Gross and Fine Motor Development in 45,X and

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1 Gross and Fine Motor Development in 45,X and 47,XXX Girls James A. Salbenblatt, MD, Deborah C. Meyers, RPT, MS, Bruce G. Bender, PhD, Mary G. Linden, MS, and Arthur Robinson, MD From the National Jewish Center for Immunology and Respiratory Medicine and the University of Colorado School of Medicine, Denver ABSTRACT. Neuromuscular deficits have been described in 47,XXY and 47,XYY boys, but gross and fine motor development of girls with sex chromosome aneuploidy has not been extensively studied. Twenty-one propositae, 8 to 19 years of age, identified through newborn screening to be 45,X, 47,XXX, or 45,X mosaic, and 11 control girls were evaluated by a physical therapist unaware of their genetic constitution. The Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) was administered, and the quality of neuromuscular function was determined. The 45,X and 47,XXX propositae exhibited both gross and fine motor dysfunction, with 12 of 15 BOTMP composite scores below the 1th percentile. The clinical assessment confirmed the BOTMP findings, with 13 propositae exhibiting dysfunctional sensory-motor integration. A delay in the age of independent walking confirmed the consistency of motor developmental dysfunction throughout time. Sex chromosome mosaics were more similar to control girls. The gross and fine motor delays were frequently associated with a moderate to severe language dysfunction which adversely affected classroom performance. Regular developmental assessments of children with sex chromosome aneuploidy, including sensory-motor integration, should assist in the identification of early developmental delays and permit appropriate intervention. Pediatrics 1989;84: ; sex chromosome, motor development. type. The availability of these data will enable parents to anticipate the therapeutic and educational needs of their children. The longitudinal evaluation of persons with sex chromosome aneuploidy, identified by newborn screening, has provided an opportunity to prospectively observe their development during a 24-year period in the Denver Family Development Study.2 3 The cognitive,2 speech-language,4 and learning disability5 status of these persons have been documented. The gross and fine motor development of the boys revealed a mild to moderate dysfunctional sensory-motor integration which adversely affected school performance.6 The visual-spatial deficit in Turner syndrome has been well studied,7 although the gross and fine motor development of 45,X and 47,XXX girls has not been reported. Therefore, the purpose of this study was to describe the neuromuscular status and sensory-motor integration of sex chromosome aneuploid girls, unselected for phenotype, to increase our understanding of the effect of sex chromosome aneuploidy on neuromuscular development and its possible association with learning problems. Sex chromosome aneuploidy is a common chromosomal abnormality, occurring in approximately 2 per 1 female newborns. More of these individuals are identified because of the increased availability of amniocentesis and chromosome analysis, resulting in a need for information regarding the clinical findings of subjects unselected for pheno- Received for publication Oct 24, 1988; accepted Dec 2, Reprint requests to (AR.) National Jewish Center for Immunology and Respiratory Medicine, 14 Jackson St, Denver, CO 826. PEDIATRICS (ISSN 31 45). Copyright 1989 by the American Academy of Pediatrics. MATERIALS AND METHODS The 21 propositae were identified through X chromatin examination of the amniotic membranes obtained from placentas of 4 consecutive newborns at two Denver hospitals, and all were confirmed by karyotype analysis. Individuals available for this motor study included five 45,X (8 to 16 years of age), ten 47,XXX (1 to 19 years of age), and two partially monosomic X chromosome variants and four sex chromosome mosaics without morphologically abnormal X chromosomes (9 to PEDIATRICS Vol. 84 No. 4 October 1989 years of age). Seven X chromatin-positive sisters of propositae and four additional eukaryotic female siblings chosen from other families within the Den- Downloaded from by guest on July 19, 218

2 ver Family Development Study were available as a control group (8 to 18 years of age), with no more than one girl from any family. Informed consent was obtained from the parents. The Bruininks-Oseretsky Test of Motor Proficiency (BOTMP)8 was administered to each girl by a physical therapist who was unaware of the karyotype of the subjects. Propositae and control chilthen were presented for evaluation in random order. The complete BOTMP battery consists of eight subtests of motor proficiency and three composite scores. The test results were compared to the ageand sex-differentiated subtest and composite standard score norms of the standardization sample. The individual girl s battery composite results are presented as a percentile, and group subtest and composite standard scores are used for a more detailed comparison. Older subjects were compared to the 14-year test norms. In addition to the standardized test, the examiner clinically rated the quality of neuromuscular function in the areas of neurologic status, gross and fine motor development, and perceptual integration. This clinically derived framework included 16 observations of nonlocalizing or soft neurologic signs and sensory-motor integration: neurologic statusmuscle tone, primitive reflex retention, sensorymotor integration; gross motor development-joint stability, muscle strength, coordination, balance, gait, eye-hand coordination, eye-foot coordination; fine motor development-bilateral coordination, eye-hand coordination, prehension/manipulation, writing; perceptual development-visual perception, visual-motor integration. These were rated on a 5-point scale developed for this study: 5 = adaptive skills within average range, 4 = one area of weakness and/or soft neurologic sign, 3 = multiple signs of sensory-motor dysfunction and/or developmental delays, 2 = developmental deficits secondary to neurologic interference, and 1 = significant neurologic impairment. The 16 ratings were summed with a maximum score of 8 and a minimum of 16. This total is referred to as the Neurologic/Sensory-Motor Integration score. The age of independent walking was available for all aneuploid girls but was not documented for the control girls. Therefore, the age of independent walking was compared to published norms for the Denver Developmental Screening Test.9 A psychologist administered the original or revised edition of the Wechsler Intelligence Scale for Children to provide a comparison of the general intellectual skills of all groups, and a speech language pathologist administered five language tests to sample receptive language, expressive language, and auditory-memory skills. Historical information in the record documented educational special services RESULTS 45,X intervention. Four of the five nonmosaic 45,X girls performed markedly below average limits on the BOTMP with a battery composite score below the first percentile (Table 1). All three composite standard scores were significantly less than were those of the control girls, as were half of their subtests (Table 2). Except for subject 4, they experienced difficulty with most of the clinical observations. Neurologically, they had hypotonia, retention of primitive asymmetric and symmetric tonic neck reflexes, and dysfunctional sensory-motor integration. The clinical Neurologic/Sensory-Motor Integration scores are also presented in Table 1. Subject 1 received the lowest cumulative score of 37 and was the only girl to receive ratings of 1 on the 5-point scale, indicating significant neurologic impairment. In contrast, subject 4 did relatively well with evidence of good sensory-motor integration and normal muscle tone which was consistent with her strong cognitive and language skills and absence ofeducational intervention. It was also noted that she had fewer physical stigmata than the other members of this group, including a lack of short stature, although she is short compared with other members of her family. The others had classic stigmata of Turner syndrome. The developmental status of two girls with partially monosomic X chromosome variants are presented in Table 1, although the information was not included in the group comparisons. Subject 6, with a terminal deletion of the long arm of the X chromosome, 46,X,del(X)(pter-q21.2:), had relatively short stature and secondary amenorrhea. Her motor skills were excellent in early childhood, and she continued to demonstrate evidence of good sensory-motor integration. She received the highest battery composite percentile of 99 on the BOTMP and did well on the clinical assessment. Subject 7, with 45,X/46,X,r(X), did better clinically in contrast to her standardized battery composite percentile of 1. Early motor problems were recognized, and she was observed to have some weaknesses in sensory-motor integration. Physically, she had short stature and no evidence of spontaneous puberty. Four propositae with sex chromosome mosaicism were followed up. Subjects 8 through 11 had BOTMP composite percentiles from 8 to 72 (Table 1). Their three composite standard scores and all Downloaded from by guest on July 19, 218 ARTICLES 679

3 TABLE 1. Developmental Status of Girls With 45,X, 45,X Variants, Sex Chromosome Mosaics and 47,XXX* Karyotype and Walked Late BOTMP Battery Neurologic/Sensory Sensory-Motor Full-Scale Language School Subject No. after 15 mos. Composite Percentile Motor Integration Score Integration Dysfunction IQ Dysfunction Intervention 45,X 1 + < FT 2 < PT 3 + < FT < PT Mean (SD) 5.6 (1.3) 48.8 (15.) 82.4 (26.4) 46,X,del(X) (pter -*q21.2:) 6 45,X/46,X,r(X) PT [35:65] 7 45,X/46,XX [48.52] 8 45,X/46,XX [27:73] 9 45,X/47,XXX [37:63] 1 46,XX/47,XXX [9:1] 11 Mean (SD) 37.3 (26.5) 68.5 (9.7) 12. (2.) 47,XXX PT 14 < PT 15 + < FT FT 18 + < FT 19 + < PT 2 + < FT PT Mean (SD) 7.4 (15.3) 48.9 (8.1) 84.5 (19.1) Control 22 ND ND PT 24 ND ND ND PT 27 ND ND ND ND 28 ND ND ND 29 ND ND ND 3 ND ND PT 32 ND Mean (SD) 44.3 (23.7) 71.6 (5.8) 12.3 (16.6) * Symbols and abbreviations: +, present;, absent; ND, no data;pt,parttime; FT, full time; ratio; BOTMP, Bruininks-Oseretsky Test of Motor Proficiency. ], newborn chromosome subtests were not significantly different from the 47,XXX control subjects (Table 2). They did relatively well on the clinical assessment with a Neurologic/Sensory-Motor Integration score mean of 68.5, which was not significantly different from that of the control girls at Nine of the ten girls with 47,XXX had BOTMP composite percentiles at or below 12, except for subject 16 with 5% (Table 1). Both the gross motor and battery composite standard scores were signif ,X AND 47,XXX GIRLS Downloaded from by guest on July 19, 218

4 TABLE 2. Comparison of Standard Score Means of Aneuploid Subjects to Controls on Bruininks-Oseretsky Test of Motor Proficiency Subtests and Battery Composites* Test Controls (n 45,X (n = 5) 47,XXX (n = 1) Mosaics (n = 4) 11) Mean SD P Value Mean SD P Value Mean SD P Value Mean SD Gross motor Running speed and agility Balance Bilateral coordination Strength Gross and fine motor: upper limb coordination Fine motor Response speed Visual-motor control Upper-limb speed and dex terity Gross motor composite Fine motor composite Battery composite * All scores were converted to a mean of 5 with a SD of 1. A one-way analysis of variance was conducted on all of the scores. Each SCA group was contrasted with the control group using a one-tailed significance level of P =.2, obtained by dividing the number of subtest contrasts by a composite a of.5. icantly below the control girls, although they performed relatively stronger on fine motor tasks. The subtest profile was consistent with these results (Table 2). Nine girls with XXX received clinical Neurologic/Sensory-Motor Integration scores that were at or below 56 (range 16 to 8) and lower than any control subject. In contrast, subject 16 received a score of 67, which was consistent with the control girls and her prior positive test results. Nine of the 1 girls with 47,XXX showed evidence of sensorymotor integration dysfunction (Table 1). Low tone was present in six girls and was associated with diminished strength, poor joint stability, and gait abnormalities. At least 7 of the 1 subjects experienced difficulty with balance, rapid alternating movements (diadokokinesis), motor planning, and bilateral coordination. These problems were evident in both gross and fine motor skills. They also experienced difficulty with visual perception, visual-motor integration, and prehension. Control Subjects The control group performed significantly better than the nonmosaic 45,X and 47,XXX aneuploid groups. Only control subject 27 had a BOTMP battery composite percentile of 8, and the other 1 had percentiles of 24 and above. Their clinical Neurologic/Sensory-Motor Integration scores had a mean of 71.6 of a maximum of 8, and in only subject 27 was dysfunctional sensory-motor integration diagnosed. The control subjects BOTMP composite standard scores were consistent with the test standardization sample. Early Motor Development The age at which each proposita achieved the developmental milestone of independent walking was compared to the standardization data of the Denver Developmental Screening Test which mdicated that 9% of all girls were walking by 14.8 months. Of the entire 21 propositae, 11 (52%) were delayed in this area when the Denver Developmental Screening Test criteria were used; they walked independently at 15 to 22 months of age (Table 1). This is a marked increase in motor developmental failure relative to the normative population for this item. DISCUSSION The 45,X and 47,XXX propositae frequently exhibited both gross and fine motor dysfunction. Their neuromuscular evaluations documented hypotonia associated with joint instability and sensory-motor integration dysfunction which adversely affected coordination, visual-motor integration, joint stability, and strength. Of 15 girls, 12 (8%) had BOTMP battery composite scores below the 1th percentile. Their subtest profiles were relatively flat, although girls with XXX performed slightly stronger on fine motor tasks. The BOTMP scores were consistent with the clinically derived Neurologic/Sensory Motor Integration scores. These scores for control subjects ranged from 61 to 78 of a maximum 8 and minimum 16. With the exception of one 45,X girl who achieved a 75 and a 47,XXX girl with a 67, there was no overlap between the aneuploid and control Downloaded from by guest on July 19, 218 ARTICLES 681

5 subjects. Only one control girl was identified as having sensory-motor integration dysfunction, in contrast to 13 of 15 subjects with monosomy X and xxx. The partially monosomic x chromosome variants and the sex chromosome mosaics are more similar to the controls. One ofthe six girls, 45,x/46,x,r(x), who had a Turner syndrome phenotype, had a BOTMP battery composite score below the 1th percentile. Subject 1 who was a xixxx mosaic had an adequate clinical score and no other developmental problems. The Neurologic/Sensory-Motor Integration scores for this group were 55 to 77 of the possible 16 to 8, and only one demonstrated sensory-motor integration dysfunction. A retrospective review of the age of independent walking confirms the consistency of motor developmental dysfunction throughout time. Of 15 girls with 45,x and 47,xxx, 9 walked after 15 months of age, in contrast to the expected 1% of the general population. All propositae walked independently by 22 months of age. In addition to the early motor delay, other areas of difficulty were identified independently at different ages. These included 11 of 15 girls with 45,X and 47,xxx with a moderate to severe language dysfunction, and 12 of 15 who were independently referred for full- or part-time educational special services. The 3 nonmosaic subjects with the fewest developmental problems and no special education referral had the highest IQ scores as determined on the Weschler Intelligence Scale for Children. Developmental concerns were rare among the sex chromosome mosaics and control subjects. Results of this study indicate that gross and fine motor delays associated with a mild to moderate sensory-motor integration dysfunction are frequent findings in this group of girls with 45,X and 47,xxx. Although our number of 45,X subjects is small, there are indications that this group has a more global neurologic dysfunction than is generally recognized. The study of sensory-motor integration by Ayres #{176}suggested that adequate feedback and integration of the sensory modalities are necessary for maximal function of an individual. Dysfunctional sensory-motor integration is likely to be an additional factor that adversely influences classroom performance. In addition to affecting learning, the decreased perceptual organization may also contribute to a diminished self-concept and madequate peer interaction. It is our conclusion that sex chromosome aneuploidy in girls is associated with an increased risk for sensory-motor integration dysfunction. This is likely to be an additional factor that negatively influences classroom performance along with language delays and depressed cognitive abilities. There is variability within the groups, and mosaic subjects are developmentally closer to the control subjects. The longitudinal assessment has also suggested that sex chromosome aneuploid subjects demonstrate an increased vulnerability to adverse environmental conditions. Continued evaluations with a greater number of subjects is desirable. We encourage regular developmental assessments to provide anticipatory guidance through early identification and intervention. Neuromuscular status and sensory-motor integration should be a part of the ongoing periodic evaluation in children with sex chromosome aneuploidy, and appropriate intervention should be recommended. ACKNOWLEDGMENTS This study was supported, in part, by grant 5R1- HD132 from the US Department of Health and Human Services, Public Health Service; grant RR-69 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health; and The Genetic Foundation. The authors thank Dr John F. LaBrecque for statistical consultation and Jean Clyne for help in preparation of the manuscript. REFERENCES 1. Jacobs PA. The incidence and etiology of sex chromosome abnormalities in man. Birth Defects. 1979;15: Robinson A, Bender B, Borelli J, et al. Sex chromosornal aneuploidy: prospective and longitudinal studies. Birth Defects. 1986;22: Linden MG, Bender BG, Robinson A. 47,XXX: what is the prognosis? Pediatrics. 1988;82: Bender B, Fry E, Pennington B, Puck M, Salbenblatt J, Robinson A. Speech and language development in 41 chilthen with sex chromosome anomalies. Pediatrics. 1983;71: Pennington BF, Bender B, Puck M, et al. Learning disabilities in children with sex chromosome anomalies. Child Dev. 1982;53: Salbenblatt JA, Meyers DC, Bender BG, Linden MG, Robinson A. Gross and fine motor development in 47,XXY and 47,XYY males. Pediatrics. 1987;8: Bender B, Puck M, Salbenblatt J, Robinson A. Cognitive development of unselected girls with complete and partial x monosomy. Pediatrics. 1984;73: Bruininks RH. Bruininks-Oseretsky Test of Motor Proficiency, Examiner s Manual. Circle Pines, MN: American Guidance Service; Frankenburg WK, Dodds JB, Fandal AW, et al. Denver Developmental Screening Tests, Manual. Denver, CO: University of Colorado Medical Center; Ayres AJ. Sensory Integration and Learning Disorders. Los Angeles, CA: Western Psychological Services; Bender BG, Linden MG, Robinson A. Environment and developmental risk in children with sex chromosome abnormalities. J Am Acad Child Adolesc Psychiatry. 1987;26: ,X AND 47,XXX GIRLS Downloaded from by guest on July 19, 218

6 Gross and Fine Motor Development in 45,X and 47,XXX Girls James A. Salbenblatt, Deborah C. Meyers, Bruce G. Bender, Mary G. Linden and Arthur Robinson Pediatrics 1989;84;678 Updated Information & Services Permissions & Licensing Reprints including high resolution figures, can be found at: Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: Downloaded from by guest on July 19, 218

7 Gross and Fine Motor Development in 45,X and 47,XXX Girls James A. Salbenblatt, Deborah C. Meyers, Bruce G. Bender, Mary G. Linden and Arthur Robinson Pediatrics 1989;84;678 The online version of this article, along with updated information and services, is located on the World Wide Web at: Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 67. Copyright 1989 by the American Academy of Pediatrics. All rights reserved. Print ISSN: Downloaded from by guest on July 19, 218