1
Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2
Obstetrics and Gynecology Unit, Mahdyeh Hospital, Shahid Beh eshti University of Medical Sciences, Tehran, Iran
Abstract
Premature ovarian failure (POF) causes hypergonadotrophic amenorrhea in 1-3% of females, occurring before the age of 40 among women with chromosomal rearrangements in the long arm of the X chromosome 'critical region'. In this article, we report a case of POF and primary amenorrheain a girl with a de novo reciprocal translocation between chromosomes X and 9. The proband was a 17 years old girl with a history of irregular menstruation and high level of follicle-stimulating hormone (FSH) (151 mlU/mL) and luteinizing hormone (LH) (56 mlU/mL). In ultrasound examination, left ovarian gonad was atrophic without any follicles. Right ovarian gonad was not seen. Cytogenetical analysis was performed on the patient and her parents. Her karyotype results was 46, X, rcp (X; 9) (q24; q13) dn. Her parents had normal karyotype. This reciprocal translocation between chromosome X and 9 and observed POF in the patient suggest either the disruption of a critical gene expression due to 'position effect' or deletion of one or more POF-related genes in the disrupted long arm of the affected X chromosome.
Premature ovarian failure (POF) is one of the
major causes of hypergonadotrophic amenorrhea
among females before the age of 40, with
the frequency range of about 1-3% (1). This syndrome
was first described among young women
having menopausal levels of follicle stimulating
hormone (FSH), low estrogen levels and amenorrhea
(2). Most causes of POF cases are unknown
(3), but in the remaining cases diverse
etiologies have been reported including: genetic
aberrations, autoimmune ovarian damage, iatrogenic
factors, infectious agents, toxins and
environmental factors (4). Chromosome anomalies
are responsible for 6-8% of POF cases (1).
Abnormal X chromosome was seen in the majority
of the cases and its association with ovarian
dysgenesis was suggested (5). POF-related
abnormalities range from partial to complete
absence of one X chromosome to mutations at
the DNA level. The disease is genetically heterogeneous
(6).
Although in many cases, X monosomy is the
major chromosomal finding, but other chromosomal
abnormalities such as X-chromosome
rearrangements, containing inversions, X/autosomal
balanced translocations has been also reported
(7). On the X-chromosome, the majority
of the breakpoints are concentrated on the long
arm, spreading over about half of its length.
This region has been called the "Xq critical region"
since it is necessary for the ovarian function and normal reproductive function (8). These
regions are located between Xq13 and Xq26 (9)
containing two groups of candidate POF-related
genes: POF1 within Xq26-q27 (10) and POF2
within Xq13-q21 (11). Heterochromatic Region 1
supposes to yield a position effect on autosomal
genes in reciprocal balanced translocations. POF
correlated to this region is perhaps due to unbalanced
expression of one or more translocated autosomal
genes. No known X linked genes exist with
ovarian-specific expression in this region.
Region 2, in the distal part of long arm of chromosome
X is a fairly gene-rich region. Ovary
expressed genes in this region may be needed
in a double dose for the function of ovary, and
their alterations by mutations maybe responsible
for POF. Disturbing either of these regions,
could cause different symptoms (12, 13). In our
country many people refer to infertility centers
for treatment. Finding and reporting chromosomal
anomalies of POF could help to understand
and improve the knowledge on the genetic
causes of their condition and family planning.
The aim of the present study was exploring the
new causes of infertility and helping to reach to
new insights in this scope.
Cytogenetical analysis was carried out on the
patient and her parents, according to standard cytogenetical
procedures with some modification
(14). From each sample a minimum of 50 metaphases
was surveyed, by using the Applied Imaging
CytoVision Karyotyping System (Santa Clara,
CA).Informed written consent was obtained from
the parents of the patient. This study was approved
in the Ethics Committee of Shahid Beheshti University
of Medical Sciences.
Case Report
The proband was an Iranian 17 years-old girl
of non-consanguineous parents with a history
of irregular menstruation, every 7-8 months. No
history of birth defects, mental retardation and
congenital malformations was seen in the family.
Pregnancy was normal and at birth the patient
had no dysmorphic characteristics. In ultrasound
examination, her uterine was normal but her left
ovarian gonad was small and atrophic without any
follicles. Right ovarian gonad was not seen. Her
serum follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) levels were high, 151
mlU/mL and 56 mlU/mL respectively. Her height
was 160 cm at the time of diagnosis.
GTG banded karyotype of the patient showed a
de novo reciprocal translocations between chromosomes
X and 9. Her karyotype was 46, X, rcp
(X; 9) (q24; q13)dn. No chromosomal abnormalities
were noticed in her parents (Fig 1).
Cytogenetical analysis was carried out on the
patient and her parents, according to standard cytogenetical
procedures with some modification
(14). From each sample a minimum of 50 metaphases
was surveyed, by using the Applied Imaging
CytoVision Karyotyping System (Santa Clara,
CA). Informed written consent was obtained from
the parents of the patient. This study was approved
in the Ethics Committee of Shahid Beheshti University
of Medical Sciences.
GTG banded chromosome typig in the daughter of the
family showing reciprocal X; 9 translocation.
Discussion
The pattern of X inactivation has been moderately
unchanged and the normal X having been selectively
inactivated in almost all cases. A normal
phenotype would be anticipated in the existence
of a balanced karyotype and seemingly normally
functional X genes, even if they were divided into
two translocated segments (15). De novo translocations
between chromosome X and autosomal
chromosomes are rare (16) but still chromosomal
rearrangements are the major causes of POF (6).
Balanced chromosomal translocation in the POFrelated
genic regions could lead to the POF by several
genetic mechanisms including reduced gene dosage, position effect and non-specific chromosome
effects that impair eiosis. These can result
in the failure of ovaries by decreasing the number
of primordial follicles, increased atresia of
the ovarian follicles due to apoptosis, or failure
of follicle maturation (4, 17). Genes involved in
balanced translocations signify new candidates
for POF (12, 13). Deletions of the distal region of
the POF1 locus are related with POF at ages 24-
39 years but POF at an earlier age of 16-21 years
has been associated with translocations affecting
the POF2 locus (18). Various translocations have
been reported between X and other somatic chromosomes
that lead to POF such as t (X; 17) (q22;
q25) (19), 46, X, t (X; 15) (q24; q26.3) (20), 46, X,
der (Y) t (X; Y)(q13.1; q11. 223) (1) and der (X) t
(X; 11) (q28; p13) (21). Many of these translocations
occur in critical regions of X chromosome
which contain various genes necessary for ovarian
normal reproductive function (1, 8) such as
FMR1 (Xq27), FMR2(Xq28), DIAPH2 (Xq22),
XPNPEP2 (Xq25), FSHPRH1 (Xq22) and some
autosomal genes like, FSHR (2p21-p16), Inhibin
A (2q33-q36), GALT (9p13) and NOGGIN
(17q22) (18). Though, population-specific studies
are still limited, occasionally a single mutation
may prove significant in certain populations like
FSHR in Finland and INH-A in Iran (4, 22). Here
we report a case with irregular menstruation due
to reciprocal translocation involving Xq24 and
9q13 regions. This breakpoint of the X chromosome
was well inside the "critical region" of the X
chromosome, therefore it is probable that her chromosome
abnormality is responsible for her clinical
state. A similar translocation at Xq22 region in
a girl was reported who had delayed puberty and
primary amenorrhea (16). In addition similar phenotype
was reported in an 18-year-old girl with an
X-autosome translocation t (X; 9) (q22; q12) (23).
Based on these findings including ours, it is recommended
to carry out karyotyping as part of the
basic evaluation of women diagnosed with POF
due to repeated abnormal karyotypes (13-50%) in
this situation. Having this information may aid and
impact the family with their future decision making.
Omrani, M., Saleh Gargari, S., Azizi, F. (2013). A de novo Reciprocal X; 9 Translocation in A Patient with Premature Ovarian Failure. International Journal of Fertility and Sterility, 7(2), 130-133.
MLA
Mir Davood Omrani; Soraya Saleh Gargari; Faezeh Azizi. "A de novo Reciprocal X; 9 Translocation in A Patient with Premature Ovarian Failure". International Journal of Fertility and Sterility, 7, 2, 2013, 130-133.
HARVARD
Omrani, M., Saleh Gargari, S., Azizi, F. (2013). 'A de novo Reciprocal X; 9 Translocation in A Patient with Premature Ovarian Failure', International Journal of Fertility and Sterility, 7(2), pp. 130-133.
VANCOUVER
Omrani, M., Saleh Gargari, S., Azizi, F. A de novo Reciprocal X; 9 Translocation in A Patient with Premature Ovarian Failure. International Journal of Fertility and Sterility, 2013; 7(2): 130-133.