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 emphysema, 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 bifocal spectacles. Genetic testing of the ACTA2 gene revealed the p.R179H mutation.
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 caliber 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 modulated by arterial wall components.
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).
Alpha-actin is expressed in the dilator and sphincter muscles of the normal iris (11). Optical coherence tomography 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 consistent with absence of the pupillary dilator muscle. Absence of the pupillary sphincter and dilator muscles awaits histopathologic 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 permeability 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 abnormalities in these patients included abdominal aortic aneurysm and myocardial infarction in an 8-year-old girl (16) and retinal tortuosity in 2 other patients (14,15). Neurologic 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 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 hypoperistaltis syndrome, in association with impaired vesical and intestinal peristaltis (19). The genetic basis remains unknown as ACTA2 screening was not performed.
Fixed dilated pupils in a young child is an extremely rare condition and should alert pediatricians and ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders, including MSMDS. Genetic testing is essential in evaluating this patient population.
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