Table 1.
Clinical manifestations, molecular profile, treatment, and outcome of patients with type I interferonopathies (n = 12).
| Center | Patient (Age at diagnosis/Sex) | Age of onset of symptoms | Clinical features | Laboratory features | Family history (Consanguinity/siblings affected) | Initial Diagnosis | Molecular details | Treatment details | Follow-up duration and outcomes |
|---|---|---|---|---|---|---|---|---|---|
| Deficiency of Adenosine Deaminase 2 (DADA2) (n= 6) | |||||||||
| PGIMER | Pt. 1 (31y/M) |
3.3y | • Fever • Rash • Hypertension • Recurrent strokes at 3 and 16 years of age |
CRP: 32 mg/L ESR: 20 mm/h MRI brain: multiple infarcts right MCA territory and right posterior circulation CTA: microaneurysms in branches renal artery Muscle biopsy: healed arteritis |
Third degree consanguinity | PAN |
ADA2
exon 2; c.140G>T; p.Gly47Val Homozygous; missense Previously reported: Yes |
CS, AZR, enalapril, aspirin Change in treatment after diagnosis: Aspirin stopped, HCQs added and planned for ant-TNF |
34 years and doing well |
| Pt. 2 (13 y/F) |
5 y | • Fever • Recurrent abdominal pain • Hypertension • Optic atrophy • Left hemiparesis and facial palsy intestinal perforation |
CRP: 45 mg/L ESR: 40 mm/h DSA: multiple microaneurysms involving bilateral interlobar and segmental branches of renal artery, branches of gastroduodenal artery, distal branches of SMA and IMA GI Biopsy: Ulcer, ischemic, gangrene, perforation in ileum. Chronic inflammation in recto-sigmoid junction Plasma ADA2 activity: 1.1 mU/g protein mL Plasma ADA2 activity (Father): 42.5 mU/g protein mL Plasma ADA2 activity (Mother): 69.5 mU/g protein mL |
Sister of Pt. 3 | PAN |
ADA2
exon 2; c.139G>C; p.Gly47Arg Homozygous missense Previously reported: Yes |
CS, CYC (10 pulses), AZR, aspirin Change in treatment after diagnosis: Aspirin stopped, HCQs added and planned for anti-TNF |
8 year and doing well | |
| Pt.3 (18 y/M) | 17 y | • Sudden Painless loss of vision • Raynaud phenomenon, CRAO |
CRP: 10 mg/L ESR: 12 mm/h CTA: Normal study Plasma ADA2 activity: 0.3 mU/g protein mL |
Brother of Pt. 2 | PAN |
ADA2
exon 2; c.139G>C; p.Gly47Arg Same as the sibling (Pt. 2) |
CS, CYC (6 pulses), AZR, aspirin, LMWH Change in treatment after diagnosis: Aspirin stopped, HCQs added and planned for anti-TNF |
3 years and doing well | |
| SGPGI | Pt. 4 (17 y/M) (29) | 5 y | • Fever • Vasculitic ulcers • Seizures, • Recurrent stroke with neurological deficits • VIth Cranial Nerve palsy, median nerve neuropathy, • GI bleed |
Skin Biopsy: Necrotizing cutaneous vasculitis | No | PAN |
ADA2
exon 2; c.139G>C; p.Gly47Arg; exon 2; c.278T>C; p.Ile93Thr Previously reported: Yes Homozygous missense variation |
CS, AZR Change in treatment: anti-TNF commenced |
1 year and doing well |
| Pt. 5 (48 y/M) (29) |
8 y | • Fever • Ulcers and rash • Recurrent stroke along with neurological deficits, mononeuritis multiplex, CRAO |
CRP: 5.11 mg/L ESR: 30 mm/h C3/C4: 129/32.3 |
PAN |
ADA2
exon 2; c.139G>C; p.Gly47Arg Homozygous missense variation Previously reported: Yes |
CS, MMF Change in treatment: Stopped aspirin |
doing well | ||
| Aster CMI | Pt. 6 (0.9 y/F) (29) |
5 months | • Fever • Anemia • generalized lymphadenopathy, splenomegaly |
CRP: 102 mg/L ESR: 155 mm/h Bone marrow: Normocellular bone marrow with trilineage hematopoiesis IgG: 1,640 mg/dL IgA: 101 mg/dL IgM: 96 mg/dL IgE: 3.7 mg/dL |
No | - |
ADA2
exon 2; c.139G>C; p.Gly47Arg Homozygous missense variation Previously reported: Yes |
Injection etanercept | Doing well |
| STING-associated vasculopathy with onset in infancy (SAVI) (n= 3) | |||||||||
| PGIMER | Pt 7 (10 y/F) (19) |
0.91 y | • Fever, • Failure to thrive, • Deforming inflammatory arthritis with contractures of small and large joints • ILD, corneal • Opacity in right eye |
CRP: 97.23 mg/L ESR: 120 mm/h CT chest: ILD RA factor: positive ANA: 4+ RIM IgG: >2,535 (540–1,610) IgA: 436 (70–250) C3: 166 mg/dl (89–187) C4: 20 mg/dl (16–38) Anti ds-DNA: 10.8 IU/ml (<25- Negative) Serum IL-6: 3,700 pg/ml Serum IL-10: 13,900 pg/ml Interferon levels elevated |
Brother and Father affected (Pt. 8 and Pt. 9) | JIA, COPA |
TMEM173
exon5; c.463G>A; p.Val155Met heterozygous missense variation Previously reported: Yes |
CS, MTX, AZR, Naproxen, HCQ | Alive |
| Pt 8 (3 y/M) (19) |
2 y | • Fever • Polyarthritis (bilateral knee, small joints of the hands) • Rash ILD |
CRP: 12.98 mg/L ESR: 108 mm/h CT chest: ILD RA factor: negative ANA: 2+ Speckled IL-6: 3,500 pg/ml IL-10: 14123 pg/ml Interferon levels elevated |
B/o Pt. 7 | JIA, COPA |
TMEM173
exon5; c.463G>A; p.Val155Met heterozygous missense variation Same as Pt. 7 |
AZR, MTX | Well | |
| Pt 9 (4y/-) (19) | • Deforming inflammatory polyarthritis involving small and large joints • ILD • Peripheral vascular disease of bilateral lower limbs with guillotine amputation of right midfoot and 2nd toe in the year 2008 |
ESR: 12 mm/h RA Factor: 6.49 mg/L ANA (IF): 3 + diffuse CT chest: Emphysematous changes and interstitial thickening in bilateral lungs consistent with ILD |
F/o Pt. 7 | RA |
TMEM173
exon5; c.463G>A; p.Val155Met heterozygous missense variation Same as Pt. 7 |
- | - | ||
| Spondyloenchondrodysplasia (SPENCD) (n= 2) | |||||||||
| SGPGI | Pt. 10 (15 y/F) |
13 y | • Fever • Seizure • Stroke • Optic atrophy • Hypertensive • Short stature |
MR brain: Basal ganglion calcification Renal biopsy: IgA nephropathy ANA–Positive Anti dsDNA: 67.5 IU C3/C4: 105 mg/dL/29.6 mg/dL IgG: 3,590 mg/dl IgA: 621 mg/dl IgM: 60.9 mg/dl |
No | SLE |
ACP 5
exon 3; c.550C>T; p.Gln184* exon 4; c.740T>G; p.Leu247Arg |
HCQs, antihypertensive drugs | NA |
| Lilavati Hospital | Pt. 11 (4y/F) | 1y | • Fever • Bleeding (Skin, mucosal and intracranial) • Anemia • Facial dysmorphism (delay in motor and cognitive milestones, fronto-parietal bossing, hyperteleorism, low set ears |
X-ray wrist: metaphyseal dysplasia CT brain: Symmetrical bilateral basal ganglion calcifications and gliotic area noted in left Parieto- Temporal area Bone marrow biopsy: hypercellular marrow with erythroid and megakaryocytic hyperplasia. Increased bone marrow fibrosis DCT ICT: strongly positive multiple antibodies Cold agglutinin: positive |
No | Early onset Immune thrombocytopenia |
ACP 5
exon 1; c.136delc; p.R46Gfs*24 Homozygous nucleotide deletion Parents heterozygous for the same variant |
Multiple packed cell transfusions and platelet transfusions IVIg, CS, dapsone, cyclosporine |
Doing well |
| Coatomer protein complex subunit alpha (COPA) defect (n= 1) | |||||||||
| PGIMER | Pt. 12 (11 y/M) (30) |
5 Y | Polyarthritis, ILD | CRP: 32 mg/L ESR: 23 mm/h HRCT: ILD IgG: 1,453 mg/dL IgA: 131 mg/dL IgM: 135 mg/dL RA, CCP: Positive ANA: 3+ speckled ANCA: negative |
Father died due to progressive lung disease | Poly JIA |
COPA
exon 9 (intron 9-10 junction) c.841C>T, p.Arg281Trp Novel heterozygous splice-site mutation Sangers (PGI) |
CS, MTX, HCQs | Alive |
ACP5, Acid phosphatase 5; ANCA, Anti neutrophil cytoplasmic antibody; ADA2, Adenosine deaminase 2; ANA, Antinuclear antibodies; anti TNF, Tumor necrosis factor; Aster CMI, Aster CMI Hospital, Bengaluru, India; AZR, Azathioprine; BJWHC, Bai Jerbai Wadia Hospital for Children, Mumbai, India; CMC, Christian Medical College and Hospital, Vellore, India; CRAO, Central retinal artery occlusion; CRP, C-reactive protein; CS, Corticosteroids; CT, Computed tomography; CTA, Computed tomography angiography; CYC, intravenous pulse cyclophosphamide; DCT, Direct Coombs test; DSA, Digital subtraction angiography; ESR, Erythrocyte sedimentation rate; HCQS, Hydroxychloroquine; HRCT, High resolution computed tomography GI, Gastrointestinal; ILD, Interstitial lung disease; IMA, Inferior mesenteric artery; JIA, Juvenile idiopathic arthritis; Lilavati Hospital, Lilavati Hospital and Research Center, Mumbai, India; LMWH, Low molecular weight heparin; MCA, Middle cerebral artery; MRI, Magnetic resonance imaging; MTX, Methotrexate; MMF, Myocphenolate mofetil; PAN, Polyarteritis nodosa; PGIMER, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India; RA, Rheumatoid arthritis; SGPGI, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGI), Lucknow, India; SLE, Systemic lupus erythematosus; SMA, Superior mesenteric artery; TMEM173, Transmembrane protein 173; Y, years.