Table 1 Clinical details of the three affected individuals with biallelic mutations in DNASE2
From: Type I interferon-mediated autoinflammation due to DNase II deficiency
F1:V-1 | F1:V-3 | F2:II-4 | |
|---|---|---|---|
Gender (relationship) | Female (sister of F1:V-3) | Male (brother of F1:V-1) | Male |
Current age | 10 years | 8 years | 17 years |
Current growth status | Height-0.2 SD; weight-0.7 SD | Height-2.2 SD; weight-0.9 SD | Height-5.95 SD; weight-4.39 SD |
Features at presentation | Neonatal HSM, cholestatic hepatitis and pancytopenia requiring multiple RBC and platelet transfusions | Neonatal HSM, cholestatic hepatitis and pancytopenia requiring multiple RBC and platelet transfusions | Neonatal HSM, cholestatic hepatitis and pancytopenia requiring multiple RBC and platelet transfusions |
Hematological status | Resolving neonatal pancytopenia; mild thrombocytopenia and neutropenia from age 10 years | Neonatal pancytopenia resolving by age 1 month; persistence of a mild thrombocytopenia with fluctuating neutropenia, and an episode of pancytopenia at age 4 years followed by progressive non-regenerative normocytic anemia from 7 years of age requiring recurrent blood transfusions | Neonatal pancytopenia resolving by age 2–3 months; normocytic anemia noted at age 8 years; bone marrow analysis showed normal cell composition but reduced cell numbers, considered indicative of inflammatory damage |
Recurrent fevers | Starting at age 7 years, typically lasting 48 h, associated with raised ESR but essentially normal CRP | Starting at age 5 years, typically lasting 48 h, associated with raised ESR but essentially normal CRP | Starting at age 5 years, typically lasting 4–5 days, associated with swollen and painful knees, elbows, feet, wrists, raised ESR and CRP |
Postnatal hepatic disease | HSM present at age 7 years with increased liver stiffness (no biopsy performed) | Longstanding HSM with fibrotic changes noted on biopsy at age 5 years | Liver biopsies performed in the neonatal period (cholestatic hepatitis), and then at the age of 3 (‘possible cirrhosis’) and 8 years (fibrosis in the absence of active inflammatory infiltrates); normal fibroscan recorded at 17 years of age |
Renal status | Proteinuria recorded at age 10 years, presumed secondary to MGN but not biopsied | MGN without features of SLE at age 6 years (immunofluorescence staining negative for IgA, IgM, C3 and C1q) | Proteinuria with features of MGN diagnosed at age 8 years; normal values of C3 and C4; proteinuria no longer apparent at age 14 years, although renal biopsy showed immunocomplex deposition with abundant C1q accumulation |
Neurological status | Developmentally normal | Normal early motor and cognitive milestones, now demonstrating moderate learning difficulties at school; cranial MRI at age 8 years showing patchy sub-cortical white matter hyperintensities on T2 weighted imaging, and possible subtle calcification in the basal ganglia | Headaches and mild learning difficulties; cranial MRI at age 15 years showing small sub-cortical white matter hyperintensities on T2 weighted imaging |
Joint disease | None | None | Non-destructive deforming arthropathy beginning at age 8 years, particularly affecting the knees, hips, elbows and wrists, hands and temporo-mandibular joints, which has been refractory to broad-spectrum immunosuppression, anti-IL-1 receptor, anti-IL-1β and anti-TNFα therapies |
Immune status | Normal; fluctuating significant elevation of anti-DNA antibodies | Transient B-cell lymphopenia at birth, recurring at age 4 years, with frank hypogammaglobulinemia from 7 years of age requiring IVIG; progressive CD4+ and CD8+ lymphopenia first recorded at age 6 years; fluctuating significant elevation of anti-DNA antibodies | Mild lymphopenia; fluctuating significant elevation of anti-DNA antibodies |
Endocrinological status | Normal | IDDM from age 5 years (negative for anti-GAD, anti-IA2, anti-Langerhans islet and anti-ZnT8 antibodies) | Reduced response to arginine suggestive of growth hormone deficiency noted at age 17 years |
Skin involvement | None | None | Lipodystrophy of the limbs and chilblain-like lesions of the hands and feet since the age of 13 years |
Current status and treatments | Clinically asymptomatic but exhibits mild thrombocytopenia, neutropenia and proteinuria, as well as continued upregulation of ISGs and ESR; not currently treated, but due to start MMF and steroids in view of persistent proteinuria | Dependent on immunosuppression for renal disease; MMF, low dose steroids, IVIG replacement therapy, insulin, and RBC transfusions | Continued joint disease with Cushingoid features and failure to thrive, without signs of puberty; hydroxychloroquine, mepacrine, abatacept and low-dose steroids |
