American Journal of Medical Genetics 44:365-368 (1992)

Prognosis of Prenatally Diagnosed Children With Sex Chromosome Aneuploidy

Arthur Robinson, Bruce G. Bender, and Mary G. Linden Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine (A.R., B.G.B., M.L.), and Departments of Biochemistry, Biophysics, and Genetics (A.R.), Pediatrics (A.R.), and Psychiatry (B.G.B.), University of Colorado School of Medicine, Denver

Sex chromosome aneuploidy (SCA) occurs in about 11250 amniocenteses, and the signifi- cance of the long-term prognosis of fetuses with SCA is of concern to prospective parents and health care providers. Longitudinal studies in an unselected group of newborn infants with SCA diagnosed postnatally have refuted allegations of mental retardation but have documented an increased risk for devel- opmental problems. Of the 530 phone consul- tations with parents faced with a prenatal &- agnosis of SCA, 68% continued the pregnancy. Twenty of the oldest subsequently born chil- dren (now 7-14 years old) were available for follow-up. In this small sample and age group, the propositi are progressing developmen- tally at a rate comparable to their sibs and are doing better at school and in peer relations than the SCA group diagnosed postnatally. Only 2 have documented IQs as low as 90. The documented IQs of the remainder, none of whom are sex chromosome mosaics, are all over 110. The parent population in this pre- natally diagnosed group is unique and differ- ent from that of the postnatally diagnosed group in that over 85% of them are college graduates, often professionals, and upper so- cioeconomic individuals. The developmental competence of this SCA sample may be attrib- utable to the supportive environment pro- vided by these families, all of whom made a conscious decision to continue the pregnancy. 0 1992 Wiley-Liss, Inc.

KEY WORDS: sex chromosome anomalies, prenatal diagnosis

Received for publication December 23, 1991; revision received March 16, 1992.

Address reprint requests to Arthur Robinson, M.D., National Jewish Center for Immunology and Respiratory Medicine, 1400 Jackson Street, Denver, CO 80206.

0 1992 Wiley-Liss, Inc.

INTRODUCTION Prenatal diagnosis by amniocentesis or chorionic

villus sampling (CVS) is performed many thousands of times per year, most being done by second-trimester amniocentesis. Among the amniocenteses, sex chromo- some aneuploidy (SCA) is diagnosed about 1/250 times [Ferguson-Smith and Yates, 1984; Hsu, 19861 making it the most common group of chromosome anomalies found, even more frequent than Down syndrome or other autosomal trisomies. The incidence of SCA diagnoses in a large number of cases of CVS is currently unknown, but it is at least as common as in amniocentesis.

The long-term prognosis of fetuses with SCA is of concern to prospective parents and health care pro- viders. Our longitudinal studies of unselected newborn infants with SCA diagnosed postnatally, started in 1964 and still in progress, have refuted allegations of mental retardation but have documented an increased risk for developmental problems [Robinson et al., 19901. These studies also demonstrated marked variability among the propositi, suggesting that environmental factors play an important part in determining their develop- mental course [Bender et al., 19871. Information about the prognosis of prenatally diagnosed children with SCA has not been available to date.

METHODS Because of our publications on SCA and our known

interest in these conditions and because of the uncer- tainty of many counselors about their significance, we have received over 500 phone calls from all over the United States by physician-referred parents faced with a prenatal diagnosis of SCA. These parents ask for the latest information about these anomalies, especially concerning intellectual development, personality, re- productive competence, and physique. During the dis- cussion we request that we be informed of their final decision regarding the continuation or termination of pregnancy. If we have not been notified within 6-8 weeks, we contact them. We ask those continuing the pregnancy to send us a birth announcement with birth statistics, comments about their child, and a photo. With the consent of the parents, we then annually send a questionnaire appropriate for the child's age to assess

366 Robinson et al.

development, comparison with sibs and peers, and par- ental concerns. School ratings, IQ tests, and physician reports are sent when available. Anonymity is assured, and parents usually respond very positively to our re- quest for information, often expressing interest in being evaluated by our team.

RESULTS Table I describes the number of phone calls received,

grouped by karyotype and parental decision. This, of course, is a biased sample of parents facing a pregnancy decision; only those who were ambivalent about what action to take and who had the desire and ability to contact us are included. Of the total group, 32% inter- rupted the pregnancy. The largest number of termina- tions occurred in the 45,X and 47,XXY groups, in both of which the prospect of infertility may be a factor in the parents’ decision. In contrast, only 19% of the mosaic fetuses were aborted.

Twenty of the oldest of these prenatally diagnosed children, now 7-14 years old, have been available for follow-up and are the subject of this report (Table 11). Eleven have been seen and are being followed annually by our group. Communication with the other 9 occurs by mail as described above. The question we are asking is: “How do these prenatally diagnosed SCA children com- pare with the SCA children who were ascertained in our earlier screening of newborn infants when they were also between 7 and 14 years old?”

The following compares some demographic and de- velopmental parameters in 7-14-year-old propositi di- agnosed prenatally (Prenatal) with a similar group diagnosed in our original screening of 40,000 newborn infants (Newborn Screen) [Robinson et al., 19901. In Tables 111-VII, SES (socioeconomic status) is a compo- site of occupation, education, and income. Walking was considered to be delayed if 215 months. Motor deficits

TABLE I. Prenatal Diagnosis Consults

% Karyotype Consults Kept Terminated Terminated 4 7 , x x x 162 104 57 35 47,XXY 127 76 51 40 47,XYY 111 79 31 28 45 ,x 13 6 7 54 48,XXYY 4 1 3 75 Mosaics 111 90 21 19 Variants 2 1 1 50 Total 530 357 171 32

were determined either by our physical exams or by reports of awkwardness and deficient motor skills com- pared to sibs. Language deficits and learning problems were noted when intervention was recommended by therapists or teachers.

The XXY boys (Table 111) in the prenatal group showed mild motor deficits contrasted to more severe deficits in those in the newborn-screen group. Only one in the prenatal group had delay in walking, whereas half of the newborn-screen infants showed some delay. Similarly, the prenatal XXY boys exhibited none of the language deficits present in 9/14 boys in the newborn screen group. All of the prenatal group members are doing well at school thus far. Their IQs range between 90 and 131 with a mean of 114, whereas 11/14 of the new- born screen group have had learning problems. Their mean IQ was 98 with a range between 71 and 122. The boys in both groups were somewhat immature, but the prenatal boys have related more easily to others.

Table IV compares XYY males in both groups. Again, the SES backgrounds of the prenatally detected boys were skewed to more educated and economically secure families. There were fewer language deficits and learn- ing problems in the prenatal group, who were reported to be getting As and Bs at school. They had a mean I& of 123 with a range of 109-147. All of the newborn screen boys were in part-time special education. They had a mean I& of 102 with a range of 93-109. In both groups there was a tendency to be hyperactive with occasional temper tantrums.

The triple X girls are described in Table V. The motor deficit, language deficit, and learning problem listed in the prenatal column all occurred in the same child, who was in a local, lower SES, somewhat dysfunctional fam- ily. The other prenatal girls had high normal IQs and were doing well at school, getting As and Bs. The mean

TABLE 111. 47,XXY (7-14 Years)

Prenatal Newborn Screen (n = 5) (n = 14)

Upper SES 415 2/14 Delayed walking 115 8/14 Motor deficits 5/5 mild 7/14 moderate to severe Language deficits 015 9/14 Learning problems 015 11/14 Personality 515 sociable 2/14 sociable

115 immature 9/14 Dassive. shv

TABLE IV. 47,XYY (7-14 Years)

Prenatal Newborn Screen (n = 6) (n = 4)

TABLE 11. F’ropositi 7-14 Years .- .

Karyotype 47,XXY 47,XYY

Upper SES 616 014 Examined Delayed walking 1 I6 114

Not Examined

414 moderate to 4 1 Motor deficits 316 mild 3 3 severe

4 7 ; x x x 1 4 Language deficits 016 414 46,XY/47,XXY 2 1 Learning problems 016 414 45,x/47,xxx 1 0 Personality 516 sociable 414 mild Total 11 9 116 ADHD depression

Sex Chromosome Anomalies 367

IQ of this group was 108 with a range of 90-128. Nine of 11 of the newborn screen girls were in special education. Their mean I& was 88 with a range between 50 and 109. The girl with an I& of 50, the only mentally retarded proposita, came from a dysfunctional family, none of whose members had particularly high IQs. Person- alities of the triple X girls were somewhat similar with shyness being characteristic of both groups.

The mosaics (Table VI) were very similar to each other and showed little pathology. This was characteristic of our entire newborn screening study in which mosaics of all ages were more similar to the sib controls than to the propositi with a “pure” form of aneuploidy [Robinson et al., 19901. The mean I& of the prenatal mosaics was 117 with a range of 108-129, whereas that of the newborn screen mosaics was 106 with a range of 81-129.

DISCUSSION It is of particular interest that only 20 of the calls were

from women who had a CVS. Whereas 32% of the total group interrupted the pregnancy, 50% of those who had CVS interrupted. It may be emotionally less traumatic to interrupt a pregnancy at 10 weeks than at 18-20 weeks, and hence, fewer of the parents who had CVS were ambivalent as to what to do, knowing that they had a fetus with an increased risk of developmental prob- lems in later life.

These are obviously small data with some meth- odological flaws, but the results are suggestive enough to warrant concluding that the children in the pre- natally diagnosed group are in general developing bet- ter than those diagnosed postnatally (Table VII). This may be due at least partially to environmental factors. It is known that events preceding pregnancy, during the

TABLE V. 47,XXX (7-14 Years)

Prenatal Newborn screen (n = 5) (n = 11)

Upper SES 415 2/11 Delayed walking 215 6/11 Motor deficits 1 I5 8/11 Language deficits 1 I5 7111

Personality 215 shy 8/11 shy Learning problems 1 I5 9/11

TABLE VI. Mosaics (7-14 Years)

Prenatal Newborn screen (n = 4) (n = 6)

Upper SES 414 316 Karyotypes 3 46,XY/47,XXY 1 45,X/46,XX/47,XXX

3 45,XJ46,XX

1 46,XX/47,XXX 145,X/47,XXX 145,X/47,XXX

Delayed walking 014 016 Motor deficits 014 016 Language deficits 014 216 Learning problems 014 016 Personality 314 sociable 516 sociable

114 shy 116 shy

TABLE VII. Summarv of All SCA Karvotvms

Prenatal Newborn screen (n = 20) (n = 35)

Upper SES 18/20 (90%) Mean I& 116 Delayed walking 4/20 (20%) Motor deficits 9/20 (45%)

mild

Language deficits 1/20 (5%) Learning problems 1/20 (5%)

7/35 (20%) 99 15/35 (43%) 19/35 (54%) moderately

severe 22/35 (63%) 24/35 (69%)

pregnancy, and during the perinatal period can result in a major impact on the parents’ perception of their child and upon the nature of their parenting [Harmon et al., 19821. Furthermore, the prenatal diagnosis of an SCA fetus carries the requirement that the parents make a decision about whether to terminate or continue the pregnancy. The decision to “keep” their SCA baby likely has a very large impact on the parents’ feelings about their child and their commitment to their parenting responsibilities. The parents of the original cohort, in contrast, did not have an opportunity to make such a decision but were informed shortly after birth that their child had an SCA. Given the important role of family environment in exacerbating or attenuating the devel- opmental risks of SCA [Bender et al., 19871, it follows that the experiences and selection factors that define the prenatally diagnosed SCA population, a group of “wanted babies,” will significantly affect their develop- ment.

It is of importance to note that the parents of the 530 prenatally diagnosed SCA fetuses who originally con- sulted with us represent a unique group in that over 85% of them are college graduates, often professionals with postgraduate training, the great majority of whom were economically secure. This is a very different group com- pared to the parents of the screened newborn infants, many of whom were patients of a public hospital, were lower SES, and had a dysfunctional family background. The difference between the two groups is mirrored in the summary of SES of the two populations (Table VII).

However, there is no question that the study children are indeed affected by the extra sex chromosome in a manner similar to the newborn screening group but to a lesser degree. We are still cautious in predicting their ultimate outcome since we have noticed that some of the children who seemed to be doing very well at first have a slightly lower rate of development later, even though they are still better than those in the newborn screening group. As mentioned before, these are very small data but confirm the impressions of other SCA investigators that a prenatally diagnosed cohort of SCA children may well be different developmentally from an unselected sample of the newborn population [Evans et al., 1990; Leonard, 1990; Ratcliffe et al., 19901. Obviously, larger groups need to be studied.

Finally, it is important to mention that in talking to 530 families about their prenatal counseling, we have been concerned by how few patients are told about the

368 Robinson et al.

possibility of SCA. Most of the discussion is about Down syndrome and other autosomal aneuploidies, even though these conditions are diagnosed prenatally less often than the group of SCA. The trauma these parents face is made even worse by their being confronted by a condition about which they have never heard. We strongly urge that a discussion of SCA should be insti- tuted as a routine part of preamniocentesis counseling.

REFERENCES Bender BG, Linden MG, Robinson A (1987): Environment and develop-

mental risk in children with sex chromosome abnormalities. J Am Acad Child Adolesc Psychiatry 26499-503.

Borelli JB, Bender BG, Puck MH, Salbenblatt JA, Robinson A (1984): The meaning of early knowledge of a child‘s infertility in families with 47,XXY and 45,X children. Child Psychiatr and Hum Develop

Evans JA, MacDonald K, Hamerton JL (1990): Sex chromosome anom- alies: Prenatal diagnosis and the need for continued prospective studies. In Evans JA, Hamerton JL, Robinson A (4s ) : “Children and Young Adults With Sex Chromosome Aneuploidy.” New York: Wiley-Liss for the National Foundation-March of Dimes, BD:OAS

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26(4):273-281.

Ferguson-Smith MA, Yates JRW (1984): Maternal age specific rates for chromosome aberrations and factors influencing them: Report of a collaborative European study on 52,965 amniocenteses. F’renat Diagn 4:5-44.

Harmon FLJ, Glicken AD, Good WV (1982): A new look at maternal- infant bonding. Perinatol Neonatol 6(5):27-31.

Hsu LYF (1986): Prenatal diagnosis of chromosome abnormalities. In Milunsky A (ed): “Genetic Disorders of the Fetus.” New York: Plenum Press, pp 115-183.

Leonard MF (1990): A prospective study of development of children with sex chromosome anomalies: New Haven study. V. Young adulthood. In Evans JA, Hamerton JL, Robinson A (eds): “Children and Young Adults with Sex Chromomme Aneuploidy.” New York Wiley-Liss for the National Foundation-March of Dimes, BD:OAS

Etatcliffe SG, Butler GE, Jones M (1990): Edinburgh study of growth and development of children with sex chromosome abnormalities. IV. In Evans JA, Hamerton JL, Robinson A (eds): “Children and Young Adults With Sex Chromosome Aneuploidy.” New York: Wiley-Liss for the National Foundation-March of Dimes, BDOAS 26(4):1-44.

Robinson A, Bender BG, Linden MG, Salbenblatt JA (1990): Sex chro- mosome aneuploidy: The Denver prospective study. In Evans JA, Hamerton JL, Robinson A (eds): “Children and Young Adults With Sex Chromosome Aneuploidy.” New York: Wiley-Liss for the Na- tional Foundation-March of Dimes, BD:OAS 26(4):59-115.

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