Congenital Oropouche in Humans: Clinical Characterization of a Possible New Teratogenic Syndrome

Abstract

Oropouche fever is caused by the Oropouche virus (OROV; Bunyaviridae, Orthobunyavirus), one of the most frequent arboviruses that infect humans in the Brazilian Amazon. This year, an OROV outbreak was identified in Brazil, and its vertical transmission was reported, which was associated with fetal death and microcephaly. We describe the clinical manifestations identified in three cases of congenital OROV infection with confirmed serology (OROV-IgM) in the mother-newborn binomial. One of the newborns died, and post-mortem molecular analysis using real-time RT-qPCR identified the OROV genome in several tissues. All three newborns were born in the Amazon region in Brazil, and the mothers reported fever, rash, headache, myalgia, and/or retro-orbital pain during pregnancy. The newborns presented with severe microcephaly secondary to brain damage and arthrogryposis, suggestive of an embryo/fetal disruptive process at birth. Brain and spinal images identified overlapping sutures, cerebral atrophy, brain cysts, thinning of the spinal cord, corpus callosum, and posterior fossa abnormalities. Fundoscopic findings included macular chorioretinal scars, focal pigment mottling, and vascular attenuation. The clinical presentation of vertical OROV infection resembled congenital Zika syndrome to some extent but presents some distinctive features on brain imaging and in several aspects of its neurological presentation. A recognizable syndrome with severe brain damage, neurological alterations, arthrogryposis, and fundoscopic abnormalities can be associated with in utero OROV infection.

Keywords: Oropouche fever; congenital anomalies; microcephaly; vertical transmission.

Figure 1

Case 1. Photographs taken at three months of life (A) Exacerbation of the tonic-cervical reflex and dystonia. (B) Retrognathia. (C) Small skull, head circumference 34.3 cm (−4.2 Z), epicantal folds, supratemporal depression, eyes are closed. (D) Redundant and folded loose skin and the appearance of a short neck, sparse and fine hair. (E–G) CT scan at six days of life showing overlapping cranial sutures ((E,F) blue arrowheads; (G) white arrow) and marked bilateral cerebral volume loss, with variable parenchymal thinning and irregularity ((F) white arrow), ventriculomegaly ((F) asterisk), with some tiny hyperdense foci along the cortico-pial surface (hemorrhage residues versus calcifications—(E) blue arrows). (H–N) MRI at three months of life demonstrating striking supratentorial parenchymal volume loss ((H) blue arrow) and areas of smooth cortical surface that might represent lissencephaly ((J,K) blue arrowheads). There is also secondary detachment of dura ((J) blue arrow) and subdural effusion ((F) white star; (L,M) asterisks). Cysts along the brain surface are either areas of cystic encephalomalacia and/or evidence of prior subpial hemorrhage ((L,M) arrows; (H) asterisk). Suspected striatal fusion is shown on (K) (blue arrow). The posterior fossa seems unaffected, with the brainstem and cerebellum essentially normal, allowing for image resolution ((H,I) white arrowheads, and (N)).

Figure 2

Case 2. Photographs taken at birth. (A) Fetal hydrops and fetal akinesia syndrome, genu recurvatum, arthrogryposis multiplex, hand camptodactyly. (B) X-rays showing bilateral humerus bone fractures, congenital hip dislocation, and scoliosis. (C) Microcephaly, skull with loose and folded skin, short neck, curly hair. (D) Bulging single fold, with a crease above the nose, (E) Overlapping cranial sutures, significant subcutaneous edema. (F) Craniofacial disproportion. (G–J). Thirty days old. (G) Multiple arthrogryposis, hyperextension of the elbows, wrists, and knees. (H) Spontaneous eye opening. (I) Cranial facial disproportion, short neck. (J) Consolidated bilateral humeral fracture, scoliosis, pleural effusion, bilateral hip dislocation. (K–O) Fetal MRI at the 33rd week of pregnancy showing oligohydramnios ((K) blue arrow) as well as microcephaly and hydrops stigmata, with redundant, folded, and diffusely thickened scalp ((K) blue arrowheads). Severely hypoplastic brainstem and cerebellum ((L,O,P,R) blue arrows and arrowheads), associated with an enlarged IV ventricle ((K,L,P) asterisk) and an increased posterior infratentorial subdural space, possibly effusion due to volume loss ((L,O,P,R) star). Bilateral cerebral mantle thinning, with a smooth outer surface ((N) blue arrows; (Q) blue arrowheads), and severe ventriculomegaly. The corpus callosum was not discerned, with a possible interhemispheric cyst. Peripherally located cystic collections appear to be present adjacent to temporal lobes, either representing cystic encephalomalacia or chronic subpial hemorrhage ((M) arrowheads). Cranial deformity with partially overlapping sutures and a caput succedaneum is seen on postnatal CT (P, downward arrowhead, Q).

Figure 3

Case 3. (A) Photograph at birth: microcephaly, arthrogryposis multiplex, clubfeet, ankylosis, camptodactyly, subcutaneous edema. (B) Nineteen days of life: microcephaly, craniofacial disproportion, short neck, arthrogryposis multiplex, clubfeet, camptodactyly (C). Eyes are closed, epicantal folds, camptodactyly, (D). Microcephaly, cranial disproportion, retrognathia, reduction of edema. (E) X-ray with joint contractures and hip dislocation. (F) Right eye fundus image showing a large, well-defined chorioretinal macular scar with pigment dispersion on its margin and macular region. (G) Left eye fundus image showing optic disc pallor, increased disc cupping, vascular attenuation, and a well-defined chorioretinal macular scar with focal pigment mottling on its margin and macular region. (H–N) MRI at the 13th day of life: severe brainstem (H, arrowhead) and cerebellar hypoplasia, with an upwardly-rotated vestigial vermis (H, arrow); cystic dilatation of the posterior fossa (H,J, asterisk; K,L, star), communicating fourth ventricle and cisterna magna, reminiscent of Dandy–Walker malformation. Diffuse smooth-surfaced cerebral hemispheres (I–M, arrows) with shallow sylvian fissures (I, arrowheads) indicate lissencephaly type I pattern. Trace intraventricular hemorrhage is seen on occipital horns (M,N, blue arrowheads). No calcification was seen on the CT scan (O). MRI of the spine (P) revealed global spinal cord thinning (blue arrowheads), mainly on the thoracic segment.