Track: Case Reports

Abstract:

Phacomatosis pigmentokeratotica (PPK), a mosaic RASopathy characterized by nevus sebaceous and speckled lentiginous nevi, is frequently driven by postzygotic  HRAS mutations in a multipotent progenitor. With age, patients develop tumors from mutation-bearing epithelial or neural-crest-derived precursors.

We present follow-up on a previously-reported 34-year-old male with segmental cutaneous (basal cell carcinoma/epithelioma (BCC), nevus sebaceous and syringocystadenoma papilliferum (SCAP)) and extra-cutaneous (retroperitoneal embryonal rhabdomyosarcoma of infancy) tumors. While early findings were typical for PPK, follow-up revealed a duodenal neuroendocrine tumor (NET), parotid basal cell adenoma, and esophageal squamous papillomas. The SCAP and parotid tumor harbored HRAS G13R mutation, confirmed in the other tumors by immunohistochemistry. Germline PTCH1 VUS (Arg41Cys) was identified but deemed unlikely pathogenic, with Gorlin-syndrome features absent.

This case highlights the systemic nature of HRAS mosaicism, linking known sporadic HRAS-driven neoplasia. Infantile retroperitoneal rhabdomyosarcoma (RMS) is a well-known early-onset malignancy in HRAS mosaicism. BCC-like proliferations, SCAP, and nevus sebaceous are common in mosaicism including PPK. Intriguingly, sporadic salivary gland basal cell adenomas are frequently associated with HRAS mutations.  Esophageal squamous papillomas are linked to sporadic HRAS G13R mutations, as are foregut neuroendocrine tumors (pheochromocytoma and paraganglioma). Given the novel neuroendocrine tumor in mosaic RASopathy, we reviewed cBioPortal data, and found HRAS G13R mutation in one gastric and two lung neuroendocrine tumors.

Our patient demonstrates PPK as a multisystem disorder requiring surveillance for diverse neoplasms, predictable from correlative sporadic tumor mutation data. Modeling the propensity for tumor development from a specific mutation may improve follow-up for patients with mosaic tumor syndromes.