Knowledge on rare diseases and orphan drugs

The birth prevalence in Europe is estimated at around 1/20,000 to 1/50,000.

The facial port-wine birthmark is present at birth and covers the forehead and/or the upper eyelid (at risk zone). Glaucoma is the most common ocular complication, affecting 30 to 60% of patients with a risk of early visual impairment. Epilepsy is often the first neurological manifestation. Around 80% of patients develop seizures at a median age of 6 months. First seizures are usually focal motor. Drug resistant seizures are reported in up to 50% of patients and status epilepticus is commonly seen. Fever induced seizures are frequently reported. A pattern of seizure clustering followed by prolonged period of seizure freedom occurs in 40% of cases. The natural history is highly variable but typically marked by seizures in early childhood, stroke-like events, progressive hemiparesis and developmental impairment, glaucoma and visual field defects. Later manifestations include headaches, academic difficulties, behavioral and psychiatric disorders. An increased risk of growth hormone deficiency is reported.

The syndrome is caused by a somatic mosaic mutation in GNAQ (9q21) that codes for the protein guanine nucleotide-binding protein G(q) subunit alpha which is critical to the intracellular signaling of a large group of G protein coupled receptors important to vascular development and function. Mutations in GNAQ can also result in an isolated PWB phenotype. The phenotypic presentation is thought to be determined by the developmental time point at which the somatic mutation occurs.

Diagnosis is suspected at birth in newborns presenting facial PWB in the at risk zone. The risk of cerebral involvement in such situation ranges between 15 and 40%. Diagnosis can be confirmed by a contrast-enhanced cerebral magnetic resonance imaging showing direct (angioma) and indirect (enlargement of choroid plexus unilaterally) radiological signs of the leptomeningeal angioma. A computer tomography scan can help diagnosis showing localized calcifications and atrophy, although they might develop later during the course of the disease. Electroencephalogram (EEG) recording can show decreased amplitude of the EEG signal on the side of brain involvement.

The main diagnostic concern is to separate infants with an isolated facial PWB from those with Sturge-Weber syndrome (SWS) brain involvement. Differential diagnosis includes PIK3CA-related overgrowth syndromes, especially megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome.

Prenatal ultrasounds are usually normal.

The disease is sporadic and due to somatic mutations.

A multidisciplinary approach is needed from onset to monitor disease progression in the skin, eye, and brain. Laser treatment is proposed in infancy to reduce the PWS. Regular ocular monitoring is recommended throughout life. Eye drops are used to lower intraocular pressure but surgical interventions may be required. Parental education for early seizure recognition and individualized emergency plans including the use of rescue benzodiazepine therapy is recommended. Low-dose aspirin might be useful to prevent the stroke-like episodes and possibly seizures but the risk-benefit ratio of such approach is not well established. Antiseizure medications are used to treat epilepsy. Patients with focal drug-resistant seizures should be considered early for pre-surgical evaluation at a reference center. Neuropsychological assessments and rehabilitation are needed and physiotherapy is required for functional deficits.

The prognosis of SWS is highly variable. Early seizure onset, drug-resistant seizures and bilateral intracranial involvement have been associated with poor cognitive outcomes.

Last update: January 2021 - Expert reviewer(s): Pr Katarzyna KOTULSKA-JÓŹWIAK | EpiCARE* - Pr Rima NABBOUT | EpiCARE*

* European Reference Network