Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis): Recent Advances and Future Challenges.

REVIEW ARTICLE

Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis): Recent Advances and Future Challenges Jessica S. Maslin, MD,* Syril K. Dorairaj, MD,Þ and Robert Ritch, MDþ

Abstract: Sturge-Weber syndrome (SWS) is a congenital, sporadically occurring, neurocutaneous syndrome that presents classically with portwine stain, leptomeningeal angiomas, and glaucoma. The systemic implications of SWS are vast and involve not only ophthalmic manifestations but also dermatologic, neurologic, and oral manifestations. Neuroimaging, in particular, plays an important role in the diagnosis and management of this disease. Recent discoveries have been made regarding the genetic pathogenesis of SWS. In addition, recent advances have been made in the management of the 2 most common ophthalmic manifestations of SWS: diffuse choroidal hemangioma and glaucoma. Despite these new contributions to the field, many challenges still remain. The management of diffuse choroidal hemangioma is wide ranging and includes photodynamic therapy, brachytherapy, radiotherapy, and antivascular endothelial growth factor injections, but all have had limited or varied success. Although there have been recent advances in knowledge and technique, the management of glaucoma is extremely complex, given the high surgical risks for complications and a poor response rate to medical therapy. Further studies are critical to maximize our knowledge of this difficult disease. Key Words: pediatric glaucoma, ocular imaging, vascular malformations, neurocutaneous syndromes, ocular nevus (Asia Pac J Ophthalmol 2014;3: 361Y367)

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turge-Weber syndrome (SWS) is a congenital syndrome characterized by a classic triad of facial capillary malformation [port-wine stain (PWS)], intracranial vascular abnormalities (leptomeningeal angiomas), and glaucoma. Management of this disease involves multiple specialties, spanning not only ophthalmology but also pediatrics, neurology, dermatology, cardiology, anesthesia, and even dentistry. This review summarizes the most recent literature updates regarding the clinical features and management of ocular complications of these syndromes with a focus on glaucoma.

From the *Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT; †Department of Ophthalmology, Mayo Clinic, Jacksonville, FL; and ‡Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai School of Medicine, New York, NY. Received for publication August 25, 2014; accepted October 13, 2014. Dr Ritch is the associate editor in chief of Asia-Pacific Journal of Ophthalmology and, as such, has not reviewed this article for consideration to publish. He is a board member of Sensimed and iSonis Medical and a consultant of Aeon Astron; has received travel expenses and speaker fees from Allergan, Merck, Pfizer, Taejoon Pharmaceutical, and the Ministry of Health of Kuwait; receives royalties from Ocular Instruments; and owns stock at Aeon Astron and Diopsys; none of which was used to support any part of this work. The remaining authors have no funding or conflicts of interest to disclose. Reprints: Syril K. Dorairaj, MD, Department of Ophthalmology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. E-mail: [email protected]. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000093

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MATERIALS AND METHODS We performed a literature search on PubMed for articles containing the text ‘‘Sturge-Weber.’’ Filters used included English only. Articles that were used for updated information included only those from 2010 onward. Other cited articles are for background information only.

PATHOGENESIS AND GENETICS Sturge-Weber syndrome occurs sporadically, with an estimated incidence of 1 in 50,000 live births.1 It has been theorized to result from a somatic mutation that causes a primordial embryonic venous plexus, which normally present at 5 to 8 weeks of gestation, to fail to regress.2 This, in turn, leads to venous hypertension, tissue hypertrophy, and formation of developmental vascular malformations that grow with the body, fail to regress, and have normal endothelial mitotic activity.2,3 These vascular malformations lead to increased permeability, stasis, thrombosis, and ischemia throughout the body, resulting in a wide variety of systemic symptoms. A recent study published by the New England Journal of Medicine used whole-exome sequencing to identify the same somatic mutation in the GNAQ gene on chromosome 9q21 that occurs in nonsyndromic PWS and SWS.4 The authors found a single nucleotide variant from an amino acid substitution in the guanine nucleotideYbinding protein (G protein), also known as q polypeptide or G>q subunit that is encoded by the GNAQ gene. This variant occurs in a region that is normally highly conserved and has been identified in the affected skin of patients with nonsyndromic PWS and in both the affected skin and the leptomeningeal angiomas of patients with SWS. This variant is noticeably absent from unaffected tissues. The G>q subunit acts in the signaling between G protein-coupled receptors, including endothelin and downstream effectors. One known effect that GNAQ has is that it hyperactivates extracellular signal regulated kinase (ERK)-phosphorylation.5 There has been a speculation that ERK inhibitors may be a potential treatment of not only SWS but also PWS.5 Although no research has yet been conducted on this potential treatment, the revolutionary GNAQ somatic mutation discovery may pave the way for more effective treatments of SWS and PWS.

DISEASE FEATURES Systemic Manifestations Sturge-Weber syndrome can be classified into 3 types using the Roach Scale (Table 1).6 The most common is type 1, which is the classic manifestation of PWS and intracranial leptomeningeal angioma. Type 1 may or may not have ocular abnormalities, such as glaucoma. Type 2 is characterized by a PWS and an ocular involvement but with no brain abnormalities. Type 3 is characterized by leptomeningeal angiomatosis without cutaneous lesions or ocular abnormalities. This form is usually diagnosed during imaging for epilepsy. Classically, SWS is associated with a PWS in the ophthalmic division of the trigeminal nerve (V1; Fig. 1). Although PWS can be extracephalic, 78% of PWS that affect the entire

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TABLE 1. Roach Classification for SWS

Facial angioma Leptomeningeal angioma Glaucoma

Type 1

Type 2

Type 3

Present Present May be present

Present Not present May be present

Not present Present Not present

V1 distribution are associated with neurological or ocular findings.7 Port-wine stain is present at birth and consists of loosely arranged, dilated, thin-walled capillaries in the dermis and subcutaneous tissue. A recent retrospective study of 192 children with a facial PWS suggested that PWS appear to follow the embryological vasculature of the face rather than the V1 distribution.8 This study suggests that PWS of the forehead area, rather than the V1 area, should be highly suspicious for SWS and that these patients should receive an ophthalmology consult and magnetic resonance imaging (MRI) of the brain with contrast. Another recent cross-sectional study of 259 patients with PWS found that SWS was significantly associated with facial PWS that is bilateral and involves the upper eyelid in particular.9 Vascular malformations in SWS may also manifest in the other areas of the body. Vascular malformations can involve the mouth,10 leading to difficulty with intubation. One recent case report highlighted a patient with SWS undergoing glaucoma surgery who experienced a difficult intubation because of an extensive angiomatous soft tissue swelling in the upper airway.11 Oral manifestations can also include large tongue, vascular hypertrophy of the lips, buccal mucosa, gums, and periodontal area. These vascular lesions can hemorrhage, causing uncontrolled bleeding. Localized or diffuse visceral vascular malformations may occur in the kidneys, spleen, intestine, pancreas, lungs, and thyroid. Leptomeningeal vascular malformations are present in 98% of all patients with SWS and typically occur over the pia mater in the occipital and parietal lobes ipsilateral to the PWS.12

FIGURE 1. Unilateral PWS in the V1 distribution. This figure is under a Creative Commons license and taken from Waelchli et al.8 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

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Leptomeningeal angiomas can cause strokelike symptoms, hemiparesis, epilepsy, mental retardation, and developmental delay. Seizures occur in 75% of patients with SWS before the age of 1 year.13 Aspirin prophylaxis has been recently suggested as a method to prevent episodes of vascular ischemia that may lead to neurological events such as transient hemiparesis.14

Ocular Manifestations In SWS, vascular abnormalities of the conjunctiva, episclera, retina, and choroid lead to ocular complications. These include congenital glaucoma, which is the most common and discussed in a separate section later; episcleral hemangioma or dilation of the episcleral vessels (Fig. 2); choroidal hemangioma; iris heterochromia (8%)15; and even iris neovascularization in rare cases.16 In 1939, the suggestion of Anderson17 that vascular malformations involving the upper lid lead to ipsilateral intraocular involvement became known as Anderson’s rule17 but has since proved to have many exceptions18 and should be used as a general guideline rather than a rule. The second most common ocular abnormality in SWS is choroidal hemangioma,19 which occurs in at least 40% of cases.20 Sturge-Weber syndrome choroidal hemangiomas tend to be diffuse, unilateral, and ipsilateral to the PWS and are typically present at birth. Vision loss in patients with SWS with choroidal hemangiomas occurs because of hyperopic shift, destruction of the choriocapillaris and degeneration of the overlying retinal pigment epithelium, or subretinal fluid and exudative retinal detachment.21 The ‘‘tomato ketchup’’ fundus that has been historically described as being typically associated with choroidal involvement in SWS is actually diffuse uveal involvement of the choroidal hemangioma (Fig. 3).22 Choroidal hemangiomas can be identified on ultrasound by their high internal

FIGURE 2. Dilation and tortuosity of conjunctival and episcleral vessels in a young adult with SWS and severe glaucoma. There is prominent ‘‘corkscrewing’’ of the conjunctival vessels. This figure is taken from Parsa2 and republished with permission of the American Ophthalmological Society. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. * 2014 Asia Pacific Academy of Ophthalmology



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SWS (Encephalotrigeminal Angiomatosis)

THE ROLE OF IMAGING

FIGURE 3. Fundus photo of a ‘‘tomato ketchup’’ fundus from diffuse choroidal hemangioma. This figure is under a Creative Commons license and taken from Monteiro et al.36 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

reflectivity and increased choroidal thickening (Fig. 4). On fluorescein angiography, they show early hyperfluorescence with late leakage and dye stain (Figs. 5A, B). Although numerous therapeutic options currently exist for diffuse choroidal hemangiomas in SWS, including external beam radiation therapy, proton beam therapy, brachytherapy, photodynamic therapy (PDT), and antivascular endothelial growth factor treatment, there has been limited success and each treatment has its own challenges.23Y26 The decision to treat rests on the extent of the serous retinal detachment and vision loss. Recently, systemic propranolol has been tried as a potential treatment of diffuse choroidal hemangioma, with conflicting results in the literature. In a study published by Krema et al,27 oral propranolol failed as a treatment modality in 2 cases. However, in another study, oral propranolol at a similar dose was used successfully to treat exudative retinal detachment from diffuse choroidal hemangioma in a young boy with SWS,28 with complete resolution of the retinal detachment. Treatment of diffuse choroidal hemangioma in patients with SWS remains controversial. Two cases have been reported with successful treatment with antivascular endothelial growth factor29,30 and 2 cases with brachytherapy.31,32 Treatment with radiation is often seen as the best management for diffuse choroidal hemangioma, especially those with extensive subretinal fluid, but radiation may cause vision-threatening subretinal fibrosis and optic neuropathy.26 Recent advances in technique for low-dose proton radiotherapy may help minimize these complications and has had moderate success in 2 recent studies.23,33 Photodynamic therapy has emerged as another potentially effective treatment option.26 There have been 7 case reports of successful single PDT treatment of diffuse choroidal hemangiomas26,34 and, more recently, 2 case reports that required multiple treatments of PDT for successful treatment.35,36 Spectral domain optical coherence tomography can be used to measure increased choroidal thickness in patients with SWS and thus can measure response to PDT as well.34 Photodynamic therapy may indeed be a good treatment option in the management of diffuse choroidal hemangiomas, with potentially multiple treatment sessions required for its success. * 2014 Asia Pacific Academy of Ophthalmology

Imaging has an important role in the diagnosis, detection, and follow-up of patients with SWS. Although, historically, the imaging finding that SWS is most known for is a ‘‘tramline’’ of progressive calcification seen on x-ray, which occurs secondary to vascular stasis affecting the subintimal layer of the meningeal arteries, MRI is now considered a superior imaging modality. Magnetic resonance imaging specifically T1-weighted MRI with gadolinium contrast and susceptibility-weighted imaging37 is the best imaging modality to diagnose the intracranial manifestations of SWS and is often cited as the ‘‘criterion standard’’ to diagnose SWS.14,38 This is especially important in asymptomatic cases. Magnetic resonance imaging may demonstrate thickened cortex, decreased convolutions, abnormal white matter, and gadolinium enhancement of leptomeningeal angioma14 as well as enlargement of transmedullary and periventricular veinsYassociated dilation and enhancement of the choroid plexus on the involved side, and dilated deep draining venous vessels (Figs. 6A, B).39Y41 Other typical MRI findings include atrophy and calcification underlying the leptomeningeal angioma, which is thought to be secondary to chronic cortical hypoxia due to vascular stasis.12,42 In addition to diffusion MRI, susceptibility-weighted imaging may be able to detect small venous abnormalities and microstructural white matter changes missed by conventional MRI.43 Fludeoxyglucose positron emission tomography may demonstrate markedly depressed glucose metabolism in the affected cerebral hemisphere (Fig. 6C) and single-photon emission computed tomography may demonstrate cerebral perfusion abnormalities in patients with SWS who have not yet manifested symptoms.44,45 Magnetic resonance imaging of diffuse choroidal hemangiomas may demonstrate thickening of the posterior wall of the globe on unenhanced T1-weighted images (Fig. 7). On injection of contrast material, there is a crescentic enhancement, thickest at the posterior pole, extending to the anterior portion of the globe.

FIGURE 4. Ultrasonography of a diffuse choroidal hemangioma. There is diffusely thickened choroid with high internal reflectivity (arrows) and total retinal detachment (arrowhead). This figure is used with permission from Yonekawa et al.33 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. www.apjo.org


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FIGURE 5. Fluorescein angiography demonstrating the slight leakage in the superior and temporal macular area at early (A) and late phase (B). This figure is used with permission from Cacciamani et al.34 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

Electroencephalographic (EEG) findings can also offer an important diagnostic clue in patients suspected of having SWS. It has previously been suggested that EEG may be helpful as a noninvasive test to screen for neurological involvement in asymptomatic infants with a suspicious facial PWS.46 A typical EEG in SWS is asymmetric, with the affected hemisphere showing a reduction in voltage of the posterior basic rhythm and a slowing of the background 5 activity.46

STURGE-WEBER SYNDROME AND GLAUCOMA Congenital glaucoma is the most common ocular abnormality found in SWS, occurring in an estimated 30% to 70% of cases.47Y50 It is typically unilateral and ipsilateral to a PWS involving the lid or a vascular malformation involving the episclera or choroid. Diffuse choroidal hemangioma, which is seen in approximately half of the patients with SWS,50 has been known to increase the risk for developing glaucoma. For example, 88% of patients with choroidal hemangioma develop glaucoma.51 Presentation of glaucoma is trimodal, with 40% in 1 peak during the first year of life, 23% presenting between the age of 5 and 9 years, and 20% presenting after the age of 20 years. Because of this possibility of late-onset glaucoma, continued yearly ophthalmologic examination of both eyes is necessary.49

Pathogenesis Multiple theories have been established and elucidated further in recent years as to what is the exact mechanism that causes glaucoma in SWS. It was previously demonstrated that SWS may be associated with a disorder of neural crest migration and differentiation. Because the trabecular meshwork cells also derive from the embryonic neural crest, developmental anomalies of the angle may occur in these syndromes, accounting for congenital glaucoma52,53 that occurs in the patients with SWS who develop glaucoma before the end of the first year of life. The patients with SWS with congenital glaucoma typically have gonioscopic abnormalities similar to children with primary congenital glaucoma, with a high insertion of the iris and increased opacification of tissues over the angle. There potentially may also be a factor of hypersecretion of the aqueous from the ciliary body or from the choroidal hemangioma present at birth as well.54 A recent retrospective review of 55 patients with SWS and gonioscopic findings demonstrated possible association with iris heterochromia as an example of the potential role neural crest cells have on the development of glaucoma in the infantile SWS group.55 Genetic analysis of infants with SWS and glaucoma demonstrates that nearly half of the infants with SWS and glaucoma have mutations in the CYP1B1 gene, a major cause of primary congenital glaucoma.19

FIGURE 6. Magnetic resonance images of a 3-year-old boy with bilateral facial PWS, left-sided hemiparesis, and seizures. Axial (A) and coronal (B) T1-weighted MRI with gadolinium contrast respectively showing asymmetric leptomeningeal enhancement, prominent choroidal vessels, and right-sided atrophy. C, Fludeoxyglucose positron emission tomography of the same patient showing right-sided hypometabolism most prominent in the right frontal region. These figures are used with permission from Sudarsanam et al.37 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

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Management

FIGURE 7. Magnetic resonance image showing choroidal thickening (arrow), overlying subretinal fluid (arrowhead), and vitreous (asterisk). This figure is used with permission from Yonekawa et al.33 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

In older patients, the angle is typically of a normal anatomy. The common mechanisms for glaucoma pathogenesis in this age group, which can be classified as a type of late-onset juvenile glaucoma, include elevated episcleral venous pressure (EVP) and angle closure secondary to choroidal hemangioma hemorrhage causing forward displacement of the iris.56 Neovascular glaucoma can also occur secondary to diffuse choroidal hemangioma and may be so severe as to require enucleation. 57 Elevated EVP is hypothesized to occur because of episcleral angiomas, which lead to increased EVP and ocular hypertension. This second group, in particular, has been strongly associated with ipsilateral diffuse choroidal hemangiomas.58 Previously, ultrasound biomicroscopy has shown dilated intrascleral vessels and supraciliary fluid, supporting the hypothesis of elevated EVP as the cause of open-angle glaucoma.59 These patients often have choroidal hemangiomas or episcleral hemangiomas as well and require trabeculectomy or glaucoma drainage device surgery.56 In a recent study on the ocular hemodynamics of 16 patients with SWS, Conway and Hosking60 found that ocular blood flow velocities are reduced in patients with SWS compared with healthy controls, irrespective of whether these patients had glaucoma. It is not known at this point whether this particular vascular alteration associated with SWS plays a significant role in the development of glaucoma in these patients. There has been controversy about the possibility of laser treatment of PWS increasing the risk for glaucoma in the ipsilateral eye. A proposed theory suggests that pulsed dye laser used to treat facial PWS by occluding venous channels could potentially worsen already impaired ocular venous flow and thus increase the development or worsening of glaucoma in patients with SWS.61 However, recent studies suggest that there may be no association at all. In a cross-sectional observational study of 15 patients with SWS who each received 1 session of pulsed dye laser therapy, Quan et al61 found no association with an increase in intraocular pressure (IOP). A retrospective review of 41 patients with SWS, 28 of whom underwent laser for facial PWS, did not identify any evidence, suggesting that laser treatment of PWS may increase the risk for developing glaucoma or worsen preexisting glaucoma54; however, the study was noted to have many limitations.62 * 2014 Asia Pacific Academy of Ophthalmology

Medical management with drops may be attempted at first. A recent prospective case series examined the effect of oral propranolol on lowering IOP in 4 infants with SWS with congenital glaucoma.63 In 3 of the 4 patients, the IOP-lowering effect was temporary and additional medical and surgical intervention was necessary.63 Most cases of SWS glaucoma eventually require surgical intervention, but there is no current consensus in the literature about the best method. In general, goniotomy and trabeculotomy are attempted in infants with SWS with glaucoma because the disease is similar to primary congenital glaucoma. Goniotomy offers the advantage of preserving the conjunctiva in case future filtration surgery is required. Historically, the success rate of goniotomy or trabeculotomy in the long-term control of IOP has been relatively low.64Y66 Recent studies demonstrate conflicting evidence about the success of trabeculotomy in treating congenital glaucoma in patients with SWS. In a retrospective study by Saltzmann et al,67 38 eyes with congenital glaucoma (6 of which were from patients with SWS) were analyzed for success rate after trabeculotomy. The study found that, of the eyes achieving complete success (IOP control without additional medical therapy), none were patients with SWS. The study found that eyes with SWS had a significantly higher failure rate and a relative risk of failure of 5.81, more cup-to-disc ratio progression, as well as higher IOP both before and after surgery.67 Similarly, Ikeda et al68 found that, of the secondary glaucomas, eyes with SWS fared the worst after trabeculotomy in a 20-year follow-up study. Despite this, a study of 133 eyes with pediatric glaucoma found that SWS glaucomatous eyes (16 eyes), in addition to primary congenital glaucoma, had a better visual prognosis than the other subtypes.69 The study demonstrated that good IOP control did not necessarily mean a good visual outcome and that amblyopia and vision at diagnosis were the biggest determinants to final visual potential.69 Although trabeculectomy may be the best choice if the angle appears clinically normal, as in the second group of older patients as discussed previously with late-onset juvenile glaucoma, it is important to note that the success of trabeculectomy in a pediatric population is diminished because of lower scleral rigidity and a rapid and exuberant healing response.70 Trabeculectomy bypasses any component of the glaucoma caused by elevated EVP, whereas goniotomy does not, and may have less risk for choroidal hemorrhage.48 Filtering surgery in SWS is fraught with more complications and risks than in the patient with typical glaucoma. There is an increased risk for choroidal hemorrhage because of hemangioma during or after the globe is entered71 as well as sudden choroidal effusion. A recent case report described cilioretinal artery occlusion after glaucoma drainage device surgery and highlights this rare complication.72 Radiotherapy of the choroidal hemangioma might protect against expulsive hemorrhage. Other surgical techniques, such as replacing the flap quickly, preplaced posterior sclerotomies, prophylactic laser photocoagulation, and cauterization of the anterior episcleral vascular anomalies, may help as well.73 A recent study of 2 patients who received transpupillary thermotherapy observed an IOP decrease and proposed that transpupillary thermotherapy may be a good option for patients with both late-onset juvenile glaucoma and diffuse choroidal hemangioma.74 Another recent article described a modified approach to the conventional trabeculectomy technique in 1 successful case, which the authors believe may lower the risk for expulsive hemorrhage. In this technique, a viscoelastic www.apjo.org


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device, Healon (Abbott Medical Optics, Abbott, Ill), was injected before penetrating the inner window to maintain a steady IOP and a good anterior chamber depth throughout the procedure and postoperatively as well.75 Glaucoma drainage implants have been used with varying amounts of success in patients with SWS with late-onset glaucoma and are associated with complications, including choroidal hemorrhage, tube-corneal touch, transcorneal/conjunctival tube erosion, tube retraction, iritis, hypotony, cataract, and retinal detachment. There have been no studies in the literature comparing the success of filtering surgery with glaucoma drainage devices for patients with SWS in particular, and often, the decision must be made on a case-by-case basis. Sturge-Weber syndrome is a congenital syndrome that has wide-ranging and profound systemic and ocular manifestations that can result in permanent disability and vision loss. Recent studies have dramatically improved our understanding of the pathogenesis of SWS, but the management of this complex disease still remains challenging and often must involve the ophthalmologist working together across multiple specialties. The most common among ocular complications is glaucoma, which is often seen together with diffuse choroidal hemangioma, the second most common ocular manifestation. The management of both entities remains challenging, despite recent advances in technique and in knowledge. REFERENCES 1. Thomas-Sohl KA, Vaslow DF, Maria BL. Sturge-Weber syndrome: a review. Pediatr Neurol. 2004;30:303Y310. 2. Parsa CF. Focal venous hypertension as a pathophysiologic mechanism for tissue hypertrophy, port-wine stains, the Sturge-Weber syndrome, and related disorders: proof of concept with novel hypothesis for underlying etiological cause (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2013;111:180Y215. 3. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69:412Y422. 4. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368:1971Y1979. 5. Comi AM, Marchuk DA, Pevsner J. A needle in a haystack: Sturge-Weber syndrome gene discovery. Pediatr Neurol. 2013;49:391Y392. 6. Roach ES. Neurocutaneous syndromes. Pediatr Clin North Am. 1992; 39:591Y620. 7. Ch’ng S, Tan ST. Facial port-wine stains - clinical stratification and risks of neuro-ocular involvement. J Plast Reconstr Aesthet Surg. 2008; 61:889Y893. 8. Waelchli R, Aylett SE, Robinson K, et al. New vascular classification of port-wine stains: improving prediction of Sturge-Weber risk. Br J Dermatol. 2014;17:861Y867. 9. Piram M, Lorette G, Sirinelli D, et al. Sturge-Weber syndrome in patients with facial port-wine stain. Pediatr Dermatol. 2012;29:32Y37. 10. Pontes FS, Conte Neto N, da Costa RM, et al. Periodontal growth in areas of vascular malformation in patients with Sturge-Weber syndrome: a management protocol. J Craniofac Surg. 2014;25:e1Ye3. 11. Wong HS, Abdul Rahman R, Choo SY, et al. Sturge-Weber-Syndrome with extreme ocular manifestation and rare association of upper airway angioma with anticipated difficult airway. Med J Malaysia. 2012; 67:435Y437. 12. Baselga E. Sturge-Weber syndrome. Semin Cutan Med Surg. 2004; 23:87Y98.

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Letter to the Editor Regarding Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis): Recent Advances and Future Challenges.

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