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Original Article

XXY

The Hidden Disability and a Prototype for an Infantile Presentation of Developmental Dyspraxia (IDD)

Samango-Sprouse, Carole EdD; Rogol, Alan MD, PhD

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Abstract

INTRODUCTION

Approximately one in 500 to one in 1,000 children are born with at least one extra sex chromosome and the majority of these children have developmental differences in the domains of motor function, language, and learning. 1 Although some of these chromosomal conditions occur more frequently than the Down syndrome or cystic fibrosis, they are not among the common diagnoses considered when boys and girls are experiencing developmental delays with related learning and/or behavioral challenges. 2 These neurodevelopmental disturbances necessitate formalized early intervention services during the first year of life and some of these disturbances extend into frank learning disabilities and mental retardation by school age. In spite of the prevalence of sex chromosome variations (SCV) in the general population, they are markedly underrecognized and underdiagnosed disorders in both the medical and early intervention communities. 3 The delay in prompt diagnosis of these very common genetic disorders has hindered families from obtaining necessary medical care and appropriate early therapeutic services.

In this article, we will focus principally on 47,XXY (the classic form of Klinefelter syndrome). Diagnosis is elusive for most children with this disorder since they do not have significant congenital birth defects or noteworthy dysmorphology. 3 They are not readily brought to the attention of medical personnel at any stage in their life. More than two thirds of individuals with the XXY karyotype remain undiagnosed; it is estimated that only 10% are identified through prenatal diagnosis, with another 26% diagnosed during either childhood or adulthood. In spite of the significantly increased prevalence of motor development disturbances, language learning differences, education difficulties, and in selected cases secondary behavioral disturbances and emotional problems, 70% of the children with XXY are not diagnosed. 3 The neurodevelopmental profile of the child with XXY is postulated to be a prototype of an infantile presentation of developmental dyspraxia rather a neuromaturational lag or delay. There is a growing amount of information concerning the increased incidence of these neurodevelopmental disturbances in infancy for children with XXY and the importance of early intervention to minimize them. 4

SEX CHROMOSOME VARIATIONS

Humans typically have a total of 46 chromosomes, including two sex chromosomes, with males represented by XY and females by XX. Sex chromosome disorders include five types: XO (Turner syndrome), XXX (Triple X), XYY, XXY (Klinefelter syndrome), and Fragile X (Table 1). The altered chromosomal complement occurs by nondisjunction of the sex chromosomes during meiotic or mitotic division of the cells. The sex chromosomes inappropriately divide during cell division, resulting in an uneven number of sex chromosomes in the cells throughout the body. This chromosomal imbalance may affect the development and function of the central nervous, endocrine, and cardiac systems. 2

Table 1
Table 1:
Sex chromosome variations

Mosaicism occurs when some cells have 46 chromosomes and others have 47 chromosomes with either an additional X or Y. Mosaicism occurs in about 10% of this population, and these children are often less affected in their overall neurodevelopmental performance with intellectual abilities usually higher than in the classic form of sex chromosome variation. 5 When the variant forms of sex chromosomes disorders occurs, there are 48 or 49 chromosomes such as XXXY or XXXX. The greater the number of additional X or Y chromosome, the greater are the phenotypic consequences and the neurodevelopmental differences. 6 Children with one of the variant forms are about one in 50,000 to one in 100,000 and usually are identified early in life because of their unusual physical features and more global developmental delay. 6

XXY (Klinefelter syndrome)

In 1942, endocrinologist Harry Klinefelter described the main attributes of an endocrine syndrome in a small group of adult men with atypical physical appearance. These attributes included hypogonadism (small, firm testes), gynecomastia (breast tissue development), sparse body hair, and eunuchoid body habitus (slender upper body with rounded hips) with above average height and infertility. The combination of these symptoms thereafter came to be known as “Klinefelter syndrome.” 7 After the normal chromosomal complement of 46,XX or XY was identified in humans, the chromosomal etiology for XXY and other sex chromosome variations was described. 8

XXY is most likely to be recognized at several common junctures in a child's life. Most boys are identified during pubescence or early adolescence because of delayed pubertal development, or in adulthood, when fertility issues bring them to the attention of reproductive endocrinologists. However, with technological advances in obstetrical procedures and the passing of Public Law IDEA, increasing numbers of children with XXY have been identified through prenatal diagnosis and occasionally at school age when reading differences and behavioral symptoms become apparent to educational personnel and primary care professionals. 9 Boys identified through prenatal diagnosis are believed to have milder deficits since the postnatal population is ascertained because of more significant global deficits, which bring them to medical attention. 10, 11, 12

The prevalence of this disorder suggests that there should be nearly 250,000 males in the United States with XXY; however, the ascertainment of this disorder continues to lag significantly, more so in minority populations. 13 Although there is no formalized registry for children with sex chromosome variations, Klinefelter Syndrome and Associates, the oldest parent advocacy for this disorder, has few minority families and less than 3,000 active members. 14

CHARACTERISTIC FEATURES OF XXY

Males with 47,XXY have a high degree of variability in their presentation. The additional X chromosome affects physical, cognitive, motor, and language development. Some boys have only minor symptoms and others are severely affected, requiring a cadre of therapeutic services. There are minor physical differences, or dysmorphic features, such as curved fifth finger (clinodactyl) or flat feet associated with XXY (Table 2). In a small subset of boys with XXY, the phallus may be of subnormal length, but not considered in the category of “microphallus.” 15 Boys with XXY are average length at birth but between three and seven years of age, their growth accelerates and by adulthood, they are usually at the 75th percentile for height. 2 Birth weight is average at 7 pounds and three ounces and these boys are usually lanky throughout childhood. 16 Boys with XXY have an insufficiency of the male sex hormone, testosterone. 2 The influence of testosterone on brain maturation of boys with XXY is not well understood and has not been thoroughly investigated yet. It is believed that the primary effects of this insufficiency are not evident until early adolescence when sexual maturation and pubertal development may be delayed or incomplete. 2,11 Most boys with 47,XXY require hormonal replacement therapy as they enter adolescence and this treatment usually continues throughout their lives. Such testosterone replacement therapy has been shown to help alleviate some of the physical attributes described by Dr. Klinefelter in most males with the condition, especially when started at, or slightly prior to, the onset of puberty. 17,18

Table 2
Table 2:
Common symptoms of XXY

NEURODEVELOPMENTAL PROFILE OF THE CHILD WITH XXY

Boys with XXY provide an excellent field for research investigations because of the homogeneity of the disorder and the increased prevalence of language and learning disorders associated with them. The prenatal population affords the opportunity to observe the evolution of learning differences and motor disturbance from infancy through adulthood. With an 80% chance of dyslexia in boys with XXY, the infant and toddler with XXY provides a window of opportunity to study a rare occurrence, the natural history of the reading disturbance from infancy through preschool years.

Although studies with this population have been flawed by small sample size and ascertainment bias, XXY is not typically related to mental retardation, autism, or serious psychiatric disorders. 19,20,21 Intellectual development remains consistently within normal limits, with children with XXY identified through prenatal diagnosis having higher intelligence quotient (IQ) scores than those diagnosed postnatal. 10,11,12 IQ is often shifted to the left by 10–15 points from sibling controls. 22,23,24 Samango-Sprouse (2001) assessed the cognitive capabilities of infants and toddlers, finding a Medical Development Index (MDI) of 95.58 with standard deviation (SD) of 17.79 with a wide range of capabilities. 16 Decreased verbal ability is evident with language-based learning problems, with reading disturbance consistently described in many studies. 20,23 Bone age maturation has been correlated to verbal deficits in boys with XXY. 25 Studies reveal slow processing, inattention, and language dysfunction. 20,25,26,27

The neurobehavioral phenotype of the infant and toddler with XXY has become more distinct as small cohorts of boys were identified from the comprehensive prenatal diagnosis and newborn screening and evaluated. A retrospective review of research studies on the early development of boys with XXY reveals areas of deficits in motor and language development. Until now, a comprehensive and prospective analysis of a large group of infants with XXY and their learning differences has not been undertaken. Boys with XXY have a subtle combination of language differences, learning difficulties, and some secondary behavioral problems. Although the profile evolves and “changes faces” in many ways from infancy through preschool, childhood, and adolescence, there are consistent difficulties with language and motor dysfunction throughout their lifetime. If the profile is reviewed from the perspective of the brain and behavior relationship over time, the child with XXY appears to have a motor planning deficit that influences learning, speech, and movement. This neurodevelopmental constellation appears as more than language and learning deficits with motoric clumsiness. The profile is consistent with mild developmental dyspraxia that is influencing language, motor, attention, and learning.

Motor development of the young child with XXY

There have been few investigations of motoric capacities in the child with XXY; however, motor awkwardness with clumsiness and generally an avoidance of team sports has been described. 29 One study reveals synkinesis, dysmetria, and tremors in 14 adolescents with XXY. 30 Robinson and colleagues (1991) conducted a comprehensive study on 40,000 newborns in Denver, and then followed a small group of boys with XXY (n = 16) and compared them to typically developing sibling controls. 5,10,31 The boys with XXY had delayed ambulation skills (mean age of independent walking = 18 months) and speech (mean age of first words = 24 months). Samango-Sprouse and Law (2001) have studied a large cohort of young children with XXY (n = 73), who were identified through prenatal diagnosis. 16 Twenty percent of the infants had a “pseudo-torticollis” with flattening of the occipital area and decreased range of motion to the contralateral side of the pseudo-torticollis. These findings suggest a decrease in motoric activity as early as 2–3 months of age with preferred posturing secondary to truncal hypotonia. (Samango-Sprouse, manuscript in preparation). The psychomotor development was significantly delayed in comparison to population controls with a motor index of 87.63 (SD 17.03). 16 The majority of the infants had received physical therapy services in community intervention programs because of the diagnosis with decreased muscle tonus and atypical movement patterns (Samango-Sprouse, unpublished data). Independent ambulation was at 12 months, which is significantly improved when compared to the early studies in XXY. However, the gait was wide-based into the second year of life, with unsteadiness and frequent falling. Balance problems were evident between 24 and 36 months of age with delay in coordinated running and persistence in “toddler gait.” Motor planning difficulties were evident in sequencing such as repetitive jumping or hopping. As the complexity in motor tasks increased, acquisition of these intricate skills was delayed and there was difficulty reproducing them in a novel pattern and repeatedly rather than the isolated production of any single skill (Samango-Sprouse, raw data, 2000). While completing these multifaceted tasks, there is significant overflow of and compensatory postures (Samango-Sprouse, raw data, 2000).

NEUROBEHAVIORAL ASPECTS OF XXY

From a neurobehavioral perspective, infants with XXY reveal well-modulated alert states with a strong preference for visual stimulation evident within the first months of life. 16 In contrast, many infants required repeated exposures to localize to certain sounds. Several infants were evaluated for hearing loss because of atypical responses although hearing was determined to be intact by formal assessment.57 Hypothetically, the clinical significance of this visual preference could be related to Giedde's findings of enlarged occipital and parietal areas on MRI in boys with XXY in comparison to normal controls58 (unpublished data). This is a tantalizing concept since boys with XXY often have accelerated development in visual-spatial cognition. Perhaps, in infancy this is an early view of their advanced development in visual perception. The infant's delayed response to auditory stimuli may be connected to previously described auditory processing deficits and phonological differences observed with reading deficits in the older child with XXY. 26 MRI findings by Patwardhan et al provide further support for this hypothesis since there was significant reduction in temporal lobe gray matter on males with XXY. 32 The temporal lobe is often called “the social brain” because it is related to language development and auditory processing. These are areas of deficits for the boy with XXY.

Speech and Language Development in XXY

The early speech and language development of the infant and toddler with XXY is not well understood since the primary observations have been limited by parental report or small sample size. In Samango-Sprouse and Law's findings, speech differences were evident in most infants at 12 months of age with some demonstrating difficulties with suck/swallow coordination at birth, particularly with breastfeeding. 16 These infants had atypical phonemic development, delays with sound production in imitation, and babbling by their first birthday.

There was decreased muscle tonus in the oral facial musculature with difficulties transitioning to textured foods and a preference for soft foods. Parents reported that the “their babies listened intently and understood everything but were often very quiet.” These infants had age-appropriate or advanced receptive language skills (p < 0. 001) in contrast to delays in expressive language skills. 6 As toddlers, differences were observed in acquisition of single words, with difficulty in transitioning to three and four word phrases. Fifty-two percent of all children required speech and language services beginning by 18 months, typically lasting for several years. The constellation of the delayed speech acquisition, difficulties with imitation of simple speech sounds and words, and subtle oral motor dysfunction with sensory differences suggests a motor planning deficit that is consistent with the dyspraxia observed in the gross motor movement.

As the boys with XXY became preschoolers, the motor planning differences in speech production evolved into language formulation and memory deficits with word recall and organization issues evident. Diminished verbal fluency and memory difficulties 26,34 with syntactical and grammatical differences were observed in preschool years. 16,34,35 Several studies have described deficits in auditory processing, short-term auditory memory, word recall, and phonological development. 21,31 Samango-Sprouse has evaluated 38 preschoolers (age range: 36 to 60 months) with sex chromosome variations. These study results corroborated previous findings and also revealed significant deficits on auditory recall of short story with enhanced visual memory. The preschooler with XXY ‘s profile has findings consistent with developmental dyspraxia and has been described in the nonsyndromic child with developmental dyspraxia. 36 However, preliminary data describes enhanced visual-perceptual skills in spite of the deficits in motor planning and copying.

Is this developmental dyspraxia?

These deficits in infancy strongly resemble the profile of the older child with developmental dyspraxia. Developmental dyspraxia has been investigated in the research literature for over a hundred years, but it is not a well-understood disorder. 36 It is characterized by difficulties in the planning and integration of motor movements from simple to complex and often across developmental domains. 36 Perceptual-motor, language, and attention impairments are commonly observed in this disorder. There is an increased association between developmental dyspraxia and later learning disabilities. 36,37 The constellation of developmental disturbances in the young child with XXY strongly suggests an infantile form of developmental dyspraxia. There are significant motor disturbances affecting both expressive language and neuromotor development noted within the first year of life. Perceptual tasks, which are non-motor-dependent, are preserved. Later, those motor-dependent tasks such as handwriting, timed visual-perceptual items, and dexterity are impaired. 16 Atypical balance reactions and difficulty acquiring complex intricate motor skills as young children are present. Discrepancy in speech versus comprehension has been identified in the infants as early as the first year of life with decreased phonemic repertoire and difficulties with imitation, with normal cognitive development. The neurodevelopmental profile in the young child with XXY is highly suggestive of a manifestation of developmental dyspraxia that has not been appreciated previously. Several studies have shown an increased association between dyslexia and developmental dyspraxia. 36 The relationship of this infantile presentation of developmental dyspraxia and the reading dysfunction in XXY is not yet understood but warrants further investigation.

SUMMARY

Throughout their lifetime, the developmental differences in the boys with XXY are often subtle and can be easily dismissed for a variety of reasons from “He is a boy and boys talk late” to “He does not look abnormal—he cannot be chromosomal.” Yet, one in every 600 births is a boy with an additional X. Some of the children in infant programs with developmental issues of unknown etiology may be children with these disorders. The diagnosis of sex chromosome variations should be considered and evaluated whenever there are any developmental differences. This is particularly important when there is a history of speech, language, or motor delays in infancy. Chromosomal analysis is necessary in order to diagnose these children since they have no overt dysmorphology. Early identification and intervention increases the child's developmental outcome, educational success, social and behavioral skills, and integration into an independent lifestyle. Once a child has been properly identified as having a sex chromosome variation, the interventionist can provide individualized and syndrome-specific strategies and, therefore, increase the possibility of optimal outcome and success. The child with an XXY generally responds extremely well to therapeutic intervention throughout life. 27

Further investigation is warranted into the relationship between MRI findings, developmental performance, and hormone replacement in boys with XXY from infancy throughout adulthood. The infant with XXY presents with an early presentation of developmental dyspraxia, which provides a window into the relationship between brain, behavior, and later language/learning disorders in a very homogeneous population. The relationship between testosterone, learning, and neurodevelopment is not well understood, but the child with XXY provides an opportunity to investigate this connection prospectively. With greater understanding of these infants, our knowledge of learning disorders in general and its effect on development should be greatly enhanced.

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      Keywords:

      developmental dyspraxia; sex chromosome; xxy

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