Primer on Microcephaly

Alison Chu, MD,* Taylor Heald-Sargent, MD, Joseph R. Hageman, MD

*Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine,
University of California Los Angeles, Los Angeles, CA

Comer Childrens Hospital, Pritzker School of Medicine, University of Chicago, Chicago, IL

Pritzker School of Medicine, University of Chicago, Chicago, IL

Education Gaps
1. There is a lack of consensus on diagnostic evaluation of the neonate with
microcephaly.
2. Clinicians need to identify at-risk populations for congenital Zika infection
and make basic recommendations on screening and care of these infants.

Objectives After reading this article, readers should be able to:

1. Dene microcephaly and understand the terminology related to

classication of microcephaly.
2. Describe the most common etiologies underlying microcephaly.
3. Plan a targeted diagnostic evaluation, based on the available evidence.
4. Understand what is currently known about Zika virus and its contribution
to congenital microcephaly.

AUTHOR DISCLOSURE Drs Chu, Heald-

Sargent, and Hageman have disclosed no
Abstract nancial relationships relevant to this article.
This commentary does not contain a
Microcephaly can present in the newborn period, either at birth or discussion of an unapproved/investigative
postnatally. In large cohorts, genetic factors and perinatal brain damage use of a commercial product/device.

secondary to maternal exposures and prenatally acquired infections are the ABBREVIATIONS
leading causative factors. However, in up to w40% of children with CDC Centers for Disease Control and
microcephaly, no etiology is identied. Although many classications exist, it Prevention
CGH comparative genomic
is important to remember that both congenital microcephaly and postnatal- hybridization
onset microcephaly can be due to genetic or acquired causes. Careful CMV cytomegalovirus
history and physical examination is the initial step in evaluating a neonate CNS central nervous system
HC head circumference
with microcephaly. Diagnostic evaluation should be tailored based on these MRI magnetic resonance imaging
ndings. In all-comers with microcephaly, neuroimaging proves to have the OFC occipital frontal head
highest diagnostic yield, with magnetic resonance imaging providing the circumference
PCR polymerase chain reaction
highest sensitivity. Genetic testing has the next highest diagnostic yield, and
RT reverse-transcriptase
if presentation does not suggest a specic genetic disorder, comparative SD standard deviation
genomic hybridization would be the recommended rst-line genetic testing. TORCH toxoplasmosis, other (syphilis,
Denitive treatment for microcephaly does not exist, but supportive varicella-zoster, parvovirus B19),
rubella, CMV, and herpesvirus
treatment aimed at preventing further damage or mitigating untoward infections
WES whole-exome sequencing

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effects of existing comorbidities may be available. Overall prognosis relates to
severity of disease, underlying diagnosis, and comorbid conditions identied.
Zika virus is emerging as an infectious pathogen leading to congenital
microcephaly. Given its potentially devastating effects, a low threshold of
suspicion is warranted at this time for women presenting with a fever and
rash during pregnancy with a personal history or sexual contact with a person
who has a history of travel to affected regions, or with ndings of
microcephaly on prenatal ultrasonography.

INTRODUCTION/DEFINITION numbers of neurons in the gray matter, and preferentially

Microcephaly is a diagnosis with myriad causes, which differ
in their prognosis. Therefore, in evaluating a neonate with
microcephaly, it is important to not only be aware of many of
the causes of microcephaly, but to also use a diagnostic
approach to avoid unnecessary testing and to reach a diag-
nosis in a timely manner, when possible. Microcephaly is
dened as an occipitofrontal head circumference (OFC)
between the glabella and occipital protuberance of less than
2 standard deviations (SDs) below the mean for age and
gender using the Centers for Disease Control and Prevention
(CDC) growth charts. (1)(2)(3) Severe microcephaly is dened
as values less than 3 SDs below the mean. It is crucial that
providers accurately measure head circumference (HC), by
using a nonstretchable measuring tape pulled tightly across
the most prominent parts of the back and front of the head,
from the occiput to supraorbital ridge. Inaccurate measure-
ments are often recorded in newborns because of a number
of factors (eg, scalp edema, cephalohematoma, molding), and
repeat measurement may be indicated past the rst few days
after birth. Also of note, microcephaly is the best available
noninvasive measurement on physical examination that may
be indicative of an underlying central nervous system (CNS)
abnormality. However, it is extremely nonspecic and as
such, experts in the eld still debate where the cut-off
for microcephaly should be, with some requiring an OFC
less than 3 SDs below the mean as signicant.
Microcephaly, in general, is associated with reduced
brain volumes and later intellectual/neurodevelopmental
disabilities. Because brain development is inuenced in a
multifactorial manner, the pathogenesis of microcephaly
can involve genetic or environmental inuences affecting
progenitor cell proliferation, differentiation, and death, or
brain growth. In general, congenital microcephaly is often
due to lack of or abnormal development of the neurons
during important stages of neuronal maturation, such as
induction and migration. These alterations lead to decreased
affects the forebrain, as seen in holoprosencephaly. Postnatal
microcephaly is often associated with perinatal insult to a
previously normal brain, which results in decreased dendritic
processes and synaptic connections. Because of heterogeneous
causes, the presentation of microcephaly is variedsometimes
occurring in isolation and sometimes with associated extracra-
nial signs and symptoms, sometimes present at birth and
sometimes developing postnatally. Published estimates sug-
gest that fewer than 1% of all newborn infants are microcephalic,
but that approximately 25,000 neonates in the United States are
annually diagnosed with microcephaly.
The purpose of this article is to review the denition,
categorization, etiologies, diagnostic evaluation, and long-
term outcome of congenital (decreased HC at birth) and
postnatal-onset microcephaly (normal HC at birth, then poor
head growth with decreased HC for gestational age post-
natally). (1) The terms are used inconsistently in the literature,
with primary or congenital often being used interchangeably,
and secondary, acquired, progressive, and postnatal-onset being
used interchangeably. However, many of these terms can
be misleading (or misused), because both congenital and
postnatal-onset micocephaly may be due to genetic or acquired
causes. It is, therefore, important in interpreting the literature
to distinguish how each group denes these terms.
Of special note, clinicians have become more aware of
microcephaly because the Zika virus, initially in Brazil and
subsequently in Central America, Puerto Rico, and the
Southern United States (Florida), has been documented
(4) as a cause of microcephaly. Given the timeliness of this
issue, we also include a review of what is known about Zika
virus transmission, congenital infection, and management of
(suspected) disease.
CLASSIFICATION OF MICROCEPHALY
There are a number of different categorical classication
systems for microcephaly. As noted before, congenital and

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 acquired microcephaly are suggested as the preferred cat-
egories by the American Academy of Neurology and Child
Neurology Society. (1) More recently, von der Hagen and
colleagues (3) described a large clinical cohort of 680 in-
fants and children with microcephaly, and their categories
include primary and secondary microcephaly. Largely, the most
accepted classication distinguishes whether or not the
neonate has a normal OFC at birth (postnatal versus con-
genital). It is important to note that these categorizations do
not imply causative etiologies; for example, genetic causes of
microcephaly can lead to postnatal OFC growth failure or
can result in microcephaly at birth. Postnatal microcephaly
is usually apparent by age 2 years, when caused by acquired
insults to the CNS from progressive genetic or metabolic
causes. This peak window of detection is largely because the
highest rate of brain growth occurs in the rst 3 years after
birth. (3) Other subcategorizations of patients are dened by
etiology (genetic vs environmental), by relation to somatic
growth (proportionate [where HC, length, and weight are all
<3rd percentile for sex and age] vs disproportionate [where
HC is <3rd percentile but length and weight are >3rd
percentile for sex and age]), or by other association to other
anomalies (syndromic vs nonsyndromic). These subcate-
gories also relate to the causes of microcephaly.
CAUSES OF MICROCEPHALY
The causes of microcephaly are diverse and myriad, there-
fore, a global view of the causes of microcephaly is helpful to
the clinician. In the largest retrospective study published to
date on patients with microcephaly, the authors reported
interesting statistics on the diagnosis of microcephaly. (3)
Of note, their cohort of patients identied through medical
record review presented at a mean age of 7 to 8 months.
More cases of postnatal-onset microcephaly were seen than
congenital cases. Neonatologists providing inpatient care en-
counter more congenital than postnatal-onset cases. In their
review of 680 patients, von der Hagen et al were able to dene
the etiology in 59% of all patients. Of these patients, genetic
etiologies were identied in about half, perinatal brain damage
in 45%, and postnatal brain damage in 3%. (3) We list specic
diagnoses within these categories in the Table.
As of 2014, more than 900 disorders associated with micro-
cephaly were included in the Online Mendelian Inheritance in
Man website. (3) Given that genetic causes accounted for about
half of all microcephalic individuals with known diagnoses, it is
important to note that chromosomal abnormalities and
monogenic disorders accounted for about half, and the
remaining half were due to putative genetic syndromes based
on clinical presentation and/or familial hereditary patterning.
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Among nongenetic causes, prenatal or perinatal brain
injury by exogenous factors is the next leading cause of
microcephaly (likely accounting for about one-third of cases).
These factors can include intrauterine infections, teratogens,
disruptive incidents, or maternal disease. Characteristically,
congenital toxoplasmosis, other (syphilis, varicella-zoster,
parvovirus B19), rubella, cytomegalovirus (CMV), and her-
pesvirus (TORCH) infections can present with microcephaly.
These transplacentally transmitted infections often have
additional ndings on examination, such as hepatosplenome-
galy, rashes, ophthalmologic ndings, and ultrasonography
ndings of intracranial calcications. With the advent of
maternal prenatal screening guidelines, when properly exe-
cuted, these congenital infections are seen less commonly.
However, routine testing for maternal CMV infection is not
conducted, even though it is ubiquitous in the general pop-
ulation. Therefore, practitioners should have a high index of
suspicion for CMV if characteristic TORCH symptoms are
seen on examination. In addition, we dedicate a more
detailed discussion to Zika virus, an emerging infectious
pathogen causing microcephaly. Teratogens include mater-
nal alcohol or cocaine use, antiepileptic drugs, or rarely,
lead/mercury intoxication. Inborn errors of metabolism and
craniosynostoses are less common causes of microcephaly.
It is also worth mentioning that etiologies of postnatal-
onset microcephaly include systemic illnesses for which the
neonatal population, especially the preterm group, is at risk.
Multiple studies have shown acquired postnatal microcephaly
to be associated with many of the comorbidities of prema-
turity, largely bronchopulmonary dysplasia, though other
studies have also shown associations with necrotizing entero-
colitis, neonatal sepsis, and intraventricular hemorrhage.
(5)(6) Though the exact mechanisms underlying this pre-
dilection are unknown, it is believed that the severity of the
inammatory response in these sick neonates may also be
accompanied by a local inammatory response in the brain,
leading to impaired neurodevelopment and head growth
and, in some cases, may be coupled with poor postnatal
growth. (7)
In published studies, up to w40% of microcephalic
patients do not have a known etiology identied. However,
with ever-expanding understanding of microcephaly, espe-
cially underlying genetic mechanisms, this estimate may
decrease in the future. (3)
DIAGNOSTIC APPROACH TO MICROCEPHALY
The most important initial step in the evaluation of micro-
cephaly is a thorough history and physical examination.
For the neonatologist, history should include review of the
TABLE. Etiologies for Congenital and Postnatal-Onset Microcephaly
CONGENITAL POSTNATAL-ONSET

Genetic factors
Numerical chromosomal aberration or Trisomy 13, 18, 21 Williams syndrome
microdeletion or duplication
syndromes
Monogenetic causes Aicardi-Goutires syndrome, Cockayne Aicardi-Goutires syndrome, ataxia
syndrome, Cornelia de Lange, Rubinstein- telangiectasia, Cohen syndrome, Marden
Taybi, Rett syndrome, Smith-Lemli-Opitz syndrome, Mowat-Wilson syndrome, Rett
syndrome, autosomal recessive syndrome, Rubinstein-Taybi syndrome
microcephaly, X-chromosomal
microcephaly
Imprinting disorders Angelman syndrome Angelman syndrome
Exogenic factors
Infection Intrauterine infection with toxoplasmosis, Perinatal infection with HSV, rubella, syphilis
rubella, CMV, HSV, VZV, syphilis, HIV, Postnatal infections (meningitis,
Zika virus encephalitis)
Teratogens Maternal exposure to alcohol, cocaine, Perinatal teratogen exposures, toxin
antiepileptic drugs, lead/mercury exposure (lead)
intoxication
Disruptive incident Vascular incident
Maternal disease Hyperphenylalaninemia, anorexia nervosa
Perinatal brain damage Hypoxic-ischemic encephalopathy,
perinatal/postnatal hemorrhagic and
ischemic insult
Postnatal brain damage Traumatic brain injury, hemorrhagic/
ischemic insult, malnutrition
Structural brain anomalies Holoprosencephaly
Other Extreme placental insufciency Endocrine disorders (hypothyroidism,
hypopituitarism), chronic or systemic
disorders
Metabolic factors
Serine biosynthesis disorder, sterol Phenylketonuria, glycine encephalopathy,
biosynthesis disorder, mitochondriopathy, disorders of serine biosynthesis, urea cycle
congenital disorders of glycosylation disorders, organic aciduria, galactosemia,
syndrome, etc glucose transporter defect,
leukodystrophies, mitochondriopathies,
peroxisomal disorders, lysosomal storage
disorders, etc
Craniosynostosis
Craniosynostoses Craniosynostoses

CMVcytomegalovirus; HIVhuman immunodeciency virus; HSVherpes simplex virus; VZVvaricella zoster virus.
Adapted with permission from von der Hagen et al. (3)

prenatal history (pregnancy course for the mother, including
ultrasonography/imaging ndings, genetic screening, mater-
nal exposures), as well as a detailed family history of neuro-
logic disorders or recurrent miscarriage. Of note, for a child
presenting with microcephaly at an older age, history may
also include a timeline of onset of microcephaly (including
serial HC measurements) and neuropsychiatric assessment.
Physical examination should not only include a thorough
neurologic examination, including tone and reexes and
evaluation for sensory or motor decits, but also be aimed
at uncovering other ndings that may point to specic diag-
noses (eg, genetic syndromic etiologies, metabolic disorders,
congenital infection). An ophthalmologic examination by a
pediatric specialist should also be considered.

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 The next steps in diagnostic evaluation should be appro-
priately tailored, depending on the history and physical
examination ndings. These ancillary tests may include
neuroimaging to identify structural causes or targeted and
specic genetic testing in a neonate with ndings suggestive
of a specic diagnosis. We propose a simplied algorithm for
evaluating a child with microcephaly (Figure), based on the
reported diagnostic yields of various tests, which we will
further describe in detail.
Neuroimaging has the highest diagnostic yield, when
considering all newborns presenting with microcephaly.
Published studies suggest that overall diagnostic yield ranges
from w40% to 80%. The highest diagnostic yield is among
patients with a known history of perinatal or postnatal brain
injury (w90%). (1) The next highest yield groups were those
with extracranial congenital anomalies (w70%) or with sus-
pected genetic etiologies (also w70%). Reported imaging nd-
ings can range from normal to varying degrees of atrophy/
ventricular dilation, to isolated parenchymal abnormalities.
Taken together, these studies suggested that increasing severity
of microcephaly positively correlated with diagnostic yield and
prognostic capability of neuroimaging. Magnetic resonance
imaging (MRI) was more sensitive than computed tomogra-
phy, especially for the diagnosis of migrational disorders,
callosal malformations, structural abnormalities in the poste-
rior fossa, and disorders of myelination. (1) Although in some
cases MRI may enable a specic diagnosis to be made, in most
cases, ndings may be nonspecic. However, these ndings
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may help to direct further testing. Cranial ultrasonography,
although less sensitive, is relatively inexpensive, easy to perform
in the neonatal population, and noninvasive. Therefore, per-
forming cranial ultrasonography before MRI may be useful.
The value of genetic testing is more difcult to quantify,
because the diagnostic yields for various genetic tests are
not well-dened and depend on the indications for testing.
However, it is estimated that anywhere between 15% and
50% of cases of microcephaly may have an underlying
genetic etiology. Therefore, specic and targeted genetic
testing should be considered, based on individual presen-
tation. Testing includes genetic screening via karyotype,
array comparative genomic hybridization (CGH) analysis,
chromosomal breakage analysis, and selected gene sequenc-
ing or next-generation panel sequencing. Of note, the more
nonspecic tests (karyotyping and CGH) have the lowest
diagnostic yield and may be interpreted as normal, even
when a genetic cause is eventually uncovered using more
specic/directed testing. However, CGH provides higher
diagnostic yield (estimated 15%20%) than karyotyping,
and should be considered as the rst-line genetic test in a
patient without ndings suggestive of a specic genetic
cause. In a small cohort of patients in whom an underlying
genetic etiology is still highly suspected based on presen-
tation and/or family history, and nonspecic genetic testing
is negative, whole-exome sequencing (WES) may identify
genetic abnormalities. However, only some abnormalities
identied with WES have known clinical correlates.
Figure. A diagnostic approach to evaluating
the neonate with microcephaly, with
a focus on congenital microcephaly.
CGHcomparative genomic hydridization;
CMVcytomegalovirus; MRImagnetic
resonance imaging; PCRpolymerase chain
reaction.
 Testing for metabolic disorders should be considered for 3
specic conditions: maternal phenylketonuria (fetal brain
exposure to toxic levels of phenylalanine can result in micro-
cephaly), phosphoglycerate dehydrogenase deciency, and
2-ketoglutaric aciduria (Amish lethal microcephaly). Other
risk factors that, if present, may increase the diagnostic yield
of metabolic testing, include a history of parental con-
sanguinity, a positive family history for similar symptoms,
an episodic nature to symptoms, developmental regres-
sion, other organ failure, or specic neuroimaging ndings.
Otherwise, metabolic disorders rarely present with non-
syndromic congenital microcephaly and are estimated to
account for 1% to 5% of all children with microcephaly.
Therefore, metabolic testing may have higher diagnostic
yield in the population with postnatal-onset microcephaly,
compared to those with congenital microcephaly.
Testing for infection may be indicated, but if currently rec-
ommended maternal prenatal screenings are negative for the
newborn being evaluated and the mother took appropriate
preventive medication or precautions, the diagnostic yield for
this infectious testing is likely lower except in the case of CMVor
Zika virus. The most common infectious causes of microceph-
aly are TORCH infections. Targeted testing should be performed
as directed by ndings and may include culture, DNApolymerase
chain reaction (PCR), or serologic testing for specic pathogens.
A urine CMV test is a minimally invasive, relatively low-cost test
that can be easily performed and results obtained quickly. Given
its ubiquitous nature and the ease of testing, a neonate present-
ing with congenital microcephaly should be evaluated for CMV.
Lastly, screening for coexistent conditions such as epilepsy,
sensory decits, and cerebral palsy may be indicated, depend-
ing on the severity, associated ndings, or suspected/
conrmed diagnosis. The estimated prevalence of epilepsy
in this population is 40%, and some studies suggest that
epilepsy is more common in secondary microcephaly. Care-
givers should be taught to monitor for signs/symptoms of
seizures, and electroencephalography performed when clin-
ical suspicion is high. Caregivers and primary care physicians
should also monitor affected children for early signs of
cerebral palsy and/or developmental delays (w60%), to ini-
tiate supportive treatments in a timely manner. Although
ophthalmologic and hearing disorders are more common
in children with microcephaly than in the general population,
the estimates of frequency of ophthalmologic or audiologic
disorders in all children with microcephaly are varied (from
<1%30%) or unknown, respectively.
TREATMENT
Treatment for any individual diagnosed with microcephaly
should be aimed at the underlying disorder whenever
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possible. For example, in some metabolic causes of micro-
cephaly, dietary restrictions, in combination with pharmaco-
logic agents, may help to minimize accumulation of
metabolic toxins that lead to progressive brain damage.
However, there is no currently available treatment per se
for the underlying cause, as generally seen with genetic
etiologies. In this exciting time of development of gene-
editing platforms such as Crispr/Cas9, this limitation may
be potentially addressable in the future. In the meanwhile,
supportive treatment may be targeted at minimizing mor-
bidity from coexisting conditions. For example, pharmaco-
logic treatment for seizures should be initiated when
indicated. Developmental therapies should be offered to
high-risk patients. A recently published study by Rosman
et al (8) suggests that better somatic growth (weight, height)
in patients with postnatal-onset microcephaly is associated
with better neurodevelopmental outcomes, thus supporting
the role for optimization of diet and growth (though both
decient and excessive growth can negatively affect develop-
mental outcome). However, this study only reports association,
so the causative relationship between optimal somatic growth
and brain growth, while linked in theory and shown to be linked
in other human diseases, remains undened in microcephalic
patients. In addition, in this cohort, children with better
somatic growth may have less severe disease phenotype, thus
displaying better associated outcomes.
MORBIDITY AND MORTALITY
Long-term outcomes for infants with microcephaly are re-
lated to the underlying etiology and coexisting conditions.
More severe microcephaly (HC < -3 SD) generally portends a
worse prognosis, in terms of neurodevelopmental outcomes,
compared with milder microcephaly. Coexistent conditions
may include intellectual disability, cerebral palsy, epilepsy,
and ophthalmologic disorders (ranging from w20%50%
for each condition).
ZIKA VIRUS AS AN EMERGING CAUSE OF CONGENITAL
MICROCEPHALY
Clinicians have become more aware of microcephaly as Zika
virus transmission by the Aedes Aegypti mosquito initially
reported in Brazil has now been reported to have affected
pregnancies in Central America, Puerto Rico, and the south-
ern United States in Florida. (4) Zika virus is an arbovirus
of the Flavivirus genus, and was rst described in Rhesus
monkeys in Uganda in the 1940s. The rst signicant
epidemic was in Micronesia in 2007. With the acquisition
of the virus by pregnant women and subsequent infection of
the fetus, congenital CNS abnormalities, including intracranial
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 calcications, brain malformations, and microcephaly, have
been reported in these cases. (4)(9) A recent review of MRI
ndings in a cohort of 28 fetuses or newborns with suspected
congenital Zika virus also described a high incidence of
abnormalities of the corpus callosum and ndings suggesting
a developmental interruption in normal neuronal migration.
(10) Also of note, on radiography, intracranial calcications can
be seen at the grey-white matter junction and basal ganglia,
different from other congenital infections. (10)(11) Besides
CNS abnormalities, congenital infection has also been associ-
ated with fetal loss and stillbirth. (12)(13)(14)
In addition to being spread by mosquitos, Zika virus
appears to be transmitted during sexual intercourse and
via blood transfusion. (15) It is believed that the virus travels
from the bloodstream of the infected mother transplacen-
tally into the fetus. Zika virus RNA has recently been
detected in the amniotic uid of pregnant women who were
identied as potentially infected when fetal microcephaly was
noted on prenatal ultrasonography. (16) In addition, a mouse
model of Zika virus infection found that the virus could infect
fetuses, leading to intrauterine growth restriction and micro-
cephaly, and affects human cortical progenitor cells in vitro,
leading to cell death. In addition, Zika virus infection in human
brain organoids reduces proliferative zones and disrupts cor-
tical layers. (17) Supporting the fact that the virus directly infects
the human brain, Zika virus (by means of RNA detection and
genome sequencing) has been identied in the brain tissue of
affected human fetuses and infants. (18) These ndings, in
combination with the fact that Zika virus exposure and micro-
cephaly are rare events, especially in the United States, support
a causal relationship between the virus and adverse neurologic
outcomes, including microcephaly. (4) Furthering the causal
relationship, a recent report on a large number of suspected
cases of Zika virusinfected infants found a peak in microce-
phalic infants in November 2015, which correlated with the
Zika virus epidemic in February and early March 2015. (19)
Currently, the CDC is recommending that all infants
born to mothers with laboratory-conrmed Zika virus or
infants with clinical/neuroimaging concerning for infection
(regardless of maternal testing) should be screened for Zika
virus. (9) Infants born to mothers with a history of travel
to affected areas and symptoms of infection, which can in-
clude fever, rash, arthralgias, and conjunctivitis, should also
be tested. A mother with a concerning clinical history as well as
sexual contact, along with travel to the affected regions, should
also be considered for testing. Clinical physical examination
ndings in the neonate suggestive of congenital Zika infection
include a characteristically microcephalic head with redundant
skin folds. It has been hypothesized that the external man-
ifestations of Zika virus are due to the development of
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ventriculomegaly initially followed by ventricular and
brain atrophy. (10) In any suspected case, one must bear
in mind that an infant may have Zika infection and a
normal HC, especially if the infection was late in gestation.
Normal HC can result from decreased brain volumes but
severe ventriculomegaly. In fact, a recent report described a
term infant born in Brazil to a mother with a history of
symptoms suggestive of Zika virus, who had an HC of 32.5
cm, but MRI ndings showed reduced brain parenchyma,
subcortical calcications, and compensatory dilation of the
infratentorial supraventricular system. Serum, saliva, urine,
and cerebrospinal uid were tested for Zika virus with quan-
titative reverse-transcriptase (RT) PCR 54 days after birth, and
were all positive for Zika virus RNA. At this point, the infant
had no neurologic abnormalities, but at age 6 months, had
neuropsychomotor developmental delay, with global hyperto-
nia and spastic hemiplegia. (20) This case suggests that the
Zika virus can persist in congenitally affected newborns, and
close monitoring should be continued after birth for comor-
bidities associated with microcephaly.
Infection can be diagnosed with RT-PCR or serologic
immunoglobulin M testing. Additional testing in infants
with abnormalities consistent with congenital Zika virus
syndrome should include complete blood cell count, met-
abolic panel including liver function tests, ophthalmo-
logic examination, audiology evaluation, and neuroimaging.
Pediatric infectious disease and neurologic specialists
should be consulted. The CDC recommends that in asymp-
tomatic infants, testing for Zika and head ultrasonography
should be performed but no other special tests are neces-
sary, aside from routine newborn care including stan-
dard newborn screening. Any diagnosed cases should be
reported to the CDC. Infants with laboratory evidence of
Zika virus infection should receive close follow-up on an
outpatient basis, with special attention paid to growth and
neurodevelopment. Infants with proven infection and ab-
normalities consistent with congenital Zika should have
additional testing, including thyroid testing, repeat ophthal-
mologic examination, and audiology evaluation. (15)
CONCLUSIONS
Microcephaly can present in the newborn period and be
categorized as present at birth or developing postnatally.
The top 2 reported etiologies for microcephaly in cases
with a known underlying diagnosis are genetic disorders
and perinatal brain damage secondary to exogenous factors.
However, no etiology is identied in up to w40% of chil-
dren with microcephaly. Although many classications
exist, it is important to remember that both congenital
microcephaly and postnatal-onset microcephaly can be due
to genetic or acquired causes. Careful history and physical
examination can help to direct further diagnostic evaluation.
Published studies suggest that in all-comers with micro-
cephaly, neuroimaging proves to have the highest diagnostic
yield, with MRI providing the highest sensitivity. Even when
neuroimaging ndings are nonspecic and not diagnostic
per se, they can help tailor further testing. Genetic testing
has the next highest diagnostic yield, and if presentation
does not suggest a specic genetic disorder, CGH would be
the rst-line genetic testing recommended by experts in the
eld. In some cases, evaluation for infectious or metabolic
etiologies may be warranted. Denitive treatment for micro-
cephaly does not exist, but supportive treatment for comor-
bidities should be provided. Overall prognosis relates to
severity of disease, underlying diagnosis, and comorbid
conditions identied. Zika virus is emerging as an infec-
tious pathogen leading to congenital microcephaly. Given
its potentially devastating effects, a low threshold of suspi-
cion is warranted to initiate evaluation of a neonate with
risk factors for congenital infection.
American Board of Pediatrics
NeonatalPerinatal Content
Specications
Know the indications for and limitations of various neuroimaging
studies and be able to recognize normal and abnormal structures
and changes during development and growth.
Know the causes, diagnosis, management, and outcome of an
infant with microcephaly.
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Vol. 18 No. 1 JANUARY 2017 e51
 Primer on Microcephaly
Alison Chu, Taylor Heald-Sargent and Joseph R. Hageman
NeoReviews 2017;18;e44
DOI: 10.1542/neo.18-1-e44

Updated Information & including high resolution figures, can be found at:
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References This article cites 19 articles, 3 of which you can access for free at:
http://neoreviews.aappublications.org/content/18/1/e44#BIBL
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 Primer on Microcephaly
Alison Chu, Taylor Heald-Sargent and Joseph R. Hageman
NeoReviews 2017;18;e44
DOI: 10.1542/neo.18-1-e44

The online version of this article, along with updated information and services, is
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