title: Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR.
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.
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Campbell
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.
authors.forename: Penny E
authors.initials: PE
authors.lastname: Morton
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK; Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Takeichi
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Amr
authors.initials: A
authors.lastname: Salam
authors.affiliation: Department of Paediatrics, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: Nerys
authors.initials: N
authors.lastname: Roberts
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Proudfoot
authors.affiliation: 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.
authors.forename: Jemima E
authors.initials: JE
authors.lastname: Mellerio
authors.affiliation: Department of Paediatrics, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: Kingi
authors.initials: K
authors.lastname: Aminu
authors.affiliation: Department of Paediatrics, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Wellington
authors.affiliation: Department of Paediatrics, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: Sachin N
authors.initials: SN
authors.lastname: Patil
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: GSTS Pathology, St Thomas' Hospital, London, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: GSTS Pathology, St Thomas' Hospital, London, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: McMillan
authors.affiliation: GSTS Pathology, St Thomas' Hospital, London, UK.
authors.forename: Sophia
authors.initials: S
authors.lastname: Aristodemou
authors.affiliation: Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Alya
authors.initials: A
authors.lastname: Abdul-Wahab
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Petrof
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Fong
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Sarawin
authors.initials: S
authors.lastname: Harnchoowong
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Kristina L
authors.initials: KL
authors.lastname: Stone
authors.affiliation: Department of Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: John I
authors.initials: JI
authors.lastname: Harper
authors.affiliation: The Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, UK.
authors.forename: W H
authors.initials: WH
authors.lastname: Irwin McLean
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, UK.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.affiliation: 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.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D001706:Biopsy; D002454:Cell Differentiation / Q000502:physiology; D002675:Child, Preschool; D003872:Dermatitis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D017809:Fatal Outcome; D006720:Homozygote; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology*
chemical_list: D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt