Disorders In Depth

Sturge-Weber Syndrome (SWS) - Leptomeningeal Angiomatosis

Sturge-Weber syndrome: Definition, epidemiology and pathology. Classically, Sturge-Weber Syndrome (SWS) is defined by a facial capillary malformation (port-wine birthmark/ PWB aka port-wine stain) in association with ipsilateral vascular malformations of the eye and/or the brain (Bodensteiner JB, 1999). The brain vascular malformation affects the leptomeninges, and is termed a leptomeningeal angioma. Variants exist where only one of these three structures is involved with the vascular malformation (Comi, 2003). SWS is a congenital syndrome that occurs almost exclusively sporadically, and not in families. Precise population-based data does not exist for the prevalence or incidence of SWS. However, port-wine stains occur in 3 per 1000 live births, and when a capillary malformation involves the forehead to one side and/or the upper eyelid, that individual is at risk for brain and/or eye involvement. The risk ranges between 10-35% depending on the size of the port-wine stain and whether it is unilateral or bilateral (Enjolras et al., 1985; Tallman et al., 1991). Prevalence data obtained from large dermatologic clinics (Enjolras et al., 1985; Tallman et al., 1991) suggests that about 5-10,000 individuals in the United States have SWS.





Many important clinical questions about SWS remain unanswered or controversial. For example, how does family history of strokes, migraines, and endocrine, vascular or immune disorders impact the clinical manifestation of the individual affected by SWS? What pregnancy exposures or factors occur with increased frequency in individuals with SWS? Which patients would be best served by a hemispherectomy? What is the cognitive outcome after hemispherectomy versus medical management of seizures in SWS? Which patients should be treated with low-dose aspirin and what are the risks and side effects? How often does central hypothyroidism and growth hormone deficiency occur in patients with SWS? The answers to these and other questions will eventually be addressed with the aid of the consortium database.

Given the clinical variability inherent in SWS, another important goal is the development of safe, minimally invasive biomarkers and tools to monitor clinical status. Urine vascular biomarkers are a promising area of new investigation. Pioneered by Dr. Moses’ group, urine profiling of vascular biomarkers has previously been used successfully to profile different vascular disorders (infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation) and to separate progressive vascular lesions from stable lesions (Marler et al., 2005), thus providing proof-of-principle that this approach can be used to non-invasively differentiate vascular disorders, sub-group patients, and provide predictive information. A similar approach has proven successful using urine biomarkers to predict breast cancer risk (Pories et al., 2008). Published work with brain tumors also demonstrates that urinary biomarkers can be used to predict response to treatment (Smith et al., 2008). Hence, this method might also be a powerful means of rapid screening for potential vasculostatic drug effects in the context of a large, simple clinical trial.  This project will apply these biomarkers to predicting the neurologic course in SWS.

Etiology and pathogenesis of SWS. Sturge-Weber syndrome occurs almost entirely sporadically and with equal frequency in the sexes (Comi, 2003). The localized abnormalities of blood vessel development and function affecting the facial skin, eye and brain suggest a developmental disruption occurring in the first trimester of pregnancy. Since the abnormal blood vessels in SWS are usually localized to a single region on one side of the body, a somatic mutation (somatic mosaicism) model for the etiology of SWS has been proposed (Happle, 1987). During the first trimester of fetal development the primitive vascular plexus invades the adjacent developing brain, skin and eye in this region and a somatic mutation could prevent the normal maturation of these vessels. A report of typical bilateral Sturge-Weber syndrome in only one member of a pair of monozygotic twins reinforces the thought that any genetic basis for SWS is likely due to somatic, rather than germline mutation (Pedailles et al., 1993). We (Drs. Comi and Pevsner) have previously reported consistent differences in gene expression between affected and unaffected tissue from the same individual with SWS. Microarray and RT-PCR data revealed an increase in fibronectin expression in fibroblasts derived from the port-wine stains of subjects with Sturge-Weber syndrome compared to fibroblasts from the normal skin of the same subjects (Comi et al., 2003). Chromosomal abnormalities have also been noted in fibroblast cultures derived from affected regions (dilated leptomeningeal blood vessels in one case and port-wine derived skin tissue in the other) of two of four studied individuals with Sturge-Weber syndrome (Huq et al. 2002).  Research to better understand and treat SWS has been hindered by the lack of a firm understanding of the molecular pathogenesis of the syndrome. Identification of the causative somatic mutation(s) would determine the pathogenic pathways involved and provide clues to direct research into the prevention and treatment of SWS.



Assie, G., LaFramboise, T., Platzer, P., Bertherat, J., Stratakis, C. A., and Eng, C. (2008). SNP arrays in heterogeneous tissue: highly accurate collection of both germline and somatic genetic information from unpaired single tumor samples. Am J Hum Genet 82, 903-915.




Comi, A. M., Hunt, P., Vawter, M. P., Pardo, C. A., Becker, K. G., and Pevsner, J. (2003). Increased fibronectin expression in sturge-weber syndrome fibroblasts and brain tissue. Pediatr Res 53, 762-






Huq AH, Chugani DC, Hukku B, Serajee FJ. (2002)  Evidence of somatic mosaicism in Sturge-Weber syndrome. Neurology 59, 780-782.








Pedailles, S., Martin, N., Launay, V., Sentias, C., Barre, M., Saintive, J. P., and Bessis, J. L. (1993). [Sturge-Weber-Krabbe syndrome. A severe form in a monozygote female twin]. Ann Dermatol Venereol 120, 379-382.






Ting, J. C., Roberson, E. D., Miller, N. D., Lysholm-Bernacchi, A., Stephan, D. A., Capone, G. T., Ruczinski, I., Thomas, G. H., and Pevsner, J. (2007). Visualization of uniparental inheritance, Mendelian inconsistencies, deletions, and parent of origin effects in single nucleotide polymorphism trio data with SNPtrio. Hum Mutat 28, 1225-1235.