title: Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin.
abstract: BACKGROUND
  Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported.
  
  
  OBJECTIVE
  We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis.
  
  
  METHODS
  Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents.
  
  
  RESULTS
  No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide.
  
  
  CONCLUSIONS
  SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.
authors.affiliation: Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Pediatric Dermatology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: McAleer
authors.affiliation: Dermatology and Genetic Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pohler
authors.affiliation: Dermatology and Genetic Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: Frances J D
authors.initials: FJ
authors.lastname: Smith
authors.affiliation: Dermatology and Genetic Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Wilson
authors.affiliation: Division of Computational Biology, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Cole
authors.affiliation: Division of Computational Biology, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGowan
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Koetsier
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Godsel
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Harmon
authors.affiliation: Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, San Francisco, and the Department of Dermatology, University of California, San Francisco, Calif.
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, San Francisco, and the Department of Dermatology, University of California, San Francisco, Calif.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: McDermott
authors.affiliation: Infectious Disease Department, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
authors.forename: Karina
authors.initials: K
authors.lastname: Butler
authors.affiliation: Department of Gastroenterology, Our Lady's Children's Hospital Crumlin and School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Broderick
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Sarig
authors.affiliation: Department of Gastroenterology, Our Lady's Children's Hospital Crumlin and School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
authors.affiliation: Dermatology and Genetic Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.affiliation: Clinical Medicine, Trinity College Dublin, Dublin, Ireland; Pediatric Dermatology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland. Electronic address: irvinea@tcd.ie.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003872:Dermatitis / Q000175:diagnosis / Q000235:genetics*; D051183:Desmoglein 1 / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics*; D018450:Disease Progression; D006801:Humans; D006967:Hypersensitivity / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics; D012867:Skin / Q000473:pathology; D019282:Wasting Syndrome / Q000175:diagnosis / Q000235:genetics*
chemical_list: C495294:DSP protein, human; D051183:Desmoglein 1; D051180:Desmoplakins
keywords: Atopy; atopic dermatitis; atopic sensitization; desmoplakin; desmosome; eosinophilic esophagitis; skin barrier