title: Loss of ADAM17 is associated with severe multiorgan dysfunction.
abstract: ADAM metallopeptidase domain 17 (ADAM17) is responsible for processing large numbers of proteins. Recently, 1 family involving 2 patients with a homozygous mutation in ADAM17 were described, presenting with skin lesions and diarrhea. In this report, we describe a second family confirming the existence of this syndrome. The proband presented with severe diarrhea, skin rash, and recurrent sepsis, eventually leading to her death at the age of 10 months. We performed exome sequencing and detailed pathological and immunological investigations. We identified a novel homozygous frameshift mutation in ADAM17 (NM_003183.4:c.308dupA) leading to a premature stop codon. CD4(+) and CD8(+) T-cell stimulation assays showed severely diminished tumor necrosis factor-α and interleukin-2 production. Skin biopsies indicated a focal neutrophilic infiltrate and spongiotic dermatitis. Interestingly, the patient developed unexplained systolic hypertension and nonspecific hepatitis with apoptosis. This report provides evidence for an important role of ADAM17 in human immunological response and underscores its multiorgan involvement.
authors: The Division of Pediatric Gastroenterology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands. Electronic address: r.h.j.bandsma@umcg.nl.
authors: Robert H J
authors: RH
authors: Bandsma
authors: Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
authors: Harry
authors: H
authors: van Goor
authors: Departments of Human Genetics, Pathology and Laboratory Medicine David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
authors: Michael
authors: M
authors: Yourshaw
authors: Department of Dermatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
authors: Rudolf K
authors: RK
authors: Horlings
authors: Department of Dermatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
authors: Marcel F
authors: MF
authors: Jonkman
authors: Division of Pediatric Infectious Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
authors: Elisabeth H
authors: EH
authors: Schölvinck
authors: Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
authors: Arend
authors: A
authors: Karrenbeld
authors: The Division of Pediatric Gastroenterology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands.
authors: Rene
authors: R
authors: Scheenstra
authors: Division of Nephrology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
authors: Martin
authors: M
authors: Kömhoff
authors: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
authors: Patrick
authors: P
authors: Rump
authors: The Department of Pediatrics, Hagaziekenhuis Juliana Kinderziekenhuis, Sportlaan 600, 2566 MJ The Hague, the Netherlands.
authors: Yvonne
authors: Y
authors: Koopman-Keemink
authors: Departments of Human Genetics, Pathology and Laboratory Medicine David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
authors: Stanley F
authors: SF
authors: Nelson
authors: The Department of Pediatric Gastroenterology, Sophia Children's Hospital-Erasmus Medical Center, Dr. Molewaterplein 60, 3015 GJ Rotterdam, the Netherlands.
authors: Johanna C
authors: JC
authors: Escher
authors: The Division of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto M5G 1X8, Canada.
authors: Ernest
authors: E
authors: Cutz
authors: Departments of Human Genetics, Pathology and Laboratory Medicine David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
authors: Martín G
authors: MG
authors: Martín
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency*; D000072198:ADAM17 Protein; D017809:Fatal Outcome; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D009102:Multiple Organ Failure / Q000209:etiology* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ADAM17; Congenital enteropathy; Exome sequencing; Immunodeficiency; Inflammation