1169: Periodontitis in neutropenic DADA2 patients

Background/Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease caused by pathogenic mutations in ADA2. Severe and refractory neutropenia is a hematologic feature in the phenotypic spectrum of DADA2. Periodontal disease is often recognized as a manifestation of severe neutropenia, but not previously highlighted in neutropenic DADA2 patients.

Methods: Retrospective review of DADA2 patients identified with known periodontal disease and severe neutropenia in the NIH DADA2 cohort. Medical records from 12/18/2005 to 12/01/2024 were reviewed.

Results: Patient 1 (R169Q/deletion in exon 7) is a 57-year-old edentulous female with a 28-year history of neutropenia (ANC = 0), fevers, cervical lymphadenopathy, splenomegaly, and splenectomy. No known history of strokes. Periodontal disease manifested by chronic tooth decay, gingivitis, severe mandibular regression, dental extractions, and poor osseointegration of dental implants. Dental imaging demonstrated severe bone loss. She was treated with cyclosporine, prednisone, and an induction dose of infliximab, followed by adalimumab, with positive treatment response and neutrophil count normalization without periodontitis recurrence.

Patient 2 (H112Q/R34W) is a 44-year-old female with a history of transient neutropenia (ANC = 0.8), Raynaud’s, fevers, arthralgia, genital ulcers, livedo reticularis, splenomegaly, and recurrent skin ulcers in lower extremities. No history of strokes. Periodontal disease manifested by extensive painful oral ulcerations and mucositis which correlated with episodes of severe neutropenia. She was treated with adalimumab with resolution of neutropenia and without oral ulcers and fever recurrence.

Patient 3 (R169Q homozygous) is a 43-year-old female with a history of neutropenia (ANC = 0), Raynaud’s, two episodes of central retinal artery occlusions leading to right eye blindness, fevers, headaches, arthralgia, livedo reticularis, lymphadenopathy, esophageal necrosis, and common variable immunodeficiency. Periodontal disease manifested by oral ulcers and gingivitis. She was treated with etanercept, response was not observed due to medication discontinuation after patient’s decision to withdraw all medical care. Patient expired 07/2024.

Patient 4 (H112Q/R169Q) is a 26-year-old male with a history of neutropenia (ANC = 0.3), fevers, skin rashes, and splenomegaly. Periodontal disease manifested by periodontal abscess and oral ulcers. No history of strokes. He received a hematopoietic stem cell transplant with resolution of DADA2 and periodontitis.

Conclusion: This retrospective review highlights periodontitis in severe neutropenia of DADA2. We hypothesize that DADA2 neutropenia induces IL-23 and IL-17 release by resident macrophages in the gingiva, similar to leukocyte adhesion deficiency. Since the neutropenia of DADA2 is at least partially due to destruction of precursors in the bone marrow, local cytokine production is unabated, leading to hyperinflammation. To further understand the mechanisms, we plan to conduct careful assessments of DADA2 patients’ oral history, dental exams, and when appropriate, gum biopsies.