Duane眼球后退综合征的诊治要点

Duane眼球后退综合征（Duane retraction syndrome,DRS）的共同临床特征为眼球水平运动障碍,内转时睑裂缩小、伴眼球后退,外转时睑裂开大,部分患者眼球内转时伴有急速的上射或下射;其可分为Ⅰ、 Ⅱ、 Ⅲ型。DRS的发病机制既往认为是解剖结构异常所致,但目前多认为神经肌肉支配异常是其根本原因。因DRS患者临床表现各异,需对其特征性表现仔细观察方可做出正确诊断。同时,在治疗上,也需遵循一定的原则针对每例患者的特点设计出个性化的治疗方案。     

Partial Duplication of Chromosome 19 Associated with Syndromic Duane Retraction Syndrome

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

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

Results: The proband had unilateral Duane retraction syndrome (DRS) type III on the right with low-set ears, prominent forehead, clinodactyly, and a history of frequent infections during early childhood. Motor development and cognitive function were normal. Parents were not related, and no other family member was similarly affected. MRI revealed multiple small areas of high signal on T2 weighted images in cerebral white matter oriented along white matter tracts. Sequencing of HOXA1, KIF21A, SALL4, and CHN1 did not reveal any mutation(s). Array CGH showed a 95?Kb de novo duplication on chromosome 19q13.4 encompassing four killer cell immunoglobulin-like receptor (KIR) genes.

Conclusions. KIR genes have not previously been linked to a developmental syndrome, although they are known to be expressed in the human brain and brainstem and to be associated with certain infections and autoimmune diseases, including some affecting the nervous system. DRS and brain neuroimaging abnormalities may imply a central and peripheral oligodendrocyte abnormality related in some fashion to an immunomodulatory disturbance.     

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

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

Methods: A retrospective case series (2002–2012).

Results: Eighteen patients (four families) were identified; all affected individuals had confirmed homozygous recessive PHOX2A mutations except one individual for whom genetic testing was not done because of multiple genetically confirmed family members. Age at assessment ranged from 5–62 years old (median 10 years old). All patients had decreased best-corrected visual acuity not completely explainable by amblyopia in both the preferred and non-preferred eye. In those patients who had further ancillary testing, visual fields (five patients) and electroretinography (10 patients) confirmed abnormalities not ascribable to amblyopia.

Conclusions: In addition to a distinct form of congenital incomitant strabismus, the phenotype of CFEOM2 includes subnormal vision consistent with retinal dysfunction. This could be the direct result of PHOX2A mutations or a secondary effect of orbital dysinnervation.     

Lower Eyelid Epiblepharon Associated with Lower Eyelid Retraction

Purpose

To describe a series of patients with lower eyelid epiblepharon associated with lower eyelid retraction.

Methods

We retrospectively reviewed the medical records of patients who underwent surgery for lower eyelid retraction, epiblepharon, or thyroid-associated ophthalmopathy (TAO) between October 1999 and March 2007. Patients with both lower eyelid retraction and epiblepharon on preoperative examination were included in this study.

Results

Twenty-seven eyelids of 20 patients with both lower eyelid retraction and epiblepharon were enrolled. The underlying causes of lower eyelid retraction included congenital retraction (seven eyelids), congenital fibrosis of the extraocular muscles (CFEOM; seven eyelids), TAO (seven eyelids), post-operative cicatricial retraction (five eyelids), and facial nerve palsy (one eyelid). Eight of 27 eyelids were successfully corrected after the repair of retraction without the repair of epiblepharon, regardless of the cause of lower eyelid retraction. Another four eyelids with epiblepharon associated with TAO resolved after only orbital decompression. Cilia-everting sutures were additionally applied for epiblepharon in another 14 eyelids, 12 of which did not require the excision of a skin fold or the orbicularis muscles. Only one eyelid with mild retraction and epiblepharon underwent simple epiblepharon repair. Recurrence of retraction or epiblepharon developed in three eyelids during follow-up.

Conclusions

In cases with both lower eyelid retraction and epiblepharon, the retraction should be repaired first, and then the epiblepharon can be corrected selectively according to the severity of the case.     

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

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

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

Results: The proband had bilateral Duane retraction syndrome (DRS) with severe hearing loss bilaterally and an absent right vertebral artery, mimicking the major features of the Bosley-Salih-Alorainy variant of the HOXA1 spectrum. However, he also had developmental delay, mild mental retardation, and seizures. His parents were not related, but his father had milder sensorineural hearing loss bilaterally, and two paternal uncles and a paternal cousin had seizures. Neuroimaging revealed moderate maldevelopment of inner ear bony anatomy bilaterally. HOXA1 sequencing was normal, but arrayCGH revealed a small partial duplication of chromosome 7 encompassing only the PTPRN2 gene (protein tyrosine phosphatase, receptor type, N polypeptide 2) that was not present in his parents, an unaffected brother, or 53 normal ethnically-matched individuals.

Conclusions: PTPRN2 is not yet linked to a genetic syndrome, although its expression has been identified in the adult human brain, in certain tumors, and in association with type 1 diabetes mellitus. The phenotype of this patient is strikingly similar to, but not identical to, that of the HOXA1 spectrum disorder. The findings in this patient raise the possibility that PTPRN2 may be active during early development of the human brainstem and that its overexpression may cause bilateral DRS with hearing loss as occurs in patients with homozygous HOXA1 mutations.     

Analysis of the SALL4 Gene in Patients with Duane Retraction Syndrome in a South Indian Population

Duane retraction syndrome (DRS) is a congenital eye movement disorder characterized most typically by partial or complete failure of abduction and narrowing of palpebral fissure with globe retraction on adduction. Recently mutations of the SALL4 gene on chromosome 20 have been linked to DRS associated with radial forearm malformations (Okihiro syndrome). In this prospective, non-interventional study we screened for SALL4 mutations in 72 patients clinically diagnosed as having isolated DRS or DRS associated syndromes. All four exonic and the neighboring intronic regions of SALL4 gene were amplified by sixteen sets of primers using polymerase chain reaction and were subjected to bi-directional sequencing and BLAST analysis. No genetic variations were detected in the coding region and in the neighboring intronic regions of the SALL4 gene suggesting an alternative mechanism in the pathogenesis of these disorders in the South Indian population.     

Wildervanck syndrome associated with cleft palate and short stature

We report a case of Wildervanck syndrome exhibiting Klippel-Feil anomaly, Duane retraction syndrome and deafness. Since the first case was reported in 1952, there have been more reports describing this triad, either complete or incomplete. Our patient had the complete triad of the syndrome along with cleft palate and short stature. Also, a review of the literature regarding this syndrome is presented here.     

内外直肌后徙联合Y形分开术治疗Duane眼球后退综合征

目的探讨内外直肌后徙联合Y形分开术治疗Duane眼球后退综合征的新型手术方法和效果。方法对8例Duane眼球后退综合征患者行手术治疗。7例正向型Duane眼球后退综合征患者中,6例行内外直肌后徙联合Y形分开术,1例行外直肌后徙联合Y形分开术;1例反向性Duane眼球后退综合征患者行双眼内外直肌后徙联合双眼内直肌Y形分开术。术后随访1～12个月,观察患者的眼位、眼球运动及代偿头位变化情况。结果患者代偿头位、急速上转或下转消失;眼球后退及睑裂变小得到改善;术后6例眼位为正位,2例仍有残余斜视。结论内外直肌后徙联合Y形分开术可有效地治疗Duane眼球后退综合征,达到矫正斜视、改正头位、消除眼球后退的目的。（中华眼科杂志．2007。43：972-976）     

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).     

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

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

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

Results: The proband had unilateral Duane retraction syndrome (DRS) with low-set ears bilaterally, a high arched palate, and clinodactyly. Motor development and cognitive function were normal. Parents were first cousins, but no other family member was similarly affected. No mutations were detected in the HOXA1. KIF21A. SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 16?Kb de novo deletion at chromosome 8p11.2 that encompassed a portion of only one gene, the Cholinergic Receptor, Nicotinic, Beta-3 (CHRNB3, Neuronal). This gene encodes a protein that is involved in the nicotinic acetylcholine receptor on neurons. It interacts functionally with other genes that code components of the acetylcholine receptor.

Conclusions: This patient’s chromosomal abnormality affected only one gene that is highly expressed in the brainstem and brain, involved in neurotransmission, and could be related to her Duane retraction syndrome.     

Duane retraction syndrome in a patient with Duchenne muscular dystrophy

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

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

Results: The proband had bilateral DRS with otherwise normal ocular motility; he also had developmental delay, mild mental retardation, and seizures. Clinical diagnosis of DMD included progressive proximal weakness, highly elevated creatine kinase levels, and a muscle biopsy showing significant dystrophic changes including contracted, degenerative, and regenerative fibers, and negative dystrophin immunostaining. MLPA documented duplication of exons 3 and 4 of the dystrophin gene.

Conclusions: This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.     

Small margin (2 mm) excision of peri-ocular basal cell carcinoma with delayed repair

Successful surgical treatment of peri-ocular basal cell carcinomas requires complete excision. Mohs' micrographic surgery achieves this, but is not readily available in all hospitals. The standard 3-4 mm margin does not guarantee complete excision and histology is often not available until after a repair has been undertaken. The 3-4 mm margin has evolved to deal with all forms of BCC. In our opinion, this margin is unnecessarily large for nodular/ulcerative BCC. We report our interim results of excision of localised BCCs using a 2 mm margin in conjunction with a delayed repair following confirmation of histological clearance. Thirty-one patients were treated in this manner; there have been no recurrences after an average follow-up period of 36 months (range 24-57 months).     

Vertical muscle transposition augmented with lateral fixation (Foster) suture for Duane syndrome and sixth nerve palsy

Purpose

To report the postoperative results of full-tendon vertical rectus transposition (VRT) augmented with lateral fixation suture for the treatment of type 1 Duane syndrome and sixth nerve palsy and to determine whether there was a decrease in the effect of the Foster suture over time.

Methods

This retrospective, consecutive case series included patients who underwent a full-tendon VRT transposition with lateral fixation for type 1 Duane syndrome or sixth nerve palsy. The primary outcome measures included deviation, abnormal head posture(AHP), abduction deficiency, and postoperative binocular single visual field (BSVF).

Results

Eighty-seven patients (87 eyes: 40 eyes with Duane syndrome and 47 eyes with sixth nerve palsy) were included in this study. In Duane syndrome patients, the deviation was reduced by a mean of 95%, the AHP was eliminated in 86% of patients, the abduction was improved by 42%, and a useful BSVF of ∼67% of normal was achieved at 1 year post operation. In sixth nerve palsy patients, the deviation was reduced by 99%, the abduction was improved by 59%, and a useful BSVF of ∼71% of normal was achieved at 1 year post operation. In both groups, the improvements in deviation angle and abduction were stable postoperatively. Sixteen patients needed reoperation for undercorrection.

Conclusion

VRT surgery with posterior fixation is an effective treatment method for complete sixth nerve palsy and Duane syndrome with esotropia, AHP, and abduction deficiency. The procedure carries a small risk of reoperation for undercorrection. The effect of the Foster suture did not decline over time.     

先天性脑神经异常支配眼病的分子遗传学与神经科学研究进展

先天性脑神经异常支配眼病(CCDDs)为一组先天性、非进行性一条或多条脑神经发育异常或缺失,从而导致的原发或继发脑神经异常支配眼外肌的斜视综合征,可散发或家族遗传,可伴有全身系统异常。近年来随着神经病理学、神经影像学、遗传学的研究进展,不仅明确了CCDDs的病因是神经源性的眼球运动障碍,也发现了CCDDs的致病基因,包括SALL4、HOXA1、KIF21A、PHOX2A、TUBB3及HOXB1等。针对基因突变影响大脑神经发育从而进一步导致先天性脑神经支配异常性病变发生这一问题,文章回顾了近年国内外相关文献,就已知的CCDDs的分子遗传学和神经科学研究进展作一综述,以期为CCDDs的临床和基础研究提供参考。     

Circulating retinoblastoma cells in a patient with metastatic disease

We report an unusual case of a two-year-old girl with metastatic retinoblastoma and massive bone marrow involvement who showed the overt presence of circulating retinoblastoma cells in peripheral blood smears a few days before death. This extended disease developed after an early relapse that followed abandoned primary chemotherapy. To the best of our knowledge, there are no previous reports about the presence of circulating retinoblastoma cells in peripheral blood films. We conclude that the search for bone marrow invasion in patients with disseminated retinoblastoma should be exhaustive to achieve an accurate staging assessment. Peripheral blood smears should be examined cautiously to detect occasional circulating retinoblastoma cells when the bone marrow is massively involved.     

Ocular abnormalities in a patient with congenital disorder of glycosylation type Ig

ABSTRACT

Background: Congenital disorders of glycosylation (CDG) are a group of hereditary multisystem disorders characterized by hypoglycosylation of glycoproteins. CDG type I results in a defect in the assembly of lipid-linkedoligosaccharides or their transfer onto nascent glycoproteins. Ocular abnormalities are common in CDG, but there is no report of detailed ophthalmologic evaluation in patients with CDG type Ig in the literature.

Materials and Methods: Retrospective chart review of a case of CDG type Ig with novel variant in the associated gene: ALG12.

Results: In addition to typical systemic findings of CDG, our case was found to have exotropia, bilateralcataracts, and retinitis pigmentosa with extinguished electroretinography in photopic and scotopic conditions.

Conclusions: We hope to extend the understanding of ALG12-related CDG type Ig with these ophthalmologic observations.     

A Novel NOD2-associated Mutation and Variant Blau Syndrome: Phenotype and Molecular Analysis

Purpose: To describe the clinical and molecular implications of a novel mutation in the NOD2/CARD15 gene on a family and its seven affected members.

Methods: We reviewed the clinical presentations of family members who came to our center for refractory uveitis. Genetic testing and molecular testing was performed.

Results: All affected members had adult onset recurrent non-granulomatous panuveitis. The inheritance pattern suggested an autosomal dominant disease and genetic analysis identified a novel mutation in the NOD2 gene that converted amino acid 600 from glutamate to alanine (E600A). Transfection of the E600A NOD2 into human embryonic kidney-293 (HEK293) cells revealed constitutive activation and a reduced ability to respond to the NOD2 ligand, muramyl dipeptide (MDP) as compared with wild-type NOD2.

Conclusions: The E600A mutation in the NOD2 gene may confer a higher penetrance of uveitis but a later onset of milder forms of non-ocular involvement.     

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.