Comparative clinical features of dominant-negative PSMB10 disease, dominant-negative PSMB9 disease, POMP deficiency (PRAID), and autosomal recessive PRAAS
| . | Dominant-negative PSMB10 (10 patients) . | Dominant-negative PSMB9 (2 patients) . | POMP deficiency (5 patients) . | Autosomal recessive PRAAS (<100 patients) . |
|---|---|---|---|---|
| Inheritance | De novo, heterozygous | De novo, heterozygous | De novo, heterozygous | Autosomal recessive |
| Age at onset | Neonatal/infancy | Neonatal/infancy | Infancy | Infancy/early childhood |
| Systemic inflammation | − (not prominent) | ++ | ++ | ++ |
| Liver involvement | +++ (frequent, severe VOD, liver failure, and high mortality) | ++ (early cirrhosis, CMV-triggered hepatitis, and fatal liver failure) | + (mild-moderate, rarely severe) | + (mild-moderate, hepatomegaly common, failure rare) |
| Gastrointestinal involvement | ++ (mild to severe enteropathy) | | | |
| Pulmonary hypertension | − | ++ | − | − |
| Skin involvement | Erythroderma and severe atopic dermatitis | Erythroderma and neonatal rash | Neutrophilic dermatosis | Panniculitis, lipodystrophy and chronic rash |
| Lipodystrophy | − | − | − | ++ |
| Muscle/Joint involvement | − | Myositis | − | Myositis, muscle atrophy, and joint contractures |
| Infections | ++, recurrent opportunistic infections | − | ++, recurrent opportunistic infections | +/− |
| Immunological Features | Severe SCID/CID | T cell lymphopenia and CD8+ T cell loss | CID | Mild to moderate lymphopenia |
| | Profound T and B cell lymphopenia | | T and B cell lymphopenia | Pancytopenia (variable) |
| | Low naïve T cell (variable) | | | Hypergammaglobulinemia |
| | Hypogammaglobulinemia | | | |
| IFN-I signature | Normal in 2 tested patients | High | High in 1 | High |
| | | | Normal in 1 (under treatment) | |
| JAK-inhibitor | Not tested | Efficient on pulmonary hypertension and autoinflammation (1 patient) | Might control autoinflammation increased risk of infection | Indicated for autoinflammation |
| HSCT outcome | Very high morbi-mortality | 1 patient transplanted and cured | 2 patients transplanted and cured | 1 PSMB4-deficient patient and cured |
| . | Dominant-negative PSMB10 (10 patients) . | Dominant-negative PSMB9 (2 patients) . | POMP deficiency (5 patients) . | Autosomal recessive PRAAS (<100 patients) . |
|---|---|---|---|---|
| Inheritance | De novo, heterozygous | De novo, heterozygous | De novo, heterozygous | Autosomal recessive |
| Age at onset | Neonatal/infancy | Neonatal/infancy | Infancy | Infancy/early childhood |
| Systemic inflammation | − (not prominent) | ++ | ++ | ++ |
| Liver involvement | +++ (frequent, severe VOD, liver failure, and high mortality) | ++ (early cirrhosis, CMV-triggered hepatitis, and fatal liver failure) | + (mild-moderate, rarely severe) | + (mild-moderate, hepatomegaly common, failure rare) |
| Gastrointestinal involvement | ++ (mild to severe enteropathy) | | | |
| Pulmonary hypertension | − | ++ | − | − |
| Skin involvement | Erythroderma and severe atopic dermatitis | Erythroderma and neonatal rash | Neutrophilic dermatosis | Panniculitis, lipodystrophy and chronic rash |
| Lipodystrophy | − | − | − | ++ |
| Muscle/Joint involvement | − | Myositis | − | Myositis, muscle atrophy, and joint contractures |
| Infections | ++, recurrent opportunistic infections | − | ++, recurrent opportunistic infections | +/− |
| Immunological Features | Severe SCID/CID | T cell lymphopenia and CD8+ T cell loss | CID | Mild to moderate lymphopenia |
| | Profound T and B cell lymphopenia | | T and B cell lymphopenia | Pancytopenia (variable) |
| | Low naïve T cell (variable) | | | Hypergammaglobulinemia |
| | Hypogammaglobulinemia | | | |
| IFN-I signature | Normal in 2 tested patients | High | High in 1 | High |
| | | | Normal in 1 (under treatment) | |
| JAK-inhibitor | Not tested | Efficient on pulmonary hypertension and autoinflammation (1 patient) | Might control autoinflammation increased risk of infection | Indicated for autoinflammation |
| HSCT outcome | Very high morbi-mortality | 1 patient transplanted and cured | 2 patients transplanted and cured | 1 PSMB4-deficient patient and cured |
HLH: hemophagocytic lymphohistiocytosis; PRAID: POMP-related autoinflammation and immune dysregulation.