Mosaic pathogenic variants in AKT3 cause capillary malformation and undergrowth

Abstract

Capillary malformations are slow-flow vascular malformations that affect the microcirculation including capillaries and post capillary venules and can be associated with growth differences. Specifically, the association of capillary malformations with undergrowth is a vastly understudied vascular syndrome with few reports of genetic causes including PIK3CA, GNAQ, and GNA11. Recently, a somatic pathogenic variant in AKT3 was identified in one child with a cutaneous vascular syndrome similar to cutis marmorata telangiectatica congenita, undergrowth, and no neurodevelopmental features. Here, we present a male patient with a capillary malformation and undergrowth due to a somatic pathogenic variant in AKT3 to confirm this association. It is essential to consider that mosaic pathogenic variants in AKT3 can cause a wide spectrum of disease. There is a need for future studies focusing on capillary malformations with undergrowth to understand the underlying mechanism.

Keywords: AKT3; capillary malformation; postzygotic pathogenic variant; somatic mosaicism; undergrowth; vascular malformation.

FIGURE 1

Photographs of the legs demonstrating capillary malformation with undergrowth. (a, b) Photograph of a male infant taken at 1-month-old when the girth discrepancy of the left leg was first noticed. A diffuse capillary malformation encompasses the left leg in purplish-brown patches. (c) Photographs at 5 years old. (c) The frontal view highlights the left lower extremity undergrowth. (d) The diffuse capillary malformation is more evident in the lateral view but has become less apparent with darker skin pigmentation.

FIGURE 2

Maximum intensity projection image from lower extremity MR angiogram performed at 2 months old demonstrating undergrowth of the left lower extremity, involving the bones, (producing limb length discrepancy), musculature (arrows depict asymmetry), and subcutaneous fat (white lines depict asymmetry).