Case Report ARTICLE
Novel PLCG2 Mutation In a Patient With APLAID And Cutis Laxa.
- 1Hospital de Dona Estefânia, Portugal
- 2Centro de Estudos de Doenças Crónicas (CEDOC), Portugal
- 3Addenbrooke's Hospital, Cambridge University Hospitals, United Kingdom
- 4Department of Medicine, University of Cambridge, United Kingdom
- 5Genetics Institute, University College London, United Kingdom
- 6Faculdade de Medicina, Universidade de Lisboa, Portugal
- 7Department of Biological Sciences, Institute of Structural and Molecular Biology, University of London, United Kingdom
- 8Laboratorio de Inmunologia, FES-Cuautitlan, UNAM, Mexico
Background: The autoinflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome is a rare primary immunodeficiency caused by a gain-of-function mutation S707Y in the PLCG2 gene previously described in two patients from one family. The APLAID patients presented with early-onset blistering skin lesions, posterior uveitis, inflammatory bowel disease (IBD) and recurrent sinopulmonary infections caused by a humoral defect, but lacked circulating autoantibodies and had no cold-induced urticaria, contrary to the patients with the related PLAID syndrome.
Case: We describe a new APLAID patient who presented with vesiculopustular rash in the first weeks of life, followed by IBD, posterior uveitis, recurrent chest infections, interstitial pneumonitis, and also had sensorineural deafness and cutis laxa. Her disease has been refractory to most treatments, including IL1 blockers and a trial with ruxolitinib has been attempted.
Results: In this patient we found a unique de novo heterozygous missense L848P mutation in the PLCG2 gene, predicted to affect the PLCγ2 structure. Similarly to S707Y, the L848P mutation led to the increased basal and EGF-stimulated PLCγ2 activity in vitro. Whole blood assays showed reduced production of IFN-γ and IL-17 in response to polyclonal T-cell stimulation and reduced production of IL-10 and IL-1β after LPS stimulation. Reduced IL-1β levels and the lack of clinical response to treatment with IL-1 blockers argue against NLRP3 inflammasome hyperactivation being the main mechanism mediating the APLAID pathogenesis.
Conclusion: Our findings indicate that L848P is novel a gain-of-function mutation that leads to PLCγ2 activation and suggest cutis laxa as a possible clinical manifestations of the APLAID syndrome.
Keywords: APLAID syndrome, PLCG2, phospholipase C, gamma 2 (phosphatidylinositol-specific), Cutis Laxa, Sensorineural Deafness, IL10, IL1b, Autoinflammatory syndromes
Received: 28 Sep 2018;
Accepted: 20 Nov 2018.
Edited by:Fabio Candotti, Lausanne University Hospital (CHUV), Switzerland
Reviewed by:Silvia C. Giliani, Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Italy
John B. Ziegler, Sydney Children's Hospital, Australia
Copyright: © 2018 Neves, Doffinger, Martins, Papapietro, Plagnol, Curtis, Martins, Kumararatne, Cordeiro, Neves, Borrego, Katan, Nejentsev and Barcenas Morales. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. João F. Neves, Hospital de Dona Estefânia, Lisbon, Portugal, email@example.com