PLCG2 variants in cherubism - 24/09/24

Doi : 10.1016/j.jaci.2024.08.016

Jennifer G. Chester, MD ^a, Benjamin Carcamo, MD ^b, David A. Gudis, MD ^c, Daniel Bustamante, MD ^d, Sidney B. Eisig, DDS ^e, Michael J. Ombrello, MD ^f, Wendy K. Chung, MD, PhD ^g, Joshua D. Milner, MD ^h,^⁎
^a Department of Medicine, Division of Pulmonary, Allergy, and Critical Care, Columbia University, New York, NY
^b Department of Pediatrics, Division of Pediatric Hematology Oncology, Texas Tech University Health Sciences Center, El Paso, Tex
^c Department of Otolaryngology–Head and Neck Surgery, Division of Rhinology and Anterior Skull Base Surgery, Columbia University, New York, NY
^d Department of Pathology, Texas Tech University Health Sciences Center, El Paso, Tex
^e Section of Hospital Dentistry, Division of Oral and Maxillofacial Surgery, Columbia University, New York, NY
^f Translational Genetics and Genomics Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md
^g Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^h Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, Columbia University, New York, NY

^∗Corresponding author: Joshua D. Milner MD, 3959 Broadway, New York, NY 10032.3959 BroadwayNew YorkNY10032

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Tuesday 24 September 2024

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.

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Key words : PLAID, autoinflammation, cherubism, immune dysregulation, phospholipase C gamma 2

Abbreviations used : GOF, IVIG, NK, PLAID, PLCG2, RANK