Phacomatosis Pigmentokeratotica: A Mosaic RASopathy with Malignant Potential

Abstract

Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a nevus sebaceous arranged along the lines of Blaschko with a speckled lentiginous nevus (SLN). We report a novel KRAS mutation in a patient with a large nevus sebaceous and an SLN who subsequently developed a vaginal botryoid rhabdomyosarcoma, an association not previously reported in the literature. This case expands our knowledge of the genetic basis for phacomatosis, in which mutations in HRAS have been previously described, although this report provides evidence that activating mutations in KRAS or HRAS may cause PPK. This report confirms that PPK is a mosaic RASopathy with malignant potential and raises the question of whether screening for other RAS-associated malignancies should be performed for all children with PPK.

Phacomatosis pigmentokeratotica: a case of HRAS mosaicism causing rhabdomyosarcoma

“…Mutations in these Ras signalling pathways have an important role in tumorigenesis and are present in about 30% of human cancers . Likewise, a higher incidence of neoplasia has been observed in patients with germline RASopathies, such as Noonan or Costello syndrome, as well as in patients with epidermal naevus syndromes . Furthermore, a relationship with cancer has also been noticed in PPK, especially urothelial carcinomas and rhabdomyosarcomas, with a recent report of a case of this tumour in a patient with KRAS ‐mutated PPK .…”

“…Mutations in these Ras signalling pathways have an important role in tumorigenesis and are present in about 30% of human cancers . Likewise, a higher incidence of neoplasia has been observed in patients with germline RASopathies, such as Noonan or Costello syndrome, as well as in patients with epidermal naevus syndromes .…”

Mosaic pathogenic HRAS variant in a patient with nevus spilus with agminated Spitz nevi and parametrial-uterine rhabdomyosarcoma

“…There is a growing literature reporting rhabdomyosarcoma in association with mosaic RASopathies. KRAS mutations have been reported in association with phakomatosis pigmentokeratotica and rhabdomyosarcoma in the same patient . Congenital melanocytic nevi (CMN) are known to be caused by NRAS mutations .…”

What do mosaic RASopathies tell us about carcinogenesis?

“…Thus, it has not been a surprise that deep genomic sequencing techniques have demonstrated somatic mutations that are limited to the affected tissue and not present in the germline of affected individuals. What is noteworthy, however, is that virtually all of these genes have been previously associated with a wide variety of human cancers . Specifically, in genes that govern cell proliferation, cell‐cycle progression and apoptosis.…”

“…With mosaic mutations, the earlier the mutation, the more likely multiple tissues will be involved. Although rare, an increasing number of mosaic RASopathies have been associated with solid tumours . This issue of the BJD includes a case of mosaic HRAS mutation in a patient with phacomatosis pigmentokeratotica who developed a rhabdomyosarcoma .…”