Next-Generation Sequencing of Nevus Spilus–Type Congenital Melanocytic Nevus: Exquisite Genotype–Phenotype Correlation in Mosaic RASopathies

Nevus spilus is a descriptive term used to denote any cutaneous lesion with a café-au-lait macular background and superimposed on more pigmented areas. Small single nevus spilus are relatively common, and they have recently been described to be due to somatic activating HRAS mutations (Sarin et al., 2014). Larger superficial lesions with small superimposed junctional nevi in associ-ation with phakomatosis pigmentokera-totica have also been found to contain HRAS mutations (Groesser et al., 2013). However, another nevus spilus–type phenotype has also been well described in which large café-au-lait macules have superimposed lesions that are indistin-guishable both clinically and histopatho-logically from medium/large congenital melanocytic nevi (CMN), exhibit a wide variety of colors and sizes (Schaffer et al., 2001a, b), and continue to develop post-natally in many cases. This is termed nevus spilus–type CMN. In our experi-ence, there may be delayed appearance of the café-au-lait background after birth, but the lesion is still usually predictable on the basis of clustering of many CMN in one anatomical area. Smaller separate lesions in the same individual are often indistinguishable clinically from café-au-lait macules, and are so faint that they can be easily missed (Figure 1). Our primary aim in this study was to look for the genetic basis of this defined phenotypic subset of CMN, in the con-text of the recent discovery that NRAS Q61K and Q61R mutations are the cause of most causes of multiple CMN (Kinsler et al., 2013b). In particular, we were interested in determining the mutation in See related commentary on pg 2493LETTER TO THE EDITOR Figure 1. Clinical images of nevus spilus–type CMN in six different patients. The café-au-lait macule background is often invisible at birth. Two separate lesions are indicated in one patient. CMN, congenital melanocytic nevi. Written consent was obtained for publication of all photographs