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Genotype-phenotype correlations
Review
Mosaic RASopathies concept: different skin lesions, same systemic manifestations?
  1. Marie-Anne Morren1,
  2. Heidi Fodstad2,
  3. Hilde Brems3,
  4. Nicola Bedoni2,
  5. Emmanuella Guenova4,
  6. Martine Jacot-Guillarmod5,
  7. Kanetee Busiah6,
  8. Fabienne Giuliano7,
  9. Michel Gilliet8,
  10. Isis Atallah2
  1. 1 Pediatric Dermatology Unit, Department of Dermatology and Venereology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  2. 2 Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  3. 3 Department of Human Genetics, University of Leuven, Leuven, Belgium
  4. 4 Department of Dermatology and Venereology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  5. 5 Pediatric Gynecology Unit, Department of Mother-Woman-Child, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  6. 6 Pediatric Endocrinology, Diabetology, and Obesity Unit, Department of Mother-Woman-Child, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  7. 7 Medical Genetics, Synlab, Lausanne, Switzerland
  8. 8 Dermatology and Venereology Department, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
  1. Correspondence to Dr Marie-Anne Morren, Pediatric Dermatology Unit, Department of Dermatology and Venereology, Lausanne University Hospital and University of Lausanne, Lausanne,1011, Switzerland; marie-anne.morren{at}chuv.ch

Abstract

Background Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in HRAS, KRAS, and less frequently, NRAS and BRAF may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders.

Methods In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic HRAS variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in HRAS, KRAS, NRAS or BRAF.

Results Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. KRAS pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in HRAS are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica.

Conclusion This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic RAS and BRAF pathogenic variants and may help improve their follow-up.

  • Dermatology
  • Genetic Variation
  • Genetic Testing
  • Phenotype

https://doi.org/10.1136/jmg-2023-109306

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    Footnotes

    • Contributors M-AM and AI: planning, conception and design, acquisition, analysis and interpretation of data, reporting and writing of manuscript, final approval. HF and NB: acquisition of data, analysis and interpretation of data, writing of methods part of manuscript, reviewing of manuscript, final approval. KB, MJ-G, EG and FG: acquisition of data, reviewing of manuscript, final approval. HB and MG: writing and reviewing of manuscript, final approval.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.