J Med Genet: first published as 10.1136/jmg.28.9.609 on 1 September 1991. Downloaded from

J Med Genet 1991; 28: 609-612 609 49,XXXXY syndrome: behavioural and developmental profiles

Cathy A Lomelino, Allan L Reiss

Abstract Methods Behavioural, psychological, and cognitive The behaviour of our subjects was examined using a profiles of three cases, including a 5 year old modified version of the Aberrant Behavior Checklist male with a 49,XXXXY and a (3;15) (ABC),3 which covers five aspects of behaviour fre- translocation, a 9 year old male with a quently encountered in developmentally disabled 49,XXXXY karyotype, and a 32 year old male persons: irritability and agitation, lethargy and with- with 48,XXXY/49,XXXXY mosaicism, are pre- drawal, stereotypy, hyperactivity and non-com- sented. Significant behavioural problems pliance, and inappropriate speech. The checklist was were seen in the two older patients. The degree completed by both a parent and a teacher. Indi- of mental retardation and impairment of lan- vidual behaviour items were rated from 0 to 3, guage abilities were shown to be more severe according to the severity of the problem. in the older subjects as well. These findings are Language abilities were assessed through an inter- discussed with respect to the effects of the X view with the parent(s) of the subject using the chromosome on brain development. Vineland Adaptive Behavior Scale, Survey Form.4 Language impairments were also noted by observa- tion.

Cognitive assessment using the Stanford Binet, copyright. 4th edition was performed on.one subject at the time of evaluation. General was obtained Cases of are not cognitive ability uncommon and a broad spectrum of developmental for the other subjects from reports of previous outcome has been described. Since the first report of testing. a patient with a 49,XXXXY karyotype by Fraccaro et all in 1960, a clinical description has been estab- lished for this syndrome. However, relatively little is Case reports known regarding the behavioural, psychological, CASE 1 http://jmg.bmj.com/ and cognitive profile of these patients. Evidence Case 1 was a 4 year 10 month old male with a indicates that despite inactivation, karyotype of 49,XXXXY, t (3;15) (q29; q26.1) who an increased number of X chromosomes is associ- was ascertained as a control subject for a research ated with an increase in cognitive and language project. The translocation noted in this patient was disability.2 This report describes three subjects with also present in his mother, maternal uncle, and partial or complete 49,XXXXY sex chromosome maternal grandfather. The maternal uncle was de- scribed as a slow learner with possible mild cognitive aneuploidy. Particular emphasis is placed on the on September 29, 2021 by guest. Protected severity and range of disability associated with this delays, although no formal diagnosis of mental re- condition and the possible mechanisms by which it tardation had been made. He weighed 2728 g at is produced. birth. His IQ was 78 ± 6 as measured by the Stanford Binet, 4th edition. Case 1 was reported to have no significant beha- vioural problems. There were no significant findings Division of Child Psychiatry, Department of Psy- from the ABC data. Vineland score in the communi- chiatry, Johns Hopkins University School of Medi- cation domain was low with a mild deficit. Expres- cine and The Kennedy Institute, Baltimore, MD, USA. sive subdomain score was low, while his receptive C A Lomelino, A L Reiss subdomain score was adequate. He had a statistically Correspondence to Dr Reiss, Behavioral Genetics Unit, significant weakness in the communication domain Room 507, 550 North Broadway, Baltimore, MD 21205, when compared to his mean domain score. When USA. compared to a National Standardization Sample,4 the difference between his communication domain Received for publication 27 July 1990. score and mean domain score was found to fall in the Revised version accepted for publication 5 January 1991. extreme 16th centile, indicating significant weakness J Med Genet: first published as 10.1136/jmg.28.9.609 on 1 September 1991. Downloaded from

610 Lomelino, Reiss

Clinical data for the three patients Patient 1 Patient 2 Patient 3 Age 4y lOmth 9y 5mth 32y Karyotype 49,XXXXY 49,XXXXY 48,XXXY/49,XXXXY t(3;15)(q29;q26.1) IQ Low average Mild MR Moderate MR Behavioural problems None Irritability/agitation, Irritability/agitation, hyperactivity/non-compliance, lethargy/withdrawal, inappropriate speech stereotypy, hyperactivity/non-compliance, inappropriate speech Vineland Low Low Low Communication domain Mild deficit, Moderate deficit, Profound deficit, low expressive, low expressive, low expressive, normal receptive low receptive normal receptive

in communication skills as compared to other overall adverse change in mental status, showed extreme developmental abilities. behaviour problems in the following areas: irritab- ility and agitation, lethargy and social withdrawal, hyperactivity and non-compliance, and inappro- CASE 2 priate speech. Stereotypic behaviour was also a Case 2 was a 9 year 5 month old white male with a serious problem. Teacher ABC data, rating overall 49,XXXXY karyotype. At birth he weighed 1936 g. behaviour, showed extreme problems with inappro- His IQ was in the mildly mentally retarded range. priate speech. His family history was significant for depression. He exhibited abnormal speech form and content. He had a long history, beginning around the age of His score in the Vineland communication domain 6, of disruptive and oppositional behaviour, irritab- was low with a profound deficit. Expressive sub- ility, and temper tantrums. Problems with self- domain score was low, while receptive subdomain

control and impulsivity were present and included score was adequate. A statistically significant weak- copyright. aggression with peers such as throwing things, hit- ness in the communication domain was noted in ting, kicking, and pinching. On the ABC, case 2 was comparison to the mean domain score. This dif- rated by his parent and teacher as having significant ference between the communication domain score behaviour problems in the following areas: irritab- and mean domain score represented a difference ility and agitation, hyperactivity and non-com- found in only 1 to 5% of the National Standardiza- pliance, and inappropriate speech. tion Sample.4 This indicates a severe deficit in Speech contained significant problems with communication ability as compared to general

dysarticulation. Vineland Adaptive Behavior score developmental abilities. A summary of the clinical http://jmg.bmj.com/ was low with a moderate deficit in the communica- data for all three patients is shown in the table. tion domain. A statistically significant weakness in the communication domain was noted when com- pared to the mean domain score. The difference Discussion between his communication domain score and the COGNITIVE DEVELOPMENT mean domain score represented a difference seen in Borghgraef et al5 reported a widespread variation of only the extreme 5% of the National Standardiza- intellectual performance in 49,XXXXY syndrome tion Sample,4 indicating a significant weakness in with IQ ranging from 20 to 70 with a mean of 35; the on September 29, 2021 by guest. Protected communication ability as compared to his general majority of adult patients fell in the moderate to developmental functioning. severe range of mental retardation. For the patients described in this report, the youngest subject had an IQ of 78 ± 6 as measured by the Stanford Binet, 4th CASE 3 edition, showing that IQ in this population can fall Case 3 was a 32 year old male with a 48,XXXY/ in the low average range. Shapiro et al,6 Schmidt et 49,XXXXY karyotype. He weighed 1496 g at birth. al,7 and Borghgraef et al5 noted a decline in intellec- His IQ was in the moderately mentally retarded tual development with age in 49,XXXXY males. range. In our report, language impairment and degree of Case 3 suffered from recurrent episodes of dra- mental retardation appeared to be most severe in the matic change in mental status involving psychomo- older subjects. Although this cross-sectional evalu- tor behaviour, affect, social withdrawal, self-injury, ation cannot definitely address the issue of intellec- and possible psychotic symptoms. He also showed tual decline in 49,XXXXY syndrome, our findings problems with self-control, including grabbing at suggest the need for other longitudinal investiga- people. Parent ABC data, rated during times of tions. J Med Genet: first published as 10.1136/jmg.28.9.609 on 1 September 1991. Downloaded from

49,XXXXY syndrome: behavioural and developmental profiles 611

BEHAVIOUR Rovet"3 showed a significant deficit in verbal ability, Patients with 47,XXY karyotype have been de- while non-verbal skills were intact. Rovet and Net- scribed by Walzer et al8 as exhibiting low activity, ley"4 found a group of X girls to be deficient low intensity of responsiveness, and high with- in verbal skills. They found greater impairments drawal, especially from new situations. Stewart et al2 with verbal tasks than with spatial tasks. In the case described 47,XXY patients as less social, less assert- ofdeficient amounts ofX chromosome material (that ive, and less active than 46,XY males. These patients is, 45,X Turner's syndrome), the opposite pattern of have also been described as having problems with ability, defined by a marked spatial deficit with impulsivity and self-control.9 10 Subjects with normal verbal skills, has been reported."3 Similar 49,XXXXY, which is often considered a variant of results were stated by Money,'5 who reported that the 47,XXY syndrome, have been noted as exhibit- when verbal and performance values are compared, ing behavioural problems, but no consistent profile it is found that subjects with sex chromosome mono- has been described. Borghgraef et al5 described somy (45,X) have a lower performance IQ than 49,XXXXY patients as very timid and shy, with low verbal IQ. These studies seem to suggest that as the frustration tolerance and very anxious reactions to number of excess X chromosomes increases the minor charges. Stereotyped language and hyperacti- severity of verbal impairment also increases. vity were also described. Of the patients described in In a study of 47,XXY males, Graham et al'6 our report, cases 2 and 3 were shown to exhibit described greater impairment in language produc- serious behavioural problems, especially in the areas tion than in language comprehension. These find- of irritability and agitation, hyperactivity and non- ings suggest a relation between the amount of X compliance, and inappropriate speech. However, in chromosome material and the relative development this study, cases 2 and 3 were both ascertained after of verbal and non-verbal abilities. These authors referral for evaluation of behavioural problems. As report that specific deficits in expressive language previously noted, case 1 was ascertained as a control may be indicative of left hemisphere dysfunction subject for a research project and was shown to that results from the reversal of the usual left-right exhibit no behavioural problems on the ABC. asymmetry of the brain, leaving the left hemisphere Therefore, behavioural problems in the two older anatomically ill suited to perform language func- copyright. subjects may not be representative of the general tions. 49,XXXXY population. However, case 2 did not Severe retardation in language development in exhibit major behavioural difficulties until an age at 49,XXXXY patients has been described by Borgh- which the demands of a structured setting were graef et a15 and others. Moric-Petrovic et al'7 de- encountered. This suggests that our youngest sub- scribed a significant discrepancy between expressive ject, case 1, may have not yet reached an age at which ability and comprehension in these patients. In our behavioural problems are exhibited. study, all three patients with the 49,XXXXY karyo- type were found to have a significant deficit in http://jmg.bmj.com/ language abilities. Cases 1 and 3 were shown to have TRANSLOCATION low expressive language skills while their receptive Ockey and de la Chapelle" and de la Chapelle and language skills were adequate according to the Vine- Schroder"2 described a 49,XXXXY male with a land Scale. balanced 4;11 translocation. The translocation was Netley and Rovet"3 have suggested that in cases of inherited and present throughout the family mem- a supernumerary X, slow rates of prenatal neuronal bers. The patient showed no clinical abnormality growth selectively retard the development of the left on September 29, 2021 by guest. Protected other than that characteristic of 49,XXXXY syn- hemisphere, thereby disturbing the normal process drome. In this study, case 1 was shown to have an ofhemispheric lateralisation, specifically the special- inherited 3;15 translocation that appeared to be isation of the left cerebral hemisphere for language balanced. There seems to be no evidence of a rela- functioning. This hypothesis (along with that pre- tionship between the presence of a translocation as sented by Graham et al'6) may explain the severe shown in these two subjects and the occurrence of language disorder found in the 49,XXXXY subjects the 49,XXXXY karyotype. in this study. Recent evidence indicates that non- contiguous genes on the X chromosome escape the normal processes leading to inactivation and remain LANGUAGE capable of genetic expression.'8 Therefore, gene Poor language development is well documented in dosage effects may cause disruption of specific as- cases of excess X chromosome material. It has been pects of brain development in subjects with X chro- shown that anomalous numbers of X chromosomes mosome aneuploidy. are associated with specific deficits in intellectual ability. A study of the intellectual abilities of chil- This study was supported in part by grant dren with excess X chromosomes by Netley and MH00726 from the National Institute of Mental J Med Genet: first published as 10.1136/jmg.28.9.609 on 1 September 1991. Downloaded from

612 Lomelino, Reiss

9 Bumard G, Hunter H, Haggart K. Some psychological test Health, grants HD25806 and HD24061 from the characteristics of . Br J7 Psychiatry National Institutes of Health, and a grant from the 1967;113:1091-6. Merck Fund. 10 Jablensky AJ, Janota J, Sheperd M. Neuropsychiatric illness John and neuropathological findings in a case of Klinefelter syn- drome. Psychol Med 1970;1:18-29. 11 Ockey CH, de la Chapelle A. Autoradiographic re-appraisal of 1 Fraccaro M, Kaijser K, Lindsten GJ. A child with 49 chromo- an XXXxY male as a probable XXXXY with a 4/11 transloca- somes. Lancet 1960;ii:899-902. tion. Cytogenetics 1967;6:178-92. 2 Stewart DA, Bailey JD, Netley C, Rovet J, Park E. Growth and J. Autoradiographically identified development from early to midadolescence ofchildren with X 12 De la Chapelle A, Schroder and aneuploidy: the Toronto study. Birth karyotype 49,XXXXY, t(4;1 1) (q35;q23) confirmed by band- Defects 1986;22(3):119-82. ing. Hereditas 1973;74:291-2. 3 Aman MG, Singh NN. Aberrant behavior checklist. New York: 13 Netley C, Rovet J. Verbal deficits in children with 47,XXY and Slosson Educational Publications, 1986. 47,XXX : a descriptive and experimental study. 4 Sparrow S, Balla DA, Cicchetti DV. Vineland Adaptive Beha- Brain Lang 1982;17:58-72. vior Scale, Survey Form. Circle Pines, Minnesota: American 14 Rovet J, Netley C. The triple X chromosome syndrome in Guidance Service, 1984. childhood: recent empirical findings. Child Dev 1983;54:831- 5 Borghgraef M, Fryns JP, Smeets E, Marien J, Van den Berghe 45. H. The 49,XXXXY syndrome. Clinical and psychological 15 Money J. Cytogenetic and psychosexual incongruities with a follow-up data. Clin Genet 1988;33:429-34. note on space-form blindness. AmJ Psychiatry 1963;1 19:820- 6 Shapiro LR, Brill CB, Hsu LY, Calvin ME, Hirschhorn K. 7. Deceleration of intellectual development in a XXXXY child. 16 Graham JM, Bashir AS, Stark RA, Silbert A, Walzer S. Oral AmJ Dis Child 1971;122:163-4. and written language abilities of XXY boys: implications for 7 Schmidt R, Pajewski M, Rosenblatt M. Epiphysial dysplasia: a anticipatory guidance. Pediatrics 1988;81:795-806. constant finding in the XXXXY syndrome. Med Genet 17 Moric-Petrovic S, Laca Z, Markovic S, Markovic V. 1978;15:282-7. 49,XXXXY karyotype in a mentally retarded boy. J Ment 8 Walzer S, Bashir AS, Graham JM Jr, et al. Behavioral develop- Defic Res 1973;17:73-80. ment of boys with X chromosome aneuploidy: impact of 18 Page DC, Disteche CM, Simpson EM, et al. Chromosomal reactive style on the educational intervention for learning localization of ZFX - a human gene that escapes X inactiva- deficits. Birth Defects 1986;22(3):1-21. tion - and its murine homologs. Genomics 1990;7:37-46. copyright. http://jmg.bmj.com/ on September 29, 2021 by guest. Protected