PA33 Mosaic KRAS mutation associated with epidermal naevus and somatic limb overgrowth

Abstract Mosaic KRAS variants are recognized to cause a range of features including somatic overgrowth, lymphatic and vascular malformations and other anomalies. We present a child with a mosaic variant in this gene and discuss the phenotype of this condition. A 2-year-old boy was noted at birth to have an extensive keratinocytic epidermal naevus and swelling of the left lower limb. The child was born after an uncomplicated pregnancy to unrelated parents. No anomalies had been detected prenatally. The naevus was large, affecting the left side of the body with a central demarcation down the midline of his chest to the left groin. The naevus continued down the volar aspect of the left arm onto the palm of the hand. The left lower limb was hypertrophic throughout, with nonpitting oedema. The perfusion and movement of the limb appeared normal. An infantile haemangioma was noted on the lower back, and later a deeper haemangioma of the anterior neck; neither required treatment. The left testis was undescended initially, with subsequent overgrowth of the skin of the penis and scrotum. Investigations soon after birth revealed a cystic dysplastic left kidney. A magnetic resonance imaging scan of the brain was normal. Initial genetic analysis was performed on blood. Diagnostic testing for a panel of genes associated with segmental overgrowth (R110) detected no pathogenic variant. The mosaic skin disorders deep sequencing panel (R327) showed no pathogenic variant using DNA extracted from blood. This panel was subsequently repeated on DNA extracted from skin, and a mosaic pathogenic KRAS variant c.35GA, p.Gly12Asp was identified in 30% of next-generation sequencing reads. Mosaic RASopathies affect genes involved in the RAS–mitogen-activated protein kinase signalling pathway. Phenotypes of mosaic RASopathies are often distinct from their germline counterparts. The c.35GA variant seen in our patient is widely reported, and leads to constitutive overactivation and increased signal transduction in downstream pathways. Epidermal naevi, both keratinocytic and sebaceous, are a common finding resulting from mosaic RAS mutations. Good developmental progress was made; milestones were generally met and although the leg remained enlarged due to lymphatic overgrowth, he was able to walk. No neurological symptoms have been noted, and the eyes have been checked with no anomalies found. The kidneys will be kept under review, as renal tumours have been reported in patients with mosaic KRAS variants. Our patient highlights aspects of the phenotype of a mosaic KRAS variant and adds to the growing knowledge of these conditions.