MosaicNRASQ61R mutation in a child with giant congenital melanocytic naevus, epidermal naevus syndrome and hypophosphataemic rickets

Abstract

The association of hypophosphataemic rickets with verrucous epidermal naevus (EN) and elevated fibroblast growth factor 23 levels is known as cutaneous-skeletal hypophosphataemia syndrome (CSHS), and can be caused by somatic activating mutations in RAS genes. We report a unique patient with CSHS associated with giant congenital melanocytic naevus (CMN), neurocutaneous melanosis and EN syndrome, manifesting as facial linear sebaceous naevus, developmental delay and ocular dermoids. An activating mutation Q61R in the NRAS gene was found in affected skin and ocular tissue but not blood, implying that the disparate manifestations are due to a multilineage activating mutation (mosaic RASopathy). We speculate on the apparently rare association of CSHS with CMN compared with EN. We also report the favourable outcome of this patient at the age of 8 years after extensive neonatal curettage of the giant CMN and use of vitamin D and phosphate supplementation.

The patterns of birthmarks suggest a novel population of melanocyte precursors arising around the time of gastrulation

“…Imagining this circular lesion translated onto the newborn human, after lateral embryonic folding and the development of head and limbs (Figure 8c,d), it can be seen that this correlates with the post-natal phenotype in different mosaic clonal disorders (Figures 2a-f, 5a-b and 8e-f). At a later embryonic stage (estimated week 4 human, E10-11 mouse), non-segmental melanocyte precursors appear within the can be involved as well as the caudal truncal field (Gupta et al, 2016;Nanda et al, 2017), or facial fields as well as cranial and caudal truncal fields (Raina & Chaudhuri, 2010;Ramesh et al, 2017), support this hypothesis. The alternative would be that the non-segmental melanocyte precursor for each of these fields arises independently in that new structure.…”

“…In EDM and PPV, these can be seen as a single field (Figure k,l). In very few published cases of CMN, these have been seen as a single field, and of note, these children also had epidermal abnormalities (Raina & Chaudhuri, ; Ramesh et al., ). The two dorsal truncal fields are bilateral and roughly symmetrical around the posterior/dorsal midline and include the proximal portions of the respective limbs.…”

“…At a later embryonic stage (estimated week 4 human, E10‐11 mouse), non‐segmental melanocyte precursors appear within the developing head (Figure ) and in the limb buds. Whether the founder cells for the developing head and limb buds are specified before the development of the face and limb buds is unknown; however, data from rare cases of CMN and EDM where one or both distal limb fields can be involved as well as the caudal truncal field (Gupta et al., ; Nanda et al., ), or facial fields as well as cranial and caudal truncal fields (Raina & Chaudhuri, ; Ramesh et al., ), support this hypothesis. The alternative would be that the non‐segmental melanocyte precursor for each of these fields arises independently in that new structure.…”

Detection of a multilineage mosaic NRAS mutation c.181C>A (p.Gln61Lys) in an individual with a complex congenital nevus syndrome

“…Genetic results have been reported in only one case where a mosaic NRAS mutation p.Gl-n61Arg was found ( (Chan et al, 2018) and personal communication with Geoffrey C. Lam). Finally, CMN has also been reported in cases with cutaneous-skeletal hypophosphatemia syndrome (CSHS), another variant of mosaic RASopathies (Lim et al, 2014;Ramesh et al, 2017). CSHS with CMN was found to be associated with mosaic NRAS mutations (p.Gln61Arg), while its association with epidermal nevi is rather caused by mosaic HRAS mutations (Lim et al, 2014;Ramesh et al, 2017).…”

Rickets in association with skin diseases and conditions: A review with emphasis on screening and prevention

“…Epidermal nevi represent a heterogeneous group of mosaic lesions that are typically distributed along the Blaschko lines. 47,48 Epidermal nevus syndrome represents the association of epidermal nevi and extracutaneous abnormalities. 49 Hypophosphatemic rickets was described in patients with extensive epidermal and/or melanocytic nevi and phakomatosis pigmentokeratotica.…”