Current Therapeutic Options in Sturge-Weber Syndrome

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Sturge-Weber syndrome is a vascular malformation syndrome consisting of a facial port-wine birthmark associated with malformed leptomeningeal blood vessels and a choroid “angioma” of the eye. It is a rare neurocutaneous disorder that occurs sporadically, is not inherited, and is caused by a somatic mosaic mutation in GNAQ. In patients with Sturge-Weber syndrome, brain involvement typically presents in infancy with seizures, strokes, and stroke-like episodes, and a range of neurologic impairments. Standard treatment includes laser therapy for the birthmark, control of glaucoma through eyedrops or surgery, and the use of anticonvulsants. Increasingly low-dose aspirin is offered. Treatment with propranolol has been tried generally without the dramatic results seen in hemangiomas. Treatment with an anticonvulsant or low-dose aspirin or both before the onset of seizures is an option. Surgical resection may be offered to those whose seizures are medically refractory. Endocrine, medical rehabilitation and cognitive comorbidities are important to manage. In the future, new therapeutic options are likely to be offered stemming from preclinical studies and small pilot clinical trials currently ongoing. Discovery of the causative somatic mosaic mutation suggests new insights into the pathophysiology of this vascular malformation disorder, and potential novel treatment strategies for future study. The mutation results in constitutive overactivation of the Ras-Raf-MEK-ERK and the HIPPO-YAP pathways and inhibitors of these pathways may in the future prove useful in the treatment of 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

References (54)

  • J. Powell

    Update on hemangiomas and vascular malformations

    Curr Opin Pediatr

    (1999)
  • M.D. Shirley et al.

    Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ

    N Engl J Med

    (2013)
  • J.W. Harbour

    The genetics of uveal melanoma: An emerging framework for targeted therapy

    Pigment Cell Melanoma Res

    (2012)
  • A. Poduri et al.

    Somatic mutation, genomic variation, and neurological disease

    Science

    (2013)
  • C.D. Bachur et al.

    Sturge Weber syndrome

    Curr Treat Options Neurol

    (2013)
  • N.J. Fischbein et al.

    Sturge-Weber syndrome with no leptomeningeal enhancement on MRI

    Neuroradiology

    (1998)
  • L. Porto et al.

    Accelerated myelination associated with venous congestion

    Eur Radiol

    (2006)
  • E. Sujansky et al.

    Sturge-Weber syndrome: Age of onset of seizures and glaucoma and the prognosis for affected children

    J Child Neurol

    (1995)
  • U. Kramer et al.

    Outcome of infants with unilateral Sturge-Weber syndrome and early onset seizures

    Dev Med Child Neurol

    (2000)
  • T.J. Sullivan et al.

    The ocular manifestations of the Sturge-Weber syndrome

    J Pediatr Ophthalmol Strabismus

    (1992)
  • M.G. Norman et al.

    The ultrastructure of Sturge-Weber disease

    Acta Neuropathol

    (1977)
  • B. Maton et al.

    Medically intractable epilepsy in Sturge-Weber syndrome is associated with cortical malformation: Implications for surgical therapy

    Epilepsia

    (2010)
  • A.J. Kimple et al.

    Regulators of G-protein signaling and their Galpha substrates: Promises and challenges in their use as drug discovery targets

    Pharmacol Rev

    (2011)
  • N. Murakami et al.

    Focal cortical dysplasia type IIa underlying epileptogenesis in patients with epilepsy associated with Sturge-Weber syndrome

    Epilepsia

    (2012)
  • B.R. Smoller et al.

    Port-wine stains. A disease of altered neural modulation of blood vessels?

    Arch Dermatol

    (1986)
  • M. Rydh et al.

    Ectatic blood vessels in port-wine stains lack innervation: Possible role in pathogenesis

    Plast Reconstr Surg

    (1991)
  • M. Sa et al.

    Innervation pattern of malformative cortical vessels in Sturge-Weber disease: An histochemical, immunohistochemical, and ultrastructural study

    Neurosurgery

    (1997)
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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.

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