Gene discovery in extensive dermal melanocytosis reveals multiple mosaic causes

Extensive or atypical dermal melanocytosis (EDM) is abnormal macular blue/black skin pigmentation that can be associated with other congenital abnormalities and an increased risk of melanoma. It is probably 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 only one gene, GNAQ, described in only a handful of cases to date.

To improve our understanding of EDM by combining deep phenotyping with genetic investigations in a large paediatric cohort.

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 magnetic resonance imaging (MRI) of the central nervous system (CNS) performed in five patients where there was clinical suspicion of neurological abnormalities.

Ophthalmological involvement was seen in 40% (n = 19/47) of patients. Importantly, this was not restricted to those with periocular cutaneous involvement. Two of five patients who underwent MRI had evidence of ischaemic infarcts. Previously undescribed mosaic causes of EDM were found in HRAS, ACTB, PIK3CA and GNA11, alongside further cases of mosaic GNAQ. The HRAS variant has previously been reported in the germline causing Costello and Noonan syndromes.

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 performed if there are concerns. Genetically, these results not only expand the causative genotypes of EDM, but also challenge our concept of the mosaic disorders currently described in association with HRAS, ACTB, PIK3CA and GNA11 variants. 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 as for this HRAS variant.