Triple-X females

AN ORIENTATION

PUBLISHED BY THE TURNER CENTER, RISSKOV, DENMARK

CONTENTS

Introduction	5
The name triple-X?	7
How frequent is triple-X?	7
What is the cause of triple-X?	7
What is the cause of the chromosome aberration in triple-X?	8
How is the development of these girls during childhood?	9
Are triple-X girls of average intelligence?	10
How do they manage at school?	10
Do they have increased risk of any diseases?	11
How is the height growth?	11
How is the physical sexual development?	12
Can triple-X women have children?	12
Are triple-X women normal females?	12
How about occupation and work stability?	13
Is triple-X a disease?	13
Is there an increased risk of getting mentally ill?	14
Should parents have ful information?	14
Should women with triple-X have full information?	15
What kind of information should be given to parents, with a triple-X foetus diagnosed prenatally?	15
Should the public have information on triple-X?	17
Triple-X contact groups	17
Literature	19

Introduction

This booklet was written and published in the light of a tremendous need for further information about triple-X females.

It is in no way an attempt of giving a complete description of all aspects of triple-X.

The booklet was written in order to give a better information to triple-X girls and their parents as well as to adult women with triple-X, but it is also our hope that it will be read by genetic counsellors, physicians, teachers and others who come into contact with girls and adult women with triple-X. More information on all levels will, however, first and foremost be valuable to triple-X females and their relatives.

Publication by the Turner Center in Risskov, Denmark, should be seen as part of the work in this center with information, counselling and research concerning Turner and triple-X females and Klinefelter and XYY males.

Johannes Nielsen

Klinefelter's syndrome with an extra X-chromosome and Turner's syndrome with lack of X-chromosome material have their names after the physicians who first described the syndromes in 1942 and 1937, respectively.

Since 1960 geneticists have given new names to chromosome aberrations from the chromosome constitution and not as previously from the name of the person who first described the chromosome aberration.

When Patricia Jacobs and co-workers first found and described the chromosome constitution 47,XXX in 2 women in Scotland the name became triple-X in accordance with XYY for males with the chromosome constitution 47,XYY as first described by Sandberg and co-workers in 1961.

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Triple-X is found in approximately 1 per 1,000 females. Thus in Denmark with a population of 5 mill. there are approximately 3,000 women with triple-X.

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Women usually have only 2 X-chromosomes, that is the chromosome constitution 46,XX. Women with triple-X have 3 X'es (47,XXX) or in rare cases 4 X-chromosomes (48,XXXX) also called tetra-X. In extremely rare cases there may be 5 X-chromosomes (49,XXXXX) also called penta-X.

The chromosome constitution 47,XXX is found in approximately half of the women with an extra X-chromosome. In approximately 5% there is 48,XXXX and in approximately 50% of women with extra X-chromosome there is so-called chromosome mosaicism, that is a normal chromosome constitution 46,XX in part of the cells and 47,XXX in the rest.

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Certain chromosome aberrations appear more frequently in children of elderly mothers, and this also seems to be the case to a certain extent in triple-X. Apart from this nothing definitely is known about the causes of the chromosome aberration, which leads to an abnormal partition (a so-called non-disjunction) of the X-chromosome leading to an increase in the number of X-chromosomes as found in triple-X (47,XXX), tetraX (48,XXXX) or in very rare cases penta-X (49,XXXXX).

Do new-born girls with triple-X present any signs of this?

No! Girls with triple-X are usually quite normally developed at birth, but their average birth weight is slightly lower than that of girls with normal chromosomes.

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Girls with triple-X are often slightly more quiet and passive as babies, and they usually have a less pronounced assertive age than their siblings. It is, however, conditions that do not play any great role for their development if there is awareness of the fact that it is important to take as much care of the baby who is quiet and passive as of the baby who is active and demanding. It is also important not to suppress the triple-X girls in their relatively weak independence period.

More often than other girls, triple-X girls have a somewhat delayed motoric and linguistic development as well as a delayed emotional maturing which, however, in no way makes them patients or in need of special treatment. This tendency to a somewhat delayed development in the above mentioned areas can, however, to a great extent be counteracted or prevented by increased psychological, social and motoric stimulation at home as well as in the day institution -kindergarten. It is important that these girls attend a good day institution quite early during childhood, and that there is a close cooperation between the parents and the staff in the institution /kindergarten.

If there is a retardation in language development it is important to have speech pedagogue assistance during a period. With regard to the motoric development, participation in parent/child sport activities, group activities and creativity of any kind is of great value. The same is the case with regard to stimulation of the slightly delayed emotional maturity development. In this connection it might be mentioned that it is important to stimulate these girls to independence and in no way to overprotect them.

In the Århus group of 17 unselected triple-X girls there is a single girl who is very introvert and has difficulties getting into contact with others. This is described in rare cases in the literature, but it is not typical for triple-X girls.

Triple-X girls often have slightly more difficulties than their siblings in functioning in group connections, but if one is aware of these difficulties from the earliest childhood and stimulate and support these girls with regard to function in different group relations, they will function quite normally later on with regard to these conditions.

During puberty triple-X girls may have slightly more difficulties than girls the same age, which to a certain extent may be due to the fact that in spite of being slightly taller than girls their age they are usually more emotionally immature than according to age, especially if they have not been stimulated and supported all through childhood, or if they have not got sufficient support, stimulation and help at school.

These girls have an increased tendency to back problems compared to their siblings. This can, however, be counteracted by stimulation and development of motoric abilities from the earliest childhood, especially by participation in gymnastics, swimming and other sport activities. Such activities are not only valuable with regard to a good development of the musculature, especially the back musculature, but also with regard to stimulation and development of motoric abilities and social relations with other children.

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If the triple-X girls grow up in a good, stable and stimulating environment at home as well as at school, their intelligence will be within the normal range in the great majority of cases, even if it is slightly skewed, so that there are fewer than expected with intelligence level above 110. The average intelligence for triple-X girls is slightly lower than for the siblings and a control group. However, none of the 17 triple-X girls diagnosed among 35,000 liveborn children in Århus are mentally retarded.

There is a connection between intelligence and conditions concerning stimulation and conditions during childhood in general with a tendency to a higher intelligence level connected with better and more stimulating conditions during childhood.

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Girls with triple-X manage within the normal range at school, but they have a tendency to certain learning difficulties, especially during the first years at school. This can, however, be remedied by an increased pedagogical effort in relation to need. The learning difficulties are most pronounced during the first years at school, and they are not present in nearly all triple-X girls. It is, however, important to know that if such difficulties are present they need to be investigated and dealt with accordingly, both at home and at school. Learning difficulties can be overcome by remedial teaching, support and stimulation at school as well as at home. It is extremely important that both parents and teachers know about this and deal with it accordingly. If there are problems in relation to speech development it is also important that speech therapy is given. Speech problems are more frequent in triple-X girls than in their sib-siblings.

If conditions at home are good, stable and stimulating, and if there have been good conditions in the day institution, where the triple-X girl has been as well as in the school, learning problems rarely have any serious consequences. However, most triple-X girls need remedial teaching at school at one time or another, and it is important that they get this help if and when they need it.

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Girls with triple-X have no increased risk of any diseases in childhood.

It has been mentioned that they have a slightly increased frequency of back problems, and it is important that one pays attention to this; it can be remedied by participation in sport activities, which strengthen back musculature, general information about lifting technique and maybe also choice of occupation. which is not especially hard for the back. Triple-X women have, however, no increased risk of disorders in adult life.

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Girls with triple-X have a somewhat greater growth acceleration than other girls up till the age of 8 years, and their final height is a few cm above the expected final height. Bone age for these girls is in average somewhat lower than expected till around the age of 10-12 years. They have in the same way as the KIinefelter-boys comparatively long legs in comparison with body length and height in general. Triple-X girls in general have a comparatively low weight in comparison with height.

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Triple-X girls have a normal physical sexual development including puberty development with first menstruation at an average age of 12 and normal development of breasts, body hair growth and secondary sex characteristics in general. There is nothing that indicate that women with triple-X deviate from women with normal chromosomes with regard to sexual relation and sex hormone conditions, and there is no indication for any type of hormone treatment.

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Knowledge about fertility in triple-X women is scanty and dates exclusively from selected, single cases of triple-X women with children. The only investigation of non-selected triple-X girls diagnosed by investigation of all new-born children comprises 50 triple-X girls from Denmark, Canada, USA and Scotland. The oldest of these girls are 20 years old at the present time. Not till these triple-X girls have reached the age of 40 will we have sufficiently good knowledge about fertility of triple-X women.

We know, however, that triple-X women are fertile and able to have children, and their fertility is most probably normal. We also know that in nearly all cases, where children of triple-X women have had chromosome examination made, there have been normal chromosomes and not as one might expect several children with either triple-X (47,XXX) or KIinefelter's syndrome (47,XXY).

In previous studies it has been mentioned that triple-X women may have an early menopause, that is cessation of menstruations. There are, however, no real evidence for this. Also conditions concerning the age at menopause cannot be determined until the above mentioned group of unselected triple-X women have reached the age of 40-50 years.

In Denmark and countries with the possibility of having prenatal chromosome examination made, triple-X women may have such an examination made, but these women most probably do not have any increased risk of having children with chromosome aberrations.

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During the first years after the triple-X constitution had been described, these women were occasionally described as "superfemale". This is, however, not the case. They are neither more, nor less females than other women with normal sex chromosomes, 46,XX. They have a normal female identification, they can marry and have children and become as good wives and mothers as other women.

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As previously mentioned we still know comparatively little about occupation and work stability concerning triple-X women in adult age, but on the background of follow-up of the previously mentioned approximately 50 triple-X girls, who have been followed since birth and now are between 14 and 20 years of age, there is much that indicate that the main occupational area will be in manual occupations, and that there will be relatively few of these women with academical education.

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No! Girls and women with triple-X should definitely not be considered patients. With full information to the parents and themselves and with a good and stimulating environment, extra stimulation and remedial teaching at school it is our experience here in Denmark that the triple-X girls we have followed from the time of birth till between 14 and 18 years will manage within the normal range. Triple-X girls have no special disorders or increased risk of any disorders and no special physical signs that part them from other women.

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In the above mentioned group of 50 triple-X girls diagnosed at birth and followed till between 14 and 20 years of age there is nothing that indicate any increased risk of mental illness compared with siblings and a control group. For triple-X women who grew up in a good environment with love, support and stimulation at home as well as special stimulation and remedial teaching in school if needed, there will be no increased risk of mental illness.

For triple-X women who grew up in a poor environment without sufficient stimulation, support and assistance there is most probably a slightly increased risk of having mental problems compared with siblings in the same way as found in KIinefelter males (47,XXY). Our knowledge about the risk of mental illness in triple-X women is, however, very scanty at the present time. The knowledge we have dates to a great extent from triple-X women who have been diagnosed because they had mental disorder, and such data give a very skewed picture of the actual risk of mental illness. If, however, triple-X women have mental illness, they should be treated like others with the same type of illness.

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Yes! Parents of girls with triple-X should always have full information. It is very important that parents get as much knowledge as possible about triple-X as early as possible in the life of their daughter and preferably already from birth. This is important for many reasons, but especially because it makes it possible for them to create the best possible conditions for their daughter with triple-X with maximum stimulation in all aspects and with the possibility of getting help to this through day institution, kindergarten, school and youth centre. It is important that these children are supported with regard to functioning in group activities and with regard to independence, maturity and avoidance of overprotection.

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It is our experience that women with triple-X in the same way as KIinefelter men and Turner women should have full information, especially if they have difficulties in school and in general. They should know why they have these difficulties and that something can be done by remedial teaching, help and support at school as well as at home. They should also know that it is important that they participate in sport, creative activities and group activities in general.

It is wrong to protect a girl with triple-X by avoiding to tell her what triple-X is. She will always try to find out herself anyway, and being secretive about it can only lead to anxiety and lack of confidence in parents, physicians and adults in general. Information about triple-X should be given by persons with a good knowledge and experience concerning triple-X girls, both during childhood and in adult age and persons with a lot of time. Information should also be given by members of triple-X contact groups, if such groups exist and if the women in question or the parents in question are interested in talking to members of a contact group.

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Twenty-two of the 33 foetuses with triple-X diagnosed by prenatal chromosome examination in Denmark were aborted during the period 1970-84 (76%), and 9 of 16 foetuses with triple-X were aborted during the period 1985-87 (56%). There has been a decrease with regard to induced abortion of foetuses with triple-X at the same time as information about triple-X has improved, especially from investigations at the Cytogenetic Laboratory, Risskov, and of groups of unselected girls with triple-X in USA, Canada, Great Britain and Denmark.

The parents make their own decision whether to carry through the pregnancy in case of a triple-X foetus or have it interrupted with induced abortion, but they make it on the background of the information, they are given by the counsellors, and the weight they have put on the positive contra the negative aspects as well as to some degree on the background of the counsellor's attitude to abortion of a triple-X foetus.

It is very important for prenatal counsellors to put much weight on information dating from the previously mentioned investigation of approximately 50 unselected girls with triple-X rather than on the literature on selected cases where the diagnosis of triple-X often has been made because the woman or girl in question has had some other physical or mental disorders.

It must be stressed that the triple-X girl's development concerning intelligence, learning and with regard to development during adult age to a great extent is related to conditions during childhood, especially stimulation given at home, in day institutions and school. If these conditions are good, it is our experience that girls with triple-X develop within the normal range, even if they intellectually often will be in the lower part of the normal range.

To hint at or have the attitude that foetuses with triple-X should be aborted in relation to prenatal examination is in my opinion a clear discrimination against women with triple-X who usually develop within the normal range, especially if they have grown up under previously mentioned good environmental conditions.

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Information to the public about triple-X should be given by professionals with good knowledge of girls and adults with triple-X. The information should be given in close cooperation with triple-X contact groups where such groups are in existence.

We physicians have got and still get rather poor education with regard to giving full information to the public about disorders and deviations in general. It is my experience that the value of good understanding of any chromosome aberration and easily available information cannot be overestimated, and this is also the case of triple-X.

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In the same way as there are Turner contact groups in many countries: Canada, USA, Australia, Denmark, Great Britain, Germany, Spain, France, Switzerland and national societies of Turner contact groups in Canada, USA, Denmark and other countries there should definitely also be triple-X contact groups. In Denmark we have recently taken the initiative to start a triple-X/Klinefelter contact group. This group has so far met 3 times, and the group has published a folder with the following text: "The background for the establishment of a contact group for people/families with KIinefelter and triple-X is that Johannes Nielsen in 1988 invited to a meeting where some KIinefelter and triple-X families met for the first time. We found it exiting and informative to discuss thoughts and problems we had in common, and as a natural consequence of this meeting we made a contact group which will meet approximately every second month.

We think that there is a need for contact groups for several reasons. Most important is our need of talking with and having contact with families having a child with the same chromosome aberration. It is our wish to contribute with better information to coming parents of a child with either KIinefelter or triple-X, and later on also to encourage and support ongoing research and if possible improve this. If there should be a need for a national association of Klinefelter/triple-X contact groups we will of course discuss this.

The intention with the contact group meetings on the short run is to have a cosy time together, where adults and children get to know each other, exchange experiences and support each other. We will most probably also invite persons who can contribute with some further information, both specialists and adult KIinefelter and triple-X individuals. Further information: Bente Nielsen, telf. 86 - 29 29 61 (representing triple-X families), and Hakon Wellnitz, telf. 86 - 17 47 63 (klinefelter families).

Concerning information about KIinefelter males and triple-X females as well as about the Klinefelter/triple-X contact group you may call Johannes Nielsen, Cytogenetic Laboratory, Århus Psychiatric Hospital, DK-8240 Risskov, telf. 86 - 17 77 77, ext. 3680.

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Netley, C.T. (1986): Summary overview of behavioural development in individuals with neonatally identified X and Y aneuploidy. In: Prospective studies on children with sex chromosome aneuploidy (S.G. Ratcliffe & N. Paul, eds.). Birth Defects: Original Article Series 22. Alan R. Liss, Inc., New York, pp.293-306.

Nielsen, J., I. Sillesen, A.M. Sørensen & K. Sørensen (1979): Follow-up until age 4 to 8 of 25 unselected children with sex chromosome abnormalities, compared with sibs and controls. In: Sex chromosome aneuploidy: Prospective studies on children (A. Robinson, H.A. Lubs & D. Bergsma, eds.). Birth Defects: Original Article Series 15. Alan R. Liss, Inc., New York, pp.15-73.

Nielsen, J. (1979): Fejludvikling af kromosomerne. En orientering. Arkona, Århus, 1979.

Nielsen, J., A.M. Sørensen & K. Sørensen (1982): Follow-up until age 7 to 11 of 25 unselected children with sex chromosome abnormalities. In: Children with sex chromosome aneuploidy: Follow-up studies (D.A. Stewart, ed.). Birth Defects: Original Article Series 18. Alan R. Liss, Inc., New York, pp.61-97.

Nielsen, J. (1984): Information, rådgivning og hjælp. I: Børn - Ja! Men hvilke? (N. Carstensen. P.K. Graugaard, V.E. Knudsen. B. Windelborg & J.H. Østergaard, eds.). FADL'S Forlag, København, pp.154-163.

Nielsen, J., M. Wohlert, J. Faaborg-Andersen. G. Eriksen, K.B. Hansen. L. Hvidman, B. Krag-Olsen, I. Moulvad & P. Videbech (1986): Chromosome examination of 20,222 new-born children: Results from a 7.5-year study in Århus, Denmark. In: Prospective studies on children with sex chromosome aneuploidy (S.G. Ratcliffe & N. Paul. eds.). Birth Defects: Original Article Series 22. Alan R. Liss, Inc., New York, pp. 209-219.

Nielsen, J. (1986): The importance of early diagnosis of children with sex chromosome abnormalities. In: "From Man to Gene. From Gene to Man". Proceedings of the International Symposium, Florence, Italy, pp.204-216.

Ratchife, S.G. & N. Paul (1986): Prospective studies on children with sex chromosome aneuploidy. Birth Defects: Original Article Series 22. Alan R. Liss, Inc., New York. Robinson, A., H.A. Lubs & D. Bergsma (1979): Sex chromosome aneuploidy: Prospective studies on children. Birth Defects: Original Article Series XV. Alan R. Liss, Inc., New York.

Stewart, D.A. (1982): Children with sex chromosome aneuploidy: Follow-up studies. Birth Defects: Original Article Series 18. Alan R. Liss, Inc., New York.