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Normal Intelligence with Severe Insulin-Like Growth Factor I Deficiency due to Growth Hormone Receptor Deficiency: A Controlled Study in a Genetically Homogeneous Population¹

Department of Foundations of Education, University of Florida College of Education (J.H.K.), Gainesville, Florida 32611-7047; the Department of Pediatrics, University of Florida College of Medicine (A.L.R.), Gainesville, Florida 32610-0296; and the Institute of Endocrinology, Metabolism, and Reproduction, Quito (V.M., J.G.-A.), Ecuador

Address all correspondence and requests for reprints to: John H. Kranzler, Ph.D., P.O. Box 117047, University of Florida, Gainesville, Florida 32611-7047. E-mail: jkranzler{at}coe.ufl.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References

 
Superior school performance was reported for 52 Ecuadorian probands with severe deficiency of insulin-like growth factor I (IGF-I) due to GH receptor deficiency (GHRD) resulting from homozygosity for the E180 splice mutation of the GHR. In contrast, subnormal intelligence was reported in a study of 18 genetically heterogeneous Israeli patients, attributed to frequent hypoglycemia or IGF-I dependence of brain development. This study is the first controlled evaluation of the intellectual ability of patients with GHRD. We compared the intelligence of 18 patients of school age (mean ± SD age, 11.5 ± 2.8 yr), 42 of their relatives (11.5 ± 2.8 yr), and 28 community controls (10.0 ± 0.8 yr), using a battery of intelligence tests that have been validated in cross-cultural research, designed to minimize the effects of physical size, motor coordination, and cultural background. Because all patients had the same GHR mutation, for which the carrier state could be determined, this study also investigated whether heterozygosity for mutation of the GHR among unaffected relatives is associated with intelligence. The intellectual ability of the patients with GHRD was not significantly different from that of their relatives (P > 0.05) on the psychometric tests of intelligence and was comparable to that of the community controls on the chronometric tests. Homozygosity or heterozygosity for the mutation in the GHR gene common to Ecuadorian patients was unrelated to intelligence (P > 0.05). These results indicate that the gene defect causing GHRD is not related to intelligence in the Ecuadorian population. They also indicate that GH-induced IGF-I production is not required for normal brain growth in utero or for postnatal intellectual development.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References

 
GH RECEPTOR deficiency (GHRD) resulting from mutation of the GH receptor (GHR) causes GH resistance, with severe deficiency of the GH-dependent growth-activating hormone, insulin-like growth factor I (IGF-I) (1). The original patients reported with this condition, from Israel, were described as having serious intellectual disabilities in early reports (2) and in more recent studies (3). This suggested a role for GH-dependent IGF-I in brain development. A critical role for IGF-I in brain development has also been suggested by the recent report of an intellectually disabled patient with a mutation of the IGF-I gene that precludes synthesis of functional IGF-I (4). Alternatively, the high frequency of fasting hypoglycemia in infancy and childhood with GHRD might be considered a cause of intellectual deficits in patients with GHRD, as proposed by the Israeli investigators (2).

In the studies in Israel the performance of patients with GHRD was not compared with that of siblings or of community controls. Moreover, reports of patients with GHRD from outside Israel, although sporadic and mainly anecdotal, have failed to substantiate intellectual impairment as a consistent clinical feature (5). In the largest cohort of subjects with proven GHRD, nearly 70 patients in Ecuador, comprising approximately one third of the reported patients, exceptional school performance was typical (6). This was despite common hypoglycemia and psychosocial problems related to severe growth impairment. These observations suggested that Ecuadorian patients with GHRD might be more intelligent than their peers due to associated genetic factors, unknown physiological effects of their IGF-I deficiency, or social circumstances.

The present study was designed as an objective evaluation of the intellectual capability of Ecuadorian patients with GHRD. Because of the unavailability of intelligence (IQ) tests with substantiated validity in Ecuador (7), we used a battery of tests that have been applied extensively in cross-cultural research on intelligence to compare the intelligence of patients with GHRD to their relatives and to community controls (8, 9, 10, 11). This battery of tests also minimized the effects of differences in physical size and motor coordination on test performance. The principal hypothesis tested was that GHRD in this population was associated with superior intelligence. In addition, the genetic homogeneity for the defect in the GHR responsible for IGF-I deficiency in this population permitted comparisons between heterozygous (carrier) and homozygous normal relatives. Thus, we were also able to test the secondary hypothesis that heterozygosity for mutation of the GHR in this population was associated with enhanced intelligence.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References

 
Subjects

To avoid the effects of age and illness among older patients, we confined our basic analyses to children who were attending school, including 18 patients with GHRD (12 males and 6 females), 42 of their relatives (20 males and 22 females, including 15 siblings), and 28 community controls (14 males and 14 females). In addition, not only were community controls only available for schoolgoing patients, but analysis of a larger group of patients (n = 35) and close relatives (n = 94) that included adults gave similar results (our unpublished observations). All identified schoolgoing patients with GHRD in Ecuador participated in this study. Community controls were volunteers in the general education classes attended by patients with GHRD. The mean age of the patients with GHRD was 11.5 ± 2.7 (±SD) yr (range, 6–16), that for their siblings was 11.5 ± 2.8 yr (range, 6–17), and that for the community controls was 10.0 ± 0.8 yr (range, 9–12 yr). All patients were proven to be homozygous for the E180 splice mutation of the GHR gene responsible for GHRD in this population by restriction analysis of a PCR product from exon 6 by the enzyme MnlI (12). This method was also used to identify 9 heterozygous (carrier) and 12 homozygous normal relatives. Approval for this study was obtained from the University of Florida Health Science Center institutional review board and from the ethical committee of the Institute of Endocrinology, Metabolism, and Reproduction in Quito, Ecuador. Written informed consent was obtained from the parents and all participants.

Methods

Subjects were administered a battery of nonverbal psychometric and chronometric tests of intelligence. The two psychometric tests used were the Matrix Analogies Test-Expanded Form (MAT-EF) (9) and Raven’s Standard Progressive Matrices (SPM) (10). These tests were administered individually using the standard instructions and under nonspeeded conditions. The chronometric tests consisted of four brief tests of the speed and efficiency of elementary cognitive processing. For each of these tasks, subjects were instructed to perform as fast as possible on each trial without making errors. They were also given as many practice trials as needed to understand the tasks before testing began. The entire battery of psychometric and chronometric tests was administered in one test session lasting approximately 1–1 1/2 h.

Psychometric tests. The MAT-EF has 64 items and the SPM has 60 items. All items on both tests involve the presentation of nonpictorial figural material in a matrix format (e.g. 3 x 3) as a basis for relation education (10). The figures consist of geometric designs, shapes, and symbols that are universally recognizable (11). Each matrix has several response alternatives, but only one that successfully completes the pattern. Subjects responded by either pointing to or saying the number corresponding to their answer to each item. Both tests have demonstrated reliability and validity and have been used extensively in cross-cultural research on intelligence (7, 9, 10, 11).

Elementary cognitive tasks (ECTs). Individual differences in the speed and efficiency of elementary cognitive processing are measured on ECTs, which minimize the role of task-relevant knowledge and strategies in task performance and maximize the measurement of information processes (e.g. encoding, short term memory scanning, and retrieval of information from long term memory) (13, 14, 15, 16, 17, 18, 19, 20). The battery of ECTs used in this study, for example, did not involve the presentation of symbolic stimuli (viz. digits, letters, or words). ECTs thus overcome, or at least minimize, many of the shortcomings associated with the use of traditional psychometric tests in the cross-cultural assessment of intelligence (12). Subjects were administered the following ECTs: simple reaction time (SRT; one choice), choice reaction time (CRT; eight choices), the odd-man-out paradigm (OMO), and inspection time (IT). Subjects were administered 20 SRT trials, 32 CRT trials, and 36 OMO trials. The exact number of trials to administer IT varies (according to resolution of IT), but typically requires fewer than 100 trials. Detailed descriptions of the ECTs used in this study are provided in the Appendix.

Data analysis

The simple unit-weighted sum of the raw scores on the MAT-EF and SPM (after transformation to z-scores) was calculated to provide one estimate of psychometric intelligence, which we called IQ, due to the high correlation observed between the MAT-EF and the SPM. Four experimental variables were measured for each ECT, except IT. Reaction time (RT) and movement time (MT) were measured as the median of each subject’s RT and MT trials, whereas RT and MT intraindividual variability were measured as the SD of each subject’s RT and MT trials. Only the results for RT are presented here, because the MT parameters, as measures of peripheral sources of variance, are of little theoretical importance (12). For IT, only the resolved IT in phase 3 was used. Pearson product-moment correlations (r) and multiple regression were used to examine relationships between the chronometric and psychometric tests of intelligence.

To minimize the possibility of committing a type I error while examining the principal hypothesis of this study, a one-way multivariate analysis of covariance (MANCOVA) was initially conducted with group (i.e. patients with GHRD vs. relatives vs. community controls) as the group factor and age (in months) as the covariate. Age was used as the covariate to control for a significant difference between groups in age (P < 0.05). Univariate analyses of covariance (ANCOVAs) were then conducted for each of the dependent variables with age (in months) as the covariate. Post-hoc comparisons of pairs of adjusted means were conducted following a significant ANCOVA main effect. To examine the secondary hypothesis of this study, the Dunn method of planned pairwise comparisons (with a familywise type I error P of 0.05) was used to examine mean differences after adjusting for age (in months) between the unaffected relatives heterozygous for the defective gene for GHRD and the unaffected relatives homozygous for the normal GHR.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References

 
The mean raw score for the total sample (n = 88) was 28.6 ± 15.1 on the MAT-EF and 28.4 ± 12.6 on the SPM. The r of 0.86 (P < 0.001) between the raw scores on the MAT-EF and the SPM, which is almost as high as the reliabilities of the respective instruments permit, indicates that individual differences on these two tests largely reflect the same source of variance. Given such considerable overlap, the simple unit-weighted sum of the raw scores on the MAT-EF and the SPM (after transformation to z-scores) was calculated to provide one estimate of psychometric intelligence (IQ).

Descriptive statistics for the ECTs for the total sample are shown in Table 1. The pattern of results for the RT and RTSD parameters of the ECTs are comparable to those obtained in nonclinical settings from children of similar age in the United States (17, 18, 20, 21). Also presented in this table are correlations between the ECT parameters and IQ. Prior research indicates that the true (uncorrected) correlation between the single ECT parameters used in this study and measures of intelligence varies from approximately -0.30 to -0.50 (12, 16). These correlations are negative because higher intelligence is related to lower and less variable reaction times (i.e. faster and more efficient cognitive processing). To estimate the maximum correlation between the chronometric and psychometric measures of intelligence used in this study, the RT and RTSD parameters of the ECTs were entered in a simultaneous multiple regression analysis to predict IQ. Results indicated that the overall multiple correlation (r) is 0.53 (r² = 0.28). The findings reported in Table 1 are comparable to those with subjects of similar age in the United States, Great Britain, Australia, and elsewhere (12, 15, 16, 17, 18, 21, 22). Taken as a whole, these results support the validity of the battery of psychometric and chronometric tests of intelligence used in this study in Ecuador.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References

The only previous psychometric testing to examine the potential relationship between IGF-I deficiency and intellectual functioning in a group of patients with GHRD have been uncontrolled studies from Israel (2, 3). Frankel and Laron (2) reported greater intellectual impairment in patients with GHRD than in those with GH deficiency on the Wechsler Intelligence Scale for Children (24). Only 3 of 18 children and adolescents with GHRD (mean age, 13.3 ± 5.2 yr; range, 7–19) obtained IQs within the average range of functioning (IQ = 90–110). Of the remaining 15 patients, 3 scored in the low average range (IQ = 80–89), 3 scored in the borderline range (IQ = 70–79), and 9 scored in the intellectually disabled range (IQ < 70). Visual-motor functioning among these patients was deficient, and none excelled in school according to teacher report. In a follow-up study 25 yr later, Galatzer et al. (3) reexamined 8 of the original 18 patients and tested 4 new patients with GHRD (mean age, 28.9 ± 8.6 yr; range, 12–43). Five patients with mental disabilities who participated in the original study were excluded. Mean verbal and performance IQs were 86.6 and 91.9 on Wechsler tests for these 12 patients. They had no evidence of visual-motor integration difficulties, but results suggested that patients with GHRD may have deficient short term memory and attention. Based on these results, Galatzer et al. (3) hypothesized that early and prolonged IGF-I deficiency may impair normal development of the central nervous system or may be related to serious and long standing hypoglycemia, resulting in the lowered intellectual functioning of individuals with GHRD.

Neither of these studies, however, compared the performance of patients with GHRD to that of siblings or community controls. Moreover, reports of patients with GHRD from outside Israel, although sporadic and mainly anecdotal, suggest a normal range of intelligence in GHRD, with retardation being unusual (23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36). For example, intellectual development was reported to be normal by history in 24 of 26 children enrolled in a European IGF-I treatment study (5). Najjar et al. (25) described Lebanese siblings with IQs of 95 and 105. Patients from Denmark (26), Italy (27), The Netherlands (28), and Russia (29) were believed to be normal intellectually. Patients from Saudi Arabia (30), Mexico (31), and Africa (32) were described as excellent students. Affected brothers from Brazil had mental ages of 10 and 5 yr at 13 and 8 yr, respectively (33). Italian siblings from France included an intellectually normal adult and a delayed child who had severe recurrent hypoglycemic seizures (34). The other family reported by Pierson et al. (34) included a 6-yr-old girl with normal development, a 5-yr-old boy with a tested IQ of 100, and a 4-yr-old with a mental age of 3 yr. In the largest cohort of patients with GHRD, from Ecuador, Guevara-Aguirre and Rosenbloom (23) reported that exceptional school performance was typical. Among the 51 affected individuals of school age or older who had attended school, 44 were in the top 3 places in classes of 15–50 students, and most were considered by family members to be as bright or brighter than the smartest of their unaffected siblings. This was despite a high frequency of overt hypoglycemic symptoms and social adaptation problems (e.g. frequent social ostracization and teasing because of small stature), although data on social adaptation problems were not systematically assessed. Given the comparable rates and severity of hypoglycemia in the Israeli (2, 3), European (5), and Ecuadorian (23) populations, a metabolic explanation for the intellectual impairment of the Israeli patients appeared untenable.

Woods et al. (35, 36) recently reported an increased frequency of mental subnormality (13.5%) in a group of 82 children with GH insensitivity from Europe, Australia, the Indian subcontinent, and Africa. Only 27 of these children were found to have mutations of the GHR, and many of the others did not have the typical clinical features or severe short stature of classic GHRD. Further, the intellectual data were not based on testing, and there were no comparisons to relatives unaffected by GH insensitivity. There was no correlation of intellectual impairment with hypoglycemia. These researchers acknowledged the enhanced risk for mental retardation conferred by the high rate of consanguinity in families of children with GHRD, which would also explain the findings of the lower intelligence of the Israeli patients with GHRD (1, 2, 3).

The absence of controlled and objective evaluation of subjects with proven GHRD emphasized the importance of such a study with a homogeneous population to determine whether lack of GH action in utero or during postnatal brain growth might have deleterious effects on intellectual functioning. Children with total absence of GH due to GH gene deletion and, therefore, comparable deficiency of GH stimulation of IGF-I in utero have not been described as intellectually delayed (37, 38, 39, 40). It is of interest that intrauterine growth in both GHRD and GH gene deletion is usually normal (5, 6, 38, 39), although other phenotypic abnormalities of severe IGF-I deficiency may be seen at birth. This suggests that either there is an alternative means of stimulating IGF-I production in utero, or other growth factors are more important at this stage. The former explanation is suggested by the single instance of intellectual impairment and intrauterine growth retardation with a defect in the IGF-I gene, an association that requires confirmation (4).

Based on our results, the intellectual capability of the patients with GHRD in Ecuador is best described as normal compared to that of relatives or community controls of approximately the same age. The somewhat better performance of schoolmates (community controls) than patients with GHRD or relatives of patients may reflect a selection bias, because teachers were involved in determining who served as controls, and volunteers may have been the better students. Comparison of patients with GHRD with their relatives, however, is likely to be unbiased, as all schoolgoing patients and available relatives were tested. Our analyses were confined to schoolgoing subjects (patients with GHRD, their relatives, and controls), because we had only such a community control group. Analysis of a larger group of patients (n = 35) and close relatives (n = 94) that included adults gave similar results (our unpublished observations).

Despite the fact that the hypothesis of intellectual superiority among patients with GHRD was not substantiated by the results of this study, the proof of normality in this population is an important finding that contrasts with findings in the only other tested population (2, 3). Unlike the Ecuadorian population with GHRD, the Israeli patients are genetically heterogeneous, making it unlikely that their intellectual impairment is genetically linked to their GHRD. Furthermore, there is a broad range of capability in the Israeli population of patients with GHRD, including a few with superior achievement (3). The single Israeli patient identified to have the Ecuadorian mutation is said to be highly intelligent (Z. Laron, personal communication).

The results of this study also indicate that higher intellectual ability is not a plausible explanation of the exceptional scholastic performance that is typical of Ecuadorian patients with GHRD (23). Reports of their superior performance in school were obtained in a nonleading manner and were usually supported by documents. Academic achievement has also been exceptional for some adults. It is possible that reduced social opportunity due to extremely short stature permitted greater devotion to studies and superior achievement in school for the subject’s IQ level. Also possible is that patients with GHRD compensate for their short stature by overachieving in school.

In conclusion, the results of this study do not confirm the hypothesis that the gene defect causing GHRD is related to intelligence in the Ecuadorian population. Compared to their unaffected relatives and to community controls, patients with GHRD were found to be of normal intelligence, as measured by psychometric and chronometric tests of intelligence. The results of this study, therefore, indicate that GH-induced IGF-I production is not required for normal brain growth or cognitive development.

	Appendix

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References

 
The integral relationship between intelligence and the speed and efficiency of cognitive processing, as measured by ECTs, has been substantiated in numerous independent studies (13, 14, 15, 16) and supported by the results of meta-analyses (17, 18). Significant differences in processing speed and efficiency have also been reported between groups with disparate levels of intelligence, such as that between normal, mentally disabled, and gifted individuals (19, 20).

Simple and choice reaction time

SRT measures the speed of making a ballistic response. CRT reflects all that is required in SRT, plus decision time. The same apparatus and procedure were used to measure SRT and CRT. The apparatus consists of a 13 x 17-in. console tilted at a 30° angle. The "home button," a black pushbutton 1 in. in diameter, is located at the lower center of the panel. The response buttons are an array of eight green pushbuttons, 1/2 in. in diameter, which can be illuminated. They are arranged equidistantly from the home button in a semicircle with a 6-in. radius. Plastic flat black overlays can be fastened to the console, exposing different pushbutton combinations. Only one pushbutton was exposed for SRT. All eight pushbuttons were exposed for CRT.

The procedure for a single trial includes the following. The subject depresses the home button, activating an auditory warning signal (a beep of 1-sec duration); after a random interval of 1–4 sec, one of the pushbuttons is illuminated, and the subject, as quickly as possible, removes his or her finger from the home button and depresses the illuminated pushbutton. The apparatus allows the separate measurement of RT and movement time (MT). RT is the amount of time it takes to lift a finger off the home button after one of the pushbuttons has been illuminated. MT is the interval between releasing the home button and depressing the pushbutton. RT and MT are recorded in milliseconds by two electronic timers. Central cognitive processing is measured by RT, whereas peripheral, noncognitive sources of variance are reflected by MT (17).

OMO

The OMO taps spatial discrimination speed and efficiency. The procedure for the OMO is identical to that described for the SRT and CRT, except that instead of one pushbutton being lit, three pushbuttons are illuminated simultaneously, two of which are closer together than the third. The participant must depress the pushbutton that is further away from the other two. RT and MT are recorded in milliseconds by two electronic timers.

Inspection time

IT, which measures the rate at which information can be taken in for further processing, is the only index of mental speed that does not involve motor (output) components (21). The IT apparatus consists of a 16 1/2 x 9 1/5-in. gray metal box, the front side of which is black. Flush with the face of the apparatus are two vertical columns of multiple segment red bar light-emitting diodes (LEDs) 6 in. in length, 1 1/2 in. apart. Connected to the apparatus are two 4 3/4 x 2 1/2-in. pushbutton boxes. In the middle of each pushbutton box is a pushbutton 3/8 in. in diameter. For the IT paradigm, a single trial includes the following: 1) an auditory warning signal (a beep of 1 s duration) is presented; 2) after a random interval of 1–3 s, both of the parallel columns of LEDs are illuminated, one of which is 30% longer than the other; 3) almost immediately after the LEDs are illuminated, both columns of LEDs are lit completely (this backward masking stimulus is presented to limit the amount of processing from stored traces); and 4) the subject indicates which line (left or right) was longer by depressing the corresponding (left or right) pushbutton. IT is defined as the minimum duration of exposure (step 2 above) necessary for reliable discrimination between the two lines.

The total number of trials and the specific exposure durations of the stimuli for each trial were determined by the BRAT algorithm, a heuristic procedure for measuring IT to 2-msec resolution and 90% accuracy. Briefly, the BRAT algorithm has three phases. In phase 1, a quick estimate of IT is determined by starting well above the participant’s IT and decreasing in relatively large increments (10 msec after the stimulus exposure duration is <100 msec) until at least 90% accuracy has been attained in the last 10 trials. In phase 2, this estimate is further refined by first overshooting it by 30 msec and then slowly increasing (in 6-msec steps) the stimulus duration until at least 90% response accuracy has been attained in the last 10 trials. Finally, in phase 3, the subject’s IT is determined by initially overshooting the IT estimate provided in phase 2 by 20 msec and then increasing the stimulus duration (in 2-msec steps) until the subject makes nine consecutive responses. The exact number of trials and the time to administer this test vary (according to resolution of the IT), but typically fewer than 100 trials are required and approximately 5 min are needed for resolution.

	Acknowledgments

 
We thank Drs. Mary Anne Berg and Uta Francke, Howard Hughes Medical Institute (Stanford, CA) for the genotyping data, and Ms. Briley Proctor, University of Florida, for assistance with data entry and analysis.

	Footnotes

 
¹ This work was supported by grants from the March of Dimes-Birth Defects Foundation and the University of Florida Center for Latin American Studies.

Received January 9, 1998.

Revised February 19, 1998.

Accepted February 26, 1998.

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