Summary of the 10 patients reported with PSMB10 heterozygous de novo variations
| . | PI . | PII . | PIII . | P4 . | P5 . | P6 . | P7 . | P8 . | P9 . | P10 . |
|---|---|---|---|---|---|---|---|---|---|---|
| Variant | p.Asp205Ala | p.Ser208Phe | p.Ser208Phe | p.Gly201Arg | p.Gly201Arg | p.Gly201Arg | p.Gly201Arg | p.Asp56His | p.Gly201Arg | p.Gly201Arg |
| Reported in | Present report | Present report | Present report | (5) | (5) | (5) | (5) | (5) | (5) | (6) |
| Clinical features | ||||||||||
| Enteropathy (age at onset) | No | Chronic diarrhea with transient TPN (2 wk)a,b | Chronic diarrhea (8 wk)a | Chronic diarrhea (8 wk) | Chronic diarrhea with TPN (colitis, no CMV) (1 mo) | Chronic diarrhea (3 wk) | Chronic diarrhea (6 wk) | Chronic diarrhea with TPN (birth) | Blood and mucus in stools (8 wk) | Chronic diarrhea (8 mo) |
| Liver disease | No | VOD with multiple flares of liver failure, cholestasis, cytolysis, and esophageal varices (2 mo) | Liver failure with ascites (8 mo) | NR | Chronic hepatocellular and cholestatic liver failure (1 mo) | NR | NR | NR | NR | Transaminitis (10 mo) and elevated liver function tests (13 mo) |
| TMA | No | Yes (1 year) | No | NR | NR | NR | NR | NR | NR | NR |
| Skin | No | No | Generalized erythroderma with desquamation (7 mo) | Generalized erythroderma with desquamation (1 wk) | Moderate facial erythroderma (2 wk) | Generalized erythroderma with desquamation (3 wk) | Generalized erythroderma with desquamation (1 wk) | Generalized maculopapular rash (8 wk) | Generalized dry skin (8 wk) | Pruritic rash (8 mo) |
| Infection | Pneumocystis pneumonia | Primary CMV infection at first VOD flare | Pneumocystis pneumonia | Oral candidiasis | CMV disseminated disease and encephalitis (1 mo) | Oral candidiasis | Pneumocystis in BAL (3 mo) | Adenovirus detected in blood and stools | No | Pneumocystis pneumonia |
| Four catheter-related bacteremia | Primary CMV infection at liver failure | Oral candidiasis | Parainfluenza 3 respiratory infection (9 mo) | |||||||
| HSCT characteristics | ||||||||||
| Age at HSCT | 5 mo | NA | NA | 2.8 mo | 2.5 years | 2.5 mo | 16 wk | 2.8 mo | 2 mo | 2.8 mo |
| Donor | MMRD | NA | NA | MSD | MRD | URD cord blood | MMRD | Mismatched cord blood | MMRD | MSD |
| Conditioning regimen | MAC-reduced toxicityc (Bu, Flu, and ATG) | NA | NA | RIC (Cy and ATG) | RIC (Cy and ATG) | RIC (Mel and Flu) | MAC (Bu, Cy, and ATG) | RIC (Treo and Flu Alem) | RIC (Treo, Flu, ATG, and Rx) | RIC (Cy and ATG) |
| Complications after HSCT | ||||||||||
| | Early and fulminant VOD (fatal); P. aeruginosa sepsis | | | Encephalopathy, quadriplegia, neurogenic bladder (Csa toxicity) (Y3); myocarditis and dilated cardiomyopathy after P B19 infection (Y4); adulthood: Skin hypersensitivity | TMA (fatal) | Skin GVHD; severe VOD; chronic liver disease with cirrhosis and varices (sinusoidal obstruction syndrome); chronic enteropathy; glomerulonephritis (mid-childhood) requiring kidney transplant | Capillary leak syndrome and pneumonitis; GVHD skin and gut; fatal encephalopathy and VZV recurrence | Severe mucositis; skin toxicity; liver dysfunction (histology: marked ductular cholestasis); chronic enteropathy with norovirus infection; relapsing-remitting skin rash; profound and severe hypothyroidism | Severe acute encephalopathy (M1, diffuse white matter involvement on MRI) | |
| Outcome | ||||||||||
| Outcome | Deceased (VOD and sepsis, 7 mo) | Deceased (edematous flare of VOD, 2 years) | Deceased (liver failure and with ascites, 8 mo) | Alive (18 years) | Deceased (TMA, 2 years) | Deceased (sepsis after kidney transplantation, 16 years) | Deceased (encephalopathy, 11 wk) | Deceased (sepsis, 4 years) | Alive (1 year) | Alive (>13 mo) |
| Immune parameters | ||||||||||
| T cells | Low | Low | Low | Low | Low | Low | Low | Low | Low | Low |
| No naïve T cells | No naïve T cells | Normal naïve CD8 | Mildly decreased naïve CD4 | No naïve T cell | No naïve T cells | No naïve T cells | No naïve T cells | No naïve T cells | Naïve T cells: normal at 5 and 8 mo; decreased at 14 mo | |
| TREC | NP | NP | NP | NR | Low | NR | NR | NR | Low | Normal (Birth) |
| T cell repertoire diversity | NP | Reduced | Normal | Reduced | Reduced | Reduced | NR | NR | Normal | Reduced |
| B cells | Very low | Very low | Normal | Very low (Near complete medullar block) | Very low | Subnormal | Very low | Very low (Near complete medullar block) | Very low | Very low |
| NK cells | Low | Normal | Normal | Low | High | Low | Normal | Low | Normal | Low |
| Eosinophilia | Present | Absent | Present | Present | Present | Present | Present | Absent | Present | Present |
| T cell Proliferation | NP | PHA: normal | PHA: normal | PHA: reduced | PHA: reduced | PHA: reduced | PHA: reduced | PHA: reduced | PHA: reduced | PHA: normal |
| OKT3: normal | OKT3: reduced | OKT3: normal | ||||||||
| IgGAM levels | Decreased IgGAM | Decreased IgGAM | Decreased IgGA | Decreased IgGAM | Decreased IgGAM | Decreased IgGA | Decreased IgG | Normal | Decreased IgGAM | Normal |
| Radiation sensitivity | Decreased (PBMC) | NP | Normal (PBMC) | Normal (fibroblast) | NR | NR | NR | NR | NR | NR |
| Type-1 interferon signature | NP | NP | Normal | NR | NR | NR | NR | NR | Normal | NR |
| . | PI . | PII . | PIII . | P4 . | P5 . | P6 . | P7 . | P8 . | P9 . | P10 . |
|---|---|---|---|---|---|---|---|---|---|---|
| Variant | p.Asp205Ala | p.Ser208Phe | p.Ser208Phe | p.Gly201Arg | p.Gly201Arg | p.Gly201Arg | p.Gly201Arg | p.Asp56His | p.Gly201Arg | p.Gly201Arg |
| Reported in | Present report | Present report | Present report | (5) | (5) | (5) | (5) | (5) | (5) | (6) |
| Clinical features | ||||||||||
| Enteropathy (age at onset) | No | Chronic diarrhea with transient TPN (2 wk)a,b | Chronic diarrhea (8 wk)a | Chronic diarrhea (8 wk) | Chronic diarrhea with TPN (colitis, no CMV) (1 mo) | Chronic diarrhea (3 wk) | Chronic diarrhea (6 wk) | Chronic diarrhea with TPN (birth) | Blood and mucus in stools (8 wk) | Chronic diarrhea (8 mo) |
| Liver disease | No | VOD with multiple flares of liver failure, cholestasis, cytolysis, and esophageal varices (2 mo) | Liver failure with ascites (8 mo) | NR | Chronic hepatocellular and cholestatic liver failure (1 mo) | NR | NR | NR | NR | Transaminitis (10 mo) and elevated liver function tests (13 mo) |
| TMA | No | Yes (1 year) | No | NR | NR | NR | NR | NR | NR | NR |
| Skin | No | No | Generalized erythroderma with desquamation (7 mo) | Generalized erythroderma with desquamation (1 wk) | Moderate facial erythroderma (2 wk) | Generalized erythroderma with desquamation (3 wk) | Generalized erythroderma with desquamation (1 wk) | Generalized maculopapular rash (8 wk) | Generalized dry skin (8 wk) | Pruritic rash (8 mo) |
| Infection | Pneumocystis pneumonia | Primary CMV infection at first VOD flare | Pneumocystis pneumonia | Oral candidiasis | CMV disseminated disease and encephalitis (1 mo) | Oral candidiasis | Pneumocystis in BAL (3 mo) | Adenovirus detected in blood and stools | No | Pneumocystis pneumonia |
| Four catheter-related bacteremia | Primary CMV infection at liver failure | Oral candidiasis | Parainfluenza 3 respiratory infection (9 mo) | |||||||
| HSCT characteristics | ||||||||||
| Age at HSCT | 5 mo | NA | NA | 2.8 mo | 2.5 years | 2.5 mo | 16 wk | 2.8 mo | 2 mo | 2.8 mo |
| Donor | MMRD | NA | NA | MSD | MRD | URD cord blood | MMRD | Mismatched cord blood | MMRD | MSD |
| Conditioning regimen | MAC-reduced toxicityc (Bu, Flu, and ATG) | NA | NA | RIC (Cy and ATG) | RIC (Cy and ATG) | RIC (Mel and Flu) | MAC (Bu, Cy, and ATG) | RIC (Treo and Flu Alem) | RIC (Treo, Flu, ATG, and Rx) | RIC (Cy and ATG) |
| Complications after HSCT | ||||||||||
| | Early and fulminant VOD (fatal); P. aeruginosa sepsis | | | Encephalopathy, quadriplegia, neurogenic bladder (Csa toxicity) (Y3); myocarditis and dilated cardiomyopathy after P B19 infection (Y4); adulthood: Skin hypersensitivity | TMA (fatal) | Skin GVHD; severe VOD; chronic liver disease with cirrhosis and varices (sinusoidal obstruction syndrome); chronic enteropathy; glomerulonephritis (mid-childhood) requiring kidney transplant | Capillary leak syndrome and pneumonitis; GVHD skin and gut; fatal encephalopathy and VZV recurrence | Severe mucositis; skin toxicity; liver dysfunction (histology: marked ductular cholestasis); chronic enteropathy with norovirus infection; relapsing-remitting skin rash; profound and severe hypothyroidism | Severe acute encephalopathy (M1, diffuse white matter involvement on MRI) | |
| Outcome | ||||||||||
| Outcome | Deceased (VOD and sepsis, 7 mo) | Deceased (edematous flare of VOD, 2 years) | Deceased (liver failure and with ascites, 8 mo) | Alive (18 years) | Deceased (TMA, 2 years) | Deceased (sepsis after kidney transplantation, 16 years) | Deceased (encephalopathy, 11 wk) | Deceased (sepsis, 4 years) | Alive (1 year) | Alive (>13 mo) |
| Immune parameters | ||||||||||
| T cells | Low | Low | Low | Low | Low | Low | Low | Low | Low | Low |
| No naïve T cells | No naïve T cells | Normal naïve CD8 | Mildly decreased naïve CD4 | No naïve T cell | No naïve T cells | No naïve T cells | No naïve T cells | No naïve T cells | Naïve T cells: normal at 5 and 8 mo; decreased at 14 mo | |
| TREC | NP | NP | NP | NR | Low | NR | NR | NR | Low | Normal (Birth) |
| T cell repertoire diversity | NP | Reduced | Normal | Reduced | Reduced | Reduced | NR | NR | Normal | Reduced |
| B cells | Very low | Very low | Normal | Very low (Near complete medullar block) | Very low | Subnormal | Very low | Very low (Near complete medullar block) | Very low | Very low |
| NK cells | Low | Normal | Normal | Low | High | Low | Normal | Low | Normal | Low |
| Eosinophilia | Present | Absent | Present | Present | Present | Present | Present | Absent | Present | Present |
| T cell Proliferation | NP | PHA: normal | PHA: normal | PHA: reduced | PHA: reduced | PHA: reduced | PHA: reduced | PHA: reduced | PHA: reduced | PHA: normal |
| OKT3: normal | OKT3: reduced | OKT3: normal | ||||||||
| IgGAM levels | Decreased IgGAM | Decreased IgGAM | Decreased IgGA | Decreased IgGAM | Decreased IgGAM | Decreased IgGA | Decreased IgG | Normal | Decreased IgGAM | Normal |
| Radiation sensitivity | Decreased (PBMC) | NP | Normal (PBMC) | Normal (fibroblast) | NR | NR | NR | NR | NR | NR |
| Type-1 interferon signature | NP | NP | Normal | NR | NR | NR | NR | NR | Normal | NR |
Manifestations associated or very likely-associated to endothelial disease are bolded. Severe manifestations that persisted after HSCT with no argument for GVHD and despite full-donor chimerism are bolded and italicized. ATG: anti-thymoglobulin; Alem: alemtuzumab; BAL: bronchoalveolar lavage; Bu: busulfan; Cy: cyclophosphamide; Flu: fludarabine; GVHD: graft-versus-host disease; MAC: myeloablative conditioning regimen; Mel: melphalan; MMRD: mismatched-related donor; MSD: matched sibling donor; NA: not applicable; NR: not reported; NP: not performed; RIC: reduced-intensity conditioning regimen; Rx: rituximab; Treo: treosulfan; TMA: thrombotic microangiopathy; TPN: total parenteral nutrition; TREC: T cell receptor excision circles; URD: unrelated donor.
Microbiological, endocrine, metabolic, and immunological data for digestive tract involvement were negative during symptoms: viral, parasitic, and bacterial stool investigation; anti-AIE75, -Saccharomyces, transglutaminase antibodies; amino acids chromatography, congenital glycosylation disorder testing; thyroid tests.
Digestive tract histology showing total villous atrophy with inflammation at 7 mo and villous regeneration with B and T cell infiltrates at 12 mo.
CD34-positive selection of the graft. Busulfan with measured total AUC 68,940 ng/mLxh, fludarabine 160 mg/m², and thymoglobulin 7.5 mg/kg.