Axenfeld-Rieger syndrome/anomaly (ARS) is a rare genetic disorder with an autosomal dominant inheritance pattern, characterized by dysgenesis of the anterior segment of the eye. It may present with systemic anomalies (Axenfeld-Rieger syndrome) or without (Axenfeld anomaly) and may sometimes be associated with multiple congenital malformations. The estimated prevalence ranges from 1 in 50,000 to 1 in 200,000 live births, with an approximate rate of 1 in 100,000, but no epidemiological studies have been conducted to date. A clinical diagnosis of Axenfeld-Rieger syndrome requires the presence of both Axenfeld and Rieger ocular anomalies, accompanied by extraocular systemic features. Ocular manifestations include iris abnormalities, posterior embryotoxon, juvenile-onset glaucoma (a common complication), and dysgenesis of the iridocorneal angle with iridocorneal adhesions. The most commonly observed systemic anomalies include: umbilical defects; craniofacial dysmorphism; dentofacial abnormalities, such as Class III malocclusion due to maxillary hypoplasia, oligodontia, dental malformations (taurodontism, root dysplasia), microdontia, hypodontia, and anodontia; hearing impairment (partial or complete sensorineural hearing loss); and cardiac anomalies, including non-congenital heart disease and mitral valve insufficiency. Additional anomalies may include hypospadias in males, anal stenosis, endocrine disorders (notably growth retardation) secondary to pituitary dysfunction, psychomotor delay, and various neurological malformations such as Dandy-Walker malformation, mega cisterna magna, posterior fossa cysts, cerebellar vermis hypoplasia, ventriculomegaly, aprosencephaly, cerebral atrophy, microcephaly, arteriovenous malformations (AVM), and digital anomalies such as camptodactyly. Diagnosis is typically made in infancy, based on iris anomalies such as corectopia (displacement of the pupil), polycoria (multiple pupils), and iris hypoplasia. Posterior embryotoxon is frequently observed upon slit-lamp examination. Given the clinical variability, a comprehensive pediatric assessment is essential to identify systemic anomalies and distinguish Axenfeld-Rieger syndrome from the isolated Axenfeld anomaly.

Bovine frontonasal dysplasias like arhinencephaly, synophthalmia, cyclopia and anophthalmia are sporadic congenital facial malformations. In this study, computed tomography, necropsy, histopathological examinations and whole genome sequencing on an Illumina NextSeq500 were performed to characterize a stillborn Limousin calf with frontonasal dysplasia. In order to identify private genetic and structural variants, we screened whole genome sequencing data of the affected calf and unaffected relatives including parents, a maternal and paternal halfsibling. The stillborn calf exhibited severe craniofacial malformations. Nose and maxilla were absent, mandibles were upwardly curved and a median cleft palate was evident. Eyes, optic nerve and orbital cavities were not developed and the rudimentary orbita showed hypotelorism. A defect centrally in the front skull covered with a membrane extended into the intracranial cavity. Aprosencephaly affected telencephalic and diencephalic structures and cerebellum. In addition, a shortened tail was seen. Filtering whole genome sequencing data revealed a private frameshift variant within the candidate gene ZIC2 in the affected calf. This variant was heterozygous mutant in this case and homozygous wild type in parents, half-siblings and controls. We found a novel ZIC2 frameshift mutation in an aprosencephalic Limousin calf. The origin of this variant is most likely due to a de novo mutation in the germline of one parent or during very early embryonic development. To the authors' best knowledge, this is the first identified mutation in cattle associated with bovine frontonasal dysplasia.

Holoprosencephaly (HPE) is a primary disorder of neural induction and patterning of the rostral neural tube resulting in noncleavage of the forebrain with failure to form two separate distinct hemispheres. The spectrum of HPE is very broad and encompasses various neuropathological phenotypes of different severity. The recent literature has demonstrated that the phenotypic variability of HPE ranges from aprosencephaly-atelencephaly, at the most severe end, to milder forms such as the "middle interhemispheric variant" of HPE at the less severe end of the spectrum. Between them, different intermediate forms demonstrate a continuum in a wide phenotypic spectrum rather than well-defined categories. Although the term "HPE" suggests a disorder affecting only the prosencephalon, other brain structures are involved, underlining the complexity of the malformation. Because of close spatiotemporal interactions and common signaling pathways contributing to the development of both brain and face, concomitant facial and ocular anomalies are associated with brain malformation. In this review, the characteristic neuropathological features of the various forms of HPE are described as well as their associated brain, face, and ocular malformations, to delineate the different phenotypes.

Malformations of the forebrain are characterized by abnormalities in size, shape, and arrangement of the cerebral hemispheres and ventricles. We present the morphological picture of a brain with failure of the forebrain complementary to holoprosencephaly coexisting with absence of the anterodorsal part of the prosencephalic ventricles. The anomaly can be graded within the holoprosencephalic spectrum due to the main morphological features. However, such alterations as aplasia of the forebrain ventricles and prominent leptomeningeal gliomesodermal proliferation are related to atelencephaly. The observations confirm the common pathogenic mechanism of aprosencephaly/atelencephaly and holoprosencephaly. The malformation corresponds to a wide continuous spectrum with no clear-cut boundaries of abnormal formation of the prosencephalon.

Structural malformations of the brain are an important cause of childhood mortality and morbidity, with the latter having long-term financial and psychosocial implications for the affected child and family. Holoprosencephaly (HPE) is a severe brain malformation characterized by abnormal cleavage of the prosencephalon in the 5th gestational week. Aprosencephaly and atelencephaly occur earlier because of failure in the formation of the prosencephalon and telencephalon, respectively. The HPE holoprosencephaly spectrum classically includes alobar, semilobar, and lobar forms, although there are no clear-cut defining features. The middle interhemispheric variant (MIH), also known as syntelencephaly, is classified as a variant of HPE holoprosencephaly with midline interhemispheric fusion. Other conditions sometimes included in the spectrum of HPE holoprosencephaly include septo-optic dysplasia (SOD); "minimal" HPE holoprosencephaly , which is associated with subtle craniofacial malformations and mild developmental delay; and microform HPE holoprosencephaly , which by definition excludes brain involvement. The focus of this article will be on the spectrum of findings visible in fetal manifestation of the HPE holoprosencephaly spectrum. Brain embryology; the imaging characteristics, epidemiology, and embryology of HPE; and the more common associated anomalies, particularly those of the face ("the face predicts the brain") are reviewed. Recognition of these anomalies is important for accurate parental counseling, since the prognosis is poor but not invariably lethal; children with the milder forms may live well into their teens with severe developmental delays, endocrine dysfunction, and disrupted homeostasis. Available data on outcome in surviving children are summarized. Illustrative fetal ultrasonographic and magnetic resonance images are presented with clinical, autopsy, and postnatal imaging correlation.