Turner syndrome

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					SSBP Information Sheet
Turner syndrome
Alternative names: Ullrich-Turner syndrome

First description: Otto Ullrich published an account in 1930 of an 8-year-old girl with a variety of
physical anomalies that seemed to indicate a possible underlying syndrome. They included short
stature, lymphodema of the neck, hands and feet, and increased carrying angle of the elbows
(cubitus valgus), as well as a variety of other phenotypic anomalies. It was not until 1938 that
Henry Turner described a series of seven patients who had the features we now associate with his
eponymous syndrome.

The genetic basis of Turner's eponymous syndrome remained a mystery. Then, in 1949, Barr and
Bertram first described a morphological distinction between the male and female neurons of the cat,
with the presence of an intranuclear body, being found
at the periphery of interphase nuclei of females but not in males. Ten years later, Ohno et al [1959]
showed this 'sex chromatin' represented a single X chromosome, which it was assumed replicated
out of phase with the rest of the genome. Around the
same time, Jacobs and Strong [1959] examined the chromosomes of patients with Klinefelter's
syndrome and found they possessed this additional sex-chromatin (known as a Barr body) despite
their male phenotype. In the same year, an exciting one for cytogeneticists, Charles Ford and
colleagues [1959] described a patient with the karyotype XO (now known as 45,X or X-
monosomy), and 45 rather than the usual 46 chromosomes. She lacked the second sex chromosome,
and no Barr body was visible, despite having a female phenotype. Her sexual immaturity and other
phenotypic characteristics corresponded to the syndrome described by Turner.

Incidence/Prevalence:Overall the incidence of all abnonnalities that include partial or complete
monosomy X is between 1 in 2000 and 1 in 5000 live female births. Monosomy X is more frequent
than structural anomalies among spontaneous abortions. It accounts for
nearly 10% of all miscarriages and perhaps 1-2% of all human conceptions. As many as 99% of all
45,X fetuses do not survive to term, and most die by 28 weeks gestation. Unlike common human
trisomies such as Down syndrome (trisomy of chromosome
21) the risk of Turner syndrome does not increase with maternal (or paternal) age.

Genetic aspects: Most investigators believe that the phenotype in TS is the result of a deficiency of
specific genes, most of which are as yet unidentified, rather than to the consequence of a single X
chromosome (45,X) per se. One half of clinically identified cases possess part of a second X
chromosome too, which is structurally abnormal, usually in association with some 45,X cells
[Jacobs et al. 1997]. Most of the phenotypic features of TS are thought to be due to haploid (i.e.
single and insufficient) dosage of these specific genes. Because of X-inactivation, a random process
occurring early in embryogenesis, only one X-chromosome is normally active during most of
development. If a single X chromosome is associated with a phenotype (IS) this implies that in
humans, X-inactivation is incomplete, and some essential gene products are transcribed from the
'silent' X chromosome too. They are needed in two expressed copies (i.e. diploid dosage) for normal
development to take place. To maintain dosage equivalence in gene products between males and
females, there are functionally equivalent genes on the Y chromosome too. SHOX, a gene that
contributes to the short stature associated with the syndrome, lies in the pseudoautosomal region at
the tip of the short arm of the X-chromosome, a region of homology with the Y chromosome in
which pairing takes place during meiosis. No other 'Turner' gene has yet been discovered.

Cytogenetically, there is great variation within the Turner population in terms of chromosomal
constitution. Approximately 50% have a single X-chromosome in all cells examined, of which most
(70%) are maternal in origin. The great majority of the other 50% are mosaics, possessing at least
two cell lines, one of which is 45,X. A small proportion has an additional normal 46,XX cell line
(5%). In the remainder (40%) there is a second X which is structurally abnormal. In a few cases
(6%), there is a structurally abnormal Y. The presence of a partial Y chromosome increases the risk
of gonadoblastoma in situ, but how risk relates to the structure of that partial Y, or to specific Y-
linked genes, is as yet uncertain. There is a significantly increased risk of global learning difficulties
and behavioural maladjustment in the nearly 30% of mosaic Turner subjects with a ring-X

Physical aspects: The most striking physical characteristics include short stature. This is not due to
growth hormone deficiency as such, but is associated with the deletion of the distal portion of the
short arm of the X-chromosome, which contains genes that are
important for normal growth in stature. Short stature reflects a generalised growth defect that is first
manifest in utero and not simply the absence of the pubertal growth spurt. In the USA the adult
height of women with Turner syndrome rarely exceeds 150 cm, but such height is reduced in
proportion to average parental stature so females with exceptionally tall parents may nevertheless
be of average stature. Growth hormone treatment (not replacement therapy) which is started in early
childhood may be associated with an increase in adult height of 8-10 cm at best. There is a failure of
secondary sexual characteristics to develop in most cases, and oestrogen replacement therapy is
now given routinely in adolescence. The ovaries fail to develop, and the uterus and vagina are often
small and immature. Other physical features are much more variable. Those most easily observed
include a webbed neck
(50%), a wide carrying angle (50%), and broad chest with widely spaced nipples (60%), low
posterior hairline (75%), and characteristic facial features. Approximately 20% have coarctation of
the aorta, and a minority has renal abnormalities. Deafliess,
of both sensorineural origin and secondary to persistent middle ear disease, is increasingly
recognised to affect a substantial minority of women by middle age.

Cognitive aspects: The verbal intelligence of females with Turner syndrome is usually normal
although specific cognitive deficits may exist, especially in visuospatial skills. There is no increased
risk of mental retardation, except in cases of ring-X chromosome.
Performance IQ is impaired relative to verbal IQ in about 80% of monosomic IS females, the latter
being normal. Maximal difficulties are found in Performance IQ tasks involving visuoconstructional
abilities. Poor performance in copying complex
designs and in a speeded pegmoving task (a motor task with visuospatial demands) is also found.
45,X subjects have substantial impairment in simple numerical tasks, including biologically based
abilities to subitize and to compare number magnitudes.
Face recognition ability is poor, both the ability to recognise a familiar face and the detection of
facial emotions. The underlying neurocognitive basis of the visuospatial deficit remains poorly
understood, but is undoubtedly complex and probably due to
the dysfunction of several neurocognitive systems whose normal development is dependent on X-
linked genes.

Behavioural aspects: There appears to be no relationship between psychosocial adjustment and
stature for any age group. The main predictor of outcome is general intelligence, and this in turn
varies according to karyotype. The contribution to poor adjustment made by dysmorphism may be
causal, or may reflect an underlying developmental disorder that contributes to both outcomes.
Common psychiatric problems include attention deficit disorder in elementary school age children,
and social adjustment problems in
adolescence and early adulthood. Among those with moderate or severe learning difficulties,
comorbidity with autism is common. The specificity of this association requires further
investigation but its frequency is substantially greater than would be expected within a population
selected solely on the grounds of mental retardation. Obsessive-compulsive symptoms are also
common throughout childhood and adolescence, and clinical experience suggests they become more
disabling in early adulthood. This finding demands closer examination in a systematic investigation
of the disorder. The apparent influence of age on adjustment is mainly upon the nature of the
disturbance rather than in terms of its degree, and the same females are probably vulnerable
throughout life. Self-perception, affected by visible stigmata, may be a contributory factor. Family
variables, such as parenting styles, are probably not very important influences upon adjustment, in
view of the striking differences in prevalence of problems between karyotypes. Certain aspects of
social behaviour are relatively less adaptive in X-monosomy where the single X chromosome is
in origin.

Life expectancy: Women with Turner's syndrome have a reduced life expectancy, primarily as a
result of diseases of the circulatory system, especially congenital heart disease and dissection of the
aorta. The reduction in life expectancy is in the order of 12 years at age 1 year, 11 years at age 20,
and 10 years at age 40. They are also susceptible to a number of other disorders including
autoimmune thyroiditis, osteoporosis, and renal and gastrointestinal disease. Following discharge
from paediatric care, women with Turner's syndrome should be followed up by a multidisciplinary
team of physicians with experience of the disorder, but unfortunately in the United Kingdom few
specialist clinics exist at present.

Jacobs P, Dalton P, James R, Mosse K, Power M, Robinson D, Skuse D. (1997)
Turner syndrome: a cytogenetiC and molecular study. Ann Hum Genet 61:471-483.

Lippe BM. (1996) Turner syndrome. In: Sperling MA. (Ed) Pediatric
Endocrinology. Philadelphia: 'YB Saunders, 387-421.

Elsheikh M, Conway GS, Wass JA. (1999) Medical problems in adult women with
Turner's syndrome. Ann Mcd Apr; 31(2): 99-105