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Show Congenital Fixed Dilated Pupils Due to ACTA22 Multisystemic Smooth Muscle Dysfunction Syndrome Françoise M. J. Roulez, MD, Fran Faes, MD, Patricia Delbeke, MD, Patrick Van Bogaert, MD, PhD, Georges Rodesch, MD, PhD, Julie De Zaeytijd, MD, Fanny Depasse, MD, Paul J. Coucke, PhD, Francoise M. Meire, MD, PhD Abstract: Congenital fixed dilated pupils (congenital mydri-asis) 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 congen-ital 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 pa-tients. Congenital fixed dilated pupils is a rare condition and should alert ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders. Journal of Neuro-Ophthalmology 2014;34:137-143 doi: 10.1097/WNO.0000000000000090 © 2014 by North American Neuro-Ophthalmology Society Congenital fixed dilated pupil, sometimes referred to as congenital mydriasis, or partial aniridia, is a rare oph-thalmic condition. Hypoplasia or aplasia of the iris sphincter and dilator muscles results in fixed dilated pupils from birth, with no reaction to light, convergence, pilocarpine, tropica-mide, or phenylephrine. The iris is described as hypotrophic, often with a persistent pupillary membrane. Although iris morphology is pathognomonic, it has sometimes been mis-diagnosed as aniridia. In 2010, Milewicz et al (1) reported a severe and highly penetrant phenotype with congenital fixed dilated pupils, cardiovascular and cerebrovascular abnormalities, and mul-tisystemic smooth muscle dysfunction, associated with the p.R179H mutations of the ACTA2 gene. We describe 3 unrelated young girls with congenital fixed dilated pupils observed since birth, associated with progressive neurological deterioration and smooth muscle cell (SMC) dysfunction. CASE REPORT Case 1 A 19-year-old girl, the fourth child of healthy nonconsan-guinous parents, had an unremarkable antenatal birth history. Congenital mydriasis, with absence of direct and consensual pupillary light reflexes, was observed in the first day of life, and agenesis of the left toes and syndactyly of 2 toes of the right foot. Patent ductus arteriosus was surgically repaired at 1 year of age. Initial development was normal, but the patient experienced left hemiparesis at 2 years of age. Cerebral angiography, performed at ages 2, 3.5, and 6 years, demonstrated stenosis of the supraclinoid segment of both internal carotid arteries, with a straightened course of the cerebral vessels (Fig. 1). Subsequently, the patient developed severe neurological and cognitive handi-caps, including dysarthria and tetraparesis. Magnetic reso-nance imaging (MRI) of the brain showed diffuse cortical and subcortical ischemic lesions (Fig. 2). As the patient became older, she developed aortic valvular dysfunction, pulmonary hypertension, and progressive vas-culopathy of the aorta. She also experienced multisystemic pathologies, including constipation, gallstones, recurrent urinary tract infections, hypotonic bladder, hypothyroidism, Department of Pediatric Ophthalmology (FMJR, FMM), HUDERF, ULB, Brussels, Belgium; Departments of Neuropediatrics (FF) and Ophthalmology (PD, JDZ), Ghent University, Belgium; Department of Neuropediatrics (PVB), Erasme, ULB, Brussels, Belgium; Depart-ment of Neuroradiology (GR), Foch Hospital, Paris, France; Depart-ment of Ophthalmology (FD), Erasme, ULB, Brussels, Belgium; Department of Medical Genetics (PJC), Ghent University, Ghent, Belgium; and Vista Alpina (FMJR), Sierre, Switzerland. The authors report no conflicts of interest. Address correspondence to Françoise M. Meire, MD, PhD HUDERF, ULB, avenue J.J. Crocq 15, 1020 Brussels, Belgium; E-mail: francoise. meire@telenet.be Roulez et al: J Neuro-Ophthalmol 2014; 34: 137-143 137 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. deep venous thrombosis, asthma, and acute dyspnea, with multiple episodes of bronchial pneumonia. Examination at 6 years of age revealed visual acuity of 20/50 in both eyes. Extraocular movements were full. The pupils measured 6 mm and was nonreactive to light, accommodation, 2% pilocarpine, 1% cyclopentolate, and 5% phenylephrine eye drops (Fig. 3). Ophthalmoscopy was normal. Visual function at 19 years of age was unchanged, but the fundus revealed peripheral retinal arteriolar stenosis (Fig. 4). Because of the iris features associated with SMC dysfunction, we obtained genetic mutation analysis of the ACTA2 gene, with identification of the c.5536G.A (p.R179H) heterozygous mutation. Case 2 A 14-year-old girl, the second child of nonconsanguinous parents, was born after an uneventful pregnancy. At 3 weeks of age, she underwent repair of a patent ductus arteriosus. She began to walk at an age of 15 months, but developmental delay prompted a neurologic evaluation. Her balance was unsteady, and there was mild impairment of both fine and coarse motor skills. At age 19 months, MRI showed multifocal parieto-occipital white matter lesions. At 5 years of age, the patient developed rapidly progressive loss of motor control, with dystonic gait, poor balance, and dysarthria. Brain MRI revealed numerous multiple periventricular white matter abnormalities (Fig. 5). Magnetic resonance angiogra-phy showed dilation of both proximal internal carotid arteries and stenosis of distal internal carotid arteries extending to anterior and middle cerebral arteries (Fig. 6). At 12 years of age, the patient underwent echocardiography, and an aneurysm of the ascending aorta was detected. The patient's mother had noted both pupils of her child had been dilated since 6 weeks of age. Ophthalmologic exam-ination at 6 years revealed blue irides, with hypotrophic stroma, without crypts, and no iris tissue central to the FIG. 1. Case 1: Anteroposterior view of subtracted cerebral angiogram shows filiform supraclinoid left internal carotid artery (long arrow), dilation of the proximal internal carotid artery (short arrow), cerebral arteries with areas of focal stenosis, and no moya-moya-type collaterals in the region of the basal ganglia. FIG. 2. Case 1: Axial T2 magnetic resonance imaging re-veals cortical and subcortical ischemic lesions in the dis-tribution of both carotid arteries, predominantly in the watershed zones. FIG. 3. Case 1: Fixed dilated pupil of the right eye with remnants of persistent pupillary membrane. 138 Roulez et al: J Neuro-Ophthalmol 2014; 34: 137-143 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. collarette. Filiform strands of persistent pupillary membrane projected from the collarette onto the anterior lens capsule, producing a scalloped pupillary margin (Fig. 7). Both pupils measured 6 mm, with no reaction to light or accommoda-tion. A right esotropia was present, but extraocular move-ments were full. Funduscopic examination demonstrated retinal vascular tortuosity (Fig. 8). At 14 years of age, visual acuity corrected to 20/40, right eye, and 20/25, left eye, and the patient was prescribed bifocal spectacles. DNA analysis revealed a p.R179H mutation of the ACTA2 gene. Case 3 A 16-year-old girl was sent for genetic testing by her ophthalmologist due to fixed dilated pupils discovered at birth. Her medical history consisted of patent ductus arteriosus, operated at 4 weeks of age, frequent respiratory and urinary tract infections, dyspnea, and deep venous thrombosis. A thoracic scan showed pulmonary emphy-sema, bronchiectasis, and dilation of the ascending aorta. Although no abnormalities were detected on clinical and neurologic examinations, MRI of the brain showed diffuse periventricular and deep subcortical white matter changes. Examination revealed visual acuity of 20/20 in each eye. The pupils were nonreactive, with hypoplastic irides and numerous iris strands projecting onto the anterior lens capsule (Fig. 9). Funduscopic examination demonstrated retinal vascular tortuosity. The patient was prescribed bifo-cal spectacles. Genetic testing of the ACTA2 gene revealed the p.R179H mutation. DISCUSSION The ACTA2 gene encodes the contractile protein alpha-actin in SMCs. Heterozygous ACTA2 mutations cause a predisposition to a variety of vascular diseases, including thoracic aortic aneurysms and dissections, early onset FIG. 4. Case 1: Stenosis and thrombosis of a peripheral retinal arteriole (arrow) is seen in the right eye. FIG. 5. Case 2: Axial T2 magnetic resonance imaging demonstrates periventricular white matter abnormalities and atrophic and gliotic cortical scarring in the left frontal and insular regions. FIG. 6. Case 2: Lateral projection of magnetic resonance angiogram shows dilation of proximal left internal carotid artery (short arrow), stenosis of the most distal left internal carotid artery (long arrow) and proximal portions of the left anterior and middle cerebral arteries, and absent basal moya-moya collaterals. FIG. 7. Case 2: Fixed dilated pupil. Strands of persistent pupillary membrane project from the collarette onto the anterior lens capsule (inset). Roulez et al: J Neuro-Ophthalmol 2014; 34: 137-143 139 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. coronary artery disease, and strokes (2). It has been sug-gested that ACTA2 missense mutations disrupt alpha-actin polymerization and lead to decreased contractility of aortic SMCs, which in turn leads to thoracic aortic disease (3). Occlusive disease of smaller vessels associated with ACTA2 mutations is likely due to increased vascular SMC prolifer-ation (2), resulting in stenosis or occlusion. In 2010, Milewicz et al (1) reported 7 unrelated patients with a de novo missense mutation in the ACTA2 gene (p.R179H) and multisystemic smooth muscle dysfunction syndrome (MSMDS), including aortic and cerebrovascular disease, patent ductus arteriosus, and congenital fixed dilated pupils. Möller et al (4) reported the ophthalmic features of 3 patients with MSMDS. They all presented with normal visual acuity, dilated nonreactive pupils, impaired accommodation, and retinal vascular tortuosity. In 2012, Munot et al (5) described a typical cerebrovascular phenotype with this ACTA2 (p179H) mutation: stenosis of the supraclinoidal segment of both ICAs; dilation of prox-imal portions of the ICAs; straight course of the cerebral vessels, which also show focal stenosis; and absence of basal collaterals. This cerebrovascular phenotype is not strictly identical to moya-moya angiopathy. The occlusive vascular disease found in the smaller diameter arteries of these patients probably results from an increased vascular SMC proliferation in the intimal and medial arterial layers. Elastin, found in large arteries, inhibits SMC proliferation (2,5). The change in vessel cal-iber of the internal carotid artery, from dilation to stenosis, occurs within the cavernous portion, where there is no external elastic lamina within the vessel wall. This supports the hypothesis that abnormal SMC proliferation is modu-lated by arterial wall components. Table 1 summarizes the systemic features of the reported patients with congenital fixed dilated pupils together with our 3 cases. All patients test positive for the ACTA2 gene mutation (p.R179H). Severe clinical manifestations became manifest early in life. This included surgery for patent duc-tus arteriosus in the first year of life, and during the first 2 decades of life, aortic or great vessel aneurysms or dissec-tions. Many also developed cerebrovascular anomalies with transient neurological deficits and stroke-like presentation. Regarding our patients, Case 1 had a stroke with a hemi-paresis at 2 years of age, and Case 2 developed dystonia and dysarthria at 5 years. It is noteworthy that no neurological abnormalities were detected in Case 3 until the age of 16, although cerebral MRI showed chronic ischemic white mat-ter changes. Indeed, white matter abnormalities have been reported in nearly all ACTA2 patients and increased in number as an age-related phenomenon, reflecting occult small vessel disease (5,7). As seen in Table 1, these patients experienced altered function of other SMC-dependent organs, including decreased contractile function of the bladder and gastrointes-tinal tract, resulting in hypotonic bladder, recurrent urinary tract infections, hypoperistaltism, and gallstones. Decreased SMC function of pulmonary alveoles leads to tachypnea at birth, pulmonary hypertension, asthma, bronchiectasis, and emphysema. Reported patients with congenital fixed dilated pupils had pupil diameters ranging from 5.5 to 7 mm. The pupils were nonreactive to light and convergence, as well as a variety of topical eye drops. The marginal portion from the collarette to the pupillary border (pars pupillaris) is absent, resulting in a scalloped pupillary margin. The remaining portion of the iris (pars ciliaris) is hypoplastic with the absence of crypts, but does not transilluminate. Numerous strands of persistent pupillary membrane extend from the collarette to the anterior lens capsule. Our Case 1 had cortical visual impairment, resulting in vision reduced to 20/50 bilaterally, but otherwise distance vision is usually good in ACTA2 patients. In most cases, accommodation is reported to be very poor (4,10). FIG. 8. Case 2: Right fundus reveals retinal arteriolar tor-tuosity. FIG. 9. Case 3: Scalloped pupillary borders with no iris tissue central to the collarette. 140 Roulez et al: J Neuro-Ophthalmol 2014; 34: 137-143 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Reported cases of ACTA2-multisystemic smooth muscle dysfunction syndrome with congential fixed dilated pupils Reference Gender, Age (Yrs) Development Delay CNS Abnormalities Cardiovascular Retinal Vascular Tortuosity Systemic Involvement Milewicz 2010 (1) Case A F, 12 Mild WM signal changes, Moya-moya-like, infarcts PDA, AAA + Hypotonic bladder, tachypnea at birth Khan 2004 (6) Case 1 Möller 2012 (4) Case 1 Milewicz 2010 (1) Case B M, 16 2 WM signal changes, Moya-moya-like, infarcts PDA, AAA + Hypotonic bladder, tachypnea at birth Khan 2004 (6) Case 2 Microaneurysms, leakage Möller 2012 (4) Case 2 Milewicz 2010 (1) Case C M, 17 + WM signal changes, Moya-moya-like, colpocephaly, small vermis PDA, AAA Hypotonic bladder, tachypnea at birth, pulmonary hypertension, hypoperistaltism Milewicz 2010 (1) Case D F, 11 Mild WM signal changes, Moya-moya-like PDA, AAA, aortic coarctation 2 Hypotonic bladder, tachypnea at birth, cystic lung, hypoperistaltism, malrotation, gallstones Lemire 2004 (10) RE ophthalmic artery occlusion Milewicz 2010 (1) Case E F, 26 2 WM signal changes, Moya-moya-like, stroke PDA, AAA Hypotonic bladder, pulmonary hypertension Milewicz 2010 (1) Case F M, 17 2 PDA, aortic dissection Inguinal hernia, asthma, phalanges hypoplasia, cutaneous striae distensae Adès 1999 (8) Milewicz 2010 (1) Case G F, 27 Moya-moya-like PDA, AAA Malrotation, asthma, gallstones Möller 2012 (4) Case 3 M, 6 2 WM signal changes PDA, AAA + Hypotonic bladder Richer 2012 (9) M, 2 Mild WM signal changes, Moyamoya-like PDA, mild AAA Prune-belly sequence,megacystis, skin dimples Moosa 2012 (7) F, 7 + neonatal infarcts, progressive WM anomalies PDA Hypoperistaltism Roulez et al: J Neuro-Ophthalmol 2014; 34: 137-143 141 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Alpha-actin is expressed in the dilator and sphincter muscles of the normal iris (11). Optical coherence tomog-raphy of the iris and biomicroscopic imaging suggests absence of the iris sphincter muscle (Fig. 10). Absence of the concentric circular folds in the peripheral iris is consis-tent with absence of the pupillary dilator muscle. Absence of the pupillary sphincter and dilator muscles awaits histopath-ologic confirmation. Retinal arteriolar stenosis and occlusion progressively appearing in the second decade of life is similar to the occlusive arteriolar disease occurring in the brain. SMC proliferation can progressively obstruct the vessels since the elastic lamina is lacking in retinal arteriolar walls. Möller et al (4) reported retinal vascular tortuosity with increasing age, and this could be related to vessel wall changes and loss of contractility. One of his patients also developed areas of arteriolar dilation and microvascular changes with leakage. Two of our patients (Cases 2 and 3) developed retinal vascular tortuosity. These vascular abnormalities support the experimental findings of Tomasek et al (12) that alpha-actin in the pericytes and the SMCs of the retinal vessel walls is necessary for normal retinal vascular perme-ability and for a normal blood-retina barrier. There are a few published reports of children with congenital mydriasis associated with isolated patent ductus arteriosis or aorticopulmonary septal defects (13-17), but screening for ACTA2 was not performed. Systemic abnor-malities in these patients included abdominal aortic aneu-rysm and myocardial infarction in an 8-year-old girl (16) and retinal tortuosity in 2 other patients (14,15). Neuro-logic status was normal, but all patients were very young (oldest was 9 years of age). Association between patent ductus arteriosus and fixed dilated pupils is suggestive of MSMDS, as alpha-actin is expressed by cardiomyocytes FIG. 10. Case 1: Anterior segment optical coherence tomography shows aplasia or extreme hypoplasia of iris sphincter and dilated muscles (A) compared with appear-ance of iris musculature in a normal individual (B). (Continued ) Reference Gender, Age (Yrs) Development Delay CNS Abnormalities Cardiovascular Retinal Vascular Tortuosity Systemic Involvement Case 1 (current report) F, 19 + Moya moya-like, infarcts PDA, aortic valvular dysplasia Stenosis, ischemia Hypotonic bladder, hypoperistaltism, asthma, restrictive pulmonary sd, gallstones, deep venous thrombosis, aplasia of left toes Case 2 (current report) F, 14 Mild WM signal changes, infarcts PDA + Case 3 (current report) F, 16 2 WM signal changes, infarct PDA + Emphysema, urinary infections, deep venous thrombosis AAA, abdominal aortic aneurysm; CNS, central nervous system; F, female; M, male; PDA, patent ductus arteriosus; WM, white matter. 142 Roulez et al: J Neuro-Ophthalmol 2014; 34: 137-143 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. during heart embryogenesis between the 9th and 33rd weeks of development (18). Recently, congenital mydriasis has been described in 2 neonates with megacystis microcolon intestinal hypoper-istaltis syndrome, in association with impaired vesical and intestinal peristaltis (19). The genetic basis remains unknown as ACTA2 screening was not performed. In 1965, Gillespie (20) described 2 individuals with cerebellar ataxia, mental retardation, and iris abnormalities similar to those seen in our report. These patients demon-strate hypoplasia of the cerebellar vermis on MRI but do not develop cerebrovascular complications. To date, the inheritance and genetics of this disorder remain unknown. Fixed dilated pupils in a young child is an extremely rare condition and should alert pediatricians and ophthalmolo-gists to the possibility of the coexistence of systemic life-threatening disorders, including MSMDS. Genetic testing is essential in evaluating this patient population. REFERENCES 1. 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