Genetically defined systemic autoinflammatory diseases in pediatric patients with Behçet's disease.

Whole-exome sequencing identified genetically defined systemic autoinflammatory diseases (SAIDs) in 10 of 34 pediatric patients presenting with Behçet's disease or mimics.

• The study retrospectively analyzed 34 pediatric BD and mimic patients who underwent WES at a single center from 2020 to 2025.
• 10 probands were classified as SAID+ (approximately 29% of the cohort).
• The remaining 24 patients were classified as pediatric BD (ped-BD group) without genetically determined SAID.
• One proband was found to have trisomy 8 rather than a point mutation.

Pathogenic or likely pathogenic germline variants were identified in RELA, TNFAIP3 (encoding A20), or GATA2 among the SAID+ probands.

• Nine of the 10 SAID+ probands carried pathogenic or likely pathogenic germline variants in these three genes.
• Five of the SAID+ probands exhibited parentally inherited variants.
• The remaining four probands possessed de novo variants.
• TNFAIP3 encodes the protein A20, which is involved in NF-κB signaling regulation.

The SAID+ group exhibited earlier disease onset compared to the pediatric BD group without genetically determined disease.

• Earlier disease onset was identified as a distinguishing clinical feature of the SAID+ group versus the ped-BD group (n=24).
• Earlier onset was flagged as a key indicator for which genetic evaluation should be considered.
• The comparison was made between the SAID+ group (n=10) and the ped-BD group (n=24).

The SAID+ group had greater prevalence of recurrent fever episodes, intestinal involvement, and hematologic abnormalities compared to the ped-BD group.

• Recurrent fever episodes were more prevalent in the SAID+ group than in the ped-BD group.
• Intestinal involvement, including enteritis and intestinal ulcers, was more common in the SAID+ group.
• Hematologic abnormalities were more frequently observed in the SAID+ group.
• These clinical features were identified as indicators warranting genetic evaluation in BD cases.

Laboratory studies revealed higher levels of inflammatory markers and serum cytokines in the SAID+ group compared to the ped-BD group.

• Elevated serum cytokines in the SAID+ group included IL-1β, IL-2, IL-10, and TNF-α.
• Higher levels of inflammatory markers were also observed in the SAID+ group.
• These laboratory findings indicate heightened systemic inflammation in genetically defined SAID patients.

Biologic disease-modifying antirheumatic drugs (DMARDs) were used more commonly in the SAID+ group, while corticosteroids were utilized across all patients.

• Corticosteroid treatment was commonly utilized in all patients regardless of genetic status.
• Use of biologic DMARDs was more common in the SAID+ group than in the ped-BD group.
• The authors characterized this as 'intensified immunosuppressive regimens' required by the SAID+ group.
• Greater organ involvement in the SAID+ group was cited as necessitating more aggressive treatment.

The authors concluded that genetic evaluation should be considered for BD cases with early disease onset, recurrent fever, enteritis, intestinal ulcers, or hematologic abnormalities.

• These clinical features were identified as red flags distinguishing genetically defined SAIDs from typical pediatric BD.
• The recommendation stems from findings that nearly 30% of the pediatric BD/mimic cohort had an identifiable genetic etiology.
• Identifying genetic diagnoses has implications for treatment selection, particularly use of biologic DMARDs.
• The study period spanned 2020 to 2025 at a single center.