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 forZikafrom 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.

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

A hypothesis is presented to explain the pathogenesis of the Poland, Klippel-Feil, and Mobius anomalies, isolated absence of the pectoralis major with breast hypoplasia, isolated terminal transverse limb defects, and the Sprengel anomaly. We propose that these conditions are the result of an interruption of the early embryonic blood supply in the subclavian arteries, the vertebral arteries and/or their branches, and hypothesize that the occlusions occur at specific locations in these vessels during or around the sixth week of embryologic development and produce predictable patterns of defects. The term subclavian artery supply disruption sequence (SASDS) is suggested for the group of birth defects represented by the above conditions. Possible causes for interruption of embryonic blood supply are discussed.

Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Möbius anomalies.

Exstrophy-epispadias complex (EEC) represents a spectrum of genitourinary malformations ranging in severity from epispadias (E) to classical bladder exstrophy (CEB) and exstrophy of the cloaca (EC). Depending on severity, EEC may involve the urinary system, musculoskeletal system, pelvis, pelvic floor, abdominal wall, genitalia, and sometimes the spine and anus. Prevalence at birth for the whole spectrum is reported at 1/10,000, ranging from 1/30,000 for CEB to 1/200,000 for EC, with an overall greater proportion of affected males. EEC is characterized by a visible defect of the lower abdominal wall, either with an evaginated bladder plate (CEB), or with an open urethral plate in males or a cleft in females (E). In CE, two exstrophied hemibladders, as well as omphalocele, an imperforate anus and spinal defects, can be seen after birth. EEC results from mechanical disruption or enlargement of the cloacal membrane; the timing of the rupture determines the severity of the malformation. The underlying cause remains unknown: both genetic and environmental factors are likely to play a role in the etiology of EEC. Diagnosis at birth is made on the basis of the clinical presentation but EEC may be detected prenatally by ultrasound from repeated non-visualization of a normally filled fetal bladder. Counseling should be provided to parents but, due to a favorable outcome, termination of the pregnancy is no longer recommended. Management is primarily surgical, with the main aims of obtaining secure abdominal wall closure, achieving urinary continence with preservation of renal function, and, finally, adequate cosmetic and functional genital reconstruction. Several methods for bladder reconstruction with creation of an outlet resistance during the newborn period are favored worldwide. Removal of the bladder template with complete urinary diversion to a rectal reservoir can be an alternative. After reconstructive surgery of the bladder, continence rates of about 80% are expected during childhood. Additional surgery might be needed to optimize bladder storage and emptying function. In cases of final reconstruction failure, urinary diversion should be undertaken. In puberty, genital and reproductive function are important issues. Psychosocial and psychosexual outcome depend on long-term multidisciplinary care to facilitate an adequate quality of life.

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The Exstrophy-epispadias complex

Objective To describe the clinical, radiological, and electromyographic features in a series of children with joint contractures (arthrogryposis) associated with congenital infection presumably caused by Zika virus. Design Retrospective case series study. Setting Association for Assistance of Disabled Children, Pernambuco state, Brazil. Participants Seven children with arthrogryposis and a diagnosis of congenital infection presumably caused by Zika virus during the Brazilian microcephaly epidemic. Main outcome measures Main clinical, radiological, and electromyographic findings, and likely correlation between clinical and primary neurological abnormalities. Results The brain images of all seven children were characteristic of congenital infection and arthrogryposis. Two children tested positive for IgM to Zika virus in the cerebrospinal fluid. Arthrogryposis was present in the arms and legs of six children (86%) and the legs of one child (14%). Hip radiographs showed bilateral dislocation in seven children, subluxation of the knee associated with genu valgus in three children (43%), which was bilateral in two (29%). All the children underwent high definition ultrasonography of the joints, and there was no evidence of abnormalities. Moderate signs of remodeling of the motor units and a reduced recruitment pattern were found on needle electromyography (monopolar). Five of the children underwent brain computed tomography (CT) and magnetic resonance imaging (MRI) and the remaining two CT only. All presented malformations of cortical development, calcifications predominantly in the cortex and subcortical white matter (especially in the junction between the cortex and white matter), reduction in brain volume, ventriculomegaly, and hypoplasia of the brainstem and cerebellum. MRI of the spine in four children showed apparent thinning of the cord and reduced ventral roots. Conclusions Congenital Zika syndrome should be added to the differential diagnosis of congenital infections and arthrogryposis. The arthrogryposis was unrelated to the abnormalities of the joints themselves, but was possibly of neurogenic origin, with chronic involvement of central and peripheral motor neurones leading to deformities as a result of fixed postures in utero. Based on the neurophysiological observations, we suggest two possible mechanisms: tropism of neurones, with involvement of peripheral and central motor neurones, or a relation with vascular disorders.

https://www.bmj.com/content/bmj/354/bmj.i3899.full.pdf

Congenital Zika syndrome with arthrogryposis: retrospective case series study.

Of 253 infants with oesophageal atresia treated over an eight year period, 122 (48%) had a total of 213 other anomalies. Most commonly affected were the cardiovascular (61 cases, 29%), anorectal (30 cases, 14%), and genitourinary (29 cases, 14%) systems. The VATER (or VACTERL) association was present in 10% of cases, but occurred more often in patients who had oesophageal atresia without an associated tracheo-oesophageal fistula (3/13, 23%). The level of the associated anorectal malformation was not associated with the type of oesophageal atresia. The presence and severity of other anomalies did not influence the basic approach to treatment of the oesophageal atresia--that is, primary repair whenever possible. Despite aggressive treatment, cardiac malformations were the most common cause of death. There were five infants with the CHARGE association, two with Potter's syndrome, and two with 'SCHISIS' syndrome (cleft lip and palate, omphalocoele, and hypogenitalism).

https://adc.bmj.com/content/archdischild/64/3/364.full.pdf

Oesophageal atresia and associated anomalies.

Features of both the Goldenhar and the caudal regression syndromes were found in the patient described. A search of the literature revealed two other patients having both conditions. However, a number of other individuals have been reported with Goldenhar or related syndromes who have malformations in the caudal region or, conversely, who have the caudal regression syndrome and possess cranial anomalies. Possible explanations for the commonality of malformations seen in these syndromes are presented and discussed. It is suggested that the term, "axial mesodermal dysplasia spectrum" be used in patients manifesting this overlap to emphasize the importance of searching for the other malformations seen in this spectrum of anomalies.

The Axial Mesodermal Dysplasia Spectrum

Three infants are reported with a recognizable pattern of defects consisting of severe microcephaly, overlapping sutures, prominence of the occipital bone, and scalp rugae. This condition, which we think represents microhydranencephaly, appears to be produced by partial brain destruction during the second or third trimester, diminution in intracranial hydrostatic pressure, and subsequent collapse of the fetal skull. Several different causes for this condition have been suggested including partial disruption of the blood supply to the brain and prenatal viral infection.

In utero brain destruction resulting in collapse of the fetal skull, microcephaly, scalp rugae, and neurologic impairment: The fetal brain disruption sequence

Laura J. Russell

Papers

The Axial Mesodermal Dysplasia Spectrum

In utero brain destruction resulting in collapse of the fetal skull, microcephaly, scalp rugae, and neurologic impairment: The fetal brain disruption sequence

A Child With Radius Aplasia, Cleft of Lip and Palate, Microcephaly, and Unusual Chromosome Findings