Research in Developmental Disobibries, Vol. 9, pp. 171-176. 1988 Printed in the USA. All nghts reserved.

0891.4222188 $3.00 + .OO Copyright S 1988 Pergamon Press plc

Mild Intellectual Deficits in a Child with 49,XXXXY

Joseph H. Hersh, Allan S. Bloom, Frank Yen, Carolyn Topinka, and Bernard Weisskopf

Universitv of Louisville

Severe mental retardation usually is present in males with a 49,XXXXY karyo- type, although occasionally, intellectual functioning has been reported to be in the mild range of mental retardation. One child was previously described to have normal development at 15 months, but had mental retardation at 41 months. We present a male with 49,XXXXY who had mild-cognitive and motor delays and age-appropriate adaptive skills at 59 months. Greatest deficits were in expressive verbalizations similar to other male sex chromosome abnormalities. Mosaicism could not be demonstrated in blood or skin specimens. Although most males with 49,XXXXY syndrome will have significant mental retardation, findings in our patient and other reports suggest that variability in intellectual functioning may OCCUT, in some instances, and may justify guarded optimism in affected males demonstrating close to or age-appropriate developmental skills through early childhood.

INTRODUCTION

Fraccaro, Kaijser, and Lindsten (1960) were the first to describe a male with mental retardation resulting from a 49,XXXXY karyotype. Numerous re- ports of males with this chromosomal abnormality have enabled the delinea- tion of a fairly characteristic phenotype (Nyhan & Sakati, 1976; Zaleski, Houston, Pozsonyi, & Ying, 1966). Affected individuals have facial features somewhat reminiscent of Down syndrome with a round and flat face, ocular

Requests for reprints should be sent to Joseph H. Hersh, M.D., Child Evaluation Center, 334 East Broadway, Louisville, KY 40202.

The authors thank Ms. Pat Jones for her assistance in this project. This study is supported in part by Special Projects of Regional and National Significance

from the Public Health Service, United States Department of Health and Human Services, and the Division of Maternal and Child Health Services, Bureau for Health Services, Cabinet for Human Resources, Commonwealth of Kentucky.

I71

I72 J. H. Hersh et al.

hypertelorism, epicanthal folds, slightly upslanting palpebral fissures, a flat- tened nasal bridge and lowset, malformed ears (deGrouchy & Turleau, 1984; Schinzel, 1984). The external genitalia is hypoplastic and skeletal abnormali- ties include proximal radio-ulnar synostosis, multiple epiphyseal dysplasia and fifth finger clinodactyly (deGrouchy & Turleau, 1984; Schinzel, 1984; Schmidt, Pajewski, & Rosenblatt, 1978). Congenital heart disease is an occasional manifestation (Karsh, Knapp, Nora, Wolfe, & Robinson, 1975). Mental retardation is a constant feature and generally is severe in degree (deGrouchy & Turleau, 1984; Hecht, 1982; Nyhan & Sakati, 1976; Schinzel, 1984; Schmidt et al., 1978; Zaleski et al., 1966).

Our purpose is to present a child with 49,XXXXY syndrome whose cognitive and motor skills were only mildly delayed at almost five years of age. Normal psychomotor development, followed by significant decelera- tion in intellectual abilities in early childhood, which has been described in this condition (Shapiro, Brill, Hsu, Calvin, & Hirschhorn, 1971; Shapiro, Hsu, Calvin, & Hirschhorn, 1970) was not observed in our case. Cognitive skills observed in this patient suggest the potential for higher intellectual functioning in some instances of this chromosomal abnormality.

METHOD

J.B. was born at full term to a 24-year-old primigravida who had a high school education and was a homemaker. The conception was achieved by artificial insemination because of oligospermia in her husband, although his chromosome studies were normal. Labor and delivery were uncomplicated and birth weight was 3,000 grams. At 51/z months of age, he was evaluated because of delayed development, dysmorphic features, and small external genitalia. At that time, his length was 66 cm (50th percentile), weight 7 kg (25th percentile), and head circumference 43 cm (25th percentile). Signifi- cant phenotypic abnormalities included a round face, flat nasal bridge, apparent hypertelorism, lowset, mildly dysplastic ears and a right preauricu- lar eat pit. He had a Grade II/VI murmur and the external genitalia was small with a stretch penile length of 2.2 cm (< 10th percentile) and a left undescended testes. Both testes measured 1 cm (< 10th percentile). His hands and feet were small and there was clinodactyly of the fifth fingers. No resistance to supination or pronation of the forearms was noted. On neuro- logic examination, he had generalized muscular hypotonia and slight hyper- reflexia. Chromosome analysis on peripheral blood using GTG and QFQ banding revealed 49,XXXXY in all 59 cells counted. Cardiac catherization was subsequently performed and revealed an atria1 septal defect.

Infant therapy services, including physical therapy, were initiated at 6 months and speech and language therapy was added to developmental ser- vices at 28 months. The boy walked independently at 24 months. Expressive

Mild Intellectual Deficits 173

language delays were noted after 2 years of age. Speech and language thera- py, as well as a preschool for children with developmental disabilities, have continued to be important components in his overall management. Surgical procedures have included bilateral inguinal herniorrhaphies, left orchido- pexy and closure of the atria1 septal defect.

At 4 years of age, he had a length of 100.5 cm (25th percentile), weight 19.2 kg (75th percentile), and head circumference 50 cm (>25th percentile, < 50th percentile). A second chromosome analysis on peripheral blood was performed with 45 metaphases counted and in all instances there was a 49,XXXXY karyotype. A skin fibroblast culture was also obtained and chromosome analysis revealed 49,XXXXY in 100% of 62 cells counted. Therefore, in none of the 166 cells analyzed was there evidence of sex chromosome mosaicism.

RESULTS

J.B. was evaluated psychologically on several occasions; the results from those evaluations are shown in Table 1. When evaluated initially at 19 months of age, he exhibited pronounced fine-motor and gross-motor delays,

TABLE 1. Psychological Findings

Chronological Age

Psychomotor Development

Social Development

19 months

38 months

48 months

59 months

Bayley Scalesa Mental= 16 months Motor= 10 months

Binetb Vinelandc Mental Age = 34 months Social Age=34 months IQ=77

Bineth Vinelandc Mental Age=37 months Social Age=49 months IQ=66

Merrill-Palmerd Mental Age=34 months IQ=70

Bineth Vinelandc Mental Age=44 months Social Age=55 months IQ=63

Leitere Mental Age=44 months IQ=74

aBayley Scales of Infant Development Ctanford-Binet Intelligence Scale, Form L-M CVineland Social Maturity Scale dMerrill-Palmer Scale of Mental Tests CLeiter International Performance Scale

174 .J H. Hersh et al.

as seen in his performance on the Bayley. His cognitive skills, while also delayed for his chronological age, were more advanced than his motor devel- opment. Subsequent evaluations revealed a consistent rate of mental devel- opment with IQ’s ranging from the 60s to 70s on the Binet and Merrill- Palmer. However, he exhibited marked variability in cognitive skills with isolated nonverbal, visual-perceptual abilities reaching into and above chronological age level. His greatest deficits were in expressive language skills, with receptive capabilities only borderline delayed for chronological age. The propositus also displayed a consistent developmental pattern in- volving more advanced social and adaptive skills in comparison to his over- all intellectual capabilities. As can be seen from Table 1, the child’s Vineland Social Age was commensurate with his chronological age when last evaluated.

When 48 months old, he was able to dress himself well, bathe himself with minimal assistance and interact appropriately with other children at an early kindergarten level.

DISCUSSION

In males with sex chromosome abnormalities, a general assumption is that the probability of mental retardation increases proportionately with the number of X chromosomes present (Nyhan & Sakati,. 1976; Zaleski et al., 1966). Mental retardation is present in all reported cases of 49,XXXXY syndrome, usually is severe in degree, manifesting significant delays of early onset (deGrouchy & Turleau, 1984; Hecht, 1982; Nyhan & Sakati, 1976; Schinzel, 1984; Zaleski et al, 1966). In affected individuals, the IQ usually falls between 20 and 50, although in rare instances IQ scores are higher and fall within the mild range of mental retardation (Blatch, 1964; Day, Levison, Larson, & Wright, 1963). Shapiro et al. (1970, 1971) reported an affected male with normal developmental skills at 15 months on the Gesell Adaptive Maturity Level; however, when the child was evaluated at 41 months of age, cognitive abilities were in the mentally retarded range. Although decelera- tion of intellectual development, at least as reflected in poor concordance between test scores over time, is typical in Down Syndrome by the end of the first year of life (Smith, 1973), a similar pattern in intellectual development had not been reported in patients with 49,XXXXY.

In contrast to most previously described cases of this sex chromosome abnormality, intellectual abilities, on multiple evaluations in our patient, from 19 to 59 months of age were in the mild range of mental retardation to borderline range with marked variability in cognitive development. In addi- tion, adaptive skills were consistently age appropriate.

On the other hand, mild-receptive language delays were observed, while more significant expressive language deficits were present, findings similar

Mild Intellectual Deficits 175

to that observed in males with other sex chromosome abnormalities (Robin- son, et al., 1982). Overall developmental abilities were quite different than those observed in Shapiro’s patient, without evidence of normal develop- ment in infancy followed by a significant decline in intellectual abilities in early childhood; however, test scores at this time do not permit us to exclude the possibility of some degree of deceleration in cognitive development even- tually resulting in a more global degree of mental retardation.

Results of test scores in our patient raise the possibility of an underlying sex chromosome mosaicism as the basis for his current performance cognitivity. This could not be demonstrated after an extensive search for varying numbers of X chromosomes in both peripheral blood on two sepa- rate occasions and skin fibroblasts. In a total of 166 cells counted, only a 49,XXXXY karyotype was identified. We recognize that even with these results, we cannot completely rule out a low grade sex chromosome mo- saicism, although this seems unlikely, based on our studies.

in view of previous reports, most individuals with a 49,XXXXY karyo- type will have significant mental retardation. Findings in our patient, as well as others found to have mild mental retardation however, and the case reported by Shapiro et al. (1970, 1971) suggest that variability may occur cognitively in some instances even in the presence of a chromosome abnor- mality that is generally regarded to be associated with severe handicaps. The relatively good outcome in our patient may have been a function, at least in part, of early identification of his problems and the provision of early intervention services. In the 49,XXXXY syndrome, three patterns of devel- opment may exist. The more common one results in severe psychomotor delays which occur from early onset. Another, less common form, is charac- terized by milder delays which are present from infancy. A third and uncom- mon form involves normal functioning that occurs early with later decelera- tion in cognitive skills, subsequently resulting in severe intellectual deficits. Although information provided to families of a child newly diagnosed as having 49,XXXXY syndrome should not be unrealistic, results in our pa- tient may justify guarded optimism in the presence of this diagnosis, partic- ularly with the demonstration of close to, or age appropriate psychomotor development through early childhood.

REFERENCES

Blatch, S. (1964). Klinefelter’s syndrome. Proceedings of fhe Royal Society of Medicine, 57, 842.

Day, R. W., Levinson, .I., Larson, W., & Wright, S. W. (1963). An XXXXY male. Journal of Pediatrics, 63, 589-598.

deGrouchy, J., & Turleau, C. (1984). Clinical otlus of human chromosomes. New York: John

Wiley & Sons.

176 J. H. Hersh et al.

Fraccaro, M., Kaijser, K., & Lindsten, J. (1960). A child with 49 chromosomes. Loncet, 2, 899- 902.

Hecht, F. (1982). Observations on the natural history of 49,XXXXY individuals. Americun Journol of Medical Genetics, 13, 335-336.

Karsh, R. B., Knapp, R. F., Nora, J. J., Wolfe, R. R., & Robinson, A. (1975). Congenital heart

disease in 49,XXXXY syndrome. Pediutrics, 56, 462-464. Nyhan, W. L., & Sakati, N. 0. (1976). Generic ond malformorion syndromes. Chicago: Year-

book Medical Publishers.

Robinson, A., Bender, B., Borelli, J., Puck, M., Salbenblatt, J., & Webber, M. L. (1982). Sex

chromosome abnormalities (SCA): A prospective and longitudinal study of newborns iden-

tified in an unbiased manner. Birth Defecrs, 18(4), 7-39. Schinzel, A. (1984). Catalogue of unbalanced chromosome aberrations in man. Berlin: Walter

de Gruyter.

Schmidt, R., Pajewski, M., & Rosenblatt, M. (1978). Epiphyseal dysplasia: A constant finding

in the XXXXY syndrome. Journal of Medical Genetics, 15, 282-287. Shapiro, L. R., Hsu, L. Y. F., Calvin, M. E., & Hirschhorn, K. (1970). XXXXY boy: A 15-

month old with normal intellectual development. American Journal of Diseases of Child- hood, 119,79-81.

Shapiro, L. R., Brill, C. B., Hsu, L. Y. F., Calvin, M. E., & Hirschhorn, K. (1971). Decelera-

tion of intellectual development in a XXXXY child. American Journal of Diseases of Childhood, 122, 163-164.

Smith, D. W. (1973). The child with Down syndrome. London: W. B. Saunders.

Zaleski, W. A., Houston, C. S., Pozsonyi, J., & Ying, K. K. (1966). The XXXXY chromosome

anomaly: Report of three new cases and review of 30 cases from the literature. Cunodian Medical Association Journal, 94, 1143-l 154.