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Introduction: Möbius syndrome typically presents as a sporadic trait with congenital facial palsy and abduction impairment. We used high-resolution magnetic resonance imaging (MRI) and genetic analysis to examine a family with features of Möbius syndrome. Methods: We examined 3 related family members having congenital complete opthalmoplegia with ptosis and facial diplegia. Orbits were imaged in quasi-coronal and sagittal planes of 2 mm thickness. Subarachnoid cranial nerves were imaged in planes of 1 mm thickness. Linkage and mutation analysis were performed to determine whether the pedigree harbored mutations in 4 candidate genes. Results: In affected subjects, MRI showed marked hypoplasia of extraocular muscles and intraorbital motor nerves. In the anterior orbit, rectus extraocular muscles were less hypoplastic but markedly curved toward insertion. Oblique extraocular muscles were hypoplastic and abnormally inserted. Posterior bony orbits were hypoplastic. Optic nerves were markedly straightened. Brainstems and cranial nerves III, VI, VII, and VIII were normal bilaterally. No pathogenic mutations were detected in affected individuals. Conclusions: Previous MRI studies have demonstrated brainstem hypoplasia and cranial nerve aplasia in Möbius syndrome. The current family had normal brainstems and subarachnoid portions of motor cranial nerves innervating the orbit but marked extraocular muscle hypoplasia. These clinical and MRI findings are atypical for Möbius syndrome and other congenital cranial dysinnervation disorders. Congenital facial weakness and complete ophthalmoplegia may occur despite MRI evidence of normal brainstem anatomy. The endophenotype appears to result from a genetic defect distinct from the congenital cranial dysinnervation disorders defined thus far, rather than a global brainstem insult. [Copyright &y& Elsevier]

The HOXA1-related syndromes result from autosomal-recessive truncating mutations in the homeobox transcription factor, HOXA1. Limited horizontal gaze and sensorineural deafness are the most common features; affected individuals can also have facial weakness, mental retardation, autism, motor disabilities, central hypoventilation, carotid artery, and/or conotruncal heart defects. Möbius syndrome is also phenotypically heterogeneous, with minimal diagnostic criteria of nonprogressive facial weakness and impaired ocular abduction; mental retardation, autism, motor disabilities, additional eye movements restrictions, hearing loss, hypoventilation, and craniofacial, lingual, and limb abnormalities also occur. We asked, given the phenotypic overlap between these syndromes and the variable expressivity of both disorders, whether individuals with Möbius syndrome might harbor mutations in HOXA1. Our results suggest that HOXA1 mutations are not a common cause of sporadic Möbius syndrome in the general population. [Copyright &y& Elsevier]

Objective: To improve diagnostic assessment in Moebius syndrome by (1) creating more selective diagnostic subgroups and (2) conducting genetic evaluation in a large patient cohort. Design: Prospective, observational study. Participants: Attendees of 3 consecutive Moebius syndrome conferences held in the United States, with a prior diagnosis of Moebius syndrome, were invited to participate. Methods: Participants underwent standardized ophthalmologic examination for Moebius syndrome minimum diagnostic criteria (MDC) (congenital, nonprogressive facial palsy, and abduction deficit) and genetic testing for HOXA1, HOXB1, and TUBB3 mutations. Main Outcome Measures: The number of patients meeting MDC and the number of patients with confirmed genetic mutation. Results: A total of 112 participants from 107 families enrolled. Nineteen percent of participants (21/112) did not meet accepted MDC for Moebius syndrome because they had abduction deficits without facial palsy or facial palsy with full ocular motility. All 5 families with 2 affected individuals had at least 1 family member in this category, including 2 siblings with comitant strabismus who harbored aHOXB1 mutation. Four unrelated participants, also not meeting MDC, had large-angle exotropia, vertical gaze deficiency, and ptosis consistent with congenital fibrosis of the extraocular muscles type 3 (CFEOM3); 1 patient harbored a novel TUBB3 mutation, and 3 patients harbored previously reported de novo TUBB3 mutations. Three percent of participants (3/112) met MDC but also had restricted vertical gaze. The remaining 88 participants (79%) met MDC and had full vertical gaze. This group had relatively homogeneous findings, and none had a family history of Moebius syndrome. Two previously undescribed phenomena were observed in this category: (1) volitional Bell's phenomenon and (2) intorsion with fixation. Conclusions: Although the genetic contributors to classic Moebius syndrome remain elusive, accuracy in clinical evaluation will properly subdivide patients to facilitate genetic testing as new candidate genes are identified. Failure to test ocular motility may lead to misdiagnosis of Moebius syndrome, especially in patients who have facial palsy with full ductions. Patients with exotropia, vertical gaze limitation, and ptosis do not have classic Moebius syndrome and may haveTUBB3 mutations associated with CFEOM3. To optimize genetic analysis, we propose adding "full vertical motility" to the MDC for Moebius syndrome. [ABSTRACT FROM AUTHOR]

Abstract: Background: Horizontal gaze palsy and progressive scoliosis is caused by mutations in the ROBO3 gene, which plays a role in axonal guidance during brain development. Horizontal gaze palsy and progressive scoliosis is characterized by the congenital absence of conjugate lateral eye movements with preserved vertical gaze and progressive scoliosis as well as dysgenesis of brainstem structures and ipsilateral projection of the pyramidal tract. Patient: A 4-year, 11-month, girl presented with psychomotor retardation and autistic traits. Magnetic resonance imaging revealed hypoplasia and malformation of the ventral portion of the pons and medulla oblongata. Diffusion tensor imaging revealed the absence of decussation of the bilateral pyramidal tracts. These findings were similar to the typical findings for horizontal gaze palsy and progressive scoliosis. However, restriction of horizontal eye movement was minimal, and bilateral polymicrogyria were also noted in the occipitotemporal cortex in the present patient. These findings have not been previously reported in patients with horizontal gaze palsy and progressive scoliosis. No mutations in the ROBO3, SLIT1, SLIT2, NTN1, SEMA3 A, or SEMA3 F genes were identified. Conclusion: This child may have a disorder caused by an unidentified factor, other than a mutation in the genes analyzed, involved in corticogenesis, axonal guidance, and brainstem morphogenesis. [Copyright &y& Elsevier]

Purpose: To characterize and grade the spectrum of foveal hypoplasia based on different stages of arrested development of the fovea. Grading was performed using morphologic findings obtained by ultra high-resolution spectral-domain optical coherence tomography. Best-corrected visual acuity (BCVA) was calculated for different grades. Design: Observational case series. Participants and Controls: Sixty-nine patients with foveal hypoplasia (albinism, n = 34; PAX6 mutations, n = 10; isolated cases, n = 14; achromatopsia, n = 11) and 65 control subjects were examined. Methods: A 7×7-mm retinal area was sampled using a 3-dimensional scanning protocol (743×75, A scans×B scans) with ultra high-resolution spectral-domain optical coherence tomography (SOCT Copernicus HR; 3-μm axial resolution). Gross morphologic abnormalities were documented. B-scans at the fovea were segmented using a longitudinal reflectivity profile. Logarithm of the minimum angle of resolution BCVA was obtained. Main Outcome Measures: Grading was based on presence or absence of foveal pit and widening of the outer nuclear layer (ONL) and outer segment (OS) at the fovea. Quantitative measurements were obtained for comparing atypical foveal hypoplasia in achromatopsia. Best-corrected visual acuity was compared with the grade of foveal hypoplasia. Results: Four grades of foveal hypoplasia were distinguished: grade 1, shallow foveal pit, presence of ONL widening, presence of OS lengthening; grade 2, grade 1 but absence of foveal pit; grade 3, grade 2 but absence of OS lengthening; grade 4, grade 3 but absence of ONL widening. There was significant difference in visual acuity (VA) associated with each grade (P<0.0001). Grade 1 was associated with the best VA (median VA, 0.2), whereas grades 2, 3, and 4 were associated with progressively poorer VA with a median VA of 0.44, 0.60, and 0.78, respectively. The atypical features seen with foveal hypoplasia associated with achromatopsia were characterized by decreased retinal and ONL thickness and deeper foveal depth. Conclusions: A structural grading system for foveal hypoplasia was developed based on the stage at which foveal development was arrested, which helps to provide a prognostic indicator for VA and is applicable in a range of disorders associated with foveal hypoplasia. Atypical foveal hypoplasia in achromatopsia shows different characteristics. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]