Concepts regarding certain forms of congenital eye movement disorders have recently changed, due ... more Concepts regarding certain forms of congenital eye movement disorders have recently changed, due in large part to new genetic evidence identifying causative genes and their role in the development of extraocular muscle innervation. This group is now referred to as the Congenital Cranial Dysinnervation Disorders (CCDDs). Careful assessment of phenotypic features that include both ophthalmological and non-ophthalmological features in genetically defined individuals has led to the development of a more robust classification system. Correlating phenotypes with new genetically defined syndromes has improved the ability of the clinician/researcher to better determine a definitive diagnosis in patients with complex ocular motility disorders. Nevertheless, more work is still required.
We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfit... more We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD). All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed. Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients. ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy.
Abstract Purpose:To review ocular motility disturbances in patients with orbitofacial neurofibrom... more Abstract Purpose:To review ocular motility disturbances in patients with orbitofacial neurofibromatosis type 1 (OFNF) who have neurofibromas on the lid, brow, or face during infancy or early childhood. OFNF is commonly associated with enlargement of the ipsilateral globe, sphenoid and orbital dysplasia, and neurofibromas involving the orbit and cavernous sinus, all of which can affect ocular motility. Methods:Retrospective medical record review and re-examination of selected patients from one institution. Results:Forty-nine patients met National Institutes of Health criteria for OFNF and had adequate clinical and neuroimaging information to assess ocular motility and factors affecting eye movements. Fourteen patients had no strabismus, all of whom had good vision with no ductional abnormalities on either side despite large globes, sphenoid dysplasia, and neurofibromas in the orbit and/or cavernous sinus in many. Eight patients with comitant strabismus also had no ductional abnormali...
The Canadian Journal of Neurological Sciences, 2014
We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfit... more We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD). All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed. Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients. ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy.
The Canadian Journal of Neurological Sciences, 2014
Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bi... more Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bilateral profound deafness. This study evaluates the possible role of HOXA1 mutations in familial, non-syndromic sensorineural deafness. Forty-eight unrelated Middle Eastern families with either consanguinity or familial deafness were identified in a large deafness clinic, and the proband from each family was evaluated by chart review, audiogram, neuroimaging, and HOXA1 sequencing. All 48 probands had normal neuro-ophthalmologic and general medical examinations except for refractive errors. All had congenital non-syndromic sensorineural hearing loss that was symmetric bilaterally and profound (>90 dBHL) in 33 individuals and varied from 40 to 90 dBHL in the remainder. Thirty-nine of these individuals had neuroimaging studies, all documenting normal internal carotid arteries and normal 6th, 7th, and 8th cranial nerves bilaterally. Of these, 27 had normal internal ear structures with the remaining 12 having mild to modest developmental abnormalities of the cochlea, semicircular canals, and/or vestibular aqueduct. No patient had homozygous HOXA1 mutations. None of these patients with non-syndromic deafness had HOXA1 mutations. None had major inner ear anomalies, obvious cerebrovascular defects, or recognized congenital heart disease. HOXA1 is likely not a common cause of non-syndromic deafness in this Middle Eastern population.
Purpose: Some individuals are born with congenital limitation of ocular motility, often associate... more 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 conta...
Duane retraction syndrome (DRS) is the most common of the congenital cranial dysinnervation disor... more Duane retraction syndrome (DRS) is the most common of the congenital cranial dysinnervation disorders (CCDDs). CCDDs can be monogenic or chromosomal in origin. Identification of the genetic cause(s) in patients and families with DRS facilitates definitive diagnosis and provides insights into these developmental errors. This study described a young girl with DRS on the left and several additional developmental abnormalities. Clinical examination including neuroimaging, sequencing of candidate genes associated with DRS, and array comparative genomic hybridization (array CGH) were performed. The proband had unilateral DRS type 3 on the left with somewhat low-set ears, mild motor delay with normal intelligence, and an asymmetric neck without a palpable right sternocleidomastoid muscle. Spine X-rays revealed a Klippel-Feil syndrome (KFS) and an MRI showed a webbed neck. She also had spina bifida at C8-T1 and a submucosal cleft palate. The parents of the proband were related with no other...
To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with pa... more To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with particular attention to ophthalmologic features. Ophthalmologic and neuro-ophthalmologic examination; neuroimaging; conventional karyotyping; and array comparative genomic hybridization (CGH). The proband was the only affected child of a non-consanguineous family. At birth she was noted to have facial dysmorphism including telecanthus, low set ears, prominent nares, and an everted lower lip. She had an accommodative esotropia with otherwise normal globes, optic nerves, retinae, and orbits. She also had delayed motor milestones and mild mental retardation associated with agenesis of the corpus callosum. Both karyotyping and array CGH documented mosaic partial trisomy of chromosome 8 that included all of the "q" arm and part of the proximal "p" arm. This girl had a number of the classic features of mosaic trisomy 8, including an accommodative esotropia with none of the other ocular and orbital anomalies described in patients with mosaic trisomy 8. This report constitutes an initial effort to create a virtual database of patients with mosaic chromosome 8 in which careful phenotype-genotype correlation employing high resolution array CGH may help identify clues regarding the genetic etiology of ophthalmologic features of this syndrome.
To evaluate possible monogenic and chromosomal anomalies in a patient with bilateral Duane retrac... more 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. Sequencing HOXA1 and performing high resolution array comparative genomic hybridization (arrayCGH). 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. 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.
Abstract Background: To evaluate possible monogenic and chromosomal anomalies in a patient with u... more Abstract 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.
Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome ... more Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome (DRS), the Klippel-Feil anomaly, and congenital deafness. It is much more common in females than males and could be due to an X-linked mutation that is lethal to hemizygous males. We present the genetic evaluation of a male with WS and his family. Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization. The patient had bilateral type 1 DRS, fusion of almost the entire cervical spine, and bilateral severe sensorineural hearing loss due to bilateral cochlear dysplasia; he also had congenital heart disease requiring surgery. His parents were unrelated, and he had eight unaffected siblings. The patient had no mutation found by Sanger sequencing of HOXA1, KIF21A, SALL4, and CHN1. He had a 3kB deletion in the X-chromosome at Xq26.3 that was not found in his mother, one unaffected sibling, or 56 healthy controls of matching ethnicity. This deletion encompassed only one gene, Fibroblast Growth Factor Homologous Factor 13 (FGF13), which encodes a 216-amino acid protein that acts intracellularly in neurons throughout brain development. Analysis of this patient's phenotype and genotype open the possibility that X-chromosome deletions may be a cause of WS with larger deletions being lethal to males and that FGF13 mutations may be a cause of WS.
Abstract Background: To evaluate possible monogenic and chromosomal anomalies in a patient with u... more Abstract 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.
In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substit... more In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substitute for the traditional concept of congenital fibrosis of the extraocular muscles (CFEOM) based on mounting genetic, neuropathologic, and imaging evidence, suggesting that many, if not all, of these disorders result from a primary neurologic maldevelopment rather than from a muscle abnormality. This report provides an update 8 years after that original report. Review of pertinent articles published from January 2003 until June 2010 describing CCDD variants identified under PubMed MeSH terms congenital fibrosis of the extraocular muscles, congenital cranial dysinnervation disorders, individual phenotypes included under the term CCDD, and congenital ocular motility disorders. At present, a total of 7 disease genes and 10 phenotypes fall under the CCDD umbrella. A number of additional loci and phenotypes still await gene elucidation, with the anticipation that more syndromes and genes will be identified in the future. Identification of genes and their function, along with advances in neuroimaging, have expanded our understanding of the mechanisms underlying several anomalous eye movement patterns. Current evidence still supports the concept that the CCDDs are primarily due to neurogenic disturbances of brainstem or cranial nerve development. Several CCDDs are now known to have nonophthalmologic associations involving neurologic, neuroanatomic, cerebrovascular, cardiovascular, and skeletal abnormalities.
We describe a patient who received cosmetic botulinum toxin type A injections to the brow and sub... more We describe a patient who received cosmetic botulinum toxin type A injections to the brow and subsequently developed unilateral ptosis that was variable during examination and was transiently improved after the ice pack test. Ptosis gradually resolved spontaneously over approximately 3 months. This is the third patient to have variable ptosis documented after botulinum toxin type A injection to the brow and the second to have a positive ice test. The ice test is not completely specific for myasthenia gravis but may, at times, improve ptosis resulting from other defects at the neuromuscular junction. Wound botulism now is much more common because of illicit drug use, and the ice test also might be positive in this setting.
We describe the clinical characteristics of 3 siblings from 1 family with congenital myasthenic s... more We describe the clinical characteristics of 3 siblings from 1 family with congenital myasthenic syndrome due to homozygous mutations of the gene coding for the epsilon subunit of the acetylcholine receptor (CHRNE). Onset of symptoms occurred in the first few months of life with ptosis, restricted ocular motility, mild proximal weakness, and difficulty swallowing. Multiple hospital admissions were required due to recurrent pulmonary infections. There was no decremental conduction on repetitive nerve stimulation, but jitter was increased on single fiber electromyographic. Since early childhood, our patients have done well without pulmonary or bulbar symptoms and with partial improvement on pyridostigmine therapy. Response of ptosis to diagnostic ice pack test was striking. Although these siblings have a clinical history and examination findings typical of homozygous CHRNE mutations, the clinical presentation of congenital myasthenia subtypes is variable, and accurate genotyping is essential in choosing the appropriate treatment.
Concepts regarding certain forms of congenital eye movement disorders have recently changed, due ... more Concepts regarding certain forms of congenital eye movement disorders have recently changed, due in large part to new genetic evidence identifying causative genes and their role in the development of extraocular muscle innervation. This group is now referred to as the Congenital Cranial Dysinnervation Disorders (CCDDs). Careful assessment of phenotypic features that include both ophthalmological and non-ophthalmological features in genetically defined individuals has led to the development of a more robust classification system. Correlating phenotypes with new genetically defined syndromes has improved the ability of the clinician/researcher to better determine a definitive diagnosis in patients with complex ocular motility disorders. Nevertheless, more work is still required.
We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfit... more We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD). All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed. Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients. ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy.
Abstract Purpose:To review ocular motility disturbances in patients with orbitofacial neurofibrom... more Abstract Purpose:To review ocular motility disturbances in patients with orbitofacial neurofibromatosis type 1 (OFNF) who have neurofibromas on the lid, brow, or face during infancy or early childhood. OFNF is commonly associated with enlargement of the ipsilateral globe, sphenoid and orbital dysplasia, and neurofibromas involving the orbit and cavernous sinus, all of which can affect ocular motility. Methods:Retrospective medical record review and re-examination of selected patients from one institution. Results:Forty-nine patients met National Institutes of Health criteria for OFNF and had adequate clinical and neuroimaging information to assess ocular motility and factors affecting eye movements. Fourteen patients had no strabismus, all of whom had good vision with no ductional abnormalities on either side despite large globes, sphenoid dysplasia, and neurofibromas in the orbit and/or cavernous sinus in many. Eight patients with comitant strabismus also had no ductional abnormali...
The Canadian Journal of Neurological Sciences, 2014
We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfit... more We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD). All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed. Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients. ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy.
The Canadian Journal of Neurological Sciences, 2014
Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bi... more Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bilateral profound deafness. This study evaluates the possible role of HOXA1 mutations in familial, non-syndromic sensorineural deafness. Forty-eight unrelated Middle Eastern families with either consanguinity or familial deafness were identified in a large deafness clinic, and the proband from each family was evaluated by chart review, audiogram, neuroimaging, and HOXA1 sequencing. All 48 probands had normal neuro-ophthalmologic and general medical examinations except for refractive errors. All had congenital non-syndromic sensorineural hearing loss that was symmetric bilaterally and profound (>90 dBHL) in 33 individuals and varied from 40 to 90 dBHL in the remainder. Thirty-nine of these individuals had neuroimaging studies, all documenting normal internal carotid arteries and normal 6th, 7th, and 8th cranial nerves bilaterally. Of these, 27 had normal internal ear structures with the remaining 12 having mild to modest developmental abnormalities of the cochlea, semicircular canals, and/or vestibular aqueduct. No patient had homozygous HOXA1 mutations. None of these patients with non-syndromic deafness had HOXA1 mutations. None had major inner ear anomalies, obvious cerebrovascular defects, or recognized congenital heart disease. HOXA1 is likely not a common cause of non-syndromic deafness in this Middle Eastern population.
Purpose: Some individuals are born with congenital limitation of ocular motility, often associate... more 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 conta...
Duane retraction syndrome (DRS) is the most common of the congenital cranial dysinnervation disor... more Duane retraction syndrome (DRS) is the most common of the congenital cranial dysinnervation disorders (CCDDs). CCDDs can be monogenic or chromosomal in origin. Identification of the genetic cause(s) in patients and families with DRS facilitates definitive diagnosis and provides insights into these developmental errors. This study described a young girl with DRS on the left and several additional developmental abnormalities. Clinical examination including neuroimaging, sequencing of candidate genes associated with DRS, and array comparative genomic hybridization (array CGH) were performed. The proband had unilateral DRS type 3 on the left with somewhat low-set ears, mild motor delay with normal intelligence, and an asymmetric neck without a palpable right sternocleidomastoid muscle. Spine X-rays revealed a Klippel-Feil syndrome (KFS) and an MRI showed a webbed neck. She also had spina bifida at C8-T1 and a submucosal cleft palate. The parents of the proband were related with no other...
To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with pa... more To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with particular attention to ophthalmologic features. Ophthalmologic and neuro-ophthalmologic examination; neuroimaging; conventional karyotyping; and array comparative genomic hybridization (CGH). The proband was the only affected child of a non-consanguineous family. At birth she was noted to have facial dysmorphism including telecanthus, low set ears, prominent nares, and an everted lower lip. She had an accommodative esotropia with otherwise normal globes, optic nerves, retinae, and orbits. She also had delayed motor milestones and mild mental retardation associated with agenesis of the corpus callosum. Both karyotyping and array CGH documented mosaic partial trisomy of chromosome 8 that included all of the "q" arm and part of the proximal "p" arm. This girl had a number of the classic features of mosaic trisomy 8, including an accommodative esotropia with none of the other ocular and orbital anomalies described in patients with mosaic trisomy 8. This report constitutes an initial effort to create a virtual database of patients with mosaic chromosome 8 in which careful phenotype-genotype correlation employing high resolution array CGH may help identify clues regarding the genetic etiology of ophthalmologic features of this syndrome.
To evaluate possible monogenic and chromosomal anomalies in a patient with bilateral Duane retrac... more 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. Sequencing HOXA1 and performing high resolution array comparative genomic hybridization (arrayCGH). 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. 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.
Abstract Background: To evaluate possible monogenic and chromosomal anomalies in a patient with u... more Abstract 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.
Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome ... more Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome (DRS), the Klippel-Feil anomaly, and congenital deafness. It is much more common in females than males and could be due to an X-linked mutation that is lethal to hemizygous males. We present the genetic evaluation of a male with WS and his family. Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization. The patient had bilateral type 1 DRS, fusion of almost the entire cervical spine, and bilateral severe sensorineural hearing loss due to bilateral cochlear dysplasia; he also had congenital heart disease requiring surgery. His parents were unrelated, and he had eight unaffected siblings. The patient had no mutation found by Sanger sequencing of HOXA1, KIF21A, SALL4, and CHN1. He had a 3kB deletion in the X-chromosome at Xq26.3 that was not found in his mother, one unaffected sibling, or 56 healthy controls of matching ethnicity. This deletion encompassed only one gene, Fibroblast Growth Factor Homologous Factor 13 (FGF13), which encodes a 216-amino acid protein that acts intracellularly in neurons throughout brain development. Analysis of this patient's phenotype and genotype open the possibility that X-chromosome deletions may be a cause of WS with larger deletions being lethal to males and that FGF13 mutations may be a cause of WS.
Abstract Background: To evaluate possible monogenic and chromosomal anomalies in a patient with u... more Abstract 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.
In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substit... more In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substitute for the traditional concept of congenital fibrosis of the extraocular muscles (CFEOM) based on mounting genetic, neuropathologic, and imaging evidence, suggesting that many, if not all, of these disorders result from a primary neurologic maldevelopment rather than from a muscle abnormality. This report provides an update 8 years after that original report. Review of pertinent articles published from January 2003 until June 2010 describing CCDD variants identified under PubMed MeSH terms congenital fibrosis of the extraocular muscles, congenital cranial dysinnervation disorders, individual phenotypes included under the term CCDD, and congenital ocular motility disorders. At present, a total of 7 disease genes and 10 phenotypes fall under the CCDD umbrella. A number of additional loci and phenotypes still await gene elucidation, with the anticipation that more syndromes and genes will be identified in the future. Identification of genes and their function, along with advances in neuroimaging, have expanded our understanding of the mechanisms underlying several anomalous eye movement patterns. Current evidence still supports the concept that the CCDDs are primarily due to neurogenic disturbances of brainstem or cranial nerve development. Several CCDDs are now known to have nonophthalmologic associations involving neurologic, neuroanatomic, cerebrovascular, cardiovascular, and skeletal abnormalities.
We describe a patient who received cosmetic botulinum toxin type A injections to the brow and sub... more We describe a patient who received cosmetic botulinum toxin type A injections to the brow and subsequently developed unilateral ptosis that was variable during examination and was transiently improved after the ice pack test. Ptosis gradually resolved spontaneously over approximately 3 months. This is the third patient to have variable ptosis documented after botulinum toxin type A injection to the brow and the second to have a positive ice test. The ice test is not completely specific for myasthenia gravis but may, at times, improve ptosis resulting from other defects at the neuromuscular junction. Wound botulism now is much more common because of illicit drug use, and the ice test also might be positive in this setting.
We describe the clinical characteristics of 3 siblings from 1 family with congenital myasthenic s... more We describe the clinical characteristics of 3 siblings from 1 family with congenital myasthenic syndrome due to homozygous mutations of the gene coding for the epsilon subunit of the acetylcholine receptor (CHRNE). Onset of symptoms occurred in the first few months of life with ptosis, restricted ocular motility, mild proximal weakness, and difficulty swallowing. Multiple hospital admissions were required due to recurrent pulmonary infections. There was no decremental conduction on repetitive nerve stimulation, but jitter was increased on single fiber electromyographic. Since early childhood, our patients have done well without pulmonary or bulbar symptoms and with partial improvement on pyridostigmine therapy. Response of ptosis to diagnostic ice pack test was striking. Although these siblings have a clinical history and examination findings typical of homozygous CHRNE mutations, the clinical presentation of congenital myasthenia subtypes is variable, and accurate genotyping is essential in choosing the appropriate treatment.
Uploads
Papers