The Principles of Clinical Cytogenetics - Extra Materials - Springer

Sex Chromosomes and Sex Chromosome Abnormalities 215
Studies have suggested that the more severely affected patients have smaller rings that are deleted
for XIST. It has been hypothesized that the lack of XIST causes the ring to fail to inactivate, thus
causing functional disomy for genes present on the ring, resulting in phenotypic abnormalities (66–68).
Larger rings have XIST present and are preferentially inactivated. However, Turner et al. (69) reported
that in seven females with 45,X/46,r(X) and an XIST negative ring, only one had a severe phenotype
and this was explained by the absence of XIST expression, a large amount of Xp material in the ring,
and, possibly, the concomitant maternal uniparental isodisomy (see Chapter 19). The remaining six
patients had physical phenotypes consistent with Turner syndrome. The size of the ring X chromosome
lacking XIST correlates with the degree of clinical severity (63,68–70). Those with extremely
small rings have been found to have cognitive functioning similar to those with 45,X. There could be
particular gene sequences that when functionally disomic, result in the severe physical phenotype.
Other factors that could contribute to the phenotype in patients with small ring X chromosomes are
the tissue-limited distribution of the ring X cell line or ring formation from an inactive X after the
establishment of X inactivation. In patients with an inactivated ring X chromosome, having a larger
proportion of cells with the ring was associated with lower verbal and nonverbal IQ scores (70). Migeon
et al. reported two patients with inactive ring X chromosomes, mental retardation, and a severe phenotype
(71). Cultured fibroblasts from these patients showed a second ring in a small percentage of cells.
The authors hypothesized that the severe phenotype with an inactive X chromosome is the result of the
presence of a second ring X that was active in some tissues during embryogenesis.
The prognosis for patients with small ring X chromosomes might be better than previously proposed
(69). However, a ring X chromosome appears to be associated with a substantially increased
risk of significant learning difficulties, requiring special educational provision, compared to 45,X
(70). It might not be possible to accurately predict prenatally the phenotype that will be associated
with the ring X chromosome after birth. Although a relatively large, active ring X (XIST not expressed)
is more likely to be associated with severe phenotypic abnormalities, demonstration of an inactive
ring X is not necessarily reassuring (71). The etiology of the abnormal phenotype in ring X is
complex and cannot be based solely on the inactivation status of the ring. Size and gene content,
extent of X inactivation, parental origin, and timing of ring formation and of cell selection likely play
a role in the broad phenotypic variability (62).
45,X/47,XXX Mosaicism
Approximately 2% of patients with Turner syndrome have a 45,X/47,XXX mosaic karyotype
(45,72). A study of seven girls with this type of mosaicism aged 6.1–20.4 years found that three of
seven did not require growth hormone, five of six girls older than 10 years had spontaneous puberty,
and four or five girls older than 12 years had spontaneous menarche with regular menstrual cycles
without medication. No renal or cardiac anomalies and no cognitive or behavioral problems were found
in this small group of patients. In general, patients with Turner syndrome caused by 45,X/47,XXX
mosaicism are more mildly affected clinically with regard to phenotype and ovarian function (72).
Marker Chromosomes in Patients with Turner Syndrome
It is important to identify the origin of a marker chromosome in a patient with Turner syndrome,
because of the risk of gonadoblastoma if it is made up of Y material (see the section 45,X/46,XY
Mosaicism above) or the increased risk of phenotypic and developmental abnormalities if the marker
is of autosomal origin. This can be done either with FISH or molecular techniques.
47,XXX
This is the most frequent sex chromosome abnormality present at birth in females, occurring in 1
in approximately 1000 live female births (73). It was first described in 1959 by Jacobs et al. (74).
Unfortunately, the term originally used for this cytogenetic abnormality was “superfemale,” which
gives a misconception of the syndrome and is no longer in use.