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We retrospectively reviewed the clinical and radiologic findings in 17 children with an aberrant cisternal cranial nerve 7 (CN7), and found that these patients had additional anomalies involving other pontine cranial nerves (CNs). The hallmark imaging feature identified in all patients was an aberrant cisternal segment of an enlarged-appearing CN7. The abnormal nerve coursed anteriorly toward the Gasserian ganglion, where it fanned out toward the internal auditory canal, Meckel cave, or both. This finding was accompanied by a small cisternal CN5, which often had a lateral bowed appearance. CN5 and CN7 were abnormally close to each other. Meckel's cave appeared widened posteriorly and often was close to or merged with the internal auditory canal. Other abnormalities in the pontine CNs included CN8 deficiency in most children and variable CN6 deficiency. This constellation of findings was most often discovered in children having an MR evaluation for sensorineural hearing loss, and most patients had preserved facial nerve function. In patients with available genetic testing, no pathogenic variants were observed. Interestingly, in 13 children with an available birth history, 9 were notable for maternal or gestational diabetes (69%), suggesting a possible early intrauterine insult to the developing nerves., (© 2024 by American Journal of Neuroradiology.)

Purpose: To investigate the alterations in extraocular muscles (EOMs) by magnetic resonance imaging (MRI) among patients diagnosed with Duane retraction yndrome (DRS) and congenital fibrosis of the extraocular muscles (CFEOM), who present with various cranial nerve anomalies in an attempt to enhance the clinical diagnostic process., Methods: A case-control study was conducted to evaluate 27 patients with DRS and 14 patients with CFEOM. All patients underwent MRI scans of the brainstem and orbital examination. Neurodevelopmental assessments were conducted through MRI, and maximum cross-sectional area and volumes of EOMs were obtained. Three types of models were constructed using machine learning decision tree algorithms based on EOMs to predict disease diagnosis, cranial nerve abnormalities, and clinical subtypes., Results: Patients with bilateral CN VI abnormalities had smaller volumes of LR, MR, and IR muscles compared to those with unilateral involvement (P < 0.05). Similarly, patients with CFEOM and unilateral third cranial nerve abnormalities had a smaller maximum cross-section of the affected eye's SR compared to the contralateral eye (P < 0.05). In patients with both CN III and CN VI abnormalities, the volume of SR was smaller than in patients with CN III abnormalities alone (P < 0.05). The prediction model using EOMs volume showed a diagnostic precision of 82.5% for clinical cases and 60.1% for predicting cranial nerve abnormalities. Nonetheless, the precision for identifying clinical subtypes was relatively modest, at only 41.7%., Conclusion: The distinctive volumetric alterations in EOMs among individuals exhibiting distinct cranial nerve anomalies associated with DRS or CFEOM provide valuable diagnostic insights into to Congenital Cranial Neurodevelopmental Disorders (CCDDs). MRI analysis of EOMs should thus be regarded as a crucial diagnostic modality., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Despite its clinical implications, the MRI features of developmental facial paresis (DFP) were described in a few case reports. This study aims to describe MRI features of DFP in relation to the embryological development with a proposed radiological new grading system., Methods: The clinical records and MRI of the brain and internal auditory canal of 11 children with DFP were retrospectively reviewed. The following sequences were analyzed: axial, oblique sagittal SPACE of the internal auditory canal and brainstem; axial T2, T1WI and coronal T2WI of the brain. The severity of the maldevelopment of the seventh nerve was graded from 0 to 4: 0 = no abnormalities, 1 = unilateral facial nerve hypoplasia, 2 = unilateral facial nerve aplasia, 3 = aplasia or hypoplasia involving facial nerves on both sides, and 4 = facial nerve aplasia or hypoplasia associated with other cranial nerve palsy., Results: Isolated facial nerve palsy was diagnosed in seven patients. It was of grade 1 in five and grade 3 in two. Hypoplasia of the nerve with interrupted course was encountered in two cases. Other associated cranial nerve abnormalities (grade 4) were seen in four patients; two of them were diagnosed previously as Moebius syndrome. In addition to inner ear anomalies, middle and external ear and parotid gland anomalies were described., Conclusion: To our knowledge, this is the largest series of patients with DFP that represents a continuum of isolated and combined malformations. Understanding of embryological basis can give insights into the anomalous development of the facial nerve.

Cranial nerve disease outside the skull base is a common cause of facial and/or neck pain, which causes significant disability for patients and frustration for clinicians. Neuropathy in this region can be traumatic, idiopathic, or iatrogenic secondary to dental and surgical procedures. MR neurography is a modification of conventional MRI techniques dedicated to evaluation of peripheral nerves and is being increasingly used for imaging of peripheral neuropathies at various sites in the body. MR neurography facilitates assessment of different causes of craniofacial pain and cranial nerves and allows elegant depiction of a multitude of regional neuropathies. This article discusses the anatomy, pathologic conditions, and imaging findings of the commonly implicated but difficult to image infratentorial nerves, such as the peripheral trigeminal nerve and its branches, facial nerve, glossopharyngeal nerve, vagus nerve, hypoglossal nerve, and greater and lesser occipital nerves. © RSNA, 2018.

Background: Surgical decompression of peripheral cranial and spinal nerves at several anatomically studied trigger sites has demonstrated significant efficacy in bringing permanent relief to migraine sufferers. In their experience performing frontal nerve decompression on migraine patients, the authors noticed a previously undescribed accessory nerve and vessel in the frontotemporal area, and report its implication in migraine surgery and cosmetic filler injection., Methods: A retrospective review of 113 patients who underwent frontal migraine decompression surgery with the senior author at the University of Texas Southwestern Medical Center from July of 2012 to May of 2016 was performed. For the included 76 patients, measurements of this nerve had been taken intraoperatively using high-definition endoscopic assistance, and topographic measurements were correlated with endoscopic location of the nerve., Results: This frontotemporal nerve (FTN) was present in 55 percent, and the bilateral incidence was 57 percent of those. An accompanying vessel was also present in 81 percent of nerve complexes. Both nerve and vessel varied in size. A large vessel was present in 8 percent of all patients, and a medium vessel was present in 20 percent. Consistently, the nerve exited a foramen in the frontal bone on average 3.4 ± 0.47 cm superior to the lateral canthus., Conclusions: The identification and proper avulsion neurectomy of this newly described sensory FTN may lead to better surgical response rate during migraine surgery. In addition, this nerve should be considered during nerve block and botulinum toxin injections in migraine treatment. The existence of the accompanying vessel could have significant implications in the safety of filler and fat injections to this area.

See Meschia (doi:10.1093/brain/awy066) for a scientific commentary on this article.Vein of Galen aneurysmal malformation is a congenital anomaly of the cerebral vasculature representing 30% of all paediatric vascular malformations. We conducted whole exome sequencing in 19 unrelated patients presenting this malformation and subsequently screened candidate genes in a cohort of 32 additional patients using either targeted exome or Sanger sequencing. In a cohort of 51 patients, we found five affected individuals with heterozygous mutations in EPHB4 including de novo frameshift (p.His191Alafs*32) or inherited deleterious splice or missense mutations predicted to be pathogenic by in silico tools. Knockdown of ephb4 in zebrafish embryos leads to specific anomalies of dorsal cranial vessels including the dorsal longitudinal vein, which is the orthologue of the median prosencephalic vein and the embryonic precursor of the vein of Galen. This model allowed us to investigate EPHB4 loss-of-function mutations in this disease by the ability to rescue the brain vascular defect in knockdown zebrafish co-injected with wild-type, but not truncated EPHB4, mimicking the p.His191Alafs mutation. Our data showed that in both species, loss of function mutations of EPHB4 result in specific and similar brain vascular development anomalies. Recently, EPHB4 germline mutations have been reported in non-immune hydrops fetalis and in cutaneous capillary malformation-arteriovenous malformation. Here, we show that EPHB4 mutations are also responsible for vein of Galen aneurysmal malformation, indicating that heterozygous germline mutations of EPHB4 result in a large clinical spectrum. The identification of EPHB4 pathogenic mutations in patients presenting capillary malformation or vein of Galen aneurysmal malformation should lead to careful follow-up of pregnancy of carriers for early detection of anomaly of the cerebral vasculature in order to propose optimal neonatal care. Endovascular embolization indeed greatly improved the prognosis of patients.

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. The type and degree of ophthalmoplegia can be similar between CCDD subtypes as well as with non-congenital forms of ophthalmoplegia. Therefore diagnostic confirmation often requires neuro-imaging and/or genetic investigations. The clinician should consider this category in cases of ophthalmoplegia that are congenital and nonprogressive in nature.

The European Neuromuscular Centre (ENMC) derived the term Congenital Cranial Dysinnervation Disorders in 2002 at an international workshop for a group of congenital neuromuscular diseases. CCDDs are congenital, non-progressive ophthalmoplegia with restriction of globe movement in one or more fields of gaze. This group of sporadic and familial strabismus syndromes was initially referred to as the 'congenital fibrosis syndromes' because it was assumed that the primary pathologic process starts in the muscles of eye motility. Over the last few decades, evidence has accumulated to support that the primary pathologic process of these disorders is neuropathic rather than myopathic. This is believed that for normal development of extra ocular muscles and for preservation of muscle fiber anatomy, normal intra-uterine development of the innervation to these muscles is essential. Congenital dysinnervation to these EOMs can lead to abnormal muscle structure depending upon the stage and the extent of such innervational defects. Over last few years new genes responsible for CCDD have been identified, permitting a better understanding of associated phenotypes, which can further lead to better classification of these disorders. Introduction of high-resolution MRI has led to detailed study of cranial nerves courses and muscles supplied by them. Thus, due to better understanding of pathophysiology and genetics of CCDDs, various treatment modalities can be developed to ensure good ocular alignment and better quality of life for patients suffering from the same.

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent., (© 2017 Wiley Periodicals, Inc.)

Congenital cranial dysinnervation disorders are developmental abnormalities of cranial nerves that often include abnormal synkinesis. Among the most common ophthalmic congenital cranial dysinnervation disorders are Duane retraction syndrome and the Marcus-Gunn jaw-winking phenomenon. This report documents gustatory lid retraction as an unusual congenital cranial dysinnervation., (Copyright © 2017 American Association for Pediatric Ophthalmology and Strabismus. All rights reserved.)

Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209&#95;2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.

Congenital cranial dysinnervation disorders (CCDD) is a new term describing a collection of non-progressive neurogenic syndromes. Initially referred to as congenital fibrosis syndrome, it was thought that the primary problem was extraocular muscular maldevelopment. Recent advancements in genetics and neuro-radiology have now determined the initial observation of fibrotic muscles is secondary to a primary lack of innervation from deficient, absent, or misguided cranial nerves. This presentation provides an overview of the known genes and phenotypes currently recognized within the CCDD domain. It will also highlight areas of current research being done in the area of cranial nerve development. Increased knowledge and awareness of these disorders has resulted in more research being conducted. These studies have provided a more complete understanding of efferent motor system development and are leading to improved treatment strategies for patients., (© 2017 Board of regents of the University of Wisconsin System, American Orthoptic Journal, Volume 67, 2017, ISSN 0065-955X, E-ISSN 1553-4448.)

Introduction: Pontine tegmental cap dysplasia (PTCD) is a recently described brain malformation associated with multiple cranial neuropathies, most commonly congenital sensorineural hearing loss. The purpose of this study is to systematically characterize the cranial nerve and temporal bone findings in a cohort of children with this rare condition., Methods: Sixteen patients with PTCD and diagnostic quality imaging were retrospectively reviewed. All patients had high-resolution MR of the brain and/or internal auditory canals, and seven patients had additional high-resolution CT of the temporal bones. Studies were evaluated by two pediatric neuroradiologists for cranial nerve and temporal bone anomalies., Results: Fifteen of 16 patients (94%) had duplication of one or both internal auditory canals. Of the 24 total duplicated internal auditory canals, all 24 (100%) demonstrated stenosis or atresia of the vestibulocochlear nerve canal, as well as ipsilateral vestibulocochlear nerve aplasia. Of the non-duplicated internal auditory canals, 63% (5/8) were atretic or stenotic. Thirty-eight percent (3/8) were associated with absent vestibulocochlear nerve, and 38% (3/8) demonstrated isolated cochlear nerve aplasia. Twenty-five percent (2/8) demonstrated normal vestibulocochlear nerves, both in the same patient. Fifteen of 16 patients overall (94%) demonstrated bilateral cochlear nerve aplasia. Of the 32 total temporal bones, 4 (13%) demonstrated facial nerve aplasia. Seventy-nine percent (22/28) of facial nerves that were present demonstrated an aberrant origin or course., Conclusion: Patients with PTCD have highly characteristic temporal bone and cranial nerve findings on both CT and MR. Recognition of these findings is important for improved diagnosis of this rare disorder, particularly by CT.

Cranial neuropathy is usually idiopathic and familial cases are uncommon. We describe a family with 5 members with cranial neuropathy over 3 generations. All affected patients were women, indicating an X-linked dominant or an autosomal dominant mode of inheritance. Our cases and a review of the literature suggest that familial idiopathic cranial neuropathy is a rare condition which may be related to autosomal dominant vascular disorders (e.g. vascular tortuosity, sclerosis, elongation or extension), small posterior cranial fossas, anatomical variations of the posterior circulation, hypersensitivity of cranial nerves and other abnormalities. Moreover, microvascular decompression is the treatment of choice because vascular compression is the main factor in the pathogenesis. To the best of our knowledge, this is the first report of familial cranial neuropathy in China.

Background: Gustatory sweating syndrome (also known as Frey syndrome or auriculotemporal nerve syndrome) is thought to result from a lesion of the auriculotemporal nerve. A lesion of this nerve can lead to aberrant regeneration of nerve fibers to the sweat glands and blood vessels. The occurrence of signs outside the region of the auriculotemporal nerve prompted the author to search for another anatomical basis for this syndrome., Methods: The author dissected 46 great auricular nerves from their origin to the parotid gland and in the infratemporal fossa. The author investigated the different connections of the great auricular nerve with the facial nerve and the auriculotemporal nerve., Results: The great auricular nerve was found to essentially be a parotid nerve. There was a set of intraparotid nerve connections on 14 of the 46 half-heads that were dissected. The author was able to discern three types of parotid great auricular nerve connections, which he designates as either type 1, connection with the trunk of the facial nerve and its branches; type 2, connection with the auriculotemporal nerve; or type 3, connection with the auriculotemporal nerve and the facial nerve with the formation of an intraparotid nerve circle., Conclusions: Having clearly established the nerve connections of the great auricular nerve, the author believes that it is primarily this nerve that is responsible for gustatory sweating syndrome. This allows for a better understanding of the sympathetic nervous system features and the manifestation of the syndrome outside the region of the auriculotemporal nerve.

Background and Purpose: Cranial nerve abnormalities might be observed in hemifacial microsomia and microtia (oculo-auriculo-vertebral spectrum), but the rate, features, and relationship with functional impairment or phenotype severity have not yet been defined. This study aimed at investigating absence/asymmetry, abnormal origin, morphology and course of cranial nerves, and presence/asymmetry of the foramen ovale and inferior alveolar nerve canal in a cohort of oculo-auriculo-vertebral spectrum patients., Materials and Methods: Twenty-nine patients with oculo-auriculo-vertebral spectrum (mean age, 7 years; age range, 0.2-31 years; 12 females) underwent brain MR imaging, CT, and neurologic evaluation; 19 patients had a more severe phenotype (Goldenhar syndrome)., Results: Cranial nerve abnormalities were detected only in patients with Goldenhar syndrome (17/19, bilaterally in 8) and were involved the second (4/19), third (1/18), fifth (11/19), sixth (8/16), seventh (11/18), and eighth (8/18) cranial nerves. Multiple cranial nerve abnormalities were common (11/17). Eleven patients showed bone foramina abnormalities. Trigeminal and facial nerve dysfunctions were common (44% and 58%, respectively), especially in patients with Goldenhar syndrome. Trigeminal abnormalities showed a good correlation with ipsilateral dysfunction (P = .018), which further increased when bone foramina abnormalities were included. The facial nerve showed a trend toward correlation with ipsilateral dysfunction (P = .081). Diplopia was found only in patients with Goldenhar syndrome and was associated with third and sixth cranial nerve abnormalities (P = .006)., Conclusions: Among patients with oculo-auriculo-vertebral spectrum, cranial nerve morphologic abnormalities are common, correlate with phenotype severity, and often entail a functional impairment. The spectrum of cranial nerve abnormalities appears wider than simple hypo-/aplasia and includes an anomalous cisternal course and partial/complete fusion of diverse cranial nerves., (© 2015 by American Journal of Neuroradiology.)

Purpose of Review: Brown syndrome is an ocular motility disorder characterized by limited volitional and passive elevation of the eye in adduction. Although originally thought due to abnormalities in the trochlea or tendon sheath (limiting the free movement of the tendon through the trochlea), recent evidence suggests that some cases of congenital Brown syndrome may be related to neurodevelopmental abnormalities of the extraocular muscles (congenital cranial dysinnervation disorders, CCDD)., Recent Findings: CCDD is a term encompassing congenital abnormalities of eye movements caused by congenital innervational abnormalities. The abnormal development of cranial nerve nuclei or abnormalities in cranial nerve axonal transport affects the development of the extraocular muscle(s). Currently, congenital fibrosis of the extraocular muscles, Duane syndrome, Moebius syndrome, Horizontal gaze palsy and progressive scoliosis, and synergistic divergence are included as CCDDs. In addition, congenial ptosis, Jaw Wink ptosis, and congenital superior oblique palsy are also included. Recently, it has been suggested that some cases of congenital Brown syndrome and congenital superior oblique paresis are related, and these entities may be part of the CCDDs spectrum., Summary: Important findings regarding the cause of congenital Brown syndrome will be reviewed.

"Mirror movements" are an axonal guidance disorder that consists of involuntary contralateral movements that mimic unilateral intentional ones, typically involving the fingers of the hand. They can be isolated or associated with conditions such as Klippel-Feil syndrome, Kallmann syndrome, or congenital hemiplegia. Isolated congenital mirror movements are sometimes caused by autosomal dominant mutation in the genes DCC or RAD51. At least 4 previously reported cases had strabismus, 3 with Moebius syndrome and 1 with Duane retraction syndrome. We report the case of a boy with an unusual incomitant strabismus consistent with orbital dysinnervation and suggest that for some patients with congenital mirror movements the neurological miswiring extends to the orbit, causing congenital cranial dysinnervation disorder., (Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

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., Methods: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization (array CGH)., Results: The patient was a four-year-old girl with mild dysmorphism; bilateral mild ptosis; substantial limitation of abduction OS with milder limitations of abduction OD, adduction OS, and vertical gaze OS; and retraction OS > OD on attempted adduction. No mutations were detected in the HOXA1, KIF21A, SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 8 Kb de novo deletion on chromosome 2 (2q24.3) that encompassed a portion of only one gene, the Xin Actin-binding Repeat containing 2 (Gene Symbol XIRP2; NM&#95;001079810). This gene encodes a protein that is involved in muscle development and protecting actin filaments from depolymerization. It interacts functionally with 10 other proteins playing a similar role in muscle development., Conclusions: This patient's chromosomal abnormality affected only one gene that currently seems involved only in muscle development. All other genes currently associated with the CCDDs affect neurologic development. Genetic information from this patient implies that genes involved in development and maintenance of extraocular muscles can cause congenital ocular motility disorders as well.

Ptosis is defined as an abnormally low position of the upper eyelid margin. It can be congenital or acquired, uni or bilateral, and isolated or associated with other ocular and nonocular defects. We report a case of a female child, aged 8 years, with congenital right ptosis increased on right adduction and with left ptosis on left adduction. There was no horizontal ocular movement limitation. Apparent underaction of the right inferior oblique muscle was also present. We believe that within the possible mechanisms it is more likely that it is a congenital innervation dysgenesis syndrome (CID)/congenital cranial dysinnervation disorder (CCDD).

Background: Congenital fibrosis of extraocular muscles (CFEOM) is a rare group of disorders with variable phenotypes that result from aberrant innervation to the EOMs leading to synergistic vertical and/or horizontal deviations. We report our experience with the surgical management of patients with CFEOM., Materials and Methods: We reviewed the clinical findings, the surgical management, and outcomes of 52 consecutive CFEOM patients operated by one surgeon at a university hospital setting between 1993 and 2014. Patients were divided into CFEOM1, 2, or 3 based on clinical and/or molecular genetic findings., Results: Thirty-seven (71.2%) cases were bilateral and 15 (28.8%) were unilateral. Six of the bilateral cases had CFEOM2, and the rest of the patients had either CFEOM1 or CFEOM3. The median age at the first surgery was 10 (1-43) years. Twenty-five were females and 27 were males. Nineteen patients had previous strabismus and/or ptosis surgeries elsewhere. The mean number of operations at our center was 1.6 ± 0.7 (1-4). A temporary stay suture was used in eight patients and permanently in seven. Of the 40 patients with abnormal head position, 18 achieved excellent, 15 good, and seven poor outcomes and ocular alignment in primary position following the latest surgery was excellent in 19, good in 18, and poor in 14 of the patients, as defined in the "Methods" section of the paper., Conclusions: Although patients with CFEOM present significant strabismus surgical challenges because of EOM dysinnervation, fibrosis, and/or heterotopia, satisfactory alignment and improvement of the head posture can be attained in a significant proportion of patients using an individually tailored surgical approach.

Background: Congenital cranial dysinnervation disorders (CCDDs) are phenotypes of congenital incomitant strabismus and/or ptosis related to orbital dysinnervation. CCDDs have been associated with dominant or recessive monogenic mutations in at least 7 different genes (CHN1, SALL4, HOXA1, KIF21A, PHOX2A, TUBB3, ROBO3) that cause phenotypes such as Duane retraction syndrome, congenital fibrosis of the extraocular muscles, and horizontal gaze palsy with progressive scoliosis. Recently, arthrogryposis with or without strabismus has been shown to be caused by recessive mutations in ECEL1, a gene likely involved in neuromuscular junction formation. The strabismus phenotype in ECEL1-related cases has not always been detailed but may be a form of CCDD. To better define the ECEL1-related ophthalmic phenotype, we detail ophthalmic findings in 4 affected siblings from a consanguineous family and review documented ophthalmic findings for other reported mutation-positive cases., Methods: Affected family members were prospectively examined and the relevant literature was reviewed., Results: Ophthalmic findings were present in 3 of the 4 siblings with ECEL1-related distal arthrogryposis: bilateral ptosis with bilateral congenital fibrosis of the extraocular muscles, right ptosis with ipsilateral Y exotropia (exotropia increasing in upgaze), and right ptosis with ipsilateral Duane retraction syndrome. The fourth affected sibling, who had the mildest arthrogryposis, had no ophthalmic abnormalities. Of 26 other reported recessive ECEL1 mutation cases (14 families), all had arthrogryposis, 19 had documented ptosis, and 4 had documented complex strabismus. One of these cases had both documented ptosis and complex strabismus., Conclusions: Our clinical findings are consistent with recessive ECEL1 mutations causing variably penetrant orbital dysinnervation phenotypes (ptosis and/or complex strabismus with abnormal synkinesis) in the context of arthrogryposisis, that is, with the ECEL1-related ophthalmic phenotype being a form of CCDD., (Copyright © 2014 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

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. More information is available regarding neurodevelopmental and clinical effects of various gene mutations associated with individual CCDDs. For certain CCDDs, the phenotype of a particular individual may not completely predict the genotype, and conversely, the genotype may not always predict the phenotype., Summary: The CCDD concept has focused attention on specific congenital disturbances of human ocular motility and on the fact that these disorders are typically neurogenic in origin. The past decade has seen rapid evolution within this field with the last 2 years yielding additional information about existing diagnoses, genes, and phenotypes that may result in better classification of these disorders and new genotype-phenotype correlations in the future.

Aims: To report our neonatal management experience in patients who received a diagnosis of brainstem dysgenesis (BSD)., Patients and Methods: This study retrospectively reviewed the medical records of 15 neonates with BSD diagnosed between 1984 and 2011. Data on the perinatal period, physical examination, laboratory findings, and management by systems were systematically analyzed., Results: All cases were sporadic. Cocaine abuse and misoprostol use were recorded in two pregnancies. The reason for admission was prematurity (2 of 15), respiratory distress (8 of 15), gastroschisis (1 of 15), and abnormal neurological examination (4 of 15). Clinically, the most commonly affected cranial nerves were the 7th (13 of 15), 9th (11 of 15), 10th (8 of 15), 5th (7 of 15), 12th (7 of 15), 6th (3 of 15), 4th (1 of 15), and 3rd (1 of 15). Five patients required positive pressure ventilation during delivery room resuscitation, three had difficult airways, and two needed tracheostomy during admission. Most patients required nasogastric tube feeding shortly after birth, and four patients had a gastrostomy on discharge. Two patients died of respiratory and cardiac failure. Electromyography and nerve conduction velocity were used to exclude generalized neuromuscular disorders, and in conjunction with other neurophysiological and gastrointestinal tract studies, helped uncover the extent of brainstem involvement in most cases. Cranial magnetic resonance imaging supported the diagnosis in more than half of the patients., Conclusions: Early diagnosis of BSD is mainly clinical, difficult to establish unless suspected, and crucial to prevent complications. Neonatal care of patients with BSD requires a comprehensive approach that must take into consideration the etiological, anatomical, and pathogenic aspects contributing to the clinical manifestations of this disorder. Care should be provided by multidisciplinary teams, in which neonatologists, pediatric neurologists, nutritionists, physical therapists, and other professionals participate, depending on the associated morbidity in order to improve its management and prognosis.

Mycophenolic acid (MPA) is an immunosuppressive agent that acts as a selective, non-reversible inhibitor of the enzyme inosine-5'-monophosphate dehydrogenase (IMPDH). Malformations have been described in children after maternal exposure to mycophenolate. However, the causal link is unclear in most cases because women had been treated with a combination of drugs and birth defects may have other causes. Therefore, it is important to study the action of this drug and its main metabolite on embryonic tissue. We studied the teratogenic potential of MPA and its major metabolite, the mycophenolic acid glucuronide (MPAG) in the rat whole-embryo culture. A total of 147 day 9.5 embryos were cultivated for 48 h in the standard medium containing 85 % serum. We tested MPA at concentrations of 0.1; 0.25; 0.5; 0.75 mg/l (0.31; 0.78; 1.56; 2.34 μM) and MPA glucuronide at concentrations of 3; 10; 30; 100 mg/l (6.04; 20.14; 60.43; 201.43 μM). Both substances are highly protein bound, and MPA glucuronide might displace MPA from protein binding. Therefore, we examined whether the effects of MPA can be enhanced when studied in combination with the glucuronide. Furthermore, the focus was on additional endpoints to the standard evaluation of cultivated embryos, such as development of cranial nerves [trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X)] after staining with an antibody against 2H3 neurofilament. Ultrastructural changes were evaluated by electron microscopy. At a concentration of 0.75 mg MPA/l medium, all embryos showed dysmorphic changes. Embryos exposed to 0.25 mg MPA/l medium showed impaired development of nerves, and at 0.1 mg/l, no effects were detectable. Concentration-dependent ultrastructural changes, such as signs of apoptosis, were found by electron microscopy. The examination of the metabolite in this assay showed that at a concentration of 100 mg MPAG/l, the embryos exhibited distinct malformations. This is probably caused by MPA, which was detectable at 0.6 % in the material used for our experiments. The combination of the parent compound (0.03; 0.1; 0.25 mg/l) with its metabolite MPAG (3 mg/l) did not cause enhanced toxicity under our experimental conditions. IMPDH, the target enzyme of MPA, could be detected in rat embryos on day 9.5 of embryonic development as well as at the end of the culture period 48 h later. In summary, MPA impairs embryonic development at low, therapeutically relevant concentrations, but the glucuronide does not exhibit such a potential. Activity of MPA is not enhanced by MPAG.

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.

Autism is often associated with multiple developmental anomalies including asymmetric facial palsy. In order to establish the etiology of autism with facial palsy, research into developmental abnormalities of the peripheral facial nerves is necessary. In the present study, to investigate the development of peripheral cranial nerves for use in an animal model of autism, rat embryos were treated with valproic acid (VPA) in utero and their cranial nerves were visualized by immunostaining. Treatment with VPA after embryonic day 9 had a significant effect on the peripheral fibers of several cranial nerves. Following VPA treatment, immunoreactivity within the trigeminal, facial, glossopharyngeal and vagus nerves was significantly reduced. Additionally, abnormal axonal pathways were observed in the peripheral facial nerves. Thus, the morphology of several cranial nerves, including the facial nerve, can be affected by prenatal VPA exposure as early as E13. Our findings indicate that disruption of early facial nerve development is involved in the etiology of asymmetric facial palsy, and may suggest a link to the etiology of autism., (Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.)

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.

Objective: CHARGE syndrome is a heterogeneous genetic disorder comprising multiple congenital anomalies. Major clinical diagnostic criteria include ocular coloboma, choanal atresia/stenosis, characteristic ear abnormalities, and cranial nerve abnormalities. CHARGE syndrome is caused by a mutation in the gene CHD7 located on chromosome 8. Patients with CHARGE syndrome require multiple anesthetics for surgical and otorhinolaryngology procedures. This study describes the postoperative anesthetic related airway events (i.e. re-intubations for apneas and desaturations, airway obstruction due to excessive secretions) of nine individuals with CHARGE syndrome., Methods: Detailed chart audits were performed on nine patients diagnosed clinically with CHARGE syndrome who had undergone surgery at a single tertiary health centre. The CHARGE characteristics present in each individual, the number and types of surgeries and anesthetics, and the related postoperative airway events were determined., Results: The mean+/-age of the population at chart review was 11.8 years (+/-8.0). The total number of anesthetics was 147, with a mean of 16.2(+/-8.4). Of the 215 surgical procedures (mean 21.9, +/-12.2), 30% were otorhinolaryngological. Postoperative airway events occurred after 35% of anesthetics. Surgeries resulting in the most airway events involved the heart (65%), the gastrointestinal tract (39%), and airway diagnostic scopes, i.e., bronchoscopy, laryngoscopy, and nasopharyngoscopy (36%). Combining multiple surgical procedures under one anesthetic did not increase the risk of postoperative airway events. As individuals aged, they had fewer surgeries and anesthetics, as well as a lower risk of postoperative airway events., Conclusion: Individuals with CHARGE syndrome face a significant risk of postoperative airway events with anesthesia, and this is exacerbated by the high number of surgeries they require. Surgeons and anesthesiologists should be aware of potential for postoperative airway events in individuals with CHARGE syndrome and plan accordingly.

Objective: We undertook this study to describe central nervous system (CNS) abnormalities associated with congenital cranial dysinnervation disorders (CCDD)., Methods: This was a retrospective, observational, transversal and descriptive study including patients with congenital fibrotic strabismus. We analyzed clinical files of patients from 2001 to 2006. Neurological lesions were reported., Results: Restrictive strabismus was demonstrated in all cases. Sixteen patients were included: nine males and seven females. Different neurological lesions were reported: corpus callosum anomalies, severe cortipathy, epilepsy, cavum vergae, nystagmus, occipital subarachnoid cyst, and hydrocephalus. Mental retardation was reported in 56% of patients. Different malformations were reported: genital malformations, trigonocephalus, camptodactyly, mild facial hypoplasia, low set ears, and agenesis of left ear. Blepharoptosis was present in 81% of patients. The most frequent form of strabismus was exotropia (56%), hypotropia in 37.5%, hypertropia 18.7%, "A" pattern 18.7%, and esotropia in 6.25%. Affection was cranial nerve III, 93.75%; cranial nerve VI, 6.25%; cranial nerve VII, 6.25%; and lesion to cranial nerve II in eight cases (50%)., Conclusions: We have suggested that failure in early stages of embryology of the CNS can lead to the development of paralytic strabismus and generate secondary fibrotic changes, not only in muscle structures but also in other orbital tissues. That is the reason why we have used the term "congenital fibrotic strabismus" to report cases included in CCDD. We have demonstrated the strong association of mental retardation and neurological alterations. Multidisciplinary rehabilitation is relevant for these patients.

Cranial nerve (CN) anomalies have been regarded as a major criterion for a clinical diagnosis of CHARGE syndrome for some time. However, there have been relatively few studies of the extent of this involvement. A detailed questionnaire (in French or English) was distributed to all physicians who participated in the 2001-2004 Canadian Paediatric Surveillance Program (CPSP), and who identified themselves as caring for an individual with CHARGE syndrome. Clinical data were collected from multiple sources for each individual, including evidence of CN dysfunction. Evidence for CN anomalies recorded by the clinical presentations and evidence from specialized testing, were: weak chewing and/or sucking (CN V), facial palsy (CN VII), sensorineural hearing loss (CN VIII), balance vestibular problems (CN VIII), and swallowing problems (CN IX/X). Data were analyzed as to the frequency of the CN anomalies and compared to the literature. At the time of this study, there were 99 individuals identified with CHARGE syndrome across Canada. The CHARGE syndrome diagnosis was confirmed by geneticists across the country. Gene testing was not available at the time of this study. Of these 92% exhibited symptoms of at least one CN anomaly, and 72% reported involvement of more than one. Isolated CN involvement was rare. Ascertainment was highest for CN IX/X, and lowest for VIII vestibular. The frequency of CN involvement was generally higher than that reported in the literature., ((c) 2008 Wiley-Liss, Inc.)

The clinically used antimycotic fluconazole (fluco) is teratogenic in rodents. Exposure in vitro to fluco, other investigated azoles (triadimefon, triadimenol, flusilazole, ketoconazole and imazalil) or retinoic acid (RA), is correlated to branchial arch abnormalities. Inhibition of RA degradation has been suggested as the azole-related mechanism. Citral is a RA synthesis inhibitor. E9.5 rat embryos were cultured for 48 h in normal serum or exposed in vitro to fluco 125 microM, citral 200 microM or co-exposed to the two molecules to test the hypothesis that citral attenuates fluco-related teratogenic effects. Some embryos were cultured for 12 extra hours, and cranial nerves immunodetected. Fluco induced typical abnormalities, including branchial arch and cranial nerve defects. The co-exposure to fluco+citral was significantly effective in reducing branchial arch and cranial nerve defects, supporting the hypothesis that citral balances the fluco-induced RA concentration increase. However, other fluco-related effects were unalterated by citral.

Background and Purpose: Hemimegalencephaly is a rare but well-known congenital malformation with ipsilateral enlargement of the hemicerebrum. However, very little is known about changes in structures outside the involved hemisphere in patients with this condition. We investigated morphologic abnormalities occurring outside the affected hemisphere by MR imaging in a large series of patients with hemimegalencephaly., Materials and Methods: MR imaging findings for 30 patients with hemimegalencephaly were retrospectively reviewed and evaluated for structures outside the involved hemisphere on routine MR images, such as cranial nerves (I, II, V), brain vessels, subdural and subarachnoid spaces, brain stem, and cerebellum, on both the ipsilateral and contralateral sides., Results: The ipsilateral olfactory and optic nerves were enlarged in 8 (26.7%) and 1 (3.3%) of the 30 patients, respectively, without enlargement on the contralateral side. No asymmetry was noted in the trigeminal nerves. Asymmetric vascular dilations in the ipsilateral cerebral hemisphere were observed in 12 of the 30 patients (40%), in deep cerebral vessels in 11 patients (36.7%), and in superficial cerebral vessels in 8 patients (26.7%). Ipsilateral brain stem and hemicerebellar asymmetric enlargement was detected in 2 patients (6.7%) and 14 patients (46.7%), respectively. Abnormal cerebellar folia were observed on the ipsilateral side in 6 patients (20%) and on the contralateral side in 3 patients (10%)., Conclusion: Ipsilateral olfactory nerve enlargement, cerebral vascular dilations, cerebellar enlargement, and bilateral or ipsilateral abnormal architecture of the cerebellar folia are often associated with hemimegalencephaly.

Congenital cranial dysinnervation disorders (CCDDs) are congenital non-progressive, sporadic or familial abnormalities of cranial musculature that result from developmental abnormalities of, or the complete absence of, one or more cranial nerves with primary or secondary muscle dysinnervation. These disorders include vertical disorders of ocular motility, horizontal disorders of ocular motility and disorders with abnormalities of facial motility that were previously referred to as "congenital fibrosis syndromes". The advances in clinical and molecular genetics of congenital cranial dysinnervation disorders are reviewed.

The basic helix-loop-helix genes Hes1 and Hes5, known Notch effectors, regulate the maintenance of neural stem cells and the development of the central nervous system (CNS). In the absence of Hes1 and Hes5, the size, shape and cytoarchitecture of the CNS are severely disorganized, but the development of the peripheral nervous system remains to be analyzed. Here, we found that in Hes1;Hes5 double-mutant mice, the cranial and spinal nerve systems are also severely disorganized. In these mutant mice, axonal projections from the mesencephalic neurons to the trigeminal (V) ganglion become aberrant and the proximal parts of the glossopharyngeal (IX) and vagus (X) nerves are fused. The hypoglossal (XII) nerve is also formed poorly. Furthermore, the dorsal root ganglia are fused with the spinal cord, and the dorsal and ventral roots of the spinal nerves are lacking in many segments. These results indicate that Hes1 and Hes5 play an important role in the formation of the cranial and spinal nerve systems., (Copyright (c) 2006 S. Karger AG, Basel.)

Triazole-derivatives alter the pharyngeal apparatus morphogenesis of rodent embryos cultured in vitro. The hindbrain segmentation and the rhombencephalic neural crest cell (NCCs) migration are altered by Fluconazole exposure in vitro. The aim of the present work is to identify if a common pathogenic pathway is detectable also for other molecules of this class of compounds. 9.5 days post coitum (d.p.c.) old rat embryos were exposed in vitro to the teratogenic concentrations of Flusilazole, Triadimefon and Triadimenol and cultured for 24, 48 or 60 h. The expression and localisation of Hox-b1 and Krox-20 proteins (used as markers for hindbrain segmentation) were evaluated after 24 h of culture. The localisation and distribution of NCC was evaluated after 24, 30 and 48 h of culture. The morphology of the embryos was analysed after 48 h, while the branchial nerve structures were evaluated after 60 h of culture. Hindbrain segmentation and NCC migration alteration as well as pharyngeal arch and cranial nerve abnormalities were detected after exposure of the tested molecules. A common severe teratogenic intrinsic property for the tested molecules of this chemical class has been found, acting through alteration of the normal hindbrain developmental pattern.

Objective: To detail the radiologic findings in Möbius syndrome, in order to clarify its pathogenetic mechanisms., Methods: High resolution three-dimensional T1 (MP rage) and T2 (CISS) weighted MRI were used to study the cisternal and canalicular portion of the seventh cranial nerve in six Möbius patients. Also, the anteroposterior dimension of the brainstem was measured at the level of the pons in the authors' 6 patients and in 20 age-matched healthy control subjects. Furthermore, the MRIs were evaluated for associated congenital brain anomalies., Results: The facial nerves were absent in all six patients despite residual function in some facial muscles. The authors confirmed brainstem hypoplasia but did not find tegmental calcifications. The anteroposterior dimension of the brainstem ranged between 17 and 25 mm vs 20 to 27 mm for controls. In three patients there were congenital abnormalities in the posterior fossa., Conclusion: The absent facial nerves on MRI and the unusual distribution of the facial weakness, which is characteristic of Möbius syndrome, suggests that other cranial nerves, possibly the trigeminal, hypoglossal, or glossopharyngeal nerve, aberrantly innervate some lower facial muscles. Radiologic findings support the notion that Möbius syndrome is part of a more complex congenital anomaly of the fossa posterior.

Children with CHARGE syndrome commonly experience feeding and swallowing problems. Difficulties may be associated with congenital structural anomalies, motor impairment, and/or oral sensory impairment. For many children with CHARGE syndrome, the introduction of functional oral feeding is delayed and there are often long-term feeding complications. Oral aversion or defensiveness is a frequent serious issue; however, it is uncertain whether this is a primary sensory disorder or secondary to delayed and/or negative oral sensory and feeding experiences. This article examines in detail the early oral sensory and feeding experiences of five children with CHARGE syndrome, through a review of medical records and caregiver questionnaires. Findings indicate variable early oral sensory experiences in this group of children, with all of the children having some difficulty or delay in the development of oral feeding and swallowing. The nature of these difficulties and the potential contributory factors are discussed.

Members of the Spalt gene family encode putative transcription factors characterized by seven to nine C2H2 zinc finger motifs. Four genes have been identified in mice--Spalt1 to Spalt4 (Sall1 to Sall4). Spalt homologues are widely expressed in neural and mesodermal tissues during early embryogenesis. Sall3 is normally expressed in mice from embryonic day 7 (E7) in the neural ectoderm and primitive streak and subsequently in the brain, peripheral nerves, spinal cord, limb buds, palate, heart, and otic vesicles. We have generated a targeted disruption of Sall3 in mice. Homozygous mutant animals die on the first postnatal day and fail to feed. Examination of the oral structures of these animals revealed that abnormalities were present in the palate and epiglottis from E16.5. In E10.5 embryos, deficiencies in cranial nerves that normally innervate oral structures, particularly the glossopharyngeal nerve (IX), were observed. These studies indicate that Sall3 is required for the development of nerves that are derived from the hindbrain and for the formation of adjacent branchial arch derivatives.

Background: Methanol administered to C57BL/6J mice during gastrulation causes severe craniofacial dysmorphology. We describe dysmorphogenesis, cell death, cell cycle assessment, and effects on development of cranial ganglia and nerves observed following administration of methanol to pregnant C57BL/6J mice on gestation day (GD) 7., Methods: Mice were injected (i.p.) on GD 7 with 0, 2.3, 3.4, or 4.9 gm/kg methanol, split into two doses. In embryos of mice treated with 0 or 4.9 gm/kg methanol, we used histology and LysoTracker red staining on GD 8 0 hr through GD 8 18 hr to examine cell death and dysmorphogenesis, and we also evaluated cell-cycle distribution and proliferation using flow cytometry (FCM) and BrdU immunohistochemistry. On GD 10, we evaluated the effect of GD 7 exposure to 0, 2.3, 3.4, or 4.9 gm/kg methanol on cranial ganglia and nerve development using neurofilament immunohistochemistry., Results: Methanol treatment on GD 7 resulted in reduced mesenchyme surrounding the fore- and midbrain, and in the first branchial arches, by GD 8 12 hr. There were disruptions in the forebrain neuroepithelium and optic pit. Neural crest cell emigration from the mid- and hindbrain region was reduced in methanol-exposed embryos. Methanol had no apparent effect on BrdU incorporation or cell-cycle distribution on GD 8. Cell death was observed in the hindbrain region along the path of neural crest migration and in the trigeminal ganglion on GD 8 18 hr. Development of the cranial ganglia and nerves was adversely affected by methanol. Development of ganglia V, VIII, and IX was decreased at all dosage levels; ganglion VII was reduced at 3.4 and 4.9 gm/kg, and ganglion X was reduced at 4.9 gm/kg., Conclusions: These results suggest that gastrulation-stage methanol exposure affects neural crest cells and the anterior mesoderm and neuroepithelium. Cell death was evident in areas of migrating neural crest cells, but only at time points after methanol was cleared from the embryo, suggesting an indirect effect on these cells. Birth Defects Research (Part A), 2004. Published 2004 Wiley-Liss, Inc.

LMO4 belongs to a family of transcriptional regulators that comprises two zinc-binding LIM domains. LIM-only (LMO) proteins appear to function as docking sites for other factors, leading to the assembly of multiprotein complexes. The transcription factor Deaf-1/NUDR has been identified as one partner protein of LMO4. We have disrupted the Lmo4 and Deaf-1 genes in mice to define their biological function in vivo. All Lmo4 mutants died shortly after birth and showed defects within the presphenoid bone, with 50% of mice also exhibiting exencephaly. Homeotic transformations were observed in Lmo4-null embryos and newborn mice, but with incomplete penetrance. These included skeletal defects in cervical vertebrae and the rib cage. Furthermore, fusions of cranial nerves IX and X and defects in cranial nerve V were apparent in some Lmo4(-/-) and Lmo4(+/-) mice. Remarkably, Deaf-1 mutants displayed phenotypic abnormalities similar to those observed in Lmo4 mutants. These included exencephaly, transformation of cervical segments, and rib cage abnormalities. In contrast to Lmo4 nullizygous mice, nonexencephalic Deaf-1 mutants remained healthy. No defects in the sphenoid bone or cranial nerves were apparent. Thus, Lmo4 and Deaf-1 mutant mice exhibit overlapping as well as distinct phenotypes. Our data indicate an important role for these two transcriptional regulators in pathways affecting neural tube closure and skeletal patterning, most likely reflecting their presence in a functional complex in vivo.

Purpose: The clinical and molecular genetic classification of syndromes with congenital limitation of eye movements and evidence of cranial nerve dysgenesis continues to evolve. This monograph details clinical and molecular genetic data on a number of families and isolated patients with congenital fibrosis of the extraocular muscles (CFEOM) and related disorders, and presents an overview of the mechanisms of abnormal patterns of motor and sensory cranial nerve development in these rare syndromes., Methods: Clinical examination of one patient with CFEOM1, one family with clinical features of CFEOM2, one family with recessive CFEOM3, one family with horizontal gaze palsy and progressive scoliosis (HGPPS), and four patients with various combinations of congenital cranial nerve abnormalities. Genotyping of families with CFEOM and HGPPS for polymorphic markers in the regions of the three known CFEOM loci and in the HGPPS region, and mutation analysis of the ARIX and KIF21A genes in patients with CFEOM were performed according to standard published protocols., Results: The patient with CFEOM1 had the second most common mutation in KIF21A, a 2861 G>A mutation that resulted in an R954Q substitution. The family with CFEOM2 phenotype did not map to the CFEOM2 locus. The family with recessive CFEOM3 did not map to any of the known loci. The HGPPS family mapped to 11q23-q25. One patient had optic nerve hypoplasia and fifth nerve dysfunction. Two patients had the rare combination of Möbius syndrome and CFEOM. One patient had Möbius syndrome and fifth nerve dysfunction., Conclusions: There is genetic heterogeneity in CFEOM2 and CFEOM3. Abnormalities in sensory nerves can also accompany abnormalities of motor nerves, further substantiating the effect of individual mutations on developing motor as well as sensory cranial nerve nuclei.

Roles of receptor-type protein tyrosine phosphatase beta (RPTPbeta, also called PTPzeta) were investigated in the nervous system development of Xenopus embryos. We previously showed that Xenopus embryos express mRNAs for 11 receptor-type (XRPTPbeta.1-XRPTPbeta.11) and two secretory (sXRPTPbeta.1 and sXRPTPbeta.2) variants generated by alternative RNA splicing. Whole-mount in situ hybridization analyzes demonstrated central nervous system-specific gene transcription in tailbud embryos. Distributions of mRNAs for receptor-type and secretory variants partially differ in the hindbrain. Overexpression of XRPTPbeta.4 or sXRPTPbeta.2, which was brought about by microinjection of the recombinant plasmid vectors, caused abnormal development of the cranial nerve X. Deletion of the cytoplasmic segment from XRPTPbeta.4 did not affect the ability to cause the abnormality, but deletion of the extracellular segment abolished it. These results suggest that normal development of the cranial nerve X requires regulated expression of the XRPTPbeta gene products.

Aims/hypothesis: Maternal diabetes mellitus increases the risk for fetal malformations. Several of these malformations are found in organs and tissues derived from the neural crest. Previous studies have shown changes in fetal organs of neural crest origin in experimental diabetes and changes in migration of neural crest cells exposed to high glucose in vitro., Methods: We used whole-mount neurofilament staining of embryos from normal and diabetic mothers to investigate the development of cranial nerve ganglia. Neural tube explants were cultured in 10 and 40 mmol/l glucose and cell death and caspase activity was measured with flow cytometry., Results: The development of cranial ganglia V, VII, VIII, IX and X was impaired in day 10-11 embryos of diabetic rats. There was also a higher rate of cell death of neural crest derived cells cultured in 40 mmol/l glucose for 20 h (35% compared to 12% in 10 mmol/l). However, exposure of cells to 40 mmol/l glucose in culture did not increase the activation of the cell death effector proteins-caspases-measured as cellular binding of the activated caspase marker VAD-FMK. This suggests that the cell death is not caused by caspase-dependent apoptosis or that the caspases are activated at an earlier stage., Conclusion/interpretation: The development of neural crest-derived structures is disturbed already at the organogenic period in embryos of diabetic rats and this deteriorated development could be due to high-glucose induced increase in cell death of neural crest derived cells.

Targeted inactivation of the mouse retinaldehyde dehydrogenase 2 (RALDH2/ALDH1a2), the enzyme responsible for early embryonic retinoic acid synthesis, is embryonic lethal because of defects in early heart morphogenesis. Transient maternal RA supplementation from E7.5 to (at least) E8.5 rescues most of these defects, but the supplemented Raldh2(-/-) mutants die prenatally, from a lack of septation of the heart outflow tract (Niederreither, K., Vermot, J., Messaddeq, N., Schuhbaur, B., Chambon, P. and Dollé, P. (2001). Development 128, 1019-1031). We have investigated the developmental basis for this defect, and found that the RA-supplemented Raldh2(-/-) embryos exhibit impaired development of their posterior (3rd-6th) branchial arch region. While the development of the first and second arches and their derivatives, as well as the formation of the first branchial pouch, appear to proceed normally, more posterior pharyngeal pouches fail to form and the pharyngeal endoderm develops a rudimentary, pouch-like structure. All derivatives of the posterior branchial arches are affected. These include the aortic arches, pouch-derived organs (thymus, parathyroid gland) and post-otic neural crest cells, which fail to establish segmental migratory pathways and are misrouted caudally. Patterning and axonal outgrowth of the posterior (9th-12th) cranial nerves is also altered. Vagal crest deficiency in Raldh2(-/-) mutants leads to agenesis of the enteric ganglia, a condition reminiscent of human Hirschprung's disease. In addition, we provide evidence that: (i) wildtype Raldh2 expression is restricted to the posteriormost pharyngeal mesoderm; (ii) endogenous RA response occurs in both the pharyngeal endoderm and mesoderm, and extends more rostrally than Raldh2 expression up to the 2nd arch; (iii) RA target genes (Hoxa1, Hoxb1) are downregulated in both the pharyngeal endoderm and mesoderm of mutant embryos. Thus, RALDH2 plays a crucial role in producing RA required for pharyngeal development, and RA is one of the diffusible mesodermal signals that pattern the pharyngeal endoderm.