Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians

Abstract

Importance: Zika virus infection can be prenatally passed from a pregnant woman to her fetus. There is sufficient evidence to conclude that intrauterine Zika virus infection is a cause of microcephaly and serious brain anomalies, but the full spectrum of anomalies has not been delineated. To inform pediatric clinicians who may be called on to evaluate and treat affected infants and children, we review the most recent evidence to better characterize congenital Zika syndrome.

Observations: We reviewed published reports of congenital anomalies occurring in fetuses or infants with presumed or laboratory-confirmed intrauterine Zika virus infection. We conducted a comprehensive search of the English literature using Medline and EMBASE for Zika from inception through September 30, 2016. Congenital anomalies were considered in the context of the presumed pathogenetic mechanism related to the neurotropic properties of the virus. We conclude that congenital Zika syndrome is a recognizable pattern of structural anomalies and functional disabilities secondary to central and, perhaps, peripheral nervous system damage. Although many of the components of this syndrome, such as cognitive, sensory, and motor disabilities, are shared by other congenital infections, there are 5 features that are rarely seen with other congenital infections or are unique to congenital Zika virus infection: (1) severe microcephaly with partially collapsed skull; (2) thin cerebral cortices with subcortical calcifications; (3) macular scarring and focal pigmentary retinal mottling; (4) congenital contractures; and (5) marked early hypertonia and symptoms of extrapyramidal involvement.

Conclusions and relevance: Although the full spectrum of adverse reproductive outcomes caused by Zika virus infection is not yet determined, a distinctive phenotype-the congenital Zika syndrome-has emerged. Recognition of this phenotype by clinicians for infants and children can help ensure appropriate etiologic evaluation and comprehensive clinical investigation to define the range of anomalies in an affected infant as well as determine essential follow-up and ongoing care.

Figure 1. Cranial morphology supporting fetal brain disruption sequence (FBDS) phenotype in congenital Zika syndrome

A) Lateral view of an infant with congenital Zika virus infection. Note the severe decrease in cranial vault, irregularity of the skull, and scalp rugae. B) Note typical scalp folds or rugae in a 3-month-old infant with presumed congenital Zika virus infection. C) Lateral skull radiograph in a newborn showing partial collapse of the cranial bones with prominent occiput. D) Fetal MRI showing same phenotype at 29 weeks’ gestation. White arrow indicates occipital area. E) 3D skull reconstruction in a 3-month-old infant showing downward displacement of the frontal and temporal bones while occipital bone appears stable.

Figure 2. Brain findings in infants with presumed congenital Zika syndrome

CT scan in one infant and MRI in another infant with prenatal Zika exposure show very low forehead and small cranial vault (D), striking volume loss shown by enlarged extra-axial space and ventriculomegaly (all images), poor gyral development with few and shallow sulci (long white arrows in A and E), poor gyral development with irregular “beaded” cortex most consistent with polymicrogyria (black arrows in F), scattered punctate calcifications (white arrowheads in A, B, C and E), flattened pons and small cerebellum (black arrowhead and asterisk in D). The occipital “shelf” caused by skull collapse is seen in both children (large white arrows in C and D).

Figure 3. Wide-angle fundus images (RetCam®) of a male infant with congenital Zika infection

A) Right eye: Optic nerve hypoplasia with the double-ring sign, increased cup-to-disk ratio, attenuated blood vessels, gross pigment mottling and chorioretinal scar in the macular region. B) Left eye: Optic nerve hypoplasia with the double-ring sign, increased cup-to-disk ratio, attenuated blood vessels, gross pigment mottling and chorioretinal scar in the macular region.

Figure 4. Infants with congenital Zika infection and microcephaly and arthrogryposis

A) Newborn infant with bilateral contractures of the hips and knees, bilateral talipes calcaneovalgus, and anterior dislocation of the knees. Hips are bilaterally dislocated. B) Newborn infant with bilateral contractures of the shoulders, elbows, wrists, hips, knees, and right talipes equinovarus. Hips are bilaterally dislocated.