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Hindawi Publishing CorporationInternational Journal of Pediatric EndocrinologyVolume 2010, Article ID 853103, 6 pagesdoi:10.1155/2010/853103Clinical StudyNormal Intelligence in Female and Male Patients withCongenital Adrenal HyperplasiaSheri A. Berenbaum,1 Kristina Korman Bryk,2 and Stephen C. Duck31 Departments of Psychology and Pediatrics, The Pennsylvania State University, University Park, PA 16803, USA2 Department of Psychology, The Pennsylvania State University, University Park, PA 16803, USA3 Department of Pediatrics, Pritzker School of Medicine, University of Chicago, and Pediatric Endocrinology,North Shore University Health Services, 9977 Woods Drive, Skokie, IL 60077, USACorrespondence should be addressed to Sheri A. Berenbaum, sab31@psu.eduReceived 25 May 2010; Revised 30 July 2010; Accepted 16 August 2010Academic Editor: Todd NebesioCopyright © 2010 Sheri A. Berenbaum et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.We provide evidence regarding the nature, causes, and consequences of intelligence in patients with 21-hydroxylase deficientcongenital adrenal hyperplasia (CAH). Intelligence and quality of life (psychological adjustment) were measured on multipleoccasions from childhood to young adulthood in 104 patients with CAH (62 females, 42 males) and 88 unaffected relatives (31females, 57 males). Information on disease severity (CAH type, age at diagnosis, genital virilization for girls) and salt-wastingcrises was obtained from medical records. There was no evidence of intellectual deficit in either female or male patients with CAH.Intelligence was not significantly associated with psychological adjustment or disease characteristics. CAH itself does not appearto increase risk for poor intellectual function. In a sample of patients with generally good disease control, intelligence is not relatedto adjustment problems, disease severity, or salt-wasting crises.1. IntroductionControversies about the nature and causes of psychologicaloutcome in individuals with disorders of sex development(DSDs) have focused on gender identity, sexuality (especiallyrelated to surgery), and quality of life [1–3]. There has beenless attention paid to intelligence, although there has beena concern that intellectual impairment might be associatedwith adjustment problems [4]. Most of the systematicevidence about outcome in DSDs comes from congenitaladrenal hyperplasia (CAH), the most common DSD.Intelligence is composed of several key attributes, includ-ing abstract thinking, reasoning, problem-solving, and abil-ity to adapt to the environment [5]. Intelligence measuredby standard tests is important because it is associated witha variety of psychological, social, economic, and healthoutcomes [5]. A review of studies through 2000 indicatedthat overall intelligence of individuals with CAH is withinthe normal range, but might be lower in patients with salt-wasting (SW) than with simple-virilizing (SV) CAH [6].One aspect of intelligence, spatial ability, has been foundto be affected by CAH, but in different ways in the twosexes: compared to same-sex controls, females with CAHhave higher spatial ability (probably as a result of prenatalandrogen excess) and males have lower spatial ability (forunknown reasons) [6–8]. Data published since the reviewsuggest that there is a more pronounced intellectual deficit infemale patients with CAH than had been reported previously[4]. The deficit was proposed to be caused by the disease andits treatment (e.g., prenatal androgen excess, hyponatremia)and to lead to lowered quality of life, but the hypothesizedcauses and consequences of the deficit were not tested.The renewed concerns about intellectual deficits in CAHand associations with psychological adjustment [4] generatethree key questions. First, what is the nature and extent ofthe deficit, and is it found in both sexes? Although mostwork focuses on females with CAH, some factors proposed toinfluence intelligence (e.g., hyponatremia) are also present inmales with CAH. Second, what are the causes of intellectualdeficit? This can be examined through associations between
Page 2 2International Journal of Pediatric Endocrinologyintelligence and disease characteristics. Third, what arethe psychological consequences of intellectual deficit? Thiscan be examined through associations between intelligenceand psychological adjustment. We address these questionswith data from a long-term followup of individuals withCAH whose intelligence and psychological adjustment wereassessed on multiple occasions from childhood throughyoung adulthood.2. Methods2.1. Subjects. Participants were part of a behavioral studyof individuals with CAH secondary to 21-hydroxylasedeficiency studied on several occasions. They were ini-tially recruited in childhood or adolescence through eightuniversity-affiliated pediatric endocrinology clinics in themidwestern United States. Unaffected relatives similar inage served as controls. Participants represented a rangeof socioeconomic backgrounds, and most were Caucasian.There were 192 participants from 90 families studied atseveral points between the ages of 3 and 30 years, althoughnot all subjects had data at all times; there were 62 femalesand 42 males with CAH, 31 unaffected female relatives(29 sisters, 2 cousins) and 57 unaffected male relatives (54brothers, 3 cousins). 90% of families invited to participate inthe project agreed.Behavioral data from some participants have beenreported; for summary, see [1, 9]. In brief, females withclassical CAH are behaviorally more male-typical and lessfemale-typical than their unaffected sisters, with androgenhaving large effects on activity interests but minimal effectson gender identity; males with classical CAH are similar tounaffected males in gender-related characteristics studied;females and males with CAH have good psychologicaladjustment.The research was approved by Institutional ReviewBoards at all institutions. Depending on age, participantsprovided oral assent or written consent; parents of minorsprovided written consent for their children’s participation.2.2. Measures and Procedures. Subjects were tested betweenone and four times between 1989 and 2004. At the initialassessment (Time 1), they ranged in age from 3 to 13 years(M = 6.9), but cognitive testing was only conducted onthose aged 7 and older (M = 9.5). Subsequent assessmentsincluded both the initial subjects and new subjects, andincluded cognitive tests for all subjects. The second assess-ment (Time 2) occurred on average six months after thefirst, and subjects were 3 to 13 years old (M = 8.10). Thethird assessment (Time 3) occurred on average 4.6 years later,and subjects were 3 to 19 years old (M = 10.33). The finalassessment (Time 4) occurred on average 5.6 years after that,and subjects were 9 to 30 years old (M = 15.87). Mostparticipants were tested more than once: 33% had only oneassessment, 43% had two, 16% had three, and 8% had allfour assessments.Intelligence was measured with standardized tests. Raven’sProgressive Matrices Test was administered at Time 1; itcorrelates well with other measures of intelligence [10].Peabody Picture Vocabulary Test [11] was administered atTimes 2 and 3. Age-appropriate multiple-choice VocabularyTests [12, 13] were administered at Time 4. Vocabularytests were used because they correlate with measures ofintelligence [11] but are short (reducing participant burden),and prevent inflated scores in females with CAH whohave higher spatial ability than unaffected females [8] anddepressed scores in males with CAH who have lower spatialability than unaffected males [6, 7].Psychological adjustment was measured with parent-report on all four occasions, and with self-report once ortwice in adolescence. Parents completed the Child BehaviorChecklist (ages 3–18) or the Young Adult Behavior Checklist(age 18 and older) [14, 15]; analyses focused on Internalizing(withdrawal, somatic complaints, depression, and anxiety),Externalizing (aggressive and delinquent behavior), andTotal Behavior Problem scales. Adolescents completed theSelf-Image Questionnaire for Young Adolescents [16]; anaverage of all nine scales was used. Some adjustment datahave been reported [17] so only associations with intelligenceare described.Disease characteristics that might affect intelligence wererated from medical records without knowledge of behavioralresults. Data were available for approximately half thesample; there were no significant behavioral differencesbetween those with versus without data. The overwhelmingmajority of patients were diagnosed clinically, consistentwith the fact that most were born before newborn screen-ing for CAH was implemented in the states in whichthey lived. Most participants had good disease control, asmeasured by growth rate, bone age, and concentration of17-hydroxyprogesterone; see [18] for detailed informationabout assessment and results. Measures used here includeindicators of disease severity (type of CAH, age at diagnosis,degree of genital virilization in girls) and number of salt-wasting crises documented in childhood; descriptive dataare shown in Table 1. Type of CAH was classified as simplevirilizing (SV-), mild salt wasting (SW-), or severe SW. SW-CAH required elevated plasma renin activity for age andresponsiveness to mineralocorticoid therapy. Classificationas mild SW-CAH required that all measurements of serumsodium be at least 129 mmol/L, and that there be no episodesof hypotension or shock; classification as severe SW-CAHrequired that serum sodium in the neonatal period be lessthan 129mmol/L, or that there be at least one episode ofhypotension or shock.2.3. Analysis Procedure. Intelligence test scores of patientsand controls were compared using analysis of variance, withfactors of sex and status (CAH, control), and covariateof age for tests that were not age-standardized. Separateanalyses were conducted for each measure at each time point;multivariate analyses were not used because not all subjectshad complete data. Associations between intelligence andadjustment were assessed with correlations; scores wereadjusted so positive correlations reflect high intelligenceassociated with good adjustment. We examined correlations
Page 3 International Journal of Pediatric Endocrinology3Table 1: Disease characteristics of patients with CAH.Type of CAHFemalesMalesNonclassical (NC)76Simple Virilizing (SV)62Mild Salt-Wasting (Mild SW)118Severe Salt-Wasting (Severe SW)3124Age at Diagnosis of CAHFemalesMales<6 months38276–35 months30>36 months1211Prader Stage at Diagnosis (females only)NCSVMild SWSevere SW062001112120133301112401311Number of Salt-Wasting Crises (SW-CAH only)FemalesMales02923196243Note. Entries are numbers of subjects. Some participants do not have complete data, so total numbers vary across characteristics.of intelligence to adjustment at the same point in time,and at earlier and later times, in order to assess time-lagged consequences of intelligence for adjustment andvice versa. Associations between intelligence and diseasecharacteristics were also assessed with correlations. Becauseof the importance of detecting problems if they are present,Type I error was set at .05 and there were no correctionsfor multiple tests; increased Type I error with multiplecomparisons is discussed later.3. Results3.1. Group Comparisons on Intelligence. Data on intelligencetest scores and test ages for females and males with andwithout CAH at all assessments are shown in Table 2. Therewas no evidence of intellectual deficit in either females ormales with CAH at any assessment. There was one significanteffect of status, reflecting higher scores of patients with CAHthan controls at Time 2 (P<.05). This effect was qualifiedby a marginally significant interaction between sex and status(P<.07): higher scores of patients with CAH than controlswere specific to females. An interaction between sex andstatus was also seen at Time 3 (P<.01), again reflecting thehigher scores of females, but not males, with CAH comparedto controls.3.2. Associations between Intelligence and Adjustment. Intelli-gence was generally not significantly associated with adjust-ment, whether measured at the same or different pointsin time. Only a few correlations were significant, and theywere not consistently in the same direction. The mediancorrelation was −.02.3.3. Associations between Intelligence and Disease Character-istics. Intelligence was generally not significantly associatedwith disease characteristics. Median correlations with intelli-gence were as follows: type of CAH r = .12, age at diagnosisr = −.07, Prader rating r = .01, number of salt-wastingcrises r = −.05. Because few patients had more than onesalt-wasting crisis, we compared individuals with one ormore crisis to individuals with no crises; t-tests showed nosignificant group differences on any measure of intelligence.4. DiscussionAcross multiple measures and assessments, there was noevidence that patients with CAH—female or male—hadimpaired intelligence. If anything, females with CAH hadhigher ability than unaffected female relatives. Further,there was no evidence that intelligence was associated withquality of life, as measured by parents’ reports of theirchildren’s behavior problems or patients’ reports of theirown functioning, and no evidence that intelligence wasassociated with disease characteristics, including salt-wastingcrises. Published data from this sample show that thedisease was well-controlled in the majority of patients [18],which might account for their favorable outcome; restrictedvariability might also account for lack of association betweenintelligence and salt-wasting crises.These results are consistent with the bulk of the dataon intelligence in CAH from several countries and cohorts,as seen in a review [6] and recent studies [7, 19, 20].Patients with CAH are consistently seen to have normalintelligence. Intelligence may be somewhat lower in patientswith SW-CAH than SV-CAH but both groups are within thenormal range and there is variability within groups [6, 21].
Page 4 4International Journal of Pediatric EndocrinologyTable 2: Intelligence test scores and age at test by sex and status (CAH, control).Femaleswith CAHUnaffectedFemalesMales withCAHUnaffectedMalesSignificant EffectsTime 1, Progressive Matrices [10]: Number correct of 36N149916Mean30.7125.3328.2227.81SD4.808.324.124.68Age at test (years)Mean10.688.858.959.21SD1.091.301.581.47Time 2, Peabody Picture Vocabulary Test [11]: Standardized ScoreN18131819Mean105.3392.15102.56101.79F CAH>Unaff+SD15.8718.5212.7213.97Age at test (years)Mean8.518.147.428.34SD3.331.542.662.49Time 3, Peabody Picture Vocabulary Test [11]: Standardized ScoreN45253042Mean110.56101.16107.01106.95F CAH>Unaff∗SD13.2415.1712.5915.49Age at test (years)Mean10.4310.579.6410.57SD4.174.803.763.51Time 4, Vocabulary [12, 13] Percent correctaN44182931Mean0.720.620.610.71SD0.170.240.200.16Age at test (years)Mean15.7116.7615.7615.66SD4.994.285.073.61aBecause of variability in participant age, several different forms of this test were used. To increase the statistical power to detect group differences, scoreswere combined into a single Vocabulary measure.Most group differences are not significant. Significant effects are noted, +P<.07, ∗P <.01.Impairments may be associated with repeated hyponatremicepisodes. There is a greater likelihood of deficits in patientswho are not well-treated [4] than in those who are (as in thecurrent study), but one or two episodes in otherwise well-treated patients do not appear to have adverse consequencesfor intelligence. Intellectual deficits might also result fromother disease features, although this has not been tested. Forexample, elevated ACTH with undertreatment might leadto attention problems; overtreatment with glucocorticoidsmight lead to cognitive and neural changes similar to thoseseen in Cushing syndrome [22].Our findings of enhanced ability on some tests infemales with CAH most likely reflect sampling fluctuation.If intelligence does not differ in populations of peoplewith versus without CAH, then sampling fluctuations inindividual studies may produce varying group differences,including higher ability in CAH than in controls (as foundhere), lower ability in CAH than in controls (as found by[4, 23]) and, most often, no significant group differences inability [7, 19, 20, 24–28]. Group differences in intelligence areless likely to be seen when patients are compared to siblings(the best control for genetic and environmental influences onintelligence) than to unrelated controls.Our results showing few links between intelligence andadjustment are consistent with findings in typical samples[29]. Links may be found in a narrow context (e.g.,intelligence correlated with the personality dimension ofOpenness), or in selected groups (e.g., mentally ill, unusuallyhigh or low ability), but overall, adjustment and ability arenot highly correlated.Several issues bear consideration in interpreting theresults. First, intelligence was not assessed with full IQ tests,such as Wechsler scales. But the tests used correlate well withVerbal and Full Scale IQ, and are considered good indicatorsof general intelligence [10, 11]. Second, conclusions aboutassociations between intelligence and disease characteristics
Page 5 International Journal of Pediatric Endocrinology5must be tempered by the methods of assessment andthe nature of the sample: medical information was ratedretrospectively from medical records that varied in quality,and most patients had good disease control as reportedelsewhere [18]. Although medical data were not availablefor all participants, those with and without data weresimilar in intelligence and adjustment. It is important toemphasize that findings of normal intelligence in thesepatients mean that there is little need for explanatorymedical data. Third, the sample is large enough to detectmoderate-to-large differences between patients with CAHand unaffected relatives; small differences are unlikely to beof clinical significance. Indeed, there was enough power todetect a difference, but it was of an intelligence advantage(not deficit) in females with CAH. The sample was also largeenough to detect moderate-to-large associations betweenintelligence and adjustment and between intelligence anddisease characteristics. Fourth, Type I error was very high inlight of the many comparisons made. It is thus particularlynoteworthy that significant effects were not found. Fifth, thepatients studied likely represent the population of patientswith CAH, given that most individuals contacted agreed toparticipate; this increases confidence that most patients withCAH are intellectually similar to their unaffected relatives.Nevertheless, it is important to examine intelligence inpatients with CAH detected through newborn screening,who best represent the population of patients with CAH.5. ConclusionsResults of systematic assessment show that intelligence isnot impaired in females or males with CAH who generallyreceived good medical care beginning early in life, and thatability is not associated with psychological adjustment. Thisconclusion is strengthened by the consistency of findingsacross repeated assessments with multiple measures. It seemsunlikely that CAH itself causes cognitive deficits.AcknowledgmentsThe research reported here was supported by grants fromthe National Institutes of Health (HD19644) and the CARESFoundation. The authors thank the following people whocontributed to the project: Drs. Deborah Edidin, EricaEugster, Orville Green, Reema Habiby, David Klein, SongyaPang, Ora Pescovitz, Gail Richards, Julio Santiago, BernardSilverman, Kumud Sane, Robert Uhlstrom, Judson VanWyk, Neil White, and David Wyatt generously providedaccess to their patients; Lori Alegnani, Kathleen Bechtold,Jackie Ewing, Brenda Henderson, Kim Ketterling, RobynReed, and Elizabeth Snyder collected and processed data;Sarah Barcousky, Ahmareen Baten, Lauretta Brennan, CaraDesbold, Courtney Gallen, Brendan Hunt, Sheila Huff,Ellissa Mette, Janelle Sheridan, and George Vineyard assistedwith data scoring and entry. Dr. Erica Eugster and KellyLeight provided helpful comments on an earlier version ofthe paper. The authors are also very grateful to the patientsand their families for their participation in the study.References[1] S. A. Berenbaum, “Psychological outcome in children withdisorders of sex development: Implications for treatment andunderstanding typical development,” Annual Review of SexResearch, vol. 17, pp. 1–38, 2006.[2] P. E. Clayton, W. L. Miller, S. E. Oberfield et al., “Consensusstatement on 21-hydroxylase deficiency from the LawsonWilkins Pediatric Endocrine Society and The EuropeanSociety for Pediatric Endocrinology,” Journal of ClinicalEndocrinology and Metabolism, vol. 87, no. 9, pp. 4048–4053,2002.[3] I. A. Hughes, C. Houk, S. F. Ahmed, P. A. Lee, andLWPES/ESPE Consensus Group, “Consensus statement onmanagement of intersex disorders,” Archives of Disease inChildhood, vol. 91, no. 7, pp. 554–563, 2006.[4] T. H. Johannsen, C. P. L. Ripa, J. M. Reinisch, M. Schwartz, E.L. 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