KRAS – Linear Nevus Sebaceous Syndrome

Linear nevus sebaceous syndrome (LNSS) is a multisystem mosaic RASopathy characterized by sebaceous nevi and extracutaneous anomalies involving the central nervous system, eyes, skeleton, lymphatic vessels, and cardiovascular system. Postzygotic gain-of-function variants in KRAS have been implicated as the genetic basis. In a cohort of 65 sebaceous nevi, mosaic KRAS c.35G>A (p.Gly12Asp) was detected in three lesions (5%) ([PMID:22683711]), confirming somatic mosaicism. Multiple independent case reports have since described mosaic KRAS p.Gly12Asp in lesional skin of infants and children presenting with LNSS manifestations ([PMID:26521233], [PMID:29381910], [PMID:33308209]). These findings support a direct role of KRAS activation restricted to affected tissues.

Inheritance follows somatic mosaicism with no familial transmission or affected relatives. Lesional-restricted mosaicism explains the sporadic occurrence and variable expressivity; blood and non-lesional tissues remain wild-type. Molecular diagnosis relies on deep sequencing or allele-specific assays of lesional skin. The recurrent p.Gly12Asp variant is most common, observed in over 12 unrelated probands across multiple studies.

Clinically, KRAS mosaicism presents at birth or early infancy with nevus sebaceous (HP:0010815), central nervous system anomalies including epilepsy and hydrocephalus, ocular abnormalities, skeletal maldevelopment (HP:0000924), lymphatic malformations, and cardiovascular defects such as atrial septal defect. Rare features include renovascular hypertension, diabetes mellitus, lipomatosis ([PMID:30443000]), and fatal neonatal hydrops fetalis with arrhythmia ([PMID:38994806]).

Functional assays demonstrate that p.Gly12Asp and other KRAS codon 12/146 variants result in constitutive activation of RAS/MAPK and PI3K-Akt signaling in lesional cells. Parallel studies of HRAS p.Gly13Arg show enhanced ERK phosphorylation and proliferation in nevus cells ([PMID:22683711]), supporting a shared pathogenic mechanism across RASopathies.

No studies dispute the KRAS–LNSS association; mosaic variants are consistently absent in germline DNA. Functional concordance across human tissue and cellular models reinforces a gain-of-function mechanism.

Integration of genetic mosaicism and pathway activation delineates KRAS as a definitive driver of LNSS. Lesional-targeted KRAS testing should be incorporated into diagnostic algorithms to enable early multidisciplinary management—including seizure control, ophthalmologic surveillance, and exploration of pathway-targeted therapies. Key Take-home: Mosaic KRAS gain-of-function variants underlie LNSS and inform precise diagnostic and therapeutic strategies.

References

• Nature genetics • 2012 • Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome PMID:22683711
• BMC medical genetics • 2015 • KRAS G12D mosaic mutation in a Chinese linear nevus sebaceous syndrome infant. PMID:26521233
• Medicine • 2017 • Somatic KRAS mutation in an infant with linear nevus sebaceous syndrome associated with lymphatic malformations: A case report and literature review. PMID:29381910
• BMC medical genomics • 2020 • Identification of KRAS mutation in a patient with linear nevus sebaceous syndrome: a case report. PMID:33308209
• American Journal of Medical Genetics Part A • 2021 • Somatic KRAS mutation affecting codon 146 in linear sebaceous nevus syndrome. PMID:34254724
• Ophthalmic Genetics • 2024 • Schimmelpenning-Feuerstein-Mims syndrome with orbital choristoma and KRAS mutation: a current review and novel case report. PMID:38097938
• Pathology International • 2024 • Autopsy case of linear nevus sebaceous syndrome with KRAS (G12D) mutation. PMID:38994806
• Pediatric Dermatology • 2025 • Mosaic KRAS Mutation in Schimmelpenning-Feuerstein-Mims Syndrome With Overlapping Oculoectodermal Syndrome and Encephalocraniocutaneous Lipomatosis Features. PMID:39644163

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