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Year: 2018

Disorder of sexual development in a mare with an unusual tentative mosaic

karyotype (63,X/64,XYdel)

Neuhauser, Stefanie ; Handler, Johannes ; Schelling, Claude ; Pienkowska-Schelling, Aldona

Abstract: The present report describes a 4-year-old Trakehner mare which was referred to the clinic
for a breeding soundness evaluation. Clinical, histological, and postmortem examination revealed an
underdeveloped genital tract, the absence of a cervix uteri, and small inactive ovaries without male
gonadal tissue. Blood lymphocyte analysis revealed an unusual mosaic karyotype consisting of 2 cell lines.
For the majority of cells (70%), monosomy X (63,X) was observed. The remaining cells (30%) contained
64 chromosomes including one X chromosome and a small rudimentary Y chromosome consisting mostly
of heterochromatin. The centromere was retained, but its full functionality was questionable. PCR
analysis revealed that the entire male-specific region of Y (Yq14), including the SRY gene, was deleted.
It remained unclear if the pseudoautosomal region (Yq15) and parts of the heterochromatic region (Yq13)
were affected by this deletion. The phenotype of the mare with this disorder of sex development associated
with sex chromosome abnormalities is genetically comparable to 63,X monosomy which fully explains the
clinical findings.

DOI: https://doi.org/10.1159/000490861

Posted at the Zurich Open Repository and Archive, University of Zurich

ZORA URL: https://doi.org/10.5167/uzh-168126
Journal Article
Published Version

Originally published at:

Neuhauser, Stefanie; Handler, Johannes; Schelling, Claude; Pienkowska-Schelling, Aldona (2018). Dis-
order of sexual development in a mare with an unusual tentative mosaic karyotype (63,X/64,XYdel).
Sexual Development, 12:232-238.
DOI: https://doi.org/10.1159/000490861
 Original Article

Sex Dev 2018;12:232–238 Accepted: May 3, 2018

by M. Schmid
DOI: 10.1159/000490861
Published online: August 3, 2018

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Keywords phenotype of the mare with this disorder of sex develop-

DSD · Horse · Mosaic · Sex chromosome · Y chromosome ment associated with sex chromosome abnormalities is ge-
deletion netically comparable to 63,X monosomy which fully explains
the clinical findings. © 2018 S. Karger AG, Basel

Abstract
The present report describes a 4-year-old Trakehner mare
which was referred to the clinic for a breeding soundness In humans, disorders of sex development (DSD) are
evaluation. Clinical, histological, and postmortem examina- defined as congenital conditions in which the develop-
tion revealed an underdeveloped genital tract, the absence ment of chromosomal, gonadal, or anatomical sex is atyp-
of a cervix uteri, and small inactive ovaries without male go- ical [Lee et al., 2006]. Chromosomal aberrations, gene
nadal tissue. Blood lymphocyte analysis revealed an unusual mutations, and environmental factors may disrupt the
mosaic karyotype consisting of 2 cell lines. For the majority process of normal sexual development. In domestic ani-
of cells (70%), monosomy X (63,X) was observed. The remain- mals, a good reproductive performance is an important
ing cells (30%) contained 64 chromosomes including one X economic factor and is essential for any breeding pro-
chromosome and a small rudimentary Y chromosome con- gram, because a higher reproduction rate results in high-
sisting mostly of heterochromatin. The centromere was re- er selection intensity and shorter generation intervals,
tained, but its full functionality was questionable. PCR analy- permitting faster genetic progress [Eldridge, 1985]. Re-
sis revealed that the entire male-specific region of Y (Yq14), cently, Raudsepp and Chowdhary [2016] reviewed the
including the SRY gene, was deleted. It remained unclear if link between chromosomal aberrations and fertility in
the pseudoautosomal region (Yq15) and parts of the hetero- domestic animals. DSD are a well-known problem in
chromatic region (Yq13) were affected by this deletion. The horses, but their prevalence in the general horse popula-
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Verlag S. KARGER AG, BASEL

© 2018 S. Karger AG, Basel Claude Schelling

Clinic of Reproductive Medicine and Center for Clinical Studies
Vetsuisse-Faculty, University of Zurich
E-Mail karger@karger.com
Eschikon 27, CH–8315 Lindau (Switzerland)
www.karger.com/sxd
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E-Mail cschelling @ vetclinics.uzh.ch
tion remains largely unknown. One larger study encom- that she had to be treated for hypogammaglobulinemia and septi-
passing a random sample of 500 young male and female cemia at a younger age. In addition, an optimized food manage-
ment was necessary to stop intermittent colic. The horse had to be
horses in Poland found no aberrations in males and a euthanized within short time after the clinical examination be-
prevalence of 3.7% for mares with chromosomal aberra- cause of a massive and rapid deterioration of health, and a post-
tions [Bugno et al., 2007]. Based on chromosomal analy- mortem examination of the internal genital tract became possible.
ses from 204 mares selected for breeding, Nie and co- However, the owner did not agree to a dissection of other organs
workers [1993] found a lower prevalence (1.5%) for sex or any additional genetic testing.
chromosome abnormalities. Power [1990] gives a com- Cytogenetic and Molecular Analyses
prehensive overview of reported chromosomal aberra- Heparin- and EDTA-treated blood samples were collected for
tions in horses up to the year 1990. Since then, numerous cytogenetic and molecular analysis, respectively. Chromosomes
cases of intersex horses have been reported, reflecting the were prepared according to standard protocols from short-term
advances in the fields of equine genomics and cytogenet- lymphocyte cultures. Giemsa staining was applied to count the
chromosomes. DAPI- and CBG-banding of metaphase chromo-
ics [Raudsepp and Chowdhary, 2016]. Pure monosomy X somes followed the methods described by Schweizer [1980] and
[Mäkinen et al., 2001; Di Meo et al., 2009; Moreno-Millán Sumner [1972], respectively. More than 200 metaphases were an-
et al., 2012] and its mosaic forms [Moreno-Millán et al., alyzed and karyograms were prepared. FISH with an in-house de-
2012; Pieńkowska-Schelling et al., 2016] as well as DSD veloped equine whole Y chromosome painting probe [according
with sex reversal [Bannasch et al., 2007; Bodvarsdottir et to Pieńkowska-Schelling et al., 2006] was applied to identify the
sex chromosomes. This painting probe hybridizes along the entire
al., 2009; Raudsepp et al., 2010; Villagómez et al., 2011; acrocentric Y chromosome and to the heterochromatic block of
Peer et al., 2012; Anaya et al., 2014; Pieńkowska-Schelling the X chromosome (Xq17q21). However, it does not detect the
et al., 2014] are the most common findings in mares with pseudoautosomal region (PAR) on Xp. Telomeres were analyzed
fertility problems [Lear and McGee, 2012]. In addition, with FISH using a commercially available human telomeric probe
translocations [Lear et al., 2008], trisomies [Moreno-Mil- (TEL100R, ChromBios, Germany) according to the manufactur-
er’s protocol. The results of cytogenetic and FISH experiments
lán et al., 1989; Lear et al., 1999; Mäkinen et al., 1999; were analyzed with a Zeiss Axio Imager Z1 microscope and
Brito et al., 2008], deletions [Halnan, 1985; Raudsepp et Ikaros/Isis-software (MetaSytems GmbH, Germany). High mo-
al., 2010], isochromosomes [Herzog et al., 1989; Mäkelä lecular weight genomic DNA was extracted by a proteinase K/
et al., 1994; Das et al., 2012], and copy number variations phenol extraction method. PCR amplification of the SRY gene
[Ghosh et al., 2014] have been reported less frequently. from genomic DNA was performed using a primer pair described
in Han et al. [2010], which results in a 714-bp amplification prod-
The frequency of DSD in the general horse population uct. Additional PCR primers for the equine Y chromosome
is most likely underestimated, because a substantial num- (ECAY) contigs [Paria et al., 2011] were used: YM2 (contig I, 119
ber of affected individuals appear phenotypically normal bp) [Wallner et al., 2004], YE1 (contig II, 199 bp) [Wallner et al.,
and are never presented to a veterinarian for clinical ex- 2004], NLGN4Y (contig III, 156 bp) [Paria et al., 2011], AMELY
amination. Whereas the majority of mares undergoing (contig IV, 160 bp) [Hasegawa et al., 2000], ZFY (contig V, 342
bp) [Lindgren et al., 2001].
chromosome analysis have a history of sub-fertility
[Pieńkowska-Schelling et al., 2016], ambiguous external
genitalia [Bugno-Poniewierska et al., 2014], or deviant
behavior [Bodvarsdottir et al., 2009; Peer et al., 2012], Results
some DSD mares are identified on the occasion of breed-
ing soundness examinations [Pieńkowska-Schelling et Clinical Examination
al., 2014; present case]. On the day of the presentation of the mare, there were
The present report describes a phenotypically female no specific clinical findings with the exception of atro-
horse with gonadal dysgenesis and an unusual mosaic phic muscles in the croup. Examination of the external
karyotype. genitalia revealed a vulva with a vertical position and a
Caslick index <50. The total vulvar opening was 5 cm in
length and the ventral part of the vulva did not seal ap-
Materials and Methods propriately. Trans-rectal palpation and ultrasonogra-
phy revealed very small ovaries without follicular devel-
Animal opment. The estimated length, width, and height of the
A 4-year-old Trakehner mare (born 2011) showed no signs of
heat when teased to different stallions. Upon trans-rectal examina- left and right ovary were 10 × 5 × 5 and 10 × 10 × 5 mm,
tion, the private veterinarian diagnosed small ovaries and referred respectively. The uterus was also very small (estimated
the horse to the clinic. The medical history of the horse showed diameter of uterus horns was 10 mm) with a homoge-
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DSD in a Mare with 63,X/64,Xdel(Y) Sex Dev 2018;12:232–238 233

DOI: 10.1159/000490861
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 a

Fig. 1. a Longitudinal section of the left

ovary showing absence of follicles. b Dorsal
view of the uterine body with short uterine
c b
horns. c Absence of a uterine cervix.

a b c

Fig. 2. Three metaphases of the mare with DSD. CBG-banded metaphases with karyotype 63,X (a) and 64,X+mar
(b). Arrows indicate the X chromosomes and the marker chromosome (M). c Metaphase with karyotype 64,X+mar
after hybridization with a whole equine Y chromosome painting probe. Arrows indicate the marker chromosome
and the heterochromatic band on the long arm of the X chromosome (Xq17q21).

neous echotexture. It was not possible to verify the exis- Cytogenetic and Molecular Analysis
tence of the cervix uteri. The vagina appeared to be nor- After Giemsa staining, CBG- and DAPI-banding of
mal. These results were confirmed by a postmortem ex- metaphase chromosomes from blood lymphocytes, 2 dis-
amination of the genital tract. Both ovaries were very tinct cell lines were obvious. CBG-banding showed that
small without growing follicles (Fig. 1a), and histologi- in 70% of the cells only 63 chromosomes including 1 X
cally no testicular tissue could be seen (not shown). The chromosome were visible (63,X) (Fig. 2a). In the remain-
uterus was underdeveloped with very short uterine ing cells, we observed 63 chromosomes (including an X
horns (Fig.  1b), and the cervix was not developed chromosome) and an additional marker chromosome
(Fig.  1c). Histology of the endometrium revealed the (64,X+mar) (Fig.  2b). The autosomes appeared normal
presence of few uterine glands and no signs of fibrosis with no visible gross structural aberrations. CBG-band-
or inflammation (not shown). ing showed that the marker chromosome consisted of
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234 Sex Dev 2018;12:232–238 Neuhauser/Handler/Schelling/

DOI: 10.1159/000490861 Pieńkowska-Schelling
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 Discussion

Disorders of sex development are a major cause of in-

fertility and congenital abnormalities in the horse [Lear
and McGee, 2012], and consequently, reproductive fail-
ure and sexual ambiguity are among the foremost reasons
for performing chromosome analyses in this species.
Pure monosomy X and its mosaic forms as well as male-
to-female sex reversal are the most common findings in
mares with gonadal dysgenesis [Lear and McGee, 2012],
but the former are rather rarely reported in other domes-
tic species. In horses, including the present case, numeri-
cal and structural chromosomal abnormalities involving
Fig. 3. Partial metaphase with telomeric signals (counterstained the equine X chromosome are often associated with mo-
with DAPI) of the cell line with the marker chromosome. Arrow saic karyotypes [Durkin et al., 2011]. The acrocentric
points to the distal end of the rudimentary Y chromosome.
equine Y chromosome is quite particular. It is mainly
composed of heterochromatin and the euchromatic re-
gion is located distally on the long arm with a rather small
heterochromatin only (Fig. 2b), similar to the equine Y PAR region. It has been suggested that the size of the PAR
chromosome. Therefore, an equine whole Y chromo- itself might be related to the differences in frequencies for
some painting probe was hybridized to metaphase chro- X mosaicism observed between species [Raudsepp et al.,
mosomes. In the 64,X+mar cell line clear signals were 2012]. In addition, in contrast to the situation in humans,
seen on the entire length of the marker, proofing its Y the equine SRY gene is located proximally of the MSY, far
origin and along the heterochromatic band of Xq17q21 from the PAR region [Raudsepp et al., 2004].
(Fig. 2c). In the 63,X cell line, signals were restricted to Based on the results, the mare presented in this report
the heterochromatic band of the X chromosome (not showed a form of DSD associated with abnormalities of
shown). Because of the known extensive length variation the sex chromosomes. The entire internal genital tract of
of the equine Y chromosome [Power, 1988], it is difficult the mare was underdeveloped with small inactive ovaries,
to make a statement about the size of the rather small and a cervix uteri was not detectable. Histologically, there
marker chromosome. It cannot be ruled out that parts of was no evidence for the presence of testicular tissue in the
the heterochromatin were affected by the deletion. There- ovaries. Cytogenetic analyses of blood lymphocytes re-
fore, it is not possible to determine the exact breakpoints vealed an unusual mosaic karyotype consisting of 63,X
of the deletion. FISH signals with a human telomeric and 64,Xdel(Y) cells with frequencies of 70 and 30%, re-
probe (25 spreads analyzed) were observed only at the spectively. It has to be stressed that these findings may not
distal end of the marker chromosome (Fig. 3). Based on be representative for other tissues like it has been shown
the irregular segregation of this marker chromosome, for intersex horses before [Höhn et al., 1980].
without other scientific proof, we suspect that its centro- The majority of cells analyzed for the mare showed
mere is not fully functional. Taking the cytogenetic re- monosomy of the X chromosome which results in haplo-
sults together, the karyotype of the mare is best described insufficiency of PAR and non-PAR genes that escape X
by 63,X/64,Xdel(Y). inactivation. The second cell line of the mare carried a
PCR analysis revealed no amplification of a PCR prod- rudimentary Y chromosome in which the entire MSY,
uct with the expected length of 714 bp for SRY. However, and most likely also the PAR region, were deleted. Again,
there were 2 shorter amplification products visible (not there is a dosage problem for the PAR genes. PCR analy-
shown) with a length of ca. 580 and 260 bp, which were sis was applied to characterize the size of the deletion. It
sequenced, analyzed by BLAST (EquCab2.0 sequence), confirmed the deletion of the entire male-specific part of
and matched with NC_009167.2 (ECA24) and the Y chromosome, including the SRY gene. Further-
NC_009154.2 (ECA11), respectively. There was no ampli- more, without experimental prove, we assumed that the
fication of YM2, YE1, NLGN4Y, AMELY, and ZFY, repre- genes of the PAR were deleted, too. Using primer pairs
senting contigs I, II, III, IV and V of the equine male-spe- for the SRY gene, 2 clear amplification products of short-
cific region of the Y (MSY), respectively (not shown). er length were detected. Because we never observed these
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DSD in a Mare with 63,X/64,Xdel(Y) Sex Dev 2018;12:232–238 235

DOI: 10.1159/000490861
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PCR products from DNA of stallions or geldings, they with a Y isochromosome (Yq) in conjunction with a 63,X
were further characterized. The PCR primers for the SRY cell line were reported [Herzog et al., 1989; Das et al.,
gene seem to bind to 2 similar binding sites present on 2012]. Both cases had the Y isochromosomes which were
equine chromosomes 11 and 24, respectively. This ampli- composed of 2 long arms, resulting in genetic Y disomy
fication probably may have resulted just from the lack of and overdose of PAR genes. Interestingly, the cells carry-
true binding sites on the Y chromosome which are not ing the Y isochromosome strongly differed in their fre-
present in mares or in intersexes like the present case. To quencies (89 vs. 4%) without big phenotypic differences.
clarify a possible biological consequence, additional work Another report on 18 mares demonstrated molecular het-
is needed. erogeneity of sex reversal in horses [Raudsepp et al.,
Therefore, based on the cytogenetic and molecular re- 2010]. Two of these mares (SRY-negative) with gonadal
sults, the present horse should exhibit the phenotype of a dysgenesis had a large deletion of the Y chromosome, re-
mare with a pure 63,X chromosomal constitution. moving the entire euchromatic and PAR region in one
In humans, 45% of Turner patients show full aneu- case and contig I as well as parts of heterochromatin
ploidy 45,X, and the remaining 55% consist of 45,X mosa- (proximal of contig I) in the other case. Their phenotype
ics with or without a Y chromosome [Zhong and Layman, regarding the internal genital tract was similar to the mare
2012; Ackermann and Bamba, 2014]. However, the exis- presented here, and, noteworthy, one mare had a malfor-
tence of pure 45,X individuals, for at least in humans, has mation of the cervix uteri. However, these 2 mares were
been challenged. Because sex chromosome monosomies not mosaics and had normal numerical 64,XY karyo-
45,X or 45,Y are considered not to be compatible with life, types. The authors suggested that the deletions are the
it has been suspected that individuals with full 45,X aneu- result of interchromatide recombination events between
ploidy might be cryptic mosaics for which the detection repeated sequences of the Y chromosome, leading to dele-
of the 46,XX cell line is difficult [Hook and Warburton, tions and duplications. In the case of the present mare, we
2014]. Interestingly, in our certainly restricted clinical speculate that a normal oocyte of her mother with 31 au-
material consisting of 46 mares, which were karyotyped tosomes and an X chromosome was fertilized by a sperm
for subfertility (19), breeding soundness examination carrying this rudimentary Y chromosome. The lack of a
(15), deviant behavior (5), malformations (4), and abnor- SRY gene product guided the embryo into a female direc-
malities of the genital tract (3), we never observed a full tion. Because of the not fully functional centromere of the
monosomy X [Schelling, unpublished]. rudimentary Y chromosome, its segregation was dis-
Despite of the important function of the Y genes for turbed and led to a loss in part of the cells and mosaicism.
male fertility, relatively few chromosomal aberrations The clinical findings as well as postmortem and histo-
have been reported for domestic species [Raudsepp and logical examinations of the uterus and gonads together
Chodhary, 2016]. In humans, Y microdeletions are fre- with the cytogenetic and molecular results confirm the
quently found in men with fertility problems [Colaco and conclusive diagnosis of a DSD associated with sex chro-
Modi, 2018]. Large deletions of the Y chromosomes are mosome abnormalities. Although chromosomal aberra-
rarely reported and may result in infertile men with some tions are known to reduce fertility in horses, awareness
manifestations of Turner syndrome [Fitch et al., 1985]. among breeders and veterinarians for cytogenetic analy-
Several cases of 65,XXY or 65,XYY cell lines in con- ses allowing for an optimized diagnosis and reliable prog-
junction with a 63,X or a 64,XX cell line have been re- nosis on fertility in problem mares is still poor. Hence,
ported in horses [Bouters et al., 1975; Höhn et al., 1980; analysis of chromosomes along with molecular analyses
Paget et al., 2001]. In addition, similar but distinct mo- of sub-fertile mares should always be taken into consid-
saic karyotypes including a 63,X cell line have been re- eration for an encompassing breeding soundness exami-
ported in intersex horses. Bugno et al. [2008] presented a nation.
case of a male pony with 3 blood cell lines 63,X, 64,XX,
and 65,XXdel(Y)(q?). The deletion of the Y chromosome
was comparable with the one seen in the present case, re- Acknowledgement
sulting in a loss of genes of the MSY and probably in hap-
Laboratory work was partly performed using logistics of the
loinsufficiency of the PAR genes. However, this horse had
Center for Clinical Studies at the Vetsuisse Faculty (University of
a small penis inside the vulva and small inguinal testes, Zurich). The authors would like to thank Benita Pineroli for her
indicating an effect through a SRY gene product during excellent laboratory work.
development. Two other chromosomally mosaic horses
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236 Sex Dev 2018;12:232–238 Neuhauser/Handler/Schelling/

DOI: 10.1159/000490861 Pieńkowska-Schelling
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 Statements of Ethics Disclosure Statement

The authors have no ethical conflicts to disclose. The authors have no conflicts of interest to declare.

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