Current Therapeutic Options in Sturge-Weber Syndrome☆
Introduction
Sturge-Weber syndrome is a vascular malformation involving the brain, skin, and eye. In Sturge-Weber syndrome a facial port-wine birthmark (PWB), a capillary malformation (Fig. 1), is associated with abnormal blood vessels in the brain leptomeningeal “angioma” (Fig. 2) and the eye (choroid “angioma”). The vascular malformation in the brain results in epilepsy and neurologic impairments such as intellectual disability, hemiparesis, visual impairments, and severe migraines. Eye involvement with the vascular malformation produces glaucoma and can lead to vision loss. Sturge-Weber syndrome is a condition with a spectrum of clinical manifestations, which can range from isolated brain involvement (in approximately 10% of the cases), isolated eye involvement, eye and skin or eye and brain involvement, to birthmark associated with both brain and skin involvement.
The isolated birthmark is not usually referred to as Sturge-Weber syndrome, but rather it is generally called a facial PWB. Usually Sturge-Weber syndrome brain involvement is most frequently required to make the diagnosis; however the small subset of patients with the birthmark and eye involvement may sometimes be considered to have Sturge-Weber syndrome. If children with a facial PWB are older than 1 year and their contrast-enhanced magnetic resonance imaging (MRI) is normal, then they are very unlikely to have Sturge-Weber syndrome brain involvement.
A child, boy or girl, born with a PWB on the forehead or the upper eyelid, has a 10%-35% risk of brain involvement. When the PWB involves both the upper and the lower eyelid, the risk of glaucoma is approximately 50%.1 No population-based studies have been done; the estimates of prevalence range between 1 in 2000 and 1 in 50,000 live births. Isolated PWBs are very common; approximately 1 in 300 infants are born with it, most often located on the face, head, and neck.2 The somatic mosaic mutation causing Sturge-Weber syndrome is an activating mutation in GNAQ.3 Unexpectedly, the same R183Q mutation in GNAQ underlies a form of uveal melanoma.4 It has been hypothesized that the mutation occurring at a different time in development accounts for its resulting in a vascular malformation rather than a cancer. Furthermore, the timing of the mutation during fetal development probably determines the extent of Sturge-Weber syndrome involvement.5 The role of this GNAQ mutation is beginning to be understood, partly from extrapolation of data from the cancer literature.
In this article, we review the presentation, diagnosis, pathophysiology, and current treatment of Sturge-Weber syndrome, with a focus on therapeutic options both conventional and more controversial.6 The available treatment literature reviewed is primarily clinical cohort series; there are results from a few anonymous surveys. There have not been any randomized, placebo-controlled drug trials yet for Sturge-Weber syndrome. Although a couple of prospective open-label studies are currently ongoing, published drug studies to date are limited to retrospective open-label trials.
Section snippets
Diagnosis
The PWB is present at birth and may initially be confused with a bruise. However, the “bruise” does not resolve and should be evaluated by a dermatologist or other vascular specialists so that it can be appropriately identified. The presence of a facial PWB should result in referral for treatment of the birthmark, as well as consultation with a neurologist and ophthalmologist for appropriate evaluation and treatment of brain or eye (or both) involvement, if necessary.
The diagnosis of
Pathophysiology
GNAQ codes for Gαq, an alpha subunit of a heterotrimeric guanosine-5′-triphosphate-binding protein coupled to Gβ and Gγ subunits and known to couple with several GCPRs (including certain serotonin and glutamate receptors, and endothelin-1, angiotensin 2 receptor type I, alpha-1 adrenergic receptors, and vasopressin type 1 and type B) which are important to vascular development and function. The mutation is predicted to decrease efficiency of the autohydrolysis and results in constitutive
Current Treatment Options
The PWB is treated with laser procedures beginning in infancy when the flat, pink birthmark responds best and the birthmark is smaller.30 Early laser treatment may lessen later progression of the birthmark, which can consist of tissue hypertrophy, blebs, and complications affecting vision, airway, and swallowing. A variety of lasers have been developed over the years and are used, depending on color of the skin and color, thickness, and size of the birthmark; the lasers heat the hemoglobin
Future Treatment Options
Research efforts for the future would increasingly be centered around targeted therapies. This is already being seen to some extent in the Phase I-II treatment trials studying the use of mechanistic target of rapamycin inhibitors for the treatment of PWB,54 and of medically refractory seizures in Sturge-Weber syndrome (https://clinicaltrials.gov/ct2/show/NCT01997255?term=sturge-weber&rank=4). Another ongoing Phase I-II clinical trial of cannabidiol may in part target Gαq hyperactivation (//clinicaltrials.gov/ct2/show/NCT02332655?term=sturge-weber&rank=1
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The author acknowledges funding from the National Institute of Neurological Disorders and Stroke (NINDS), United States, National Institutes of Health, United States, (NIH; U54NS065705), and from Celebrate Hope Foundation. The Brain Vascular Malformation Consortium (U54NS065705) is part of Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. This consortium is funded through collaboration between NCATS and the NINDS.