Congenital Mydriasis Research Articles

BILATERAL CONGENITAL MYDRIASIS WITH ACCOMPANYING MIXED DEVELOPMENTAL DELAY

Introduction: Congenital bilateral mydriasis is a rare condition characterized by fixed dilated pupils unresponsive to light. It may occur associated with cardiovascular syndrome, gastrointestinal malformation, or developmental delay. Referred causes in comprehensive differential diagnosis for congenital mydriasis include alterations in ocular structures, ocular innervation alterations and others secondary to trauma, infection, or topical medication. Case Illustration: A 10 months-old boy presented to the hospital with large pupils in both eyes since birth. He has a persistent pupillary membrane with 9 mm diameter of pupil and unable to respond to light in both eyes. The pupillary response test using pilocarpine solution 0.1% showed no difference in diameter of pupils. Comprehensive pediatric examination revealed developmental delay. Computed tomography and laboratory result (laboratory blood count, toxoplasmosis, and cytomegalovirus) within normal limit. After eight months follow up, no significant change in pupil size or light responsiveness was found. Discussion: Comprehensive examination of anterior to posterior segments of the eyes is imperative on the lookout for underdiagnosed diseases. Clinical assessment remains vital for guiding investigations. Observation is required to detect the presence of certain systemic abnormalities that frequently do not manifest at birth. Conclusion: Congenital mydriasis can be diagnosed quickly in ordinary conditions, but it can be quite challenging when it presents as a coincidental finding of other spectrum diseases. It is important to perform a comprehensive general and eye examination to rule out any serious condition related to it. Keyword: Bilateral congenital mydriasis, dilated pupil, mixed developmental delay, pediatric ophthalmology

Abstract WP223: Cerebral Visual Impairment in ACTA2 Patients Assessed by Virtual Reality Testing

Introduction: Heterozygous missense mutations disrupting arginine 179 (Arg179) in the ACTA2 gene which codes for the smooth muscle-specific isoform of α-actin, cause Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS). The clinical manifestations of this genetic condition include congenital mydriasis, patent ductus arteriosus, stroke, and/or aortic aneurysms or dissections among many others. White matter injury, impaired autoregulation, and neurovascular coupling (due to the cerebral vasculopathy affecting cerebral perfusion) are known factors that alter neural network performance and processing speed. The lack of a standardized ophthalmologic examination that detects cerebral visual impairment (CVI), precludes an early diagnosis and creates missed opportunities for intervention. There is a paucity of data regarding CVI in MSMDS patients, and through this novel work, we present data defining their visual processing deficits. Hypothesis: We hypothesize that: 1) individuals with MSMDS will exhibit more pronounced deficits in visual-spatial processing compared to the control group, and 2) their performance will deteriorate as the complexity of visual tasks increases. Methods: Using a virtual reality (VR) based visual search task system, we characterized the impairment of higher-order visual processing in MSMDS patients (n = 4) as compared to healthy controls (n = 13). The VR-based task required searching for targets on a screen among varying levels of visual complexity. Reaction time, gaze error, shifted ellipse area, success rate, and pursuit saccade ratio were statistically analyzed with unpaired group t-tests, with significance being defined as p < 0.05. Results: Compared to controls, MSMDS patients took longer to identify the correct target, were less accurate in finding the target, and exhibited greater impairment in performance with an increasing number of distractors. Both groups showed similar task compliance, measured using an off-screen count metric. Conclusion: This novel work demonstrates that MSMDS patients exhibit impaired higher-order visual processing. This highlights the need for clinical tools that can assess these difficulties with quantitative methods to guide therapies and improve functional outcomes.

Case 319: Multisystemic Smooth Muscle Dysfunction Syndrome.

A 7-year-old Chinese girl presented to a local hospital with a 5-day history of progressive right-sided hemiplegia, expressive aphasia, mild bulbar palsy, and reduced general responsiveness. At presentation, her Glasgow Coma Scale was 11/15 (E4 V1M6). Notably, she had two strokelike episodes approximately 7 and 3 months prior to the current episode, with headache, reduced movement, and numbness in the left hand. She also had an extensive medical history at a young age, including congenital mydriasis, patent ductus arteriosus with ligation, dysautonomia, low blood pressure, hypotonic bladder requiring intermittent catheterization, poor bowel transit, and gallstones. Her immunization record was up to date, and her development was otherwise unremarkable. Her parents and younger sibling were healthy. Her blood tests revealed a mildly increased venous lactate level at 2.3 mmol/L (normal range, 0.7-2.1 mmol/L), without acidosis. Results of a coagulopathy work-up (clotting profile and protein C, protein S, antithrombin 3, and fibrinogen levels) were normal. MRI and MR angiography of the brain were performed at presentation.

Case 319.

A 7-year-old Chinese girl presented to a local hospital with a 5-day history of progressive right-sided hemiplegia, expressive aphasia, mild bulbar palsy, and reduced general responsiveness. At presentation, her Glasgow Coma Scale was 11/15 (E4 V1M6). Notably, she had two strokelike episodes approximately 7 and 3 months prior to the current episode, with headache, reduced movement, and numbness in the left hand. She also had an extensive medical history at a young age, including congenital mydriasis, patent ductus arteriosus with ligation, dysautonomia, low blood pressure, hypotonic bladder requiring intermittent catheterization, poor bowel transit, and gallstones. Her immunization record was up to date, and her development was otherwise unremarkable. Her parents and younger sibling were healthy. Her blood tests revealed a mildly increased venous lactate level at 2.3 mmol/L (normal range, 0.7-2.1 mmol/L), without acidosis. Results of a coagulopathy work-up (clotting profile and protein C, protein S, antithrombin 3, and fibrinogen levels) were normal. MRI (Fig 1) and MR angiography of the brain (Fig 2) were performed at presentation.

Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome.

Pathogenic variants in ACTA2, encoding smooth muscle α-actin, predispose to thoracic aortic aneurysms and dissections. ACTA2 variants altering arginine 179 predispose to a more severe, multisystemic disease termed smooth muscle dysfunction syndrome (SMDS; OMIM 613834). Vascular complications of SMDS include patent ductus arteriosus (PDA) or aortopulmonary window, early-onset thoracic aortic disease (TAD), moyamoya-like cerebrovascular disease, and primary pulmonary hypertension. Patients also have dysfunction of other smooth muscle-dependent systems, including congenital mydriasis, hypotonic bladder, and gut hypoperistalsis. Here,wedescribe five patients with novel heterozygous ACTA2 missense variants,p.Arg179Gly, p.Met46Arg, p.Thr204Ile, p.Arg39Cys, and p.Ile66Asn, who have clinical complications that align or overlap with SMDS. Patients with the ACTA2 p.Arg179Gly and p.Thr204Ile variants display classic features of SMDS. The patient with the ACTA2 p.Met46Arg variant exhibits exclusively vascular complications of SMDS, including early-onset TAD, PDA, and moyamoya-like cerebrovascular disease. Thepatient with the ACTA2 p.Ile66Asn variant has an unusual vascular complication, alarge fusiform internal carotid artery aneurysm. The patient with the ACTA2 p.Arg39Cys variant has pulmonary, gastrointestinal, and genitourinary complications of SMDSbut no vascular manifestations. Identifying pathogenic ACTA2 variants associated with features of SMDS is critical for aggressive surveillance and management of vascular and nonvascular complications and delineating the molecular pathogenesis of SMDS.

Triple bypass for multisystem smooth muscle dysfunction syndrome due to Arg179His ACTA2 mutation

Missense mutations in the smooth muscle-specific isoform of the alpha-actin (ACTA2) gene, which encodes smooth muscle actin, congenitally cause systemic smooth muscle dysfunction, leading to multiple systemic smooth muscle dysfunction syndrome. This disease is often diagnosed through the development of congenital mydriasis, patent ductus arteriosus, or thoracic aortic aneurysm at a young age. Some patients develop cerebrovascular lesions, also known as ACTA2 cerebral arteriopathy, which cause ischemic stroke and require surgical revascularization. However, an effective and safe treatment has not yet been established owing to the rarity of the disease. Furthermore, most reports of this disease involve children, with only a few reports on adults and few detailed reports on treatment outcomes published to date. We report a 46-year-old woman with ACTA2 cerebral arteriopathy caused by Arg179His, the most common mutation in this disease; she is the oldest patient reported with this disease to the best of our knowledge. The patient was diagnosed with multiple systemic smooth muscle dysfunction syndrome and ACTA2 cerebral arteriopathy after experiencing a stroke in the right cingulate gyrus. She underwent direct triple bypass with three anastomoses of the right superficial temporal artery to the middle and anterior cerebral arteries. She developed an ischemic stroke as a postoperative complication.The efficacy and safety of this procedure have not been clearly confirmed owing to the frailty of the donor superficial temporal artery and the poor development of collateral circulation; however, direct bypass should be considered a treatment option for patients experiencing progressive multiple strokes.

Adie's Pupil: A Diagnostic Challenge for the Physician.

Adie’s pupil, also called tonic pupil, is mainly seen in young women. Most patients have unilateral eye involvement. The pupil of the affected side is significantly larger than that on the healthy side. The direct and indirect light reflection from the pupil on the affected side disappears. The pupil on the affected side is sensitive to low concentrations of pilocarpine. The pathogeneses of Adie’s pupil are complex, some of which are insidious and lack corresponding specific diseases. Through a literature review, we found that Adie’s pupil is mainly associated with infectious diseases, most commonly syphilis, followed by immune diseases and paraneoplastic syndromes. The ophthalmological symptoms and pupil abnormalities can disappear after active treatment of the primary disease. Pilocarpine can be used to treat ophthalmologic symptoms, such as blurred vision, for which patients might visit an ophthalmologist or neurologist. It is essential for clinicians to improve their understanding of the disease to avoid misdiagnosis. Differential diagnosis between Adie’s pupil, oculomotor nerve palsy, anticholinergic drug overdose, Argyll-Robertson pupil, and congenital mydriasis need to be identified by the physician. Here, the clinical manifestations, pathogenesis, relationship between Adie’s pupil and diseases, and differential diagnosis of Adie’s pupil are reviewed.

Bilateral Congenital Mydriasis in A Patient with Family History of Dilated Pupils

Bilateral Congenital Mydriasis in A Patient with Family History of Dilated Pupils

High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: a case report

BackgroundCongenital mydriasis and retinal arteriolar tortuosity are associated with the life-threatening multisystemic smooth muscle dysfunction syndrome (MSMDS) due to mutations in the gene, ACTA2, which encodes alpha-smooth muscle actin (α-SMA). Previous reports attributed MSMDS-related congenital mydriasis to the absence of iris sphincter muscle. Similarly, it has been hypothesized that abnormal proliferation of the vascular smooth muscle cells causes the marked tortuosity of retinal arterioles in MSMDS. In this report, high-resolution ocular imaging reveals unexpected findings that reject previous hypotheses.Case presentationThe proband is a 37-year-old female with a history of neonatal patent ductus arteriosus (PDA) ligation, left-sided choreiform movements at the age of 11 and a transient aphasia with right-sided weakness at the age of 30. Her older sister also had PDA ligation and congenital mydriasis but no neurological deficit up to age 41. Magnetic resonance angiogram demonstrated cerebrovascular lesions resembling but distinct from Moyamoya disease, characterised by internal carotid artery dilatation, terminal segment stenosis and absent basal collaterals. Their mother had poorly reactive pupils with asymptomatic cerebral arteriopathy resembling her daughters. All three had prominent retinal arteriolar tortuosity. The daughters were heterozygous and the mother was a somatic mosaic for a novel c.351C > G (p.Asn117Lys) transversion in ACTA2. Iris optical coherence tomography (OCT) showed a hyporeflective band anterior to the pigment epithelium indicating the presence of dysfunctional sphincter muscle. Adaptive optics retinal imaging showed no thickening of the arteriolar vessel wall whilst OCT angiography showed extreme corkscrew course of arterioles suggesting vessel elongation.ConclusionsIn addition to the known association between Met46, Arg179 and Arg258 substitutions and ACTA2-related arteriopathy, this case illustrates the possibility that Asn117 also plays an important role in α-SMA function within the cerebrovascular smooth muscle cell. MSMDS-related congenital mydriasis is due to reduced iris sphincter contractility rather than its absence. Retinal arteriolar tortuosity might be due to longitudinal proliferation of arteriolar smooth muscle cells. The described cerebrovascular and ocular signs are consistent with predicted effects of the novel Asn117Lys substitution in ACTA2.

Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations

PurposeSmooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle–dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. MethodsMedical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. ResultsAll patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. ConclusionBased on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

Two patients with the heterozygous R189H mutation in ACTA2 and Complex congenital heart defects expands the cardiac phenotype of multisystemic smooth muscle dysfunction syndrome.

De novo heterozygous mutations changing R179 to histidine, leucine, or cysteine in the ACTA2 gene are associated with Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS). Characteristic hallmarks of this condition, caused only by these specific ACTA2 mutations, are congenital mydriasis (mid-dilated, non-reactive pupils), a large persistent ductus arteriosus (PDA), aortic aneurysms evolving during childhood, and cerebrovascular anomalies. We describe two patients, a 3-day-old newborn and a 26-year-old woman, with this unique mutation in association with a huge PDA and an aorto-pulmonary window. In addition, one showed a coarctation of the aortic arch and the other a complete interruption of the aortic arch type A; thereby expanding the spectrum of cardiac congenital heart defect of this syndrome. Each patient displayed a huge PDA and an extra-cardiovascular phenotype consistent with MSMDS. These observations exemplify that a functional alpha 2 smooth muscle actin is necessary for proper cardiovascular organ development, and demonstrate that a very exceptional congenital heart defect (aortopulmonary window) can be caused by a mutation in a gene encoding a contractile protein of vascular smooth muscle cells. © 2017 Wiley Periodicals, Inc.

Congenital Fixed Dilated Pupils Due to ACTA2– Multisystemic Smooth Muscle Dysfunction Syndrome

Congenital fixed dilated pupils (congenital mydriasis) is characterized by hypoplasia or aplasia of the iris muscles, with absence of iris between the collarette and pupillary border, creating a scalloped pupillary margin. This condition has been reported in a multisystemic smooth muscle cell dysfunction syndrome, combined with congenital patent ductus arteriosus, cerebrovascular disease (Moya-moya-like), coronary artery disease, thoracic aorta aneurysm, and dysfunction of smooth muscle cells in organs throughout the body. All affected individuals carry a p.R179H heterozygous mutation in the ACTA2 gene. We add to the ophthalmologic involvement with 3 more patients. Congenital fixed dilated pupils is a rare condition and should alert ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders.

Congenital mydriasis as an initial sign of septo-optic dysplasia

Septo-optic dysplasia (SOD) [MIM182230] consisting of a heterogeneous and uncommon condition characterized by the classic triad: optic nerve hypoplasia, abnormalities of pituitary hormone, and defects of the brain midline (including agenesis of the septum pellucidum and/or the corpus callosum; it has also been described associated cortical malformations, it was referred to as SOD plus syndrome).We report the first known case in which the initial diagnostic sign of SOD was a bilateral mydriasis as a manifestation of hypoplasia of both optic nerves, pituitary hypoplasia and cerebral dysgenesis with neuronal migration disorder. We discuss the differential diagnosis of congenital mydriasis.

Congenital Mydriasis Associated With Megacystis Microcolon Intestinal Hypoperistalsis Syndrome

We report a case of congenital mydriasis in a neonate with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS). Pilocarpine testing and gastrointestinal pathology in our patient suggest that the mydriasis is due to an underlying smooth muscle myopathy of the iris sphincter muscle. These findings may have important implications regarding the pathogenesis of MMIHS.

Midriasis congénita como signo inicial de displasia septo-óptica

Septo-optic dysplasia (SOD)[MIM182230] consisting of a heterogeneous and uncommon condition characterised by the classictriad: optic nerve hypoplasia, abnormalities of pituitary hormone, and defects of thebrain midline (including agenesis of the septum pellucidum and/or the corpus callosum; ithas also been described associated cortical malformations, it was referred to as SOD plus syndrome).We report the first known case in which the initial diagnostic sign of SOD was a bilateralmydriasis as a manifestation ofhypoplasia of both optic nerves, pituitary hypoplasia andcerebral dysgenesis with neuronal migration disorder.We discuss thedifferential diagnosis of congenital mydriasis.

A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus and congenital mydriasis, and variable presentation of pulmonary hypertension, bladder and gastrointestinal problems associated with this mutation. Distinctive cerebrovascular features were dilatation of proximal internal carotid artery, occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries, and absent basal 'moyamoya' collaterals. Patterns of brain injury supported both large and small vessel disease. Key differences from moyamoya disease were more widespread arteriopathy, the combination of arterial ectasia and stenosis and, importantly, absence of the typical basal 'moyamoya' collaterals. Evaluation of previously published cases suggests some of these features are also seen in the ACTA2 mutations disrupting Arg258. The observation that transition from dilated to normal/stenotic arterial calibre coincides with where the internal carotid artery changes from an elastic to muscular artery supports the hypothesis that abnormal smooth muscle cell proliferation caused by ACTA2 mutations is modulated by arterial wall components. Patients with persistent ductus arteriosus or congenital mydriasis with a label of 'moyamoya' should be re-evaluated to ensure the distinctive neuroimaging features of an ACTA2 mutation have not been overlooked. This diagnosis has prognostic and genetic implications, and mandates surveillance of other organ systems, in particular the aorta, to prevent life-threatening aortic dissection.

Akomodasyon Kaybıyla Seyreden Konjenital Midriyazis

A 14-year-old patient presented to our hospital with dilated pupils and decreased near vision. Complete ocular examination was done and pupil responses to pharmacological agents were evaluated. The patient had bilateral congenital mydriasis. The pupils were mydriatic. At pupil margins there were pigmented rudimentary nipple-like structures and remnants of persistent pupillary membrane. Pupils did not respond to pharmaceutics. The patient was not able to accommodate. Ultrasound biomicroscopy demonstrated hypoplasia of ciliary processes. Congenital mydriasis may be associated with absence of accommodation. Patients with that condition may need near vision correction first.

Congenital mydriasis combined with aneurysmal dilatation of a persistent ductus arteriosus Botalli: a rare syndrome

Abstract. A child with congenital mydriasis and aneurismal dilatation of persistent ductus arteriosus is described. We discuss congenital mydriasis as a separate entity and in combination with heart diseases.

Congenital mydriasis: spontaneous resolution in one of two cases

Congenital mydriasis, the appearance of fixed and dilated pupils at birth without other ocular or systemic involvement, is extremely rare. The condition has been explained as a result of diminished muscle function, decreased cholinergic sensitivity or production, and iris sphincter aplasia.1–5 We report 2 cases. The first case was associated with iris sphincter aplasia. Although the sphincter was hypoplastic in the second case, we observed the unique occurrence of spontaneous reversal of pupillary function.

Gillespie syndrome reported as bilateral congenital mydriasis.

Gillespie syndrome reported as bilateral congenital mydriasis.