Recent groundbreaking research by Shirley et al. has identified the causative mutation underlying both Sturge–Weber syndrome and the majority of isolated PWSs. This is a somatic activating mutation in the gene GNAQ, which increases cell proliferation and inhibits apoptosis due to increased downstream signalling through the RAS effector pathways. The cell of origin affected by the mutation is not yet known, but it is likely that the mutation occurs earlier in development in SWS than in isolated PWS, thus affecting a more primitive progenitor with wider potential effects. As all the manifestations of SWS are thought to be related to abnormal vasculature, we hypothesized that the identified high-risk 'forehead' area might correspond to the vascular distribution of the face.
We therefore considered the adult arterial supply, the adult venous drainage and the embryological vasculature of the face. The central forehead in adult life is supplied by the supratrochlear and supraorbital arteries, which are branches of the internal carotid artery, whereas the lateral forehead is supplied by the superficial temporal artery, a branch of the external carotid. While this supply corresponds to the forehead area (with central and lateral areas often affected separately), the adult arterial supply to the cerebral cortex comes only from the internal carotid, and we therefore discounted adult arterial supply as a satisfactory explanation for the strong association between the forehead and cerebral involvement. Adult venous drainage is far more interconnected and could conceivably be a reasonable distribution for the observed pattern of facial PWS. The internal and external jugular veins (unlike their carotid artery counterparts) communicate at the level of the midneck, which could help to explain the importance of both the central and lateral forehead, and as the primary abnormality in the brain is venous, this seemed a plausible model. However, it was more difficult to see how the venous patterning could be related to PWS on other areas of the face, particularly the relatively common lesions with a sharp lower-edge cut-off joining the angle of the mouth to the bottom of the ear, which do not correspond to the venous drainage patterns.
We therefore considered the embryological origin of the face, which involves the fusion of placodes and the formation of the optic vesicles (Fig. 2a). Each placode brings its own developing vasculature from the neural crest, and the primitive vasculature therefore maps to the placode shaping. We found that the forehead corresponds to the frontonasal prominence plus the skin in the optic vesicle area. Crucially, these two structures are the only parts of the face that are formed by the migration of neural crest cells from the developing prosencephalon (forebrain) and anterior mesencephalon (midbrain), whereas the maxillary and mandibular prominences formed from the first branchial arch consist of neural crest cells from the posterior mesencephalon and rhombencephalon, respectively. As the cerebral cortex and the eye both develop from the forebrain, the co-occurrence of forehead involvement and neurological and ophthalmological abnormalities is strongly suggestive of a single mutation affecting the neural crest cells emanating from the forebrain region. In some support of this embryological theory is the notable similarity between the regions identified here and those identified as being affected by infantile haemangiomas.[34,35] For haemangiomas clear patterns of distribution have been delineated, where the authors described an association of the nose and philtrum region with the midline forehead (in that publication so-called segment 4), suggesting that this midline forehead region was narrower than in previous publications, and described a temporal region with a lower border running horizontally from the outer canthus (segment 1). While it is possible that our forehead region corresponds to segments 4 and 1 together, we have not looked for associations between PWS in different regions of the face, as we were focused primarily on adverse outcomes. We do however have patients with wider central forehead involvement that does correspond to the more classical descriptions of the frontonasal prominence (Fig. 2b–d).
(a) Configuration of the facial placodes. The blue area represents the 'forehead', constituting a central frontonasal placode (marked by the dotted lines) and lateral optic vesicle areas. (b) Frontonasal prominence port-wine stain (PWS) – not to be confused with a salmon patch (naevus simplex). (c) PWS sparing the majority of the frontonasal prominence. (d) Unilateral PWS in the 'forehead', suggesting a mutation after division of vasculature into right and left.
Anecdotally we tested our theory of vasculature-based classification of PWS using archived pictures of PWS on the limbs in our patient cohort. We found a striking visual correlation between the vascular but not the neural supply of both extremities and the distribution of PWS (examples in Fig. 3), strengthening our finding in the face. As there were only a few patients presenting with a PWS on their hands or feet, a separate study including a larger group of patients with PWS on their limbs is needed to examine the concept of vascular-based distribution of PWS on the extremities.
Comparison of port-wine stain with the vascular and neural distribution, showing similarity to the vascular distribution in (a) the palm and (b) the sole. Figure adapted from Anatomy of the Human Body.36
This study was not designed to assess the controversial issue of the optimal timing of brain MRI in the investigation of PWS; however, it is known that the features of SWS can be missed through early MRI. As our study demonstrates that an abnormal MRI is the best predictor of all adverse clinical outcomes for these patients, we propose that a gadolinium-enhanced brain MRI be done within the first 3 months of life, with the caveat that a negative result should not be considered conclusive if neurological symptoms develop (Fig. 4). In the context of clinical suspicion of SWS the MRI should be repeated at a later date if negative. In addition, it is important that the appropriate information be given to families surrounding the use of gadolinium enhancement in young children. The potential benefits of diagnostic MRI and use of prophylactic aspirin need to be considered in relation to the potential adverse effects in the individual patient by the clinician. Given the severity of seizures and the association with acute neurological deficit, there is a rationale for the diagnosis of brain involvement in asymptomatic infants and children. These guidelines will now be followed by a prospective study in our department to assess their validity, and ideally would also be assessed in secondary-care settings.
Great Ormond Street Hospital management guidelines for children with facial port-wine stain (PWS) on the forehead. MRI, magnetic resonance imaging.
In conclusion, the distribution of facial PWS appears to follow the embryological vasculature of the face rather than the trigeminal nerve distribution, and this new classification improves the prediction of SWS based on facial PWS phenotype. In this cohort, only children with PWS involving the 'forehead' had any seizures, neurodevelopmental abnormalities, glaucoma or abnormal MRI of the brain, making this the most useful clinical feature. We propose that children with a PWS affecting any part of the forehead should have an ophthalmology review as early as possible, ideally on the first day of life, and a brain MRI with gadolinium contrast. Given the potential use of prophylactic aspirin therapy for those with abnormal MRI we propose that MRI should be performed ideally within the first 3 months, with the understanding that it may need to be repeated at a later date if reported as normal but with a clinical suspicion of SWS. Children with an abnormal MRI should have an electroencephalogram and regular neurological, neurodevelopmental and ophthalmological follow-up. A prospective study has been set up to test these new guidelines.
R.W. is funded by OPO-Foundation, Switzerland; Gottfried und Julia Bangerter-Rhyner Foundation, Switzerland; and University Children's Hospital Zurich Foundation. V.A.K. is funded by the Livingstone Skin Research Centre, UCL Institute of Child Health.
Conflicts of interest
A.E.M. and V.A.K. contributed equally to this work.
The authors would like to acknowledge the expert input of Professor Peter Scambler, UCL Institute of Child Health, regarding the embryonic vasculature.
The British Journal of Dermatology. 2014;171(4):861-867. © 2014 Blackwell Publishing