Sturge weber syndromeQ85.8

Sturge-Weber syndrome, also known as "encephalofacial angiomatosis" or "Sturge-Weber-Krabbe syndrome", is a congenital, neuro/cutaneous vascular disorder (see also Neurocutaneous syndromes) that occurs as a sporadic, congenital disorder; it is characterized by a capillary malformation (nevus flammeus) that affects approximately the skin in the distribution of the ophthalmic branch of the trigeminal nerve and is associated with venous-capillary anomalies of the leptomeninges and the eye.

The following triad characterizes the syndrome:

• mostly unilateral capillary malformation(nevus flammeus) in the area of the ophthalmic nerve (V1 nerve) (Note: this neurogenic association with the known distribution pattern is disputed by various authors). authors)
• vascular malformation of the uvea (development of glaucoma with risk of blindness)
• calcifying hemangiomas of the leptomeninx with pathological changes in the underlying cerebral cortex (neurological symptoms - seizures).

Incidence: approx. 1-2/100,000 inhabitants.

A child born with a port-wine stain on the face has a probability of around 6% of having Sturge-Weber syndrome (Piram M et al. 2012). This risk increases to 26% if the port-wine stain is located in the distribution of the ophthalmic branch of the trigeminal nerve (V1) (Ch'ng S et al. 2008). The capillary malformations in the facial area usually develop "soft tissue and bone tissue overgrowth" to varying degrees (Greene AK et al. 2009).

Sturge-Weber syndrome, as well as non-syndromic port wine stains, are caused by a somatic activating mutation in the GNAQ gene. In Sturge-Weber-Krabbe syndrome, a "non-synonymoussingle nucleotide variant -c.548G→A, p.Arg183Gln- (Note: non-synonymous single nucleotide polymorphisms are SNPs that lead to an amino acid change at the codon in question) in the GNAQ gene in samples of lesional skin (also in lesional brain samples) (Shirley MD et al. 2013).
While the activating somatic R183Q-GNAQ mutation is the most common somatic mutation underlying SWS, more recent research suggests that somatic GNA11 and GNB2 mutations are also associated with SWS (Yeom S et al. 2022).

Somatic single nucleotide polymorphisms in the GNAQ gene can also be detected in non-syndromic facial " port wine stains ".

In Sturge-Weber syndrome, the following hypotheses are discussed: a congenital weakness of the vessel walls, defects in perivascular dermal elements, abnormalities in neuromodulation and a dysmorphogenesis of the cephalic neuroectoderm. The two main hypotheses supported by recent studies are defective nerve innervations to the dermal blood vessels and genetic mutations that lead to dysregulation of angiogenic signaling (Nguyen V et al. 2019). The vessels in PWS lack normal nerve innervations, as evidenced by the significant decrease in S-100-positive nerve fibers affecting only the vessels in the dermis (Nguyen V et al. 2019). As a result, there is a decrease in the basal tone of the vessels and/or a loss of neurotrophic factors, which could lead to the pathological changes of PWS. It has been discussed that there is a defective maturation of sympathetic fibers in the dermal vessels that occurs embryologically, resulting in a loss of sympathetic control, which in turn results in vascular ectasia.

Dermal blood vessels in PWS co-express both arterial markers (EfnB2) and venous markers (EphB1), leading to abnormalities in the normal differentiation of the primary capillary plexus into dermal arterioles and venules. The result is a vein-like vascular system that undergoes progressive dilatation. Abnormal activation of mitogen-activated protein kinases(MAPK) and phosphoinositide 3-kinase(PI3K), which play a key role in angiogenesis, has also been implicated(Nguyen V et al. 2019). Mutations in RASA1, GNAQ, EphB4 and the co-expression of EphB1 and EfnB2 are some of the triggering factors for this abnormal activation.

The causes of abnormal and dilated blood vessels in nevus flammeus (PWS) can be summarized as follows (Liu L et al. 2022):

• Somatic GNAQ (R183Q) mutations that induce angiopoietin-2 lead to the formation of enlarged capillary-like vessels
• Decreased number of perivascular nerve elements
• Coexistence of Eph receptor B1 and ephrin B2
• Lack of expression of alpha-smooth muscle actin

Predominantly unilaterally localized (up to 15% bilateral) capillary malformation(nevus flammeus, also known as port wine stain) of one half of the face, often only in the area of spread of the 1st trigeminal branch (see below). More rarely, the entire half of the head and the oral mucosa (with gingival hyperplasia) are affected.

Eye: In the eye, an ipsilateral vascular malformation (angiomatosis) of the choroid (in about 60% of cases - especially if the area of distribution of the 1st and 2nd trigeminal branch is affected). trigeminal branch is affected) can lead to complications such as glaucoma, open buphthalmos and retinal detachment. A prevalence rate of 30 to 70 % is found in patients with moles on the upper and lower eyelids.

Glaucoma can develop at any time, with the most common periods being in infancy and young adulthood. In 60 % of patients, glaucoma occurs in early infancy, in 40 % of patients it begins later.

In Sturge-Weber syndrome patients, open-angle glaucoma is the most common form of glaucoma. Symptoms of open-angle glaucoma include loss of vision, the development of dilated conjunctival vessels, eye pain, excessive tearing and, in infants, enlargement of the eye (buphthalmos). If left untreated, glaucoma can threaten vision by causing ischemic damage to the optic nerve (Yeom S et al. 2022).

Children with SWS often develop seizures by the age of 2 years, which may be associated with contralateral neurological deficits. Earlier onset of seizures has been associated with intellectual and language disabilities; active epilepsy has been associated with language impairment. The cause is involvement of leptomeningeal vessels with focal calcifications). Also possible: spastic hemiparesis, migraine.

Full manifestation of the syndrome is only present in about 50% of cases. In the absence of eye involvement, it is also referred to as angiomatosis encephalo-cutanea, in the absence of CNS involvement as angiomatosis oculo-cutanea .

Neurological and ophthalmological examination (in particular measurement of intraocular pressure), X-ray of the skull (characteristic, double-contoured, tortuous calcifications), computer tomogram and possibly magnetic resonance tomogram of the skull and EEG.

Imaging of the brain may show cerebral atrophy with gyriform calcifications described as a "tram-track sign".

Children with Surge-Weber syndrome often develop seizures by the age of 2 years, which can be accompanied by contralateral neurological deficits and learning difficulties. In the eye, choroidal angioma can lead to complications such as glaucoma, buphthalmos and retinal detachment. A facial nevus flammeus involving any area of the forehead, including the upper eyelid and the midline of the frontonasal projection, is the most important indicator of Sturge-Weber syndrome. It is noteworthy that not all patients with naevus flammeus develop Sturge-Weber syndrome; manifestation on the forehead is the strongest independent predictor (Sánchez-Espino LF et al. 2023).

Treatment of the skin lesions with the laser (argon, pulsed dye laser).

The clinical efficiency of latanoprost on glaucoma associated with vascular malformation has to be considered unsatisfactory (Altuna JC et al.1999).

Formation of vascular nodules in the area of the nevus flammeus with age (PWS=Portwine stains).

High-risk factors for associated abnormalities of the central nervous system in patients with nevus flammeus (Sánchez-Espino LF et al. 2023)

• Extensive bilateral involvement
• Hemifacial involvement of the forehead
• Median PWS
• >50% contiguous hemifacial involvement of the forehead

The long-held view that the distribution of vascular malformations is due to the trigeminal nerve is challenged by the observation that the distribution pattern appears to follow the course of embryologic vessels.

The somatic-activating mutations in GNAQ encoding p.Gln209Leu and p.Arg183Gln are also found in patients with uveal melanoma (Shirley MD et al. 2013). The more common p.Gln209Leu has been shown to overactivate the mitogen-activated protein kinase (MAPK) signaling pathway (Van Raamsdonk CD et al. 2009).

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