EDITORIAL

Gender Bias, Female Resilience, and the Sex Ratioin Autism

John N. Constantino, M.D., AND Tony Charman, Ph.D.

I n this issue of the Journal, Dworzynski et al.1

capitalize on the Twins Early DevelopmentStudy to shed new light on possible gender

differences in autism. In this report, they examinechildren in the Twins Early Development Studywho scored above the screening cutoff of 14 onthe Childhood Autism Spectrum Test (CAST) orcarried a community diagnosis of an autismspectrum disorder (ASD) endorsed by parentreport and whose diagnoses were subsequentlyconfirmed on the Development and WellbeingAssessment (DAWBA).

Children with high CAST scores were consid-ered “diagnosed” if they received a DAWBA andthe DAWBA was positive. An important limita-tion of the study is that 34 of 227 high-CAST boysand 23 of 75 high-CAST girls did not receiveDAWBAs yet were assigned to the “undiag-nosed” category. Therefore, the most informativesubjects were those who had both measurements.Assuming the DAWBA validly differentiates af-fectation from nonaffectation in this context (thisis an assumption), the study yields the followinginteresting findings: 227 boys and 75 girlsscreened in TEDS exceeded the CAST cutoff(indicative of a significant gender disparity in thedistribution of CAST scores in the population—itis not reported which proportion of each hadcommunity diagnoses of ASD by parent report inthe Twins Early Development Study); of thosewho exceeded the CAST cutoff and were as-sessed with the DAWBA, 56% of the boys butonly 38% of the girls met the criteria on theDAWBA (suggestive of a bias in diagnosis); the sy-mptom profile for those who exceeded the cutoffdiffered by gender (more social deficits in boys,more communicative deficits in girls); and thegirls who were diagnosed exhibited more intel-lectual and behavioral deficits, on average, thantheir diagnosed male counterparts, suggesting

that it requires a relative increase in the total

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symptom burden to result in a female crossingthe threshold of diagnosis.

The emphasis in the authors’ interpretation ofthe results is on the ratio of male-to-female highCAST scorers who received a diagnosis: givencomparably high levels of ASD traits, girls aresubstantially less likely to be diagnosed thanboys unless their conditions are compounded bycognitive and other behavioral deficits. This, theauthors suggest, reveals a significant problem incurrent diagnostic approaches (at least as per-tains to the instruments used in this particularstudy) or indicates that, in the absence of accom-panying cognitive or behavioral deficits, girlsexhibit better adaptation to the same levels ofASD liability that typically result in the clinicaldiagnosis in boys. Both may be true, and thefindings constitute an important observation thatis convergent with the results of previous studiesshowing that at standardized 99th and 98th per-centile cutoffs for autistic trait severity, boys aretwice as likely as girls to carry a communitydiagnosis of ASD.2,3 A similar pattern has beenfound in a large community sample in which themedical records abstraction method used by theCenters for Disease Control Autism/Develop-mental Disabilities Monitoring Network wereexamined against a community diagnosis, inparticular for girls with an IQ higher than 70.4

What is largely missing from the discussion inthis article, however, is a consideration of per-haps the more powerful contributor to the ob-served sex ratio in autism, which is that threetimes more boys than girls in the general popu-lation (227 versus 75) exceed the CAST cutoff inthe first place. A comprehensive approach tounderstanding gender disparities in autism re-quires the incorporation of this fact and its mean-ing, which is left largely untended in the articlebut for which a substantial amount is now

known. Therefore, we wish to highlight two

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EDITORIAL

issues that relate to the observed disparity inthe proportions of boys and girls reaching clinicalthresholds on trait measurements of ASD whomeet the criteria on diagnostic instruments and/or receive community diagnoses. First, such dis-parities underscore the need for the field tocarefully consider developing gender-specificthresholds for ASD screening and diagnosis. Sec-ond, there is an emerging story from geneticstudies that resilience or protective factors infemale individuals might explain the 4:1 male:female ratio observed for most familial autisticsyndromes.

Several large studies, using various methodsfor quantifying the severity of autistic symptom-atology, have demonstrated that autistic traits arecontinuously distributed in nature, and thatthroughout the entire population, the distributionof the scores of female individuals are shiftedtoward the nonpathologic end compared withthose of male individuals.5 This makes it poten-tially critical (especially when attempting to clar-ify the origins of gender disparities in autism) toimplement standardized assessment methodsthat are normed for gender; this is not a feature of

FIGURE 1 Pedigree of family 1. Note: Pedigree of a mvariation that deletes one copy of SHANK1. Individuals wphenotype) are indicated by filled symbols and striped syNA � unavailability of DNA; WT � individuals with thefrom the American Journal of Human Genetics, Vol. 90,Spectrum Disorder,” 879–87.8 Copyright 2012, with per

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raditional autism screening/trait or diagnosticeasurements, which may contribute to gender

iases by imposing absolute cutoffs for categori-al designation of affected status. Elsewhere, onef us has argued that rather than expanding thever-increasing list of instruments to measureSD, it would be beneficial to the field to knowore about the instruments that currently exist.6

Developing gender-specific thresholds for scre-ening and diagnostic instruments would be oneimportant goal; age-specific thresholds would beanother.

When considering standardized quantitativedefinitions for affectation (percentile cutoffs foreach respective gender), it has been shown thatthe male:female autism recurrence ratio in famil-ial autism actually narrows to 3:2.2 This might bexpected based on “relaxing” the criteria foremale individuals, but the number of femalendividuals meeting the relaxed criteria has beenbserved to occur an order of magnitude moreommonly in autism-affected families than in theeneral population. In other words, althoughhey do not reach the threshold for clinical diag-osis, female individuals identified in this man-

enerational family carrying a rare copy numberutism spectrum disorder and BAP (broader autism

ls, respectively. The proband is indicated by an arrow.al copy number of two at the SHANK1 locus. Reprintedet al., “SHANK1 Deletions in Males with Autismion from Elsevier, Inc.

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CONSTANTINO AND CHARMAN

ner heavily aggregate in autism-affected families.Using a separate design, Constantino et al.7 ex-amined autism recurrence in full siblings versushalf siblings and showed that, in familial autism,inherited susceptibility is equally transmitted byunaffected female individuals (mothers) andmale individuals (fathers).

Notwithstanding sex biases in diagnosis un-der the condition of equal levels of symptomacquisition, the picture that is emerging is thatwithin family pedigrees and across numerousmechanisms of genetic causation—includingsuch disparate causes as SHANK1 deletions8 andfragile X syndrome9—most girls who carry ge-netic susceptibility may be relatively protectedfrom expressing the autistic syndrome phenotyp-ically. Figure 1 depicts the powerful example ofan extended pedigree in which a rare hemi-deletion of the SHANK1 gene is transmittedacross four generations: all male offspring in thefamily who inherited the deletion exhibited anautistic syndrome; all female offspring in thefamily who inherited the deletion were unaf-fected (“silent carriers”). Now that it has beenestablished that the genetic underpinnings ofautistic syndromes are markedly heterogeneousand largely autosomal, how can it be that allconverge on a sex ratio of 4:1?

Although it is appealing to consider the pos-sibility that this is explainable on the basis of adifferential threshold for the symptomatic ex-pression of inherited susceptibility to autism inboys versus girls, it does not fit with the follow-

ing observation: girls affected by autism do not

diagnostic instruments for autism spectrum disorders—lessonsfrom research and practice [published online ahead of print April

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xhibit denser levels of familial loading thanoys affected by autism.10 Rather, it remains an

intriguing possibility that most—but not all—female individuals are categorically protectedfrom expressing the condition. Virkud et al.11

showed that, in contrast to the unimodal distri-bution observed for male individuals, the symp-tom scores for female individuals in multiplexautism families were bimodally distributed. Ifthere discrete mechanisms exist by which such“resilience” occurs in female individuals, and ifthose mechanisms are more parsimonious thanautism’s many causes, their elucidation mightuncover highly effective approaches for “protect-ing” children who otherwise express inheritedsusceptibility in the form of lifelong disability. &

Accepted May 24, 2012.

Dr. Constantino is with Washington University in St. Louis. Dr.Charman is with the Centre for Research in Autism and Education,Institute of Education, London.

Disclosure: Dr. Constantino has received grant or research supportfrom the National Institutes of Health, the National Institute of ChildHealth and Human Development, the National Institute of MentalHealth, the Department of Health and Human Services, AutismSpeaks, and the Centers for Disease Control and Prevention. He hasreceived royalties for the authorship of assessment tools from WesternPsychological Services (SRS). Dr. Charman has received grant supportfrom the U.K. Medical Research Council, the European ScienceFoundation, Autistica, Research Autism, the Autism Education Trust,and Autism Speaks. He has received royalties from Guilford Press andSage.

Correspondence to John N. Constantino, M.D., 660 S. Euclid,Campus Box 8134, St. Louis, MO 63110; e-mail: constantino@wustl.edu

0890-8567/$36.00/©2012 American Academy of Child andAdolescent Psychiatry

http://dx.doi.org/10.1016/j.jaac.2012.05.017

REFERENCES1. Dworzynski K, Ronald A, Bolton P, Happé F. How different are

girls and boys above and below the diagnostic threshold forautism spectrum disorders? J Am Acad Child Adolesc Psychiatry.2012;51:788-797.

2. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. Siblingrecurrence and the genetic epidemiology of autism. Am J Psychi-atry. 2010;167:1349-1356.

3. Russell G, Steer C, Golding J. Social and demographic factors thatinfluence the diagnosis of autistic spectrum disorders. Soc Psy-chiatry Psychiatr Epidemiol. 2011;46:1283-1293.

4. Giarelli E, Wiggins LD, Rice CE, et al. Sex differences in theevaluation and diagnosis of autism spectrum disorders amongchildren. Disabil Health J. 2010;3:107-116.

5. Constantino JN. The quantitative nature of autistic social impair-ment. Pediatr Res. 2011;69(Pt 2):55R-62R.

6. Charman T, Gotham K. Measurement issues: screening and

4, 2012]. Child Adolesc Mental Health. doi:10.1111/j.1475-3588.2012.00664.x.

7. Constantino JN, Todorov A, Hilton C, et al. Autism recurrence inhalf siblings: strong support for genetic mechanisms of transmis-sion in ASD [published online ahead of print February 28, 2012.Mol Psychiatry. DOI:10.1038/mp.2012.9.

8. Sato D, Lionel AC, Leblond CS, et al. SHANK1 deletions in maleswith autism spectrum disorder. Am J Hum Genet. 2012;90:879-887.

9. Hall SS, Lightbody AA, Hirt M, Rezvani A, Reiss AL. Autism infragile X syndrome: a category mistake? J Am Acad ChildAdolesc Psychiatry. 2010;49:921-933.

10. Goin-Kochel RP, Abbacchi A, Constantino JN. Lack of evidencefor increased genetic loading for autism among families ofaffected females: a replication from family history data in twolarge samples. Autism. 2007;11:279-286.

11. Virkud YV, Todd RD, Abbacchi AM, Zhang Y, Constantino JN.

Familial aggregation of quantitative autistic traits in multiplexversus simplex autism. Am J Med Genet. 2009;150B:328-334.

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