sign in sign up
<<
Home , List of geneticists

Refer to: Krone LR, Prichard LL, Bradshaw CL, et al: Antenatal diagnosis of an XXX female-A dilemma for . West I Med 123:17-21, Jul 1975

Antenatal Diagnosis of an XXX Female

A Dilemma for Genetic Counseling

LAWRENCE R. KRONE, BS, LORRAINE L. PRICHARD, PHN, CHRISTY L. BRADSHAW, BS, and OLIVER W. JONES, MD, La Jolla, RAYMOND M. PETERSON, MD, and BARBARA K. DIXSON, RN, MN, San Diego

This report describes the first antenatal diagnosis of an XXX female. Over 150 postnatal cases of XXX females have been described. There is no specific phe- notype associated with the sex abnormality and most such per- sons are fertile. The frequency of XXX females in mental institutions is 3.9 per 1,000 female subjects whereas the frequency in consecutive newborn infants is 1.1 per 1,000 newborns. Chi-square analysis shows this difference cannot be due to chance. On the other hand, data from consecutive newborn studies sug- gest that intellectual development in XXX newborns is within normal range. Available evidence favors normal development in XXX female infants although the risk for developmental disabilities may be higher for the XXX than for the XX infant.

ANTENATAL DIAGNOSIS of chromosome disorders autosomes (such as trisomy 9) also pose little which are known to result in the birth of infants difficulty in counseling since the odds overwhelm- with serious defects (such as 21-trisomy, 13-tri- ingly favor a severely defective fetus. In contrast, somy) rarely poses any difficulty in arriving at a the decision may be less straightforward or based decision to support termination of pregnancy. Un- upon less objective data when one is faced with a expected results other trisonmic prenatal diagnosis of nondisjunc- showing tion or structural rearrangement. Moreover, since From the Department of Medicine, Division of , all forms of involving sex chromo- University of California, San Diego, School of Medicine, La Jolla, and the Regional Center for Developmental Disabilities, Children's somes represent new or initial spontaneous abnor- Health Center, San Diego. Submitted, revised, February 6, 1975. malities and since in virtually all prenatal analysis This study was supported in part by a grant from the National of fetal one is looking for abnormalities NationalFoundation,InstitutesMarchofofHealth.'Dimes, and GM17702, a grant from the in the autosomes, the finding of a sex chromosome RMepr)UivereusitytoffCalifornoina, SanDiego, La Jolla, CA 92037. variation is usually unanticipated. Often the par-

THE WESTERN JOURNAL OF MEDICINE 17 1 * * 14 ,,i

Figure 1.-Fetal karyotype from cultured fetal fibroblasts. were stained with Giemsa and classified according to the 1971 Paris Conference on Standardization in Human .1 ents have not been prepared by prior counseling fluid were obtained, the cells removed and cultured that sex chromosome abnormalities have much in F-12 media (Grand Island Biological Company) less certainty as to severe handicaps, such as in a 10 percent CO2 atmosphere. After 2½/ weeks mental retardation. There are limited factual data of cell growth, the culture was harvested and upon which to advise couples regarding the risks karyotype analysis was made on cells arrested in of all birth defects, including mental retardation, metaphase. Of 30 cells examined, all had a 47, in infants with sex chromosome abnormalities. XXX pattern (Figure 1). Subsequent culture of the This report describes the first known antenatal mother's peripheral blood lymphocytes showed a diagnosis of an XXX female fetus and the diffi- normal 46, XX pattern. culty in counseling based upon current knowledge The prospective parents elected to continue the of this sex chromosome nondisjunction and asso- pregnancy after all current knowledge regarding ciated clinical manifestations. 47, XXX females was discussed with them. The remaining gestational period was uneventful and Report of a Case the infant was delivered at term with no compli- The mother is a 39-year-old (gravida 1, para 0, cations. An Apgar score of 9 was recorded at one abortions 0) Caucasian who was referred for minute. A neonatal lymphocyte karyotype con- amniocentesis because of maternal age. At 16 firmed the diagnosis of 47, XXX. On neonatal weeks gestation, an uneventful amniocentesis was examination, the infant appeared normal and had done. Fifteen milliliters of straw-colored amniotic no physical abnormalities. Measurements included

18 JULY 1975 * 123 * 1 XXX FEMALE a weight of 2.8 kg, height of 47.5 cm, head cir- display normal sexual development and are fertile. cumference of 33 cm, and chest circumference of At least 33 children have been borne by 11 such 32 cm. females,2-17 with only one case of nondisjunction The infant was subsequently examined at age being reported exhibiting 21-trisomy.14 The 32 weeks. In general, the infant is thriving and mother of this child with Down's was appears healthy at this age. The weight is 7.3 kg identified as a phenotypically and mentally normal (16th percentile for age), height 67.5 cm (25th XXX female. Theoretically, it is expected percentile for age), head circumference 43 cm that half of the births to XXX females would (33rd percentile for age). Results of complete karyotypically display three sex chromosomes. physical examination and motor developmental Although four XXY sons and one XXX/XX milestones are both considered normal at this age. daughter have been borne to XXX mothers,"8 the Developmental testing using Gesell Standards large majority of progeny have a normal karyo- showed that at 32 weeks of age the motor develop- type. It may be possible that some selective mecha- ment is 32 weeks; adaptive, 28 weeks; language, nism exists to reduce the stability of the XX 28 weeks; and personal-social, 28 weeks-all of gametes. which are well within normal limits. Annual de- Of the 152 XXX females described previously, velopmental evaluation of this child will be con- 97 were considered to be mentally retarded. How- tinued. ever, a large majority of retarded XXX females were ascertained by surveying mental institutions Discussion and hospitals. Once the antenatal diagnosis of 47, XXX In surveys of 8,300 female patients in mental female was established, we were confronted with institutions,19-26 the composite frequency of XXX the problem of what to advise the prospective females is 3.9 per 1,000 female subjects whereas parents. A major concern was the possibility of an the frequency of XXX females in a large com- intellectual handicap in this child because of the bined consecutive newborn study of 26,000 fe- reported relationship between 47, XXX and men- male infants is 1.1 per 1,000 newborn females.27-3' tal retardation. However, virtually all published A chi-square analysis involving approximately studies of this association are from studies of such 26,000 newborn females and 8,300 female pa- females in various mental institutions. In contrast, tients in 'institutions gives a value of 29.01. This consultation with several, but by no means an ex- shows that chance alone could not possibly ac- haustive list of throughout the country count for the difference between the XXX fre- showed that from personal experience with 47, quency found in the studies of patients in institu- XXX females, the incidence of mental retardation tions and in the consecutive newborn studies. The and other birth defects is low. Moreover, we were greater the chi-square value, the less the role that influenced by the fact that this was the mother's chance plays. These results appear significant. first pregnancy, one that she wanted very much, Accepting this, how detrimental, if at all, are the and by the fact that the mother was 39 years old. effects of possessing a 47, XXX karotype? What Thus, we supported their wish to continue this are the chances that an XXX female will be placed pregnancy. in an institution because of mental retardation? Since Jacobs and co-workers described the first These questions are important for a gravida who, XXX female,2 over 150 cases have been docu- through amniocentesis and fetal karyotyping, mented. Much evidence has been reported about knows that she is carrying an XXX fetus and seeks a high incidence of mental retardation in XXX advice from a genetic counselor. At present, it females. However, the sampling is biased and this may not be possible to give accurate figures for correlation is not clearly established. the probability for an XXX female infant to have No characteristic has been found in a developmental disability, either mental or physi- XXX females, unlike other sex chromosome ab- cal. However, one might be able to make a reason- normalities, for example, Turner's (XO) syn- able assessment of the probability that an XXX drome. However, a variety of physical abnormal- female will be admitted to an institution. For ex- ities has been cited.2'7 A proportion of XXX fe- ample, in the state of California there are currently males have underdeveloped secondary sex char- 4,065 females in institutions for the mentally re- acteristics, occasionally leading to an onset of tarded. In 1970, there were 10,136,000 women secondary amenorrhea early in life. The majority residing in the state of California. Therefore, there

THE WESTERN JOURNAL OF MEDICINE 19 XXX FEMALE is a 0.4 percent chance for any woman in the state than that found associated with the mothers of to be in a state institution for the mentally re- children with Down's syndrome. The cumulative tarded at some time during her life. Conversely, combined results of 152 cases of XXX children any normal California female would then possess show a median maternal age at the infant's birth a 99.96 percent chance of not residing in a state to be 29 years. The median maternal age for 28 mental institution. For XXX females there would cases discovered during consecutive newborn be a 99.86 percent chance of not residing in a studies is 25 years. Both of these results are California mental institution. These figures cor- higher than the California median maternal age respond to 16 XXX women in state mental insti- which is in the range of 20 to 24 years, but the tutions out of the theoretical possibility that ap- variance may be due to the small sample size. It proximately 10,000 XXX women reside in the would be informative to know the average mater- state (XXX frequency: 1 per 1,000 females). Since nal age for patients in institutions. If this number there is only a 0.10 percent greater chance for an is significantly higher than the median maternal XXX female to be in an institution for the men- age of the population, then maternal age for XXX tally retarded compared with XX females, this infants may possibly be related through other particular sex chromosome aberration does not effects to mental disease. If the maternal age for appear to significantly increase the probability for patients in institutions is not higher than that for admission to a hospital. the general population, the increased maternal It is known that the average length of stay for age in XXX cases may be thought to be related both men and women patients in California state to a small sample size. We have not found any mental institutions is 322 days. This turnover rate information regarding the maternal age for pa- shows that there are probably more mentally re- tients in institutions. tarded XXX females in the general population Conclusion than estimated above. Thus, using the probabilities for admission to an institution can only give an In conclusion, the XXX chromosome abnor- approximation of the chances that an XXX female mality is found randomly with a frequency of will not have a developmental disability. One approximately one per 1,000 in the general popu- must also bear in mind that chi-square analysis lation and four per 1,000 in institutionalized pa- strongly suggests a significance to the frequency tients. There does not appear to be any strong of XXX females in mental institutions. correlation between these two populations, be- In examining the mental development of XXX cause of the relatively small number of mental females, Close and co-workers7 have discovered retardates in institutions. Information to date from two apparently normal XXX females, one during consecutive newborn studies shows that intelli- a routine examination. Kohn,9 Kadotani"4 and gence quotients of the tested XXX children appear Fujita20 have also reported XXX females of nor- to be within the normal range. Increased maternal mal intelligence. Robinson, Harris and Puck at age is possibly associated with XXX children, but the University of Colorado Medical Center (per- the effects of this remain unknown. Until more sonal communication) have detected 12 XXX in- data become available, it seems reasonable to fants during consecutive newborn studies (40,000) advise parents that probabilities favor normal in- from 1964 to 1974. One infant died in the neo- tellectual development with an XXX karyotype natal period. Seven of these girls have been tested although the risk for developmental disabilities by the Wechsler Preschool and Primary Scale of may be higher for the XXX than for the XX fetus. Intelligence with quotients of 109, 109, 96, 96, For all prenatal counseling in pregnancies at 89, 82 and 76. Two had significant delays in high risk for chromosome abnormalities, couples language ability development and two had mild should be advised that an abnormal karyotype perceptual difficulties. These results are not sig- might not necessarily mean an unequivocally de- nificantly lower than their siblings' scores. It is fective fetus. At the same time, assurance of a anticipated that with the complete results of normal infant bearing an abnormal karyotype is Robinson, Puck and co-workers, further insight probably impossible to guarantee. In these ex- about the mental capabilities of these children tremely sensitive considerations it is crucial that will be learned. the primary genetic counselor be skilled in his in- Maternal age appears to be important in dis- terpretation of all available data, use every con- cussing XXX female infants, but to a lesser extent sultation source possible, be able to communicate

20 JuLY 1975 *123 * 1 XXX FEMALE

Barr ML: The sex chromosomes in and medicine. effectively and above all else, be sensitive to the Canad16. Med Ass J 95:1137-1148, 1966 feelings, needs and degree of understanding of the 17. Hienz HA, Michael CM, Sclhulz FW, et al: Zur trisomie des X chromosoms. Klin Wschr 41:996-1001, 1963 couple he counsels. 18. Barr ML, Sergovich FR, Carr DH, et al: Triplo-X female: An appraisal based on a study of 12 cases and a review of litera- REFERENCES ture. Canad Med Ass J 101:247-258, 1969 19. Fraser JIL, Campbell J, Macgillivray RC, et al: The XXX 1. Hamerton JL. Jacobs PA, Klinger HP (Eds.): Paris Con- syndrome frequlency among mental defectives and fertility. Lancet ference (1971), Standardization in human cytogenetics, Birth De- 2:626-627, 1960 fects: Original Article Series, Vol 8, #7. White Plains, The Na- 20. Hamerton JL, Jagiello GM, Kirman BH: Sex chromosome tional FouLndation, 1973 abnornmalities in a popuLlation of mentally defective children. Br 2. Jacobs PA, Bailie AG, Court-Brown WM, et al: Evidence for Med J 5273:220-223, 1962 the existence of the human "super-female". Lancet 2:423-425, 1959 21. Maclean N, Mitchell JM, Harnden DG, et al: A survey of 3. Jacobs PA, Harnden DG, Court-Brown WM, et al: Abnor- sex chromosome abnormalities ainong 45i4 mental defectives. malities involving the in women. Lancet 1:1213- Lancet 1:293-296, 1962 1216, 1960 22. De la Chapell A: Sex chromosome abnormalities among 4. Day RW, Wright SW, Koons A, et al: XXX, 21-trisomy and mentally defectives in Finland. J Ment Defic Res 7:129-146, 1963 retinoblastoma. Lancet 2:154-155, 1963 23. Ridler MA, Shapiro A, McKibben WR: Sex ab- 5. Ricci N: XXX 18-trisomy. Lancet 2:1276-1277, 1963 normalities in femnale subnormal patients. Br J Psychiatry 109: 6. Anderson IF: The triplo-X syndrome: Clinical and cytological 390-394, 1963 features. S Afr Med J 39:841-844, 1965 24. Anderson IF, Goeller EA, Wallace C: Sex chromosome ab- 7. Close HG: Two apparently normal triplo-X females. Lancet normalities in a population of 1,662 mental defectives. S Afr Med 2:1358-1359, 1963 J 38:346-349, 1964 8. Stewart JSS, Sanderson AR: Fertility and oligophrenia in an 25. Breg WR, Castilla EE, Miller OJ, et al: Sex chromatin and apparent triplo-X female. Lancet 2:21-23, 1960 chromosome stuLdies in 1,562 institutionalized mental defectivcs. J 9. Kohn G, Winter JSD, Wellman WJ: Trisomy X in three Pediat 63:738-739, 1963 children. J Pediat 72:248-252, 1968 26. Fujita H, Yoshida Y, Tanigawa Y, et al: A survey of sex 10. Johnston AW, Ferguson-Smith MA, Handmaker SD, et al: chromiosome anomalies aong normal children and mental de- The triplo-X syndroine. Brit Med J 2:1046-1052, 1961 fectives. Jap J Hum Genet 16:198-211, 1972 27. Maclean N, Harnden DG, WM: Abnormalities ll. Breg WR, Cornwell JG, Miller OJ: The associationon oof the of sex Ccurt-Brown triple-XtripBregsyndromne,Wyndr,eCrnwdand mongolismJ,oMileiJin twothefamilies.fasoiatie.Am J DIS 406-408, chromosome1961 constitution in newborn babies. Lancet 2: Chlild 104:534-535, 19624048,16 12. Day RW, Larson W, Wright SW: Clinical and cytogenetic fan8. Mbksatet GyKnecl 326hr8m699sm9anmalies in newborn in- studies on a group of females with XXX sex chromosome comple- nments. J Pediat 64:24-33, 1964 29. Robinson A, Puck TT: Studies on chromosomal nondis- 13. Uchida A, Lewis AJ, Bowman JM, et al: A case of double junction in man 11. Am J Hum Genet 19:112-129, 1967 trisomy: Trisomy No. 18 and triplo-X. J Pediat 60:498-502, 1962 30. Robinson A, Goad WB, Puck TT, et al: Studies on chro- 14. Kadotani T, Ohama K, Makino S: A case of 21-trisomic mosomal nondisjunction in man ll1. Am J Hum Genet 21:466-485, Down's syndrome from the triplo-X mother. Proc Jap Acad 46: 1969 709, 1970 31. Lubs HA, Ruddle FH: Chromosomal abnormalities in the 15. Raphael T, Shaw MW: Chromosome studies in schizo- human populationi: Estimation of rates based on the New Haven phrenia. JAMA 183:1022-1028, 1963 newborn study. Science 169:495-497, 1970

THE WESTERN JOURNAL OF MEDICINE 21