Clinical science
Iris anomalies and the incidence of ACTA2 mutation
UPMC Eye Center, Children’s
Hospital of Pittsburgh of UPMC,
University of Pittsburgh School
of Medicine, Pittsburgh, PA, USA
Correspondence to
Dr Ken K Nischal, UPMC Eye
Center, Children’s Hospital of
Pittsburgh of UPMC, Floor 5,
4401 Penn Avenue, Pittsburgh,
PA 15224, USA; ​nischalkk@​
upmc.​edu
A portion of this work was
presented at the International
Society for Genetic Eye Diseases
and Retinoblastoma (ISGEDR)
Annual Meeting, Leeds, UK,
14–16 September 2017.
Received 26 March 2018
Accepted 11 May 2018
To cite: Taubenslag KJ,
Scanga HL, Huey J, et al.
Br J Ophthalmol Epub ahead
of print: [please include Day
Month Year]. doi:10.1136/
bjophthalmol-2018-312306
Kenneth J Taubenslag, Hannah L Scanga, Jennifer Huey, Jennifer Lee,
Anagha Medsinge, Christin L Sylvester, Kenneth P Cheng, Ken K Nischal
ABSTRACT
Background  Central cysts of the iris pigment
epithelium, or iris flocculi, are frequently reported in the
literature in association with thoracic aortic aneurysm
and dissection due to smooth muscle alpha-actin 2
(ACTA2) mutations. Children with ACTA2 mutations may
also present with congenital mydriasis. We report our
experience regarding the frequency of ACTA2 mutation
in children with the above iris anomalies.
Methods  This is a retrospective, consecutive case series
of all children presenting for iris flocculi or congenital
mydriasis at a single tertiary centre from October 2012
to December 2016.
Results  13 children with iris flocculi and 3 with
congenital mydriasis presented during the study period.
10 children with iris flocculi completed genetic testing,
and none were positive for ACTA2 mutation. All children
with congenital mydriasis presented with a multisystem
smooth muscle dysfunction syndrome; two of these
three children tested positive for missense R179 ACTA2
mutations.
Conclusions  In this series, ACTA2 mutation or
copy number variation was not detected in children
presenting for iris flocculi, whereas congenital mydriasis
was associated with R179 mutation in both cases
that tested positive for ACTA2 mutation. The case of
congenital mydriasis without typical cardiac features of
the R179 ACTA2 phenotype or intracranial vasculopathy
was negative for ACTA2 mutation. While all children
presenting with these iris anomalies should be offered a
genetic evaluation, incidence data should inform genetic
counselling, particularly in the absence of a family history
of aneurysm or sudden death, or systemic signs of
smooth muscle dysfunction.
Central cysts of the iris pigment epithelium, or iris
flocculi, first appeared in the American literature
in the 1930s.1 2 Iris flocculi are uncommon; in the
largest study on iris cysts in children, only 3 of 57
cysts were located centrally.3 In another large study
including patients of all ages, 6 of 234 iris pigment
epithelial cysts were located centrally.4 Iris flocculi
are often bilateral and may exhibit autosomal domi-
nant inheritance. They are frequently asymptom-
atic, but life-threatening systemic associations have
been reported.5–7
In 1976 Bixler and Antley5 reported an associa-
tion between iris flocculi and familial thoracic aortic
aneurysm and dissection (TAAD). Confirming this
association, Lewis and Merin6 identified another
family where iris flocculi, livedo reticularis and
TAAD segregated together. In the mid-2000s,
genetic bases to irido-aortic syndromes were
identified. Two pathological mutations in smooth
Taubenslag KJ, et al. Br J Ophthalmol 2018;0:1–5. doi:10.1136/bjophthalmol-2018-312306
Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312306 on 6 June 2018. Downloaded from http://bjo.bmj.com/ on 6 June 2018 by guest. Protected by copyright.
muscle alpha-actin 2 (ACTA2) have been detected
in eight families with iris flocculi and TAAD. In
the majority, R149C is the causative substitution,
although one family demonstrated an intron muta-
tion affecting ACTA2 splicing.7–11 A mutation in
β-myosin heavy-chain (MYH11) has also been iden-
tified in a family with iris flocculi and TAAD.12
Additionally, a highly penetrant ACTA2 mutation
at the R179 residue causing iris anomalies has also
been described.13–20 Rather than flocculi, mutations
at this point cause congenital mydriasis in conjunc-
tion with a multisystem smooth muscle dysfunction
syndrome (MSMDS) characterised by gastrointes-
tinal and urinary anomalies, cardiac defects, pulmo-
nary hypertension, and intracranial vasculopathy.
While these iris anomalies can signal a life-threat-
ening diagnosis, they may also be incidental find-
ings; yet the frequency of ACTA2 mutations in
patients with iris flocculi and congenital mydriasis
remains unknown. Estimating this incidence from
the literature is challenging as even some recent
reports do not include genetic testing.21–23 The
rationale for this study is to examine the frequency
of ACTA2 mutation in a cohort of patients with iris
flocculi and congenital mydriasis. A better under-
standing of the incidence of ACTA2 mutation in
these patients can help inform genetic counselling
and management strategies.
Materials and methods
We conducted a retrospective review of all cases of
iris flocculi and congenital mydriasis presenting to
the Division of Pediatric Ophthalmology and Stra-
bismus at the Children’s Hospital of Pittsburgh of
the University of Pittsburgh Medical Center from
1 October 2012 through 31 December 2016.
Patients were identified by a review of logs of all
patients referred to the ophthalmic genetic coun-
selling service. No patients were previously treated
with echothiophate. Age at presentation, sex,
laterality, visual acuity, family history of iris floc-
culi, thoracic or intracranial aneurysms, or sudden
cardiac death, and the results of cardiac echocardi-
ography were recorded. Progression and regression
of flocculi at follow-up were documented if noted.
For patients with positive genetic testing concomi-
tant diagnoses were reviewed.
Genetic testing was performed by Connective
Tissue Gene Tests (Allentown, Pennsylvania). All
coding exons and exon boundaries were ampli-
fied and sequenced using Applied Biosystems 3730
sequencers. In select cases, exon boundaries were
analysed for copy number variation by high-den-
sity targeted array. The minimum detectable copy
number variation was 300–500 nucleotides.
1
 Clinical science

Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312306 on 6 June 2018. Downloaded from http://bjo.bmj.com/ on 6 June 2018 by guest. Protected by copyright.
Table 1  Demographics and clinical characteristics
ACTA2 analysis
Patient/Sex/Age Deletion/
(months) Iris phenotype Family history Echocardiogram Course Sequencing Duplication
1/F/0.17 Flocculi Aneurysm – Resolved, 12 months Negative –
2/M/37 Flocculi None Normal Deflated Negative Negative
3/M/31 Flocculi None Normal Resolved, 33 months Negative Negative
4/M/2.7 Flocculi None – – – –
5/M/2.8 Flocculi Aneurysm PFO Persistent – –
6/F/45 Flocculi None ASD – Negative Negative
7/F/26 Flocculi Aneurysm – Persistent Negative Negative
8/M/0.23 Flocculi None – Ruptured Negative Negative
9/M/0.47 Flocculi None PFO Resolved, 31 months Negative Negative
10/M/3.0 Flocculi None Normal Persistent Negative Negative
11/M/4.2* Flocculi None – Resolved, 15 months – –
12/M/0.43 Flocculi Aneurysm PFO Persistent Negative Negative
13/M/3.1 Flocculi None PFO Persistent Negative Negative
PDA, ASD, aortic arch c.535C>T
14/F/1.9 Mydriasis None dilation NA (p.R179C) Not done
c.536G>A
15/M/0.67 Mydriasis None PDA, ASD NA (p.R179H) Not done
16/M/4.2 Mydriasis None PFO NA Negative Negative
*Right eye only.
–, no data; ACTA2, alpha-actin 2; ASD, atrial septal defect; F, female; M, male; NA, not applicable; PDA, patent ductus arteriosis; PFO, patent foramen ovale.

Patients were managed by several ophthalmologists at a single
tertiary centre. Thus, work-up, including the decision to pursue
deletion/duplication testing and cardiac evaluation, was variable
and subject to physician discretion and family preference.
Results
Iris flocculi
Thirteen patients presented with iris flocculi during the study
period. As per table 1, the average age at presentation was 10
months (range 0.17–45).
Twelve of thirteen patients and all of the patients who received
genetic testing had bilateral iris flocculi. Patient 6 (figure 1) had
a family history of iris flocculi, with flocculi noted in the mother
during the child’s clinic visit. The parents also described possible
iris flocculi in the maternal grandmother. Eight children were
evaluated with echocardiography by the cardiology service.
Four had a small patent foramen ovale, and patient 6 had a
large atrial septal defect (ASD) requiring repair. None had aortic
dilation. No patient had first-degree relatives with a history of
aneurysm or sudden cardiac death; however, four patients had
a history of thoracic or intracranial aneurysm or sudden death
in a second-degree or third-degree relative. Ten families were
agreeable to genetic testing for ACTA2 mutation, with nine of
these ten also receiving deletion/duplication analysis. None were
positive for mutation or copy number variation.
Figure 1  External photograph of patient 6, after dilation,
demonstrating large, bilateral central cysts of the iris pigment
epithelium.
2 Taubenslag KJ, et al. Br J Ophthalmol 2018;0:1–5. doi:10.1136/bjophthalmol-2018-312306
Over a mean follow-up period of 1.7 years (range 0–3.6
years), 4 of 13 children were noted to have complete resolu-
tion of iris flocculi at a mean age of 23 months (range 15–33
months). Another two patients were noted to have deflated but
still visible flocculi at the most recent follow-up. Iris cysts in
five patients were persistent at all follow-up visits, while two
had insufficient follow-up to assess natural history. None of the
pigment epithelial cysts obstructed the visual axis.
Congenital mydriasis
Case 1
Patient 14 presented in the neonatal period with signs of MSMDS.
At 2 weeks post partum, she was admitted for respiratory distress
secondary to a haemodynamically unstable patent ductus arteri-
osus (PDA). Echocardiogram also demonstrated multiple ASDs
and mild dilation of the ascending aorta. The child underwent
PDA ligation, aortic arch augmentation, pulmonary arterioplasty
and ASD closure. Additional findings included a large urachal
diverticulum, intestinal malrotation, arachnodactyly, and lentic-
ular opacity prompting ophthalmology consultation.
Examination by the ophthalmology service was notable for
fixed, mydriatic pupils measuring 6 mm and 5 mm in the right
and left eyes, respectively. The pars pupillaris appeared absent,
while the pars ciliaris was hypoplastic, with minimal crypt archi-
tecture. Short wisps of persistent tunica vasculosa lentis extended
from a collarette. Mild anterior cortical lenticular changes in the
right eye and anterior polar cataract in the left eye were noted
(figure 2A). Fundus examination revealed retinal arterial atten-
uation and corkscrew tortuosity (figure 2B). Neuroimaging was
recommended, with MRI of the brain demonstrating extensive
periventricular T2 hyperintensities. Magnetic resonance angi-
ography (MRA) of the head and neck demonstrated dilation of
the infraclinoid internal carotid and basilar arteries with supra-
clinoid stenosis and vessel straightening without the lenticulo-
striate collateralisation seen in Moyamoya (figure 2C–D). ACTA2
sequencing was positive for an R179C missense mutation.
 Clinical science

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Figure 2  (A) External photograph of the left eye of patient 14, undilated, demonstrating the mydriatic pupils and anterior lenticular opacity.
(B) RetCam fundus photograph of the right eye showing arteriolar without venous tortuosity with aneurysmal-like corkscrew course. (C) Magnetic
resonance T2 fluid attenuation inversion recovery (FLAIR) showing extensive periventricular T2 abnormality. (D) Magnetic resonance angiography
without contrast of the head and neck with internal carotid dilation and distal arterial stenosis bilaterally. The basilar artery is also enlarged and the
distal vasculature is straightened, reminiscent of Moyamoya.

At 20 months of age, dynamic retinoscopy revealed accommo-
dative failure. The patient also had a 30 prism-dioptre (D) basic,
non-accomodative left esotropia with left amblyopia. Retinos-
copy measured +2.00 D, and she was given full refraction. At
subsequent follow-up visual acuity improved from 20/127 in
both eyes to 20/32 in the right eye and 20/40 in the left eye. She
maintained a comitant left esotropia despite spectacle correc-
tion. At 3 years of age, the child was alive and well.
Case 2
Patient 15 also presented with stigmata of MSMDS. Prenatal
ultrasound detected hydronephrosis, with postnatal ultrasound
also demonstrating hydroureter and urachal diverticulum.
Examination revealed bilateral cryptorchidism and laxity of the
abdominal wall consistent with prune belly syndrome. At 10
days post partum, the child developed respiratory distress, with
echocardiography showing a moderate ostium secundum defect
as well as a large PDA requiring ligation.
Taubenslag KJ, et al. Br J Ophthalmol 2018;0:1–5. doi:10.1136/bjophthalmol-2018-312306
At 2 weeks of age, mydriasis was noted and ophthalmology
was consulted. At initial examination pupils were 8 mm and
non-reactive. As with patient 14, no pars pupillaris was observed,
and the pars ciliaris was hypoplastic with short spokes of tunica
vasculosa lentis and areas of iridolenticular adhesion (figure 3).
Corkscrew retinal arteries were also noted with normal venous
circulation. MRI revealed areas of decreased T2 signal and
restricted diffusion in the bilateral periventricular white matter,
suggesting acute to subacute necrosis as well as increased T1 and
T2 signal in the same areas indicative of haemorrhage or coagu-
lative necrosis. Repeat MRI of the brain at 4 months showed an
area of cystic encephalomalacia in the left frontal lobe, as well
as encephalomalacic changes in the left basal ganglia and a thin
corpus callosum.
At first follow-up with ophthalmology at age 4, visual acuity
was 20/40 in both eyes. Refraction was −2.00 and −2.75 D
for the right and left eyes, respectively. At this time, ACTA2
sequencing was ordered and returned positive for an R179H
3
 Clinical science
Figure 3  Photograph of patient 15 during an exam under
anaesthesia of the right eye, undilated, demonstrating mydriasis with
wisps of iris tissue extending from the iris collarette with no well-
defined pars pupillaris. The pars ciliaris is hypoplastic with minimal crypt
architecture.
mutation. The patient had repeat MRI and MRA due to gener-
alised weakness, which showed worsening leucodystrophy, a
cystic pontine infarct, and infraclinoid internal carotid dilation
and supraclinoid stenosis and vessel straightening characteristic
of R179 ACTA2 mutations. The boy passed away from respira-
tory failure at age 5.
Case 3
Patient 16, the final patient with congenital mydriasis, presented
to the emergency department for bilious emesis 5 days after
an uncomplicated, full-term delivery. He was found to have
intestinal malrotation with volvulus requiring exploratory lapa-
rotomy and Ladd’s procedure. During his admission, a heart
murmur was noted and echocardiography demonstrated a patent
foramen ovale and branch pulmonary artery stenosis. Renal eval-
uation demonstrated left pelviectasis secondary to vesicoureteral
reflux without urachal diverticulum.
At 4 months of age the child returned for failure to thrive.
The neurology service was consulted, prompting magnetic reso-
nance of the brain without contrast, which was normal. Cere-
bral angiographic studies were not pursued. Ophthalmology
was consulted due to concern for aniridia; however, the patient
had no nystagmus and the fovea demonstrated a normal reflex.
Optical coherence tomography during examination under anaes-
thesia showed a normal foveal contour. The irides were non-re-
active and hypoplastic. As in cases 14 and 15, a persistent tunica
vasculosa lentis was present, although it was more extensive than
in the other two cases (figure 4). No retinal arterial tortuosity
was present. A diagnosis of congenial mydriasis was made, but
ACTA2 sequencing and deletion/duplication analysis were nega-
tive. The patient was lost to follow-up and genetic diagnosis
remains unknown.
Discussion
This is the first study to examine the frequency of ACTA2 muta-
tions in children with iris anomalies. Iris flocculi are uncommon,
and prior descriptions are limited to case reports and smaller
series.6 9–12 21 24 While a majority of extant reports discuss iris
flocculi in association with familial TAAD secondary to ACTA2
mutation, our study suggests that ACTA2 mutation is actually
4 Taubenslag KJ, et al. Br J Ophthalmol 2018;0:1–5. doi:10.1136/bjophthalmol-2018-312306
Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312306 on 6 June 2018. Downloaded from http://bjo.bmj.com/ on 6 June 2018 by guest. Protected by copyright.
Figure 4  Photograph of patient 16 during an exam under
anaesthesia of the right eye, undilated, showing mydriasis with an
extensive persistent pupillary membrane. The pars pupillaris is absent
and the pars ciliaris is devoid of crypts.
uncommon in children with iris flocculi, as no patient tested
positive for mutation or copy number variation.
We continue to recommend offering a genetic evaluation to
all patients with iris flocculi. However, discussing data on the
frequency of ACTA2 mutations in children with iris flocculi
during genetic counselling will lead to more informed deci-
sion-making for families. Based on these results, observation
may be a reasonable management strategy in cases where there is
no first-degree relative with aneurysm or iris flocculi, and when
examination does not show livedo reticularis. For patients with a
concerning family history or particularly prominent iris flocculi,
we continue to strongly recommend gene sequencing and base-
line echocardiography.
It is important to note that the absence of positive genetic
testing for ACTA2 mutation in this study does not exclude alter-
native genetic diagnoses for these patients. For instance, none
of the subjects were tested for mutations of MYH11, which
has been reported to cause iris flocculi and TAAD in a single
family.12 Additionally, it is possible that unidentified genes cause
iris flocculi as part of the TAAD syndrome. In a recent report
by Shields et al, a patient with bilateral iris flocculi and nega-
tive genetic testing for ACTA2 and MYH11, including testing for
copy number variation, developed an ascending thoracic aortic
aneurysm with dissection necessitating surgical repair at the age
of 55. Shields et al’s24 report suggests that select patients with
iris flocculi may benefit from repeat cardiac evaluation despite
normal echocardiography in childhood and negative genetic
testing.9 11 24 Currently there are no clinical features known to
signal elevated risk for TAAD in patients with iris flocculi who are
negative for ACTA2 mutation. The patient reported by Shields et
al24 had no family history of aortic aneurysm or sudden cardiac
death; yet the iris flocculi were prominent and persistent. Six
patients with iris flocculi in the present study had small floc-
culi, which regressed or deflated during follow-up. Many of the
case reports of ACTA2 mutation and TAAD demonstrate partic-
ularly large flocculi, and we speculate that small, self-limited iris
flocculi may represent a more benign entity.6 11 Further study is
merited to confirm or refute this hypothesis.
With respect to congenital mydriasis, this iris finding was
associated with R179 ACTA2 missense mutations in two of three
cases. Patients with R179 site mutations presented in a character-
istic fashion with MSMDS. Both demonstrated renal anomalies,
including hydronephrosis, hydroureter and urachal divertic-
ulum, and developed respiratory distress related to haemody-
namically significant PDA and ASD. The patient negative for

ACTA2 mutation lacked these characteristic cardiac findings.
He also did not demonstrate several other features seen with
R179 ACTA2, including urachal diverticulum and white matter
abnormalities. Ophthalmic differences between patient 16 and
typical patients with ACTA2-associated congenital mydriasis
include absence of retinal arterial tortuosity and the appearance
of the tunica vasculosa lentis, which was more extensive than the
persistent pupillary membrane seen with ACTA2 mutations. It is
possible that this patient had a mutation in a hitherto unknown
gene or that there was a mutation in the intronic, regulatory
regions of ACTA2. Nevertheless, close attention to details of the
ophthalmic examination may assist in the genetic diagnosis of
these complex patients.
Regarding the children with congenital mydriasis, this study
also highlights several salient ophthalmic associations. First,
patient 14 presented with right cortical lenticular changes and
left anterior polar cataract. This finding is not unexpected,
however, as cataract is a known sequela of anterior persistent
fetal vasculature, of which these children appear to have a mild
variant. Second, esotropia in the setting of congenital mydri-
asis is infrequently reported. Roulez et al18 report one patient
with a right esotropia, but the esotropia is not further charac-
terised. Given the child’s accommodative insufficiency, expected
in MSMDS due to ciliary smooth muscle dysfunction, we antic-
ipated a component of the esotropia to be due to high accom-
modative convergence to accommodation ratio. Yet the child
demonstrated a basic, non-accomodative esotropia. Regardless,
periodic surveillance is recommended as these children may be
at above-average risk for the development of strabismus. Further
reporting is merited to better define the phenotype from the
ophthalmic perspective.
In addition to the aforementioned limitations of the study,
other limitations include its retrospective design, small sample
size and the lack of long-term follow-up. However, while the
sample size is small, these are rare iris findings, and this is the
first report to include this many patients with iris flocculi. The
findings suggest that patients presenting with congenital mydri-
asis should be tested for ACTA2 mutations, consistent with prior
reports. While no patients in this study with iris flocculi were
found to have ACTA2 mutations, a review of systems and family
history is necessary to identify patients who may benefit from
cardiology evaluation and genetic testing for ACTA2-related
TAAD given the decreased penetrance of this gene.
Contributors  KJT and KKN had full access to all the data in the study and take
responsibility for the integrity of the data and the accuracy of data analysis. Study
concept and design: KJT, HLS and KKN. Acquisition, analysis or interpretation of
data: all authors. Drafting of the manuscript: KJT and KKN. Critical revision of the
manuscript for important intellectual content: all authors. Administrative, technical or
material support: all authors. Study supervision: KKN.
Funding  Supported in part by a Research to Prevent Blindness Unrestricted Grant
to the UPMC Eye Center. The sponsor or funding organisation had no role in the
design or conduct of this research.
Competing interests  None declared.
Patient consent  Not required.
Ethics approval  The protocol, compliant with the Health Insurance Portability and
Accountability Act and adherent to the Declaration of Helsinki, was approved by the
Institutional Review Board of the University of Pittsburgh.
Taubenslag KJ, et al. Br J Ophthalmol 2018;0:1–5. doi:10.1136/bjophthalmol-2018-312306
Clinical science
Provenance and peer review  Not commissioned; externally peer reviewed.
Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312306 on 6 June 2018. Downloaded from http://bjo.bmj.com/ on 6 June 2018 by guest. Protected by copyright.
Data sharing statement  Additional unpublished data may be available from the
corresponding author.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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