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Archives of Disease in Childhood 1995; 72: 285-286
Molecular biology of Turner's syndrome
Turner's syndrome was first described in 19381 and results
in a clinical picture most frequently comprising short
stature and gonadal dysgenesis. Other features may
include coarctation of the aorta, renal anomalies, neck
webbing, and lymphoedema. The clinical phenotype can
be extremely variable even in patients with the same
karyotype. The chromosomal basis of the condition was
established in 1959 when a patient was described who
exhibited loss of one sex chromosome.2 Approximately
50% of cases have a 45,X karyotype with the remainder
having mosaic karyotypes with one 45,X cell line and
another cell line often containing a structurally abnormal
X chromosome such as a ring X.
Turner's syndrome is one of the commonest chromosomal anomalies in man with an incidence of at least one in
1850 live female births.3 Recently more interest has been
focused on this condition because of the advent of recombinant growth hormone treatment,4 and patients with
Turner's syndrome now comprise a large proportion of the
cases attending paediatric growth clinics. In spite of the
fact that it has been recognised as an entity for a considerable length of time, the molecular biology of the condition
has not been fully elucidated. Recent research using
molecular genetic techniques has improved our understanding of the condition but more work is still required in
this field.
Parental origin of the retained X chromosome
The loss of one of the sex chromosomes that is the basis for
Turner's syndrome probably occurs after the zygote has
formed or just after the fusion of the gametes. This being
the case one would expect an equal chance of either
parental X being retained. In practice, however, in
70-80% of cases the retained X is maternal in origin.5 This
observation has led to the speculation that there may be
genes present on the X chromosome which are expressed
differently depending upon whether they are maternally or
paternally derived. This process is called 'genomic
imprinting' and has been described in a number of conditions including Prader-Willi and Angelman's syndromes.
It has been postulated that imprinting may play a part in
the high intrauterine mortality and variable phenotype
seen in Turner's syndrome. Evidence for this has been
contradictory. One study showed that the morphological
appearances of fetuses retaining the paternal X differed
from those retaining the maternal X in a small sample,
perhaps indicating that fetuses retaining the paternal X did
'less well' than those retaining the maternal X.6 This led to
conjecture that loss of the maternal sex chromosome may
be less compatible with intrauterine survival than loss of
the paternal sex chromosome. However, the pathological
descriptions of 45,X abortuses do not indicate any unusual
degree of developmental abnormality7 and the percentage
of aborted fetuses retaining the maternal X chromosome is
the same as in liveborns.7 8 Therefore imprinting does not
seem to play an important part in the high fetal loss in
Turner's syndrome conceptuses.
Imprinting may affect the phenotype and recent work
has indicated that patients retaining the maternal X have a
greater incidence of cardiovascular anomalies and neck
webbing than those retaining the paternal X and also that
the pretreatment height of those retaining the maternal X
correlates very strongly with maternal height but not with
paternal height.9 The interpretation of such findings are
complicated by the possibility of undetected mosaicism for
a second sex chromosome.
Sex chromosome mosaicism in Turner's syndrome
Approximately one in 50 of all conceptuses are associated
with a 45,X genotype but there is high intrauterine lethality such that only 1% of such conceptuses survive to term.
There is a higher percentage of mosaic karyotypes than
monosomy X in liveborns compared with fetuses which
has led to the speculation that all liveborn infants with
Turner's syndrome are mosaic in a cell line critical for fetal
survival.10 This hypothesis has not been supported by
studies on blood using Southern blotting with hypervariable probes from the X chromosome11 or on cytogenetic
studies examining multiple tissues'2 where the authors
found that 20% of patients still appear to have monosomy
X. It is possible that with more sensitive techniques low
level mosaicism may be detected. As mentioned previously, approximately 70-80% of cases of Turner's
syndrome retain the maternal X. As the missing sex
chromosome may be either an X or a Y theoretically
35-40% of cases may have occult Y mosaicism.13 This has
clinical relevance because if Y material is present there is a
risk of up to 30% of gonadoblastoma developing in the
dysgenetic gonads.14 At present if a Y chromosome is
identified on cytogenetic analysis, gonadectomy is recommended but counselling is more difficult if there is an
abnormal Y or a fragment of the Y. It would be helpful to
define an 'at risk' locus, the presence of which would indicate a need for gonadectomy and there is a postulated
'gonadoblastoma locus' on the Y chromosome which is
believed to be situated on the long arm of the Y just below
the centromere.15 16 Although there is debate about the
need to screen patients with Turner's syndrome for occult
Y mosaicism, if such screening were to be implemented it
would be logical to include analysis for this particular area
of the Y chromosome in the screening strategy, and recent
publication of polymerase chain reaction (PCR) primers
covering the whole of the Y chromosome makes this a
fairly straightforward procedure.'7
Although theoretically 35-40% of patients with
Turner's syndrome may have Y mosaicism, in practice this
has not been demonstrated. Studies to date have used
either Southern blotting with Y specific probes or PCR
with one or two Y specific primers'3 18 and have shown
between 4-8% of cases of Turner's syndrome have Y
material present. Recently a new technique using Southern
blotting of DNA previously amplified by PCR has
purported to demonstrate a very high incidence of unsuspected Y mosaicism in patients with Turner's syndrome.'9
This particular technique is extremely sensitive but is also
very prone to contamination from external sources so that
such results should be interpreted with care.16 An added
difficulty in interpreting these findings is the uncertainty of
the effects of very low level mosaicism found in blood.
X inactivation of structurally abnormal X
chromosomes
Another factor which may affect the phenotype in Turner's
syndrome is X inactivation of structurally abnormal
X chromosomes. Inactivation of most of one of the two X
chromosomes occurs in normal females at an early stage of
embryogenesis so that there is equal gene dosage between
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286
males and females. Thus only one X chromosome should
be active in each cell. Inactivation of the X chromosome is
controlled from the X inactivation centre situated on the X
long arm. Although X inactivation is initially thought to be
random, in cases with a structurally abnormal X chromosome the cell line in which the normal X is active gradually
takes over.20
Anomalous X inactivation has been postulated to be
implicated in the phenotype found in a subgroup of
patients with Tumer's syndrome and small ring X
chromosomes who have dysmorphic facies, syndactyly of
the hands and feet, and severe mental retardation.2' A proportion of these small rings remain active in the same cells
as the normal X and these cells therefore have functional
duplication of areas of the X. The mechanism for these
rings remaining active was initially thought to be simple
loss of the X inactivation centre situated on the X long arm
(Xq 13) due to the small size of the rings. However, recent
work looking at expression of a gene that is only expressed
from the inactive X-XIST (X inactive specific transcripts)
has shown that the inactivation centre is often present in
these small rings22 but its expression may not be normal,
possibly due to mutations in the gene.23
The search for Turner 'genes'
The particular phenotype seen in Turner's syndrome can
occur with a number of different karyotypic pictures and
certain features have been tentatively mapped to areas of
the X chromosome, for instance short stature to the X
short arm, ovarian function to both the long and short
arms.24 The phenotype in Turner's syndrome is thus not
thought to be due to loss of the entire X chromosome but
rather to haploid dosage of a gene or genes. If there is a
Turner's syndrome gene it must have the following characteristics: it must escape inactivation and it must have a
homologue on the Y chromosome or all XY individuals
would have the Turner phenotype. One gene fulfilling
these criteria, RPS4X/RPS4Y, was put forward as a likely
candidate but has the disadvantage of being located on the
X long arm and gene expression studies in patients with X
isochromosomes have shown that it is expressed from the
abnormal X.25 Several other genes also fulfil these criteria:
XE7 whose function is unknown, MIC2 which encodes a
glycoprotein involved in T cell adhesion, and ZFX/ZFY
which encodes a zinc finger protein. It is probable that
more genes with these characteristics have yet to be discovered.
In conclusion, Turner's syndrome is a relatively
common condition and its variable phenotype causes difficulties in diagnosis and counselling. The various factors
affecting the phenotype have not yet been fully elucidated
but include occult mosaicism, imprinting, and anomalous
X inactivation. Thus far investigations have mainly concentrated on blood but analysis of other tissues may also
Chu, Connor
help explain the variability and make counselling patients
easier.
Duncan Guthrie Institute ofMedical Genetics,
Yorkhill,
Glasgow G3 8SJ
C E CHU
J M CONNOR
CEC was funded by Kabi-Pharmacia but is now in receipt of a grant from
SHERT.
1 Turner HH. A syndrome of infantilism, congenital webbed neck, and
cubitus valgus. Endocrinology 1938; 23: 566-74.
2 Ford CE, Jones KW, Polani PE, de Almeida JC, Briggs JH. A sex chromosome anomaly in a case of gonadal dysgenesis (Turner's syndrome).
Lancet 1959; i: 711-3.
3 Nielsen J, Wohlert M. Chromosome abnormalities found among 34 910
newborn children: results from a 13-year incidence study in Arhus,
Denmark. Hum Genet 1991; 87: 81-3.
4 Rosenfeld RG, Frane J, Attie KM, et al. Six-year results of a randomised,
prospective trial of growth hormone and oxandrolone in Turner syndrome.7 Pediatr 1992; 121: 49-55.
5 Lorda-Sanchez I, Binkert F, Maechler M, Schinzel A. Molecular study of
45,X conceptuses: correlation with clinical findings. Am 7 Med Genet
1992; 42: 487-90.
6 Hassold T, Benham F, Leppert M. Cytogenetic and molecular analysis of
sex-chromosome monosomy. Am J Hum Genet 1988; 42: 534-41.
7 Epstein CJ. Mechanisms leading to the phenotype of Turner syndrome. In:
Rosenfeld RG, Grumbach MM, eds. Turner syndrome. New York: Marcel
Dekker, 1990: 13-28.
8 Jacobs PA, Betts PR, Cockwell AE, et al. A cytogenetic and molecular reappraisal of a series of patients with Turner's syndrome. Ann Hum Genet
1990; 54: 209-23.
9 Chu CE, Donaldson MDC, Kelnar CJH, et al. Possible role of imprinting in
the Turner phenotype. JMed Genet 1994; 31: 840-2.
10 Hook EB, Warburton D. The distribution of chromosomal genotypes
associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated
with structural X abnormalities or mosaicism. Hum Genet 1983; 64: 24-7.
11 Gicquel C, Cabrol S, Schneid H, Girard F, Le Bouc Y. Molecular diagnosis
in Turner's syndrome. J Med Genet 1992; 29: 547-51.
12 Held KR, Kerber S, Kaminsky E, et al. Mosaicism in 45,X Turner syndrome: does survival depend on the presence of two sex chromosomes?
Hum Genet 1992; 88: 288-94.
13 Ostrer H, Clayton CM. Y chromosome mosaicism in 45,X Turner syndrome [Letter]. Am J Med Genet 1989; 34: 294-6.
14 Verp MS, Simpson JL. Abnormal sexual differentiation and neoplasia.
Cancer Genet Cytogenet 1987; 25: 191-218.
15 Page DC. Hypothesis: a Y chromosomal gene causes gonadoblastoma in
dysgenetic gonads. Development 1987; 101 (suppl): 151-5.
16 Page DC. Y chromosomal sequences in Turner's syndrome and risk of
gonadoblastoma or virilisation [Letter]. Lancet 1994; 343: 240.
17 Vollrath D, Foote S, Hilton A, et al. The human Y chromosome: a 48interval map based on naturally occurring deletions. Science 1992; 258:
52-9.
18 Yankowitz J, Neely EK, Hajdu K, Norton ME, Rosenfeld RG, Golbus MS.
Screening of Turner subjects by PCR for occult Y chromosomal DNA.
Am JHum Genet 1993; 53: 1766A.
19 Kocova M, Siegal SF, Wenger SL, Lee PA, Trucco M. Detection of Y
chromosomal sequences in Turner's syndrome by Southern blot analysis
of amplified DNA. Lancet 1993; 342: 140-3.
20 Therman E, Denniston C, Sarto GE, Ulber M. X chromosome constitution
and the female phenotype. Hum Genet 1980; 54: 133-43.
21 Kushnick T, Irons TG, Wiley JE, Gettig EA, Rao KW, Bowyer S.
45,X/46,Xr(X) with syndactyly and severe mental retardation. Am Y Med
Genet 1987; 28: 567-74.
22 Dennis NR, Collins AL, Crolla JA, Cockwell AE, Fisher AM, Jacobs PA.
Three patients with ring (X) chromosomes and a severe phenotype. J Med
Genet 1993; 30: 482-6.
23 Migeon BR, Luo, S, Stasiowski BA, et al. Deficient transcription of XIST
from tiny ring X chromosomes in females with severe phenotypes. Proc
NadAcad Sci USA 1993; 90: 1205-9.
24 Therman E, Susman B. The similarity of phenotypic effects caused by Xp
and Xq deletions in the human female: a hypothesis. Hum Genet 1990; 85:
175-83.
25 Fisher EMC, Beer-Romero P, Brown LG, et al. Homologous ribosomal
protein genes on the human X and Y chromosomes: escape from Xinactivation and possible implications for Turner syndrome. Cell 1990; 63:
1205-18.
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Molecular biology of Turner's syndrome.
C E Chu and J M Connor
Arch Dis Child 1995 72: 285-286
doi: 10.1136/adc.72.4.285
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