CDC Defines Congenital Zika Syndrome

Laurie Barclay, MD

November 03, 2016

Recognizing the congenital Zika syndrome (CZS) phenotype defined by the Centers for Disease Control and Prevention (CDC) allows clinicians to provide comprehensive workup and management for infants and children, according to a literature review published online November 3 in JAMA Pediatrics.

"[Zika virus (ZIKV)] infection in pregnancy appears to be the cause of a recognizable pattern of congenital anomalies that is consistent and unique," write Cynthia A. Moore, MD, PhD, from the Division of Congenital and Developmental Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, and colleagues. "Although many of the components of this syndrome, such as cognitive, sensory, and motor disabilities, are shared by other congenital infections, 5 features differentiate CZS from other congenital infections."

Distinctive features reported in CZS are:

  1. severe microcephaly (>3 SD below the mean), with findings consistent with fetal brain disruption sequence, including partially collapsed skull, overlapping cranial sutures, prominent occipital bone, redundant scalp skin, and neurologic impairment;

  2. brain anomalies, including cerebral cortex thinning, abnormal gyral patterns, increased fluid spaces, subcortical calcifications, corpus callosum anomalies, reduced white matter, and cerebellar vermis hypoplasia;

  3. ocular findings, such as macular scarring, focal pigmentary retinal mottling, structural anomalies (microphthalmia, coloboma, cataracts, and posterior anomalies), chorioretinal atrophy, and optic nerve hypoplasia/atrophy;

  4. congenital contractures, including unilateral or bilateral clubfoot and arthrogryposis multiplex congenita; and

  5. neurological impairments, such as pronounced early hypertonia/spasticity with extrapyramidal symptoms, motor disabilities, cognitive disabilities, hypotonia, irritability/excessive crying, tremors, swallowing dysfunction, vision impairment, hearing impairment, and epilepsy.

Diagnostic Workup Needed

Many of these features can also occur in other congenital infections, such as congenital cytomegalovirus, rubella, varicella, and coxsackie B, mandating thorough workup. Brain anomalies may also occur in genetic syndromes, such as Aicardi-Goutières syndrome, pseudo-TORCH syndrome, and gene mutations in JAM3, NDE1, and ANKLE.

Congenital infections with HIV, varicella-zoster, and rubella virus may cause microcephaly, but distinctive findings such as hepatomegaly and rash help differentiate these from ZIKV infection. To date, hematologic, hepatic, or renal laboratory abnormalities have not been reported in infants with congenital ZIKV infections.

Clinical, epidemiologic, and laboratory evidence thus far is sufficient to determine that ZIKV infection can be transmitted from a pregnant woman to the fetus, resulting in microcephaly and serious brain anomalies. As with other newly recognized teratogens, these characteristics most likely reflect only the tip of the iceberg, and underlying pathogenetic mechanisms are incompletely determined. This is the first review characterizing the full spectrum of congenital abnormalities related to prenatal ZIKV infection.

"In particular, more data are needed on infants with congenital ZIKV infection who do not have microcephaly at birth and the brain findings in these infants," the reviewers conclude. "In addition, knowledge about the frequency in which the various components co-occur in an infant, as well as whether any component(s) are mandatory features, is lacking at this time."

The authors note that most congenital anomalies associated with Zika infection appear to be related to the neurotropic nature of the virus. However, other sporadic reports of anomalies, such as congenital heart defects, will need further investigation in epidemiologic studies to exclude coincidental associations and define a more complete CZS phenotype.

The authors developed the current definition of CZS based on a comprehensive English literature search using Medline and EMBASE from inception through September 30, 2016. They identified 34 published reports of congenital anomalies occurring in fetuses or infants with presumed or laboratory-confirmed intrauterine ZIKV infection.

After considering these in light of presumed, underlying pathogenesis related to the neurotropic characteristics of ZIKV, the reviewers conclude that CZS is a distinctive pattern of structural anomalies and functional disabilities caused by damage to the central and possibly peripheral nervous system.

On the basis of maternal symptoms, the most common timing of infection is late first and early second trimester, but third trimester infection can also cause CZS.

ZIKV infection has been reported in at least 45 countries in the Americas, three US territories, and Florida, with spread to other US states possible based on the estimated range of the Aedes mosquito vectors. Sexual transmission has also been reported.

Limitations of this review include the lack of testing for ZIKV infection and incomplete description of the full range of anomalies in most reported infants.

The authors have disclosed no relevant financial relationships.

JAMA Pediatr. Published online November 3, 2016. Full text

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