Gene discovery in extensive dermal melanocytosis reveals multiple mosaic causes

Abstract

Background: Extensive and/or atypical dermal melanocytosis (EDM) is abnormal macular blue/black skin pigmentation which can be associated with other congenital abnormalities and an increased risk of melanoma. It is likely underdiagnosed due to phenotypic overlap with common transient dermal melanocytosis (so-called "blue spots"), and is frequently misdiagnosed as congenital melanocytic naevi. The genetic cause has remained largely unknown, with mosaic variants in one gene GNAQ described in only a handful of cases to date.

Methods: Forty-seven patients with EDM only were recruited for phenotypic and targeted deep next generation sequencing of affected skin. Ophthalmological examination was performed routinely, and CNS MRI performed in five patients where there was clinical suspicion.

Results: Ophthalmological involvement was seen in 40%, and importantly was not restricted to those with periocular cutaneous involvement. Two patients of five scanned had evidence of ischaemic infarcts. Mosaic causes of EDM were found in four new genes HRAS, ACTB, PIK3CA, and GNA11 alongside further cases of GNAQ. The HRAS variant has previously been reported in the germline.

Conclusions: Clinically, our findings highlight the importance of differentiating EDM from common blue spots, and we recommend ophthalmological investigation even in the absence of periocular cutaneous involvement. The association with CNS infarct is unclear, but we suggest clinical neurological features be sought and MRI undertaken if there are concerns. Genetically, these results not only expand the causative genotype of EDM, but also challenge our concept of the Mosaic Disorders currently described with HRAS, ACTB, PIK3CA, and GNA11. Stratification by genotype may help determine patient melanoma risk more accurately in the future. Patient- and variant-specific genetic counselling should be given where there is a potential risk of germline transmission to offspring.