Table 3.

Clinical manifestations, molecular profile, treatment and outcomes of patients with non-inflammasome-related conditions (n = 16).

Center	Patient (age of diagnosis, years/sex)	Age of onset of symptoms	Clinical features	Laboratory features	Family history	Initial diagnosis	Molecular details	Treatment details	Follow-up duration and outcomes
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (n= 3)
PGIMER	Pt. 34 (2.75 y/F)	1 y 9 months	• Periodic fever • Subcutaneous swellings, rash, periorbital edema • Recurrent episodes of abdominal pain	CRP: 41 mg/L ESR: 120 mm/hr IgG: 1,301 mg/dL (270–1,580) IgA: 135 mg/dL (30–130) IgM: 250 mg/dL (50–220) NBT: Normal	Father affected; migratory lymphedema (same mutation)	Periodic fever	TNFRSF1A exon3; c.215G>A p.Cys72Tyr previously unreported	CS, NSAID Change in treatment: etanercept	Alive
	Pt. 35 (45 Y/F)	Since adoloscence	• Fever, • Arthralgia • Conjunctivitis, • Pustular psoriasis (recurrent sterile pustular lesions)	CRP: 87 mg/L ESR: 65 mm/hr Skin biopsy: neutrophilic infiltrate in upper spinous and subcorneal layers	No	Pustular psoriasis	TNFRSF1A exon9; c.902C>A p.Pro301His Missense Reported in gnomAD. Predicted to be pathogenic by polyphen and SIFT	CS, cyclosporine MTX	Died
Aster CMI	Pt. 36 (10 y/M)	3 months	• Recurrent fevers since early infancy (each episode for 3-4 weeks, afebrile intervals up to 10 days), • Rash over trunk and limbs, • Limb pains and limp, • Abdominal pain • Vomiting • Eye puffiness	CRP: 150 mg/L ESR: 120 mm/hr ANA: Negative	No	TRAPS	TNFRSF1A exon 9; c.146A>G; p.Tyr49Cys Previously reported	CS, antimicrobials Change in treatment: Etanercept - partial response Tocilizumab – responded	Alive and doing well
Deficiency of the interleukin-1 receptor antagonist (DIRA) (n= 2)
PGIMER	Pt. 37 (5 months/F) (26)	21 days	• Reduced movement and pain of left hip, left shoulder, right wrist, bilateral elbows since early infancy (multifocal osteitis) • Pustules	CRP: 110.7 mg/L ESR: 113 mm/h Bone scan: increased uptake in multiple joints (bilateral hip, shoulders, and sternoclavicular joints, lower ribs near costochondral junction and left elbow) X-ray: osteolytic lesions at humerus, left proximal femur, ribs and clavicle Bone biopsy: Bone inflammation	No	DIRA	IL1RN deletion, at chr2_hg19_113,865,011 and chr2_hg19_113,887,227 homozygous 22,216bp deletion spans the first four exons of IL1RN, Parents carrier for same mutation (NM_173843) Homozygous deletion Exon 1-4 deletion	Change in treatment done: Anakinra	Well
	Pt. 38 (2.58 y/M)	7 days	Paucity of bilateral upper limb movements since day 7 of life Pustular lesions	CRP: 1.8 mg/L ESR: 8 mm/hr X-ray: bilateral humerus, clavicle and rib metaphyseal widening,	No	DIRA	Mutation for ILRN deletion as in patient 36 screened but not found	CS	Alive, healed lesions
Pyogenic Arthritis, Pyoderma gangrenosum and Acne (PAPA) (n= 1)
PGIMER	Pt. 39 (5 y/F)	2.5 y	• Fever • Pyoderma gangrensosum • Colitis • Multiple abscess • Pus drainage, fistula, oral ulcers, pustules • Abdominal pain • Recurrent diarrhea	CRP: 101 mg/L ESR: 35 mm/hr Platelets: 964 × 109/L Colonoscopy: ileocecal valve thickened and distorted. Ileum shows active ulceration, cobble stone appearance, pseudo-polyp. Alteration of vascular pattern in cecum and ascending colon. Few active ulcers in hepatic flexure, transverse colon, recto sigmoid junction with pseudo-polyps Impression: Crohn's disease or tuberculous colitis Gut biopsy: Crohn's disease ANA, ANCA: negative C3/C4: 182/23 IgG: 869 NBT, CD3: Normal	-	Crohn's disease	PSTPIP1 exon3; c.203C>T; p.Thr68Met Missense Place: Gasilini, italy	ATT, CS, infliximab, AZA	Died
A20 haploinsufficiency (TNFAIP3) (n= 4)
PGIMER	Pt. 40 (6 y/F)	6 M	• Recurrent fever • Oro-genital ulcers • Ocular inflammation, blurring of vision • Headache • Papilledema • Abdominal pain • Arthritis • Colitis	CRP: 73.9 mg/L ESR: 26 mm/hr MR brain: type 2 Arnold Chiari malformation, HLAB51: positive ANA, ANCA: negative Gut Biopsy: no vasculitis	Younger brother has recurrent oral ulcers since 8 months age; Mother heterozygous for same variant	Behcet disease	TNFAIP3 exon 7;c.1504C>T; p.Arg502Trp Heterozygous missense	colchicine, AZA	Alive and well
CMC Vellore	Pt. 41 (7 y/M)	NA	• Autoinflammatory syndrome • Inflammatory ulcers duodenum to caecum, gastritis	IgG: NA IgA: 579 mg/dL IgM: NA IgE: NA CD3:487 CD19: 22 CD56: 410	NA	NA	TNFAIP3 exon7; c.1316_1317del; p.Gly440ArgfsTer4 Heterozygous Novel Likely pathogenic	NA	NA
CMC Vellore	Pt. 42 (7y/M)	NA	• AIHA, • Skin rashes • Immune deficiency	IgG: 2148mg/dL IgA: 145mg/dL IgM: 14mg/dL IgE: NA Direct coombs test 3+, Ferritin normal. No increase in Double negative TCRαβ+ T cells	NA	NA	TNFAIP3 exon8; c.2036T>C; p.Ile679Thr Heterozygous VUS	NA	NA
CMC Vellore	Pt. 43 (3 y/M)	NA	Osteomyelitis/CGD	NA	NA	NA	• TNFAIP3 • exon7; c.1807G>A; • p.Gly603Arg • Heterozygous • VUS	NA	NA
TRNT1 deficiency (Sideroblastic anemia, immune deficiency, periodic fever, delay) (SIFD) (n= 2)
ASTER CMI	Pt. 44 (3y/M)	6 months	• Recurrent fever (each episode for 4-7 days and recur twice a month) • Diarrhea • Vomiting • Panhypogmmaglobulinmeia	IgG: 223 mg/dL IgA: 17mg/dL IgM: 24 mg/dL CD3: 77% (1927) CD19: 2.5% (62) CD56: 18% (460)	Two brothers had died within the first 2 years of life with recurrent fever	X-linked agammaglobulinemia	TRNT1 exon 2; c.143_144insTT p.Thr49Ter and exon 7;c.1043A>T p.Asp348Val compound heterozygous mutation	Replacement IVIg	Doing well
CMC Vellore	Pt. 45 (5y/M)	NA	• Hypogammaglobulinemia • Bronchiectasis	IgG: 478 mg/dL IgA: 31 mg/dL IgM: 50mg/dL IgE: 22.8 mg/dL CD3: 2,897 CD19: 96 CD56: 747 Elevated ferritin	NA	NA	TRNT1 exon5; c.569G>T; p.Arg190Ile Homozygous	NA	NA
CARD14 mediated psoriasis (CAMPS) (n= 1)
CMC Vellore	Pt. 46 (8 y/M)	NA	Psoriasis	NA	NA	NA	CARD14 exon7; c.458G>C; p.Cys153Ser homozygous	NA	NA
Laccase Domain Containing 1 (LACC1) defect (n= 3)
PGIMER	Pt. 47 (5.75y/F) (27)	9 M	• Polyarticular joint disease. • Joint symptoms with involvement of knee and ankle and rapidly progressed to involve small joints and cervical spine, multiple joint involvement, pain, deformities and contractures, bed bound, stunted, nail dystrophy, marked swelling, deformity of large and small joints	X-ray: osteopenia, erosion of vertebrae without any platyspondyly RA Factor: positive	Sibling of Pt. 49 and 50	Torg Winchester syndrome, Pseudorheumatoid chondrodysplasia and Familial inflammatory arthropathy	LACC1 exon4; c. 832G>C, p.Ala278Pro Parents heterozygous for the same	Naproxen, CS, MTX	Doing satisfactory
	Pt. 48 (3y/F) (27)	9 M	• Polyarticular joint disease. • Joint symptoms with involvement of knee and ankle and rapidly progressed to involve small joints and cervical spine, multiple joint involvement, pain, deformities and contractures, bed bound, stunted, nail dystrophy, marked swelling, deformity of large and small joints	X-ray: osteopenia, erosion of vertebrae without any platyspondyly	Sibling of Pt. 48 and 50	Similar to Pt 48	Same as Pt 48	Naproxen, CS, MTX	Doing satisfactory
	Pt. 49 (0.91y/F) (27)	9 M	• Polyarticular joint disease. • Joint symptoms with involvement of knee and ankle and rapidly progressed to involve small joints and cervical spine, multiple joint involvement, pain, deformities and contractures, bed bound, stunted, nail dystrophy, marked swelling, deformity of large and small joints	X-ray: ostopenia, erosion of vertebrae without any platyspondyly	Sibling of Pt. 48 and 49	Similar to Pt 48	Same as Pt 48	Naproxen, CS, MTX	Doing satisfactory

ANA, Antinuclear antibodies; Aster CMI, Aster CMI Hospital, Bengaluru, India; AZR, Azathioprine; CARD14, Caspase recruitment domain family member 14; CMC, Christian Medical College and Hospital, Vellore, India; CRP, C-reactive protein; COPA, Coatamer complex 1 protein alpha subunit; CS, Corticosteroids; CT, Computed tomography; CTA, Computed tomography angiography; ESR, Erythrocyte sedimentation rate; HCQS, Hydroxychloroquine; IL1RN, Interleukin 1 Receptor Antagonist; IVIg, Intravenous immunoglobulin; JIA, Juvenile idiopathic arthritis; LACC1, Laccase domain containing 1; MRI, Magnetic resonance imaging; MTX, Methotrexate; PGIMER, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India; PSTPIP1, Proline-serine-threonine phosphatase interacting protein 1; Reference of previously reported paper; TNFAIP3, TNF alpha induced protein 3; TNFRSF1A, TNF receptor superfamily member 1 A; TRNT1, TRNA nucleotidyl tranferase 1; Y, year.