The RASA-1 gene (RAS p21 protein activator 1; OMIM 139150) located on chromosome 5q13.3 encodes the protein p120 RasGAP, a negative regulator of the Ras p21 oncogene. Mouse embryos with targeted disruptions in rasGAP fail to transform their initial aggregation of endothelial cells into a functioning vascular network [3, 4]. The RASA-1 related syndromes are inherited as an autosomal dominant trait with a penetrance estimated between 89-96% [5–7].
Several families with varying inactivating mutations in the RASA-1 gene have been studied [5, 6, 8–12]. The phenotypic hallmark of the RASA-1 malformation appears to be the presence of multifocal capillary malformations however fast-flow vascular malformations are seen in more than one third of affected individuals. Capillary malformations in this syndrome often have a pale halo around the pink or red macular stains which is atypical for a sporadic CM . The location of the associated fast-flow vascular malformations is variable. These may be identified in the intracranial space, such as a vein of Galen malformation, intradurally, or in extracranial locations, such as the face, trunk, or extremities. Visceral AVMs are not typically seen. Some patients with a RASA-1 mutation present with Parkes-Weber syndrome, characterized by multiple fast-flow vascular anomalies, including extensive intramuscular microfistula, capillary malformations, and limb overgrowth. Previously thought to be a sporadic condition, its shared genetic basis with CM-AVM suggests that the two entities are merely different manifestations of the same genetic entity. Mutations in the RASA-1 gene also underlie at least some cases of vein of Galen malformation . In addition, there is evidence of defective lymphangiogenesis  although this is generally clinically unapparent.
The localized nature of the vascular lesions and their multifocality are intriguing in the setting of a disease caused by a germ line mutation. Some authors have invoked a somatic “second hit” mechanism to explain the large areas of unaffected tissues. Indeed, such a mechanism is reported to underlie several genetic vascular anomalies, such as glomuvenous malformation, cerebral cavernous malformation, and the PTEN mutation syndromes. Of further interest are the variable phenotypes appearing within each affected family. Our patient, for example, has a strong family history of multiple capillary malformations but without AVM or AVF. It is possible that such lesions are present and have been clinically silent, as the family members have not undergone imaging screening. However, previous work involving screened family members who carry identical mutations have documented phenotypic variability, with many genetically affected family members entirely lacking a high-flow vascular lesion. For example, this patient’s genetic alteration in the (c.2603 + 1 G > A) is identical to a patient reported by Revencu , et al. That patient manifested CM’s without fast-flow vascular anomalies but also was reported to have chylous ascites.
To our knowledge, this case represents the youngest reported patient diagnosed with CM-AVM and highlights the importance of early clinical detection. The presence of multiple capillary malformations should raise suspicion of a syndrome with mixed vascular anomalies. The family history and physical examination may offer important clues. Complete assessment and the broader differential diagnosis are beyond the scope of this article; however, evidence for an underlying fast-flow lesion should be sought on physical exam. This includes local warmth, palpable thrill, or an audible bruit. Any limb enlargement should be noted.
Imaging workup generally begins with ultrasound and Doppler. This case demonstrates the classic features of a fast-flow vascular malformation. There is absence of a definable mass on gray-scale ultrasound. Large, macroscopic anechoic vessels are present. There is an abnormally low resistive pattern on the spectral tracings in the feeding artery and increased pulsatility in the draining veins. We also detected a plethora of vessels, completing the assessment of an AVM. The MRI corroborated these findings.
Of interest, the ultrasound revealed abnormal echotexture and the MRI demonstrated abnormal signal within the distal musculature. Although regional edema might explain such a finding, we suspect rather that this represents numerous microfistulae in the musculature that are too small to resolve with our imaging technique. In support of this interpretation is the mild general enhancement of the involved muscles noted after gadolinium administration (Figure 3C). This underscores the overlap with PKWS. The above findings, in the context of the clinical history should strongly suggest a RASA-1 mutation.
When a significant fast-flow vascular lesion is present, a cardiac echo should also be obtained to exclude high output heart failure.