REVIEW

C URRENT
OPINION Novel insights in Turner syndrome
Jasmine Aly a and Paul Kruszka b

Purpose of review
Turner syndrome is the most common sex chromosome abnormality in female individuals, affecting
1/2000--1/2500 female newborns. Despite the high incidence of this condition, the mechanisms
underlying the development of multiorgan dysfunction have not been elucidated.
Recent findings
Clinical features involve multiple organ systems and include short stature, dysmorphic facial features,
delayed puberty and gonadal failure, cardiac and renal abnormalities, audiologic abnormalities, and a
high prevalence of endocrine and autoimmune disorders. Paucity of available genotype/phenotype
correlation limits the ability of clinicians to provide accurate guidance and management. Given the advent
of robust genetic testing and analysis platforms, developments in the genetic basis of disease are
materializing at a rapid pace.
Summary
The objective of this review is to highlight the recent advances in knowledge and to provide a framework
with which to apply new data to the foundational understanding of the condition.
Keywords
cytogenetics, mosaicism, oocyte cryopreservation, ovarian tissue cryopreservation, Turner syndrome

INTRODUCTION a high prevalence of endocrine and autoimmune

Turner syndrome is the most common sex chromo-
some abnormality in female individuals, affecting 1/
&
2000–1/2500 female newborns [1–3,4 ] and at least
10% of all spontaneous abortions [1–3]. The true
prevalence of Turner syndrome is unknown, as 99%
of fetuses with Turner syndrome do not survive to
term. In those surviving to term, there is often a
delay in diagnosis, with the average age at diagnosis
of 15 [5]. Involvement of a multitude of organ
systems in Turner syndrome makes it difficult for
any single clinician to appropriately diagnose
Turner syndrome and contributes to delayed diag-
nosis. We have compiled a comprehensive list of
common physical features with dysmorphology
diagnostic criteria for facilitated reference (Table 1)
[3,6–36]. Diagnosis requires the presence of charac-
teristic physical features in a phenotypic female and
complete or partial absence of one X chromosome,
with or without cell line mosaicism. Despite the
high incidence of this condition, the mechanisms
underlying the development of multiorgan dysfunc-
tion have not been elucidated. Clinical features
include short stature, dysmorphic facial features,
delayed puberty and gonadal failure, cardiac and
renal abnormalities, audiologic abnormalities, and
disorders [3]. Mortality in Turner syndrome is
increased by three to four times compared with
controls with a mean age at time of death of 53
[5]. The leading causes of death are cardiovascular
disease, liver disease, and malignancy. Paucity of
available genotype/phenotype correlation limits
the ability of clinicians to provide accurate guidance
and management. However, given the advent of
robust genetic testing and analysis platforms, devel-
opments regarding the genetic basis of disease are
materializing at a rapid pace. The objective of this
review is to highlight the recent advances in knowl-
edge and to provide a framework with which to
apply new data to the foundational understanding
of the condition.
a
Program in Reproductive Endocrinology and Infertility, Eunice Kennedy
Shriver National Institute of Child Health and Human Development, NIH,
Bethesda and bGeneDx, Gaithersburg, Maryland, USA
Correspondence to Paul Kruszka, MD, FACMG, Chief Medical Officer-
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Tel: +1 516 622 5070; e-mail: pkruszka@genedx.com
Curr Opin Pediatr 2022, 34:447–460
DOI:10.1097/MOP.0000000000001135

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Special commentary

KEY POINTS
 Early and accurate diagnosis of Turner syndrome is
imperative as it allows for timely interventions, which
greatly impact quality of life, such as growth and
fertility preservation.
 Regarding the pathogenesis of Turner syndrome, there
is a likely a multitude of converging mechanisms
involved, including imprinting, epigenetic changes, and
alterations in RNA expression.
 Multisite cytogenic analysis (buccal mucosa, bladder
epithelium and skin fibroblasts), coupled with a higher
resolution methods of analysis, such as FISH and/or
SNP may provide a more accurate genotypic
diagnosis, which can inform care.
PATHOGENESIS
There are two primary questions regarding Turner
syndrome pathogenesis. The first is regarding the
origin of the initial partial or total loss of one X
chromosome. The second question is how the loss
of genetic material results in the milieu of varied
phenotypes.
The initial loss of X chromosome material is
primarily hypothesized to occur as a result of a
meiotic error, the cause of which is not well under-
stood. In Turner syndrome, the remaining X chro-
mosome is maternal in 70–80% of cases, suggesting
preferential loss of the paternal X chromosome.
This was recently reaffirmed in a study examining
multiple tissue sources and utilizing FISH [37].
There is limited information regarding the mecha-
nism of paternal X chromosome loss in Turner

Table 1. Turner syndrome dysmorphology examination features: incidence and subjective/objective diagnostic criteria
Physical feature Incidence (%) Dysmorphology examination diagnostic criteria Comments

Facial features
Low-set and/or 30--50% [6] Objective criteria: imaginary horizontal line passing The most common ear findings in TS are low-set
deformed ears through the inner canthi of the eye to the ear. If the ears, with abnormal sloping of the helix
top of the pinna (upper insertion of the ear) falls downward, cupped ears, abnormal fusion of
below the line drawn, ear is considered low set [7]. the inferior and superior crus of the antihelix,
See Fig. 1a. loss of the triangular fossa, and absence of the
antihelix [8].
Dysmorphic palate: 68% [9] High-arched palate:
including high- subjective criteria: palatal height at the level of the first
arched or prominent permanent molar is more than twice the height of the
palatal ridges teeth [10].
Objective criteria: height of the palate is more than 2
SD above the mean [10].
Prominent palatal ridges:
Subjective criteria: increased size and/or number of
soft tissue folds on the palatal side of the maxillary
alveolar ridge [10]. See Fig. 1b.
Micrognathia 60--70% [11] Subjective criteria: apparently reduced length and This is a bundled term constituting shortening and
width of the mandible when viewed from the front narrowing of the mandible and chin [12].
but not from the side [12].
Ptosis 5% [13] Subjective criteria: the upper lid margin obscures at
least part of the pupil [14].
Objective criteria: the upper eyelid lid margin is
positioned 3 mm or more lower than usual and
covers the superior portion of the iris [14].
Epicanthal folds 20% [13] Subjective criteria: a fold of skin starting above the In extreme cases, the skin fold can start as high as
medial aspect of the upper eyelid and arching the eyebrow. This is called epicanthus
downward to cover, pass in front of and lateral to superciliaris [14].
the medial canthus [14]. See Fig. 1c.
Dense eyebrows, 42--74% Dense eyebrows: Thickness can be regional (medial, middle
long eyelashes Subjective criteria: (central), lateral) or total.
Increased density/number and/or increased diameter Measurement should be done on the longest
of eyebrow hairs. lashes, which are usually at the center of the
Long eyelashes: lid.
Subjective criteria: increased length of the eyelashes. Normal values are 7.99  1.05 mm in boys and
Objective criteria: mid upper eyelash length greater 7.76  1.03 mm in girls [14]
than 10 mm [14].
Color vision 17% [13] Objective criteria: there are multiple methods of testing. The Lanthony Desaturated 15 D test [3] Hue) can
disturbance Lanthony D-15 Color Test Hue is sensitive and only be administered to children 12 years old
relatively undemanding test. It consists of a set of 15 and older.
different colored papers or discs, which need to be
arranged in the correct color-coded order to create a
continuum of gradually changing hue.

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 Novel insights in Turner syndrome Aly and Kruszka
Table 1 (Continued)
Physical feature Incidence (%) Dysmorphology examination diagnostic criteria
Low posterior 73% [9] Subjective criteria: hair on the neck extends more
hairline inferiorly than usual particularly in the lateral
aspects. See Fig. 1d.
Melanocytic Nevi 98.4--100% [15] Subjective criteria: common nevi have a wide variety of
clinical appearances. However, they tend to be 6 mm
or less in diameter and symmetric with a
homogeneous surface, even pigmentation, round or
oval shape, regular outline, and sharply demarcated
borders [16]. Multiple melanocytic nevi (moles)
appear in late childhood mainly over the face, back
and limbs. The average number of moles is much
higher in TS than the general population, particularly
in fair skin. The moles are usually small (1--5mm)
and typical in appearance [17]. See Fig. 1e. Halo
naevi, moles surrounded by a white rim, are more
commonly seen in patients with TS than the general
population.
Skeletal features
Neck anomalies 40--60% [11,15] Short neck:
(short/webbed) subjective criteria: decreased distance from the point
where neck and shoulders meet to the inferior margin
of the occipital bone.
Webbed neck:
Subjective criteria: a paravertically oriented fold of skin
on the posterolateral aspect of the neck, usually
extending from the mastoid region of the skull to the
acromion, and best appreciated in frontal or
posterior view [12].
Hand and feet 30--51% [18] Subjective criteria: most commonly diagnosed based on
edema subjective visual examination noting swollen or
(lymphoedema) engorged extremities. See Fig. 1f.
Objective criteria: multiple methods have been
developed to qualify degree of lymphoedema.
Cheng’s Lymphedema Grading tool [19] is one
example and assigns a grade based on objective
limb measurements:
Grade 1: spontaneously reversible on elevation. Mostly
pitting edema.
Grade 2: nonspontaneously reversible on elevation.
Mostly nonpitting edema.
Grade 3: gross increase in volume and circumference
of Grade 2 lymphedema.
Cubitus valgus 47--69% ([11] Objective criteria: carrying angle is measured by a
(increased carrying manual goniometer with two drawing axes of the
angle) arm and forearm (Fig. 1g). The axis of the arm is
defined by the lateral border of the cranial surface of
the acromion to the midpoint of the lateral and
medial epicondyles of the humerus [21]. The
carrying angle of the elbow averages about 128 in
the general female population and can be 20--308
or more in patients with TS. See Fig. 1h and i.
Short fourth 35--73.8% Subjective criteria: diminished length of one or more
metacarpal [11,15] metacarpal bones in relation to the others of the
same hand or to the contralateral metacarpal [22].
See Fig. 1j.
Genu valgum 35% [23] Subjective criteria: Genu valgum refers to internal
(knock-knee) proximal tibial torsion, that is, an inward twisting of
the tibia, which leads to in-toeing of the foot. The
tibia is turned outward in relation to the femur,
resulting in a knock-kneed appearance [24]).
Objective criteria: The intermalleolar measurement
quantifies genu valgum and is the distance between
the medial malleoli with the medial femoral condyles
touching. Individuals with pathological genu valgum
have tibiofemoral angles that are outside two
standard deviations of the mean [24]. See Fig. 1k.
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Comments
Sun exposure does not appear to be a trigger for
melanocytic nevi in TS; however, the number of
moles increases with age.
Large numbers of melanocytic nevi are a risk
factor for melanoma. Whether an increased
number of melanocytic nevi in the TS
populationconfers an increased risk of
melanoma is debated in the literature. It is
recommended that TS women undergo periodic
skin examinations and use sunscreen regularly
[17].
Referral to a dermatologist is generally warranted
when nevi have marked asymmetry, mottled
pigmentation, or a large size (6 mm).
Neck webbing (pterygium coli) follows resolution
of a cystic hygroma, which commonly forms on
the back of neck during fetal development but
resolves before birth.
In TS patients, the hands and feet are most
commonly affected by lymphoedema, which is
thought to be the result of the underdevelopment
or lymphatic malformations/obstructions,
primarily at the junction of the jugular lymphatic
sac and the internal jugular vein [3].
The lymphedema seen at birth usually resolves by
2 years of age without therapy. However,
lymphedema may occur or reoccur at any age
[20] .
If the fingernails, toenails and/or skin are
compromised, professional edema therapy
should be initiated early [3].
Cubitus valgus is a known cause of ulnar
neuropathy, caused by compression of the ulnar
nerve, and may result in numbness, tingling,
and occasionally weakness. Treatment for ulnar
neuropathy is generally supportive and includes
limiting physical activity and wearing a brace.
If conservative methods fail, surgery may be
indicated [17].
The assessment of isolated short metacarpal can
be made by viewing the dorsum of the hand
when clenched [22].
Intermalleolar and intercondylar have the
disadvantage of being relative measurements
that are affected by the child’s size.
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Special commentary
Table 1 (Continued)
Physical feature Incidence (%) Dysmorphology examination diagnostic criteria
Madelung deformity 5% [23] Madelung deformity is a shortened radius that curves
(bayonet deformity palmarly and ulnarly, a dorsally prominent ulnar
of the wrist) head, and a triangular arrangement of the carpal
bones characterize the deformity.
Subjective criteria: on physical examination, the
deformity is most noticeable observing the
subluxation from the ulnar side. The hand is dropped
palmarly. The diameter of the wrist is almost twice
normal. The extensor tendons, which pass over the
radius towards the dorsum of the hand, bridge and
obscure the step that is so noticeable on the ulnar
side [25]. See Fig. 1l.
Objective criteria: Several radiographic parameters
have been proposed to identify, quantify, and
categorize Madelung deformity. McCarroll et al.
identified three reliable and reproducible
measurements for quantifying the severity of
Madelung deformity on X-rays including ulnar tilt,
lunate subsidence, and palmar carpal displacement
[26].
Scoliosis 20% [23] Subjective criteria: scoliosis is an asymmetry in the
upper thoracic, midthoracic, thoracolumbar, or
lumbar region.
Objective criteria: measured with a scoliometer during
and forward bend test (Fig. 1m). The Adams forward
bend test (Fig. 1n) is performed by observing the
patient from the back while he or she bends forward
at the waist until the spine becomes parallel to the
horizontal plane, with feet together, knees straight
ahead, and arms hanging free [29,30]. The
scoliometer measures the angle of trunk rotation
(ATR). Scoliosis can also be measured on a
radiographic image by determining the Cobb angle
(Fig. 1o).
Kyphosis 50% [23] Subjective criteria: cosmetic deformity seen as a
rounded back because of the excessive forward
curvature of the spine. See Fig. 1p.
Objective criteria: the gold standard method for
measuring the thoracic kyphosis is a standing
radiograph. Using the Cobb angle or modified Cobb
angle, computer-assisted methods are employed to
derive the radius of thoracic spine, curvature, and
thoracic vertebral centroid angles [31,32].
Short stature 88--100% [23] Objective criteria: the height of TS patients should be
plotted on growth curves specific for this disorder. If
left untreated, the adult height in Turner syndrome is
approximately 20 cm below that of the general
female population (1--2 SD below mean [3]. When
assessing the growth of any girl with short stature,
the provider should compare that girl’s height
percentile not only with the general female
population but also with the expected target height
percentile based on the parental heights. Adult
height is correlated with parental stature, as in the
general population, but the height is significantly less
than would be predicted for a girl without TS.
Shield chest: broad 20--32.5% [11,35] Objective criteria: measured by calculation of the
chest with widely Internipple Index [internipple distance (cm)  100 
spaced nipples circumference of chest (cm)]. Values for male and
female infants are correlated with weight, length,
chest circumference for gestational age/age.
Nipples can be considered widely spaced if greater
than 97th percentile and narrowly spaced if less than
third percentile [36]. See Fig. 1q.
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Comments
This condition caused by asymmetric growth at the
distal radial physis secondary to partial ulnar-
sided arrest.
The primary complaint is often that of wrist pain
and stiffness.
Reduced range of motion is with compromised
forearm rotation is often present. Loss of wrist
extension is common and proportional to the
degree of sagittal deformity [27] Radiocarpal
pain is frequently found particularly on wrist
extension as is pain from ulnar abutment [27].
Individuals may also report reduced grip
strength and difficulty executing normal daily
activities [28].
Thoracic (rib) or lumbar (loin) prominence on one
side is a sign of scoliosis.
It is recommended to refer the patient to an
orthopedic surgeon based on the following
criteria [30]:
ATR 78 in patients with body mass index (BMI)
<85th percentile
ATR 58 in patients with BMI 85th percentile
Cobb angle between 20 and 298 in males or
premenarchal females age 12 to 14 years
 Cobb angle >308 in any patient
Progression of Cobb angle of 58 in any patient
In hyperkyphosis, there will be stiffness and loss of
range of motion.
Although there are typically no neurological
findings, severe kyphosis can present with
numbness, tingling, weakness, bowel, and
bladder incontinence. In these cases, an MRI
should be ordered to rule out cord compression.
In TS, linear growth remains slow during infancy
and throughout childhood. The growth failure is
further compounded by delayed puberty, with
lack of a pubertal growth spurt.
Although TS women are not growth hormone (GH)
deficient, treatment with GH has been
demonstrated to increase adult height by
several inches [33]. Timing of initiated growth
hormone is crucial as growth hormone is
ineffective after growth plate fusion. Maximal
growth potential requires initiation at age 4--6
years old [34].
Height should be monitored every 3--4 months in
the first year of therapy and every 4--6 months
thereafter and GH can be discontinued after
linear growth is complete [3].
The internipple index stays constant during various
gestational ages, and an index >28% [>2
standard deviations (SD)] at any gestational age
in the immediate postnatal period is considered
consistent with widely spaced nipples [36].
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 Novel insights in Turner syndrome Aly and Kruszka

syndrome. Sperms are specifically vulnerable to
meiotic error as homologous recombination occurs
between the X and Y chromosomes, which are not
exact homologs. This may result in aberrant recom-
bination between areas of homologous sequence
repeats between the X and Y chromosomes, aber-
rant intrachromosomal recombination by unbal-
anced sister chromatid exchange, or slippage
during DNA replication. Therefore, the paternal
X chromosome may contain areas of structural
anomalies, and thus, be more prone to instability
and subsequent partial or total loss. In addition to
aberrant recombination between the X and Y chro-
mosomes, the Y chromosome itself is highly unsta-
ble because of the presence of palindromic
sequences. In mitosis, the two sister chromatids
of the Y chromosome may abnormally recombine
resulting in the presence of two centromeres in
dicentric Y chromosome. In a recent study evaluat-
ing Turner syndrome cases with partial Y chromo-
some, three of eight abnormal Y chromosomes
were found to be dicentric [38]. Thus, in the case
of a 46 XY embryo, dynamic instability of Y chro-
mosome may be initiated in the prezygotic stage
and continue in the postzygotic stage resulting in
loss of the Y chromosome, and thus leaving a
maternally derived monosomy X (Fig. 1a) [39].
An alternative method, which explains the high
proportion of mosaicism in Turner syndrome is
postzygotic nonsegregation in mitosis (Fig. 1b)
[39].
With regard to the second question of how the
loss of genetic material results in the milieu of varied
phenotypes, multiple theories have been purported.

FIGURE 1. (a) Predicted mechanism for the isodicentric Y chromosome. Chromosomal recombination can occur in human
cells during mitosis; however, most commonly is described in meiosis. As the human Y chromosome is highly enriched with
palindromes, somatic formation of idic (Y) may be facilitated by various palindromes. Theidic (Y) is predicted to have been
caused through aberrant mitotic crossover between P1 palindromes on sister chromatids. (b) Predicted mechanism for the
mosaic karyotype. X chromosomes are shown in black. White and gray boxes indicate the euchromatic and heterochromatic
regions of the Y chromosomes, respectively. The rearranged Y chromosome was subjected to mosaic loss during subsequent
mitotic divisions to create the 45, X cell line.

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Special commentary
Theories include haploinsufficiency of candidate
genes, imprinting effects, and most recently tran-
scriptional and epigenetic factors affecting gene
expression across the genome.
Haploinsufficiency
The term haploinsufficiency refers to a mutation in
one allele, wherein the mutated gene produces little
or no gene product. Historically, haploinsufficiency
was the prevailing pathogenic mechanism in Turner
syndrome. However, the role of haploinsufficiency
was largely based on SHOX gene-associated short
stature. This hypothesis has since been challenged
by an updated understanding of SHOX-mediated
mechanisms. The tall stature of individuals with
extra copies of SHOX (i.e. 47, XXY or 47, XXX)
support the role of haploinsufficiency. However,
data regarding heterozygous mutations provides
additional insight. Leri–Weill dyschondrosteosis
(LWS) is a skeletal dysplasia, associated with hetero-
zygous mutations in the SHOX gene or its enhancers.
As both LWS and Turner syndrome involve one miss-
ing copy of SHOX, the resultant short stature is
expected to be the same in both conditions. However,
the mean growth deficit of LWS is estimated to be
12 cm, compared with 20 cm in Turner syndrome,
indicating that haploinsufficiency accounts for most,
but not all, of the short stature in Turner syndrome.
Patients with CNVs involving the downstream
enhancer regions lead to slightly milder phenotypes
than mutations or deletions in the SHOX intragenic
exons [40,41]. These findings suggest that there may
be some phenotypic difference between SHOX exonic
mutations/deletions and enhancer mutations.
Recently haploinsufficiency for the transcription fac-
tor ZFX, a mediator of genome-wide expression, was
suggested to underpin multiple relevant phenotypes
[42]. Taken together, these data suggest a partial role
of haploinsufficiency; however, simultaneously
highlight the role of alternative converging mecha-
nisms.
X chromosome imprinting
Evidence of imprinting as a causative mechanism in
Turner syndrome phenotypes is mixed. The stron-
gest evidence involves paternal imprinting for IQ
and higher order social cognition [43,44]. A study
examining brain morphology in Turner syndrome
found those who inherited a paternal X had a
thicker cortex in the temporal regions vs. enlarge-
ment of gray matter in superior frontal regions in
those with a maternally inherited X [45]. Contrast-
ingly, other studies suggest no association between
parental X and IQ scores [46–48].
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A recent study found no influence of the paren-
tal X chromosome on the presence of a bicuspid
aortic valve, coarctation of the aorta, lymphedema,
pterygium colli, coeliac disease, IVF, thyroiditis,
otitis media, diabetes mellitus, renal abnormalities,
or spontaneous puberty [47]. Although imprinting
may be relevant for cognition-related phenotypes,
studies show a limited role in the wider array of
phenotypic features.
Epigenetic mechanisms
Epigenetic and RNA expression studies indicate that
the Turner syndrome genome is globally hypome-
thylated, in comparison with euploid women.
IL3RA, which encodes a subunit of the IL-3 receptor
is differentially methylated in Turner syndrome
women and is linked to the increased risk of auto-
immune disease [49,50]. Methylation studies show
escape genes, such as RPS4X, JPX, KDM5C, and
KDM6A were differentially expressed in individuals
with Turner syndrome. RPS4X encodes the riboso-
mal protein S4, which participates in multiprotein
complexes [51,52]. JPX encodes a nonprotein cod-
ing RNA, which activates XIST (X-inactive specific
transcript) and is downregulated in Turner syn-
drome [53]. Changes in JPX likely contribute to
the lack of X-inactivation that occurs in Turner
syndrome. KDM5C participates in the transcrip-
tional repression of neuronal genes, and thus has
been implicated in the neurocognitive profile of
Turner syndrome patients [54]. KDM6A encodes a
histone demethylase and is hypothesized to play a
role in the reestablishment of pluripotency, germ
cell development, and congenital cardiovascular
malformations in Turner syndrome [55]. Recent
studies also suggest that changes in gene expression
not only occur on X chromosome genes but also in
many autosomes, revealing the genome-wide
impact of X chromosome aberrations [56–58].
Authors purport that this could take the form of
genes encoding transcription factors located on the
X chromosome that subsequently regulate func-
tional targets on autosomes as well as on the X
chromosome itself [58]. In total, the multitude of
implicated mechanisms suggests a complex network
of genomic alterations, which contribute to the
Turner syndrome phenotype including haploinsuf-
ficiency, imprinting, epigenetic changes, and alter-
ations in RNA expression.
DIAGNOSIS
The standard diagnostic test for Turner syndrome is
a peripheral blood leukocyte karyotype with analy-
sis of 20 cells to identify mosaicism. The frequency
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 Novel insights in Turner syndrome Aly and Kruszka

Table 2. Incidence of genotypes in Turner syndrome based on peripheral blood karyotype and known genotype–phenotype
correlations

Genotype Percentage Pathogenesis Associated Features

45, X 40--50% Sex chromosome nondisjunction in the postzygotic Most common

cell division
45X with 15--25% Varied
Mosaicism
Isochromosome 10% Two copies of the long arm of the X chromosome Higher risk for autoimmune disease
Xq connected head-to-head, with some intervening
centromeric or short arm chromosome material
Ring 10--12% Formed if part of the end of both the short and If XIST is also missing, risk of developmental delay
chromosome long arms of the X chromosome are missing increases
-may present with atypical features such as atypical
facial dysmorphisms and syndactyly
Xp or Xq 10--12% Deletion of a portion of the short or long arm of If only terminal Xq deletion, may only have ovarian
deletion the X chromosome insufficiency with no other features of TS
Y chromosome 10--12% Mosaicism involving a cell line containing Y May present with virilization or genital ambiguity
Mosaicism chromosome material may be identified if marker -increased risk of gonadoblastoma
chromosomes are detected on the karyotype

and updated genotype/phenotype correlations, Current guidelines recommended a second kar-

based on karyotypic analysis, are summarized in
Table 2. Although peripheral blood karyotype is
the gold standard of diagnostic testing, it has lim-
itations in the setting of Turner syndrome. Periph-
eral blood sampling may not provide an accurate
representation of genetic content at the organ/tissue
level because of tissue-specific mosaicism. This is
evidenced by studies on aborted fetuses indicating
a substantial degree of cytogenic variance in differ-
ent tissues [59–62]. Inaccurate determination of
mosaicism is concerning, as the presence and/or
level of mosaicism is often utilized to extrapolate
expected severity of Turner syndrome by clinicians.
For example, it is commonly purported that non-
mosaic Turner syndrome individuals have no
chance of autologous pregnancy. Recent studies
examining the utility of multisite cytogenic analysis
(buccal mucosa, bladder epithelium, and skin fibro-
blasts), coupled with a higher resolution methods of
analysis, such as FISH and/or SNP may provide a
more accurate genotype [59–62]. Studies utilizing
FISH and/or SNP have uncovered mosaicism, novel
genotype/phenotype correlations, and have
resulted in adjustments in clinical management.
One study found 12% of cases, initially diagnosed
via traditional karyotype, had an altered genetic
diagnosis after buccal cells analysis [37]. Traditional
karyotype may also be limited in detecting the
existence of a cryptic Y fragment [61]. Identification
of Y chromosome fragments is critical as it is asso-
ciated with an approximate 10% increased risk of
gonadoblastoma and may necessitate surgical exci-
sion of gonadal tissue [3].
yotype from a different tissue source in cases of
virilization, and in cases of strong clinical suspicion
of Turner syndrome despite a normal karyotype
result [3]. However, given the aforementioned lim-
itations of conventional karyotype, there should
be a lower threshold to add FISH and/or samples
from multiple tissue sources in any Turner syn-
drome individual. Furthermore, as next-generation
sequencing confers an even greater potential to
identify Y chromosome material and degree of
mosaicism compared with FISH, this may become
the modality of diagnosis in the near future.
CARDIAC DISEASE
Cardiovascular abnormalities affect 23–50% of indi-
viduals with Turner syndrome and represent a main
cause of Turner syndrome-related early mortality
[63]. In addition to structural anomalies, such as
bicuspid aortic valve (BAV) and aortic dissection,
Turner syndrome individuals have an increased risk
of hypertension, thromboembolism, myocardial
infarction, and stroke. Areas of burgeoning cardiac
research include phenotype/genotype correlation,
target genes, role of epigenetics, and predictors of
aortic dissection (AD).
BICUSPID AORTIC VALVE
Bicuspid aortic valve is one of the strongest risk
factors for aortic dissection in Turner syndrome.
About 95% of individuals with Turner syndrome
who have an AD also have BAV [64,65]. Changes

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Special commentary
involving TIMP1 and TIMP3 genes lead to more than
10 times increased risk of BAV and aortic dilation in
Turner syndrome [66]. The hypothesized mecha-
nism involves a two-hit event. The first is haploin-
sufficiency of the TurnerIMP1 gene (located on the X
chromosome). The second is the concomitant pres-
ence of a risk TIMP3 allele (located on chromosome
22). The TIMP1 gene also contains several differ-
entially methylated sites in Turner syndrome
women [67]. This is yet another example of multiple
mechanisms, such as haploinsufficiency and epige-
netic modification, converging to result in a Turner
syndrome phenotype.
AORTIC DISSECTION
The estimated incidence of AD is 40 per 100 000
person-years compared with 6 per 100 000 person-
&
years in the general population [4 ]. In a recent
study, the majority of Turner syndrome women
with AD were found to have BAV or aortic coarcta-
tion. Interestingly, the majority of women with AD
had a mosaic genotype. These findings challenge
the premise that categorical separation of monos-
omy and mosaicism can help predict cardiovascular
risk and highlights that aortic dissection can occur
with any karyotype. Prompt recognition of the signs
and symptoms of AD in eTurner syndrome is a
critical yet complex feat. The problem lies in the
identification of risk factors, as AD is not always
preceded by progressive dilatation. Additionally, AD
in Turner syndrome may occur at an age. Moreover,
aortic dilatation and enlargement of the brachioce-
phalic and carotid arteries may be present in Turner
syndrome even in the absence of structural heart
disease [68,69]. Recommended screening and treat-
ment algorithms for Turner syndrome individuals
are summarized in Fig. 2a and b [3].
OVARIAN FAILURE AND INFERTILITY
Incidence
Primary hypogonadism affects approximately 90%
of Turner syndrome female individuals [70]. The
mechanism of gonadal failure in Turner syndrome
is unknown but hypothesized to be the result of
accelerated loss of oocytes during fetal develop-
ment. The onset, severity, and clinical presentation
of ovarian failure is highly variable. Spontaneous
thelarche occurs in 21–50% of Turner syndrome
adolescents whereas spontaneous menarche occurs
in 15–30% [71,72]. Although strict genotype/phe-
notype correlations for ovarian function do not
exist, there is general consensus that mosaic karyo-
types are more likely to have ovarian function [73–
454 www.co-pediatrics.com
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
75]. However, a purely monosomic karyotype does
not preclude spontaneous puberty or pregnancy.
This is substantiated by numerous documented
cases of spontaneous puberty and spontaneous con-
ception in those with a 45X karyotype.
Fertility and conception
Conception is challenging for Turner syndrome
women as only 5–7% experience spontaneous preg-
nancy [76–78]. Autologous options include cryopre-
servation of postpubertal oocytes (i.e. egg freezing), or
cryopreservation of a portion or entire preprepubertal
ovary. Egg freezing is currently only an option in
postpubertal women. Unfortunately, in Turner syn-
drome, by the time puberty occurs, most women have
already developed premature ovarian insufficiency or
ovarian failure, and thus are not candidates for egg
freezing. This was the impetus for experimentally
trialing ovarian tissue cryopreservation (OTC). The
process of OTC entails partial or total excision of
ovarian tissue, most often performed in early child-
hood, to mitigate the effects of accelerated loss of
oocytes. The cryopreserved ovarian tissue is theoret-
ically available for transplantation to restore ovarian
endocrine function and fertility at the desired time.
Although OTC remains experimental, it is currently
the only option available for prepubertal girls with
Turner syndrome. The plausibility of OTC is based on
successful live birth after auto-transplantation in
more than 50 patients who underwent prechemo
oophorectomy to avoid chemotherapy-induced ovar-
ian toxicity [79]. However, OTC has not yet resulted in
a live birth in the Turner syndrome population. As the
safety and promise of success for this technology
remain uncertain, it is currently only performed
under approved experimental protocols [3]. A com-
parison of egg freezing and OTC techniques is sum-
marized in Table 3.
Determining which children are candidates for
OTC presents a problematic dilemma. Given the lack
of documented success and associated risks, OTC
should be reserved for cases in which there are no
alternative options. However, it is difficult to deter-
mine in childhood, which girls will grow to be those
without alternative options. Fertility potential is chal-
lenging to predict because of lack of genotype–phe-
notype correlations for ovarian dysfunction, and as
the discriminative markers for functional ovarian
tissue are unreliable in Turner syndrome. Without
accurate biomarkers of fertility potential in child-
hood, parents of Turner syndrome children and clini-
cians are placed in the precarious position, of
committing a child to a partial or total oophorectomy
within the first years of life, which may later prove to
be unnecessary, detrimental, or ineffective.
Volume 34  Number 4  August 2022
 Novel insights in Turner syndrome Aly and Kruszka

FIGURE 2. Recommended cardiovascular screening in Turner syndrome children (a) and adolescents and adults (b) at time of
diagnosis. BAV, bicuspid aortic valve; CMR, cardiac MRI; CoA, coarctation of aorta; HTN, hypertension; TSZ, Turner
syndrome-specific z score of the aorta; TTE, transthoracic echocardiography.

Although AMH has been shown to predict
spontaneous menses, it should be interpreted with
caution as a marker of fertility potential in Turner
syndrome as it is unreliable in inactive prepubertal
ovaries [75,80,81]. Ultimately response to ovarian
stimulation is the best predictor of fertility poten-
tial. Data from Turner syndrome patients who
underwent ovarian stimulation in egg freezing
cycles showed no correlation between AMH levels
and the number of oocytes retrieved. Oocyte

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Special commentary

Table 3. Comparison of oocyte cryopreservation and ovarian tissue cryopreservation in Turner syndrome
Oocyte cryopreservation Ovarian tissue cryopreservation

Frozen tissue Mature oocytes frozen (eggs) Partial/whole ovary frozen

Candidacy
Type of surgery
Type of anesthesia
Availability
Documented success
(live-birth) in general
population
Documented success
(live-birth) in TS
population
Single/multiple use of
tissue
Viability of excised
tissue
Long-term impact
Only offered to TS individuals with
functional tissue at or after puberty
Vaginal procedure for extraction of
oocytes (minimal risk)
Embryo transfer at time of desired
pregnancy (office procedure)
Conscious sedation
Minimal anesthetic risk
Widely available
Yes
Yes
Each cryopreserved oocyte can only be
used once
Viability of cryopreserved oocytes from
TS has been documented and has
resulted in live birth
If unsuccessful, no negative long-term
impact
Can be offered to all TS individuals at anytime
Laparoscopic procedure for extraction of ovarian tissue
(increased surgical risk)
Reimplantation of tissue at the time of desired fertility (surgical
procedure)
General Anesthesia
Increased anesthetic risk
Available only under IRB-approved experimental protocols
Yes
No
Ovarian tissue may be sectioned. Each section can be
reimplanted individually. Potential for multiple pregnancies
from one block of tissue
Cryopreserved ovarian tissue in TS has not yet been
documented
Viability may be compromised by aneuploid granulosa cells
If unsuccessful, may result in exacerbation of hypoestrogenic
state
Risk of unnecessary removal of ovarian tissue (i.e. in the case of
fertile TS women or those that would have required less
invasive ART)

retrieval was successful even in cases where AMH
concentrations were suggestive of diminished ovar-
ian reserve [82]. In this study, women with monos-
omy X and those with mosaic karyotypes had
comparable numbers of oocytes to cryopreserve.
This is evidence that having a low AMH, and/or
a pure 45X karyotype does not preclude success of
fertility preservation procedures. Moreover, AMH
may vary over time in Turner syndrome, especially
around the time of impending premature ovarian
insufficiency [75]. Therefore, a single value of AMH
should not be used to project lifetime fertility
potential. Other factors have been suggested to
predict the ovarian reserve in Turner syndrome
patients, such as spontaneous puberty, spontane-
ous menarche, and antral follicle count. However,
these factors have limited value in estimating the
follicle density. Given the risk of AD, hypertension,
and associated mortality, the safety of pregnancy
in Turner syndrome is debated amongst clinicians
[83]. AD and rupture during pregnancy in patients
with Turner syndrome has been reported to be as
high as 2%, with a maternal mortality of 86% [75].
If fertility preservation measures are considered,
comprehensive screening and multidisciplinary
counseling should be completed before concep-
tion.
Although the practice guidelines suggest that
young mosaic Turner syndrome women with persis-
tent ovarian function should be offered fertility pres-
ervation [3], we suggest this should be extended to all
karyotypes. This is based on the limited ability of
conventional karyotype to detect cryptic mosaicism
in the ovary and the infectivity of available tests to
predict fertility potential. In general, AMH assess-
ments should be used cautiously in the setting of
predicting Turner syndrome fertility potential. How-
ever, if utilized, serial values may provide a more
accurate picture of fertility potential. Lastly there
should be a low threshold to offer patients with all
karyotypes a trial of controlled ovarian hyperstimu-
lation, as this is the most accurate marker of fertility
potential and offers minimal risk. In summary, the
risks of premature ovarian failure and infertility in
Turner syndrome are extremely high and may occur
in utero and early childhood. Early Turner syndrome
diagnosis is imperative as it allows the opportunity to
serially monitor ovarian function and subsequently
intervene via fertility preserving interventions when
healthy ovarian tissue is still present.

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HORMONE REPLACEMENT
Due to hypogonadism, hormone replacement is
indicated in most Turner syndrome individuals to
avoid a rapid decrease in bone mineral density, and
to induce maximal peak bone mass in adolescents
and young adults. Most commonly, low-dose estro-
gen therapy via estradiol patch is initiated between
ages 11 and 12 years to mitigate fusion of epiphyseal
growth plate [84]. This is followed by progesterone
2–3 years later most commonly via oral tablet for
10–12 days every month, which aids in breast devel-
opment and decreases the risk of erratic bleeding
and endometrial malignancy [84–86].
GROWTH AND SHOX-RELATED SKELETAL
FEATURES
Turner syndrome girls exhibit a 20 cm deficit in
height because of aforementioned SHOX-related
aberrations [87]. Although Turner syndrome
women are not growth hormone (GH)-deficient,
treatment with GH has been demonstrated to
increase adult height by several inches [33]. Timing
of initiated growth hormone is crucial as growth
hormone is ineffective after growth plate fusion.
Maximal growth potential requires initiation at
age 4–6 years old [34]. This again highlights the
impact of early diagnosis. SHOX is expressed in
the first and second pharyngeal arches, which con-
tribute to the bones of the face [88]. Therefore,
abnormal SHOX expression is the likely cause of
high arched palate and other Turner syndrome-
related facial features. It is also expressed in devel-
oping long bones of the forearms and lower limbs,
thus haploinsufficiency is hypothesized result in the
madelung deformity of the wrist, cubitus valgus
(increased carrying angle of the elbow), genu val-
gum (knock-knee) or varum (bow-leggedness), and
short fourth metacarpal (knuckle) and/or metatarsal
bones [89]. As SHOX gene expression is also present
in vertebral body growth plates, aberrations result in
scoliosis in 20% of Turner syndrome individuals and
kyphosis in nearly 50% [90].
RENAL INVOLVEMENT
Congenital malformations of the renal/urinary sys-
tem are present in approximately 30–40% of
patients with Turner syndrome [91,92] and include
horseshoe kidney, hydronephrosis, duplex collect-
ing system, and single unilateral kidney. Recent
studies suggest that the congenital anomalies of
the kidney and urinary tract, which occur in turner
syndrome are not associated with chronic renal
failure but can produce clinically significant hydro-
nephrosis and risks for pyelonephritis [93].
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Novel insights in Turner syndrome Aly and Kruszka
AUTOIMMUNE DISEASE
Women with Turner syndrome have a two to three-
fold higher incidence of autoimmune disease [2].
Isochromosome Xq, and isolated Xp deletion kar-
yotypes have been associated with increased auto-
immune disease [94]. Commonly observed
autoimmune diseases observed in Turner syndrome
include Hashimoto’s thyroiditis, Graves’ disease,
celiac disease, ulcerative colitis, Crohn’s disease,
juvenile rheumatoid arthritis, Sjogren’s disease, sar-
coidosis, and psoriasis [95,96]. Autoimmune thyroi-
ditis is the most prevalent autoimmune disease in
Turner syndrome with a 40% incidence of antithy-
roid antibodies and a 25–30% incidence of overt
hypothyroidism [96]. Suggested mechanisms
include epigenetic changes and haploinsufficiency
[97]. The CD40L gene is decreased in Turner syn-
drome women and is involved in modulating the
adaptive T-cell and B-cell immune response. TLR7,
involved in innate immunity is also decreased in
Turner syndrome women [98]. The incidence of
autoimmune type 1 diabetes [99,100] and type 2
diabetes is increased in Turner syndrome [101].
Gene expression profiling in isochromosome Xq
found overexpression of genes affecting pancreatic
beta cell development, and insulin-like growth fac-
tor-2 (IGF-2) [102].
NEUROCOGNITION
Turner syndrome women have an increased fre-
quency of executive functioning disabilities (task
handling, working memory and processing speed),
visual–spatial perception, facial expression recogni-
tion, and motor coordination. About 10% of girls
with Turner syndrome may present with intellectual
disability [103–108]. Socially, Turner syndrome
individuals exhibit lower self-esteem, and a higher
incidence of social isolation, anxiety, and depres-
sion [109–112]. Early intervention has been shown
to mitigate neurocognitive deficit [109,113,114].
Both individual counseling and support group
involvement should be encouraged [115].
CONCLUSION
Developments in genetic and genomic analysis have
broadened the understanding of Turner syndrome
pathogenesis. In contrast to historic paradigms sug-
gesting haploinsufficiency as the solitary mecha-
nism, it is evident that a multitude of converging
mechanisms are involved, including imprinting, epi-
genetic changes, and alterations in RNA expression.
Early and accurate diagnosis is imperative as it allows
for timely interventions to maximize growth and
fertility preservation. Multisite cytogenic analysis
www.co-pediatrics.com 457
Special commentary
(buccal mucosa, bladder epithelium, and skin fibro-
blasts), coupled with a higher resolution methods of
analysis, such as FISH and/or SNP may provide a more
accurate genotypic diagnosis, which can inform care.
The multitude of organ systems affected in Turner
syndrome highlights the scope and complexity of the
condition and underscores the importance of a multi-
disciplinary approach to patient care. Although sev-
eral novel candidate genes across the involved organ
systems were discussed, a multitude of genotype–
phenotype correlations remain unknown. Determin-
ing, which genes predispose to the disorder of Turner
syndrome is invaluable to our overall understanding
of the condition and could potentially lead to indi-
vidualized targeted pharmacologic therapies.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 34  Number 4  August 2022