Congenital Cranial Dysinnervation Disorders Research Articles

Fourth Cranial Nerve Palsy and Brown Syndrome: Two Interrelated Congenital Cranial Dysinnervation Disorders?

Based on neuroimaging data showing absence of the trochlear nerve, congenital superior oblique palsy is now classified as a congenital cranial dysinnervation disorder. A similar absence of the abducens nerve is accompanied by misinnervation to the lateral rectus muscle from a branch of oculomotor nerve in the Duane retraction syndrome. This similarity raises the question of whether some cases of Brown syndrome could arise from a similar synkinesis between the inferior and superior oblique muscles in the setting of congenital superior oblique palsy. This hypothesis has gained support from the confluence of evidence from a number of independent studies. Using Duane syndrome as a model, we critically review the accumulating evidence that some cases of Brown syndrome are ultimately attributable to dysgenesis of the trochlear nerve.

A boy with homozygous microdeletion of NEUROG1 presents with a congenital cranial dysinnervation disorder [Moebius syndrome variant

BackgroundWe report on a 6-year-old Turkish boy with profound sensorineural deafness, balance disorder, severe disorder of oral motor function, and mild developmental delay. Further findings included scaphocephaly, plagiocephaly, long palpebral fissures, high narrow palate, low-set posteriorly rotated ears, torticollis, hypoplastic genitalia and faulty foot posture. Parents were consanguineous.Methods and resultsComputed tomography and magnetic resonance imaging showed bilateral single widened cochlear turn, narrowing of the internal auditory canal, and bilateral truncation of the vestibulo-cochlear nerve. Microarray analysis and next generation sequencing showed a homozygous deletion of chromosome 5q31.1 spanning 115.3 kb and including three genes: NEUROG1 (encoding neurogenin 1), DCNP1 (dendritic cell nuclear protein 1, C5ORF20) and TIFAB (TIFA-related protein). The inability to chew and swallow, deafness and balance disorder represented congenital palsies of cranial nerves V (trigeminal nerve) and VIII (vestibulo-cochlear nerve) and thus a congenital cranial dysinnervation disorder.ConclusionsBased on reported phenotypes of neurog1 null mutant mice and other vertebrates, we strongly propose NEUROG1 as the causative gene in this boy. The human NEUROG1 resides within the DFNB60 locus for non-syndromic autosomal recessive deafness on chromosome 5q22-q31, but linkage data have excluded it from being causative in the DFNB60 patients. Given its large size (35 Mb, >100 genes), the 5q22-q31 area could harbor more than one deafness gene. We propose NEUROG1 as a new gene for syndromic autosomal recessive hearing loss and congenital cranial dysinnervation disorder including cranial nerves V and VIII.

Adult strabismus

The surgical treatment of the adult with strabismus comprises a significant portion of the clinical and surgical volume of many pediatric ophthalmologists. This workshop is designed to educate attendees regarding surgical treatment of adults with strabismus. Pediatric ophthalmologists interestested in treating adults with strabismus. Pediatric ophthalmologists are often intimidated by adults with complicated forms of strabismus. Clinicians should have a thorough understanding of the surgical approaches and techniques which yield better outcomes in adults with strabismus. At the conclusion of the workshop, attendees will have a better understanding of effective strategies for managing adults with complicated forms of strabismus. The workshop will include discussions and presentations by a panel of experts. In addition, time for audience participation with questions of the panelists is planned. Throughout the discussions, pertinent scientific literature will be presented and reviewed. Topics will include challenging cases of adults with strabismus, congenital cranial dysinnervation disorders (CCDDs), restrictive strabismus, and surgical pearls related to adults.

Possible association of congenital Brown syndrome with congenital cranial dysinnervation disorders

Congenital cranial dysinnervation disorders (CCDDs) are known to arise from abnormal development of individual and multiple cranial nerve nuclei or abnormalities in cranial nerve axonal transport. We report our findings for several patients with Brown syndrome in association with other known abnormalities characteristic of CCDDs. The medical records of patients presenting during a 4-year period with congenital Brown syndrome were retrospectively reviewed. Patients with Brown syndrome confirmed by forced ductions were included in the study if the Brown syndrome was associated with either an abnormal development of the superior oblique muscle or superior oblique paresis, ptosis, Duane syndrome, or other known CCDDs. A total of 9 patients with Brown syndrome were identified. Of these, 3 also demonstrated a contralateral superior oblique palsy; 2, a contralateral Duane syndrome; 1, an ipsilateral congenital ptosis; and 3, a moderate to severely hypoplastic ipsilateral superior oblique muscle. Some patients with congenital Brown syndrome are associated with and possibly in the spectrum of CCDDs. We propose that Brown syndrome may be due to abnormal development of the trochlear nerve, which results in physical changes in the superior oblique muscle-tendon-trochlea complex. This results in a tendon that is either long and lax, absent, or abnormally inserted (ie, superior oblique paresis) or a tendon that is restricted in its movements through the trochlea (Brown syndrome).

Imaging Findings in Congenital Cranial Dysinnervation Disorders

In 2002, the term congenital cranial dysinnervation disorders (CCDDs) was proposed to group heterogeneous syndromes with congenital abnormalities of ocular muscle and facial innervations. The concept of neurogenic etiology has been supported by discovery of genes that are essential to the normal development of brainstem, cranial nerves, and their axonal connections. The CCDDs include Duane retraction syndrome, congenital fibrosis of the extraocular muscles, Möbius syndrome, horizontal gaze palsy with progressive scoliosis, the human homeobox-related disorders, pontine cap tegmental dysplasia, and an expanding list. The purpose of this review was to update the imaging features, as well as clinical and genetic information, regarding cases of CCDDs.

P.11 The phenotype in E410K Beta-tubulin isotype 3 mutations

IntroductionThe Congenital Cranial Dysinnervation Disorders are congenital, non-progressive disorders that result from developmental abnormalities of one or more cranial nerves/nuclei with primary or secondary dysinnervation and include Duane's syndrome, Möbius...

Congenital innervation dysgenesis syndrome (CID)/congenital cranial dysinnervation disorders (CCDDs)

Congenital loss of innervation to the extra-ocular muscles (EOMs) can have a profound effect on the target muscle. This has been well recognised in Duane's retraction syndrome. However, it has been less emphasised in other congenital oculo-motor disorders. Such congenital ocular motor defects have been expanded to include DRS, congenital fibrosis of EOMs, monocular elevation defect, Möbius syndrome, as well as several other non-ocular muscles supplied by cranial nerves such as facial muscles. Such loss of innervation to motor muscles can be unified as a defined clinical entity, which can be labelled as congenital innervation dysgenesis syndrome or CID for short. CID may also affect other muscles supplied by nerves other than the cranial nerves and may be sensory as well as motor.

Recent Progress in Understanding Congenital Cranial Dysinnervation Disorders

In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substitute for the traditional concept of congenital fibrosis of the extraocular muscles (CFEOM) based on mounting genetic, neuropathologic, and imaging evidence, suggesting that many, if not all, of these disorders result from a primary neurologic maldevelopment rather than from a muscle abnormality. This report provides an update 8 years after that original report. Review of pertinent articles published from January 2003 until June 2010 describing CCDD variants identified under PubMed MeSH terms congenital fibrosis of the extraocular muscles, congenital cranial dysinnervation disorders, individual phenotypes included under the term CCDD, and congenital ocular motility disorders. At present, a total of 7 disease genes and 10 phenotypes fall under the CCDD umbrella. A number of additional loci and phenotypes still await gene elucidation, with the anticipation that more syndromes and genes will be identified in the future. Identification of genes and their function, along with advances in neuroimaging, have expanded our understanding of the mechanisms underlying several anomalous eye movement patterns. Current evidence still supports the concept that the CCDDs are primarily due to neurogenic disturbances of brainstem or cranial nerve development. Several CCDDs are now known to have nonophthalmologic associations involving neurologic, neuroanatomic, cerebrovascular, cardiovascular, and skeletal abnormalities.

Simultaneous Occurrence of Duane Retraction Syndrome with Marfan Syndrome

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, while Duane retraction syndrome (DRS) is a congenital cranial dysinnervation disorder (CCDD) which can be transmitted as autosomal dominant disorder in 5–10% of patients. In this paper, we present an 8-year-old girl who presented with left eye DRS and bilateral subluxation of the lens associated with MFS in absence of familial involvement. To our knowledge this is the first case report of DRS with MFS. The occurrence of these syndromes together is very rare and appears to be coincidental.

Absence of the Trochlear Nerve in Patients with Superior Oblique Hypoplasia

Congenital cranial dysinnervation disorders (CCDDs) are developmental abnormalities involving the hypoplasia or aplasia of the cranial nerves with muscle dysinnervation. This study aimed to determine if congenital superior oblique palsy with superior oblique hypoplasia also can be classified as a CCDD. Observational case series. Ten patients with superior oblique hypoplasia. Ophthalmologic examination and thin-section magnetic resonance imaging (MRI) at the brainstem level as well as across the orbit were performed in 10 patients with superior oblique hypoplasia. To confirm the accuracy of the procedure, the results obtained were compared with those of a control group comprising 12 children by using the same technique. Examination of ductions and versions, 3-step test, angle of deviation, and presence of the trochlear nerve and superior oblique hypoplasia on MRI. Trochlear nerve was absent on the affected side in 10 patients with confirmed hypoplastic superior oblique muscles. The trochlear nerves as well as normal-sized superior oblique muscles were observed in 24 (100%) of 24 eyes screened as controls. Congenital superior oblique palsy with superior oblique hypoplasia also can be classified as a CCDD by the MRI documentation of congenital aplasia of the trochlear nerve. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Evidence of an Asymmetrical Endophenotype in Congenital Fibrosis of Extraocular Muscles Type 3 Resulting fromTUBB3Mutations

Orbital magnetic resonance imaging (MRI) was used to investigate the structural basis of motility abnormalities in congenital fibrosis of the extraocular muscles type 3 (CFEOM3), a disorder resulting from missense mutations in TUBB3, which encodes neuron-specific beta-tubulin isotype III. Ophthalmic examinations in 13 volunteers from four CFEOM3 pedigrees and normal control subjects, were correlated with TUBB3 mutation and MRI findings that demonstrated extraocular muscle (EOM) size, location, contractility, and innervation. Volunteers included clinically affected and clinically unaffected carriers of R262C and D417N TUBB3 amino acid substitutions and one unaffected, mutation-negative family member. Subjects with CFEOM3 frequently had asymmetrical blepharoptosis, limited vertical duction, variable ophthalmoplegia, exotropia, and paradoxical abduction in infraduction. MRI demonstrated variable, asymmetrical levator palpebrae superioris and superior rectus EOM atrophy that correlated with blepharoptosis, deficient supraduction, and small orbital motor nerves. Additional EOMs exhibited variable hypoplasia that correlated with duction deficit, but the superior oblique muscle was spared. Ophthalmoplegia occurred only when the subarachnoid width of CN3 was <1.9 mm. A-pattern exotropia was frequent, correlating with apparent lateral rectus (LR) muscle misinnervation by CN3. Optic nerve (ON) cross sections were subnormal, but rectus pulley locations were normal. CFEOM3 caused by TUBB3 R262C and D417N amino acid substitutions features abnormalities of EOM innervation and function that correlate with subarachnoid CN3 hypoplasia, occasional abducens nerve hypoplasia, and subclinical ON hypoplasia that can resemble CFEOM1. Clinical and MRI findings in CFEOM3 are more variable than those in CFEOM1 and are often asymmetrical. Apparent LR innervation by the inferior rectus motor nerve is an overlapping feature of Duane retraction syndrome and CFEOM1. These findings suggest that CFEOM3 is an asymmetrical, variably penetrant, congenital cranial dysinnervation disorder leading to secondary EOM atrophy.

Synergistic divergence: a distinct ocular motility dysinnervation pattern.

To summarize the clinical, neuroradiologic, and genetic observations in a group of patients with unilateral synergistic divergence (SD). Five unrelated patients with unilateral SD underwent ophthalmic and orthoptic examinations; three of them also had magnetic resonance imaging of the brain and orbits. Three patients underwent genetic evaluation of genes known to affect ocular motility: KIF21A, PHOX2A, HOXA1, and ROBO3. The patients did not meet the clinical criteria for CFEOM types 1, 2, or 3. Each patient had severe adduction weakness on the affected side and large-angle exotropia in primary gaze that increased on attempted contralateral gaze because of anomalous abduction. Magnetic resonance imaging revealed a much smaller medial rectus muscle in the involved SD orbit. Oculomotor cranial nerves were present in the one patient imaged appropriately. Genetic sequencing in three patients revealed no mutations in KIF21A, PHOX2A, HOXA1, or ROBO3. SD should be classified as a distinct congenital ocular motility pattern within congenital cranial dysinnervation disorders. It may be caused by denervation of the medial rectus with dysinnervation of the ipsilateral lateral rectus by the oculomotor nerve precipitated by genetic abnormalities (some currently identified) or by local environmental, teratogenic, or epigenetic disturbances.

Splitting of the Extraocular Horizontal Rectus Muscle in Congenital Cranial Dysinnervation Disorders

To analyze the horizontal rectus extraocular muscles (EOMs) by orbital magnetic resonance imaging (MRI) in patients with congenital cranial dysinnervation disorders that arises from abnormal development of cranial nerve nuclei or their axonal connections. Case series, retrospective analysis. The morphology of the horizontal rectus EOMs was analyzed in orbital MRI on 4 patients with congenital oculomotor palsy, 26 with congenital superior oblique palsy, and five with Duane syndrome. Orbital imaging was performed by 1.5 tesla (T) and 3T MRI, and quasi-coronal and sagittal images perpendicular and parallel to the long axis of the orbit were obtained at slice thicknesses of 3 and 2 mm. The horizontal rectus EOMs were split in 4 of the 35 patients (11%). Splitting was observed in 2 of the five patients (40%) with Duane syndrome, one of the 26 patients (4%) with congenital superior oblique palsy, and 1 of the 4 patients (25%) with oculomotor palsy, but in none of the 6 normal subjects and 12 patients with acquired cranial nerve palsy. Since splitting of the horizontal rectus EOMs was noted in patients with congenital dysinnervation disorders, including Duane syndrome, Sevel's theory that the horizontal rectus EOMs develop from the superior and inferior mesodermal complexes is considered to be reasonable.

A novel form of aberrant innervation in congenital cranial dysinnervation disorder

Certain forms of congenital incomitant strabismus are associated with abnormal cranial nerve development and resultant abnormal orbital innervation (eg, Duane retraction syndrome, congenital fibrosis of the extraocular muscles [CFEOM]); such conditions can be considered congenital cranial dysinnervation disorders (CCDDs). In addition to duction limitation and/or ptosis, orbital CCDD phenotypes include inappropriate extraocular muscle and/or levator innervation by nerves intended for innervation of other structures (eg, some of the innervation intended for the medial rectus muscle inappropriately innervating the ipsilateral lateral rectus muscle in Duane retraction syndrome). This report documents a unique orbital dysinnervational pattern-supraduction during attempted adduction and infraduction during attempted abduction in the left affected eye of a girl with exotropia and enophthalmos.

Large-angle congenital exotropia due to ‘absent’ medial recti: a case of congenital cranial dysinnervation disorder

Large-angle congenital exotropia due to ‘absent’ medial recti: a case of congenital cranial dysinnervation disorder

Magnetic resonance imaging of the endophenotype of a novel familial Möbius-like syndrome

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. 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. 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. 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.

Angeborene Fehlinnervationssyndrome

Congenital cranial dysinnervation disorders (CCDDs) are responsible for 1-2% of infant strabismus cases. Insufficient innervation and misinnervation of aberrant nerve fibres lead to motility restrictions and synkinesis. We present the most common CCDDs and explain their pathogenesis and the resulting clinical features. Furthermore, we emphasize essential diagnostic steps and treatment aspects.

Magnetic Resonance Imaging of Innervational and Extraocular Muscle Abnormalities in Duane-Radial Ray Syndrome

The authors used magnetic resonance imaging (MRI) to study extraocular muscles (EOMs) and nerves in Duane-radial ray (Okihiro) syndrome (DRRS) caused by mutations in the transcription factor SALL4. The authors examined four male and two female affected members of a pedigree previously reported to cosegregate DRRS and a heterozygous SALL4 mutation. Coronal T1-weighted magnetic resonance images of the orbits and heavily T2-weighted images in the plane of the cranial nerves were obtained in four subjects. MRI findings were correlated with motility examinations and published norms obtained using identical technique. Five of the six subjects with DRRS had radial ray abnormalities including thumb, radial artery, radial bone, and pectoral muscle hypoplasia. Three had bilateral and three had unilateral ocular involvement. Seven eyes had limitation of both abduction and adduction, whereas two had limitations only of abduction. Most affected eyes had lid fissure narrowing and retraction in adduction. Intraorbital and intracranial abducens nerves (CN6) were small to absent, particularly ipsilateral to abduction deficiency. All subjects undergoing MRI had normal intracranial oculomotor nerves (CN3). Optic nerve (ON) cross-section findings were similar to normal. EOMs and pulleys were structurally normal in most subjects. In some affected orbits, a branch of CN3 closely approximated and presumably innervated the LR. DRRS encompasses a Duane syndrome phenotype, with a variable and asymmetric endophenotype including marked CN6 hypoplasia and probable innervation or coinnervation of the LR by CN3. This endophenotype is more limited than reported in DURS2-linked Duane syndrome (On-line Mendelian Inheritance in Man, OMIM 604356) and CFEOM1 (OMIM 135700), which are clinically similar congenital cranial dysinnervation disorders that also feature CN3 hypoplasia and more widespread EOM abnormalities.

Oculomotility Disorders Arising From Disruptions in Brainstem Motor Neuron Development

The identification and analysis of pedigrees with rare congenital oculomotility syndromes has led to the definition of the congenital cranial dysinnervation disorders. These disorders appear to result from mutations in genes that are essential to the normal development and/or connectivity of cranial motoneurons. This review highlights the clinical features and genetic etiology of 3 congenital cranial dysinnervation disorders: the human homeobox A1 (HOXA1) syndromes, in which early motoneuron development is disrupted; horizontal gaze palsy with progressive scoliosis, in which there is aberrant axonal targeting onto abducens motoneurons; and congenital fibrosis of the extraocular muscles type 1, in which there is aberrant axonal targeting onto the extraocular muscles.

Bilateral incyclotorsion, absent facial nerve, and anotia: Fellow travelers in Möbius sequence or oculoauriculovertebral spectrum?

We report a patient with bilateral incyclotorsion, asymmetric facial palsy, monocular depression deficiency, and unilateral Type 3 Duane syndrome, along with contralateral anotia and a midline cleft palate. A dysplastic middle ear cavity and unilateral absence of the facial nerve were noted on magnetic resonance imaging scanning. The differential diagnosis includes Möbius sequence, oculoauriculovertebral spectrum, and a congenital cranial dysinnervation disorder.