knowledge about parental disorders

1. X chromosome aneuploidy is associated with so little phenotypic
abnormality, compared with autosomal imbalance. The important
factor is dosage compensation. Only one X in each cell needs to be fully
active.
 The conceptus with an X chromosome complement in excess of the
normal 46,XX or 46,XY accommodates to this imbalance .
This is nearly successful in the 47, XXX female and the 47,XXY male, in
whom there is apparently normal in utero survival and a relatively mild
postnatal phenotype .

2. The fact that some loci are not subject to inactivation and may therefore function
in the (XXY),(XXX), or even (49,XXXXX)states, is likely the predominant reason for
the phenotypic abnormalities associated with these karyotypes
In females with abnormal X chromosomes, the pattern of X-inactivation is usually
non random .
DETAILS OF MEIOTIC BEHAVIOR
Meiosis proceeds differently in each of the various sex chromosome
abnormalities .

3. XXX (Trisomy X)
• On theoretical grounds, one might expect the three X chromosomes to display 2:1
segregation, with the production of equal numbers of X and XX ova.
• But this is not the case. No discernible increased risk for chromosomally abnormal
offspring of these women has been demonstrated: in the extensive review of Oter et al.
( 2010 ),
• only one case had ever been reported of an XXX mother having had an XXX daughter.
• Apparently, only normal ova, with a single X, are regularly produced. It may be that the
extra X is lost before meiosis occurs (Neri, 1984 ), with meiosis then proceeding as in
the normal XX female.
• A few instances of premature ovarian failure (POF) in 47,XXX women are on record,
including even in adolescence (Holland, 2001 ). But since XXX and POF are both fairly
common, cause and effect remain uncertain

4. XXY AND XXY MOSAIC STATES
• Barring medical intervention, infertility is almost inevitable in Klinefelter syndrome,
although some remarkable exceptions exist.
• Terzoli et al. ( 1992 ),for example, report an XXY man who had fathered a daughter, with
paternity testing confirming fatherhood, and they quote two other such cases.
• Undetected XY/XXY mosaicism could account for some of these cases.
• Bergère et al. ( 2002 ) showed both XY and XXY cell populations in testicular biopsies
from three of four men who, on blood karyotyping and fluorescence in situ
hybridization(FISH) analysis, were nonmosaic 47,XXY. These three men had small
numbers of sperm identified in the biopsied tissue (one went on to have a child byin
vitro fertilization, IVF).
• Several workers have karyotyped sperm from XXY men, and all find an excess, albeit
not a large one, of 24,XX and 24,XYsperm. Possibly, these XY and XX sperm come from
XXY spermatogonial stem cells.
• Alternatively, the abnormal gonadal environment may of itself predispose to gonosomal
nondisjunction in the XY tissue

5. 45,X TURNER SYNDROME
• The great majority of women with 45,X Turner syndrome (TS) are infertile and do not
spontaneously menstruate or develop secondary sexual characteristics.
• The ovaries initially appear to be normal but begin to degenerate in midfetal life.
• Oocytes undergo apoptosis and disappear at an accelerated rate and,
in most cases, are gone by the age of 2 years:
• Spontaneous menstruation is uncommon but recorded (Lippe, 1991 ;Hovata, 1999 ),
• And in one series of eighteen 45,X girls, none had ovarian follicles on biopsy in
childhood or teenage (Borgström et al., 2009 ).
• Completed pregnancy in women with an apparent 45,X karyotype is very rare.
• In a Danish study based on a national TS register, none of 200 45,X women
achieved a natural pregnancy (one had twins by ovum donation) (Birkebaek et al.2002 ).
• Syber(2004) records a total of 18 cases, these women having had 42 pregnancies, of
which 17 proceeded to live birth, including one with trisomy 21, and two with 45,X.

6. • What is the explanation for fertility in these cases?
• An obvious point to consider is gonadal mosaicism, with a 46,XX cell line in the
ovary.
This has ofen been suggested, but rarely proven(Birkebaek et al., 2002 ).
• Jacobs et al. ( 1997 ) undertook a systematic search in 84 subjects with TS
whose standard blood karyotype was 45,X, with molecular testing of blood and of
a second tissue (buccal cells) and found only two cases of X/XX mosaicism.
• One very thorough study is that reported in Magee et al. ( 1998b ), concerning a
45,X woman who had had seven pregnancies, five miscarrying, one producing a
healthy male, and the last terminated following demonstration of fetal cystic
hygroma and a 45,X karyotype on amniocentesis.
• Biopsies of skin, uterus, and ovary at subsequent gynecological surgery all gave a
45,X karyotype, but molecular testing showed two alleles in ovarian DNA,
indicating the presence of occult 46,XX tissue.

7. XYY
The clinical observation is that XYY men have no discernible increase in risk to have
children with a sex chromosome aneuploidy .
 On laboratory study, XYY spermatocytes proceeding through meiosis encounter
checkpoints that lead to elimination of most of the abnormal forms (Milazzo et al.,
2006 )
But nevertheless, some men may have a small increased fraction of 24,YY and 24,XY
spermatozoa in the ejaculate.
A distinction may be drawn between XYY men presenting with infertility, and those
whose fertility is intact, with the sperm aneuploidy rate somewhat higher in the former.
 Rodrigo et al.( 2010 ) studied the next stage of development, namely, the
preimplantation embryo, from five infertile XYY men having had IVF. The rates of
chromosome abnormality were double that of a control group.

8. SEX CHROMOSOME POLYSOMY
•
The 48,XXXX female characteristically has diminished ovarian function, and
fertility in pure XXXX is on record in only one case.
• Sterility is presumably invariable in XXXY and XXYY males, who have a further sex
chromosome superadded upon the Klinefelter karyotype (Linden
et al., 1995 ).

9. GENETIC COUNSELING
• Many of the gonosomal disorders are associated with infertility, or at least
subfertility.
• Some present a phenotype of relatively mild abnormality.
• Whetherprenatal diagnosis is chosen, in those who are able to achieve
pregnancy, may depend on the parents perception of the seriousness of the
potential abnormal outcome.
• Their decision may well also be influenced by how difficult it was to achieve the
pregnancy.

10. XXX
• XXX mothers have no discernibly increased risk ofbearing chromosomally
abnormal children.
• A theoretical increased risk for children with an X aneuploidy has not been
demonstrated in practice.
• Near-silence subsequently in the literature on this issue suggests at least a rarity
of abnormal pregnancy outcomes; one such case, an XXX daughter of an XXX
mother, is mentioned in passing inHaverty et al. ( 2004 ).
• An additional risk estimate of <½ % for a chromosomally abnormal child may be
reasonable.
• A possibility of premature ovarian failure with 47,XXX can be brought to the
attention of these women, which may assist in decisions about the timing of
childbearing.

11. XXY
• Hardly ever will these men father children, without recourse to IVF (see earlier).
• The early data are certainly small (Fullerton et al., 2010 ), but one may propose
an approximate risk figure of 2 % for a sex chromosomal abnormality in the child.
• Sperm and PGD chromosome studies indicate that as well as this small increased
risk of gonosomal aneuploidy,autosomal aneuploidy might also be implicated,
albeit that an actual case in a child is yet to be observed (Staessen et al., 2003 ).
• In younger men in whom the diagnosis of XXY is made, and who do have sperm
in the ejaculate, gamete banking maybe appropriate (Schiff et al., 2005 ; Ichioka
et al.,2006 ).

12. XYY
•
To our knowledge, there is no report of a discernibly increased risk for the XYY
male to have chromosomally abnormal children.
• A slight increase in gonosomal imbalances in sperm (see earlier) might
nevertheless lead some to choose prenatal diagnosis.
• The risk might be greater in those XYY men who need fertility treatment.

13. 45,X TURNER SYNDROME
•
Natural fertility is very rare. However, a 45,X woman who has spontaneous menses may
possibly be fertile.
• Endocrine and ultrasound studies may clarify whether ovulation is occurring, or likely to occur
(Mazzanti et al., 1997 ; Paoloni-Giacobino et al.,2000a ).
• Any period of fertility is likely to be short lived; thus, a woman with 45,X TS who wishes
to have a child should not delay in trying for a pregnancy.
• Tarani et al. ( 1998 ) reviewed the literature on pregnancy outcome in (apparently) nonmosaic
TS
women.
• In all, fifeen 45,X women had 26 recorded pregnancies, with 9 miscarriages and 16 completed
pregnancies.
• From these 16 pregnancies there were 13 normal children (81 % ), 2 stillborn, and 1 with
Down syndrome.

14. • For the great majority of TS patients who cannot make their own eggs, ovum
donation with IVF may be one route to achieve childbearing (Hovata,1999 ).
• Foudila et al. ( 1999 ) report their experience with 18 women with TS, and
although the rates of embryo transfer were similar to those of other women with
primary ovarian failure, the miscarriage rate was high (40 % ); possibly, this may
have been due to uterine factors

15. SEX CHROMOSOME POLYSOMY
•
Many XXXX women are of low-normal or borderline intelligence, and the
questions of fertility and genetic risk may well be raised by their carers. In
fact, it appears that sterility is usual .
• XXXY andcXXYY men are undoubtedly sterile.