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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.
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.
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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 Physical examination should not only include a thorough
ultrasonography/imaging ndings, genetic screening, mater- neurologic examination, including tone and reexes and
nal exposures), as well as a detailed family history of neuro- evaluation for sensory or motor decits, but also be aimed
logic disorders or recurrent miscarriage. Of note, for a child at uncovering other ndings that may point to specic diag-
presenting with microcephaly at an older age, history may noses (eg, genetic syndromic etiologies, metabolic disorders,
also include a timeline of onset of microcephaly (including congenital infection). An ophthalmologic examination by a
serial HC measurements) and neuropsychiatric assessment. pediatric specialist should also be considered.
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Testing for metabolic disorders should be considered for 3 possible. For example, in some metabolic causes of micro-
specic conditions: maternal phenylketonuria (fetal brain cephaly, dietary restrictions, in combination with pharmaco-
exposure to toxic levels of phenylalanine can result in micro- logic agents, may help to minimize accumulation of
cephaly), phosphoglycerate dehydrogenase deciency, and metabolic toxins that lead to progressive brain damage.
2-ketoglutaric aciduria (Amish lethal microcephaly). Other However, there is no currently available treatment per se
risk factors that, if present, may increase the diagnostic yield for the underlying cause, as generally seen with genetic
of metabolic testing, include a history of parental con- etiologies. In this exciting time of development of gene-
sanguinity, a positive family history for similar symptoms, editing platforms such as Crispr/Cas9, this limitation may
an episodic nature to symptoms, developmental regres- be potentially addressable in the future. In the meanwhile,
sion, other organ failure, or specic neuroimaging ndings. supportive treatment may be targeted at minimizing mor-
Otherwise, metabolic disorders rarely present with non- bidity from coexisting conditions. For example, pharmaco-
syndromic congenital microcephaly and are estimated to logic treatment for seizures should be initiated when
account for 1% to 5% of all children with microcephaly. indicated. Developmental therapies should be offered to
Therefore, metabolic testing may have higher diagnostic high-risk patients. A recently published study by Rosman
yield in the population with postnatal-onset microcephaly, et al (8) suggests that better somatic growth (weight, height)
compared to those with congenital microcephaly. in patients with postnatal-onset microcephaly is associated
Testing for infection may be indicated, but if currently rec- with better neurodevelopmental outcomes, thus supporting
ommended maternal prenatal screenings are negative for the the role for optimization of diet and growth (though both
newborn being evaluated and the mother took appropriate decient and excessive growth can negatively affect develop-
preventive medication or precautions, the diagnostic yield for mental outcome). However, this study only reports association,
this infectious testing is likely lower except in the case of CMVor so the causative relationship between optimal somatic growth
Zika virus. The most common infectious causes of microceph- and brain growth, while linked in theory and shown to be linked
aly are TORCH infections. Targeted testing should be performed in other human diseases, remains undened in microcephalic
as directed by ndings and may include culture, DNApolymerase patients. In addition, in this cohort, children with better
chain reaction (PCR), or serologic testing for specic pathogens. somatic growth may have less severe disease phenotype, thus
A urine CMV test is a minimally invasive, relatively low-cost test displaying better associated outcomes.
that can be easily performed and results obtained quickly. Given
its ubiquitous nature and the ease of testing, a neonate present- MORBIDITY AND MORTALITY
ing with congenital microcephaly should be evaluated for CMV.
Long-term outcomes for infants with microcephaly are re-
Lastly, screening for coexistent conditions such as epilepsy,
lated to the underlying etiology and coexisting conditions.
sensory decits, and cerebral palsy may be indicated, depend-
More severe microcephaly (HC < -3 SD) generally portends a
ing on the severity, associated ndings, or suspected/
worse prognosis, in terms of neurodevelopmental outcomes,
conrmed diagnosis. The estimated prevalence of epilepsy
compared with milder microcephaly. Coexistent conditions
in this population is 40%, and some studies suggest that
may include intellectual disability, cerebral palsy, epilepsy,
epilepsy is more common in secondary microcephaly. Care-
and ophthalmologic disorders (ranging from w20%50%
givers should be taught to monitor for signs/symptoms of
for each condition).
seizures, and electroencephalography performed when clin-
ical suspicion is high. Caregivers and primary care physicians
ZIKA VIRUS AS AN EMERGING CAUSE OF CONGENITAL
should also monitor affected children for early signs of
MICROCEPHALY
cerebral palsy and/or developmental delays (w60%), to ini-
tiate supportive treatments in a timely manner. Although Clinicians have become more aware of microcephaly as Zika
ophthalmologic and hearing disorders are more common virus transmission by the Aedes Aegypti mosquito initially
in children with microcephaly than in the general population, reported in Brazil has now been reported to have affected
the estimates of frequency of ophthalmologic or audiologic pregnancies in Central America, Puerto Rico, and the south-
disorders in all children with microcephaly are varied (from ern United States in Florida. (4) Zika virus is an arbovirus
<1%30%) or unknown, respectively. of the Flavivirus genus, and was rst described in Rhesus
monkeys in Uganda in the 1940s. The rst signicant
TREATMENT
epidemic was in Micronesia in 2007. With the acquisition
Treatment for any individual diagnosed with microcephaly of the virus by pregnant women and subsequent infection of
should be aimed at the underlying disorder whenever the fetus, congenital CNS abnormalities, including intracranial
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microcephaly and postnatal-onset microcephaly can be due 4. Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika virus
and birth defects: reviewing the evidence for causality. N Engl J Med.
to genetic or acquired causes. Careful history and physical
2016;374(20):19811987
examination can help to direct further diagnostic evaluation.
5. Chiriboga CA, Kuban KC, Durkin M, et al. Factors associated with
Published studies suggest that in all-comers with micro- microcephaly at school age in a very-low-birthweight population.
cephaly, neuroimaging proves to have the highest diagnostic Dev Med Child Neurol. 2003;45(12):796801
yield, with MRI providing the highest sensitivity. Even when 6. Suursalmi P, Korhonen P, Kopeli T, et al. Severe bronchopulmonary
neuroimaging ndings are nonspecic and not diagnostic dysplasia, growth, nutrition, and adipokines at school age. Glob
Pediatr Health. 2016;3:2333794X16637290
per se, they can help tailor further testing. Genetic testing
7. Baxter PS, Rigby AS, Rotsaert MH, Wright I. Acquired
has the next highest diagnostic yield, and if presentation microcephaly: causes, patterns, motor and IQ effects, and associated
does not suggest a specic genetic disorder, CGH would be growth changes. Pediatrics. 2009;124(2):590595
the rst-line genetic testing recommended by experts in the 8. Rosman NP, Tarquinio DC, Datseris M, et al. Postnatal-onset
eld. In some cases, evaluation for infectious or metabolic microcephaly: pathogenesis, patterns of growth, and prediction of
outcome. Pediatrics. 2011;127(4):665671
etiologies may be warranted. Denitive treatment for micro-
9. Russell K, Oliver SE, Lewis L, et al. Update: interim guidance for the
cephaly does not exist, but supportive treatment for comor-
evaluation and management of infants with possible congenital
bidities should be provided. Overall prognosis relates to Zika virus infectionUnited States, August 2016. MMWR Morb
severity of disease, underlying diagnosis, and comorbid Mortal Wkly Rep. 2016;65(33):870878
conditions identied. Zika virus is emerging as an infec- 10. Soares de Oliveira-Szejnfeld P, Levine D, Melo AS, et al. Congenital
brain abnormalities and Zika virus: what the radiologist can expect
tious pathogen leading to congenital microcephaly. Given
to see prenatally and postnatally. Radiology. 2016;281(1):203218
its potentially devastating effects, a low threshold of suspi-
11. Hazin AN, Poretti A, Turchi Martelli CM, et al. Computed
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12. Mlakar J, Korva M, Tul N, et al. Zika virus associated with
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studies and be able to recognize normal and abnormal structures tissues from two congenitally infected newborns and two fetal
losses Brazil 2015. MMWR Morb Mortal Wkly Rep. 2016;65
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Know the causes, diagnosis, management, and outcome of an
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infant with microcephaly. cdc.gov/zika/index.html. Accessed October 12, 2016
16. Calvet GA, Santos FB, Sequeira PC. Zika virus infection:
epidemiology, clinical manifestations and diagnosis. Curr Opin
Infect Dis. 2016;29(5):459466
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