too
with deleted q arm. There have been case reports of males
with 46 XX genotypes but male phenotype with 45 X0 and
46XY in only 10% of cells and that too with deleted Y arm
have rarely been reported. In our country this underreporting
is probably because of our cultural limitations and also
because of paucity of facilities and high cost which is
required for diagnosis of these disorders.
In various case reports it has been proposed that part of the
Y chromosome can be missing or there can be an extra copy
of another part. Overall, the effects are generally
unpredictable, regardless of the form of the Y chromosome.
Some 45,X males originate from Y chromosome/autosome
translocations following a break in the proximal long arm of
the Y chromosome.2 In a male patient with a 45,X
karyotype, the terminal part of the Y chromosome short arm
may be translocated as a single block on to the X
chromosome. This rearranged X chromosome, in every
regard behaves the same as that present in XX males
resulting from an abnormal X-Y interchange.5 There have
also been case reports of nonmosaic 45,X male patients.6,
7.8,9
Ambiguous genitalia are more common when the
breakpoint is in the short arm of Y chromosome.10
As with 45,X/46,XY, no judgement can be made until
puberty about fertility in the apparently normal males.
Various case reports with 46,XX males, 46,XX/46XY or
even 49XXXXY males have been reported.11 This is
because the testis-inducing SRY (Sex-determining Region
Y) locus which is normally located on the short (p) arm of
the Y chromosome, can sometimes get translocated to an X
chromosome during meiotic division of a primary
spermatocyte.12 After having determined hermaphroditism,
assignment of an appropriate gender becomes urgent.
Traditionally, a multidisciplinary team of healthcare
professionals comprising of paediatrician, paediatric
endocrinologist, paediatric surgeon and paediatric
psychiatrist have meetings with parents and the gender of
the affected individual is assigned based on genital, gonadal
and genetic factors.13 The process by which gender is
assigned to intersex case is based on the concept that
children are gender neutral at birth and can be made to
assume male or female characteristics through a
combination of psychosocial counseling and appropriate
hormonal and surgical treatment. 14,15 In all such cases the
baby will be thoroughly examined. Ultrasound abdomen and
pelvis (and CT scan if required), hormonal profile and
cytogenetic studies need to be performed. There may be a
need to take a biopsy from the gonads. Combined
information from all these sources helps to determine the
child’s underlying gender. A decision then needs to be made
whether to bring up the baby as a girl or a boy based on the
discussions between doctors and parents. It is occasionally
not entirely clear whether the baby, while growing up, will
come to see itself as a girl or a boy. People who have been
through the boy: Girl decisions suggest that any surgery
should be delayed until the child can help to decide for
themselves. These patients are generally not told about their
intersex status during childhood to avoid mental trauma and
psychosexual conflicts.16 Whichever sex is finally chosen, it
is likely that some reconstructive surgery will be needed.
There must be adequate functioning gonadal tissue present
to sustain and develop sex characters, and gonads producing
contradictory hormones should be excised.17 As malignant
growth occurs in 1.91% of true hermaphrodites, most
commonly arising in dysgenetic or undescended testes, the
long-term follow-up and screening particularly for testicular
neoplasms is suggested.18, 19 As with 45,X/46,XY, no
judgement can be made until puberty about fertility in the
apparently normal males. In our case the child did not have
well defined genitalia but he had both the testis and a small
unicornuate uterus. He was subjected to hormonal and
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Journal of Islamabad Medical & Dental College (JIMDC);2012(4):196-199
chromosomal analysis and urogenital evaluation by a
Urologist and a Paediatric Surgeon was done.
It is thus suggested that cases of ambiguous gender should
be managed well in time to avoid psychological trauma both
to the child and other family members and various
educational programmes to understand the psychological
and social implications of these cases of gender assignment
should be conducted.
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