Activating HRAS Mutation in Nevus Spilus

Abstract

A 34-year-old Chinese man presented with an 11-year history of gradually progressive papular lesions scattered over his upper extremities and trunk. These asymptomatic papules initially started on the dorsa of his hands and fingers. Individual papule developed a central umbilication with scale or crust, and then regressed over the next 1-2 months, usually leaving a white punctate scar. Some papules with a central pin point-sized, black horny plug were observed. Gradually, lesions increased and involved bilateral forearms, right arm and trunk. There was no history of trauma, insect bites or excess solar exposure. Physical examination revealed multiple 3-6 mm, annular or arciform, flesh-coloured firm papules with central umbilicated crust or scale mainly involving the right arm and back (Fig. 1a). There were several 1-2 mm atrophic hypopigmented scars on the dorsa of his hands. A biopsy from the umbilicated papule on the back showed findings compatible with PGA (Fig. 1b). Laboratory investigations including complete blood cell count, blood biochemistry, urinalysis and chest X-ray were normal. Those lesions resolved with treatments of liquid nitrogen, and topical steroids within 3 months.The eruptions of PGA were classified into papular perforating type (P-type) and ulcerative perforating type (U-type). 4 The localization of lesions were divided into localized PGA (LPGA) and generalized PGA (GPGA), and cases with extensive lesions over extremities only were regarded as disseminated. 3 The comparison of clinical features of GPGA and LPGA variants and P-and U-type variants of 78 cases reviewed were summarized in Table 1. The entire group included 78 patients (49 female, 29 male), and data regarding age of onset and evolution time of PGA were not available in five cases. The mean age of onset was 32 years (range, 53 days to 72 years). Patients classified as P-type had a lower mean age of onset than U-type (29 vs. 48 years, P < 0.001). Furthermore, it was significantly lower in female than that in male (28 vs. 39 years, P < 0.05). The mean evolution time of PGA was 3 years (range, 1 month to 30 years), and it was significantly shorter in LPGA than GPGA (2.3 vs. 4.6 years, P < 0.05). The most common clinical presentation of PGA was flesh to redcoloured, 1-7 mm papules with central crust or scale, and/or umbilication.

Phacomatosis Pigmentokeratotica: A Mosaic RASopathy with Malignant Potential

“…The same somatic KRAS mutation found in our patient (c.35G>C [p.G12A]) has been reported with keratinocytic epidermal nevi and nevus sebaceous and in other internal malignancies such as Wilm's tumor, nephroblastomas, salivary gland adenocarcinomas, esophageal and stomach carcinomas, breast carcinomas, astrocytomas, and mandibular ameloblastomas . In our patient, the KRAS mutation was detected in the mosaic state in the nevus sebaceous, heterozygous (not mosaic) in the tumor, and not detected in the SLN or in the peripheral blood, although RAS mutations have been found in melanocytes but not keratinocytes of nevus spilus . Direct DNA culture from melanocytes from our patient was not performed, which may explain the absence of genetic alteration in this sample.…”

Spitz Nevi and Other Spitzoid Neoplasms in Children: Overview of Incidence Data and Diagnostic Criteria

“…In particular, an 11p gain was found with a secondary HRAS gene copy number increase in spitzoid tumors with distinct microscopic features (e.g., desmoplasia) and with mainly benign clinical behavior. The HRAS gene is located on the short arm of chromosome 11 (3,(70)(71)(72)(73)(74)(75).…”

Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies

“…These disorders include congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [OMIM #612918] (Kurek et al, 2012), Mafucci [OMIM %614569] (Amary et al, 2011), Proteus [OMIM #176920] (Lindhurst et al, 2011), and Sturge-Weber [OMIM #185300] (Shirley et al, 2013) syndromes, among others. More specifically, mosaicism for mutations in genes involved in the Ras/MAPK signaling pathways is the cause of a group of disorders termed mosaic RASopathies, which include keratinocytic epidermal nevus syndrome (Bourdeaut et al, 2010), sebaceous nevus syndrome (Groesser et al, 2012), phakomatosis pigmentokeratotica (Groesser et al, 2013), nevus spilus (Sarin, McNiff, Kwok, Kim, & Khavari, 2014) and neurocutaneous melanosis/congenital giant melanocytic nevi [OMIM #137550] (Kinsler et al, 2013), wooly hair nevus [OMIM #169200] (Levinsohn et al, 2014), and cutaneous-skeletal hypophosphatemia syndrome (Lim et al, 2014). Three additional syndromes with overlapping clinical findings in eye, heart, skin, and hair have been recently shown to result from somatic mosaicism for mutations in the genes involved in the Ras pathway, including KRAS [OMIM *190070], HRAS [OMIM *190020], NRAS [OMIM *164790], and FGFR1 [OMIM *136350].…”