Psychonetwoendocrinology,Vol. 16. No. 1-3, pp. 203-211, 1991
0306- 4530/91 $3.00 + 0.00 ©1991 Pergamon Pte~ pie
Printed in Great Britain
HORMONAL INFLUENCES IN DEVELOPMENTAL LEARNING DISABILITIES PAULA TALLAL Rutgers University, Center for Molecular and Behavioral Neuroscience Newark, New Jersey, U.S.A. (Received infinalform 19 September 1990)
SUMMARY Developmental language and learning disabilities in children can take many different forms and can result from a variety of causes. Research to date has focused primarily on specific disabilities in learning, which are characterized by a significant delay or disorder in one aspect of learning against a background of otherwise normal development. Learning disabilities affecting language and/or reading acquisition (developmental dysphasia and dyslexia) have been studied most thoroughly. Verbal learning disabilities occur more frequently in boys than in girls, and there is a higher than expected incidence of left-handedness among affected children. Although there are many reasons why a child may have delayed or disordered language development, differential diagnosis of specific developmental language or reading disorders calls for ruling out mental retardation, peripheral auditory or visual dysfunction, autism, frank neurological impairments such as hemiplegia or seizure disorder, and severe social deprivation or lack of educational opportunity. The typical profile of a developmentally dysphasic or dyslexic child is one who shows a marked discrepancy between nonverbal (performance) IQ and verbal IQ, with a history of delayed or disordered speech, language and/or reading development. Such a child usually performs quite normally on visual spatial tasks, while demonstrating severe deficits in tasks of auditory temporal processing, motor sequencing, phonological processing and memory, language, reading and spelling. This characteristic neuropsychological profile may suggest left hemisphere dysfunction or a failure to develop normal cerebral lateralization. The etiology of these developmental learning disorders is unknown, but there is evidence of familial aggregation, indicating a potential genetic basis. Although these children respond to remediation, longitudinal studies have shown that the symptoms often persist into adulthood (see Tallal, 1988, for a more detailed discussion). HORMONAL INFLUENCES IN THE DEVELOPMENT OF CEREBRAL ASYMMETRY There has been a growing interest in potential hormonal effects in developmental language and learning disabilities in children. Interest was spurred when Geschwind and Behan (1982) initially proposed that developmental learning disorders may be linked to both left-handedness and immune disorders through the action of testosterone on brain development. These investigators proposed that abnormal testosterone levels, or unusual sensitivity to testosterone during fetal life, can alter brain anatomy, such that left hemisphere development is delayed and normal Address correspondence and reprint requests to: Dr. Paula Tallal, Rutgers University, Center for Molecular and Behavioral Neuroscience, 197 University Avenue, Newark NJ 07102, USA. 203
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cerebral asymmetry fails to develop. In support of this hypothesis, Galaburda and Kemper (1979) reported finding neuronal migration abnormalities, as well as a lack of the expected cerebral asymmetry (left larger than fight) in the area presumed to subserve speech, from postmortem morphological eyaluations of the brains of dyslexic individuals. With the advent of noninvasive, in vivo brain imaging methods, a few studies of developmental reading disability (dyslexia) and developmental language disorder (dysphasia) have been reported (Hier et al., 1978; Rosenberger & Hier, 1980; Haslam, 1981; Rumsey et al., 1986; Jemigan et al., 1987; Plante et al., 1989; see Hynd, 1989, for review). These imaging studies support neuropathological findings of reduced or reversed hemispheric asymmetry, especially in posterior temporal cerebral areas. Of these new imaging techniques, magnetic resonance imaging (MRI) offers the most sensitive, noninvasive method for assessing brain morphology during life, thus providing a unique opportunity for examining brain structure in children with specific developmental language and learning disabilities. Normally, the left hemisphere is larger than the right. Using MRI, Jemigan et al. (1985) demonstrated a significant increase in aberrant asymmetry (right equal to or larger than the left) of post-sylvian cerebrum in developmental dysphasics, compared to matched controls. Plante et al. (1989) also reported asymmetrical left-right perisylvian configuration in a young, language-impaired boy. MRI results were also presented for this boy's dizygotic twin sister who, although not language-impaired, also exhibited abnormality in hemispheric perisylvian configuration, with the fight hemisphere larger than the left, the reverse of the pattern usually seen in normally developing children. The consistent finding of abnormalities of cerebral asymmetry in the brains of languageand learning-impaired children has led to a search for potential models which might exert an influence on the development of cerebral lateralization. The results of animal research showing that gonadal hormones may play a specific role in the development of cerebral lateralization, as well as exert an influence on sexually dimorphic cognitive behaviors, has led to a growing interest in potential hormonal influences on developmental language and learning disabilities in children. Studies investigating the role of hormones in brain development and cognition in humans are constrained by major limitations in methodology. Controlled experimental studies which manipulate specific hormones and evaluate the effects on specific aspects of brain and behavioral development, which are the hallmark of animal research, obviously are not possible in studies with human subjects. What is available are studies which carefully evaluate the cognitive profiles of individuals exposed either exogenously or endogenously to aberrant levels of gonadal hormones. These include children born with sex chromosome anomalies or genetic inborn errors of metabolism which effect the endocrine system, as well as children exposed prenatally to exogenously induced excesses of estrogen or testosterone (Reinisch et al., 1991; Nass & Baker, 1991). Historically, observations of personality as well as intellectual profile differences between normal boys and girls raised questions pertaining to the origins of sexually dimorphic behaviors. Early conflicts arose between theorists who proposed either an environmental or a genetic basis for these normal differences. Such conflicts led to an interest in studying personality and intellectual profiles in individuals with known genetic abnormalities, to determine whether there was a genetic basis to sexually dimorphic behaviors. The pioneering work of Money and colleagues (Money & Lewis, 1966; Ehrhardt & Money, 1967; Money & Ehrhardt, 1968) stimulated an explosion of interest in studying the personality and cognitive profiles of individuals with abnormal sex chromosome compliment. Interest
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focussed on aneuploid individuals, who are characterized by additions or deletions of sex chromosomes (45 X, 47 XXY, 47 XYY and 47 XXX). Results of early research with these subjects suggested an important role of the X chromosome in determining neuropsychological profiles. Females lacking X chromosome material (45 X, Turner's Syndrome) demonstrated relatively normal general IQ and verbal abilities, but impaired visual spatial ability (Garron, 1977; Robinson et al., 1979; Netley & Rovet, 1982). Conversely, subjects with additional X chromosomes (47 XXY, 47 XXX) demonstrated speech and language impairment. For example, individuals with Klinefelter's syndrome (47 XXY) were found both to be delayed in the onset of speech and language development (Puck et al., 1975) and to show an increased incidence of speech defects (Neilsen et al., 1981). However, neither of these reports defined speech and language development or deficit adequately or reported any objective measures supporting their conclusions. Graham et al. (1982) reported the first well-controlled study detailing the development of speech, language, reading and spelling abilities in XXY boys. This study compared the performance of a group of 14 XXY boys, initially ascertained during a neonatal screening procedure, with a matched control group. The XXY group showed normal nonverbal (performance) IQ, but significant reductions in verbal IQ, expressive language function, and reading and spelling abilities. Research on developmental language and learning disabilities, as well as in adults with acquired aphasia, had demonstrated that a deficit in auditory temporal processing might underlie the speech, language and reading (decoding) deficits of these patients (TaUal & Piercy 1974; 1975; Tallal & Newcombe, 1978; Tallal, 1980; Tallal et al., 1985a; 1985b; see TaUal, 1988, for review). Based on these results with language-impaired subjects, Graham et al. (1982) hypothesized that left hemisphere-based difficulties in auditory processing also may underlie the verbal deficits of Klinefelter's subjects. Further studies demonstrated significant deficits in both nonverbal and verbal auditory processing abilities for the XXY group. On nonverbal tasks the XXY group had more difficulty discriminating and sequencing nonverbal tone pulses at rapid rates of presentation. Of 11 XXY boys with difficulty sequencing nonverbal tones at rapid rates of presentation, two had a primary auditory rate discrimination problem, while the remaining nine appeared to have auditory memory problems or difficulty sequencing at rapid rates of presentation. The XXY group also had difficulty remembering and preserving the serial order of both speech and nonspeech auditoraUy presented material. These difficulties in auditory processing were significantly correlated with these boys' problems in oral language production and in reading and spelling proficiency. Thus, these findings helped pinpoint a potential basis of the language and learning disabilities demonstrated by children with Klinefelter's syndrome. They also suggested a striking similarity to the neuropsychological profile which characterizes children with language/learning disabilities. 47 XXX girls also have been shown to have receptive language problems (Pennington et al., 1980), as well as lower verbal IQ (Neilsen et al., 1981). However, unlike boys with Klinefelter's syndrome, who can demonstrate relatively normal nonverbal IQ in the presence of delayed language development and lowered verbal IQ, 47 XXX girls generally demonstrate deficient nonverbal as well as verbal abilities. Thus, it should be emphasized that it has been difficult to determine whether the language deficits that have been associated with additional X chromosomes in girls are specific, because they occur in the presence of a more general intellectual deficiency. In summary, the studies with aneuploid subjects suggest a profile of specific temporal processing and language disorder in individuals with an additional X chromosome. Furthermore, the detailed neuropsychological profile observed in individuals with Klinefelter's syndrome
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bears striking resemblance to that reported for children with developmental language/learning disabilities. Addressing the question of genetic and/or hormonal influences in language/learning disorders from the opposite perspective, children with developmental language disorders have been tested for sex chromosome abnormalities. Several investigators have reported an increased frequency of sex chromosome abnormalities in children with delayed language acquisition (Garvey & Mutton, 1973; Friedrich et al., 1982; Mutton & Lea, 1980). Although these reports are intriguing, no firm conclusions can be drawn from these data due to methodological inadequacies in defining and quantifying delayed language acquisition. Another approach to investigating a genetic and/or hormonal basis for language/learning disabilities focuses on the prevalence of boys compared to girls afflicted. One way of determining whether a sex-linked mode of genetic transmission might account for this high sex ratio is to evaluate family history data of children with specific developmental language disorders. Following this approach, we (Tallal et al., 1989a; 1989b) reported the results of a family history study of a large, well-defined cohort of 4-yr-old children with specific developmental language-impairment. The majority of the language-impaired subjects had both severe expressive and receptive language deficits, although some were more severely impaired receptively, while others had a more severe expressive language disorder. Over 60% had a speech articulation impairment as well. However, children with articulation deficits alone, without language disorders, were not included in the study. Over 75% of these children also evidenced severe reading and learning disabilities by 8 yr of age. Family history information was obtained through questionnaires completed by the biological mother and father of each subject. The questionnaire was composed of 35 detailed questions adapted from questionnaires used previously to investigate familial aggregation in other communication disorders. Given the difficulty in obtaining diagnostic histories of language disorders for parents in the study, and because of the relationship between language disorders and subsequent academic achievement, particularly reading and writing, parents were classified as "affected" if any of the following were reported: (1) a history of language problems; (2) a history of below average school achievement to the eighth grade in reading, writing or both; (3) a history of ever having been kept back a grade in elementary school. Siblings were diagnosed as "affected" if parents reported for them a positive history for difficulty in reading, writing, or language, or other learning disabilities. The results of the study demonstrated extremely interesting and in some cases unexpected sex-ratio differences in the languageimpaired children, as well as in their affected and nonaffected siblings. The 62 language-impaired probands consisted of 44 boys and 18 girls, for a 2.4:1 male:female ratio, consistent with previously reported increased boys:girls in this population. However, quite unexpectedly, we found that this higher male:female sex ratio was significantly influenced by familial aggregation for the disorder. Surprisingly, probands without an affected parent (and therefore putatively less genetic predisposition) failed to show the expected significant increase of boys to girls with language/learning disorders. However, probands with an affected parent had a significant 3:1 male:female sex ratio. When the affected parent was the father, the sex ratio was 1.8:1. However, when the affected parent was the mother, the sex ratio was 4:1. This ratio increased to 5:1 for probands with both parents affected. These data demonstrate that the increased incidents of boys to girls with language/leaming impairment, so well documented in the literature, occurred in this sample primarily in those language-impaired children with affected parents, and more so in those with affected mothers than affected fathers. Unexpected sex ratios were also found in the siblings of language-impaired probands. In
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the general population, there are roughly equal numbers of boys and girls born (Taylor & Ounsted, 1972). It, therefore, was completely unexpected to find that the language-impaired children had 65 brothers but only 35 sisters, a 1.9:1 ratio. Further analyses again pointed to parental affliction as the mode for this sex ratio difference. In terms of absolute numbers of offspring, affected fathers had only slightly more male than female offspring (not including probands: 23 and 17 respectively; 1.4:1 ratio). However, affected mothers had 2.5 times as many sons as daughters (25 boys and 10 girls). To better specify the contribution of the sex of the affected parent to offspring sex ratio, families with only one affected parent were analyzed separately. The proportion of male:female offspring was calculated for all families with only one affected parent. A significant difference was found between the proportion of male:female children born into families with affected mothers vs affected fathers.
Z
O ~
10:1 9:1
o
/
[] all offspring 1 (including proband) / affected offspring |
6:1 5:1
•
affected offspring | (incl and)
3:1
1:1
Neither
Mother Father (not Father) (not Mother)
Both
AFFECTED PARENT Sex ratio of offspring by n u m b e r and sex of affected parents.
The Figure shows the sex ratio of offspring aggregated by the number and sex of an affected parent (neither parent affected, affected mother but not father, affected father but not mother, and both parents affected). In families with an affected father and a nonaffected mother, the offspring sex ratio approached that expected in the normal population (1:1). However, when families with only an affected mother and a nonaffected father were examined a highly aberrant sex ratio was found: These mothers had a consistently higher number of male:female offspring. A sex ratio of 3.5:1 was found when all offspring, including probands were examined. The sex ratio increased to 5.3:1 for affected offspring, including probands, and when probands were excluded in calculations of affected offspring, to control for possible ascertainment bias, affected mothers had eight times as many male as female offspring. Because it is well known that more boys than girls are affected with language and learning disabilities, it was not unusual to find that, among the affected siblings, there was a 2.5:1 sex ratio. However, it was completely unexpected to find that, in absolute numbers, there were twice as many boys as girls born into the families of language-impaired children. Additional analyses revealed that this unexpected sex ratio in the siblings of language-impaired children occurred primarily in the families with an affected mother, as was the case for the probands themselves.
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Reorganizing the above data by sex of affected parent, we find that affected fathers have essentially the expected 1:1 offspring sex ratio, almost twice as many offspring nonaffected as affected, and a 1:1 sex ratio in absolute number of affected offspring (offspring ratios do not include probands). On the other hand, affected mothers have a 3:1 male:female offspring ratio, equal numbers of affected and nonaffected offspring, and an approximate 5:1 sex ratio in absolute numbers of affected offspring. This ratios rises to 8:1 when cases with only an affected mother are considered separately, but remains at 1:1 in cases where the father is the only affected parent. Thus, for those families with affected parents, male and female offspring were equally likely to be affected, but families with affected mothers had a disproportionate background frequency of male births, with these mothers being three times as likely to have male children. Half of these children were affected, giving rise to the observed preponderance of boys with language disabilities. A similar pattern was found to account for the sex ratio frequencies observed in the probands themselves. Both genetic and environmental factors have been posited for underlying sex ratio differences in language and learning-impaired children (Shaywitz et al., 1988). Whereas environmental factors might contribute to the increased incidence of affected offspring of affected mothers through mother/child interactions, they cannot explain the dramatic and consistent pattern of absolute background frequency of male:female sex ratio differences found in these families. For such explanations, factors affecting the secondary sex ratio in humans must be evaluated. Hormonal factors affecting sex ratio in humans
In studies investigating factors affecting the secondary sex ratio in humans, increased male births have been most often associated with maternal stress and abnormal levels of gonadal hormones, especially testosterone (James, 1986). James (1980a; 1980b; 1983) suggested that maternal gonadotrophin levels at the time of conception influence the sex of the human zygote, high levels of hormone being associated with the production of girls. Although there are several mechanisms which increase maternal gonadotrophin levels, resulting in an increase of female births, few mechanisms have been postulated to account for increases in male births: James (1986) cites the following studies which report increases in male births. Sas and Szollosi (1980) reported that men with low sperm counts who were given methotestosterone therapy sired 45 boys and 17 girls during treatment and up to 3 mo after. Furthermore, it has been noted that androgen levels of women correlate positively with their occupational level; professional, managerial and technical workers have higher levels than clerical workers or housewives (Purifoy & Hoopmans, 1979). Bemstein (1954) reported variations in sex ratio of offspring with the "masculinity" of the occupation of each parent ("masculinity" being defined as a proportion of men in that occupation). It is possible that these variations in sex ratio may have hormonal, perhaps androgenic, determinants. Finally, Kreuz et al. (1972) demonstrated that stress reduces testosterone levels in men and that men in stressful occupations have more male than female children. Although data in this area are scanty and somewhat circumstantial, they suggest a potential link between stress, androgen level and sex ratio in humans. This link also may play a role in helping fit together the pieces of the puzzle related to sex ratio, cerebral lateralization, and handedness differences in language and learning-impaired populations. The findings that gonadal hormones and prenatal stress have differential effects on the development of morphological cerebral lateralization and callosal size in male and female rats (Fleming et al., 1986; Diamond, 1991; Fitch et al., 1990) and that gonadal hormones also affect both neural lateraliza-
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tion and sex differences associated with vocal control in birds (Nottebohm, 1971; DeVoogd 1991) add further support to a potential link between gonadal hormones and cerebral lateralization. Future animal research may elucidate further the relationship of gonadal hormones and lateralization to sex ratios in offspring and thus lead to models for the study of developmental learning and language disabilities in humans. CONCLUSION Interest in the role hormones play in brain development and cognitive development in humans began with the observation that sexually dimorphic cognitive profiles characterize normal men and women, with women showing better verbal than visual spatial skills and men showing the opposite. In search of a biological explanation for these differences, studies of individuals with abnormal sex chromosome karyotypes were undertaken. The cognitive and personality profiles of these subjects were subsequently compared to the cognitive profiles obtained from chromosomally normal individuals who had been endogenously or exogenously exposed in utero to aberrant hormonal levels. These comparisons led to a parsimonious interpretation of the data, which directly implicated hormonal influences on the development of cerebrally lateralized cognitive functions. The finding of specific decrements in either visual spatial or verbal abilities in subjects with differential exposure to gonadal hormones or abnormal sensitivity to hormones in utero led to the development of hypotheses relating aberrant hormonal exposure to developmental language and learning disabilities. Striking similarities have been found in the neuropsychological profiles of individuals with known aberrant hormonal exposure and those of children with specific developmental language/learning disabilities. Taken together, the data on hormonal influences on sex ratio, abnormalities in cerebral morphology and brain lateralization, and abnormal cognitive profiles provide mounting evidence of a possible hormonal influence in developmental learning disabilities. Evidence taken from a broad spectrum of research approaches seem to be converging to suggest a potential hormonal basis for some developmental language/learning disorders. However, it is important to emphasize that, to date, these hypotheses are all based on circumstantial inferences pertaining to the linkage between hormones and learning disabilities, rather than on any direct test of these hypotheses in humans. By integrating data obtained from human and animal research, a synthesis should occur which eventually will lead to a better understanding of the role hormones play in brain development and cognition. Acknowledgements: I thank Holly Fitch for providing me with material and theoretical insights reflect(u1in this manuscript. This work was funded by NINCDS grant NS92332 and NINCDS Center Grant P50NS22343.
REFERENCES Bernstein ME (1954) Studies in the human sex ratio IV. Evidence of genetic variations in the primary sex ratio in man. JHered4$: 59-64. DeVoogd TJ (1991) Endocrine modulation of the development and adult function of the avian song system. Psychoneuroendocrinology 16: 41-66. Diamond MC (1991) Hormonal effects on the development of cerebral lateralization. Psychoneuroendocrinology 16: 121-129.
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Ehrhardt AA, Money J (1967) Progestin-induced hermaphroditism: I.Q. and psychosexual identity in a study of ten girls. JSexRes 3: 83-100. Fitch RH, Berrebi AS, Cowell PE, Schrott LM, Denenberg VH (1990) Corpus caUosum: effects of neonatal hormones on sexual dimorphism in the rat. Brain Res 515:111-116. Fleming DE, Anderson RH, Rhees RW, Kinghorn E, Bakahs J (1986) Effects of prenatal stress on sexually dimorphic asymmetries in the cerebral cortex of the male rat. Brain Res Bull 16: 395-398. Friedrich U, Dalby M, Staehelin-Jensen T, Bruun-Petersen G (1982) Chromosomal studies of children with developmental language retardation. Dev Med Child Neuro124: 645-562. Galaburda AM, Kemper TM (1979) Cytoarchitectonic abnormalities in developmental dyslexia: a case study. Ann Neurol 6" 94-100. Garron D (1977) Sex linked recessive inheritance of spatial and numerical abilities and Turner's syndrome. PsycholRev 77: 147-152. Garvey M, Mutton DE (1973) Sex chromosome aberrations and speech development. Arch Dis Child 48: 937-941. Geschwind N, Behan PO (1982) Left-handedness: association with immune disease, migraine and developmental learning disorders. Proc Natl Acad Sci USA 79: 5097-5100. Graham JM Jr, Bashir AS, Stark RE, Tallal P (1982) Auditory processing abilities in unselected XXY boys. Clin Res 30: l18A. Haslam RHA, Dalby JT, Johns RD, Rademaker AW (1981) Cerebral asymmetry in developmental dyslexia. Arch Neuro138" 679-682. Hier DB, LeMay M, Rosenberger PB, Perlo VP (1978) Developmental dyslexia. Arch Neuro135: 90-92. Hynd GW, Semrud-Clikeman M (1989) Dyslexia and brain morphology. Psychol Bull 3: 447-482. James WH (1980a) Time of fertilization and sex of infants. Lancet i: 1124-1126. James WH (1980b) Gonadotrophin and the human secondary sex ratio. Br Med J 281:711-712. James WH (1983a) Timing of fertilization and the sex ratio of offspring. In: Bennett NG (Ed) Sex Selection of Children. Academic Press, New York, pp 73-99. James WH (1986) Hormonal control of sex ratio. J Theoret Biol 118: 427-441. Jernigan T, Tallal P, Hesselink J (1987) Cerebral morphology on magnetic resonance imaging in developmental dysphasia. Soc Neurosci 13: 651. Kreuz LE, Rose RM, Jennings JR (1972) Suppression of plasma testosterone levels and psychological stress. Arch Gen Psychiat 26: 479-482. Money J, Lewis V (1966) IQ genetics and accelerated growth: adrenogenital syndrome. Bull Johns Hopkins Hosp 118: 365-373. Money J, Ehrhardt AA (1968) Prenatal hormone exposure: possible effects on behavior in man. In: Michael RP (Ed) Endocrinology andHuman Behaviour. Oxford University Press, London, pp 32-48. Mutton DE, Lea J (1980) Chromosome studies of children with specific speech and language delay. Dev Med Child Neuro122: 588-594. Nass R, Baker S (1991) Androgen effects on cognition: congenital adrenal hyperplasia. Psychoneuroendocrinology 16: 191-201. Netley C Robert J (1982) Verbal deficits in children with 47,XXY and 47,XXX karyotypes: a descriptive and experimental study. Brain Lang 17: 58-72. Nielsen J, Sorenson AM, Sorenson K (1981) Mental development of unselected children with sex-chromosome abnormalities. Hum Genet 59" 324-332. Nottebohm F (1971) Neural lateralization of vocal control in a passerine bird. I. Song. J Exp Zool 177: 229-262. Pennington B, Puck M, Robinson A (1980) Language and cognitive development on 47 XXX females followed since birth. Behav Genet 10: 31-41. Plante E, Swisher L, Vance R (1989) Anatomical correlates of normal and impaired language in a set of dizygotic twins. Brain Lang 37: 643-655. Puck M, Tennes K, Frankenburg W, Bryant K, Robinson A (1975) Early childhood development of four boys with 47 XXY karyotype. Clin Genet 7: 8-20. Purifoy FE, Koopmans LH (1979) Androstenedione, testosterone and free testosterone concentrations in women of various occupations. Soc Bio126: 179-188.
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Reinisch JM, Ziemba-Davis M, Sanders SA (1991) Hormonal contributions to sexually dimorphic behavioral development in humans. Psychoneuroendocrinology 16: 213-277. Robinson A, Lubs H, Nielsen J, Sorensen K (1979) Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects: Orig Art Set 15: 261-266. Rosenberger PB, Hier DB (1980) Cerebral asymmetry and verbal inteUectual deficits. Ann Neurol 8: 300-304. Rumsey JM, Dorwart R, Vermes M, Denckia MB, Kruesi MJP, Rapoport, JL (1986) Magnetic resonance imaging of brain anatomy in severe developmental dyslexia. Arch Neuro143: 1045-1046. Sas M, Szollosi J (1980) The sex ratio of children of fathers with spermatic disorders following hormone therapy. Orvosi Hetilap 121: 2807-2808. Shaywitz SE, Towle VA, Kessne DK, Shaywitz BA (1988) Prevalence of dyslexia in boys and girls in a epidcmiological sample: contrasts between children identified by research criteria and by the school system. Ann Neuro! 24: 313-314. Tallal P (1980) Auditory temporal perception, phonics, and reading disabilities in children. Brain Lang 9: 182-198. Tallal P (1988) Developmental language disorders. In: Kavanagh J, Truss T, Ross R, Curtiss S (Eds) Learning Disabilities: Proe Nail Conf. York Press, Tarkion MD, pp 181-272. Tallal P (1989) Unexpected sex-ratios in families of language/learning-impaired children. Neuropsychologia 27(7): 987-998. Tallal P, Newcombe F (1978) Impairment of auditory perception and language comprehension in dysphasia. Brain Lang 5: 13-24. TaUal P, Piercy M (1974) Developmental aphasia: rate of auditory processing and selective impairment of consonant perception. Neuropsychologia 12: 83-93. Tallal P, Piercy M (1975) Developmental aphasia: perception of brief vowels and extended stop consonants. Neuropsyehologia 13: 69-74. Tallal P, Stark RE, Mellits D (1985a) The relationship between auditory temporal analysis and receptive language development: evidence from studies of developmental language disorder. Neuropsyehologia 23: 527-534. Tallal P, Stark RE, Mellits ED (1985b) Identification of language-impaired children on the basis of rapid perception and production skills. Brain Lang 25: 314-322. Tallal P, Ross R, Curtiss S (1989) Familial aggregation in specific language impairment. J Speech Hear Disord 54: 167-173. Taylor DC, Ounsted C (1972) The nature of gender differences explored through ontogenetic analysis of sex ratio in disease. In: Ounsted C, Taylor DC (Eds) Genetic Differences: Their Ontogeny and Significance. Churchill Livingstone.
0306- 4530/91 $3.00 + 0.00 ©1991 Pergamon Pte~ pie
Printed in Great Britain
HORMONAL INFLUENCES IN DEVELOPMENTAL LEARNING DISABILITIES PAULA TALLAL Rutgers University, Center for Molecular and Behavioral Neuroscience Newark, New Jersey, U.S.A. (Received infinalform 19 September 1990)
SUMMARY Developmental language and learning disabilities in children can take many different forms and can result from a variety of causes. Research to date has focused primarily on specific disabilities in learning, which are characterized by a significant delay or disorder in one aspect of learning against a background of otherwise normal development. Learning disabilities affecting language and/or reading acquisition (developmental dysphasia and dyslexia) have been studied most thoroughly. Verbal learning disabilities occur more frequently in boys than in girls, and there is a higher than expected incidence of left-handedness among affected children. Although there are many reasons why a child may have delayed or disordered language development, differential diagnosis of specific developmental language or reading disorders calls for ruling out mental retardation, peripheral auditory or visual dysfunction, autism, frank neurological impairments such as hemiplegia or seizure disorder, and severe social deprivation or lack of educational opportunity. The typical profile of a developmentally dysphasic or dyslexic child is one who shows a marked discrepancy between nonverbal (performance) IQ and verbal IQ, with a history of delayed or disordered speech, language and/or reading development. Such a child usually performs quite normally on visual spatial tasks, while demonstrating severe deficits in tasks of auditory temporal processing, motor sequencing, phonological processing and memory, language, reading and spelling. This characteristic neuropsychological profile may suggest left hemisphere dysfunction or a failure to develop normal cerebral lateralization. The etiology of these developmental learning disorders is unknown, but there is evidence of familial aggregation, indicating a potential genetic basis. Although these children respond to remediation, longitudinal studies have shown that the symptoms often persist into adulthood (see Tallal, 1988, for a more detailed discussion). HORMONAL INFLUENCES IN THE DEVELOPMENT OF CEREBRAL ASYMMETRY There has been a growing interest in potential hormonal effects in developmental language and learning disabilities in children. Interest was spurred when Geschwind and Behan (1982) initially proposed that developmental learning disorders may be linked to both left-handedness and immune disorders through the action of testosterone on brain development. These investigators proposed that abnormal testosterone levels, or unusual sensitivity to testosterone during fetal life, can alter brain anatomy, such that left hemisphere development is delayed and normal Address correspondence and reprint requests to: Dr. Paula Tallal, Rutgers University, Center for Molecular and Behavioral Neuroscience, 197 University Avenue, Newark NJ 07102, USA. 203
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E TALLAL
cerebral asymmetry fails to develop. In support of this hypothesis, Galaburda and Kemper (1979) reported finding neuronal migration abnormalities, as well as a lack of the expected cerebral asymmetry (left larger than fight) in the area presumed to subserve speech, from postmortem morphological eyaluations of the brains of dyslexic individuals. With the advent of noninvasive, in vivo brain imaging methods, a few studies of developmental reading disability (dyslexia) and developmental language disorder (dysphasia) have been reported (Hier et al., 1978; Rosenberger & Hier, 1980; Haslam, 1981; Rumsey et al., 1986; Jemigan et al., 1987; Plante et al., 1989; see Hynd, 1989, for review). These imaging studies support neuropathological findings of reduced or reversed hemispheric asymmetry, especially in posterior temporal cerebral areas. Of these new imaging techniques, magnetic resonance imaging (MRI) offers the most sensitive, noninvasive method for assessing brain morphology during life, thus providing a unique opportunity for examining brain structure in children with specific developmental language and learning disabilities. Normally, the left hemisphere is larger than the right. Using MRI, Jemigan et al. (1985) demonstrated a significant increase in aberrant asymmetry (right equal to or larger than the left) of post-sylvian cerebrum in developmental dysphasics, compared to matched controls. Plante et al. (1989) also reported asymmetrical left-right perisylvian configuration in a young, language-impaired boy. MRI results were also presented for this boy's dizygotic twin sister who, although not language-impaired, also exhibited abnormality in hemispheric perisylvian configuration, with the fight hemisphere larger than the left, the reverse of the pattern usually seen in normally developing children. The consistent finding of abnormalities of cerebral asymmetry in the brains of languageand learning-impaired children has led to a search for potential models which might exert an influence on the development of cerebral lateralization. The results of animal research showing that gonadal hormones may play a specific role in the development of cerebral lateralization, as well as exert an influence on sexually dimorphic cognitive behaviors, has led to a growing interest in potential hormonal influences on developmental language and learning disabilities in children. Studies investigating the role of hormones in brain development and cognition in humans are constrained by major limitations in methodology. Controlled experimental studies which manipulate specific hormones and evaluate the effects on specific aspects of brain and behavioral development, which are the hallmark of animal research, obviously are not possible in studies with human subjects. What is available are studies which carefully evaluate the cognitive profiles of individuals exposed either exogenously or endogenously to aberrant levels of gonadal hormones. These include children born with sex chromosome anomalies or genetic inborn errors of metabolism which effect the endocrine system, as well as children exposed prenatally to exogenously induced excesses of estrogen or testosterone (Reinisch et al., 1991; Nass & Baker, 1991). Historically, observations of personality as well as intellectual profile differences between normal boys and girls raised questions pertaining to the origins of sexually dimorphic behaviors. Early conflicts arose between theorists who proposed either an environmental or a genetic basis for these normal differences. Such conflicts led to an interest in studying personality and intellectual profiles in individuals with known genetic abnormalities, to determine whether there was a genetic basis to sexually dimorphic behaviors. The pioneering work of Money and colleagues (Money & Lewis, 1966; Ehrhardt & Money, 1967; Money & Ehrhardt, 1968) stimulated an explosion of interest in studying the personality and cognitive profiles of individuals with abnormal sex chromosome compliment. Interest
HORMONALINFLUENCESIN DEVELOPMENTALLEARNINGDISABILITIES
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focussed on aneuploid individuals, who are characterized by additions or deletions of sex chromosomes (45 X, 47 XXY, 47 XYY and 47 XXX). Results of early research with these subjects suggested an important role of the X chromosome in determining neuropsychological profiles. Females lacking X chromosome material (45 X, Turner's Syndrome) demonstrated relatively normal general IQ and verbal abilities, but impaired visual spatial ability (Garron, 1977; Robinson et al., 1979; Netley & Rovet, 1982). Conversely, subjects with additional X chromosomes (47 XXY, 47 XXX) demonstrated speech and language impairment. For example, individuals with Klinefelter's syndrome (47 XXY) were found both to be delayed in the onset of speech and language development (Puck et al., 1975) and to show an increased incidence of speech defects (Neilsen et al., 1981). However, neither of these reports defined speech and language development or deficit adequately or reported any objective measures supporting their conclusions. Graham et al. (1982) reported the first well-controlled study detailing the development of speech, language, reading and spelling abilities in XXY boys. This study compared the performance of a group of 14 XXY boys, initially ascertained during a neonatal screening procedure, with a matched control group. The XXY group showed normal nonverbal (performance) IQ, but significant reductions in verbal IQ, expressive language function, and reading and spelling abilities. Research on developmental language and learning disabilities, as well as in adults with acquired aphasia, had demonstrated that a deficit in auditory temporal processing might underlie the speech, language and reading (decoding) deficits of these patients (TaUal & Piercy 1974; 1975; Tallal & Newcombe, 1978; Tallal, 1980; Tallal et al., 1985a; 1985b; see TaUal, 1988, for review). Based on these results with language-impaired subjects, Graham et al. (1982) hypothesized that left hemisphere-based difficulties in auditory processing also may underlie the verbal deficits of Klinefelter's subjects. Further studies demonstrated significant deficits in both nonverbal and verbal auditory processing abilities for the XXY group. On nonverbal tasks the XXY group had more difficulty discriminating and sequencing nonverbal tone pulses at rapid rates of presentation. Of 11 XXY boys with difficulty sequencing nonverbal tones at rapid rates of presentation, two had a primary auditory rate discrimination problem, while the remaining nine appeared to have auditory memory problems or difficulty sequencing at rapid rates of presentation. The XXY group also had difficulty remembering and preserving the serial order of both speech and nonspeech auditoraUy presented material. These difficulties in auditory processing were significantly correlated with these boys' problems in oral language production and in reading and spelling proficiency. Thus, these findings helped pinpoint a potential basis of the language and learning disabilities demonstrated by children with Klinefelter's syndrome. They also suggested a striking similarity to the neuropsychological profile which characterizes children with language/learning disabilities. 47 XXX girls also have been shown to have receptive language problems (Pennington et al., 1980), as well as lower verbal IQ (Neilsen et al., 1981). However, unlike boys with Klinefelter's syndrome, who can demonstrate relatively normal nonverbal IQ in the presence of delayed language development and lowered verbal IQ, 47 XXX girls generally demonstrate deficient nonverbal as well as verbal abilities. Thus, it should be emphasized that it has been difficult to determine whether the language deficits that have been associated with additional X chromosomes in girls are specific, because they occur in the presence of a more general intellectual deficiency. In summary, the studies with aneuploid subjects suggest a profile of specific temporal processing and language disorder in individuals with an additional X chromosome. Furthermore, the detailed neuropsychological profile observed in individuals with Klinefelter's syndrome
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bears striking resemblance to that reported for children with developmental language/learning disabilities. Addressing the question of genetic and/or hormonal influences in language/learning disorders from the opposite perspective, children with developmental language disorders have been tested for sex chromosome abnormalities. Several investigators have reported an increased frequency of sex chromosome abnormalities in children with delayed language acquisition (Garvey & Mutton, 1973; Friedrich et al., 1982; Mutton & Lea, 1980). Although these reports are intriguing, no firm conclusions can be drawn from these data due to methodological inadequacies in defining and quantifying delayed language acquisition. Another approach to investigating a genetic and/or hormonal basis for language/learning disabilities focuses on the prevalence of boys compared to girls afflicted. One way of determining whether a sex-linked mode of genetic transmission might account for this high sex ratio is to evaluate family history data of children with specific developmental language disorders. Following this approach, we (Tallal et al., 1989a; 1989b) reported the results of a family history study of a large, well-defined cohort of 4-yr-old children with specific developmental language-impairment. The majority of the language-impaired subjects had both severe expressive and receptive language deficits, although some were more severely impaired receptively, while others had a more severe expressive language disorder. Over 60% had a speech articulation impairment as well. However, children with articulation deficits alone, without language disorders, were not included in the study. Over 75% of these children also evidenced severe reading and learning disabilities by 8 yr of age. Family history information was obtained through questionnaires completed by the biological mother and father of each subject. The questionnaire was composed of 35 detailed questions adapted from questionnaires used previously to investigate familial aggregation in other communication disorders. Given the difficulty in obtaining diagnostic histories of language disorders for parents in the study, and because of the relationship between language disorders and subsequent academic achievement, particularly reading and writing, parents were classified as "affected" if any of the following were reported: (1) a history of language problems; (2) a history of below average school achievement to the eighth grade in reading, writing or both; (3) a history of ever having been kept back a grade in elementary school. Siblings were diagnosed as "affected" if parents reported for them a positive history for difficulty in reading, writing, or language, or other learning disabilities. The results of the study demonstrated extremely interesting and in some cases unexpected sex-ratio differences in the languageimpaired children, as well as in their affected and nonaffected siblings. The 62 language-impaired probands consisted of 44 boys and 18 girls, for a 2.4:1 male:female ratio, consistent with previously reported increased boys:girls in this population. However, quite unexpectedly, we found that this higher male:female sex ratio was significantly influenced by familial aggregation for the disorder. Surprisingly, probands without an affected parent (and therefore putatively less genetic predisposition) failed to show the expected significant increase of boys to girls with language/learning disorders. However, probands with an affected parent had a significant 3:1 male:female sex ratio. When the affected parent was the father, the sex ratio was 1.8:1. However, when the affected parent was the mother, the sex ratio was 4:1. This ratio increased to 5:1 for probands with both parents affected. These data demonstrate that the increased incidents of boys to girls with language/leaming impairment, so well documented in the literature, occurred in this sample primarily in those language-impaired children with affected parents, and more so in those with affected mothers than affected fathers. Unexpected sex ratios were also found in the siblings of language-impaired probands. In
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the general population, there are roughly equal numbers of boys and girls born (Taylor & Ounsted, 1972). It, therefore, was completely unexpected to find that the language-impaired children had 65 brothers but only 35 sisters, a 1.9:1 ratio. Further analyses again pointed to parental affliction as the mode for this sex ratio difference. In terms of absolute numbers of offspring, affected fathers had only slightly more male than female offspring (not including probands: 23 and 17 respectively; 1.4:1 ratio). However, affected mothers had 2.5 times as many sons as daughters (25 boys and 10 girls). To better specify the contribution of the sex of the affected parent to offspring sex ratio, families with only one affected parent were analyzed separately. The proportion of male:female offspring was calculated for all families with only one affected parent. A significant difference was found between the proportion of male:female children born into families with affected mothers vs affected fathers.
Z
O ~
10:1 9:1
o
/
[] all offspring 1 (including proband) / affected offspring |
6:1 5:1
•
affected offspring | (incl and)
3:1
1:1
Neither
Mother Father (not Father) (not Mother)
Both
AFFECTED PARENT Sex ratio of offspring by n u m b e r and sex of affected parents.
The Figure shows the sex ratio of offspring aggregated by the number and sex of an affected parent (neither parent affected, affected mother but not father, affected father but not mother, and both parents affected). In families with an affected father and a nonaffected mother, the offspring sex ratio approached that expected in the normal population (1:1). However, when families with only an affected mother and a nonaffected father were examined a highly aberrant sex ratio was found: These mothers had a consistently higher number of male:female offspring. A sex ratio of 3.5:1 was found when all offspring, including probands were examined. The sex ratio increased to 5.3:1 for affected offspring, including probands, and when probands were excluded in calculations of affected offspring, to control for possible ascertainment bias, affected mothers had eight times as many male as female offspring. Because it is well known that more boys than girls are affected with language and learning disabilities, it was not unusual to find that, among the affected siblings, there was a 2.5:1 sex ratio. However, it was completely unexpected to find that, in absolute numbers, there were twice as many boys as girls born into the families of language-impaired children. Additional analyses revealed that this unexpected sex ratio in the siblings of language-impaired children occurred primarily in the families with an affected mother, as was the case for the probands themselves.
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Reorganizing the above data by sex of affected parent, we find that affected fathers have essentially the expected 1:1 offspring sex ratio, almost twice as many offspring nonaffected as affected, and a 1:1 sex ratio in absolute number of affected offspring (offspring ratios do not include probands). On the other hand, affected mothers have a 3:1 male:female offspring ratio, equal numbers of affected and nonaffected offspring, and an approximate 5:1 sex ratio in absolute numbers of affected offspring. This ratios rises to 8:1 when cases with only an affected mother are considered separately, but remains at 1:1 in cases where the father is the only affected parent. Thus, for those families with affected parents, male and female offspring were equally likely to be affected, but families with affected mothers had a disproportionate background frequency of male births, with these mothers being three times as likely to have male children. Half of these children were affected, giving rise to the observed preponderance of boys with language disabilities. A similar pattern was found to account for the sex ratio frequencies observed in the probands themselves. Both genetic and environmental factors have been posited for underlying sex ratio differences in language and learning-impaired children (Shaywitz et al., 1988). Whereas environmental factors might contribute to the increased incidence of affected offspring of affected mothers through mother/child interactions, they cannot explain the dramatic and consistent pattern of absolute background frequency of male:female sex ratio differences found in these families. For such explanations, factors affecting the secondary sex ratio in humans must be evaluated. Hormonal factors affecting sex ratio in humans
In studies investigating factors affecting the secondary sex ratio in humans, increased male births have been most often associated with maternal stress and abnormal levels of gonadal hormones, especially testosterone (James, 1986). James (1980a; 1980b; 1983) suggested that maternal gonadotrophin levels at the time of conception influence the sex of the human zygote, high levels of hormone being associated with the production of girls. Although there are several mechanisms which increase maternal gonadotrophin levels, resulting in an increase of female births, few mechanisms have been postulated to account for increases in male births: James (1986) cites the following studies which report increases in male births. Sas and Szollosi (1980) reported that men with low sperm counts who were given methotestosterone therapy sired 45 boys and 17 girls during treatment and up to 3 mo after. Furthermore, it has been noted that androgen levels of women correlate positively with their occupational level; professional, managerial and technical workers have higher levels than clerical workers or housewives (Purifoy & Hoopmans, 1979). Bemstein (1954) reported variations in sex ratio of offspring with the "masculinity" of the occupation of each parent ("masculinity" being defined as a proportion of men in that occupation). It is possible that these variations in sex ratio may have hormonal, perhaps androgenic, determinants. Finally, Kreuz et al. (1972) demonstrated that stress reduces testosterone levels in men and that men in stressful occupations have more male than female children. Although data in this area are scanty and somewhat circumstantial, they suggest a potential link between stress, androgen level and sex ratio in humans. This link also may play a role in helping fit together the pieces of the puzzle related to sex ratio, cerebral lateralization, and handedness differences in language and learning-impaired populations. The findings that gonadal hormones and prenatal stress have differential effects on the development of morphological cerebral lateralization and callosal size in male and female rats (Fleming et al., 1986; Diamond, 1991; Fitch et al., 1990) and that gonadal hormones also affect both neural lateraliza-
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tion and sex differences associated with vocal control in birds (Nottebohm, 1971; DeVoogd 1991) add further support to a potential link between gonadal hormones and cerebral lateralization. Future animal research may elucidate further the relationship of gonadal hormones and lateralization to sex ratios in offspring and thus lead to models for the study of developmental learning and language disabilities in humans. CONCLUSION Interest in the role hormones play in brain development and cognitive development in humans began with the observation that sexually dimorphic cognitive profiles characterize normal men and women, with women showing better verbal than visual spatial skills and men showing the opposite. In search of a biological explanation for these differences, studies of individuals with abnormal sex chromosome karyotypes were undertaken. The cognitive and personality profiles of these subjects were subsequently compared to the cognitive profiles obtained from chromosomally normal individuals who had been endogenously or exogenously exposed in utero to aberrant hormonal levels. These comparisons led to a parsimonious interpretation of the data, which directly implicated hormonal influences on the development of cerebrally lateralized cognitive functions. The finding of specific decrements in either visual spatial or verbal abilities in subjects with differential exposure to gonadal hormones or abnormal sensitivity to hormones in utero led to the development of hypotheses relating aberrant hormonal exposure to developmental language and learning disabilities. Striking similarities have been found in the neuropsychological profiles of individuals with known aberrant hormonal exposure and those of children with specific developmental language/learning disabilities. Taken together, the data on hormonal influences on sex ratio, abnormalities in cerebral morphology and brain lateralization, and abnormal cognitive profiles provide mounting evidence of a possible hormonal influence in developmental learning disabilities. Evidence taken from a broad spectrum of research approaches seem to be converging to suggest a potential hormonal basis for some developmental language/learning disorders. However, it is important to emphasize that, to date, these hypotheses are all based on circumstantial inferences pertaining to the linkage between hormones and learning disabilities, rather than on any direct test of these hypotheses in humans. By integrating data obtained from human and animal research, a synthesis should occur which eventually will lead to a better understanding of the role hormones play in brain development and cognition. Acknowledgements: I thank Holly Fitch for providing me with material and theoretical insights reflect(u1in this manuscript. This work was funded by NINCDS grant NS92332 and NINCDS Center Grant P50NS22343.
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