UCSF UC San Francisco Previously Published Works Title Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin. Permalink https://escholarship.org/uc/item/5sn426w3 Journal The Journal of allergy and clinical immunology, 136(5) ISSN 0091-6749 Authors McAleer, Maeve A Pohler, Elizabeth Smith, Frances JD et al. Publication Date 2015-11-01 DOI 10.1016/j.jaci.2015.05.002 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin Maeve A. McAleer, MB, MRCP,a,b,c Elizabeth Pohler, PhD,d Frances J. D. Smith, PhD,d Neil J. Wilson, MSc,d Christian Cole, PhD,e Stuart MacGowan, PhD,e Jennifer L. Koetsier, BS,f Lisa M. Godsel, PhD,f,g Robert M. Harmon, PhD,f Robert Gruber, MD,h Debra Crumrine, BS,i Peter M. Elias, MD,i Michael McDermott, FRCPath,c Karina Butler, FRCPI,j Annemarie Broderick, MRCPI,k Ofer Sarig, PhD,l,m Eli Sprecher, MD, PhD,k,l,m Kathleen J. Green, PhD,f,g W. H. Irwin McLean, PhD, DSc, FRS, FRSE, FMedSci,d and Alan D. Irvine, MDa,b,c Dublin, Ireland, Dundee, United Kingdom, Chicago, Ill, Innsbruck, Austria, San Francisco, Calif, and Tel Aviv, Israel Background: Severe dermatitis, multiple allergies, and histopathologic, immunofluorescent, and ultrastructural metabolic wasting (SAM) syndrome is a recently recognized phenotype and to identify the underlying molecular mechanisms syndrome caused by mutations in the desmoglein 1 gene (DSG1). in this rare genodermatosis. To date, only 3 families have been reported. Methods: Histopathologic, electron microscopy, and Objective: We studied a new case of SAM syndrome known to immunofluorescent studies were performed. Whole-exome have no mutations in DSG1 to detail the clinical, 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. From aClinical Medicine, Trinity College Dublin; bPediatric Dermatology, cthe National Results: No mutations were identified in DSG1; however, a novel Children’s Research Centre, and jthe Infectious Disease Department, Our Lady’s de novo d heterozygous missense c.1757A>C mutation in the Children’s Hospital Crumlin, Dublin; Dermatology and Genetic Medicine, University desmoplakin gene (DSP) was identified in the patient, predicting of Dundee; ethe Division of Computational Biology, College of Life Sciences, University of Dundee; the Departments of fPathology and gDermatology, the amino acid substitution p.His586Pro in the desmoplakin Northwestern University Feinberg School of Medicine, Chicago; hthe Department of polypeptide. Dermatology and Venereology, Innsbruck Medical University; ithe Dermatology Conclusions: SAM syndrome can be caused by mutations in Service, Veterans Affairs Medical Center, San Francisco, and the Department of both DSG1 and DSP. Knowledge of this genetic heterogeneity is Dermatology, University of California, San Francisco; kthe Department of Gastroenterology, Our Lady’s Children’s Hospital Crumlin and School of Medicine important for both analysis of patients and genetic counseling of and Medical Science, University College Dublin; lthe Department of Dermatology, families. This condition and these observations reinforce the Tel Aviv Sourasky Medical Center; and mthe Department of Human Molecular importance of heritable skin barrier defects, in this Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University. case desmosomal proteins, in the pathogenesis of atopic disease. The Irvine group is funded by the National Children’s Research Centre, Dublin, Ireland. (J Allergy Clin Immunol 2015;136:1268-76.) M.A.M. is supported by the National Children’s Research Centre, Dublin, Ireland. A.D.I. and W.H.I.M. are supported by the Wellcome Trust (090066/B/09/Z and Key words: Atopy, skin barrier, atopic dermatitis, desmosome, 092530/Z/10/Z). The Centre for Dermatology and Genetic Medicine, University of Dundee, is supported a Wellcome Trust Strategic Award (098439/Z/12/Z to desmoplakin, atopic sensitization, eosinophilic esophagitis W.H.I.M.). F.J.D.S. and N.J.W. are supported by grants from the Pachyonychia Congenita Project. Work in K.J.G.’s laboratory is supported by the National Institutes of Health (R37 AR043380 and R01 AR041836) and in part by the J.L. Mayberry Mendelian skin diseases that include atopic dermatitis (AD) or Endowment. P.M.E. is supported by National Institutes of Health grant R01AR061106. C. Cole is supported by the Wellcome Trust (WT strategic awards AD-like dermatitis, food allergies, or both as part of their WT097945, WT092340, and WT083481). phenotype potentially offer significant insights into disease Disclosure of potential conflict of interest: M. A. McAleer has received research support pathogenesis. The best examples of insights into AD pathogenesis from and is employed by the National Children’s Research Centre. E. Pohler is from Mendelian disease are Netherton syndrome (Mendelian employed by the University of Dundee. C. Cole has received research support from the Wellcome Trust (092530/Z/10/Z, 098439/Z/12/Z, Strategic awards 097945, 092340, Inheritance in Man [MIM] #256500) and ichthyosis vulgaris and 083481), has received travel support from the University of Nottingham, and has (MIM #146700). The discovery of mutations in the serine received funding for bioinformatics user group meetings from Edinburgh Genomics. J. protease inhibitor Kazal-type 5 gene (SPINK5) as causative for L. Koetsier, L. M. Godsel, R. M. Harmon, and K. J. Green have received research Netherton syndrome1 highlighted the role of excessive stratum support from the National Institutes of Health. R. Gruber has received travel support corneum protease activity in patients with AD, and identification from the Rene Touraine Foundation. W. H. I. McLean has received research support from the Wellcome Trust. A. D. Irvine has consultant arrangements with Regeneron of mutations in the filaggrin gene (FLG) in patients with ichthyo- 2 and has received research support from the National Children’s Research Centre. The sis vulgaris has been transformative in our understanding of the rest of the authors declare that they have no relevant conflicts of interest. importance of the skin barrier in patients with AD and those with Received for publication March 4, 2015; revised May 1, 2015; accepted for publication allergic sensitization.3,4 Other rare genodermatoses, such as ‘‘type May 2, 2015. B’’ peeling skin syndrome, which is attributed to mutations in the Available online June 12, 2015. 5 Corresponding author: Alan D. Irvine, MD, National Children’s Research Centre, Our corneodesmosin gene (CSDN), reinforce the importance of stra- 6 Lady’s Children’s Hospital Crumlin, Dublin 12, Ireland. E-mail: [email protected]. tum corneum cohesion in the pathogenesis of AD. In 2013, a new 0091-6749 syndrome designated severe dermatitis, multiple allergies, and Ó 2015 The Authors. Published by Elsevier Inc. on behalf of the American Academy metabolic wasting (SAM) syndrome was attributed to loss-of- of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). function mutations in the desmosomal plaque protein desmoglein 7 http://dx.doi.org/10.1016/j.jaci.2015.05.002 1 (desmoglein 1 gene [DSG1]). Four cases of SAM syndrome 1268 J ALLERGY CLIN IMMUNOL MCALEER ET AL 1269 VOLUME 136, NUMBER 5 with a significant improvement in PPK and ichthyosis. Intravenous immuno- Abbreviations used globulin infusions were also effective in reducing the frequency of septic aCGH: Array comparative genome hybridization episodes. The combined beneficial effects of acitretin, intravenous immuno- AD: Atopic dermatitis globulin, and percutaneous endoscopic gastrostomy feeding have allowed DSG1: Desmoglein 1 gene improvement in the patient’s dermatitis, growth and weight gain, and DSP: Desmoplakin gene development (Fig 1, B). His hair started to grow when he was 6 years old PPK: Palmoplantar keratoderma and is a wooly hair phenotype. Also, he has had ongoing poor periodontal SAM: Severe dermatitis, multiple allergies, and metabolic wasting health, with marked hypodontia. SNP: Single nucleotide polymorphism The patient was atopic, with multiple food allergies. Blood investigations 9 SPINK5: Serine protease inhibitor Kazal-type 5 gene were consistent with atopy, with persistent eosinophilia (0.4-0.5 3 10 /L) and WES: Whole-exome sequencing increased IgE levels (611 kU/L). Analysis of specific IgEs confirmed sensitiza- tion to egg, peanut, and wheat, despite having no oral exposure to these foods. 7,8 Histopathologic findings have now been reported, all caused by DSG1 mutations. Here Skin biopsies performed when the patient was 3 and 16 months of age we report the first case of SAM syndrome (MIM #615508) attrib- showed similar findings (Fig 2, A). There was hyperkeratosis and parakeratosis uted to a missense mutation affecting the plakin domain of the overlying an acanthotic epidermis. The granular layer was absent, and there desmoplakin gene (DSP). was no evidence of acantholysis. A superficial dermal inflammatory infiltrate composed of lymphocytes, admixed neutrophils, and histiocytes was present (Fig 2, B). A skin biopsy of the pustular eruption performed when the patient METHODS was 26 months of age showed a florid pustular dermatosis superimposed