Hannah Riley
Dr. Ely
Genetics
November 1, 2014
Effects of Hormone Treatments on Turner Syndrome Patients
Turner Syndrome (TS) is a genetic condition identified by the partial or complete
absence of a second X chromosome. Only present in women, TS causes several diverse
side effects that include short stature, infertility due to genital dysfunction, learning and
social difficulties, and scoliosis (Ross, 2014). Fortunately, there are treatments that use
growth hormones to minimize these effects when administered before growth has
stopped. These treatments are not perfect, however, and may cause undesirable side
effects. Research on TS and its effects before and after treatment continues in labs across
the country in an attempt to better understand the disease and to continue to develop more
effective treatments thereof.
Turner Syndrome, like many diseases and conditions, was named after its
discoverer. In 1938, Henry Turner was faced with a mystery when the pituitary extracts
that were typically used to treat dwarfism at the time were ineffective when used on his
seven patients that exhibited signs of dwarfism and a lack of sexual development (Turner,
1938). His report on the description of his patients following this experience became the
foundation upon which research on Turner Syndrome was based. Since the initial
discovery of Turner Syndrome, many studies have been performed that have expanded on
the various symptoms, potential treatments, and, more recently, the genetic coding
common to TS patients. Karyotypes of TS patients have shown a partial or complete
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haploinsufficiency of the second X chromosome. The loss of an entire chromosome, even
in mosaic cases, results in a drastic change in gene expression that causes the phenotypic
symptoms characteristic of TS. In the study performed by Rajpathak et al. (2014), 45,X
and 46,XX karyotypes were compared in order to determine the differences in gene
expression between TS patients and an unaffected control group. Illumina RNA
sequencing was performed of both samples using the Trizol method. As seen in Figure 1,
the gene expression in the 45,X karyotype is significantly shifted from the control 46,XX
expression. Specific differentially expressed genes were selected for further
identification. The differences in expression between these genes are shown in Figure 2.
Figure 2: Relative Expression of Select Genes in 45,X and 46,XX karyotypes
The study showed that BMP2, a gene involved in bone mineralization, growth and
development, was expressed at a lower level in 45,X patients, resulting in the short
stature and scoliosis common to TS patients. CLDN11 is involved in spermatogenesis,
and so its enhanced expression may result in the gonadal dysfunction in TS. BMPER
inhibits BMP, therefore
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its increased expression results in less expression of BMP2. STC1 is involved with
paracrine regulation and follicular development, its lower expression contributing to the
frequent infections in TS patients. Xist is a long non-coding RNA that assists in X
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chromosomal inactivation. It is transcribed from the second X chromosome and so goes
unexpressed in the 45,X karyotype (Rajpathak, et al). The alteration of so many different
genes in TS patients has lead to a higher chance of other genetic conditions in these
patients.
Patients of TS have shown to be more susceptible to autoimmune diseases than
their healthy counterparts. These defects occur most often in the form of thyroid
abnormalities. In the experiment conducted by Bianco et al. (2012), the susceptibility of a
patient to these autoimmune diseases was traced to a number of genetic polymorphisms,
which in turn alter the function of the vitamin D receptor gene. In order to test the link
between Turner Syndrome and these abnormalities, 101 TS patients and a control group
of 133 fertile women had peripheral blood samples taken and examined in several ways.
A cytogenetic analysis was performed under standard protocols to determine the
karyotype of each subject, followed by a molecular analysis of the peripheral blood under
standard protocol. The VDR polymorphisms were analyzed using the TaqMan system
under the Rotor-Gene Q 6 plex Platform using primers and probes for TaqI, BsmI, FocI,
and ApaI (Table 1). While Turner’s Syndrome correlates with an increase risk of
autoimmune disease, this risk does not appear to be caused by the studied polymorphisms
of the VDR gene
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Table 1: The genotype and allele distribution of the VDR polymorphism in TS patients and controls.
TS is typically treated with growth hormone (GH) therapy with a supplement of
estrogen. The GH serves to minimize the effect of the under expressed BMP2 and
promote normal growth while the estrogen replacements counteract the effects of
CLDN11. Recent studies have discovered, however, that normalized growth is not the
only benefit to GH therapy. Kohno et al. (2012) performed a study to determine the effect
of GH therapy on the total cholesterol (TC) levels of TS patients. TC levels of 81 TS
patients were recorded before GH therapy and compared to the TC levels of unaffected
girls of the same age. GH therapy was then administered intravenously daily and TC
levels were measured after 1, 2, and 3 years of treatment for 28 of the TS patients.
Measurements before therapy showed an increase in TC with age in TS patients (Figure
3). Levels went unchanged in the healthy control group.
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Figure 3: TC levels by age
Figure 4 shows that after several years of GH therapy, the TS patients showed a
significant decrease in TC levels after 1 year with a consistently low TC level after.
Figure 4: TC levels after GH treatment
After years of GH therapy and estrogen replacements, TS patients can grow at an almost
normal rate and restore estrogen levels, allowing them to live an ordinary life. This study
suggests that there are further benefits to GH therapy than normalized growth, but with
any treatment there is sure to be a detrimental side effect.
Patients of TS often have a higher count of melanocytic nevi, commonly referred
to as moles, than healthy patients their same age. While most nevi are benign, some
become malignant and must be surgically removed, but benign nevi are often removed
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for cosmetic purposes. Kedzia et al. (2014) described a TS patient who underwent
surgery to remove four benign nevi while undergoing GH therapy. Three of the four sites
developed hypertrophic scars, an often painful, raised, and thick collection of collagen
resulting from higher production of collagen after a wound than normal, while the final
site developed a keloid, a scar that is similar to hypertrophic scars but the collagen
formation expands beyond the original wound area. While the development of
hypertrophic scars and keloids is an inherited trait that differs for each patient, the fact
that every surgical site developed one of these scars while the patient was undergoing GH
therapy suggests that the higher production of collagen was due to the growth hormones
used. As a result, it was recommended that any surgical procedures planned during the
GH therapy period be postponed if possible until after the completion of the therapy.
Despite the wide range of effects that Turner Syndrome has on a patient, effective
treatments have been developed that allow the patient to lead a life mostly unaffected by
their condition. While these treatments have flaws, research on Turner Syndrome will
continue to expand knowledge on the condition so the treatments will be improved upon
to the point where a woman with Turner Syndrome will be able to live her life with no
more difficulties than her healthy counterpart.
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Works Cited
Bianco B, Ieda Verreschi, Kelly Oliveira, et al. (2012) Analysis of Vitamin D Receptor
Gene (VDR) Polymorphisms in Turner Syndrome Patients. Gynecological
Endocrinology 28(4): 326-329. Doi: 10.3109/09513590.2011.631630
Kędzia A, Mariola Pawlaczyk, Elżbieta Petriczko. (2014) Hypertrophic Scars in a Patient
With Turner’s Syndrome Treated With Recombinant Growth Hormone. Postep
Derm Alergol 31(2): 117-120. doi: 10.5114/pdia.2014.40917
Kohno H, Yutaka Igarashi, Keiichi Ozono, et al. (2012) Favorable Impact of Growth
Hormone Treatment on Cholesterol Levels in Turner Syndrome. Clin Pediatr
Endocrinol 21(2): 29-34.
Rajpathak SN, Vellarikkal SK, Patowary A, Scaria V, Sivasubbu S, et al. (2014) Human
45,X Fibroblast Transcriptome Reveals Distinct Differentially Expressed Genes
Including Long Noncoding RNAs Potentially Associated with the
Pathophysiology of Turner Syndrome. PLoS ONE 9(6): e100076. doi:10.1371/
journal.pone.0100076
Ross, J. (n.d.). Turner Syndrome: Toward Early Recognition and Improved Outcomes.
Retrieved October 28, 2014, from http://www.medscape.org/viewarticle/445555
Turner HH. A syndrome of infantilism, congenital, webbed neck and cubitus valgus.
Endocrinology. 1938;23:566-574.