Prenatal diagnosis of bilateral anophthalmia: Identifying de novo SOX2 variant.

A 26 year old nulligravida presented at 24 weeks gestation for the second opinion of abnormal fetal profile and mid-face views on ultrasound at another institution. A detailed fetal anatomic ultrasound at our facility revealed the absence of fetal lens and globes bilaterally consistent with bilateral anophthalmia (HP: 0000528) without other anomalies. Karyotype and chromosomal microarray analysis were completed from amniocentesis sample. After these results, duo exome testing with paternal sequencing was completed from proband amniotic fluid sample and parental blood samples. A pathogenic variant in SOX2 (NM_003106.3: c.513C>G p.(Tyr171*Ter)) with heterozygous autosomal dominant inheritance resulted. On duo exome testing with paternal segregation analysis, the variant was found to be consistent with likely sporadic de novo inheritance. The SOX2 variant reported is consistent with the fetal phenotype in this case. While germline mosaicism could exist, this identified variant provided the family with a likely explanation for this proband's finding. This ultrasound and genetic testing allowed the family to make decisions related to planning in current and future pregnancies.

Language and nonverbal auditory processing in the occipital cortex of individuals who are congenitally blind due to anophthalmia.

Individuals with congenital blindness due to bilateral anophthalmia offer a unique opportunity to examine cross-modal plasticity in the complete absence of any stimulation of the 'visual' pathway even during development in utero. Our previous work has suggested that this complete sensory deafferentation results in different patterns of reorganisation compared with those seen in other early blind populations. Here, we further test the functional specialisation of occipital cortex in six well-studied cases with anophthalmia. Whole brain functional MRI was obtained while these human participants and a group of sighted controls performed two experiments involving phonological and semantic processing of words (verbal experiment) and spatial and identity processing of piano chords (nonverbal experiment). Both experiments were predicted to show a dorsal-ventral difference in activity based on the specific task performed. All tasks evoked activation in occipital cortex in the individuals with anophthalmia but not in the sighted controls. For the verbal experiment, both dorsal and ventral occipital areas were strongly activated by the phonological and semantic tasks in anophthalmia. For the nonverbal experiment, both the spatial and the identity task robustly activated the dorsal occipital area V3a but showed inconsistent activity elsewhere in the occipital lobe. V1 was most strongly activated by the verbal tasks, showing greater activity on the left for the verbal task relative to the nonverbal one. For individual anophthalmic participants, however, activity in V1 was inconsistent across tasks and hemispheres with many participants showing activity levels in the control range, which was not significantly above baseline. Despite the homogeneous nature of the cause of blindness in the anophthalmic group, there remain differences in patterns of activation among the individuals with this condition. Investigation at the case level might further our understanding of how post-natal experiences shape functional reorganisation in deafferented cortex.

Outcomes of the use of orbital hydrogel expanders in the management of congenital anophthalmia: CT-based orbital parameter analysis.

PURPOSE: To evaluate the outcomes of orbital hydrogel expanders in the management of congenital anophthalmia. METHODS: In this retrospective one-armed cohort study, a chart review was performed of eight children with congenital anophthalmia who underwent orbital expansion using orbital hydrogel tissue expander from January 2006 to July 2018. Computed tomography (CT) of orbital parameters was evaluated before and after surgery. Changes in the orbital parameters were correlated with clinical factors. RESULTS: The study sample comprised 11 anophthalmic orbits of eight children (seven males, one female; median age = 12 months), with a median postoperative follow-up of 3.8 years. The anophthalmic orbital parameters after hydrogel expander implantation improved significantly compared to preoperative assessment as follows: mean orbital height improved from 21.7 mm to 25.4 mm (P < .001); width from 19.2 mm to 23.8 mm (P < .001); depth from 27.5 mm to 32.6 mm (P = .008); and volume from 3.7 cm3 to 5.3 cm3 (P = .001). Despite enlargement in all dimensions, the anophthalmic orbits with hydrogel expander had a significantly lower development than the normal orbits, mainly in height and volume. At the last postoperative visit, four (36.4%) cases had fornices deep enough to maintain the conformer. Migration and extrusion occurred in two (18.2%) cases. CONCLUSIONS: Orbital hydrogel expander can improve the orbital development in congenital anophthalmia. However, the enlargement is not as extensive as that observed in the normal orbit. Orbital expanders associated with external conformers were not sufficient to induce normal growth of lids and fornix.

Lacrimal drainage anomalies in Tessier cleft 3 with unilateral anophthalmos.

Bilateral Tessier cleft types 3 and 4 are rare and commonly involve the lacrimal drainage system owing to their anatomical location. Such clefts commonly present with associated ocular anomalies and include colobomatous eyelids, hypertelorism, microphthalmia, punctal or canalicular agenesis, and nasolacrimal duct obstruction or exstrophy. The current report presents an 18-month-old baby with bilateral Tessier cleft 3 with a unilateral anophthalmos, symmetrical eyelid colobomas, and lacrimal drainage anomalies. The lacrimal anomalies noted include small lacrimal sac with inferior canaliculus on the right side and upper and lower punctal and canalicular agenesis on the left side. Computed tomographic dacryocystography demonstrated unilateral lacrimal sac and bilateral maldevelopment of the bony nasolacrimal duct.

A rare association of right hemicerebral dysgenesis with congenital anophthalmia in a neonate.

Congenital anophthalmia is rare and can occur due to various etiologies, including genetic defects, teratogenic exposures, and vascular disruptions. We report a rare case of right-sided congenital anophthalmia and hemicerebral dysgenesis in association with ipsilateral hemicerebral vascular dysgenesis in a neonate. Postnatal neuroimaging was conspicuous for a "bare orbit sign." A unilateral cranial neurocristopathy was suspected to be an underlying etiopathology for such a diffuse defect.

[Temporal meningocele and anophtalmia: about a case]. / Meningocèle temporale et anophtalmie: à propos d´un cas.

We here report the case of a 12-month old infant with congenital polymalformation including right temporal meningocele and homolateral eyeball aplasia. Brain CT scan confirmed this malformation with bone defect in the right temporal lobe, meningeal hernia containing cerebrospinal fluid and absence of the right eyeball. Surgery was performed to treat meningocele. Patient's outcome was favorable. The purpose of this study was to highlight the rarity of this disease on the basis of a literature review.

Evaluation of Lacrimal Drainage Function in the Anophthalmic Socket by Dacryoscintigraphy.

PURPOSE: To investigate whether impaired lacrimal pump function is a possible cause of discharge in patients wearing an artificial eye compared with the remaining healthy eye. METHODS: Consecutive patients wearing unilateral ocular prosthesis for ≥6 months were included in this retrospective study. Excluded were any deformities of eyelids or nasal passage, socket complications such as entropion, ectropion, ptosis, infection, pyogenic granuloma, contracted socket, obstruction of nasolacrimal duct diagnosed with lacrimal irrigation and a difference greater than 2 mm in terms of protrusion between two eyes detected by Hertel exophthalmometry. Patients were asked to score the levels of tearing and mucopurulent discharge between 0 and 5 to assess lacrimal drainage function subjectively. Furthermore, dacryoscintigraphy was performed to assess the functional status of the lacrimal system objectively. RESULTS: Included were 32 subjects (12 females, 20 males; aged 32.94 ±â€Š17.62, range 13-78). Mean duration of prosthetic wearing 26.41 ±â€Š21.30 (6-72) months. The mean subjective scores of tearing and mucopurulent discharge were 1.56 ±â€Š1.67 and 1.94 ±â€Š1.63, respectively. The rate of functional stenosis was significantly higher in the anophthalmic socket side as compared to the healthy side (P = 0.002). The rates of a presac, preduct, and intraduct obstruction was notes as n = 9, n = 10, n = 1 and n = 0, n = 6, n = 2 in the anophthalmic side and the companion eye, respectively (P = 0.021). CONCLUSION: Compared to paired healthy eyes, the ocular prosthesis exhibited significantly higher rates of functional lacrimal duct obstruction, especially at the presac level. The alterations in orbital volume and tear film composition in addition to reduced corneal reflex blinking may lead to the failure of lacrimal pump function in artificial eyes.

Expanding the phenotype of STRA6-related disorder to include left ventricular non-compaction.

BACKGROUND: Syndromic microphthalmia-9 (MCOPS9) is a rare autosomal recessive disorder caused by mutations in STRA6, an important regulator of vitamin A and retinoic acid metabolism. This disorder is characterized by bilateral clinical anophthalmia, pulmonary hypoplasia/aplasia, cardiac malformations, and diaphragmatic defects. The clinical characteristics of this disorder have not been fully determined because of the rarity of clinical reports. METHODS: A comprehensive genotyping examination including copy number variation sequencing (CNV-Seq) and whole-exome sequencing (WES) was applied to a fetus of Han Chinese with bilateral anophthalmia, bilateral pulmonary agenesis, interrupted aortic arch type A, and left ventricular non-compaction (LVNC). RESULTS: No aneuploidy or pathogenic CNV were identified by CNV-seq. WES analysis revealed a previously reported homozygous splice site (NM_022369.4:c.113+3_113+4del) in the STRA6 gene. This variant was confirmed by Sanger sequencing. The diagnosis of MCOPS9 was confirmed given the identification of the STRA6 mutation and the association of bilateral anophthalmia, pulmonary agenesis, and cardiac malformations. CONCLUSION: This case adds to the phenotypic spectrum of MCOPS9, supporting the association with LVNC, and the presence of interruption of aortic arch further demonstrates the variability of the cardiac malformations.

Structural and functional brain reorganisation due to blindness: The special case of bilateral congenital anophthalmia.

Investigating the changes in the brain that result from a loss of sensory input has provided significant insight into the considerable capacity of the brain to reorganise. One of the difficulties in studying sensory-deprived populations is that the time and extent of sensory loss vary significantly. In this review, we consider the changes in the human brain associated with complete absence of visual input resulting from bilateral congenital anophthalmia, in which the eyes fail to develop. We describe the functional reorganisation and associated structural and connectivity changes that occur in the brain of those affected by the condition. By considering animal models of this condition, we investigate the changes that may be occurring on a scale that is not captured by human in vivo imaging techniques. Finally, we lay out a model pathway for taking auditory information to the occipital cortex that may be specific to anophthalmia.

Growth and Behavior of Congenitally Anophthalmic Lee-Sung Pigs.

Circadian rhythm is usually regulated by the environmental light-dark cycle. Congenitally anophthalmic miniature pigs provide a valuable model for the study of factors affecting circadian rhythms in the absence of visual exposure to the light-dark cycle. This study investigated the growth and daily behavior patterns of Lee-Sung pigs with congenital anophthalmia. Growth in 5 Lee-Sung pigs (LSP) with congenital anophthalmia (LSP-A) and 10 normally developed pigs (LSP-N) was assessed when they were 1 through 6 mo old. Behavioral studies using digital video recording were completed in 6 sexually mature LSP (3 LSP-A and 3 LSP-N). MRI showed that LSP-A lose their vision because of a lack of retinal input and optic chiasm development. LSP-N and LSP-A did not differ in body weight or size at 2, 4, and 6 mo of age. Behavior and activity pattern studies showed that both LSP-A and LSP-N were active mainly during daylight, but LSP-A spent significantly more time exploring their environment during the day (28%) and night (10%) than did LSP-N. This study revealed that growth performance was similar between LSP-A and normal pigs, but their behavior and activity patterns differed. LSP-A showed circadian rhythm abnormalities similar to those in blind humans. This study provides basic data on LSP-A as a model for studying compensatory cross-modal brain plasticity and hormone regulation in the absence of retinal input is deficient and for understanding the role of circadian rhythm regulation.

Early Blindness Shapes Cortical Representations of Auditory Frequency within Auditory Cortex.

Early loss of vision is classically linked to large-scale cross-modal plasticity within occipital cortex. Much less is known about the effects of early blindness on auditory cortex. Here, we examine the effects of early blindness on the cortical representation of auditory frequency within human primary and secondary auditory areas using fMRI. We observe that 4 individuals with early blindness (2 females), and a group of 5 individuals with anophthalmia (1 female), a condition in which both eyes fail to develop, have lower response amplitudes and narrower voxelwise tuning bandwidths compared with a group of typically sighted individuals. These results provide some of the first evidence in human participants for compensatory plasticity within nondeprived sensory areas as a result of sensory loss.SIGNIFICANCE STATEMENT Early blindness has been linked to enhanced perception of the auditory world, including auditory localization and pitch perception. Here we used fMRI to compare neural responses with auditory stimuli within auditory cortex across sighted, early blind, and anophthalmic individuals, in whom both eyes fail to develop. We find more refined frequency tuning in blind subjects, providing some of the first evidence in human subjects for compensation within nondeprived primary sensory areas as a result of blindness early in life.

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men.

CONTEXT: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare. RESULTS: We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity. CONCLUSIONS: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype.

Characteristics and management of congenital anophthalmos and microphthalmos at a tertiary eye hospital.

Purpose: The purpose of the study is to evaluate demographic data and outcomes of the management of congenital anophthalmia/microphthalmia. Methods: This retrospective, descriptive, cross-sectional study evaluated patients with congenital anophthalmia/microphthalmia managed from 2004 to 2014 at a tertiary hospital in Saudi Arabia. Data were collected on patient age, gender, cause, orbital status, laterality, systemic comorbidities, ocular evaluation, and management (type of surgery, type of orbital implant, and complications). The main outcome measure was the ability to hold the prosthesis. Results: The study sample was composed of 513 eyes/sockets of 365 patients. Two-hundred and seventeen (59.4%) patients were unilateral cases. Forty-one (8%) sockets were due to congenital anophthalmia and 471 (92%) were due to microphthalmia. There were 73.2% isolated cases and 28.5% with systemic involvement. Systemic involvement was more common in bilateral cases. The most commonly associated conditions were central nervous disorders. One-hundred and nineteen (46.7%) cases had parental consanguinity. Two hundred and eighteen eyes/sockets (163 patients) underwent surgery including conjunctival flap (38; 17.4%), evisceration (38; 17.4%), enucleation (16; 7.3%), or procedures to improve the anophthalmic socket volume (45; 20.6%). Volume enhancing procedures included polymethylmethacrylate orbital implants (26; 57.8%), expanders (11; 24.4%), integrated hydroxyapatite or polyethylene implants (2; 4.4%), and dermis-fat graft (6; 13.3%). In most cases, clinical or surgical management resulted in a successful outcome. Conclusion: Anophthalmia/Microphthalmia was detected in 36.5 patients/year. The majority had isolated microphthalmia. Good outcomes were achieved with clinical or surgical management in the majority of cases.

Importancia de la neuroimagen en la anoftalmia/microftalmia congénita neonatal: a propósito de un caso / Importance of neuroimaging in neonatal congenital anophthalmia/microphthalmia: a case report

Introducción: La Anoftalmia/Microftalmia es una malformación ocular congénita que se caracteriza por la reducción variable del volumen del globo ocular, la misma requiere de estudios imagenológicos para un diagnóstico más preciso. Objetivo: Demostrar la importancia de la neuroimagen en el diagnóstico y orientación de la microftalmia/anoftalmia neonatal congénita bilateral. Presentación del caso: Se hace referencia a un recién nacido con diagnóstico clínico de anoftalmia/microftalmia de manera inicial que después de realizar estudios de neuroimagen se constataron otras malformaciones del sistema nervioso central que permitieron orientar el diagnóstico hacia un síndrome genético definido. Durante el examen físico inicial se constató hipertelorismo, orejas de implantación baja, fisura palatina, ano anterior y ausencia de los globos oculares en ambos lados. La Resonancia magnética nuclear mostró esbozos de cristalinos rudimentarios, ubicados en zona atípica y esbozo de nervio óptico incompleto del lado derecho. No se observaron globos oculares. Observándose además múltiples imágenes de aspecto quístico bilaterales en las áreas orbitarias que desplazan los cristalinos rudimentarios por conflicto de espacio. Este paciente requirió estudios de neuroimagen para determinar si se trataba de una anoftalmia/microftalmia y para orientar el diagnóstico de displasia septo-óptica que organizó el pensamiento clínico hacia un posible Síndrome de Morsier. En este caso se realizó diagnóstico diferencial con otras causas asociadas a estas malformaciones oculares. Conclusiones: Los estudios imagenológicos del cerebro de los pacientes con anoftalmia / microftalmia en la etapa neonatal permiten orientar un diagnóstico preciso y precoz que favorece una intervención multidisciplinaria temprana(AU)

Introduction: Anophthalmia/microphthalmia is a congenital eye malformation that is characterized by the variable reduction of the volume of the ocular globe, which requires imaging studies for a more precise diagnosis. Objective: To demonstrate the importance of neuroimaging in the diagnosis and management of neonatal congenital bilateral anophthalmia/microphthalmia. Case Presentation: We describe the case of a newborn with an initial clinical diagnosis of anophthalmia/microphthalmia in which, after carrying out neuroimaging studies, other malformations of the central nervous system were confirmed, allowing to guide the diagnosis towards a defined genetic syndrome. During the initial physical exam, hypertelorism, low set ears, palatine fissure, anterior anus, and absence of the ocular globes in both sides were verified. The magnetic resonance imaging showed signals of rudimentary crystalline located in an atypical area, and signals of incomplete optic nerve of the right side. Ocular globes were not observed. Multiple cyst-like bilateral images were also observed in orbital areas, displacing the rudimentary crystalline lens due to space limitations. Discussion: This patient required neuroimaging studies to determine if she had an anophthalmia/microphthalmia and present a guide for the diagnosis of septo-optic dysplasia that organized the clinical thinking towards a possible Morsier Syndrome. In this case, a differential diagnosis with other causes associated to these ocular malformations was made. Conclusions: The imaging studies of the brain of the patients with anophthalmia/microphthalmia in the neonatal period allows to guide a precise and early diagnosis that favors an early multidisciplinary intervention(AU)

Prenatal diagnosis and implications of microphthalmia and anophthalmia with a review of current ultrasound guidelines: two case reports.

BACKGROUND: Microphthalmia and anophthalmia are rare congenital fetal abnormalities. The combined incidence is estimated at 1 in 10,000 births. These two conditions arise from complex and incompletely understood genetic and/or environmental causes. Prenatal diagnosis is neither frequent nor easy and relies on precise, high-quality ultrasonography. Current antenatal ultrasound protocols for imaging of the fetal eye are inconsistent and inadequate to screen for the spectrum of ocular malformations, and there are no clear guidelines on detection of these rare abnormalities. Our study of two cases highlights the importance of early detection, and we review current practice and suggest a definitive fetal imaging protocol. CASE PRESENTATION: We present two antenatal cases, one each of microphthalmia and anophthalmia, both diagnosed at the morphology scan at our tertiary fetal medicine unit. In both cases, the parents (a 36-year-old woman of Mauritanian ethnicity and a non-consanguineous partner of Nepalese descent, and a 31-year-old Caucasian woman and non-consanguineous Caucasian partner) elected to terminate their pregnancies and made unremarkable recoveries. Subsequent fetal autopsy confirmed the ultrasound scan findings. CONCLUSIONS: We recommend that antenatal ultrasound guidelines are updated to specify use of a curvilinear transducer (2-9 MHz) to image both orbits in the axial and coronal planes, aided by use of a transvaginal probe when the transabdominal approach is inadequate to generate these images. When applicable, three-dimensional reverse-face imaging should be obtained to aid the diagnosis. The presence, absence, or non-visualization of lenses and hyaloid arteries should be documented in reports and these cases referred for a tertiary-level ultrasound scan and fetal medicine review. Imaging of the orbits should occur from 12 weeks' gestation. Magnetic resonance imaging and amniocentesis with chromosome microarray testing may provide additional genetic and structural information that may affect the overall morbidity associated with a diagnosis of microphthalmia or anophthalmia.

Pentalogy of Cantrell associated with unilateral anophthalmia: Case report and literature review.

RATIONALE: Pentalogy of Cantrell, a very rare congenital condition, has an estimated incidence of 5.5 per 1 million live births. It includes five defects: a midline supraumbilical wall defect, a diaphragmatic defect, a cleft distal sternum, a defect in the diaphragmatic pericardium, and an intracardiac defect. Very few cases of this condition have been reported in the literature, most of them diagnosed in the second or third trimester of pregnancy. PATIENT CONCERNS: We present a case of pentalogy of Cantrell associated with cranioschisis and unilateral anophthalmia diagnosed at 14 weeks of amenorrhea. DIAGNOSES: The combination of abdominal and vaginal sonography established the diagnosis of 14 weeks of amenorrhea with a plurimalformative syndrome including: ectopia cordis, large suprambilical anterior abdominal wall defect, omphalocele, anomaly of the shape of the skull, and anomalies of the brain. INTERVENTIONS: After counseling the parents, the pregnancy was interrupted, as requested by the family. OUTCOMES: Pathological examination of the fetus after the therapeutic abortion confirmed the diagnosis. LESSONS: Because of the poor prognosis of Cantrell's pentalogy, early antenatal sonographic detection is important and allows for elective abortion before viability.

Computer-Assisted Volumetric Analysis and Quantitatively Anophthalmic Orbit Reconstruction With Dorsalis Pedis Flap and Bone Graft.

Current approaches to orbit reconstruction are based on the assumption of facial symmetry and surgeons' experiences, and the reconstructed orbits are not precise. Through computer-assisted volumetric quantitative analysis, the volume of the bony orbit, and the volume of the soft tissues in both the anophthalmic orbit and the contralateral orbit are calculated in 39 anophthalmic patients. The rib graft is used for orbit reconstruction; the dosalis pedis flap and lipo-injection were used for soft tissue reconstruction and skin socket reconstruction. The size and the shape of the rib graft and soft tissues were designed according to the volumetric analysis. The size and the shape of the skin socket were designed according to measurement during surgery. Asymmetry eye sockets with adequate size were created in the 37 patients. Two patients presented with a poor asymmetry with the contralateral orbit, and got gradual extrusion of the eye prosthesis 4 months after operation, which was because of necrosis of the flaps. The flaps were remedied by frontal island flap and skin grafting. Further surgeries, such as lipoinjection, lid surgery, and canthoplasty, were applied to improve the surgical results. The eye prostheses fitted well in all of the reconstructed sockets using this technique. Our studies suggest that the computer-assisted volumetric analysis technique combined with quantitative bone graft and dorsalis pedis flap transfer, ± lipoinjection proved to be an accurate method and a quality assurance for optimization of bony orbit, soft tissue and skin socket reconstruction, and promised a successful postoperative outcome for patients' functional and esthetic appearance.