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Case Reports
. 2015 Jun;46(6):923-8.
doi: 10.1016/j.humpath.2015.02.010. Epub 2015 Mar 5.

Loss of ADAM17 is associated with severe multiorgan dysfunction

Robert H J Bandsma  1 , Harry van Goor  2 , Michael Yourshaw  3 , Rudolf K Horlings  4 , Marcel F Jonkman  4 , Elisabeth H Schölvinck  5 , Arend Karrenbeld  2 , Rene Scheenstra  6 , Martin Kömhoff  7 , Patrick Rump  8 , Yvonne Koopman-Keemink  9 , Stanley F Nelson  3 , Johanna C Escher  10 , Ernest Cutz  11 , Martín G Martín  3
Affiliations
Case Reports

Loss of ADAM17 is associated with severe multiorgan dysfunction

Robert H J Bandsma et al. Hum Pathol. 2015 Jun.

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.

Keywords: ADAM17; Congenital enteropathy; Exome sequencing; Immunodeficiency; Inflammation.

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Figures

Fig. 1
Fig. 1
Dermatological features at 3 weeks of age. Erythema of the face and flexures, axillary maceration, widespread pustules in the chest, and seborrhoeic scaling of the scalp and forehead can be seen.
Fig. 2
Fig. 2
A, Hematoxylin and eosin stain of a skin biopsy taken from an affected scaly area on the abdomen revealing marked parakeratosis, neutrophils, and spongiosis (arrow). B, Hematoxylin and eosin stain of a duodenal biopsy obtained at 6 months of age. Duodenal biopsy shows focal villous atrophy and minimal crypt hyperplasia. C, Hematoxylin and eosin stain of a liver biopsy showing mild lymphocytic infiltrate (filled arrows), hepatocellular cholestasis (horizontal open arrow), and foci of apoptotic activity (vertical open arrows).
Fig. 3
Fig. 3
Representative flow cytometry analysis of TNF-α production in the CD3+CD8+ T lymphocytes of the patient (A and B) and a healthy control (C). PBMCs were in vitro stimulated with medium only (A) or PHA (B and C) and stained for CD69 and TNF-α expression. Results show a higher percentage of TNF-α–producing cells in the healthy control subject (2.5%) compared to the patient (0.4%) upon stimulation with PHA.
See this image and copyright information in PMC

References

    1. Scheller J, Chalaris A, Garbers C, Rose-John S. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol. 2011;32:380–7. - PubMed
    1. Blaydon DC, Biancheri P, Di WL, et al. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med. 2011;365:1502–8. - PubMed
    1. Yourshaw M, Taylor P, Rao AR, Martín MG, Nelson SF. Rich annotation of DNA sequencing variants by leveraging the Ensembl Variant Effect Predictor with plugins. Brief Bioinform. in press. - PMC - PubMed
    1. Stam J, Abdulahad W, Huitema MG, et al. Fluorescent cell barcoding as a tool to assess the age-related development of intracellular cytokine production in small amounts of blood from infants. PLoS One. 2011;6:e25690. - PMC - PubMed
    1. Sharma M, Mohapatra J, Acharya A, Deshpande SS, Chatterjee A, Jain MR. Blockade of tumor necrosis factor–alpha converting enzyme (TACE) enhances IL-1beta and IFN-gamma via caspase-1 activation: a probable cause for loss of efficacy of TACE inhibitors in humans? Eur J Pharmacol. 2013;701:106–13. - PubMed

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