Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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A Somatic MAP3K3 Mutation is Associated with Verrucous Venous Malformation
Javier A. Couto, BS, Matthew P. Vivero, BA, Harry P.W. Kozakewich, MD, Amir H. Taghinia, MD, John B. Mulliken, MD, Matthew L. Warman, MD, Arin K. Greene, MD, MMSc.
Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

PURPOSE:
Verrucous venous malformation (VVM), also called “verrucous hemangioma”, is a sporadically occurring, nonhereditary congenital vascular anomaly. This hyperkeratotic skin lesion typically affects extremities, bleeds, and causes a deformity. The purpose of the study was to test the hypothesis that VVM is caused by a somatic mutation.
METHODS:
Whole-exome sequencing (WES) was performed on VVM tissue excised from 6 individuals. The sequence findings were compared to those from population databases and from patients with other types of vascular lesions. Mutations found only in VVM samples from ≥ 3 patients were further evaluated by subcloning and by droplet digital PCR (ddPCR).
RESULTS:
Three of 6 VVMs were found by WES to have a point mutation (c.1323C→G; p.I441M) in MAP3K3, that encodes mitogen-activated protein kinase kinase kinase 3. The MAP3K3 mutation was detected in 3 of 4 additional VVM specimens by ddPCR. Between 11.8% - 38.6% of cells in the affected tissues contained this mutation, which was not present in control databases or in other vascular anomalies (Figure).
CONCLUSION:
A somatic mutation in MAP3K3 was found in 6/10 VVMs. MAP3K3 is involved in vascular development, and thus a somatic missense mutation in this gene likely is responsible for VVM. Further investigation is required to determine if other MAP3K3 mutations are present in VVMs, and whether MAP3K3 mutations are sufficient to cause VVM.
FIGURE LEGEND:
Figure. (Left) 18 year-old female with verrucous venous malformation (VVM). (Right) Droplet digital PCR (ddPCR) reaction showing MAP3K3 mutation in whole tissue from patient with VVM. Left upper quadrant represents droplets with only the mutant allele. Right upper quadrant shows droplets with mutant and wild-type alleles. Left lower quadrant represents droplets that do not contain any alleles. Right lower quadrant shows droplets with only the wild-type allele.


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