Ophthalmoplegia and Congenital Cranial Dysinnervation Disorders.

Some forms of ophthalmoplegia are congenital and fall into the category of Congenital Cranial Dysinnervation Disorders (CCDDs). These disorders arise from a primary defect of cranial nucleus/nerve development or guidance. Many have substantial limitations of ocular motility with or without other associated features.

NEW OBSERVATIONS REGARDING THE RETINOPATHY OF GENETICALLY CONFIRMED KEARNS-SAYRE SYNDROME.

Purpose: To report novel retinal findings in Kearns-Sayre syndrome and correlate degree of retinopathy with other clinical findings.

Methods: Observational case series of patients from Saudi Arabia with retinal and neuroophthalmologic examinations, medical chart review, and mitochondrial genetic evaluation.

Results: The three unrelated patients had progressive external ophthalmoplegia and pigmentary retinopathy bilaterally.

The genetics of nonsyndromic bilateral Duane retraction syndrome.

Purpose: To assess the importance of monogenic mutations and chromosomal copy number variants (CNVs) in the occurrence of nonsyndromic bilateral Duane retraction syndrome (bilateral nsDRS).

Methods: The medical records of 12 patients with bilateral nsDRS were reviewed. Genes associated with DRS and associated congenital cranial dysinnervation disorders (SALL4, CHN1, HOXA1, TUBB3, and KIF21A) were sequenced in the standard fashion in each patient.

Duane retraction syndrome in a patient with Duchenne muscular dystrophy.

Purpose: We describe the clinical features of a boy with bilateral Duane retraction syndrome (DRS), Duchenne muscular dystrophy (DMD), and other medical problems.

Methods: The child was followed-up for five years; his chart was reviewed, including the results of a muscle biopsy and genetic testing. Multiplex ligation-dependent probe amplification (MLPA) was used to interrogate deletions/duplications in the dystrophin gene.

Congenital and Genetic Ocular Motility Disorders: Update and Considerations.

Concepts regarding certain forms of congenital eye movement disorders have recently changed, due in large part to new genetic evidence identifying causative genes and their role in the development of extraocular muscle innervation. This group is now referred to as the Congenital Cranial Dysinnervation Disorders (CCDDs). Careful assessment of phenotypic features that include both ophthalmological and non-ophthalmological features in genetically defined individuals has led to the development of a more robust classification system.

Ocular motility abnormalities in orbitofacial neurofibromatosis type 1.

Purpose: To evaluate the causes of ocular motility disturbances in a group of patients with orbitofacial neurofibromatosis (OFNF) with neurofibromas on the lid, brow, face, or in the orbit from infancy or early childhood.

Methods: The medical records of patients with OFNF from one institution were retrospectively reviewed; selected patients were reexamined.

Results: A total of 45 patients with unilateral OFNF and 4 with bilateral OFNF were included.

Retinal Dysfunction in Patients with Congenital Fibrosis of the Extraocular Muscles Type 2.

Introduction: Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is a distinct non-syndromic form of congenital incomitant strabismus secondary to orbital dysinnervation from recessive mutations in the gene PHOX2A. The phenotype includes bilateral ptosis, very large angle exotropia, ophthalmoplegia, and poorly-reactive pupils. Other than amblyopia, afferent visual dysfunction has not been considered part of CFEOM2; however, we have repeatedly observed non-amblyopic subnormal vision in affected patients.

HOXA1 Mutations are Not Commonly Associated with Non-Syndromic Deafness.

Objective: Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bilateral profound deafness. This study evaluates the possible role of HOXA1 mutations in familial, non-syndromic sensorineural deafness.

Methods: Forty-eight unrelated Middle Eastern families with either consanguinity or familial deafness were identified in a large deafness clinic, and the proband from each family was evaluated by chart review, audiogram, neuroimaging, and HOXA1 sequencing.

Microdeletions involving chromosomes 12 and 22 associated with syndromic Duane retraction syndrome.

Background: Duane retraction syndrome (DRS) is the most common of the congenital cranial dysinnervation disorders (CCDDs). CCDDs can be monogenic or chromosomal in origin. Identification of the genetic cause(s) in patients and families with DRS facilitates definitive diagnosis and provides insights into these developmental errors.

Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome.

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.

CCDD Phenotype Associated with a Small Chromosome 2 Deletion.

Purpose: Some individuals are born with congenital limitation of ocular motility, often associated with ptosis and retraction of the globe. Many of these disorders are now known as the congenital cranial dysinnervation disorders (CCDDs). While several genes have been associated with CCDD phenotypes, there are still patients for whom the genetic basis has not been identified.

Neurologic injury in isolated sulfite oxidase deficiency.

Background: We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD).

Methods: All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed.

Results: Data was available on six individuals from four nuclear families affected by ISOD.

Nicotinic Receptor Mutation in a Mildly Dysmorphic Girl with Duane Retraction Syndrome.

Background: To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome and modest dysmorphism.

Materials And Methods: Clinical evaluation, sequencing of candidate genes, and array comparative genomic hybridization (array CGH).

Results: The proband had unilateral Duane retraction syndrome (DRS) with low-set ears bilaterally, a high arched palate, and clinodactyly.

Comitant strabismus: Perspectives, present and future.

Comitant strabismus is a common condition affecting infants, children and adults. Its impact on the affected patient may be severe resulting in visual loss, lack of binocularity, diplopia, social stigma and multiple corrective surgeries within the affected individual's lifespan. It is therefore important that this prevalent disorder should be better understood.

Partial duplication of chromosome 19 associated with syndromic duane retraction syndrome.

Background: To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome, modest dysmorphism, cerebral white matter abnormalities, and normal cognitive function.

Materials And Methods: Performing high-resolution array comparative genomic hybridization (array CGH) and sequencing of HOXA1, KIF21A, SALL4, and CHN1 genes.

Results: The proband had unilateral Duane retraction syndrome (DRS) type III on the right with low-set ears, prominent forehead, clinodactyly, and a history of frequent infections during early childhood.

Congenital cranial dysinnervation disorders: a concept in evolution.

Purpose Of Review: We review the congenital and genetic diagnoses that are currently included in the congenital cranial dysinnervation disorders (CCDDs).

Recent Findings: Recent literature contains new genotypic and phenotypic descriptions of Duane retraction syndrome, Moebius syndrome, and other CCDDs. New genes which when mutated can result in CCDD have been identified, permitting a better understanding of associated phenotypes.

Variable ptosis after botulinum toxin type a injection with positive ice test mimicking ocular myasthenia gravis.

We describe a patient who received cosmetic botulinum toxin type A injections to the brow and subsequently developed unilateral ptosis that was variable during examination and was transiently improved after the ice pack test. Ptosis gradually resolved spontaneously over approximately 3 months. This is the third patient to have variable ptosis documented after botulinum toxin type A injection to the brow and the second to have a positive ice test.

A newly recognized autosomal recessive syndrome affecting neurologic function and vision.

Genetic factors represent an important etiologic group in the causation of intellectual disability. We describe a Saudi Arabian family with closley related parents in which four of six children were affected by a congenital cognitive disturbance. The four individuals (aged 18, 16, 13, and 2 years when last examined) had motor and cognitive delay with seizures in early childhood, and three of the four (sparing only the youngest child) had progressive, severe cognitive decline with spasticity.

Ophthalmologic observations in a patient with partial mosaic trisomy 8.

Background: To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with particular attention to ophthalmologic features.

Methods: Ophthalmologic and neuro-ophthalmologic examination; neuroimaging; conventional karyotyping; and array comparative genomic hybridization (CGH).

Results: The proband was the only affected child of a non-consanguineous family.

A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3.

Missense mutations in TUBB3, the gene that encodes the neuronal-specific protein β-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of the extraocular muscles, a form of complex congenital strabismus characterized by cranial nerve misguidance. One of the eight TUBB3 mutations reported to cause congenital fibrosis of the extraocular muscles, c.1228G>A results in a TUBB3 E410K amino acid substitution that directly alters a kinesin motor protein binding site.

Xq26.3 microdeletion in a male with Wildervanck Syndrome.

Background: Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome (DRS), the Klippel-Feil anomaly, and congenital deafness. It is much more common in females than males and could be due to an X-linked mutation that is lethal to hemizygous males. We present the genetic evaluation of a male with WS and his family.

Partial chromosome 7 duplication with a phenotype mimicking the HOXA1 spectrum disorder.

Purpose: To evaluate possible monogenic and chromosomal anomalies in a patient with bilateral Duane retraction syndrome and hearing impairment resulting in a phenotype resembling the HOXA1 spectrum disorder.

Methods: Sequencing HOXA1 and performing high resolution array comparative genomic hybridization (arrayCGH).

Results: The proband had bilateral Duane retraction syndrome (DRS) with severe hearing loss bilaterally and an absent right vertebral artery, mimicking the major features of the Bosley-Salih-Alorainy variant of the HOXA1 spectrum.

HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1-/- mice.

Members of the highly conserved homeobox (HOX) gene family encode transcription factors that confer cellular and tissue identities along the antero-posterior axis of mice and humans. We have identified a founder homozygous missense mutation in HOXB1 in two families from a conservative German American population. The resulting phenotype includes bilateral facial palsy, hearing loss, and strabismus and correlates extensively with the previously reported Hoxb1(-/-) mouse phenotype.

Visual loss in orbitofacial neurofibromatosis type 1.

Purpose: On occasion, neurofibromas in neurofibromatosis type 1 may be present on the lid, brow, or face of an infant or child, a circumstance commonly referred to as "orbitofacial neurofibromatosis" (OFNF). The present study evaluates the causes and extent of visual loss in a group of patients with OFNF.

Design: Case series.