BG09 RASA1 exon deletion in a neonate with vascular malformations

Abstract

Abstract A full-term infant was noted to have a large, macular, pale-pink vascular birthmark across the left side of the chest, extending to the upper arm. Three smaller pale-pink irregular birthmarks on the elbow, thigh and flank were noted, as was an enlarged left upper arm. He had an oxygen dependency shortly after birth for which he required admission to the neonatal unit. A detailed history revealed that his father, paternal grandmother and aunt had similar birthmarks. His paternal aunt had an episode of bleeding from a spinal arteriovenous malformation (AVM) in her teens, which had been investigated with genetic testing by Sanger sequencing, but this did not identify a variant in RASA1. Following involvement from the dermatology, neonatology, genetics and radiology teams, investigations were organized. Findings included a high-flow vascular malformation with arteriovenous shunting on magnetic resonance imaging (MRI) of the left arm, normal MRI head and spine, and normal cardiac anatomy. Genetic testing by next-generation sequencing detected a heterozygous exon 21–23 deletion in RASA1. A diagnosis of capillary malformation–AVM syndrome (CM–AVM) was confirmed. Results of genetic testing of the father are awaited. Referral to a tertiary centre for consideration of management of AVM is underway. CM–AVM is a rare autosomal dominant condition. Pathogenic variants in RASA1 result in a lack of functional p120-RasGAP protein, which leads to abnormalities in angiogenesis, although this pathway is not well understood (Wooderchak-Donahue W, Johnson P, McDonald J et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet 2018; 26:1521–36). Cutaneous vascular malformations, classically pink–red with a pale halo, are the most consistent cutaneous manifestation, but they may be subtle and can mimic other vascular birthmarks such as segmental infantile haemangioma, salmon patches or port wine stain. In our patient, pale halos were not apparent until 4 months of age. Identification is important as life-threatening complications from cutaneous vascular arteriovenous fistulas can occur (Wooderchak-Donahue et al.). This case highlights the importance of clarifying a family history, classifying vascular birthmarks and working with the multidisciplinary team. Genetic testing should be considered, even with previous negative analysis, as test sensitivity has improved and will now include analysis of EPHB4, which has also been associated with CM–AVM.