Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR

J Invest Dermatol. 2014 Oct;134(10):2570-2578. doi: 10.1038/jid.2014.164.

Patrick Campbell ¹, Penny E Morton ², Takuya Takeichi ³, Amr Salam ¹, Nerys Roberts ⁴, Laura E Proudfoot ¹, Jemima E Mellerio ⁵, Kingi Aminu ⁴, Cheryl Wellington ⁴, Sachin N Patil ⁴, Masashi Akiyama ⁶, Lu Liu ⁷, James R McMillan ⁷, Sophia Aristodemou ⁷, Akemi Ishida-Yamamoto ⁸, Alya Abdul-Wahab ¹, Gabriela Petrof ¹, Kenneth Fong ¹, Sarawin Harnchoowong ¹, Kristina L Stone ⁹, John I Harper ¹⁰, W H Irwin McLean ¹¹, Michael A Simpson ⁹, Maddy Parsons ², John A McGrath ¹²

Affiliations

1 St John's Institute of Dermatology, King's College London, London, UK.
2 Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.
3 St John's Institute of Dermatology, King's College London, London, UK; Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
4 Department of Paediatrics, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
5 St John's Institute of Dermatology, King's College London, London, UK; Department of Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
6 Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
7 GSTS Pathology, St Thomas' Hospital, London, UK.
8 Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
9 Department of Medical and Molecular Genetics, King's College London, London, UK.
10 Department of Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
11 The Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, UK.
12 St John's Institute of Dermatology, King's College London, London, UK; The Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, UK. Electronic address: john.mcgrath@kcl.ac.uk.

PMID: 24691054 DOI: 10.1038/jid.2014.164

Abstract

Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases, but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome Sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283 G>A; p.Gly428Asp) in a male infant with lifelong inflammation affecting the skin, bowel, and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules--similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient's skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died at the age of 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on Other tissues.

Name
Email *

	Sorry, but the email address you supplied was invalid.