title: Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell.
abstract: Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy.
authors: Department of Dermatology, University of Regensburg, Regensburg, Germany.
authors: Leopold
authors: L
authors: Groesser
authors: Eva
authors: E
authors: Herschberger
authors: Ana
authors: A
authors: Sagrera
authors: Tor
authors: T
authors: Shwayder
authors: Katharina
authors: K
authors: Flux
authors: Laura
authors: L
authors: Ehmann
authors: Andreas
authors: A
authors: Wollenberg
authors: Antonio
authors: A
authors: Torrelo
authors: Lorea
authors: L
authors: Bagazgoitia
authors: Blanca
authors: B
authors: Diaz-Ley
authors: Sigrid
authors: S
authors: Tinschert
authors: Ilske
authors: I
authors: Oschlies
authors: Sebastian
authors: S
authors: Singer
authors: Marion
authors: M
authors: Mickler
authors: Agusti
authors: A
authors: Toll
authors: Michael
authors: M
authors: Landthaler
authors: Francisco X
authors: FX
authors: Real
authors: Christian
authors: C
authors: Hafner
mesh_terms: D000328:Adult; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D009030:Mosaicism; D039902:Multipotent Stem Cells / Q000502:physiology*; D009508:Nevus, Pigmented / Q000235:genetics* / Q000473:pathology*; D054000:Nevus, Sebaceous of Jadassohn / Q000235:genetics / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C501009:HRAS protein, human; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras)