Hindawi Publishing Corporation
Case Reports in Genetics
Volume 2014, Article ID 597314, 5 pages
http://dx.doi.org/10.1155/2014/597314
Case Report
A Turner Syndrome Patient Carrying a Mosaic Distal
X Chromosome Marker
Roberto L. P. Mazzaschi,1 Juliet Taylor,2 Stephen P. Robertson,3
Donald R. Love,1,4 and Alice M. George1
1
Diagnostic Genetics, LabPlus, Auckland City Hospital, P.O. Box 110031, Auckland 1148, New Zealand
Genetic Health Service New Zealand-Northern Hub, Auckland City Hospital, Private Bag 92024, Auckland 1142, New Zealand
3
Department of Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, P.O. Box 913,
Dunedin 9054, New Zealand
4
School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
2
Correspondence should be addressed to Alice M. George; [email protected]
Received 31 December 2013; Accepted 5 February 2014; Published 17 March 2014
Academic Editors: M. Fenger, G. Vogt, and X. Wang
Copyright © 2014 Roberto L. P. Mazzaschi et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A skin sample from a 17-year-old female was received for routine karyotyping with a set of clinical features including clonic
seizures, cardiomyopathy, hepatic adenomas, and skeletal dysplasia. Conventional karyotyping revealed a mosaic Turner syndrome
karyotype with a cell line containing a small marker of X chromosome origin. This was later confirmed on peripheral blood cultures
by conventional G-banding, fluorescence in situ hybridisation and microarray analysis. Similar Turner mosaic marker chromosome
cases have been previously reported in the literature, with a variable phenotype ranging from the mild “classic” Turner syndrome
to anencephaly, agenesis of the corpus callosum, complex heart malformation, and syndactyly of the fingers and toes. This case
report has a phenotype that is largely discordant with previously published cases as it lies at the severe end of the Turner variant
phenotype scale. The observed cytogenetic abnormalities in this study may represent a coincidental finding, but we cannot exclude
the possibility that the marker has a nonfunctioning X chromosome inactivation locus, leading to functional disomy of those genes
carried by the marker.
1. Introduction
Turner syndrome (TS) presents with a characteristic mild
phenotype with some degree of variability [1]. The majority of
patients have short stature, are infertile, and do not develop
secondary sexual characteristics. Less consistent abnormalities include webbed neck, renal malformations (>50%),
and cardiac defects (10%), while intelligence is considered
normal. Approximately three-quarters of TS females inherit
their X chromosome maternally [2].
Turner syndrome mosaics are also well documented and
can be subcategorised according to whether the second cell
line contains a whole or part of a sex chromosome. Jacobs et
al. (1997) showed that, of 84 Turner syndrome cases with a
standard karyotype of 45,X, 16% were mosaic, with a second
cell line containing a ring X chromosome (45,X/46,X,r(X))
[3]. The phenotypic variability of these mosaics is largely
dependent on the size of the ring and the presence of a
functioning XIST.
XIST is a cis-acting gene in the X-inactivation centre
(XIC), located in band Xq13. As a general rule, when one
X chromosome has an imbalance that does not involve
an autosome, the XIC on the abnormal X chromosome
is activated. This activation leads to nonrandom skewing
of X chromosome inactivation, with the XIST transcript
inactivating the abnormal chromosome. The phenotype of
this group of patients is generally that of a mild Turner variant
phenotype [2].
Marker or ring X chromosomes (r(X)) lacking a functional XIST confer functional disomy of the duplicated
region, which is expected to lead to a more severe phenotype.
With the exception of mental retardation/developmental
delay, they also share little phenotypic concordance. Migeon
et al. (2000) described two TS variant mosaic cases with large
2
imbalances and intact XIST regions on their markers [4].
These patients presented with mental retardation and fall into
the category of “tiny ring X syndrome.”
The mechanism for generating ring chromosomes is
thought to be initiated by two chromosome breakage events
occurring at either side of a centromere, followed by fusion
of the two broken ends of the centromere-containing fragment [1]. This event is thought to occur at meiosis. Nonring marker chromosomes require the additional step of
telomere addition/formation at the broken ends. Ring chromosomes bring the added complication of “ring chromosome
syndrome,” whereby concentric rings are generated at cell
division, with the inevitable nondisjunction, leading to more
than one copy being present in some cells (also referred to as
dynamic mosaicism).
Here we report a case which, from a cytogenetic viewpoint, appears to represent a relatively straightforward example of a Turner syndrome variant mosaic karyotype, with a
small marker chromosome of X chromosome origin. However, from a clinical perspective, this case study has a rather
severe phenotype that does not fit with patients previously
reported in the literature. The final karyotype was based on
a combination of FISH analysis, as well as conventional (Gbanded) and molecular (microarray) karyotyping.
2. Case Report
The proband presented at nine months of age with poor
growth/failure to thrive (below the 3rd percentile for her
weight, length, and head circumference) and global developmental delay. There followed a lengthy period of deterioration, with additional problems including type I diabetes
(at 10 years of age), clonic seizures, cardiomyopathy, hepatic
adenomas, and skeletal dysplasia. Prior to initial karyotyping,
a DNA sample was sent for entire mitochondrial DNA
genome sequencing, which did not identify any pathogenic
mutations. The gene for Wolcott-Rallison syndrome (WRS),
EIF2AK3, was also sequenced but returned a negative result.
At 22 years of age she was assessed as functioning at the
level of a 5-year-old child. She had delayed secondary sexual
characteristic development and now presents with partial
ovarian failure and growth hormone deficiency. The medical
history of the rest of the family provided no additional
information other than the proband having a brother with
Asperger syndrome.
Three long-term closed flask fibroblast explant cultures
were set up according to the protocol adapted from Rooney
(2001) [5] when the proband was 17 years of age. G-banded
chromosome preparations (at a resolution of 400 bands per
haploid set) were made following the Seabright protocol
[6]. 20/35 (57%) cells had a 45,X karyotype with a single
X chromosome while the remaining cells had 46 chromosomes, with a single X chromosome and an additional small
marker chromosome (possibly a ring), of unknown origin.
Additional fluorescence in situ hybridisation testing was
carried out on interphase nuclei of subcultured fibroblasts
using the (Vysis) Aneuscreen FISH probe set (cenX (DXZ1),
cenY (DYZ3), 13q14 (RB1), cen18 (D18Z1), and 21q22.13q22.2 (D21S259/D21S341/D21S342)). In the case of mosaicism
Case Reports in Genetics
studies, a larger number of interphase nuclei were scored (at
least 200), compared to our standard analysis of a minimum
of 50 nuclei per probe set. The result was consistent with
a female karyotype with a single X chromosome (Turner
syndrome) in most nuclei, with a low-level two-copy X
centromere signal pattern seen in 8/214 nuclei. The apparent
discordance between the G-banded karyotype and later FISH
analysis may be due to random loss of the marker cell line
through continued subculturing.
A peripheral blood sample in lithium heparin was recommended at a higher chromosome band resolution (550 bands
per haploid set) for further characterisation of the marker.
G-banded (conventional) karyotype analysis on peripheral
blood synchronised cultures using a modified method of
Gallo et al. [7] confirmed the fibroblast culture findings,
with 16/30 (53%) cells having a single X chromosome and
14/30 (47%) having the additional marker chromosome of
unknown origin. FISH studies using the Vysis Xcen (DXZ1),
Ycen (DYZ3), and Yp11.3 (SRY) probes on metaphase spreads
were also carried out (Figure 1). The Xcen probe of centromeric alpha satellite DNA covered the region Xp11.1-Xq11.1
and hybridised to the normal X chromosome centromere and
the marker in 9/30 (30%) cells. The remaining 21/30 (70%)
cells, which lacked the marker, only showed hybridisation to
the X chromosome centromere. This was considered to be
a more reliable result than the previous interphase FISH of
cultured fibroblast cells. The proportion of the two cell lines
showed concordance with the G-banded karyotype results of
both tissue types. No hybridisation of Y centromere or SRY
probes were detected on the marker or other chromosomes.
Parental blood samples were requested but never received.
Five years later an EDTA peripheral blood sample was
received for molecular karyotyping as previously described
[8]. Microarray analysis was carried out on extracted DNA
using the Affymetrix Cytogenetics Whole Genome 2.7 M
Array, Affymetrix Chromosome Analysis Suite (ChAS)
v1.0.1/na30.1. An abnormal female mosaic molecular karyotype was determined as arr[hg18] Xq11.1q21.1(61,934,83578,510,961)x1∼2. This result indicated the presence of two
genotypes: one with a single X chromosome complement,
with no Y chromosome, and another of a single X chromosome complement with a 16.6 Mb duplication of X chromosome material from Xq11.1q21.1 (Figure 2), again with no Y
chromosome.
An estimate of the level of mosaicism could not be
made based on the microarray data. Taken together, the data
suggest a mosaic marker chromosome comprised of an X
centromere (from FISH) and pericentromeric euchromatin
from the long arm of the X chromosome, including the X
inactivation locus XIST. Due to the limits of the microarray assay (there is no probe coverage for centromeres or
telomeres), the finding of X centromeric hybridisation to the
marker detected on metaphase FISH could not be confirmed
by molecular karyotyping.
Finally, molecular X chromosome inactivation analysis
was attempted in order to determine if the marker
chromosome was being expressed. If the marker was
active, functional disomy for the included genes could
provide an explanation for the observed severe phenotype.
Case Reports in Genetics
3
(a)
(b)
Figure 1: FISH analysis of the proband’s cells. (a) The X chromosome centromere probe (Spectrum Green; DXZ1) on an inverted grey scale
DAPI-stained metaphase spread shows hybridisation to both the normal X homologue and the marker chromosome. (b) X chromosome
centromere probe (Spectrum Green; DXZ1) with a chromosome 18 centromere probe (Aqua; D18Z1) as a control. 1-2 X centromere signals
per interphase nucleus can be seen.
ChrX (q11.1q21.1)
p22.2
21.1
Xq21.1
11. 1
q22.3
Xq23
24
Xq25
Xq28
(a)
Human Mar. 2006 (NCBI36/hg18) chrX: 61,934,835–78,510,961(16,576,127 bp)
5 Mb
Scale
chrX:
65,000,000
hg18
70,000,000
75,000,000
OMIM genes, dark green, are disease-causing
300429
300647
300891
300889
300276
309845
300694
300353
300167
300127
300451
300883
300252
300025
300379
300760
313700
300035
300714
300033
300687
300181
300135
300759
300689
300139
304040
312760
314670
300656
300420
300038
300061
300149
300832
300576
301770
300084
300269
300095
300632
300332
311870
300524
300521
300452
300878
300189
300255
300026
300311
300443
308380
300188
300336
313650
300369
300574
300827
300086
300032
300529
300715
300222
300885
300011
300567
311800
300754
300201
Refseq genes
SPIN4
LOC92249
ARHGEF9
ARHGEF9
ARHGEF9
ASB12
ZC3H12B
EDA2R
ZC4H2
MSN
ZC4H2
MIR223
ZC4H2
VSIG4
ZC4H2
VSIG4
MIR1468
ZC4H2
VSIG4
AMER1
LAS1L
EDA2R
LAS1L
EDA2R
MTMR8
LAS1L
FRMD8P1
VSIG4
VSIG4
HEPH
HEPH
HEPH
AR
EFNB1
EDA
SNX12
RGAG4 NAP1L6
JPX
ABCB7
PBDC1
FGF16
ZCCHC5
AR
PJA1 AWAT2
SNX12
PIN4
CDX4
RLIM
TTC3P1
MIR384 MAGT1
LPAR4
OPHN1
PJA1
IGBP1 SNX12
PIN4 NAP1L2
FTX
UPRT
MAGEE1
ATRX
LPAR4
YIPF6
EDA
SNX12
PIN4
MAP2K4P1
RLIM
MAGEE2
ATRX
MIR4328
YIPF6
EDA
SNX12
ERCC6L
CHIC1
ABCB7
COX7B
P2RY10
STARD8
EDA
SLC7A3
NHSL2
TSIX
ABCB7
ATP7A
GPR174
STARD8
EDA
SLC7A3
FLJ44635
XIST
ABCB7
PGAM4 P2RY10
STARD8
MIR676
FOXO4
RPS4X
MIR374B
UPRT
PGK1
ITM2A
PJA1
AWAT1
IL2RG
CITED1
MIR374C ZDHHC15
TAF9B
ITM2A
FAM155B GDPD2
GJB1
CITED1
MIR545 ZDHHC15
CYSLTR1
OTUD6A
FOXO4
CITED1
MIR374A ZDHHC15
DGAT2L6 MED12
CITED1
ZCCHC13
P2RY4 NLGN3
HDAC8
SLC16A2
ARR3
GJB1
HDAC8
KIAA2022
RAB41 ZMYM3
HDAC8
ABCB7
PDZD11 ZMYM3
HDAC8
KIF4A
NONO
HDAC8
GDPD2 NONO
HDAC8
GDPD2 NONO
HDAC8
GDPD2 NONO
PHKA1
DLG3
TAF1
PHKA1
DLG3
TAF1
PHKA1
DLG3
INGX
FAM226A
TEX11
FAM226B
TEX11
LINC00684
CXorf65
DMRTC1
CXorf65
DMRTC1B
NLGN3
DMRTC1
NLGN3
DMRTC1B
ZMYM3
LINC00684
ZMYM3
FAM226B
ITGB1BP2
FAM226A
OGT
PABPC1L2B
OGT
PABPC1L2A
ACRC
CXCR3
CXCR3
CXorf49
CXorf49B
CXorf49B
CXorf49
FLJ46446
LOC100132741
RPS26P11
(b)
Figure 2: Schematic of the chromosome X region comprising the marker X chromosome (a) shows an ideogram of chromosome X, together
with the region of the marker chromosome. (b) shows the OMIM and Refseq genes that lie on the marker chromosome. These graphics were
taken from the UCSC genome browser (http://genome.ucsc.edu/).
4
Unfortunately, X chromosome inactivation could not
be assessed due to the lack of informativeness at the X
chromosome amelogenin locus.
3. Discussion
In the case of a suspicion of Turner syndrome, a standard G-banded karyotype analysis is usually requested on
a peripheral blood culture. Interestingly, the case reported
here was not referred to confirm Turner syndrome but to
confirm/exclude Wolcott-Rallison syndrome, which involved
a number of metabolic and genetic tests.
Combining the conventional karyotyping and FISH
data together with molecular karyotyping has allowed for
the full characterisation of the genetic content of the
marker chromosome. This marker contained many genes,
including twenty-four classed by OMIM (Online Mendelian
Inheritance in Man; http://www.ncbi.nlm.nih.gov/omim) as
disease-causing. Of these, OPHN1, IGBP1, DLG3, NLGN3,
and ZDHHC15 are associated with mental retardation or
Asperger syndrome phenotypes. Bedeschi et al. [9] described
a case of a male with a duplication on the X chromosome
from Xq12 to Xq13.1, a region that includes the OPHN1
gene. He had severe mental retardation but an otherwise
discordant phenotype compared to the case described here.
This represents a much smaller duplication than our case
study and was also nonmosaic but is another example of
functional disomy of a part of the X chromosome. Hemmat
et al. [10] described a rare case of an acentric marker X
chromosome containing an activated neocentromere distal to
this case study, at Xq21.2. This example raises the possibility
of a similar sequence (of DNA with a degree of homology to
centromeric sequences) being present in the marker of the
case described here, which has been forced into activation to
give it stability in cell division. This suggestion is compatible
with the observed cytogenetic findings.
Migeon et al. [4] described two TS variant mosaic cases
similar in appearance to our case study, but with larger
imbalances, with intact XIST regions on their markers.
They presented with mental retardation but an otherwise
discordant severe phenotype to the case study reported here.
These, as with most small r(X) cases in the literature, were
published before microarray analysis was available, making
gene content comparisons with this case difficult. It should
also be noted that the marker chromosome is described as
a ring based only on its G-banded appearance. However,
telomere FISH studies have not been carried out, and so the
possibility that the marker has telomeres, and is not a ring,
cannot be excluded.
SNP (Single Nucleotide Polymorphism) analysis (data
not shown) revealed homozygosity along the entire length
of the X chromosome, including the region of disomy (the
marker chromosome). Heterozygosity would have indicated
the involvement of a second nonhomologous X chromosome
(presumably from the other parent), in the formation of
the marker. While not conclusive, our data suggest that the
marker X may well have been derived from the normal X
chromosome already present, rather than from a second
chromosome X homologue.
Case Reports in Genetics
Ring chromosomes also raise the possibility of “ring
chromosome syndrome” occurring. At the DNA duplication
phase of the cell cycle, concentric rings can accidentally
be generated prior to cell division, with the inevitable
nondisjunction leading to more than one copy of the ring
segregating into some cells, which is also referred to as
dynamic mosaicism. However, there was no evidence of “ring
chromosome syndrome” in the G-banded analysis or FISH
results. For non-ring marker chromosome formation, the
additional steps of telomere generation and capping need to
occur at the broken ends of the forming marker in order to
confer chromosome stability.
For the purposes of this discussion, the mosaic marker
can be considered as a 16.6 Mb gain of X chromosome
material (from Xq11.1q21.1), against a Turner syndrome
genotype background. As already discussed, the phenotypic effect of genes on the marker would only apply if
a nonfunctioning copy of XIST was present. The marker
did contain many genes, including twenty-four classed by
OMIM as disease-causing (Online Mendelian Inheritance
in Man (OMIM); http://www.ncbi.nlm.nih.gov/omim). Of
these, OPHN1, IGBP1, DLG3, NLGN3, and ZDHHC15 are
associated with mental retardation or Asperger syndrome
phenotypes. Bedeschi et al. [9] described a case of a male
with a duplication on the X chromosome from Xq12 to
Xq13.1, a region including the OPHN1 gene. He had severe
mental retardation, but an otherwise discordant phenotype
compared to the case study. This is included here as it
represents an example of functional disomy for the region
of the X chromosome under investigation (although the
reported case was much smaller, nonmosaic, and in a
male).
Turner syndrome variants include female individuals
with partial deletions in the “p” and/or “q” arms of one X chromosome. Deletions of certain X chromosome regions/genes
can lead to specific phenotypic features which are characteristic of “full” or “classic” Turner syndrome. Deletions
of the SHOX gene, located in the PAR (pseudoautosomal
region) at Xp22.33, are associated with short stature although
this characteristic TS feature is not noted in the case study.
Primary ovarian failure (POF) has been associated with
deletions of the FMR1 gene (POF1) at Xq26–q28 [11] and the
DIAPH2 gene (POF2A) at Xq21.33 [12]. Type I diabetes has
also been linked to the Turner syndrome phenotype [13].
The difficulty presented to the genetic counselors in
this case was in trying to correlate the cytogenetic findings
with the patient’s phenotype. This patient was thought to
represent an example of the severe end of the Turner syndrome spectrum, in tandem with poorly controlled diabetes.
Hepatic adenomas had been previously reported in a child
with Turner syndrome on growth hormone supplementation
[14]. The karyotypic findings were considered to provide a
unifying diagnosis for the patient’s multiple comorbidities.
The parents of this case study have not been karyotyped,
making it impossible to give a risk of recurrence for future
pregnancies. Similarly, the presence of this ring in a parent
could also provide more information concerning a genotypephenotype correlation. Transmission of ring X chromosomes
has been previously described in both male and female
Case Reports in Genetics
offspring. However, although all these cases involved nonsupernumerary chromosomes, the rings were substantial in
size with breakpoints more distal than those seen in this case
[1].
4. Conclusions
This case study represents the coincidental finding of an
individual with a severe set of clinical abnormalities and a
Turner syndrome mosaic karyotype. The cytogenetic findings
can be used to account for some of the observed phenotypic
features, but the paucity of similar cases published in the
literature makes a genotype-phenotype correlation difficult.
We consider it likely that our patient’s observed severe
phenotype is due to functional disomy for those genes carried
on the marker chromosome.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
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