先天性颅神经异常支配性疾病及分子遗传学研究进展

先天性颅神经异常支配性疾病（congenital cranial dysinnervation disorders,CCDDs）为先天性、非进行性散发或家族性的颅神经肌肉疾病,其病因为一条或多条颅神经发育异常或完全缺如,从而引起原发或继发的对肌肉的异常支配。可表现为垂直眼球运动异常,水平眼球运动异常和面肌麻痹。以往这类疾病常被称为先天性纤维化综合征,最近的神经病理学、神经影像学和分子遗传学研究表明该类疾病是由于脑干颅神经核和（或）颅神经的发育异常引起。本文对不同类型CCDDs的临床及分子遗传学研究进展作一综述。     

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.     

The Genetic Basis of Incomitant Strabismus: Consolidation of the Current Knowledge of the Genetic Foundations of Disease

Abstract

In recent years, our understanding of the genetic foundations of incomitant strabismus has grown significantly. Much new understanding has been gleaned since the concept of congenital cranial dysinnervation disorders (CCDDs) was introduced in 2002, and the genetic basis of CCDDs continues to be elucidated. In this review, we aim to provide an update of the genetic and clinical presentation of these disorders. Disorders reviewed include Duane syndrome (DS), HOXA1 and HOXB1 syndromes, Moebius syndrome, congenital fibrosis of the extraocular muscles (CFEOM), and horizontal gaze palsy with progressive scoliosis (HGPPS).     

CCDD Phenotype Associated with a Small Chromosome 2 Deletion

Abstract

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_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.     

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.     

Congenital cranial dysinnervation disorders

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.     

Congenital Corneal Opacities: A Review with a Focus on Genetics

Congenital corneal opacities present in approximately 3/100,000 newborns. Many different disorders may result in corneal opacifications of infancy, including Peters' anomaly (PA), congenital hereditary endothelial dystrophy (CHED), congenital hereditary stromal dystrophy (CHSD) and posterior polymorphous dystrophy (PPMD). Current studies have localized defects using genetic testing in PA, CHED, CHSD and PPMD. Identifying mutations for specific disorders may lead to better understanding of the underlying pathogeneses and may help with diagnosis and prognosis. This article will review the clinical presentations, treatments and genetics of Peters' anomaly, congenital hereditary endothelial dystrophy, congenital hereditary stromal dystrophy and posterior polymorphous dystrophy.     

Extraocular muscles: Basic and clinical aspects of structure and function

Although extraocular muscle is perhaps the least understood component of the oculomotor system, these muscles represent the most common site of surgical intervention in the treatment of strabismus and other ocular motility disorders. This review synthesizes information derived from both basic and clinical studies in order to develop a better understanding of how these muscles may respond to surgical or pharmacological interventions and in disease states. In addition, a detailed knowledge of the structural and functional properties of extraocular muscle, that would allow some degree of prediction of the adaptive responses of these muscles, is vital as a basis to guide the development of new treatments for eye movement disorders.     

Management of congenital fibrosis of the inferior rectus muscle associated with high myopia: a case report

BACKGROUND: Congenital fibrosis of the extraocular muscles includes a wide spectrum of phenotypically heterogeneous disorders involving a single or multiple muscles. METHODS: We present a case of congenital fibrosis of the inferior rectus associated with ipsilateral high myopia. First we tried to treat the hypotropia with inferior rectus weakening and superior rectus strengthening procedures, but this failed, so we proceeded with an ocular sling with fascia lata and a vertical Hummelsheim procedure. RESULTS: Hypotropia improved completely after the last operation and some degree of upward movement appeared. CONCLUSION: It seems that in a highly myopic globe with fibrotic muscles, classical methods for the correction of deviation may have poor response and more innovative procedures may be required to correct the deviation.     

Congenital absence of the inferior rectus muscle--diagnosis and management.

BACKGROUND: Congenital absence of the inferior rectus muscle is a rare cause of apparent inferior rectus palsy especially in the absence of associated cranial facial anomalies. METHODS: We report three cases of isolated congenital absence of the inferior rectus muscle and its successful surgical management. RESULTS: Failure of the normal embryologic development of the mesodermal complex around the eye can lead to agenesis of the extraocular muscles. In apparent palsies of the inferior rectus muscle and no definite cause, a high index of suspicion and orbital imaging can confirm the diagnosis of congenitally absent inferior rectus preoperatively. Surgical correction may involve inferior transposition of the horizontal rectus muscles. CONCLUSIONS: Although rare, congenital absence of the inferior rectus muscle is a possible cause of apparent inferior rectus muscle palsy particularly in the absence of another identifiable cause. Strabismus surgery in conjunction with intramuscular botulinum toxin injection can offer significant improvement in function and cosmesis of these patients.     

Congenital corneal opacities: a review with a focus on genetics

Congenital corneal opacities present in approximately 3/100,000 newborns. Many different disorders may result in corneal opacifications of infancy, including Peters' anomaly (PA), congenital hereditary endothelial dystrophy (CHED), congenital hereditary stromal dystrophy (CHSD) and posterior polymorphous dystrophy (PPMD). Current studies have localized defects using genetic testing in PA, CHED, CHSD and PPMD. Identifying mutations for specific disorders may lead to better understanding of the underlying pathogeneses and may help with diagnosis and prognosis. This article will review the clinical presentations, treatments and genetics of Peters' anomaly, congenital hereditary endothelial dystrophy, congenital hereditary stromal dystrophy and posterior polymorphous dystrophy.     

Congenital fibrosis of the extraocular muscles associated with cortical dysplasia and maldevelopment of the basal ganglia.

BACKGROUND: Congenital fibrosis of the extraocular muscles (CFEOM) is a rare condition that has been traditionally regarded as a primary eye muscle disease. Recent studies, however, suggest that CFEOM may be the result of a primary neuropathy with secondary myopathic changes. PURPOSE: To describe a previously unrecognized association between congenital fibrosis of the extraocular muscles and structural abnormalities of the brain. DESIGN: Small case series. METHODS: Detailed clinical examinations and neuroradiologic studies were performed on the three affected family members. In addition, genetic analysis of the family was performed. RESULTS: The three affected family members, mother and two children, have the ocular features of 'classic' congenital fibrosis of the extraocular muscles. All showed dilation of the left lateral ventricle secondary to hypoplasia of the body and tail of the ipsilateral caudate nucleus. There was fusion of an enlarged caudate nucleus head with the underlying putamen. Both children showed widespread bilateral cortical dysplasia. Genetic analysis of the family was inconclusive but consistent with linkage to the CFEOM1 locus on chromosome 12. Chromosomal analysis of the affected individuals did not show evidence of a deletion of chromosome 12 and haplotype analysis was not suggestive of a microdeletion. CONCLUSIONS: Cerebral cortical and basal ganglia maldevelopment can be found in individuals with CFEOM. This suggests that neuroimaging should be considered in the initial diagnostic evaluation of these patients, particularly if there is developmental delay.     

Surgical treatment of congenital eyelid malpositions in children

Congenital eyelid malpositions can be isolated or associated with other structures such as the eyeball, ocular muscles, and lacrimal pathways. It is important to separate eyelid malpositions, which are topographical disorders, from eyelid malformations, which are constitutional morphological disorders. Only eyelid malpositions will be described in this paper, with a distinction made between static and dynamic disorders. Static disorders include epiblepharon, congenital ectropion and entropion, epicanthus, telecanthus, and centurion syndrome. Dynamic disorders group ptosis and congenital eyelid retractions. Epiblepharon is characterized by the absence of adhesion between the lower eyelid retractors and the orbicularis-skin layer, which allows the anterior lamella to roll over. Congenital entropion and ectropion are very rare. They most often require surgical treatment. Epicanthus involves a semi-lunar fold of skin extending from the upper eyelid across the medial canthal area to the margin of the lower eyelid. Four types (supra-ciliaris, palpebralis, tarsalis and inversus) of epicanthus are described. Treatment requires surgery. Telecanthus is defined as an increased distance between canthi. Primary telecanthus results from attenuation of the medial canthal tendons and is usually associated with other soft tIssue abnormalities such as epicanthus or blepharophimosis, or is seen after trauma. Secondary telecanthus is caused by underlying bony malpositions with an abnormal separation between the orbits because of an increased thickness of the interorbital bones such as that seen in hypertelorism or in other complex craniofacial syndromes. Euryblepharon is distinguished by an enlargement of the horizontal palpebral fissure associated with enlarged eyelids. The etiology is unknown and patients may benefit from surgery. Congenital ptosis is characterized by a deficiency of the levator muscle. They are most often unilateral and isolated. When associated with other abnormalities such as squint, synkinesis, blepharophimosis, or craniofacial syndromes, surgical treatment may require several-stage procedures. On the other hand, isolated congenital ptosis is usually treated in childhood (3-6 years) in a single stage. Congenital eyelid retractions may affect either the lower or the upper eyelid. They make up a rare condition and most cases are associated with craniofacial syndromes such as Crouzon or Apert syndromes. Upper eyelid retractions may spontaneously improve in some cases, but lower eyelid retractions do not. Treatment requires surgery, depending on the corneal consequences.     

Optic disc pit: primary diagnosis in a child

Congenital abnormalities of the optic nerve head are commonly detected by optometrists in practice. While some severe abnormalities can lead to poor visual acuity and are associated with other ocular and systemic disorders, others such as pits of the optic disc are predominantly benign with a latent risk of visual loss. This report details the primary diagnosis of unilateral optic disc pit in a seven‐year‐old patient.     

Persistent hyperplastic primary vitreous: congenital malformation of the eye

Persistent hyperplastic primary vitreous (PHPV), also known as persistent fetal vasculature, is a rare congenital developmental malformation of the eye, caused by the failure of regression of the primary vitreous. It is divided into anterior and posterior types and is characterized by the presence of a vascular membrane located behind the lens. The condition can be of an isolated type or can occur with other ocular disorders. Most cases of PHPV are sporadic, but it can be inherited as an autosomal dominant or recessive trait. Inherited PHPV also occurs in several breeds of dogs and cats. In a limited number of cases, Norrie disease and FZD4 genes are found to be mutated in unilateral and bilateral PHPV. These genes when mutated also cause Norrie disease pseudoglioma and familial exudative vitreoretinopathy that share some of the clinical features with PHPV. Mice lacking arf and p53 tumour suppressor genes as well as Norrie disease pseudoglioma and LRP5 genes suggest that these genes are needed for hyaloid vascular regression. These experiments also indicate that abnormalities in normal apoptosis and defects in Wnt signalling pathway may be responsible for the pathogenesis of PHPV. Identification of other candidate genes in the future may provide a better understanding of the pathogenesis of the condition that may lead to a better therapeutic approach and better management.     

Clinical features of congenital absence of the superior oblique muscle as demonstrated by orbital imaging.

INTRODUCTION: Absence of an extraocular muscle was considered rare when demonstrable only by surgical exploration or necropsy. This study presents advances in orbital imaging to correlate clinical findings with absence of the superior oblique (SO) muscle. METHODS: We performed high-resolution coronal orbital imaging by magnetic resonance imaging (222 orbits) or computerized radiographic tomography (32 orbits) in 127 patients with strabismus. We reviewed the histories and ocular motility examinations in patients who had absence of 1 or both SO muscles. Findings were compared with patients who were clinically diagnosed with SO palsy but had demonstrable SO muscles on orbital imaging. RESULTS: SO muscles were absent in 6 patients. All had histories suggesting congenital strabismus. In patients old enough for quantitative testing who had unilateral SO muscle absence, visual acuity was a least 20/25 in all and stereopsis was better than 80 arc/s in one. Three patients were orthotropic in primary position. Five patients with unilateral SO muscle absence had clinical findings variably consistent with SO palsy, whereas a sixth patient with Duane syndrome had clinically unsuspected bilateral SO muscle absence. Versions and patterns of hypertropia in patients with SO muscle absence overlapped findings of 20 patients with SO palsy but demonstrable SO muscles. CONCLUSIONS: Imaging can frequently demonstrate absence of the SO muscle in patients with SO palsy. Such patients may have good vision and stereopsis and clinical findings indistinguishable from SO palsy without absence of the SO muscle. Orbital imaging should be considered in the evaluation of congenital SO palsy to facilitate planning of effective surgical correction.     

Congenital ptosis and associated congenital malformations.

We report a case of unilateral congenital ptosis which is associated with ocular and systemic congenital malformations including mild microphthalmia, microcornea, cataract, iris and chorioretinal coloboma, ectopic kidney, and ventricular septal defect. An inciting factor, acting during the second month of gestation, may affect the development of the eye, heart, and abdomen and may lead to congenital malformations. Although congenital ptosis rarely presents with ocular and systemic congenital malformations, ophthalmologists should be alert for the possibility of coexisting structural defects. Congenital ptosis is a muscular dystrophy demonstrated by various degrees of muscular degeneration and it may rarely be associated with ocular and systemic congenital malformation. Here, we report a case of congenital ptosis associated with more than one ocular and systemic malformation.     

The molecular basis of the congenital fibrosis syndromes

The congenital fibrosis syndromes (CFS) are rare inherited strabismus syndromes that present as congenital, nonprogressive ophthalmoplegias with active and passive restriction of globe movement, and include classic and atypical forms of congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DS). Although historically believed to result from primary extraocular muscle fibrosis, both neuropathologic and genetic studies support the hypothesis that these disorders result from aberrant development of motor nuclei in the midbrain and pons.     

The molecular basis of the congenital fibrosis syndromes

The congenital fibrosis syndromes (CFS) are rare inherited strabismus syndromes that present as congenital, nonprogressive ophthalmoplegias with active and passive restriction of globe movement, and include classic and atypical forms of congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DS). Although historically believed to result from primary extraocular muscle fibrosis, both neuropathologic and genetic studies support the hypothesis that these disorders result from aberrant development of motor nuclei in the midbrain and pons.     

Congenital fibrosis syndrome associated with central nervous system abnormalities

Background Congenital fibrosis of extraocular muscles (CFEOM) is a complex strabismus syndrome that typically occurs in isolation and results from dysfunction of all or part of cranial nerves III (CNIII) and IV (CNIV) and/or the muscles that these nerves innervate. Only a few patients with CFEOM and additional central nervous system malformations have been reported. We describe four additional patients with CFEOM associated with central nervous system (CNS) abnormalities.Methods Four patients who presented with congenital restriction of eye movements in association with neurological abnormalities underwent complete ophthalmological examination including electroretinography (ERG) and eye movement recordings. Neurological examinations, neuroradiological studies, muscle histology, chromosomal and genetic linkage analysis were performed.Results Clinical examination and forced duction testing confirmed that all four patients met criteria for CFEOM; all had congenital restrictive ophthalmoplegia primarily affecting extraocular muscles innervated by the oculomotor nerve. Two brothers had CFEOM and Marcus Gunn jaw winking. In each of the four cases, CFEOM occurred in association with one or several neuroradiological findings, including agenesis of the corpus callosum, colpocephaly, hypoplasia of the cerebellar vermis, expansion of the ventricular system, pachygyria, encephalocele and/or hydrancephaly.Conclusions We present four cases of CFEOM in association with CNS malformations that confirm that CFEOM can be part of a more complex neurological dysfunction and provide further support to a neurogenic aetiology for this disorder. We also describe for the first time the coexistence of CFEOM and Marcus Gunn jaw winking in two siblings. This suggests a genetic mechanism. Aberrant innervation supports primary developmental abnormality of cranial nerves in CFEOM.