GNA11‐mutated Sturge–Weber syndrome has distinct neurological and dermatological features

Abstract

Background and purpose: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in G protein subunit Alpha Q (GNAQ). Five cases of subunit Alpha 11 (GNA11) mutations have been reported. We studied phenotypic features of GNA11-SWS and compared them with those of classic SWS.Methods: Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a GNA11 mutation. Clinical and radiological data were collected retrospectively and prospectively. Results:We identified three patients with SWS associated with a somatic GNA11 mutation. All had disseminated capillary malformation (CM) and hyper-or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age, evolving to a purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy with a lower degree of severity than that classically associated with SWS. Susceptibility-weighted imaging (SWI) and contrastenhanced fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrated the best sensitivity to reveal the pial angiomas. Conclusions:We have differentiated two distinct clinical/radiological phenotypes of SWS; GNAQ-and GNA11-SWS. The classic GNAQ-SWS is characterized by a homogeneous dark-red CM, commonly associated with underlying soft tissue hypertrophy. The CM in GNA11-SWS is more reticulate and darkens with time, and the neurological picture is milder. SWI and post-contrast FLAIR sequences appear to be necessary to demonstrate leptomeningeal angiomatosis. Anti-epileptic medication or future targeted therapies may be useful, as in classic SWS.

Genetic testing in the evaluation of individuals with clinical diagnosis of atypicalSturge–Webersyndrome

“…The patient with the GNA11 ‐c.547C > T (p.Arg183Cys) variant had eye and brain involvement on neuroimaging consistent with SWS, but also had overgrowth of her left leg (larger girth and longer length) and dermal hypermelanocytosis on 70%–90% of her body. While three patients who were recently reported to have the GNA11 variant of SWS had mild to moderate hemispheric atrophy (Dompmartin et al, 2022), our patient with the GNA11 ‐c.547C > T (p.Arg183Cys) variant had right hemispheric leptomeningeal enhancement and deep draining vessels that are more traditionally associated with SWS. She had previously been clinically diagnosed with Klippel‐Trenaunay syndrome.…”

“…Overactivation of Ras–Raf–Mek–Erk pathway and mTOR are supported by IHC studies (McCann et al, 2022). However, recent discoveries suggest that variants in the paralogue GNA11 , as well as in GNB2 (p.Lys78Glu), are also related to SWS (Dompmartin et al, 2022; Fjaer et al, 2021; Polubothu et al, 2020; Thorpe et al, 2021). Previous research on GNAQ and GNA11 focused on the dysregulation of the downstream MAPK pathway as the underlying factor of vascular anomalies in SWS; the somatic mosaic variant in GNB2 , noted in a single patient, may impact Yes‐associated protein (YAP), a translational co‐activator of the Hippo signaling pathway.…”

Generalized birthmarks with glaucoma and lower extremity overgrowth

“…A 2022 report describes three adult patients who presented with extensive reticulate CMs that darkened in adulthood, along with variable limb hyper-or hypotrophy, varicose veins with venous insufficiency, and/or glaucoma. 9 All had mild to moderate hemispheric atrophy and pial angiomas on MRI, relatively milder neurologic symptoms compared to classic SWS, and central or autoimmune thyroid disease. While none had pigmentary anomalies, the overlapping features with our patient underscore the potential for phenotypic variability among patients who carry GNA11 mutations, similarly to the variable clinical spectrum that results from single-gene mutations in PIK3CA and GNAQ.…”

“…Last, a distinct subtype of SWS associated with GNA11 mutations has recently been described that is particularly relevant to our case. A 2022 report describes three adult patients who presented with extensive reticulate CMs that darkened in adulthood, along with variable limb hyper‐ or hypotrophy, varicose veins with venous insufficiency, and/or glaucoma 9 . All had mild to moderate hemispheric atrophy and pial angiomas on MRI, relatively milder neurologic symptoms compared to classic SWS, and central or autoimmune thyroid disease.…”

“…Given the high rate of extracutaneous involvement, patients with PPV should be evaluated and monitored for neurovascular, ophthalmological, and/or overgrowth‐related complications. Given the established association between GNAQ mutations and central hypothyroidism, as well as a potential association between GNA11 mutations and variable thyroid dysfunction, patients should also be monitored with regular thyroid screening 9 . Finally, clinicians should also consider annual blood pressure screening, as recent reports have demonstrated a likely association between GNAQ/11 mutations and early‐onset hypertension 10 …”