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Citation: Clemente, E.G.; Penukonda,
S.K.; Doan, T.; Sullivan, B.; Kanungo,
S. Turner Syndrome. Endocrines 2022,
3, 240–254. https://doi.org/10.3390/
endocrines3020022
Academic Editor:
Yukihiro Hasegawa
Received: 29 January 2022
Accepted: 4 May 2022
Published: 13 May 2022
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Review
Turner Syndrome
Ethel Gonzales Clemente 1, *, Sasi Kiran Penukonda 2, Tam Doan 3, Brittany Sullivan 3and Shibani Kanungo 3
1Department of Pediatric Endocrinology, Valley Children’s Healthcare, 9300 Valley Children’s Place,
Madera, CA 93636, USA
2WK Children’s Health Specialists, 2032 Elizabeth Avenue, Shreveport, LA 71104, USA;
spenukonda@wkhs.com
3
Department of Pediatric & Adolescent Medicine, Western Michigan University Homer Stryker M.D. School of
Medicine, 1000 Oakland Drive, Kalamazoo, MI 49008, USA; tam.doan@med.wmich.edu (T.D.);
brittany.sullivan@med.wmich.edu (B.S.); shibani.kanungo@med.wmich.edu (S.K.)
*Correspondence: eclemente@valleychildrens.org
Abstract:
Turner syndrome (TS) affects approximately 1 out of every 1500–2500 live female births,
with clinical features including short stature, premature ovarian failure, dysmorphic features and
other endocrine, skeletal, cardiovascular, renal, gastrointestinal and neurodevelopmental organ
system involvement. TS, a common genetic syndrome, is caused by sex chromosome aneuploidy,
mosaicism or abnormalities with complete or partial loss of function of the second X chromosome.
Advances in genetic and genomic testing have further elucidated other possible mechanisms that
contribute to pathogenic variability in phenotypic expression that are not necessarily explained by
monosomy or haploinsufficiency of the X chromosome alone. The role of epigenetics in variations of
gene expression and how this knowledge can contribute to more individualized therapy is currently
being explored. TS is established as a multisystemic condition, with several endocrine manifestations
of TS affecting growth, puberty and fertility having significant impact on quality of life. Treatment
guidelines are in place for the management of these conditions; however, further data on optimal
management is needed.
Keywords: Turner syndrome; epigenetics; growth; puberty
1. Introduction
Turner syndrome (TS) is a complex multisystem genetic condition, first described
in 1938 by an endocrinologist noting growth and congenital hypergonadotropic hypog-
onadism, with a reported prevalence of 1:2000 to 1:4000 among females [
1
,
2
]. It is a
heterogenous genetic disorder with 40–50% of patients having classic genotype 45,X and
the rest having a variety of mosaicisms [
2
,
3
]. There is a diverse range of phenotypic char-
acteristics, influenced by an individual’s karyotype. However, despite extensive research
showing the effects of haploinsufficiency of the X chromosome, exact mechanisms are
still not fully understood. More recent data support the role of altered gene expression
as a result of epigenetic mechanisms as contributory to the varied clinical manifestations
of TS [
4
], and is further discussed in this review. Furthermore, TS is associated with an
increased risk for a variety of health complications, and the particular interest of this review
are the endocrine-related manifestations and their subsequent management.
2. Etiology
2.1. Chromosomal Aberrations in TS
Turner Syndrome is considered to be the most common aneuploidy, although 99% of
congenital occurrences result in spontaneous abortion [
4
]. As with other aneuploidies, the
primary mechanism believed to contribute to TS is meiotic non-disjunction, a process which
leads to an unequal distribution of genetic material amongst daughter cells, such that some
Endocrines 2022,3, 240–254. https://doi.org/10.3390/endocrines3020022 https://www.mdpi.com/journal/endocrines
Endocrines 2022,3241
cells may have additional chromosomes, whereas others will have missing chromosomes
(Figure 1) [5].
Endocrines 2022, 3, FOR PEER REVIEW 2
that some cells may have additional chromosomes, whereas others will have missing chro-
mosomes (Figure 1) [5].
(a)
(b)
(c)
Figure 1. Comparison of (a) normal meiosis with (b) non-disjunction occurring in Meiosis I and (c)
non-disjunction occurring in Meiosis II.
Approximately 40–50% of individuals with TS have a monosomy (45,X) karyotype
[2], meaning that all cells only have one X chromosome; 15–25% have 45,X/46,XX mosai-
cism and another 10–12% have 45,X/46,XY mosaicism, meaning that some cells only have
one X chromosome, whereas others have two X chromosomes or X and Y chromosomes
[2]. Interestingly, in mosaic individuals, the distribution of cells with only one X chromo-
some and cells with two sex chromosomes does not need to be split evenly [6].
Other structural abnormalities of the X chromosome (Table 1), such as deletions,
translocations, ring formation and isochromes contribute to mosaic forms [7]. Large, in-
verted repeats within the short arm (p) of X chromosome at the Xp11.2 locus have been
found to create a complex repetitive architecture that predisposes it to rearrangements
that correlate to the isodicentric X chromosome formation that is the second most common
chromosomal abnormality associated with TS [8]. Additionally, studies have shown that
the parental origin for the single complete X chromosome is maternal (Xm) in 90% of cases
[9]. The origin of the abnormal or missing chromosome is inconclusive at this point, with
some studies demonstrating increased likelihood of maternal origin (Xm) for pseudo
Figure 1.
Comparison of (
a
) normal meiosis with (
b
) non-disjunction occurring in Meiosis I and
(c) non-disjunction occurring in Meiosis II.
Approximately 40–50% of individuals with TS have a monosomy (45,X) karyotype [
2
],
meaning that all cells only have one X chromosome; 15–25% have 45,X/46,XX mosaicism
and another 10–12% have 45,X/46,XY mosaicism, meaning that some cells only have one
X chromosome, whereas others have two X chromosomes or X and Y chromosomes [
2
].
Interestingly, in mosaic individuals, the distribution of cells with only one X chromosome
and cells with two sex chromosomes does not need to be split evenly [6].
Other structural abnormalities of the X chromosome (Table 1), such as deletions,
translocations, ring formation and isochromes contribute to mosaic forms [
7
]. Large,
inverted repeats within the short arm (p) of X chromosome at the Xp11.2 locus have been
found to create a complex repetitive architecture that predisposes it to rearrangements that
correlate to the isodicentric X chromosome formation that is the second most common
chromosomal abnormality associated with TS [
8
]. Additionally, studies have shown that
the parental origin for the single complete X chromosome is maternal (X
m
) in 90% of
cases [
9
]. The origin of the abnormal or missing chromosome is inconclusive at this point,
with some studies demonstrating increased likelihood of maternal origin (X
m
) for pseudo
Endocrines 2022,3242
dicentric and deletions of long arm (q) of X chromosome (X
q
) [
10
], paternal in origin
(X
p
) for deletions of short arm (p) of X chromosome, and the extremely rare cases of
abnormal Y chromosomes, but equally likely to originate in either parent in the case of
either isochromosome Xq or Ring X abnormalities. Other studies, however, postulate that
the majority of Turner syndrome karyotypes are caused by paternal meiotic or mitotic
errors, leading to dominance of the maternal X chromosome [11].
Table 1. TS karyotypes and description of associated structural abnormalities.
TS Karyotype Structural Abnormalities Mechanism
45,X Complete loss of second sex chromosome Monosomy X
45,X/46,XY
some cells only have one X chromosome
whereas others have one X and one
Y chromosome
Mosaicism
45,X/46,XX some cells only have one X chromosome
whereas others have two X chromosomes Mosaicism
46,X,del(X)
(p11.4)
Deletion in the short arm at of one of the
X chromosomes Deletion
46,X,r(X) Ring-like structure with ends of a
chromosome fused
Telomeric aberration resulting
in ring chromosome
46,X,i(Xq)
Duplication of the long arm and loss of short
arm of one of the X chromosomes Isochromosome
The X chromosome is important not just for sex determination, but also contains
several genes responsible for growth and development during the embryonic period and
any aberration or abnormal defects can ultimately lead to pathogenesis of TS disease
conditions. The ‘Gene Dosage Effect’ hypothesis also postulates that TS features can be
mapped to particular regions of the X-chromosome that are gene dosage sensitive [
12
].
However, phenotypic variability in TS cannot be explained by genomic imbalance alone.
It is postulated that other processes such as X-chromosome inactivation and altered gene
expression as a result of epigenetic factors are also contributory [4,13].
2.2. Contributions of X-Inactivation to the TS Phenotype
The genes on the short arm of X chromosome which escape X-inactivation are im-
plicated in the TS phenotype [
14
,
15
]. X-inactivation is the process by which one of the X
chromosomes is silenced to equalize the gene dosages between male and female mammals,
resulting in one functional copy of the X chromosome on all somatic cells [
16
]. Under
normal conditions, an X inactivation epigenetic process randomly methylates one of the
two X chromosomes present in each cell, so that the genes from only one X chromosome are
actively expressed. However, certain genes in the pseudoautosomal region 1 (PAR1) and
pseudoautosomal region 2 (PAR2) of the X chromosome may escape X-inactivation and still
be expressed, even if these genes are on the silenced X chromosome [
17
]. The Y chromo-
some in males also contains genes found on PARs; hence, both 46,XX and 46,XY individuals
express two copies of the pseudoautosomal genes that escape X-inactivation in females [
17
].
In contrast, for TS, cells with only one X chromosome lack the second copy of these pseu-
doautosomal genes or other genes that would typically escape X-inactivation due to not
having a second sex chromosome present. This results in decreased expression of those
genes, which is termed haploinsufficiency [
6
]. The degree of haploinsufficiency involved in
TS depends on the karyotype; the 45,X karyotype involves greater haploinsufficiency than
mosaic karyotypes.
An example of the contribution of haploinsufficiency associated with the skewed
inactivation pattern resulting from Turner syndrome karyotype is with respect to the
previously identified short stature homeobox, or SHOX gene, which is located on Xp22.23,
and thus far is the only gene that has been compellingly associated with TS attributes. SHOX
is expressed in bone marrow fibroblasts, which can give rise to osteogenic genes that can
contribute to bone growth [
18
]. This gene’s function is dosage-dependent, with decreased
Endocrines 2022,3243
gene expression or haploinsufficiency leading to short stature and other features such
as Madelung deformity, high arched palate, scoliosis and micrognathia [
19
,
20
]. Another
gene located in PAR1 is the CSF2RA gene [
17
], which could be implicated in the high
rates of in utero deaths associated with TS [
21
]. One study has shown that expression of
various genes that are active in the placenta, including CSF2RA, was higher in wild-type
human embryonic stem cells than in cells that had spontaneously lost an X chromosome
(mimicking the 45,X karyotype) [
21
]. Although haploinsufficiency of the SHOX gene could
interfere with growth in TS patients, haploinsufficiency of CSF2RA could interfere with
proper placental function.
Other genes on the X chromosome besides those found in PARs can also escape X-
inactivation. For instance, TIMP1 usually escapes X-inactivation, so TS would involve
haploinsufficiency of TIMP1, potentially promoting the formation of a bicuspid aortic valve
(rather than a normal tricuspid aortic valve) [
22
]. Of note, certain variants of TIMP3, a gene
located on chromosome 22, are also associated with bicuspid aortic valve, and decreased
expression of TIMP1 can heighten risk for heart defects if the individual has these TIMP3
variants [
22
]. The relationship between TIMP1 and TIMP3 indicates that the inadequate
expression of X chromosome genes combined with the presence of certain autosomal genes
can bring about the clinical manifestations seen in TS.
2.3. Role of Epigenetics in TS
Epigenetic differences that influence gene expression without altering base sequences
exist between 45,X and 46,XX individuals, with extensive hypomethylation throughout 45,X
genome compared to 46,XX individuals, apart from differences in hypermethylation [
23
,
24
]
Epigenetic modification and resulting altered gene expression can contribute to various
pathogenesis seen in TS. For example, differentially methylated genes such as STAT4 and
KDM6A can affect T helper 1 (T
H
1) cell development and function [
13
], and T follicular helper
(T
FH
) cells development [
25
], respectively, and contribute to resultant inadequate immune
responses and autoimmunity in affected TS individuals. KDM6A, implicated in ovarian
dysfunction in TS [22,26], is also differentially expressed in Klinefelter syndrome [23,27].
Levels of microRNA (miRNA), which can bind to mRNA to block translation into
protein, can also differ between TS and 46,XX patients. For example, blood samples from
TS patients had lower amounts of miR-126-3p compared to controls [
28
]. Furthermore,
miR-126-3p levels were higher in TS patients who had abnormal aortic valves compared to
TS patients who did not; miR-126-3p can limit Bcl-2 expression and lead to dysregulated
apoptosis in the heart [
28
]. Fetal gonadal tissues with a 45,X karyotype have decreased
amounts of KITLG protein compared to tissues with a 46,XX karyotype, and the difference
was found to be mediated by levels of miR-320a. In 46,XX individuals, KDM5C blocks
expression of miR-320a, allowing the expression of KITLG, which supports ovarian devel-
opment. However, since KDM5C escapes X-inactivation, haploinsufficiency of KDM5C
allows for increased levels of miR-320a to be present in 45,X individuals, thus leading to
deficient KITLG expression and possibly impaired ovarian development [
29
]. Thus, this
demonstrates that differences in miRNA abundance can influence the clinical presentation
of TS. Another example is how PPARGC1A promoter DNA methylation status affects
Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) independently of BMI
or age in TS subjects [30].
RPS4X and JPX are other escape genes that are also differentially expressed in TS;
however, their precise roles in TS pathogenesis are still to be elucidated [
31
–
33
]. The gene
IL3RA, which encodes for a subunit of the IL-3 receptor, is noted to be differentially methy-
lated in TS women. This gene has been linked to increased risk for autoimmune disorders
among these patients [
34
,
35
]. One study compared the transcriptomes (the collection of
mRNA expressed) of 45,X and 46,XX fibroblasts and revealed that the BMP2 and BMPER
genes were dysregulated in 45,X cells such that normal bone mineralization could be im-
paired [
28
]. Other interesting findings in 45,X cells from this transcriptome analysis include
downregulation of STC1 that could lead to dysregulated follicle development, downregu-
Endocrines 2022,3244
lation of IGF2 and ENPP1 that could lead to metabolic pathologies, and upregulation of
CLDN11, which is involved in spermatogenesis [
32
]. Notably, these six genes are all located
on autosomes, indicating that the genetic etiologies of TS manifestations extend beyond the
X chromosome.
Another role of epigenetics that has been explored is its involvement in X chromosome
monosomy. It is postulated that differential methylation of sex chromosomes could cause
errors in chromosome alignment and spindle formation during meiosis or mitosis [
4
].
Herrera et al. studied hypomethylated cells as caused by mutations in DNA methyltransferase
3b gene (DNMT3B), and found delayed centromere separation leading to aneuploidy [
36
].
Underlying pathogenesis mechanism in various TS phenotypic presentation is evolving
with improved understanding of notable difference in RNA expression, autosomal DNA
methylation and X chromosome methylation in TS patients.
3. Clinical Presentation
As alluded to earlier, the karyotype a TS individual possesses can influence which
TS features appear and how severely these features present. A study of 656 individuals
with TS in London found that 45,X patients were diagnosed at a younger age than patients
with other TS karyotypes [
6
]. This data suggests that the 45,X karyotype gives rise to more
serious or noticeable complications to warrant an earlier diagnosis. In the same study,
a significantly higher percentage of 45,X patients had primary amenorrhea compared to
45,X/46,XX, ring X, and isochromosome Xq patients, and a significantly lower percentage of
patients with 45,X/46,XX had hearing loss, hypertension, and obesity compared with 45,X
patients [
6
]. Another study involving adults from the UK Biobank revealed that 45,X/46,XX
and 46,XX individuals had a similar age of menarche, rate of pregnancy, and number
of pregnancies [
37
]. Furthermore, 45,X/46,XX individuals had a smaller height deficit
than 45,X [
37
], and a different study found that 45,X patients had more congenital heart
malformations than other TS patients [
38
]. The difference in phenotype between 45,X and
45,X/46,XX individuals could be explained by genes that escape X-inactivation. Monosomy
X is the most extreme form of haploinsufficiency, whereas 45,X/46,XX individuals have
some cell lines with normal levels of gene expression intact. These normal cell lines in
45,X/46,XX individuals can be protective.
Table 2lists some of the more common clinical features of TS. Clinical presentation
can be very varied, ranging from having all or most classical features to minimal or no
apparent symptoms or signs. Because of heterogeneity of clinical manifestations, TS may
be diagnosed at any age. Prenatal diagnosis has increased throughout the years because
of prenatal testing, particularly for at-risk mothers. Findings suggestive of TS include
chromosome abnormalities detected with chorionic villous sampling or amniocentesis;
increased nuchal translucency, presence of cystic hygroma, coarctation or evidence of left
sided cardiac defects, brachycephaly, renal anomalies, polyhydramnios, oligohydramnios
and growth retardation on ultrasound studies; and abnormal maternal triple or quadruple
testing [
2
]. The presence of lymphedema of the extremities, dysmorphic features, failure to
thrive and developmental delay in a female infant or young child should alert the medical
provider to proceed with further evaluation and testing for TS. However, the diagnosis
can be delayed until the patient presents with short stature later in childhood or delayed
pubertal development during the adolescent period.
Endocrines 2022,3245
Table 2. Clinical features of TS.
Associated Features and Conditions in TS
Characteristic facial and
physical features
Hypertelorism, upward slanting of palpebral fissures, epicanthal
folds, flat nasal bridge, low set ears, high arched palate, low posterior
hairline, webbed neck, broad chest with widely spaced nipples
Cardiovascular
Bicuspid aortic arch, coarctation of the aorta, aortic dilatation
or aneurysm
Hypertension
Endocrine and metabolic
Autoimmune thyroiditis, glucose intolerance/diabetes mellitus,
dyslipidemia, decreased bone mineral density
Gynecologic Absent or delayed puberty development, premature ovarian
failure, infertility
Skeletal
Short stature, delayed bone maturation, spine deformities (scoliosis,
kyphosis), angular deformity of limbs (cubitus valgus, genu valgum,
madelung deformity)
Gastrointestinal Celiac disease, transaminitis, inflammatory bowel disease
Renal
Horseshoe kidney, renal ectopia, abnormal position or duplication of
ureters or vessels
Neurocognitive and
behavioral
Impaired visuospatial and perceptive abilities, deficits in non-verbal
memory and executive function
Increased risk for attention-deficit/hyperactivity disorder
4. Endocrine-Related Manifestations of Turner Syndrome
4.1. Growth and Short Stature
The short stature in TS is attributed to haploinsufficiency of SHOX gene which regu-
lates differentiation of chondrocytes. This also explains other features noted in TS including
high arched palate, obstructive sleep apnea, prominent ears, and chronic otitis media [
39
].
Although individuals with TS do not have true growth hormone deficiency, they respond
to growth hormone as seen in those with isolated SHOX gene deficiency [
40
], and can have
a mean height gain of about 7 cm; however, this is still dependent on age when related to
age of initiation and duration of treatment [
41
]. Results of a French observational multicen-
ter study published in 2016 demonstrated association between karyotype subgroup and
phenotypic variation in spontaneous intrauterine and postnatal growth and adult height
after GH therapy [
42
]. The authors concluded that haploinsufficiency of unknown Xp gene
increases the risk of deficit in prenatal and postnatal growth and short adult height after
GH treatment [42].
4.2. Ovarian Insufficiency
Ovarian insufficiency resulting from rapid and progressive loss of oocytes is another
feature of the syndrome in almost all TS individuals, presenting as absent or delayed
pubertal development in adolescent girls, or infertility in women of childbearing age. This
accelerated degeneration of oocytes is attributed to failure of chromosome pairing in the
early stage of meiotic prophase [
12
]. Spontaneous pubertal development is more common
in mosaics, occurring in about a third of this population; however, only a smaller percentage
of this group will continue to progress to the occurrence of menarche [
43
]. Consistent with
the variability of clinical presentation in TS, there is also significant differences in the size
primordial follicle pool. This explains how mosaics with a large enough pool may undergo
spontaneous puberty and menarche [
43
]; however, they will still have a faster rate of follicle
apoptosis than women with normal 46,XX [
44
]. Anti-Mullerian hormone (AMH) is a good
marker of ovarian reserve of growing follicles and Visser et al., found that AMH levels
corelate with karyotype of TS with measurable levels found in 77% of TS patients with
45,X/4XX mosaicism and in only 10% with classic 45,X karyotype [45].
Endocrines 2022,3246
4.3. Autoimmune Thyroiditis
Individuals with TS are at increased risk of developing autoimmune diseases, par-
ticularly the autoimmune thyroid diseases (ATD). As per the recent meta-analysis report
the overall prevalence of ATD in TS is 38.6% [
46
]. About 41–45% of individuals with TS
are found to have thyroid peroxidase antibodies [
47
,
48
], with prevalence of Hashimoto’s
disease (HD) is 30–50% [
48
,
49
]. Graves’ disease (GD), which is rarer than HD, still occurs
more frequently in TS compared with general population with an estimated prevalence of
1.7–3% [
50
,
51
] Although ATD is observed in all TS karyotypes, several studies have shown
that autoimmune disorders including ATD are more likely to occur in those with isolated
Xp deletion and isochromosome Xq [
47
,
52
–
54
]. Both these chromosomal anomalies lack
the short arm of X chromosome and the haploinsufficiency of immune regulatory genes
located in the Xter-p11.2 region is the most likely explanation for increased predisposition
to autoimmune disorders [
54
]. Other proposed mechanisms for the cause of increased
frequency of autoimmune disorders in TS include: maternal origin of X chromosome,
hypogonadism and cytokine imbalance with more pro-inflammatory cytokines and less
anti-inflammatory cytokines [55].
4.4. Diabetes and Metabolic Syndrome
The patients with TS are more likely to develop either type 1 or type 2 diabetes mellitus
(DM) with a relative risk of 11.56 and 4.38, respectively [
56
]. The increased risk for Type 1
diabetes is explained by the overall higher risk for development of autoimmune conditions
in TS, as previously discussed.
The associated risk for developing metabolic syndrome including Type 2 diabetes
in TS involves a more complicated pathophysiologic process, with several contributory
factors. The features of metabolic syndrome observed in patients with TS include Increased
abdominal adiposity, impaired vascular function and hypertension, dyslipidemia and
insulin resistance [
57
]. Lebenthal et al. looked at the evolution of metabolic comorbidities
in TS, with the longitudinal and cross-sectional retrospective study that showed that
increasing age and weight gain increase metabolic risks in this cohort of 98 TS patients [
58
].
Similar to previous studies, these cardiometabolic risk factors are already apparent during
childhood, and in a good number of patients who have normal BMI at this age [
58
–
60
].
X chromosome gene dosage is thought to influence the occurrence of metabolic disorders
in TS, with reports of clustering of risk factors in 45,X monosomy [3,61].
Individuals with TS were noted to have higher body mass index (BMI) and higher
waist circumference when compared with BMI matched women without TS [
62
]. As many
as 20–40% of youth and 60% of adult individuals with TS have systemic hypertension,
which may be due to renal anomalies, or idiopathic [
2
]. An atherogenic lipid profile of high
triglycerides, high low-density lipoprotein (LDL) and low high-density lipoprotein (HDL)
is also observed in some studies, with hypercholesterolemia being reported in 37–50% of
patients with TS [
2
,
61
,
63
]. Altered glucose and insulin metabolism in TS is most likely
due to decreased beta-cell responsiveness with diminished first-phase insulin release [64].
Haploid gene deficiency of PAR1 is believed to result into altered expression of molecules
that the gene encodes for, which include certain types of receptors, transcription factors,
phospholipase and protein lipases involved in appropriate insulin response [
65
]. Another
genetic mechanism explored is the association of the long arm of the X chromosome (iXq)
with higher incidence of DM, with additional copies of Xq triggering overexpression of
diabetes-related genes such as islet cell antigen (ICA) and insulin-like growth factor II [
66
].
This overexpression is then linked to immune-mediated injury to beta-cells, leading to
decreased responsiveness.
5. Diagnosis—Karyotyping and Beyond
A standard 20-cell karyotype using the peripheral blood sample is recommended for
all girls and women suspected with TS. Sampling of another tissue such as buccal mucosa
cells or skin fibroblasts may be needed if the standard karyotype is reported normal and
Endocrines 2022,3247
there is strong clinical suspicion of TS. [
2
,
67
]. If the diagnosis was made prenatally with
chromosomal analysis using chronic villous sampling or amniocentesis, it is recommended
to repeat the karyotyping postnatally [2].
Presence of Y chromosome material suggests increased risk of gonadoblastoma and
germ cell tumors [
68
]. In patients with virilizing features, fluorescent in situ hybridization
(FISH) analysis of at least two to three different tissues using X and Y probes is recom-
mended to detect cryptic Y material [
2
,
67
]. Additional testing has also been recommended
for patients with 45,X karyotype, as true sex chromosome monosomy is incompatible with
life and these patients may have cryptic mosaicism potentially with Y chromosome mate-
rial [
69
]. FISH using a probe to DYZ3 locus at Y-centromere is suggested to detect cryptic
mosaicism for Y chromosome as this region is associated with increased susceptibility
to gonadoblastoma [69].
The polymerase chain reaction test using multiple Y-chromosome-specific DNA probes
is more sensitive than FISH [
70
,
71
]; however, it may be susceptible to contamination [
72
].
Non-invasive prenatal screening tests such as cell-free fetal DNA screening in maternal
plasma by microarray or whole genome sequencing helps to detect aneuploidy, but both
methods have limitations such as failure to identify balanced translocations and triploidies,
or missing X-chromosome structural abnormalities and mosaicism, respectively [
73
,
74
].
Single nucleotide polymorphism (SNP) array genotyping has been compared with kary-
otyping in patients with TS and it was found that SNP array can better detect cryptic
Y chromosome; however, this may cause misinterpretation of rare cell lines and cannot
detect fully balanced translocations of the X chromosome [75].
Further advancements in genetic testing during the past decade have allowed for
understanding genomic mechanisms of TS, elucidating further on what affects growth,
puberty, neurocognitive development and occurrence of associated conditions in these
patients. Advances in epigenetic research has seen the use of assays that started with DNA
methylation and histone acetylation studies that were site-specific, to genome-wide assess-
ments [
76
]. More recently, bioinformatics analysis has been used to identify differentially
expressed genes that may further increase knowledge on the pathogenesis of TS [
77
,
78
].
While newer gene editing technological advances such as Crispr/Cas9 can offer potential
therapeutic options, their use in human disease can elicit multitude of ethical issues and
such discussion is beyond the scope of this review.
6. Treatment and Management
6.1. Growth Hormone Therapy
Growth hormone (GH) treatment started at an early age of 4–6 years in patients with
TS helps to achieve normal growth pattern similar to that for peers of the same age [
2
]. The
mean average height of TS patients untreated with GH is cited to be around
142–144 cm
,
which is approximately 20 cm less than the mean height of general population [
79
]. When
treated with GH, the annual height gain of TS patients increased by 1–2 cm for every year
of GH therapy [
2
,
79
]. Besides promoting growth, GH augments bone mass, regulates lipid
and glucose metabolism and increases amino acid transport in the muscle [
79
]. Long-
term therapy is also associated with positive effects on craniofacial development in TS,
mostly affecting mandibular ramus and posterior facial height [
80
]. A recent systematic
review looking at effects of GH on the cardiovascular system showed positive effect on
lipid profile, reducing the risk of cardiovascular disease, particularly if with concomitant
estradiol therapy [81].
Several factors affect success of growth hormone therapy. Dose, duration, as well as
adherence and compliance to therapy all influence final adult height [
79
]. The “Toddler
Turner” study, which looked at effects of early initiation of GH therapy beginning at
9 months to 4 years of age, revealed that the early treated group were taller all through out,
but with no significant difference in near-adult height when compared with early untreated
group. This was attributed to the catch down growth noted in the early treated group
during lapses of GH therapy, demonstrating the significance of uninterrupted treatment to
Endocrines 2022,3248
promote better adult height [
82
]. Later initiation not only limits adult height predictions but
may delay growth associated with puberty as well. The presence of other health conditions
such as congenital heart disease, hypothyroidism or celiac disease may contribute to growth
deficits, independent of growth hormone effects [
79
]. Other non-modifiable factors include
height of parents and height of the patient at the beginning of GH therapy. Specific genetic
markers have also been linked with response to GH therapy in TS, such as estrogen receptor
alpha (ESR1) and tyrosine-protein phosphatase nonreceptor type1 (PTPN1) both noted to
influence height velocity in TS [
83
], whereas homozygosity for SOCS-2, GHR exon3 full
length and IGFBP3-202 C alleles was associated with poor response to GH therapy [84].
The initial dose of GH is 0.35–0.375 mg/kg/week and patients with poor height
prognosis may be started on higher doses after careful consideration [
2
]. Concomitant
treatment with Oxandrolone is an option to improve final height if there is delay in initiation
of GH therapy due to delayed diagnosis. GH therapy along with Oxandrolone at a dose of
0.03–0.05 mg/kg/day in TS patients 10 years and older results in gain of final height by
2–5 cm as compared to those treated with GH alone [
2
]. Although Oxandrolone can have
synergistic effect on growth acceleration, it is associated with undesirable effects including
virilization and delayed pubertal development [
85
]. These side effects are modest when
treated with doses less than 0.06 mg/kg/day [86].
6.2. Estrogen Replacement
The goal of estrogen replacement therapy in TS is to induce and maintain normal
pubertal development with secondary sexual characteristics including normal breasts and
uterine size and shape. The other goals include achievement of physiological effects of
endogenous estrogens such as bone mineralization and maintenance of cardiovascular
health. The negative effects of estrogen deficiency in TS include poor intrauterine growth,
decreased cognitive and motor reaction time, reduced bone mass, poor cardiovascular
outcomes, low self-esteem and poor quality of life [
87
,
88
]. In a study by Viuff et al., hormone
replace therapy is found to reduce endocrine and cardiovascular morbidity in TS adults
with decreased use of antidiabetics, thyroid hormone replacement and antihypertensives
and reduced hospitalizations due to osteoporotic fractures and stroke [
89
]. Other studies
show that earlier induction of puberty and start of estrogen replacement may be beneficial
for adult bone density [90].
Current recommendations call for starting estrogen replacement at around age
11–12 years
,
with transdermal 17-
β
estradiol being the preferred treatment [
2
,
88
]. Monitoring go-
nadotropins, particularly follicle stimulating hormone (FSH), starting at about 11 years of
age, aid in detecting and confirming hypergonadotropic hypogonadism before puberty
induction [
2
]. Low levels of anti-Mullerian hormone (AMH) can also suggest ovarian
failure [
45
,
89
,
91
]. To mimic the normal physiologic milieu during the peripubertal period,
initiation with low doses of estrogen (3–7
µ
g/kg/day) is recommended, gradually increas-
ing every 6 months, eventually reaching adult doses of up to 100 mg/day in 2–3 years [2].
Ultra-low dose estrogen therapy using oral ethinyl estradiol during the prepubertal period
has been suggested, with studies showing normalization of onset and tempo of puberty
development, as well as improvements in cognition and memory [
92
–
94
]. However, routine
use of this therapy is not recommended due to lack of long-term safety data [2].
As mentioned, transdermal Estradiol (E
2
) is the more widely used preparation that
theoretically provides a more physiologic, systemic route of delivery. Orally administered
estrogen, on the other hand, reaches the systemic circulation after undergoing metabolism
in the liver. A randomized clinical trial by Torres-Santiago et al. demonstrated no significant
differences between the TS patients treated with oral and transdermal E2 regarding their
body composition, bone mineral density and lipid profile when their estradiol levels
were titrated to those of normal menstruating adolescents [
95
]. However, the increased
amounts of conjugated estrogen precursors and metabolites associated with oral estrogen
preparations pose a higher risk for thromboembolic events as seen in the post-menopausal
women [
96
]. To date, there are no data available to suggest the same risk in TS population, as
Endocrines 2022,3249
long-term studies assessing the optimal dose, route and duration of hormone replacement
treatment are still to be published.
TS individuals usually have normal uterus, and it is recommended to add progestin
therapy 2 years after induction of puberty or once spotting or menstrual bleeding has
commenced [
2
]. Progestins minimize risk of endometrial hyperplasia due to unopposed
estrogen therapy and thereby prevent endometrial cancer [
97
]. There are several proposed
progestin and estrogen/progestin replacement options after puberty induction [
88
]. After
establishing adult dosing for hormone replacement therapy, it needs to be continued until
the usual age of menopause. These patients need to be monitored for risks associated with
estrogen therapy on an annual basis.
6.3. Fertility Preservation
Premature ovarian failure results in infertility in majority of patients with TS with
spontaneous pregnancy reported only in 2–10% [
98
]. In those with mosaicism (45X/46XX)
salvage of existing oocytes using assisted reproductive technologies was proposed [
99
].
Oocyte retrieval and cryopreservation after ovarian stimulation in adults and post pubertal
adolescents with Turner mosaicism has been reported [
100
–
102
]. Ovarian stimulation was
initiated with FSH (recombinant or highly purified) along with LH supplementation in
the form of human menopausal gonadotropins or recombinant LH due to concerns of
hypothalamic immaturity in post pubertal adolescents with TS [101].
Ovarian tissue cryopreservation which is still experimental fertility preservation tech-
nique may be an option in prepubertal patients with TS who are at increased risk of
accelerated ovarian failure based declining AMH levels (<2 ng/mL) and cannot wait until
sufficient maturity to undergo oocyte cryopreservation [
99
]. Though fertility preservation
is no longer consider experimental in adult patients, ovarian stimulation for oocyte cry-
opreservation and ovarian tissue cryopreservation in young patients needs consent from
parents and patients above nine years of age and also approval of institutional review
board (IRB) is strongly recommended [
99
]. More recently, another approach for fertility
preservation is suggested, primarily based on the patient’s genotype (monosomy vs. mo-
saic), then subsequently based on AMH concentrations over time [
103
]. This approach
also takes into strong consideration the expected maternal risks that may vary significantly
from person to person. Prenatal genetic counseling plays an important role in prenatal
diagnostic procedures in all pregnant women and in future reproductive options such as
in vitro fertilization for TS adults.
7. Conclusions
Scientific advancements have led to improved diagnostic and management options
in the care of patients with TS. Still there is more to discover how the impact of more
detailed genetic and genomic testing could affect health outcomes, help decrease health
burdens, and ultimately improve quality of life. Although clinical manifestations could
be highly variable, more often the condition affects multiple organ systems, thus needing
multidisciplinary team approach to ensure optimal outcomes.
Author Contributions:
Conceptualization: E.G.C. and S.K.; Administrative support: E.G.C. and S.K.;
Provision of study materials or patients: E.G.C. and S.K.; Manuscript writing: E.G.C., S.K.P., T.D., B.S.
and S.K. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Endocrines 2022,3250
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