SPECIAL ARTICLE PracticeParameter ...tion and neurodevelopmental disturbances. Two Class III studies examined the diagnostic yield of either CT or MRI and the severity of microcephaly

Practice Parameter Evaluation of the child withmicrocephaly (an evidence-based review)Report of the Quality Standards Subcommittee of the American Academy ofNeurology and the Practice Committee of the Child Neurology Society

Stephen Ashwal MDDavid Michelson MDLauren Plawner MDWilliam B Dobyns MD

ABSTRACT

Objective To make evidence-based recommendations concerning the evaluation of the child withmicrocephaly

Methods Relevant literature was reviewed abstracted and classified Recommendations werebased on a 4-tiered scheme of evidence classification

Results Microcephaly is an important neurologic sign but there is nonuniformity in its definitionand evaluation Microcephaly may result from any insult that disturbs early brain growth and canbe seen in association with hundreds of genetic syndromes Annually approximately 25000infants in the United States will be diagnosed with microcephaly (head circumference 2 SD)Few data are available to inform evidence-based recommendations regarding diagnostic testingThe yield of neuroimaging ranges from 43 to 80 Genetic etiologies have been reported in155 to 533 The prevalence of metabolic disorders is unknown but is estimated to be 1Children with severe microcephaly (head circumference 3 SD) are more likely (80) to haveimaging abnormalities and more severe developmental impairments than those with milder micro-cephaly (2 to 3 SD 40) Coexistent conditions include epilepsy (40) cerebral palsy(20) mental retardation (50) and ophthalmologic disorders (20 to 50)

Recommendations Neuroimaging may be considered useful in identifying structural causes in theevaluation of the child with microcephaly (Level C) Targeted and specific genetic testing may beconsidered in the evaluation of the child with microcephaly who has clinical or imaging abnormali-ties that suggest a specific diagnosis or who shows no evidence of an acquired or environmentaletiology (Level C) Screening for coexistent conditions such as cerebral palsy epilepsy and sen-sory deficits may also be considered (Level C) Further study is needed regarding the yield ofdiagnostic testing in children with microcephaly Neurologyreg 200973887ndash897

GLOSSARYCP cerebral palsy GDD global developmental delay HC head circumference MRE medically refractory epilepsyOMIM Online Mendelian Inheritance in Man

Microcephaly is an important neurologic sign butthere is nonuniformity in the definition of micro-cephaly and inconsistency in the evaluation of af-fected children12 Microcephaly is usually defined asa head circumference (HC) more than 2 SDs belowthe mean for age and gender23 Some academics haveadvocated for defining severe microcephaly as an HCmore than 3 SDs below the mean4-7 Other thanwhere specified this parameter uses the usual defini-

tion of microcephaly Recommended methods forHC measurement are described in appendix 2

If HC is normally distributed 23 of childrenshould by definition be microcephalic Howeverpublished estimates for HC 2 SD at birth are farlower at 0568 and 0549 The difference may beaccounted for by a non-normal distribution postna-tal development of microcephaly or incomplete as-certainment Severe microcephaly would be expected

Supplemental data atwwwneurologyorg

From the Division of Child Neurology (SA DM) Department of Pediatrics Loma Linda University School of Medicine CA Division of PediatricNeurology (LP) Childrenrsquos Hospital Regional Medical Center Seattle WA and The University of Chicago (WD) Department of HumanGenetics IL

Appendices e-1 through e-6 and references e1ndashe12 are available on the Neurology Web site at wwwneurologyorg

Approved by the Quality Standards Subcommittee on November 5 2008 by the Child Neurology Society (CNS) Practice Committee on August 22009 by the AAN Practice Committee on November 20 2008 and by the AAN Board of Directors on July 7 2009

Disclosure Author disclosures are provided at the end of the article

Address correspondence andreprint requests to the AmericanAcademy of Neurology 1080Montreal Avenue St Paul MN55116guidelinesaancom

SPECIAL ARTICLE

Copyright copy 2009 by AAN Enterprises Inc 887

in 01 of children if normal distribution is as-sumed which agrees with the published estimate of014 of neonates9

Microcephaly may be described as syndromic oras pure primary or true (microcephalia vera) de-pending on the presence or absence of extracranialmalformations or dysmorphic facial features Theseterms do not imply a distinct etiology and can beseen with either genetic or environmental causes ofneurodevelopmental impairment Some of the morecommon causes are outlined in table 1

A comprehensive history growth records for thechild and close relatives and a detailed physical ex-amination will often suggest a diagnosis or directionfor further testing Advances in neuroimaging andgenetics have improved understanding of the causesof microcephaly suggesting new approaches to classi-fication and testing In developing diagnostic algo-rithms for microcephaly defined as congenital or ofpostnatal onset we also examined whether the diagnos-tic yield depended on the severity of microcephaly

DESCRIPTION OF THE ANALYTIC PROCESSLiterature examined for this parameter (1966 ndash2007) included 4500 titles and abstracts of which150 articles were selected for review See appendicese-1Andashe-1C on the Neurologyreg Web site at wwwneurologyorg for information on databases searchterms and article classification

ANALYSIS OF EVIDENCE What is the role of diag-nostic testing of children with microcephaly Neuroimaging

CT data are available from 2 Class III studies involv-ing 143 children with microcephaly (table e-1)1011

In one study 61 of 85 children with microcephaly(2 SD) had abnormal CT findings10 Patientswith a known history of perinatal or postnatal braininjury (n 22) had the highest percentage of imag-ing abnormalities (91) Patients with one or moreextracranial congenital anomalies (n 30) had anintermediate yield (67) The lowest yield (36)was in patients (n 33) with no evidence by historyor examination of a brain injury although 4 patientshad major CNS malformations that were not sus-pected clinically Imaging findings were classifiedinto 4 groups normal (39) mild atrophyventricu-lar dilatation (31) moderate to severe atrophyventricular dilatation (28) and isolated parenchymalabnormalities (2) The degree of microcephaly corre-lated with the severity of cerebral atrophy or ventriculardilatation Five cases (6) had findings that led to amore specific diagnosis (eg schizencephaly holo-prosencephaly) In a second study of 58 children withmicrocephaly (HC 2 SD) head size did not corre-late with CT findings but there were correlations be-tween CT findings and mental retardation motor

disturbance and epilepsy11 CT was felt to be useful fordetermining prognosis

Data from 2 Class III MRI studies of 88 childrenwith microcephaly found abnormalities in 67 and80 (table e-1)1213 In one study abnormalities weredetected in 68 of children in whom a genetic disor-der was suspected or diagnosed with the most fre-quent findings being neuronal migrational disordersor callosal malformations13 In the children withpostnatal onset microcephaly 100 showed abnor-malities with hydranencephaly and infarction beingmost common The second study classified MRI abnor-malities into 4 groups congenital cytomegalovirus(CMV) infection (n 6) cerebral malformationsmyelination disorders (n 16) unclassifiable patho-logic findings (n 8) and normal (n 3)12 The highprevalence of CMV infection was due to case selectionbias In this small study the authors did not find a cor-relation between the severity of the cerebral malforma-tion and neurodevelopmental disturbances

Two Class III studies examined the diagnostic yieldof either CT or MRI and the severity of microcephaly(table e-1)1415 In one study children with mild micro-cephaly (2 SD) had a yield of 688 whereas thosewith severe microcephaly (3 SD) had a yield of75 A second study also found that children with se-vere microcephaly were more likely to have imaging ab-normalities (80) than those with mild (2 to 3SD) microcephaly (43)15 There was correlation be-tween imaging findings and neurodevelopmental out-comes as measured by the Bayley Scales of InfantDevelopment or the McCarthy Scales of ChildrenrsquosAbilities depending on the patientrsquos age15 Develop-mental quotients in the normal imaging group were 70or greater whereas quotients in the abnormal imaginggroup were 52 or less

Conclusions Data from 6 Class III studies (2 CT 2MRI 2 CTMRI) of 292 children with microceph-aly found diagnostic yields ranging from 43 to80 In 2 studies children with severe microcephaly(3 SD) were more likely (ie 75 80) to havean abnormal MRI than those with milder micro-cephaly MRI detected brain abnormalities typicallybeyond the sensitivity of CT

Recommendation Neuroimaging may be considereduseful in identifying structural causes in the evaluationof the child with microcephaly (Level C)

Clinical context MRI often reveals findings thatare more difficult to visualize on CT such as migra-tional disorders callosal malformations structuralabnormalities in the posterior fossa and disorders ofmyelination and is considered the superior diagnos-tic test16 An MRI-based classification scheme of mi-crocephaly is outlined in appendix 317 While basedon retrospective review its usefulness is apparent as

888 Neurology 73 September 15 2009

certain malformations (eg lissencephaly schizen-cephaly) are well known to be associated with severeneurologic impairment and specific gene abnormali-ties have been found in several of these disordersThus MRI is often helpful for definitive diagnosisprognosis and genetic counseling

Genetic testing There are very few data as to theprevalence and specific type of genetic abnormali-ties in children with microcephaly In one Class IIstudy of 58 children referred for evaluation of mi-crocephaly 9 (155) were found to have a ge-netic etiology18 One patient had Angelmansyndrome 1 had tuberous sclerosis 2 had multiplecongenital anomalies and 5 had a family historyof microcephaly A Class III study of 30 infants inwhom prenatal microcephaly was diagnosed by ul-trasound found associations with a chromosomedisorder in 233 multiple congenital anomaliesin 233 and specific genetic syndromes in2019 In this cohort an additional 167 hadholoprosencephaly a malformation often associ-ated with genetic abnormalities19

Conclusions Genetic etiologies may be found in155 (Class II n 58) to 533 (Class III n

30) of children with microcephaly MRI studies maydetect specific malformations associated with well-described genetic conditions

Recommendation Specific targeted genetic testingmay be considered in the evaluation of the child withmicrocephaly in order to determine a specific etiol-ogy (Level C)

Clinical context Microcephaly has been associatedwith numerous genetic etiologies (appendix 4) in-cluding syndromes whose causes are as yet unidenti-fied but which may be elucidated by furtherresearch20 Because the genetics of microcephaly is arapidly evolving field currently available data likelyunderestimate the importance and relevance of ge-netic testing as part of the diagnostic evaluation ofchildren with microcephaly20 Many of the micro-cephaly genes identified to date have been associatedwith specific phenotypes allowing more targetedclinical testing Available screening tests for chromo-somal deletions and duplications include karyotyp-ing subtelomeric fluorescent in situ hybridization andbacterial artificial chromosome or oligo-based compara-tive genomic hybridization22021 As the diagnosticyields of these tests in children with microcephaly iscurrently unknown specific recommendations regard-ing their use cannot be made at this time

Metabolic testing Metabolic disorders rarely presentwith nonsyndromic congenital microcephaly with 3notable exceptions maternal phenylketonuria in whichthe fetal brain is exposed to toxic levels of phenylala-nine phosphoglycerate dehydrogenase deficiency a dis-

Table 1 Etiologies of congenital and postnatal onset microcephaly

Congenital Postnatal onset

Genetic Genetic

Isolated Inborn errors of metabolism

Autosomal recessive microcephaly Congenital disorders of glycosylation

Autosomal dominant microcephaly Mitochondrial disorders

X-linked microcephaly Peroxisomal disorders

Chromosomal (rare ldquoapparentlyrdquobalanced rearrangements and ringchromosomes)

Menkes disease

Amino acidopathies and organic acidurias

Glucose transporter defect

Syndromic Syndromic

Chromosomal

Trisomy 21 13 18

Unbalanced rearrangements

Contiguous gene deletion Contiguous gene deletion

4p deletion (Wolf-Hirschhorn syndrome) 17p133 deletion (Miller-Dieker syndrome)

5p deletion (cri-du-chat syndrome)

7q1123 deletion (Williams syndrome)

22q11 deletion (velocardiofacialsyndrome)

Single gene defects Single gene defects

Cornelia de Lange syndrome Rett syndrome

Holoprosencephaly (isolated orsyndromic)

Nijmegen breakage syndrome

Smith-Lemli-Opitz syndrome Ataxia-telangiectasia

Seckel syndrome Cockayne syndrome

Aicardi-Goutieres syndrome

XLAG syndrome

Cohen syndrome

Acquired Acquired

Disruptive injuries Disruptive injuries

Death of a monozygous twin Traumatic brain injury

Ischemic stroke Hypoxic-ischemic encephalopathy

Hemorrhagic stroke Hemorrhagic and ischemic stroke

Infections Infections

TORCHES (toxoplasmosis rubellacytomegalovirus herpes simplexsyphilis) and HIV

Meningitis and encephalitis

Congenital HIV encephalopathy

Teratogens Toxins

Alcohol hydantoin radiation Lead poisoning

Maternal phenylketonuria Chronic renal failure

Poorly controlled maternal diabetes

Deprivation Deprivation

Maternal hypothyroidism Hypothyroidism

Maternal folate deficiency Anemia

Maternal malnutrition Malnutrition

Placental insufficiency Congenital heart disease

Reprinted with permission from Elsevier from Abuelo D Microcephaly syndromes SeminPediatr Neurol 200714118 ndash127 Note that there are approximately 500 listings for mi-crocephaly in OMIM (httpwwwncbinlmnihgovomim)

Neurology 73 September 15 2009 889

order of L-serine biosynthesis and Amish lethalmicrocephaly which is associated with 2-ketoglutaricaciduria22 Metabolic disorders associated with syn-dromic congenital microcephaly are listed in appendixe-2 Metabolic disorders are more likely to cause postna-tal onset microcephaly and are typically associated withglobal developmental delay (GDD) As was publishedin a practice parameter on the topic the diagnostic yieldof routine screening for inborn errors of metabolism inchildren with GDD is about 1 and the yield mayincrease to 5 in specific situations such as when mi-crocephaly is present23

Conclusions The prevalence of metabolic disordersamong children with microcephaly is unknownBased on prior analysis of studies of children withGDD it is likely 1 to 5

Recommendation There is insufficient evidence tosupport or refute obtaining metabolic testing on aroutine basis for the evaluation of the newborn orinfant with microcephaly (Level U)

Clinical context Microcephaly is common in GDDand the yield of metabolic testing may be higher whenthe following are present a parental history of consan-guinity a family history of similar symptoms in rela-tives episodic symptoms (seizures ataxia vomiting

encephalopathy) developmental regression extracra-nial organ failure or specific findings on neuroimag-ing23 Metabolic testing may also have a higher yield inchildren whose microcephaly remains unexplained afterother evaluations have been done There are insufficientdata to recommend when and how metabolic testingshould be done although it is reasonable to test infantswith severe primary congenital microcephaly for the el-evated urine alpha-ketoglutaric acid found in Amish le-thal microcephaly23

What neurologic disorders are associated with micro-cephaly Epilepsy Data from one Class III study involv-ing 66 children with microcephaly (2 SD) foundan overall prevalence of epilepsy of 40924 Two ClassIII studies suggest that epilepsy is more common inpostnatal onset than in congenital microcephaly In onestudy epilepsy occurred in 50 of children with post-natal onset microcephaly compared to only 357 ofthose with congenital microcephaly24 The second studyfound that epilepsy was 4 times more common in post-natal onset microcephaly25

Microcephaly is a significant risk factor for medi-cally refractory epilepsy (MRE)26-28 In a Class IIIstudy of 30 children microcephaly was found in58 of those with MRE compared to 2 in whomseizures were controlled (odds ratio 6767 p 0001)27

Epilepsy is a prominent feature of some types ofsyndromic microcephaly which are summarizedin table 2 Studies have not examined the role ofobtaining a routine EEG in children with micro-cephaly In one Class III study of children withmicrocephaly EEG abnormalities were found in51 of 39 children who either had no seizures orhad occasional febrile seizures24 EpileptiformEEG abnormalities were present in 78 of 18children with MRE

Conclusions Children with microcephaly are morelikely to have epilepsy particularly epilepsy that is diffi-cult to treat Certain microcephaly syndromes are asso-ciated with a much higher prevalence of epilepsy Thereare no systematic studies regarding EEG testing of chil-dren with microcephaly with and without epilepsy

Recommendations

1 Because children with microcephaly are at risk forepilepsy physicians may consider educating caregiv-ers of children with microcephaly on how to recog-nize clinical seizures (Level C)

2 There are insufficient data to support or refuteobtaining a routine EEG in a child with micro-cephaly (Level U)

Cerebral palsy Data from a Class II study of chil-dren with developmental disabilities found cerebralpalsy (CP) in 214 of the 216 children with micro-

Table 2 Severe epilepsy and microcephaly associated genetic syndromes

Disorder Gene(s)

Structural malformations

Classic lissencephaly (isolated LIS sequence) Lis1 DCX TUBA1A

Lissencephaly X-linked with abnormalgenitalia

ARX

Lissencephaly autosomal recessive withcerebellar hypoplasia

RELN

Bilateral frontoparietal polymicrogyria (COB) GPR56

Periventricular heterotopia with microcephaly ARFGEF2

Schizencephaly EMX2 (rare)

Holoprosencephaly HPE1 21q223 HPE 6 2q371

HPE2 2p21 HPE7 9q223

HPE3 7q36 HPE 8 14q13

HPE4 18p113 HPE9 2q14

HPE5 13q32

Syndromes

Wolf-Hirschhorn syndrome 4p

Angelman syndrome UBE3A15q11-q13

Rett syndrome Xp22 Xq28

MEHMO (mental retardation epilepsyhypogonadism microcephaly obesity)

Xp2213-p211

Mowat-Wilson syndrome (microcephalymental retardation distinct facial featureswithwithout Hirschsprung disease)

ZFHX1B 2q22

Data extracted from OMIM (httpwwwncbinlmnihgovomim) and the reader is referred tothat source for updated information as new entries are added and data are revised The readercan also go directly to GeneTests (httpwwwgenetestsorg) to which OMIM links for updatedinformation regarding the availability of genetic testing on a clinical or research basis


cephaly compared to 88 of the 1159 normoce-phalic children (p 0001)29

Two Class I (n 2445) studies and one ClassIII (n 540) study of children with CP found anaverage incidence of congenital microcephaly of1830-32 In 3 Class III (n 338) studies thecombined prevalence of congenital and postnatalonset microcephaly ranged from 325 to 81and averaged 47933-35 In one of these studies(n 96) 68 were diagnosed with postnatal on-set microcephaly and 13 had congenital micro-cephaly33 Others have shown that the yield ofdetermining the etiology of CP is higher when mi-crocephaly is present36

Conclusions CP is a common disability in childrenwith microcephaly Microcephaly particularly ofpostnatal onset and identifiable etiology is morecommon in children with CP

Recommendations

1 Because children with microcephaly are at risk forCP physicians and other care providers may con-sider monitoring them for early signs so that sup-portive treatments can be initiated (Level C)

2 Because children with CP are at risk for develop-ing acquired microcephaly serial HC measure-ments should be followed (Level A)

Mental retardation What is the prevalence of microcephaly

in different populations Prevalence estimates of micro-cephaly in Class III surveys of institutionalized pa-tients vary widely from 6535 to 5337 Forchildren seen in neurodevelopmental clinics 3 ClassIII studies (n 933) found an average prevalence ofmicrocephaly (2 SD) of 247 (range 6 to404)38-40 Similarly a high rate of severe (3SD) microcephaly (20) was found in a Class IIIstudy of 836 children undergoing evaluation formental retardatione1

A number of studies have looked at the prevalenceand significance of microcephaly in children with ap-parently normal intelligence One Class II study of1006 students in mainstream classrooms found that19 had mild (2 to 3 SD) and none hadsevere (3 SD) microcephalye2 The studentswith microcephaly had a similar mean IQ to thenormocephalic group (995 vs 105) but had lowermean academic achievement scores (49 vs 70) AClass III study looking at the records of 1775 nor-mally intelligent adolescents followed by pediatri-cians found 11 (06) with severe microcephaly(3 SD)e3 Among a separate sample of 106 ad-olescents with mental retardation the prevalenceof severe microcephaly was 11

What is the prevalence of developmental disability in individu-

als with microcephaly Three Class I studies based on theNational Institute of Neurological Disorders and

Stroke Collaborative Perinatal Project examined dataon microcephaly In an early report (n 9379) halfof the children with microcephaly (males 23SD females 24 SD) at 1 year of age were foundto have an IQ 80 at 4 years of agee4 A subsequentstudy (n 35704) found congenital microcephaly(2 SD) in 13 and in certain populations thisconferred a twofold risk of mental retardation at 7years of age (153 vs 7)e5 The third study (n

28820) found that of normocephalic children 26were mentally retarded (IQ 70) and 74 had bor-derline IQ scores (71ndash80) Of the 114 (04) chil-dren with mild microcephaly (2 to 3 SD)105 were mentally retarded and 28 had border-line IQ scores9 Severe microcephaly (3 SD) wasfound in 41 (014) children of whom 512 werementally retarded and 17 had borderline IQ scoresThese findings have been supported by several ClassIII studies29e6

A Class II retrospective study of 212 childrenwith microcephaly found a significant correlation be-tween the degree of microcephaly and the presence ofmental retardation Among the 113 subjects withmild microcephaly (2 to 3 SD) mental retarda-tion was found in 11 Mental retardation was diag-nosed in 50 of the 99 subjects with severemicrocephaly (3 SD) and in all of those with anHC less than 7 SDe7

A number of Class III studies of children withmicrocephaly have examined other clinical factorsThere are conflicting data as to whether proportion-ate microcephaly (ie similar weight height andhead size percentiles) is predictive of developmentaland learning disabilities9e2 Other Class III studieshave shown that early medical illness or brain injuryare associated with microcephaly and mental retarda-tione8 The pattern of head growth can thus be apredictor of outcome infants with normal birthHCs who acquire microcephaly by 1 year of ageare likely to be severely delayed On the otherhand studies of children from countries withemerging economies have shown that when micro-cephaly and developmental delay are acquired as aconsequence of malnutrition poverty and lack ofstimulation there is significant potential for reha-bilitatione9 The findings from these and other se-lected studies are summarized in appendix e-3

Conclusions Microcephaly is commonly found indevelopmentally and cognitively impaired childrenChildren with microcephaly are at a higher risk formental retardation and there is a correlation betweenthe degree of microcephaly and the severity of cogni-tive impairment

Recommendation Because children with microceph-aly are at risk for developmental disability physicians


should periodically assess development and academicachievement to determine whether further testing andrehabilitative efforts are warranted (Level A)

Ophthalmologic and audiologic disorders One Class Istudy of 360 children with severe microcephaly (3SD) found eye abnormalities in 64 but in only 02of 3600 age-matched normocephalic controlse10 A re-lated study found 145 cases of congenital eye malforma-tions in 212479 consecutive births but prevalences forindividual malformations could not be ascertainede11

Microcephaly was among the associated malformationsin 56 of these children

Appendix e-4 lists microcephaly syndromes inwhich prominent ophthalmologic involvement hasbeen reported A Boolean search of the Online Men-delian Inheritance in Man (OMIM) database of the499 genetic syndromes associated with microcephalyfound that 241 (48) of the entries mentioned vari-ous ophthalmologic abnormalities This searchmethod provides an upper estimate of the frequencywith which ophthalmologic abnormalities might befound in patients with syndromic microcephaly

A study of 100 children with complex ear anomaliesreported that 85 had neurologic involvement and 13had microcephalye12 There are no published studiesregarding the frequency of audiologic disorders in chil-dren with microcephaly Appendix e-5 lists OMIM mi-crocephaly syndromes in which prominent audiologicinvolvement has been reported A Boolean search ofOMIM listings of genetic syndromes associated with

microcephaly found 113 (23) in which hearing losshad been described

Conclusions Ophthalmologic disorders are morecommon in children with microcephaly but the fre-quency nature and severity of this involvement has notbeen studied Data on the prevalence of audiologicdisorders in children with microcephaly have notbeen reported

Recommendation Screening for ophthalmologic ab-normalities in children with microcephaly may beconsidered (Level C)

Clinical context Certain microcephaly syndromesare classically characterized by sensory impairmentsas listed in appendices e-4 and e-5 Early identifica-tion of visual and hearing deficits may help with boththe identification of a syndromic diagnosis and thesupportive care of the child

CLINICAL CONTEXT CONGENITAL AND POSTNA-TAL ONSET MICROCEPHALY Microcephaly can becategorized as either congenital or of postnatal onsetDiagnostic approaches for each type summarized infigures 1 and 2 are general overviews of a complex eval-uation that is beyond the scope of this parameter todescribe in further detail Some online resources avail-able to assist clinicians in the evaluation are described inappendix 2

Congenital microcephaly Many medical experts ad-vocate doing a prompt and comprehensive evalua-tion of congenital microcephaly whether mild or

Figure 1 Evaluation of congenital microcephaly


severe given the risk of neurodevelopmental impair-ment and the parental anxiety associated with thediagnosis22021 Consultation with a neurologist andgeneticist are frequently helpful in guiding the diag-nostic evaluation and in supporting and educatingfamilies Establishing a more specific diagnosis pro-vides valuable information regarding etiology prog-nosis treatment and recurrence risk

The initial history examination and screening labo-ratory testing may suggest a specific diagnosis ordiagnostic category allowing further screening or con-firmatory testing to be targeted if necessary If the ini-tial evaluation is negative and the child appears to haveisolated microcephaly the results of a head MRI mayhelp to categorize the type of microcephaly using thecriteria outlined in appendix 3 Testing for specific con-ditions (table 1) may establish a diagnosis In newbornswith proportionate microcephaly and an unrevealinginitial evaluation ongoing monitoring may reveal littleneurodevelopmental impairment

Postnatal onset microcephaly Microcephaly from ac-quired insults to the CNS or from progressive metabol-icgenetic disorders is usually apparent by age 2 yearsMild or proportionate microcephaly may go unrecog-nized unless a childrsquos HC is measured accurately Mak-ing comparisons to parentsrsquo HCs may be important as

familial forms of mild microcephaly some associatedwith specific genetic disorders have been describedThe complex issues influencing the appropriate timingand extent of testing are discussed in several excellentreviews1219e11 Currently available assessment toolsmay not ultimately establish a specific etiologic diagno-sis As neurodevelopmental research progresses theneed for testing children with microcephaly of undeter-mined origin should be reassessed

RECOMMENDATIONS FOR FUTURE RESEARCH

1 Large prospective epidemiologic studies are neededto establish the prevalence of congenital and postna-tal microcephaly and the degree to which the signif-icance of microcephaly is altered by ethnicbackground a history of prematurity head shapeand parental head size Such studies may also clarifythe significance of head size that remains within thenormal range for the average population but which1) is 2 SD for the personrsquos family or 2) has de-creased more than 2 SD over time In addition theappropriate ages at and until which HC should bemeasured and plotted to evaluate for patterns of ab-normal brain growth need to be revisited

2 Large prospective studies of neuropsychologicalneuroimaging genetic metabolic neurophysiologic

Figure 2 Evaluation of postnatal onset microcephaly


(ie EEG) and ancillary (vision and hearing) testsshould be undertaken in children with microcephalyto establish the diagnostic yields of these tests andinform the development of an evidence-based algo-rithmic approach to evaluation

3 The burden of neurodevelopmental disability andcomorbid medical illness in children with micro-cephaly should be more thoroughly studied toguide the provision of preventative and rehabilita-tive services that might improve outcomes

DISCLOSUREDr Ashwal serves on the scientific advisory board of the Tuberous Sclero-

sis Association and the International Pediatric Stroke Society serves as an

editor of Pediatric Neurology and receives research support from the NIH

[1 R01 NS059770-01A2 (PI) 1 R01 NS054001-01A1 (PI) and R01

CA107164-03 (PI)] Dr Michelson reports no disclosures Dr Plawner

receives royalties from publishing PEMSoft The Pediatric Emergency Med-

icine Software (2007 and 2008) receives research support from the NIH

[NO1-HD-3-3351 (Co-investigator) and has served as an expert consul-

tant in a legal proceeding Dr Dobyns serves on the editorial advisory

boards of the American Journal of Medical Genetics and Clinical Dysmor-

phology and receives research support from the NIH [1R01-NS050375

(PI) and 1R01-NS058721 (PI)]

DISCLAIMER

This statement is provided as an educational service of the American

Academy of Neurology and the Child Neurology Society It is based on an

assessment of current scientific and clinical information It is not intended

to include all possible proper methods of care for a particular neurologic

problem or all legitimate criteria for choosing to use a specific procedure

Neither is it intended to exclude any reasonable alternative methodolo-

gies The AAN and the Child Neurology Society recognize that specific

patient care decisions are the prerogative of the patient and the physician

caring for the patient based on all of the circumstances involved The

clinical context section is made available in order to place the evidence-

based guideline(s) into perspective with current practice habits and chal-

lenges No formal practice recommendations should be inferred

CONFLICT OF INTEREST STATEMENTThe American Academy of Neurology is committed to producing inde-

pendent critical and truthful clinical practice guidelines (CPGs) Signifi-

cant efforts are made to minimize the potential for conflicts of interests to

influence the recommendation of this CPG To the extent possible the

AAN keeps separate those who have a financial stake in the success or

failure of the products appraised in the CPGs and the developers of the

guidelines Conflict of interest forms were obtained from all authors and

reviewed by an oversight committee prior to project initiation AAN lim-

its the participation of authors with substantial conflicts of interest The

AAN forbids commercial participation in or funding of guideline

projects Drafts of the guidelines have been reviewed by at least three AAN

committees a network of neurologists Neurologyreg peer reviewers and

representatives from related fields The AAN Guideline Author Conflict

of Interest Policy can be viewed at httpwwwaancom

APPENDIX 1AQuality Standards Subcommittee Members 2007ndash2009 Jacqueline French

MD FAAN (Chair) Charles E Argoff MD Eric Ashman MD Stephen

Ashwal MD FAAN (Ex-Officio) Christopher Bever Jr MD MBA

FAAN John D England MD FAAN Gary M Franklin MD MPH

FAAN (Ex-Officio) Deborah Hirtz MD FAAN (Ex-Officio) Robert G

Holloway MD MPH FAAN Donald J Iverson MD FAAN Steven R

Messe MD Leslie A Morrison MD Pushpa Narayanaswami MD

MBBS James C Stevens MD FAAN (Ex-Officio) David J Thurman

MD MPH (Ex-Officio) Dean M Wingerchuk MD MSc FRCP(C)

Theresa A Zesiewicz MD FAAN

APPENDIX 1BChild Neurology Society Practice Committee Members Bruce Cohen MD

(Chair) Diane Donley MD Bhuwan Garg MD Michael Goldstein

(Emeritus) Brian Grabert MD David Griesemer MD Edward Kovnar

MD Agustin Legido MD Leslie Morrison MD Ben Renfroe MD

Shlomo Shinnar MD Russell Snyder MD Carmela Tardo MD Greg

Yim MD

APPENDIX 2Resources for evaluating children with microcephaly

1 Accurate head circumference (HC) measurement is obtained with a

flexible non-stretchable measuring tape pulled tightly across the most

prominent part on the back (occiput) and front (supraorbital ridges) of

the head

Standardized growth charts in percentiles for boys and girls from birth

to age 36 months are available online from the Web site of the National

Center for Health Statistics

Growth charts for HC for boys and girls from birth to age 5 years and

plotted as standard deviations from the mean are available through the

World Health Organization Web site These charts updated in 2006

are based on data from 8500 well-nourished children from Brazil

Ghana India Norway Oman and the United States

Measurements from patients older than 36 months can be evaluated

using charts derived in 1968 from pooled data from a few countries

(Nellhaus G Head circumference from birth to eighteen years com-

posite international and interracial graphs Pediatrics 196841106ndash

110) made available online through the Web site of the Department of

Neurology at Emory University

Growth charts for premature infants and for children born in countries

other than the United States including China India Korea and Viet-

nam can be found online at Web sites specializing in information for

prospective adoptive parents such as that of the Center for Adoption

Medicine There is evidence that extremely premature infants (1 kg)

who survive never catch up to infants with birth weights over 1 kg In

these cases if one uses standard HC graphs many normal children will

appear microcephalic and might be subjected to unnecessary evalua-

tions (Sheth RD Mullett MD Bodensteiner JB Hobbs GR Longitu-

dinal head growth in developmentally normal preterm infants Arch

Pediatr Adolesc Med 19951491358ndash1361)

Web sites

httpwwwcdcgovgrowthcharts

httpwwwwhointchildgrowthstandardshc_for_ageenindexhtml

httpwwwpediatricsemoryedudivisionsneurologyhcpdf

httpwwwadoptmedorgtopicsgrowth-chartshtml

2 The freely searchable Online Mendelian Inheritance in Man (OMIM)

database contains close to 500 entries for genetic disorders associated

with microcephaly

Web site httpwwwncbinlmnihgovomim

3 GeneTests is a publicly funded medical genetics information resource

that provides reviews of genetic disorders causing microcephaly and a

directory of laboratories that perform confirmatory genetic and enzy-

matic testing

Web site httpwwwgenetestsorg

4 Pictures of Standard Syndromes and Undiagnosed Malformations

(POSSUM) is a computer-based system that can be purchased for

approximately $1000 It contains information on more than 3000

syndromes including chromosomal and metabolic disorders associated

with multiple malformations and skeletal dysplasias

Web site httpwwwpossumnetau

5 The London Dysmorphology Database London Neurogenetics Data-

base and Dysmorphology Photo Library on CD-ROM (2001 3rd

edition) combine 2 comprehensive databases and an extensive photo

library onto a single CD-ROM that can be purchased for $2495


There are more than 3400 nonchromosomal syndromes in the dys-

morphology database and nearly 3300 neurologic disorders in the

neurogenetics database with online updates made available to regis-

tered users

Web site httpwwwlmdatabasescom

APPENDIX 3MRI-based classification of microcephaly

1 Microcephaly with normal to thin cortex

a Autosomal recessive microcephaly

i Autosomal recessive microcephaly with normal or slightly

short stature and high function

(a) MCPH1 mutations

(b) ASPM mutations

(c) CDK5RAP2 mutations

(d) CENPJ mutations

ii Autosomal recessive microcephaly with normal or minor short

stature and very poor function

(a) Profound microcephalymdashAmish-type lethal microcephaly

(SLC25A19 mutations)

(b) Less severe microcephaly with periventricular nodular het-

erotopia (ARFGEF2 mutations)

(c) Less severe microcephaly with abnormal frontal cortex

and thin corpus callosummdashWarburg micro syndrome

(RAB3GAP mutations)

b Extreme microcephaly with simplified gyral pattern and normal

stature

i Extreme microcephaly with jejunal atresia

ii Microcephaly with pontocerebellar hypoplasia

c Primary microcephaly not otherwise classified

2 Microlissencephaly (extreme microcephaly with thick cortex)

a MLIS with thick cortex (Norman-Roberts syndrome)

b MLIS with thick cortex severe brainstem and cerebellar hypopla-

sia (Barth MLIS syndrome)

c MLIS with severe proportional short staturemdashSeckel syndrome

(ATR mutation)

d MLIS with mildly to moderately thick (6-mm to 8-mm) cortex

callosal agenesis

3 Microcephaly with polymicrogyria or other cortical dysplasias

a Extreme microcephaly with diffuse or asymmetric polymicrogyria

b Extreme microcephaly with ACC and cortical dysplasia

Adapted from Barkovich AJ Kuzniecky RI Jackson GD Guerrini R

Dobyns WB A developmental and genetic classification for malforma-

tions of cortical development Neurology 2005651873ndash1887

The reader can also go directly to GeneTests (httpwwwgenetests

org) to which OMIM links for updated information regarding the availabil-

ity of genetic testing on a clinical or research basis

APPENDIX 4Syndromic classification of primary microcephaly andassociated genes

Autosomal recessive microcephaly (OMIM 251200)

MCPH1 (Microcephalin 8p22-pter)

MCPH2 (19q131-132)

MCPH3 (CDK5RAP2 9q34)

MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )

MCPH6 (CENPJ 13q122 )

Microcephaly with severe IUGR

ATR Seckel syndrome

PCNT2 microcephalic osteodysplastic primordial dwarfism type

2 Seckel syndrome

Microcephaly with a simplified gyral pattern (OMIM 603802)

Autosomal dominant microcephaly (OMIM 156580)

Amish lethal microcephaly (OMIM 607196)

Other genes

AKT3 severe postnatal microcephaly

SLC25A19 Amish lethal microcephaly

LIS1 lissencephaly

DCX lissencephaly (X-linked)

SHH holoprosencephaly

ZIC2 holoprosencephaly

TGIF holoprosencephaly

SIX3 holoprosencephaly

DHCR7 Smith-Lemli-Opitz syndrome

CREBBP Rubinstein-Taybi syndrome

PAK3 X-linked mental retardation

NBS1 Nijmegen breakage syndrome

MECP2 Rett syndrome (X-linked)

Inheritance is autosomal recessive excepted where noted Data collated

from Mochida and Walsh20 Alderton GK Galbiati L Griffith E et al

Regulation of mitotic entry by microcephalin and its overlap with ATR

signaling Nat Cell Biol 20068725ndash733 Bond J Woods CG Cytoskel-

etal genes regulating brain size Curr Opin Cell Biol 20061895ndash101

Woods CG Bond J Enard W Autosomal recessive primary microcephaly

(MCPH) a review of clinical molecular and evolutionary findings Am J

Hum Genet 200576717ndash728


org) to which OMIM links for updated information regarding the avail-

ability of genetic testing on a clinical or research basis

Received December 18 2008 Accepted in final form July 7 2009

REFERENCES1 Leviton A Holmes LB Allred EN Vargas J Method-

ologic issues in epidemiologic studies of congenital micro-cephaly Early Hum Dev 20026991ndash105

2 Opitz JM Holt MC Microcephaly general considerationsand aids to nosology J Craniofac Genet Dev Biol 19901075ndash204

3 Roche AF Mukherjee D Guo SM Moore WM Headcircumference reference data birth to 18 years Pediatrics198779706ndash712

4 Barkovich AJ Ferriero DM Barr RM et al Microlissen-cephaly a heterogeneous malformation of cortical devel-opment Neuropediatrics 199929113ndash119

5 Dobyns WB Andermann E Andermann F et al X-linkedmalformations of neuronal migration Neurology 199647331ndash339

6 Woods CG Human microcephaly Curr Opin Neurobiol200414112ndash117

7 Jackson AP Eastwood H Bell SM et al Identification ofmicrocephalin a protein implicated in determining the size ofthe human brain Am J Hum Genet 200271136ndash142

8 Vargas JE Allred EN Leviton A Holmes LB Congenitalmicrocephaly phenotypic features in a consecutive sampleof newborn infants J Pediatr 2001139210ndash214

9 Dolk H The predictive value of microcephaly during thefirst year of life for mental retardation at seven years DevMed Child Neurol 199133974ndash983

10 Jaworski M Hersh JH Donat J Shearer LT Weisskopf BComputed tomography of the head in the evaluation ofmicrocephaly Pediatrics 1986781064ndash1069

11 Ito M Okuno T Mikawa H Computed tomographicstudy of children with microcephaly No To Hattatsu198921440ndash444

12 Steinlin M Zurrer M Martin E Boesch CH Largo RHBottshauser E Contribution of MRI in the evaluation ofmicrocephaly Neuropediatrics 199122184ndash189

13 Sugimoto T Yasuhara A Nishida N Murakami K WooM Kobayashi Y MRI of the head in the evaluation ofmicrocephaly Neuropediatrics 1993244ndash7


14 Pandey A Phadke SR Gupta N Phadke RV Neuroimagingin mental retardation Indian J Pediatr 200471203ndash209

15 Custer DA Vezina LG Vaught DR et al Neurodevelop-mental and neuroimaging correlates in nonsyndromal mi-crocephalic children J Dev Behav Pediatr 20002112ndash18

16 Wycliffe ND Thompson JR Holshouser BA Ashwal S Pe-diatric neuroimaging In Swaiman KF Ashwal S FerrieroDM Pediatric Neurology Principles amp Practice Fourth edi-tion Philadelphia Mosby Elsevier 2006167ndash202

17 Barkovich AJ Kuzniecky RI Jackson GD Guerrini RDobyns WB A developmental and genetic classificationfor malformations of cortical development Neurology2005651873ndash1887

18 Lalaguna-Mallada P Alonso-del Val B Abio-Albero SPena-Segura JL Rebage V Lopez-Pison J Microcephalusas the reason for visiting a regional referral neuropaediatricservice Rev Neurol 200438106ndash110

19 den Hollander NS Wessels MW Los FJ Ursem NTNiermeijer MF Wladimiroff JW Congenital micro-cephaly detected by prenatal ultrasound genetic aspectsand clinical significance Ultrasound Obstet Gynecol200015282ndash287

20 Mochida GH Walsh CA Molecular genetics of humanmicrocephaly Curr Opin Neurol 200114151ndash156

21 Abuelo D Microcephaly syndromes Semin Pediatr Neu-rol 200714118ndash127

22 Kelley RI Robinson D Puffenberger EG Strauss KA Mor-ton DH Amish lethal microcephaly a new metabolic disor-der with severe congenital microcephaly and 2-ketoglutaricaciduria Am J Med Genet 2002112318ndash326

23 Shevell M Ashwal S Donley D et al Practice parameterevaluation of the child with global developmental delayreport of the Quality Standards Subcommittee of theAmerican Academy of Neurology and The Practice Com-mittee of the Child Neurology Society Neurology 200360367ndash380

24 Abdel-Salam GM Halasz AA Czeizel AE Association ofepilepsy with different groups of microcephaly Dev MedChild Neurol 200042760ndash767

25 Qazi QH Reed TE A problem in diagnosis of primaryversus secondary microcephaly Clin Genet 1973446ndash52

26 Berg AT Levy SR Novotny EJ Shinnar S Predictors ofintractable epilepsy in childhood a case-control studyEpilepsia 19963724ndash30

27 Chawla S Aneja S Kashyap R Mallika V Etiology andclinical predictors of intractable epilepsy Pediatr Neurol200227186ndash191

28 Aneja S Ahuja B Taluja V Bhatia VK Epilepsy in childrenwith cerebral palsy Indian J Pediatr 200168111ndash115

29 Watemberg N Silver S Harel S Lerman-Sagie T Signifi-cance of microcephaly among children with developmentaldisabilities J Child Neurol 200217117ndash122

30 Croen LA Grether JK Curry CJ Nelson KB Congenitalabnormalities among children with cerebral palsy moreevidence for prenatal antecedents J Pediatr 2001138804ndash810

31 Pharoah PO Prevalence and pathogenesis of congenitalanomalies in cerebral palsy Arch Dis Child Fetal NeonatalEd 200792F489ndash443

32 Laisram N Srivastava VK Srivastava RK Cerebral palsyan etiological study Indian J Pediatr 199259723ndash728

33 Edebol-Tysk K Epidemiology of spastic tetraplegic cere-bral palsy in Sweden I impairments and disabilities Neu-ropediatrics 19892041ndash45

34 Lubis MU Tjipta GD Marbun MD Saing B Cerebralpalsy Paediatr Indones 19903065ndash70

35 Suzuki J Ito M Tomiwa K Okuno T A clinical study ofcerebral palsy in Shiga 1977ndash1986 II severity of the dis-ability and complications in various types of cerebral palsyNo To Hattatsu 199931336ndash342

36 Shevell MI Majnemer A Morin I Etiologic yield of cere-bral palsy a contemporary case series Pediatr Neurol200328352ndash359

37 Roboz P Microcephaly Aust J Ment Retard 19732173ndash179

38 Smith RD Abnormal head circumference in learning-disabled children Dev Med Child Neurol 198123626ndash632

39 Martin HP Microcephaly and mental retardation Am JDis Child 1970119128ndash131

40 Desch LW Anderson SK Snow JH Relationship of headcircumference to measures of school performance Clin Pe-diatr 199029389ndash392


Editorrsquos Note to Authors and Readers Levels of Evidence in Neurologyreg

Effective January 15 2009 authors sub-mitting Articles or ClinicalScientificNotes to Neurologyreg that report on clin-ical therapeutic studies must state thestudy type the primary research ques-tion(s) and the classification of level ofevidence assigned to each question basedon the classification scheme require-ments shown (top) While the authorswill initially assign a level of evidencethe final level will be adjudicated by anindependent team prior to publicationUltimately these levels can be translatedinto classes of recommendations for clin-ical care as shown (bottom) For moreinformation please access the articlesand the editorial on the use of classifica-tion of levels of evidence published inNeurology1-3

1 French J Gronseth G Lost in a jungle of evi-dence we need a compass Neurology 2008711634ndash1638

2 Gronseth G French J Practice parameters andtechnology assessments what they are whatthey are not and why you should care Neurol-ogy 2008711639ndash1643

3 Gross RA Johnston KC Levels of evidencetaking Neurologyreg to the next level Neurology2008728ndash10


DOI 101212WNL0b013e3181b783f7200973887-897 Neurology

Stephen Ashwal David Michelson Lauren Plawner et al Neurology and the Practice Committee of the Child Neurology Society

review) Report of the Quality Standards Subcommittee of the American Academy of Practice Parameter Evaluation of the child with microcephaly (an evidence-based

This information is current as of September 14 2009

ServicesUpdated Information amp

httpnneurologyorgcontent7311887fullincluding high resolution figures can be found at

Supplementary Material

httpnneurologyorgcontentsuppl200909137311887DC2 httpnneurologyorgcontentsuppl200909137311887DC1 httpnneurologyorgcontentsuppl201009127311887DC3

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References httpnneurologyorgcontent7311887fullref-list-1

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Citations httpnneurologyorgcontent7311887fullotherarticles

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Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

in 01 of children if normal distribution is as-sumed which agrees with the published estimate of014 of neonates9

Microcephaly may be described as syndromic oras pure primary or true (microcephalia vera) de-pending on the presence or absence of extracranialmalformations or dysmorphic facial features Theseterms do not imply a distinct etiology and can beseen with either genetic or environmental causes ofneurodevelopmental impairment Some of the morecommon causes are outlined in table 1

A comprehensive history growth records for thechild and close relatives and a detailed physical ex-amination will often suggest a diagnosis or directionfor further testing Advances in neuroimaging andgenetics have improved understanding of the causesof microcephaly suggesting new approaches to classi-fication and testing In developing diagnostic algo-rithms for microcephaly defined as congenital or ofpostnatal onset we also examined whether the diagnos-tic yield depended on the severity of microcephaly

DESCRIPTION OF THE ANALYTIC PROCESSLiterature examined for this parameter (1966 ndash2007) included 4500 titles and abstracts of which150 articles were selected for review See appendicese-1Andashe-1C on the Neurologyreg Web site at wwwneurologyorg for information on databases searchterms and article classification

ANALYSIS OF EVIDENCE What is the role of diag-nostic testing of children with microcephaly Neuroimaging

CT data are available from 2 Class III studies involv-ing 143 children with microcephaly (table e-1)1011

In one study 61 of 85 children with microcephaly(2 SD) had abnormal CT findings10 Patientswith a known history of perinatal or postnatal braininjury (n 22) had the highest percentage of imag-ing abnormalities (91) Patients with one or moreextracranial congenital anomalies (n 30) had anintermediate yield (67) The lowest yield (36)was in patients (n 33) with no evidence by historyor examination of a brain injury although 4 patientshad major CNS malformations that were not sus-pected clinically Imaging findings were classifiedinto 4 groups normal (39) mild atrophyventricu-lar dilatation (31) moderate to severe atrophyventricular dilatation (28) and isolated parenchymalabnormalities (2) The degree of microcephaly corre-lated with the severity of cerebral atrophy or ventriculardilatation Five cases (6) had findings that led to amore specific diagnosis (eg schizencephaly holo-prosencephaly) In a second study of 58 children withmicrocephaly (HC 2 SD) head size did not corre-late with CT findings but there were correlations be-tween CT findings and mental retardation motor

disturbance and epilepsy11 CT was felt to be useful fordetermining prognosis

Data from 2 Class III MRI studies of 88 childrenwith microcephaly found abnormalities in 67 and80 (table e-1)1213 In one study abnormalities weredetected in 68 of children in whom a genetic disor-der was suspected or diagnosed with the most fre-quent findings being neuronal migrational disordersor callosal malformations13 In the children withpostnatal onset microcephaly 100 showed abnor-malities with hydranencephaly and infarction beingmost common The second study classified MRI abnor-malities into 4 groups congenital cytomegalovirus(CMV) infection (n 6) cerebral malformationsmyelination disorders (n 16) unclassifiable patho-logic findings (n 8) and normal (n 3)12 The highprevalence of CMV infection was due to case selectionbias In this small study the authors did not find a cor-relation between the severity of the cerebral malforma-tion and neurodevelopmental disturbances

Two Class III studies examined the diagnostic yieldof either CT or MRI and the severity of microcephaly(table e-1)1415 In one study children with mild micro-cephaly (2 SD) had a yield of 688 whereas thosewith severe microcephaly (3 SD) had a yield of75 A second study also found that children with se-vere microcephaly were more likely to have imaging ab-normalities (80) than those with mild (2 to 3SD) microcephaly (43)15 There was correlation be-tween imaging findings and neurodevelopmental out-comes as measured by the Bayley Scales of InfantDevelopment or the McCarthy Scales of ChildrenrsquosAbilities depending on the patientrsquos age15 Develop-mental quotients in the normal imaging group were 70or greater whereas quotients in the abnormal imaginggroup were 52 or less

Conclusions Data from 6 Class III studies (2 CT 2MRI 2 CTMRI) of 292 children with microceph-aly found diagnostic yields ranging from 43 to80 In 2 studies children with severe microcephaly(3 SD) were more likely (ie 75 80) to havean abnormal MRI than those with milder micro-cephaly MRI detected brain abnormalities typicallybeyond the sensitivity of CT

Recommendation Neuroimaging may be considereduseful in identifying structural causes in the evaluationof the child with microcephaly (Level C)

Clinical context MRI often reveals findings thatare more difficult to visualize on CT such as migra-tional disorders callosal malformations structuralabnormalities in the posterior fossa and disorders ofmyelination and is considered the superior diagnos-tic test16 An MRI-based classification scheme of mi-crocephaly is outlined in appendix 317 While basedon retrospective review its usefulness is apparent as











Genetic Genetic






Menkes disease



Syndromic Syndromic

Chromosomal

Trisomy 21 13 18














XLAG syndrome

Cohen syndrome

Acquired Acquired









Teratogens Toxins




















Recommendations





Disorder Gene(s)




ARX


RELN






HPE3 7q36 HPE 8 14q13

HPE4 18p113 HPE9 2q14

HPE5 13q32

Syndromes





Xp2213-p211


ZFHX1B 2q22






Recommendations


















































(PI) and 1R01-NS058721 (PI)]

DISCLAIMER










































Yim MD





the head


























Web sites







with microcephaly





matic testing
















tered users







(a) MCPH1 mutations

(b) ASPM mutations


(d) CENPJ mutations









(RAB3GAP mutations)


stature









(ATR mutation)


callosal agenesis













MCPH2 (19q131-132)


MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )



ATR Seckel syndrome


2 Seckel syndrome




Other genes



LIS1 lissencephaly



























































































Reprints













Genetic Genetic






Menkes disease



Syndromic Syndromic

Chromosomal

Trisomy 21 13 18














XLAG syndrome

Cohen syndrome

Acquired Acquired









Teratogens Toxins




















Recommendations





Disorder Gene(s)




ARX


RELN






HPE3 7q36 HPE 8 14q13

HPE4 18p113 HPE9 2q14

HPE5 13q32

Syndromes





Xp2213-p211


ZFHX1B 2q22






Recommendations


















































(PI) and 1R01-NS058721 (PI)]

DISCLAIMER










































Yim MD





the head


























Web sites







with microcephaly





matic testing
















tered users







(a) MCPH1 mutations

(b) ASPM mutations


(d) CENPJ mutations









(RAB3GAP mutations)


stature









(ATR mutation)


callosal agenesis













MCPH2 (19q131-132)


MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )



ATR Seckel syndrome


2 Seckel syndrome




Other genes



LIS1 lissencephaly



























































































Reprints













Recommendations





Disorder Gene(s)




ARX


RELN






HPE3 7q36 HPE 8 14q13

HPE4 18p113 HPE9 2q14

HPE5 13q32

Syndromes





Xp2213-p211


ZFHX1B 2q22






Recommendations


















































(PI) and 1R01-NS058721 (PI)]

DISCLAIMER










































Yim MD





the head


























Web sites







with microcephaly





matic testing
















tered users







(a) MCPH1 mutations

(b) ASPM mutations


(d) CENPJ mutations









(RAB3GAP mutations)


stature









(ATR mutation)


callosal agenesis













MCPH2 (19q131-132)


MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )



ATR Seckel syndrome


2 Seckel syndrome




Other genes



LIS1 lissencephaly



























































































Reprints







Recommendations


















































(PI) and 1R01-NS058721 (PI)]

DISCLAIMER










































Yim MD





the head


























Web sites







with microcephaly





matic testing
















tered users







(a) MCPH1 mutations

(b) ASPM mutations


(d) CENPJ mutations









(RAB3GAP mutations)


stature









(ATR mutation)


callosal agenesis













MCPH2 (19q131-132)


MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )



ATR Seckel syndrome


2 Seckel syndrome




Other genes



LIS1 lissencephaly



























































































Reprints







































(PI) and 1R01-NS058721 (PI)]

DISCLAIMER










































Yim MD





the head


























Web sites







with microcephaly





matic testing
















tered users







(a) MCPH1 mutations

(b) ASPM mutations


(d) CENPJ mutations









(RAB3GAP mutations)


stature









(ATR mutation)


callosal agenesis













MCPH2 (19q131-132)


MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )



ATR Seckel syndrome


2 Seckel syndrome




Other genes



LIS1 lissencephaly



























































































Reprints


























(PI) and 1R01-NS058721 (PI)]

DISCLAIMER










































Yim MD





the head


























Web sites







with microcephaly





matic testing
















tered users







(a) MCPH1 mutations

(b) ASPM mutations


(d) CENPJ mutations









(RAB3GAP mutations)


stature









(ATR mutation)


callosal agenesis













MCPH2 (19q131-132)


MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )



ATR Seckel syndrome


2 Seckel syndrome




Other genes



LIS1 lissencephaly



























































































Reprints

















(PI) and 1R01-NS058721 (PI)]

DISCLAIMER










































Yim MD





the head


























Web sites







with microcephaly





matic testing
















tered users







(a) MCPH1 mutations

(b) ASPM mutations


(d) CENPJ mutations









(RAB3GAP mutations)


stature









(ATR mutation)


callosal agenesis













MCPH2 (19q131-132)


MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )



ATR Seckel syndrome


2 Seckel syndrome




Other genes



LIS1 lissencephaly



























































































Reprints







tered users







(a) MCPH1 mutations

(b) ASPM mutations


(d) CENPJ mutations









(RAB3GAP mutations)


stature









(ATR mutation)


callosal agenesis













MCPH2 (19q131-132)


MCPH4 (15q15-q21)

MCPH5 (ASPM 1q31 )



ATR Seckel syndrome


2 Seckel syndrome




Other genes



LIS1 lissencephaly



























































































Reprints

























































Reprints





























Reprints























Reprints




Documents

SPECIAL ARTICLE PracticeParameter ...tion and neurodevelopmental disturbances. Two Class III studies examined the diagnostic yield of either CT or MRI and the severity of microcephaly