A 17-year-old male presented since birth with a large sebaceous nevus (SN), oral papillomatous hyperplasia (OPH) lesions in the right hemimucosa, a speckled papulous nevus (SLN) with checkerboard pattern and other extracutaneous alterations including cardiac, musculoskeletal, ocular and neurological. Furthermore, the patient developed two primary rhabdomyosarcomas along his lifetime (one at 4 months and the other at 12 years of age). With the clinical diagnosis of Phacomatosis Pigmentokeratotica (PPK), genetic tests were performed in order to determine the existence of a mutation responsible for the appearance of the cutaneous, extracutaneous and tumoral manifestations. DNA was extracted and analyzed by Sanger sequencing from tissue biopsies from SN, several melanocytic lesions within SLN both acquired and congenital, OPH, both rhabdomyosarcomas and also from normal skin and peripheral blood. We found a HRAS c.37G>C mutation which corresponds to a p.Gly13Arg substitution in all of the pathological samples, while skin and blood resulted wild type. Until recently, PPK was considered a subtype of the epidermal nevus syndrome and the hypothesis of didymosis or “twin-spotting” was accepted to explain its ethiopathogenesis. However, in 2013 Groesser et al proved the existence of an activating postzygotic HRAS mutation as its cause, classifying PPK among the mosaic RASopathies. Our findings further support this idea. Nevertheless, other mutations in KRAS and BRAF have been described since in PPK. To our knowledge this is the first reported case of HRAS mutation in a patient with PPK and rhabdomyosarcoma. Patients with germline RASopathies have a higher incidence of certain tumors and dysregulation of the Ras-Raf-MEK-ERK pathways can be observed in up to 30% of human cancers. All this suggests mosaicisms could be an underdiagnosed cause of childhood neoplasias.

Phacomatosis Pigmentokeratotica: mosaic RASopathies as a key to better understand cancer