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Early Human Development (2007) xx, xxx–xxx

ARTICLE IN PRESSEHD-02874; No of Pages 7

Minor physical anomalies in children with autismspectrum disorder☆

Gabriele Tripi a,⁎, Sylvie Rouxb, Tatiana Canziani a,c,Frédérique Bonnet Brilhault b, Catherine Barthélémyb, Fabio Canziani a

a Department of Child Neuropsychiatry, “Aiuto Materno” Hospital, University of Palermo,Via Lancia di Brolo 10 bis-90100 Palermo, Italyb Department of Neurophysiological Explorations in Pedopsychiatry, INSERM U 619, Equipe n° 1, CHRU Bretonneau,Bld. Tonnellé 37044 Tours, Cedex 1, Francec Didactic Area of Scientific English, Faculty of Medicine, University of Palermo, Via del Vespro, 129-90127 Palermo, Italy

Accepted 25 April 2007

☆ The study was performed in accordMaterno” hospital (Palermo, Italy) andconsent.⁎ Corresponding author. Tel.: +39091E-mail address: gabrieletripi@hotm

0378-3782/$ - see front matter © 200doi:10.1016/j.earlhumdev.2007.04.005

Please cite this article as: Tripi G,doi:10.1016/j.earlhumdev.2007.04.0

Abstract

Aim: To investigate the rate and topological profile of minor physical anomalies (MPAs) (prenatalerrors of morphogenesis) in a group of children with Autism Spectrum Disorder (ASD), in order tobetter set a temporal framing of embryological factors involved in the neurodevelopmentaletiology.Method: A new modified Waldrop scale and a mixed approach of computerized photogrammetryand classic anthroposcopy was used to detect the presence or absence of 41 MPAs in 24 children(mean age: 7 years; sex ratio: 22M:2F) with ASD and 24 healthy comparison subjects (mean age:7 years; sex ratio: 19M:5F) selected with DSM IV and CARS.Results: We found that children with ASD presenting MPAs (n=23; 96%) had significantly higherrates of MPAs in four body areas (head, ears, mouth, hands); interestingly three of 41 MPAs bestdiscriminated ASD groups from comparison subjects: abnormal head circumference, abnormalcephalic index, abnormal palate. Moreover, our results suggest that most MPAs occurpredominantly after the first trimester of pregnancy.Conclusions: These results support a prenatal neurodevelopmental model of the autism spectrumdisorder.© 2007 Elsevier Ireland Ltd. All rights reserved.

KEYWORDSAutism spectrum disorder;Minor physical anomalies;Neurodevelopment

ance with basic principles of the Declaration of Helsinki (1); the hospital ethical committees of “AiutoCHRU Bretonneau (Tours, France) have approved all the study procedures and all parents gave informed

7035422, +393396965689.ail.com (G. Tripi).

7 Elsevier Ireland Ltd. All rights reserved.

et al, Minor physical anomalies in children with autism spectrum disorder, Early Hum Dev (2007),05

2 G. Tripi et al.

ARTICLE IN PRESS

1. Introduction

Autism Spectrum Disorder (ASD) is a heterogeneous and widespectrum [1] of neurobiological disorders [2–5] with aprevalence of 3 to 6/1000, and an approximate ratio of 3:1of affected male to female [6].

Commonly in literature, autistic disorder (AD), pervasivedevelopmental disorder-not otherwise specified (PDD-NOS),and Asperger syndrome (AS) are collectively referred to asASD [7]; a wide phenotype characterizes this spectrum byimpairments in three behavioural domains: social interac-tion; language, communication, and imaginative play; rangeof interests and activities [8].

Mental retardation [9], epilepsy [10], chromosomal andsingle gene disorders [11,12] and pre-, peri- and neonatalfactors [13] are highly associated to this wide phenotype.

Furthermore, previous studies described different pat-terns of minor physical anomalies (MPAs) in association withASD [14–19].

MPAs are mild errors of morphogenesis with a pre-natalorigin (the first or the second trimester of pregnancy); theirspecial relevance in psychiatry is determined by the commonectodermal embryonic origin with the central nervoussystem, representing external markers of abnormal braindevelopment [14,20,21].

According to the International Working Group report [22],which establishes a clear distinction between morphogeneticevents developed during or after organogenesis, MPAs may beclassified into “Minor Malformations (MM)” and “Phenoge-netic Variants” (PV).

MM are qualitative defects of embryogenesis and ariseduring organogenesis; their classification is based on theprinciple of “all or none”, being true deviations from normal.

In contrast, PV are phenogenetic quantitative defects offinal morphogenesis arising after organogenesis and contin-uously modifying from the birth until sexual maturity; theymorphologically represent the exact equivalent of thenormal anthropometric variants [21–23].

The aim of the present study was to investigate the rateand topological profile of minor physical anomalies in a groupof childrenwith ASD, in order to better set a temporal framingof embryological factors involved in the neurodevelopmentaletiology.

2. Material and methods

2.1. Subjects

The population of this study is composed by 24 subjects (22M:2 F; mean age=7 years; S.D.=2.29) affected by ASD (18subjects with AD, 2 subjects with AS , 4 subjects with PDD-NOS), and 24 healthy comparison subjects (19 M:5 F; meanage=7 years, S.D.=2.29). These subjects have been selectedat the “Bretonneau Hospital-Department of Pedopsychiatry”in Tours (France) and at the “Aiuto Materno Hospital-Department of child neuropsychiatry” in Palermo (Italy).The study was performed in accordance with the Declarationof Helsinki; the two hospital ethical comities have approvedall the study procedures and all parents gave informedconsent. The population is composed by children of Europeanorigin and ethnically Caucasian, because normative physical

Please cite this article as: Tripi G, et al, Minor physical anomalies indoi:10.1016/j.earlhumdev.2007.04.005

data have been well-defined in the Caucasian population[24,25]. The ASD group has been selected only includingsubjects reflecting the symptomatic diagnostic criteria ofDiagnostic and Statistical Manual of Mental Disorders-FourthEdition (DSM-IV) [8] and the severity threshold of theChildhood Autism Rating Scale (CARS) (autism cut-offscore: 29.5) [26]. Due to the clinical setting in which theCARS was conducted, CARS scores were not based solely onobservation, but were based on a combination of observationof the child and information given by the parent(s) duringinterviews [27]. CARS scores were independently generatedfor all children by the same psychologist (T.C.) in the twodepartments. Sixteen of the ASD children had CARS totalscore ratings that fell in the mildly to moderately autisticrange (30–36.5), and eight had ratings in the severe (N37.5)autistic range. Children with Rett Syndrome and childhooddisintegrative disorder were excluded from the study.Potential ASD subjects were also excluded if found to haveevidence of associated epileptic seizures, genetic or meta-bolic disorders (e.g.: tuberous sclerosis, neurofibromatosis,X fragile syndrome). Their exclusion has been based on adetailed clinical history, neurological and paediatric evalu-ation, metabolic tests, genetic and neuroradiological examsif necessary. As well as the ASD sample, the control group hasbeen strictly selected in order to exclude from it all thesubjects having family histories of neuropsychiatric andgenetic pathologies.

2.2. Measures

2.2.1. Assessment of minor physical anomaliesMPAs were assessed for each subject using an extended andstandardized scale consisting of 41 items, representing MPAs insix body areas (global head, eyes, ears,mouth, hands and feet)(see Appendix). The scale encompassed 19 items from theWaldrop scale [14] and 19 items based on other source [20].

We also included three items in accordance with theneuroectodermal origins of the anomalies they represent:cephalic index , philtrum length and interalar distance (nasalwidth).

The item of “cephalic index” has been added for theevidence in literature of subjects with ASD and brachyceph-aly or dolichocephaly/plagiocephaly [28,12], and becausethe only measurement of head circumference remainsinsufficient to qualify brain growth [29].

The item of “philtrum length” has been added for theevidence in literature of subjects with ASD and MPAs patternsincluding a short/long philtrum [30,9], while the item of“interalar distance” because this length gives information onmidline brain anomalies [31].

Although the original Waldrop scale items were weighted0,1 or 2 (according to the degree of deviation from thenorm), items presented in our assessment were categorizedas present (score 1) or absent (score 0) due to the complexityof categorizing a trait as more severe (weight 2) compared tomild (weight 1). A clear differentiation between MM and PVwas done according to Trixler et al. [21] (see Appendix).

All examinations were performed by the same examiner(G.T. physician, with special training in dysmorphologyexaminations) in the two departments. Anthropometric mea-surements and landmarks (see Appendix) of items: cephalicindex, head circumference, interalar distance, inner-canthal

children with autism spectrum disorder, Early Hum Dev (2007),

Figure 1 Scores for minor physical anomalies in ASD group and normal comparison children (⁎) = pb0.05.

Table 1 MPAs significantly more common in ASD group thanin normal controls

MPAs Prevalence ASD(n=24)

Control(n=24)

p value

3Minor physical anomalies in children with autism spectrum disorder

ARTICLE IN PRESS

distance, philtrum length, are borrowed from the works ofFarkas et al. [25], while standards of examination are inaccordance with Hall et al. [31], Trixler et al. [21] and Sivkovet al. [32].

2.2.2. Morphological examinationsMorphological examinations of the two groups were done bya mixed approach of computerized photogrammetry andclassic anthroposcopy.

Photographs were obtained with a high-resolution digitalcamera. The measurements based on anthropometric land-marks and the photogrammetric examinations were carriedout using an image analysis software (FlashCAD 2005®).

The standardized cranio-facial photographswere takenwiththe camera lens aligned with the subject's Frankfort horizontalplane1 [31] and with an internal measure of scale (adhesivepaper sticker) placed on the glabella landmark for the frontalview and on the condylion of the mandible for the profile view.The subject’s facial expression should be relaxed, not smiling,gently closed lips, eyes wide open, and no eyeglasses.

The hand photographs were taken with the camera lensperpendicular to the line that passes through the distalflexion crease at the wrist and the proximal flexion crease ofthe middle finger, while feet photographs with the cameralens perpendicular to the line that passes through the medialprominence of the first metatarso-phalangeal (MTP) joint andthe lateral prominence of the fifth MTP joint of the foot (forthe dorsal and plantar view).

The anthroposcopic approach was used for the items of“head circumference” (using a plastic tape measure), “softears”, “electric and fine hair”, “trichoglyphics”, and theitems of oral hollow area (palate, tongue, uvula).

1 Frankfort horizontal plane is defined by a horizontal line thatpasses through the tragion, located at the notch above thecartilaginous projection in the front of the external auditory canal(tragus), and the lowest border of the bony orbital rim (orbitale).

Please cite this article as: Tripi G, et al, Minor physical anomalies indoi:10.1016/j.earlhumdev.2007.04.005

2.2.3. Statistical analysisDescriptive statistical analyses were used to summarize theprofile of the study population. All demographic data from autis-tic subjects were compared with controls using Student's t-test.

Nonparametric statistical analyses (Mann–Whitney U-test) were used to find significance difference betweentwo groups on the means of MPAs total scores, of 6 MPAs bodyareas partial scores and the two partial scores of MPAscategories (minor malformation and phenogenetic variant).

Fisher's exact probability test, was used to determinewhich particular minor physical anomalies best discriminatedASD groups from comparison subjects. When this produced asignificant difference, we conduced the same analyses inorder to evaluate a co-occurrence of MPAs only in the ASDgroup, comparing the significantly higher anomalies with theextended scale items.

A statistical significance level was set at pb0.05 for allanalyses.

3. Results

We examined the ability of our methodology to differentiatebetween ASD groups and control subjects. Concerning theASD childrenwithMPAs (n=23; 96%), 6 subjects hadmore than

Head circumference 5 0 0.049Cephalic index 7 1 0.047High-steepled palateor narrow

11 2 0.007

children with autism spectrum disorder, Early Hum Dev (2007),

Table 2 Frequencies (percentages) for MPAs co-occurrencein ASD group

ASD group

p value

Head circumference Brachydactyly 40% p=0.036Cephalic index Clinodactyly 86% p=0.023High-steepled palateor narrow

Interalar distance 45% p=0.060

4 G. Tripi et al.

ARTICLE IN PRESS

5 anomalies, 17 had 1–5 MPAs, while 1 subject was withoutMPAs. In the control group no subject had more than 5anomalies, 18 were with 1–5 MPAs, while 6 were withoutMPAs. Further, usingMann–WhitneyU-test,we found significantdifferences, between the two groups, on the means of scaletotal score (pb0,00001) as well as on means of MPAs partialscores in head (p=0.000053), ears (p=0.027), mouth(p=0.001), and hands (p=0.02) (Fig. 1). Minor physicalanomalies in the eyes and feet were the only body areas inwhich we have not found significant differences. Fig. 1 showsalso a higher rate of differences, between the two groups, onthe means of total MM score and PV score (respectively:p=0.010, p=0.00001).

By using Fisher's exact probability test, 3 MPAs were foundsignificantly more common in the ASD groups than in normalcontrols (Table 1). Of the 3 MPAs, 2 were abnormality of thehead (abnormal head circumference, p=0.049; abnormalcephalic index, p=0.047) and 1 was abnormality of themouth (abnormal palate, p=0.007). All of them were PV.

Interestingly, in ASD group, all children with “abnormalhead circumference” were macrocephalic (head circumfer-ence ≥+1.5 SD), all children with “abnormal cephalic index”were dolichocephalic (cephalic index b75.9) and all childrenwith “abnormal palate” have a high-steepled palate; therewas no co-occurrence in the ASD group among these threeanomalies as itself.

Further we found that, the 2 significant MPAs of head area(abnormal head circumference, abnormal cephalic index)significantly co-occurred respectively with 2 MPAs in handsarea (brachydactyly and clinodactyly) (Table 2).

These analysis also shows intriguely that, “abnormal palate”(mouth) co-occurs with “abnormal nose length” (head) with adifference that approached significance (p=0.060) (Table 2).

No differences were observed between the autistic andcontrol groups for demographic data. MPAs found statisticallynon-significant differences, which needs to be furtherinvestigated due to our small number of cases.

4. Discussion

The ASD patient group showed a much higher level of minorphysical anomalies than the normal comparison subjects,corroborating the results from previous research [15–19].

The brain develops in a sequential and hierarchical way,then it is important to keep in mind that these minor physicalanomalies are fossilized imprints of early disturbance inembryonic development and are unaltered by the subse-quent illness and its consequences [20]. Rather thanexamining the total occurrence of MPAs in ASD subjects vs

Please cite this article as: Tripi G, et al, Minor physical anomalies indoi:10.1016/j.earlhumdev.2007.04.005

control, it seems more relevant to focus on specific ano-malies which are of particular relevance to the hypotheticalneurodevelopmental failure of the disorder.

In the current study , significantly higher rates of minorphysical anomalies were found nearly in all body regionsexcept for eyes and feet.

Further in the head area, the higher rate of macrocephalyin our ASD group is in accordance with previous studiesreporting increased head size in infancy in autism [19,33,34].

The results of head circumference, neuroimaging andpost-mortem studies converge to show that the brain isabnormally large in some, but not all children with autismduring post-natal development. The increased rate of headsize during infancy is an intriguing finding because itsmeaning is uncertain in regard to brain development andcourse of the disorder [34].

Furthermore, the high prevalence of dolichocephaly (notrelated to macrocephaly) in our data is a feature, distin-guishing the ASD group from the normal controls.

Gray et al. [35] and Rajlakshmi et al. [36] have pointedout that cephalic index is a gestational age-dependentbiometric parameter, in which intrinsic or extrinsic variations(unfavourable in pregnancy), may influence head shapebetween 14–28 weeks of gestation.

The results of Juul-Dam et al. [13] support previous findingsreporting that there is a consistent association of unfavourablepre-, peri- and neonatal events in pregnancy, and autism.

These observations suggest that an abnormal cephalicindex may characterize a subgroup of autism and, ifreplicated, will support the existence of disturbancesbetween 14–28 weeks of gestation, which may correspondto a critical period for cortical development.

At present the literature data shows that no one patternof head or brain growth is found in all children with autism;variability in head and brain size and rate and trajectory ofhead and brain growth appear to be part of autism, as wedefine it today [34].

The finding of a higher rate of MPAs in themouth region is ofspecial interest because high-steepled palate represents amicroform of cleft palate, which is itself frequently associatedwith midline brain anomalies as in fetal alcohol syndrome orother neurodevelopmental disorders [21]. Furthermore, thedata shows that high-steepled palate co-occur approachingsignificance, with “abnormal nasal width”. In our work all theASD subjects with “abnormal nasal width” had “widening nosebasis”. In literature previous studies have also related“widening nose basis” with midline brain anomalies [31].

The co-occurrence between the statistically higher rateMPAs of head region with respectively, brachydactyly andclinodactyly is of special interest since previous studies alsoshowed as, these anomalies are frequent features relatedto many chromosome abnormalities and autism [37,38].In contrast, our data shows no statistically significancebetween the two subject groups for these anomalies asitself. To relate MPAs in head and hand regions we needfurther investigations.

Concerning the identification of a critical period for braintrauma by using a MPA scale with distinction betweenmalformations and variants, our results suggest that mostabnormalities occur predominantly after the first trimesterof pregnancy; however, our data is insufficient to identify theexact period of developmental failure.

children with autism spectrum disorder, Early Hum Dev (2007),

Appendix A (continued )

5Minor physical anomalies in children with autism spectrum disorder

ARTICLE IN PRESS

The results observed in the current investigation appearnot consistent with some previous studies which haveattempted to determine whether specific MPAs are morefrequent in autism. Walker [15] reported that his autismpopulation had a significantly increased incidence of low-settled ear, adherent ear lobes, furrowed tongue, hyperte-lorism, 2–3 toe syndactyly. More recently Rodier et al. [18]reported that posteriorly rotated ears, small feet and largehands occurred more frequently in children with autism.

This diversity of results, could suggest a morphologicalheterogeneity of ASD, representing another feature associ-ated to the wide clinical phenotype.

However the data of this study must be tempered againstthe methodological limitations. One limitation concerns oursmall number of cases; because of this, we have notcalculated a cut-off score which optimally discriminate thepatients from control subjects (maximizing sensitivity andspecificity for ASD). Another notable limitation regards thelack of cognitive and language data in the two groups for thedifficulties to find homogeneous criteria of neuropsycholog-ical assessment in the two hospitals. It is critical that futureinvestigations will include a higher number of subjects with awide range of cognitive and communicative abilities.Although some remains sceptical regarding the etiologicalsignificance of neurodevelopmental indices such as MPAs,these stigmata occur more prominently in pervasive devel-opmental disorders [21]. Additionally, it is essential toexamine the relationship of any MPA with clinical, neuropsy-chological, or neurobiological assessments with the goalof identifying and characterizing subgroups of individualswith ASD that may facilitate future investigations of thepathophysiology of this complex disorder and more impor-tantly help in the development of effective treatmentstrategies.

Appendix A

Minor physical anomalies

Items

Please cite this articledoi:10.1016/j.earlhumd

MM/PV

as: Tripiev.2007.

Examination standards

Head

Index cephalic PV ≥±1.5 SD (euryon–euryon

line/glabella–opisthocranionline ×100)

Head circumference

PV ≥±1.5 SD (glabella–opisthocranion circumference)

Electric and fine hair

MM Hair soon awry andunmanageable

Trichoglyphics

MM None, or 2/moretrichoglyphics

Fused eyebrows

PV Apparent on inspection Prominent forehead MM Apparent on inspection Interalar distance(nasal width)

PV

≥±1.5 SD (alare–alare line)

Anteverted nostrils

PV Apparent on inspection Micrognathia PV Apparent on inspection

Eyes

Epicanthus PV

(continued on next page)

Partial/total coverage of thelacrimal caruncle.

G, et al, Minor physical anomalies in04.005

Eyes

Inner-canthaldistance (hyper–hypotelorism)

children with autism sp

PV

ectrum d

≥±1.5 SD (endocanthion–endocanthion line)

Heterochromia/Brushfields spots

MM

Unequal color of iris/yellow-grayish heterochromic spots inthe outer third part of the iris

Ptosis

PV Apparent on inspection. Coloboma MM Apparent on inspection.

Ears

Low seated ears PV A straight line is drawn from

the cutaneous auditorymeatus (porion) to meet aprofile line (glabella–labialsuperius) above/below theupper edge of the nasal ala

Adherent earlobes

MM Partly/total adherence ortotal absence (rather rare).

Asymmetric ears

PV Normal morphology butdifference in the size andprotrusion from head. If oneear is low seated this iscounted as a asymmetry aswell on this item

Soft ears

PV Soft and pliable ears that donot spring back into place

Malformed ears

MM Incomplete/absencedevelopment of helix,scapha, antihelix, tragus oranotia (rather rare)

Auricular skin-tag

MM Apparent on inspection

Mouth

Philtrum length PV ≥±1.5 SD (sellion–labial

superius)

Thin upper lip PV Apparent on inspection High-steepled palateor narrow

PV

The roof has an acute anglerather than an arch or a narrowflat area across the top

Furrowed tongue

MM One or more deep furrows notalong the center line of thetongue

Tongue with smooth-rough spots

MM

Localized thickening of thesurface of the tongue. Makesure this is not due to elevatedpapillae caused by recentconsumption of certain food

Cleft lip

MM Apparent on inspection Cleft uvula MM Apparent on inspection

Hands

Clinodactyly PV Deflection exceeding 8° Simian/Sydneycrease

MM

A single uninterrupted palmarcrease from the radial to theulnar border/proximaltransverse crease extends tothe ulnar border of the hand.

isorder, Early Hum Dev (2007),

Appendix A (continued )

6 G. Tripi et al.

ARTICLE IN PRESS

HandsBrachydactyly

Please cite this articledoi:10.1016/j.earlhumd

PV

as: Tripiev.2007.

Apparent on inspection

Tapering fingers PV Apparent on inspection Overlapping fingers PV Apparent on inspection Micronychia (nailhypoplasia)

PV

Small or almost absentfingernails

hyperconvexfingernails

PV

Apparent on inspection

Feet

Third toe PV Third toe is same length/

longer than second.

Syndactyly MM Partial or total fusion of toes Gap between firstand second toe

PV

The distance between thefirst and the second toes isthe same/exceeds the widthof the second toe

Overlapping toes

PV Apparent on inspection Retarded toes PV Apparent on inspection Deep sole crease MM The sole crease extends to

the area between the originof first and second toes

Hyperconvextoe-nails

PV

Apparent on inspection

References

[1] Wing L. The autistic spectrum. Lancet 1997;350:1761–6.[2] Lelord G, Adrien JL, Barthélémy C, Bruneau N, Dansart P, Garreau

B, et al. Further clinical evaluations elicited by functionalbiological investigations in childhood autism (article in French).Encephale 1998;24:541–9.

[3] Akshoonoff N, Pierce K, Courchesne E. The neurobiological basisof autism from a developmental perspective. Dev Psychopat2002;14:613–34.

[4] Courchesne E, Redcey E, Kennedy DP. The autistic brain: birththrough adulthood. Curr Opin Neurol 2004;17:489–96.

[5] Berthoz A, Andres C, Barthélémy C, Rogé B. L' Autisme. Dela recherche à la pratique. Paris: Ed. Odile Jacob publisher;2005.

[6] MuhleR, Trentacoste SV, Rapin I. Thegeneticsof autism. Pediatrics2004;13:472–86.

[7] Bertrand J, Mars A, Boyle C, Bove F, Yeargin-Allsopp M, DecoufleP. Prevalence of autism in a United States population: the BrickTownship, New Jersey, investigation. Pediatrics 2005;108:1155–61.

[8] American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders, DSM IV. 4th ed. Washington DC:American Psychiatric Association publisher; 1994.

[9] Gillberg C. The neurobiology of infantile autism. J Child PsycholPsychiatry 1988;29:257–66.

[10] Minshew NJ. Indices of neuronal function in autism: clini-cal and biologic implications. Pediatrics 1991;87:774–80[suppl.].

[11] Cook EH. Genetics of autism. MRDD Research Reviews, vol. 4;1998. p. 113–20.

[12] Cohen C, Pichard N, Tordjman S, Baumann C, Burglen L, ExcoffierE, et al. Specific genetic disorder and autism: clinical contribu-tion towards their identification. J Autism Dev Disord 2005;35:103–6.

[13] Juul-Dam N, Townsend J, Courchesne E. Prenatal, perinatal,and neonatal factors in autism, pervasive developmental

G, et al, Minor physical anomalies in04.005

disorder—not otherwise specified, and the general population.Pediatrics 2001;107:63–8.

[14] Waldrop MF, Pederson FA, Bell RQ. Minor physical anomaliesand behaviour in preschool children. Child Dev 1968;39:391–400.

[15] WalkerHA. Incidenceofminorphysical anomaly in autism. JAutismChild Schizophrenia 1977;7:165–76.

[16] Campbell M, Geller B, Small AM, Petti TA, Ferris SH. Minorphysical anomalies in young psychotic children. Am JPsychiatry 1978;5:573–5.

[17] Gualtieri CT, Adams A, Shen CD, Loiselle D. Minor physicalanomalies in alcoholic and schizophrenic adults and hyper-active and autistic children. Am J Psychiatry 1982;139:640–2.

[18] Rodier PM, Bryson SE,Welch JP. Minormalformations and physicalmeasurements in autism: data from Nova Scotia. Teratology1997;55:319–25.

[19] Miles JH, Hillman R. Value of a clinical morphology examinationin autism. Am J Med Genet 2000;91:245–53.

[20] Ismail B, Cantor-Graae E, McNeil TF. Minor physical anomalies inschizophrenic patients and their siblings. Am J Psychiatry1998;155:1695–702.

[21] Trixler M, Tenyi T, Csabi G, Szabo R. Minor physical anomalies inschizophrenia and bipolar affective disorders. Schizophr Res2001;52:195–201.

[22] Spranger J, Berirschke K, Hall JG, Lenz W, Lowry RB, Opitz JM,et al. Errors of morphogenesis: concepts and terms. J Pediatry1982;100:160–5.

[23] Opitz JM. Heterogeneity and minor anomalies. Am J Med Genet2000;92:373–5.

[24] Feingold M, Bossert WH. Normal values for selected physicalparameters: an aid to syndrome delineation. BD:OAS X, vol. 13;1974. p. 1–15.

[25] Farkas LG, Munro IR, Kolar JC. Anthropometric facial propor-tions in medicine, Springfield. 1987; Ed. Charles Thomaspublisher Ltd. USA.

[26] Schopler E, Reichler RJ, Renner BR. The childhood autism ratingscale (CARS). 1988 Ed. Western Psychological Services. LosAngeles. California.

[27] Teal M, Wiebe M. A validity analysis of selected instrumentsused to assess autism. J Autism Dev Disord 1986;16:485–94.

[28] Lauritsen M, Mors O, Mortensen PB, Ewald H. Infantile autismand associated autosomal chromosome abnormalities: a regis-ter-based study and a literature survey. J Child PsycholPsychiatry 1999;40:335–45.

[29] Gosselin J, Cahagan S, Amiel-Tyson C. The Amiel–Tysonneurological assessment at term: conceptual and methodolog-ical continuity in the course of follow-up. MRDD ResearchReviews, vol. 11; 2005. p. 34–51.

[30] Orstavik KH, Stromme P, Ek J, Torvik A, Skjeldal OH.Macrocephaly, epilepsy, autism, dysmorphic features, andmental retardation in two sisters: a new autosomal recessivesyndrome? J Med Genet 1997;34:849–51.

[31] Hall GH, Froster UG, Allanson JE. Handbook of normal physi-cal measurements. 1989 Ed.Oxford Medical Publications.USA.

[32] Sivkov ST, Akabaliev VH. Minor physical anomalies in healthysubjects: internal consistency of the Waldrop physical anomalyscale. Am J Hum Biol 2003;15:61–7.

[33] Gillberg C. Head circumference in autism, Asperger syndrome,and ADHD: a comparative study. Dev Med Child Neurol 2002;44:296–300.

[34] Lainhart E. Advances in autism neuroimaging research for theclinician and geneticist. Am J Med Genet C Semin Med Genet2006;142C:33–9.

[35] Gray DL, Songster GS, Parvin CA. Cephalic index: a gestationalage-dependant biometric parameter. Obstet Gynecol 1989;74:600–3.

children with autism spectrum disorder, Early Hum Dev (2007),

7Minor physical anomalies in children with autism spectrum disorder

ARTICLE IN PRESS

[36] Rajlakshmi Ch, Shyamo SM, Bidhumukhi Devi, ChandramaniSingh L. Cephalic index of foetuses of Manipuri population—abaseline study. Anat Soc India 2001;50(1):8–10.

[37] Ingram JL, Stodgell JC, Hyman SL. Discovery of allelic variantsof HOXA1 and HOXB1: genetic susceptibility to autism spectrumdisorders. Teratology 2000;62:340–93.

Please cite this article as: Tripi G, et al, Minor physical anomalies indoi:10.1016/j.earlhumdev.2007.04.005

[38] Jacquemont ML, Sanlaville D, Redon R, Raoul O. Array-basedcomparative genomic hybridization identifies high frequency ofcryptic chromosomal rearrangements in patients with syndro-mic autism spectrum disorders. J Med Genet 2006;43:843–9.

children with autism spectrum disorder, Early Hum Dev (2007),