Autism spectrum disorders: head circumference and body length at birth are both relative

REGULAR ARTICLE

Autism spectrum disorders: head circumference and body length at birth areboth relativeMarine Grandgeorge ([email protected])1,2, Eric Lemonnier1,2, Nelle Jallot1

1.Centre de Ressources Autisme, CHRU de Brest, Hopital de Bohars, Bohars, France2.Laboratory of Neurosciences de Brest, EA 4685, University of Bretagne Occidentale, Brest, France

KeywordsAutism spectrum disorders, Body length, Headcircumference, Relative macrocephaly, Relativemicrocephaly

CorrespondenceMarine Grandgeorge, CHRU de Brest, Hopital deBohars, Centre de Ressources Autisme, Bohars29820, France.Tel: +33298015337 |Fax: +33298015233 |Email: [email protected]

Received5 February 2013; revised 5 April 2013;accepted 9 April 2013.

DOI:10.1111/apa.12264

ABSTRACTAim: Although the body length and weight of an infant are related to head circumference,

little research on ASDs has examined these factors. Our study compared the head

circumferences of neonates who were later diagnosed with ASD with a control group.

Additional comparisons on morphological disproportions at birth included the head

circumference-to-height and head circumference-to-weight ratios.

Methods: We recruited 422 children with ASD and 153 typically developing children. Head

circumference, body length and weight at birth were collected and standardized as

percentile scores according to gestational age and gender.

Results: Our results revealed that genuine macrocephaly was significantly higher in

children with other pervasive developmental disorders compared with the control group.

This difference was not observed with regard to genuine microcephaly. Relative

macrocephaly and relative microcephaly were significantly more frequent in children with

autism disorder compared with the control group with regard to body length.

Conclusions: The differences in relative macrocephaly and microcephaly, as well as in

other parameters, between diagnostic subgroups suggest that the presence of several

neurological mechanisms plays a role in the later expression of different phenotypes. An

increased head circumference-to-body length ratio in newborns may be a factor to follow

that could be related to ASD.

INTRODUCTIONMethods to facilitate the early diagnosis of autism spectrumdisorders (ASD) are urgently needed. If ASD can beidentified, these children can benefit from early, intensiveinterventions. This urgency has become heightened becausethe reported prevalence of ASD has increased significantlyover the past decade (1). Although certain symptoms ofASD are present early in life, ASD is usually diagnosed afterthe age of three (2). Thus, many researchers aim to identifybiological or neurological indicators that serve as earlywarning signs, such as gene expression profiles, eye move-ments, brain functions and head size (3). Head circumfer-ence may be a valid indicator of whole brain volume andweight (4). Not only may be this measure a useful alterna-tive to magnetic resonance imaging technology (5), but it isalso a routine practice that begins at birth and continues

throughout the child’s development in numerous countries.Macrocephaly is one of the most replicated findingsconcerning head circumference in people with ASD [e.g.(6–9)]. In fact, this condition is overrepresented among theASD population, with numerous studies indicating rates ofapproximately 20% (6, 8). An accelerated growth in headcircumference within the first 12 months of life, which isnot accompanied by similar increases in body weight andlength, has been observed to be associated with ASD (7,10).Although research findings on this disproportionateincrease in head circumference are consistent, findings atbirth have yielded mixed results.

Abbreviation

ADI-R, Autism Diagnostic Interview-Revised; ASD, Autismspectrum disorders; CDC, Centers for Disease Control; DSM,IV, Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition; ICD-10, International Statistical Classificationof Diseases and Related Health Problems, 10th revision; PDD,Pervasive developmental disorders.

Key notes� Head circumference increases atypically in ASD but

individuals who are later diagnosed with ASD do nothave a significantly larger head circumference at birth.

� Here, we showed that, at birth, relative macrocephalyand microcephaly with regard to body length weremore frequently observed among individuals with ASDthan among those who developed normally.

� Morphological ratio of head circumference to length atbirth may be an early warning sign of ASD.

ª2013 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2013 102, pp. 901–907 901

Acta Pædiatrica ISSN 0803-5253

Most studies show that individuals who are later diag-nosed with ASD do not have a significantly larger headcircumference at birth than those who develop normally(10,11). Whereas some studies have referred directly tonormative datasets, such as the Centers for Disease Control(CDC) data set (12) or the Japanese infant physical growthsurvey (13), others have compared their results with a databank. For example, Torrey et al. (14) used longitudinal headcircumference data collected prospectively on 15 childrenwith autism from the National Collaborative PerinatalProject, which registered more than 55 000 children.Various studies came to different conclusions. Courchesneet al. (7) reported that 48 children with ASD had asignificantly smaller head circumference at birth comparedwith normative data from the CDC. Mraz et al. (15)compared the head circumferences of 35 children withASD with those of 37 typically developing children andfound that the latter group had smaller head circumferencesat birth. After controlling for height and weight, however,this difference disappeared. Finally, Gillberg and de Souza(16) found a higher rate of macrocephaly at birth inchildren with Asperger syndrome compared with childrenwith autism disorder. These results are consistent with thoseof Fombonne et al.’s previous study (6). Fombonne et al. (6)proposed that this higher rate of macrocephaly corre-sponded only to a subset of individuals with ASD ratherthan to a shift of the entire head circumference distributionto the right for all individuals with ASD. Interestingly, arecent study suggested that atypical brain development inpeople with ASD begins during pregnancy (17). From 10individuals with ASD and 56 controls, Whitehouse et al.(17) obtained data on head circumference and body lengthat 18 weeks gestation and at birth. They found that a fewindividuals with ASD already had a disproportionately largehead relative to their body at 18 weeks gestation (n = 5)and at birth (n = 2). Unfortunately, small sample sizes (i.e.<100 individuals) and the absence of a real control group(i.e. comparisons of normative data) limit most of thesestudies.

Although macrocephaly has been widely explored,microcephaly is less investigated in people with ASD.Fombonne et al. (6) found that 15.1% of 126 children withASD had microcephaly. This condition was more frequentamong girls and participants with mental retardation.Miles et al. (9) found a lower rate of microcephaly(7.3%) among 235 individuals with ASD. These differentresults are most likely related to the different studypopulations (i.e. whether individuals with recognizedmedical disorders were included) or definitions of micro-cephaly (i.e. head circumference under the third percentileor an occipitofrontal circumference <2 standard deviationsbelow the mean, respectively). Finally, two broader studiesaimed to determine whether specific physical anomaliesare more frequent in people with ASD. Interestingly,certain body disproportions occurred more frequently,such as hypertelorism (18). Taken together, these studieshighlight the common finding of morphological dispro-portions in people with ASD. However, we do not have

this information for neonates who are later diagnosed withASD at birth.

This study compared the head circumferences of neo-nates who were later diagnosed with ASD with a controlgroup. We also investigated the morphological dispropor-tions present at birth. Therefore, we used absolute andrelative values of head circumference, as well as bodyweight and length data standardized by gestational age andgender. We are aware of the importance of prenatal andperinatal risk factors, cognitive and developmental data.However, in this study, we focused our purpose on the topicexplained above.

MATERIALS AND METHODSParticipantsThe sample consisted of 422 ASD individuals and 153control individuals between 18 months and 18 years old.All parents (or guardians) gave verbal consent and theirchild’s health records to allow us the data collection.

Individuals in the group of ASD included in this studywere recruited in the database of the Centre de RessourcesAutisme Bretagne (France) between 2001 and 2011(n = 875). To be eligible, they had to (1) receive a diagnosisof autism disorder, Asperger syndrome or other pervasivedevelopmental disorders (other PDD) according to theICD-10 criteria (see below for details) and (2) record data atbirth about head circumference, body length, weight andgestational age and (3) be under 18 years at time of the firstevaluation. If a diagnosis was made before the age of 3, areassessment was made at the age of 5; if not, the individualwas excluded from this study. Moreover, individuals withmajor congenital, genetic or neurological abnormalitieswere excluded. Four hundred and forty-two individualswith ASD met these criteria. They were 339 males and 83females (mean age: 90.7 � 23.6 months): 224 individualswith autism disorder (F84.0), 104 individuals with Aspergersyndrome (F84.5) and 94 individuals with other PDD(F84.8). All individuals were diagnosed based on the DSMIV (19) and ICD-10 criteria (20). The ADI-R ratings (21)confirmed these diagnoses. Social interaction impairments,communication deficits, restricted interests and repetitivebehaviours constitute the triad of ASD symptoms (19).Developmental and cognitive levels were not available forall individuals; thus, we did not include these data here.

Individuals in the control group included in this studywere also recruited in France, based on a voluntaryparticipation. To be eligible, they had to (1) record data atbirth about head circumference, body length, weight andgestational age and (2) presented no developmental delay.We excluded individuals (1) with congenital, genetic orneurological abnormalities (or suspicion) or (2) withsiblings diagnosed with ASD or related disorders. Hundredfifty-three individuals met these criteria. They were 84males and 69 females (mean age: 82.0 � 23.0 months).

The individuals with ASD did not differ significantly inage at time of recruitment from the individuals in thecontrol group (Mann–Whitney U-test, p = 0.09). As sex

902 ª2013 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2013 102, pp. 901–907

Autism, head circumference and body length at birth Grandgeorge et al.

ratio in ASD is unbalanced, we had significantly morefemales in the control group (Chi-squared test, X² = 49.79,p < 0.001).

Data collectionIn France, all newborns are routinely examined at birth andpersonal information is compiled in their health records (amedical document that is completed at each life stage). In ourstudy, we collected the following data at birth for eachindividual: headcircumference (cm), body length (cm),weight(g), gender (male or female) and gestational age (weeks).

Head circumference, body length and body weight werestandardized with regard to gestational age and genderusing the French reference grid (22). We used the onlineversion of this reference, which is more reliable andaccurate than the paper version (http://www.audipog.net).The conversion of the data to percentiles enabled compar-isons to be made between males and females who were bornat different gestational ages. We obtained the percentiles forhead circumference, body length and body weight.

For the purpose of this study, we used two definitions.Genuine macrocephaly was considered to be present whenthe infant’s head circumference was above the 97thpercentile, and genuine microcephaly was considered tobe present when the infant’s head circumference was belowthe 3rd percentile. Data concerning birth length and weightfollowed the same convention (above the 97th percentileand below the 3rd percentile). Alternatively, relative mac-rocephaly and relative microcephaly were defined withregard to body length and weight. To examine headcircumference relative to an infant’s length (or weight), adifference score was calculated by subtracting the lengthpercentile (or the weight percentile) from the head circum-ference percentile according to a previous study (17). Apositive score indicated a greater standardized head cir-cumference relative to an infant’s length (or weight),whereas a negative score signified the opposite. By con-vention (23), difference scores of 40 percentiles (or more)were viewed as morphological disproportion and arereferred to as relative macrocephaly or relative microceph-aly, respectively.

Data analysisBecause our data were not normally distributed, we usednonparametric statistical tests. The mean head circumfer-

ence, length and weight percentiles were comparedbetween groups using Mann–Whitney U-tests. Fisher’sexact tests were used to compare categorical variables.Data were analysed using SPSS 19 software (IBM software,USA). The significance threshold was 0.05.

RESULTSTable 1 presents the standardized mean percentiles of headcircumference, body length and body weight. The individ-uals with ASD did not significantly differ from the controlgroup at birth (all Mann–Whitney U-tests, p > 0.05;Table 1).

Table 2 presents the percentiles of head circumference,body length and body weight with regard to the genuinemacrocephaly and microcephaly data.

Twenty-four individuals with ASD (5.7%) and fourcontrol participants (3%) had genuine macrocephaly atbirth. Although the rate of genuine macrocephaly washigher among individuals with ASD, no significant differ-ence was observed (Fisher’s exact test p = 0.092). Interest-ingly, the rate of genuine macrocephaly among individualswith other PDD was 3 times higher than that among thecontrol group (9 and 3%, respectively; Fisher’s exact testp = 0.039). Fifteen individuals with ASD (3.6%) and 4individuals in the control group (3%) had genuine micro-cephaly at birth. The control group did not differ fromindividuals with ASD with regard to head circumference(all Fisher’s exact tests, p > 0.05).

Eleven individuals with ASD (2.6%) and 5 individuals inthe control group (3%) had a body length greater than the97th percentile at birth. Twenty-two individuals with ASD(5.2%) and 6 individuals in the control group (4%) wereshorter than the 3rd percentile at birth. The control groupdid not significantly differ from individuals with ASD withregard to body length (all Fisher’s exact tests, p > 0.05).

Twelve individuals with ASD (2.9%) and 2 individuals inthe control group (1%) were heavier than the 97th percen-tile at birth. Twenty-six individuals with ASD (6.2%) and 7individuals in the control group (5%) were lighter than the3rd percentile at birth. The control group did not signifi-cantly differ from individuals with ASD with regard toweight (all Fisher’s exact tests, p > 0.05).

Figure 1 presents the relative macrocephaly and micro-cephaly rates with regard to body length.

Table 1 Birth measurement data (in mean percentiles) in individuals with ASD compared with individuals in control group (Mann–Whitney U-test, level of significance p < 0.05)

Head circumference Length Weight

Percentile (mean � SD) MW test (p-value) Percentile (mean � SD) MW test (p-value) Percentile (mean � SD) MW test (p-value)

Control 50.3 � 14.0 45.5 � 14.3 49.2 � 13.9

ASD 50.2 � 15.1 32720 (0.804) 47.7 � 15.0 30431 (0.293) 48.2 � 15.0 31783 (0.776)

Autism disorder 48.6 � 14.8 17268 (0.899) 48.6 � 14.6 16035 (0.289) 51.2 � 15.1 16812 (0.755)

Asperger syndrome 51.7 � 15.2 7552 (0.49) 50.0 � 15.5 7245 (0.224) 52.0 � 15.1 7682 (0.639)

Other PDD 44.2 � 15.3 7891 (0.199) 45.8 � 29.8 7151 (0.942) 49.5 � 14.4 7289 (0.857)


Grandgeorge et al. Autism, head circumference and body length at birth

Relative macrocephaly with regard to body length wasfound in 11.4% of the individuals with ASD (n = 48),which was significantly higher than the rate of 6% foundin the control group (n = 9; Fisher’s exact test p = 0.032).Interestingly, a similar difference was observed betweenindividuals with other PDD (n = 13, 14%) and the controlgroup (Fisher’s exact test p = 0.030). Relative macroceph-aly with regard to body length tended to be more commonamong individuals with autism disorder (n = 23, 10.3%)and Asperger syndrome (n = 12, 12%) than the controlgroup (Fisher’s exact tests p = 0.093 and p = 0.079,respectively).

Relative microcephaly with regard to length was foundamong 8.3% of individuals with ASD (n = 35), which wassignificantly higher than the rate of 2% found in the controlgroup (n = 3; Fisher’s exact test p = 0.003). Interestingly,this relative microcephaly was more frequent among indi-viduals with autism disorder (n = 18, 8.0%) and Aspergersyndrome (n = 12, 12%) than the control group (Fisher’sexact tests p = 0.008 and p = 0.001, respectively). Thesedifferences were not found between individuals with otherPDD (n = 5, 5%) and the control group (Fisher’s exact testp = 0.141).

Figure 2 presents the relative macrocephaly and micro-cephaly rates with regard to body weight.

The rate of relative macrocephaly with regard to weightdid not differ among individuals with ASD (n = 32, 7.6%),autism disorder (n = 18, 8.0%), Asperger syndrome (n = 5,5%) and other PDD (n = 9, 10%) compared with thecontrol group (n = 9, 6%) (All Fisher’s exact tests p > 0.05).

The rate of relative microcephaly with regard to weight inthe control group (n = 6, 4%) did not significantly differ fromthat of individuals with ASD (n = 32, 7.6%) or that ofindividuals in the ASD subgroups of autism disorder, Asper-ger syndrome and other PDD (n = 13, 5.8%; n = 8, 8% andn = 5, 5%, respectively; all Fisher’s exact tests, p > 0.05).

DISCUSSIONThe current study replicated earlier findings that individualslater diagnosed with ASD did not have significantly largerhead circumferences at birth than normally developingindividuals in a large cohort. In contrast, however, thisstudy found that the morphological ratio of head circum-ference to body length at birth may be an important factorto follow. Relative macrocephaly and microcephaly withregard to body length were more frequently observedamong individuals later diagnosed with ASD than amongthose who developed normally. Interestingly, differencesalso existed among the subgroups of ASD.

The finding of a normal head circumference at birthamong individuals later diagnosed with ASD is consistentwith the majority of previous studies (10,11). Similarconclusions were found concerning body length and weightat birth. When we focused on extreme head circumferencemeasurements, our results revealed that 5.7% of individuals

Table 2 The number of individuals with ASD (%) with head circumferences, lengths and weights above the 97th percentile or below the 3rd percentile compared with individualsin control group in number of individuals and per cent in brackets (Fisher’s exact test, level of significance: *p < 0.05; **p < 0.01; ***p < 0.001)

Head circumference Length Weight

<3rd perc. >97th perc. <3rd perc. >97th perc. <3rd perc. >97th perc.

Control 4 (3%) 4 (3%) 6 (4%) 5 (3%) 7 (6%) 2 (1%)

ASD 15 (3.6%) 24 (5.7%) 22 (5.2%) 11 (2.6%) 26 (6.2%) 12 (2.8%)

Autism disorder 9 (4.0%) 11 (4.9%) 12 (5.4%) 5 (2.2%) 16 (7.1%) 7 (3.1%)

Asperger syndrome 2 (2%) 5 (5%) 3 (3%) 1 (1%) 5 (5%) 4 (4%)

Other PDD 4 (4%) 8 (9%)* 7 (7%) 5 (5%) 5 (5%) 1 (1%)

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Figure 1 Rate of relative macrocephaly (A) and relative microcephaly (B) withregard to the body length of individuals with ASD compared with controlparticipants (Fisher’s exact test: NS, not significant; p > 0.05; *p < 0.05;**p < 0.01; ***p < 0.001).



had macrocephaly and 3.6% had microcephaly. Our resultsconcerning macrocephaly are in accordance with those ofnumerous other studies. For example, Dementieva et al.(24) reported that 5% of 42 participants with ASD hadmacrocephaly at birth. Stevenson et al. (25) showed thatthe head size of 18 young individuals with later macro-cephaly was normal at birth in all but one individual whowas already macrocephalous. In contrast, Courchesne et al.(7) found no incidence of macrocephaly among 48 individ-uals at birth. However, microcephaly data at birth arescarce. Our results correspond to the 3% microcephaly ratepreviously observed (24). However, our data should beconsidered with caution due to confounding factors. Forexample, microcephaly is commonly associated with lowintelligence, seizures and heredity (26). These factors mayexplain the differences in microcephaly rates in somestudies (6,9,24); however, their implications at birth havenot been established. Note that eight individuals in ourstudy had developmental delays, and only one was micro-cephalous at birth.

One of the most interesting findings was the higher rateof disproportionate head circumference-to-body lengthratios observed among individuals later diagnosed withASD compared with normally developing individuals.Although this difference was not observed in a smallersample (15), we observed that approximately 11% of

individuals later diagnosed with ASD had relative macro-cephaly at birth. These findings support the hypothesis thatthe rapid increase in head circumference characteristic ofASD begins during pregnancy. Relative macrocephaly, butnot genuine macrocephaly, may be a cue for this develop-ment. In fact, Whitehouse et al. (17) showed that 5individuals with ASD already had disproportionately largeheads relative to their body size at 18 weeks of gestation,and two people had the same condition at birth. Surpris-ingly, relative microcephaly at birth was observed inapproximately 11% of individuals later diagnosed withASD (i.e. a head that was small for their body size). To ourknowledge, this result has not been previously reported.Additional research is needed to explore this phenomenon,for example, using MRI scans in addition.

Interestingly, the head circumference-to-body weightratio did not distinguish individuals later diagnosed withASD from those who developed normally. Paediatricianstypically expect infant body weight to be more variable thanhead circumference and body length. For example, adecrease in weight has been observed in cases of chronicfoetal distress, such as occurs due to vascular problems anddefects in placental perfusion; external factors exert lessinfluence on head circumference and body length. Thisresult partially explains why the head circumference-to-weight ratio was not a discriminating factor.

The present study highlighted the variability associatedwith the ASD subgroups. On one hand, only individualslater diagnosed with autism disorder or Asperger syndrome(but not those with other PDD) were more likely to haverelative microcephaly. On the other hand, even if relativemacrocephaly was significantly higher among those indi-viduals later diagnosed with other PDD, the tendency wasmore obvious in the two other groups (i.e. the autismdisorder and Asperger syndrome groups). Gillberg and DeSouza (16) found a higher rate of genuine macrocephaly atbirth (25.6%; n = 43) among individuals later diagnosedwith Asperger syndrome compared with attention-deficithyperactivity disorders and autism disorders. This conditionis less frequent in individuals later diagnosed with ASD(9.5%; n = 42). These authors proposed that ‘high-func-tioning ASD may differ from low-functioning forms of thedisorder with regard to rate and type of macrocephalous’.They also noted that this finding is not specific to peoplewith ASD because the individuals with attention-deficithyperactivity disorder in their study also had a higher rateof macrocephaly (14.9%; n = 47) compared with Aspergersyndrome and autism disorders. Therefore, our findingssupport the hypothesis that separate neurobiological mech-anisms exist among the subgroups of ASD (16). Thus, thehigher rates of macrocephaly and microcephaly may onlybe relevant for a subset of individuals with ASD, rather thanindicating a shift of the entire head circumference distribu-tion to the right (6). The head circumference may be a validindicator of whole brain volume and weight (4); however,we suggested adding MRI scans to better understand theunderlying mechanisms. Of course, a genetic implicationcould not be excluded as showed recently (27). These

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Figure 2 Rate of relative macrocephaly (A) and relative microcephaly (B) withregard to the body weight of individuals with ASD compared with controlparticipants (Fisher’s exact test, level of significance: NS, not significant;p > 0.05; *p < 0.05; **p < 0.01; ***p < 0.001).



assumptions imply that ASD subgroups must be betterdifferentiated in future studies.

The present study focused on measurements at birth;however, we can hypothesize about the development ofindividuals with relative microcephaly or those with relativemacrocephaly with regard to body length based on theiraccelerated head circumference growth in the first12 months (7,10). On one hand, individuals with relativemacrocephaly may display disproportionate increases inhead size. This increase may lead to the macrocephalousindividuals with ASD observed in numerous studies (6, 8).On the other hand, individuals with relative microcephalymay also have accelerated increases in head size. Thisenlargement would eventually be proportional, and theseindividuals would not be considered unusual. Additionalstudies are needed to investigate the development of theseindividuals, as they represent a significant percentage ofASD individuals, including those in specific subgroups ofASD (i.e. autism disorder and Asperger syndrome) withoutcomorbidity; to our knowledge, however, no literatureexists on this population.

One limitation of this study was the fact that parentalhead circumference was not measured or controlled for theanalyses. In fact, Weaver and Christian (28) showed that acorrelation exists between the head circumference of theparents and the head circumference of their children. Thisparameter must be controlled in future research to confirmthe present findings. An additional limitation concerns therecruitment of the control group, which was based onvoluntary participation rather than on a database ofchildren. At last, we did not have data about currentcognitive and developmental level as well as prenatal andperinatal risk factors that could be informative.

In conclusion, we are aware that growth trajectories ofindividual infants are likely to be more important thansingle-point measurement. Thus, these results must bereplicated, especially in a prospective cohort study includingbrain growth. We suggest that the head circumference-to-body length ratio may serve as a screening tool with whichto identify possible children at risk of ASD. This indicatorshould be added to the early warning signs of ASD (3). Thepresence of numerous indicators, such as a breech birth, lowApgar score at 5 minutes, preterm birth and low birthweight (for girls) (29), may be more alarming to parents thanother signs; therefore, paediatricians and other healthcareproviders play an important role in identifying youngchildren who are at risk of ASD via active surveillance (30).

ACKNOWLEDGEMENTSWe thank Dr Jacques Sizun, paediatrician (CHRU Brest),for her pertinent advice, Dr Hervochon, the families anddoctors for their participation and CHRU Brest for theirsupport.

FUNDING SOURCENo specific funding.

FINANCIAL DISCLOSUREThe authors have no financial relationships relevant to thisarticle to disclose.

CONFLICT OF INTERESTThe authors have no conflicts of interest to disclose.

CLINICAL TRIAL REGISTRATIONNone.

References

1. King M, Bearman P. Diagnostic change and the increasedprevalence of autism. Int J Epidemiol 2009; 38: 1224–34.

2. Goin-Kochel RP, Mackintosh VH, Myers BJ. How manydoctors does it take to make an autism spectrum diagnosis?Autism 2006; 10: 439–51.

3. Walsh P, Elsabbagh M, Bolton P, Singh I. In search ofbiomarkers for autism: scientific, social and ethical challenges.Nat Rev Neurosci 2011; 12: 603–12.

4. Bartholomeusz HH, Courchesne E, Karns C. Relationshipbetween head circumference and brain volume in healthynormal toddlers, children and adults. Neuropediatrics 2002; 33:239–41.

5. Redcay E, Courchesne E. When is the brain enlarged in autism?A meta analysis of all brain size reports Biol Psychiatry 2005;58: 1–9.

6. Fombonne E, Rog�e B, Claverie J, Courty S, Fr�emolle J.Microcephaly and macrocephaly in autism. J Autism DevDisord 1999; 29: 113–9.

7. Courchesne E, Carper R, Akshoomoff N. Evidence of brainovergrowth in the first year of life in autism. J Am Med Assoc2003; 290: 337–44.

8. Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G,et al. Head circumference and height in autism: a study by theCollaborative Program of Excellence in Autism. Am J MedGenet 2006; 140: 2257–74.

9. Miles JH, Hadden L, Takahashi TN, Hillman RE. Headcircumference is an independent clinical finding associatedwith autism. Am J Med Genet 2000; 95: 339–50.

10. Lainhart JE, Piven J, WzorekM, Landa R, Santangelo SL, CoonH, et al. Macrocephaly in children and adults with autism.J Am Acad Child Psychiatry 1997; 36: 282–90.

11. Courchesne E, Karns CM, Davis HR, Ziccardi R, Carper RA,Tigue ZD, et al. Unusual brain growth patterns in early life inpatients with autistic disorder: an MRI study. Neurology 2001;57: 245–54.

12. Gray KM, Taffe J, Sweeney DJ, Forster S, Tonge BJ. Could headcircumference be used to screen for autism in young males withdevelopmental delay?. J Paediatr Child Health 2012; 48: 329–34.

13. Fukumoto A, Hashimoto T, Ito H, Nishimura M, Tsuda Y,Miyazaki M, et al. Growth of head circumference in autisticinfants during the first year of life. J Autism Dev Disord 2008;38: 411–8.

14. Torrey EF, Dhavale D, Lawlor JP, Yolken RH. Autism andhead circumference in the first year of life. Biol Psychiatry2004; 56: 892–4.

15. Mraz KD, Green J, Dumont-Mathieu T, Makin S, Fein D.Correlates of head circumference growth in infants laterdiagnosed with autism spectrum disorders. J Child Neurol2007; 22: 700–13.



16. Gillberg C, de Souza L. Head circumference in autism,Asperger syndrome, and ADHD: a comparative study. DevMed Child Neurol 2002; 44: 296–300.

17. Whitehouse A, Hickey M, Stanley F, Newnham J, Pennell C.Brief report : a preliminary study of fetal head circumferencegrowth in autism spectrum disorder. J Autism Dev Disord2011; 41: 122–9.

18. Walker HA. Incidence of minor physical anomaly in autism. JAutism Child Schizophr 1977; 7: 165–76.

19. American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders. 4th ed. Washington: AmericanPsychiatric Association, 1994.

20. World Health Organisation. Diagnostic Criteria for Research.10th ed. Geneva: World Health Organisation, 1994.

21. Lord C, Rutter M, Le Couteur A. Autism diagnostic interview-revised: a revised version of a diagnostic interview forcaregivers of individuals with possible pervasive developmentaldisorders. J Autism Dev Disord 1994; 24: 659–85.

22. Semp�e M, P�edron G, Roy-Pernot MP. Auxologie M�ethode etS�equences. Paris: Théraplix Edition, 1979.

23. Winter RM, Baraitser M. Multiple Congenital AnomalySyndromes: A Catalogue of Human Malformation Syndromes -First Supplement. London: Chapman & Hall, 1993.

24. Dementieva YA, Vance DD, Donnelly SL, Elston LA, WolpertCM, Ravan SA, et al. Accelerated head growth in earlydevelopment of individuals with autism. Pediatr Neurol 2005;32: 102–8.

25. Stevenson RE, Schroer RJ, Skinner C, Fender D, Simensen RJ.Autism and macrocephaly. Lancet 1997; 349: 1744–5.

26. Mochida GH. Genetics and biology of microcephaly andlissencephaly. Semin Pediatr Neurol 2009; 16: 120–6.

27. Klein S, Sharifi-Hannauer P, Martinez-Agosto JA.Macrocephaly as a clinical indicator of genetic subtypes inautism. Autism Res 2013; 6: 51–6.

28. Weaver DD, Christian JC. Familial variation of head size andadjustment for parental head circumference. J Pediatr 1980; 96:990–4.

29. Larsson HJ, EatonWW, Madsen KM, Vestergaard M, VingaardOlesen A, Agerbo E, et al. Risk factors for autism: perinatalfactors, parental psychiatric history, and socioeconomic status.Am J Epidemiol 2005; 161: 916–25.

30. Zwaigenbaum L, Bryson S, Lord C, Rogers S, Carter A, CarverL, et al. Clinical assessment and management of toddlers withsuspected autism spectrum disorder: insights from studies ofhigh-risk infants. Pediatrics 2009; 123: 1383–91.



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Autism spectrum disorders: head circumference and body length at birth are both relative