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Case Reports
. 2024 Dec;154(6):1554-1558.
doi: 10.1016/j.jaci.2024.08.016. Epub 2024 Aug 27.

PLCG2 variants in cherubism

Jennifer G Chester  1 , Benjamin Carcamo  2 , David A Gudis  3 , Daniel Bustamante  4 , Sidney B Eisig  5 , Michael J Ombrello  6 , Wendy K Chung  7 , Joshua D Milner  8
Affiliations
Case Reports

PLCG2 variants in cherubism

Jennifer G Chester et al. J Allergy Clin Immunol. 2024 Dec.

Abstract

Background: Cherubism is most commonly caused by rare heterozygous gain-of-function (GOF) missense variants in SH3BP2, which appear to signal through phospholipase C gamma 2 (PLCG2) to cause excessive osteoclast activity leading to expansile lesions in facial bones in childhood. GOF variants in PLCG2 lead to autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation (autoinflammatory PLAID, or PLAID-GOF), characterized by variably penetrant autoinflammatory, autoimmune, infectious, and atopic manifestations. Cherubism has not been reported in PLAID to date.

Objective: We determined whether GOF PLCG2 variants may be associated with cherubism.

Methods: Clinical, laboratory, and genomic data from 2 patients with cherubism and other clinical symptoms observed in patients with PLCG2 variants were reviewed. Primary B-cell receptor-induced calcium flux was assessed by flow cytometry.

Results: Two patients with lesions consistent with cherubism but no SH3BP2 variants were found to have rare PLCG2 variants previously shown to be GOF in vitro, leading to increased primary B-cell receptor-induced calcium flux in one patient's B cells. Variable humoral defects, autoinflammatory rash, and other clinical and laboratory findings consistent with PLAID were observed as well.

Conclusion: GOF PLCG2 variants likely represent a novel genetic driver of cherubism and should be assessed in SH3BP2-negative cases. Expansile bony lesions expand the phenotypic landscape of autoinflammatory PLAID, and bone imaging should be considered in PLAID patients.

Keywords: PLAID; autoinflammation; cherubism; immune dysregulation; phospholipase C gamma 2.

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Conflict of interest statement

Disclosure statement Supported by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (R24 AI 17745 to J.D.M.), and the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01-AR041198 to M.J.O.). Disclosure of potential conflict of interest: J. D. Milner is on the scientific advisory board for Blueprint Medicine and receives grant funding from Pharming. W. K. Chung is the on the board of directors of Rallybio and Prime Medicine. S. B. Eisig is cofounder of Epibone. The rest of the authors declare that they have no relevant conflicts of interest.

References

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