Non-atherosclerotic cerebral arteriopathy is the most common identified risk factor for pediatric ischemic stroke. ^{Reference Fullerton, Wintermark and Hills1} Smith–Magenis syndrome (SMS) (OMIM # 182290) is a multisystem disorder caused by deletions in RAI1, either by 17p11.2 deletions that include RAI1 or by point mutations within the RAI1 gene itself. ^{Reference Smith and Gropman2} SMS is characterized by distinct dysmorphic features, developmental delays and congenital heart abnormalities. ^{Reference Smith and Gropman2,Reference Smith, McGavran and Robinson3} Stroke has been described four times in SMS. ^{Reference Smith and Gropman2–Reference Freeman, Deleyiannis, Bernard, Fenton, Somme and Wilkinson4} Here, we describe a now 5-year-old female with SMS who presented with recurrent strokes and progressive multifocal intra- and extracranial arteriopathy involving large vessels.

At 4 days of age, coarctation of the aorta and aortic arch hypoplasia were diagnosed. At 7 days of age, she underwent coarctation repair surgery and subsequently underwent four aortic arch balloon dilatations to date. At 2 years and 4 months of age, an aortic stent was placed, and she was started on aspirin.

Due to noted dysmorphic features, a postnatal chromosomal microarray was done and revealed a 6.67 Mb 17p12p11.2 deletion, confirmed by fluorescence in situ hybridization and consistent with SMS. On follow-ups, she was noted to have global developmental delay with mild axial and appendicular hypotonia.

At 2 years and 11 months of age, she presented with acute-onset left hemiparesis, 1 week following a viral gastroenteritis: CT head with CT angiogram showed an acute infarction of the right middle cerebral artery (MCA) territory, an unremarkable appearance of the aortic arch and bilateral narrowing of the cavernous and supraclinoid segments of the internal carotid arteries (ICAs) but with normal distal opacification. An MRI head with MR angiography (MRA) was done 2 days after her presentation and showed an acute/subacute right watershed infarction pattern at the junction of the anterior cerebral artery/MCA territories, with scattered tiny ischemic foci also noted in the left cerebral hemisphere (Figure 1-B); ICA narrowing was re-demonstrated at the same segments but more severe on the right side (Figure 1-A). Day 8 (D8) from presentation, she underwent balloon dilatation of her aorta due to re-coarctation and had moderate residual aortic obstruction: a bubble study was negative, and the stent was noted to be distal to the ICA. The patient was postoperatively admitted to the intensive care unit for blood pressure control.

Figure 1.

(A) Axial oblique (top) and coronal (bottom) 4 cm thick maximum intensity projection (MIP) reconstruction of MR angiography (MRA) of the circle of Willis at three different times showing progressive severe stenosis of the intracranial internal carotid arteries, anterior cerebral artery and middle cerebral artery (dotted circle) to reach a complete absence of flow-related signal of the anterior-most circulation (triangle). No development of collaterals. (B) Fluid attenuated inversion recovery (FLAIR) (top row), diffusion b1000 (mid row) and apparent diffusion coefficient (ADC) map (bottom row) at the level of the body of the ventricles (left-hand column) and at the vertex (right-hand column) at the same times of the MRAs shown in Figure 1(A). These images show progressive bilateral ischemic infarcts of different ages with progressive development of extensive cystic encephalomalacia and brain volume loss with ex vacuo ventriculomegaly.

Her hospital stay was then stable: on D28, she underwent conventional cerebral angiography (Figure 2), which demonstrated focal stenosis of the proximal supraclinoid segments of the bilateral ICAs, measuring approximately 60% on the right and 40% on the left, as well as a straightened or twig-like course of the cerebral arterial tree. No irregular basal collateral or moyamoya networks were identified; however, diffuse severe narrowing was noted along the bilateral iliac and femoral arteries, with the common femoral artery measuring approximately 1.6 mm in diameter. She was discharged in stable condition on D37.

Figure 2.

Internal carotid artery cerebral angiography in the (A, C) anteroposterior and (B, D) lateral projections for the right (A, B) and left (C, D) sides. “Twig-like” straightening of the cerebral arterial tree (A, C) is noted, with stenoses of the supraclinoid segment of the internal carotid arteries bilaterally (red arrowheads, B, D). (E) Angiography through the left femoral arterial access demonstrates symmetric narrowing of the common femoral and iliac arteries (red scale bar = 5 mm).

At 3 years and 6 months, she re-presented to the emergency room with transient momentary unsteadiness with right-sided upper-limb shaking when standing up, in the context of a viral upper respiratory infection; she was otherwise stable. An MRI head with MRA on re-admission day 2 (RA-D2) showed new left subacute watershed infarcts, right frontal infarcts and progression of the stenoses demonstrated on previous imaging (Figure 1-A and 1-B). On RA-D4, the patient had transient right hemiparesis and left eye deviation, with a CT head confirming a left MCA, mainly M1 segment, ischemic stroke. Continuous electroencephalography monitoring showed occasional clusters of epileptic spasms, different from her presenting limb-shaking events, responsive to levetiracetam. Between RA-D4 and RA-D5, the patient was intubated due to irritability and blood pressure variability.

On RA-D5, bosentan was started every 12 hours, in addition to the patient’s milrinone and furosemide infusions, to initiate cerebral vasodilatation and manage urinary output. Between RA-D5 and RA-D16, sildenafil was started, and a repeat MRI head showed new cortical infarcts in the right inferior parietal lobule. Since then, the patient has had no recurrence of clinical or radiographic strokes and is presently stable at almost 2 years after RA. She was weaned off levetiracetam, but epileptic spasms recurred within 2 months post-RA discharge, for which vigabatrin was started, and levetiracetam, valproic acid and topiramate were added; the patient’s seizures have been controlled. The patient remains at her baseline developmental delays after discharge and is developing at her own pace; she also remains on daily aspirin, bosentan, sildenafil, trihexyphenidyl and baclofen.

Given the vasculopathy, a custom vasculopathy gene panel (Prevention Genetics) was performed and was unrevealing. Thereafter, an exome-based trio Blueprint Genetics Developmental Disorders panel that interrogates ∼17,000 genes, including MYH11, did not reveal any likely pathogenic/pathogenic variants in any disease genes.

Stroke-like episodes in people with SMS have been described four times: twice in pediatric-aged Asian-descent females with moyamoya disease without an embolic source, once post-cardiac surgery due to severe atherosclerotic disease in a 32-year-old female of undisclosed descent and once due to emboli from a congenital heart defect in a 4.5-year-old male of undisclosed descent; no other non-aortic vasculopathy is known to be associated with SMS. ^{Reference Smith and Gropman2–Reference Freeman, Deleyiannis, Bernard, Fenton, Somme and Wilkinson4}

From a genetic perspective, SMS most commonly encompasses a ∼4 Mb genomic deletion within chromosome 17p11.2, without a gene known to be associated with vasculogenesis or vasculopathies. ^{Reference Bi, Yan and Stankiewicz5} Interestingly, our patient exhibited bilateral symmetric narrowing of intracranial and extracranial large vessels, which highly suggested a genetic vasculopathy. Multifocal intracranial arterial stenoses in addition to decreased arterial curvature/a straightened arterial appearance in the absence of moyamoya collaterals suggested a neurovascular phenotype reminiscent of ACTA2 or MYH11 vasculopathies. ^{Reference Munot, Saunders and Milewicz6,Reference Raghuram, Sanchez and Lu7} However, the sent gene panels were negative for both genes; at this time, it is unclear to what degree SMS has contributed to the patient’s presentation.

A specific clinical point of interest in our case is the presentation with a limb-shaking transient ischemic attack (LSTIA). LSTIA is rarely reported in arterial steno-occlusive disease, especially in the pediatric population, where moyamoya disease has been reported as a cause of attacks. ^{Reference Das, Ghosh, Dubey, Pandit, Ray and Kraemer8} Our patient presented with transient episodes of subtle unsteady gait after or during an infection, which may be misdiagnosed as parainfectious cerebellitis or even febrile-related fatigue. Although LSTIA is rare, we highlight the consideration of LSTIA in pediatric cerebral arteriopathies, given the morbidity and potential fatal implications.

In conclusion, we extend the phenotypic spectrum of SMS and highlight the importance of considering LSTIA in patients with cerebral and extra-cerebral arteriopathy in the pediatric age group.