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Table 1.  

No/year of HCT Country of origin (ethnicity) Age at dx, mo Genetics Lymphocyte subset (cells/µL) at presentation/prior to HCT (abnormal result according to age-based reference range) DR expression (%) Ig (g/L) Autoantibodies*
Lymp CD3 CD19 CD56 CD4 CD8 CD4/CD8 ratio Total naive T cells CD27+IgMIgD (%) T B M G A M
1/1995 England (Pakistan) 4.9 Homozygous CIITA mutation 5 796 4 750 640 460 640 (↓) 4120 (↑) 0.15 (↓) ND ND 0 0 0 1.64 0.11 1.76 ND
2†/1997 England (Pakistan) At birth Homozygous CIITA mutation 4 200 1 905 368 (↓) 368 500 (↓) 1 395 0.35 (↓) ND ND 0 0 0 6.16‡ 0.02 0.18 ND
3/1997 England (Bangladesh) 4.0 Homozygous CIITA mutation 1950 (↓) 858 (↓) 839 215 332 (↓) 585 0.57 (↓) ND ND 0 0 0 0.77 <0.13 0.08 ND
4/2003 England (Pakistan) 4.7 Homozygous RFX5 c.1198C>T (p.R400X) 2876 (↓) 1 409 (↓) 1167 252 249 (↓) 1 109 0.22 (↓) 73 ND 0 0 0 0.76 <0.07 0.10 ND
5/2008 Scotland 8.4 Compound heterozygous CIITA mutation c. 2582T>A (p.L861Q); c.2888+1G>A 1856 (↓) 1 194 (↓) 400 (↓) 139 135 (↓) 1 030 0.13 (↓) ND ND 0 0 0 0 0 0 ND
6/2008 England 15.3 Homozygous RFX5 c.1198G>T (p.E413X) 20 838 (↑) 17 780 (↑) 2253 805 1259 14 434 (↑) 0.09 (↓) 711 ND 0 0 0 1.6 <0.07 <1.1 ND
7/2011 England 7.8 Homozygous CIITA mutation§ c.3003C>G (p.D1001E) 952 (↓) 331 (↓) 443 (↓) 164 106 (↓) 222(↓) 0.48(↓) 162 <1 0 0 0 2.3 0.53 0.96 ND
8/2012 Scotland (Pakistan) 89.9 Homozygous CIITA mutation c.1595T>C (p.532P) 5 446 3851 956 611 519 (↓) 3203 (↑) 0.16 (↓) 616 4 0 0 0 14.9 <0.04 1.30 Negative
9/2012 Scotland (Pakistan) 22.7 Homozygous CIITA mutation c.1595T>C (p.L532P) 8 066 4 478 3009 425 989 3 520 (↑) 0.28 (↓) 1165 <1 0 0 0 NA NA NA Negative
10/2015 Saudi Arabia 8.0 Homozygous RFXANK mutation c.362A>T (p.D121V) 2842 (↓) 1 402 1056 329 777 (↓) 553 1.40 686 0 0 0 0 <1.0 0 0 ND
11†2015 Saudi Arabia 6.0 Homozygous RFAXNK mutation c.362A>T (p.R121V) 2988 (↓) 1 059 1163 685 453 (↓) 209 (↓) 2.17 ND ND 0 0 0 2.3 0 0 ND
12†/2015 Saudi Arabia 7.6 Homozygous RFAXNK mutation c.362A>T (p.R121V) 6 011 1 987 3563 382 1581 300 (↓) 5.27 596 0 0 0 0 <1.0 0.05 0.18 ND
13†/2015 Saudi Arabia 6.6 Homozygous RFAXNK mutation c.362A>T (p.R121V) 3 161 1 015 1621 436 695 (↓) 209 3.32 233 0 0 0 0 NA NA NA ND
14/2015 Saudi Arabia 6.4 Homozygous RFAXNK mutation c.362A>T (p.R121V) 3 361 1 474 1529 304 1097 277 3.96 575 0 0 0 0 <3.2 0.43 <0.25 Negative
15/2016 Saudi Arabia At birth Homozygous RFXANK mutation§ c.477C>A (p.S159R) 6 939 5 963 (↑) 722 217 1077 4 009 (↑) 0.27 (↓) 358 0 0 0 0 NA NA NA ND
16/2016 Kuwait At birth Homozygous RFXANK mutation c.271+1G>C (IVS4+1G>c) 5 679 4 327 939 311 3126 1 106 2.83 2652 0 0 0 0 NA NA NA ND
17/2017 Saudi Arabia 17.0 Homozygous RFXANK mutation c.362A>T (p.D121V) 1 126 (↓) 744 (↓) 198 (↓) 172 265 (↓) 390 0.68 (↓) ND ND 0 0 0 NA NA NA ND
18/2017 Saudi Arabia 6.0 Homozygous RFXANK mutation c.271+1G>C (IVS4+1G>c) 1004 (↓) 755 (↓) 123 (↓) 106 374 (↓) 445 0.84 (↓) 8 0 0 0 0 NA NA NA ND
19†/2017 Saudi Arabia 13.3 Homozygous RFXANK mutation§ c.477C>A (p.S159R) 1928 (↓) 1 555 323 32 (↓) 378 (↓) 648 0.58 (↓) 218 <1 0 0 0 NA NA NA ND
20/2017 Kuwait 4.6 Homozygous RFXANK mutation c.271+1delGinsTCAC 2615 (↓) 1 551 (↓) 797 227 849 (↓) 530 1.60 ND ND 0 0 0 0.66 0.07 0.3 ND
21†/2017 Saudi Arabia At birth Homozygous RFXANK mutation§ c.477C>A (p.S159R) 1196 (↓) 483 (↓) 603 94 (↓) 158 (↓) 266 (↓) 0.59 (↓) ND ND 0 0 0 NA NA NA ND
22/2017 Saudi Arabia 6 Homozygous RFXANK mutation c.271+1G>TCAC (IVS4+1G>TCAC) 1 761 (↓) 1 372 365 12 (↓) 509 (↓) 684 0.74 (↓) ND ND 0 0 0 NA NA NA ND
23/2018 Saudi Arabia 6 Homozygous RFXANK mutation c.362A>T (p.D121V) 2 010 (↓) 850 (↓) 971 151 414 (↓) 322 (↓) 1.28 206 0 0 0 0 NA NA NA ND
24/2018 Saudi Arabia 60 Homozygous RFAXNK mutation c.362A>T (p.R121V) 918 (↓) 626 (↓) 193 (↓) 87 (↓) 190 (↓) 292 (↓) 0.65 (↓) ND ND 0 0 0 0.3 0.25 0.17 ND
25/2018 Bulgaria 6 Homozygous RFXANK mutation p.R78*C>T 4 246 2 287 1530 388 759 (↓) 1 311 0.58 (↓) 297 ND 0 0 0 3.8 0.08 0.26 ND

Table 1: Genetics and immunological features at diagnosis (N = 25)

B, B cells; dx, diagnosis; Lymp, lymphocytes; M, monocytes; NA, not available; ND, not done; T, T cells. ↑, higher than normal reference range for age; ↓, lower than normal referance range for age.
*Autoantibodies: antinuclear antibody, double-stranded DNA, rheumatoid factor, antigastric parietal cell antibody, antimitochondrial antibody, antismooth muscle antibody, centromere antibody, tissue transglutaminase antibody, extractable nuclear antigen (ENA) nuclear ribonucleoprotein (RNP) anti-Smith antibody (Sm), anti-Ro antibody, anti-La antibody, Scl-70 antibody, Jo-1 antibody.
†Siblings: 1 and 2; 12 and 13; 19 and 21.
§IgG level was tested on day 12 of life (normal level due to maternal transplacental IgG transfer).
‡Novel variant.

Table 2.  

No./year of HCT Age at dx, mo Age at HCT, mo Interval between dx and HCT, mo Pretransplant infections and medical issues Donor Stem cell source Conditioning and GvHD prophylaxis Acute GvHD Significant complications during and after HCT Outcome
1/1995 4.9 7.0 2.1 Disseminated CMV infection (blood, liver, stools, NPS, urine). MFD (paternal uncle) BM Oral Bu 16 mg/kg (Bu AUC 1837 μmol × min). None Pneumonitis required mechanical ventilation. Died of CMV pneumonitis (postmortem) at day +17.
Poliovirus and rotavirus (stools). Cy 200 mg/kg. AKI, seizures, toxic epidermal necrolysis (skin biopsy proven).
Haemophilus influenzae (NPS). Maternal T-cell engraftment (skin biopsy proven). Alemtuzumab 1 mg/kg.
CSA.
2/1997 At birth 0.9 0.8 Staphylococcus aureus septicemia. MFD (great-granduncle) BM Oral Bu 16 mg/kg (no Bu pK). None Engraftment pneumonitis required mechanical ventilation and responded IST (treated with neb budesonide, neb Ig, systemic steroid, ATG, anti-TNF monoclonal antibody). Secondary autologous reconstitution at day +76.
Cy 200 mg/kg. Rabbit ATG 2.2 mg/kg. Severe hypertension with seizures. Second HCT using a different 7/8 MMFD at 5.6 mo of age.
CSA/MTX. CMV viremia. Staphylococcus epidermidis bacteremia. Died of interstitial pneumonitis at day +88 postsecond HCT.
Diagnosed as pyloric stenosis at day +56 and underwent pyloromyotomy on day +69.
3/1997 4.0 5.8 1.8 PCP (BAL). MSD BM Oral Bu 16 mg/kg (no Bu pK). None Worsening pretransplant respiratory dysfunction from day +9 and required mechanical ventilation from day +17. Died of parainfluenza virus 3 pneumonitis at day +19.
Candida perianal ulcers. Cy 200 mg/kg. NPS was positive for parainfluenza virus 3 and rhinovirus.
Congenital retinal dystrophy. No serotherapy. Treated with neb budesonide, neb IVIg, systemic steroid, ATG, and neb and IV ribavirin.
CSA/MTX.
4/2003 4.7 6.2 1.5 PCP (BAL). 7/8 MMUD CB Flu 150 mg/m2. Melph 140 mg/m2. Alemtuzumab 1 mg/kg. None Staphylococcus epidermidis bacteremia. Alive
Fungal (hyphae on BAL). CSA/steroid. CMV pneumonitis rotavirus.
Poliovirus (gut and NPS).
5/2008 8.4 11.3 2.9 PCP (BAL). MFD BM Treo 36 mg/m2. Grade 1 skin Pneumonitis. Cryopreserved marrow top-up at day +54 for slipping chimerism.
Norovirus type 2 enteropathy. Cy 200 mg/kg. Capillary leakage syndrome. Second conditioned HCT using the same donor at day +186.
HHV6 viremia. No serotherapy. CSA/MMF. Diagnosed to have pelvic ureteric junction obstruction at 2 y of age following urosepsis. Died of urosepsis 3.8 y postsecond HCT.
Maternal T-cell engraftment. Had stenting done.
Seizure with neurodevelopmental delay and absent corpus collusum. Had sterile liver nodules 2.8 y of age.
Operated gut malrotation. Required ventricular peritoneal shunt at 3 y of age.
6/2008 15.3 17.7 2.4 CMV (NPS). MSD BM Treo 42 mg/m2. Grade 1 skin CMV viremia. Died of pneumonitis with multiorgan failure at day +261.
Norovirus type 2 enteropathy. RSV and parainfluenza virus 3 (NPS). Cy 200 mg/kg. Adenovirus (stools). Post mortem examination revealed positive HHV6 in lung and liver.
Probable autoimmune hepatitis (isolated raised hepatic transaminases). No serotherapy. CSA/MMF. Developed respiratory failure required mechanical ventilation at 8 mo post-HCT.
7/2011 7.8 9.8 2.0 PCP. MRD PBSC Treo 36 g/m2. Grade 1 skin Engraftment pneumonitis (treated with neb budesonide). Alive
Chronic diarrhea (normal gut biopsy and negative pathogens). Flu 150 mg/m2.
Alemtuzumab 1 mg/kg.
CSA/MMF.
8*/2012 89.9 93.3 3.5 Polyarticular juvenile idiopathic arthritis since 14 mo of age, treated with steroid, etanercept and infliximab. MUD PBSC Treo 42 g/m2. Grade 1 skin Disseminated adenovirus (blood, stools, and NPS). Alive
Macrophage-activating syndrome at 7 y of age, treated with steroid and CSA. Mycobacterium avium-M. intracellulare (sputum and BAL). Flu 150 mg/m2. CMV viremia.
H. influenzae (BAL). Alemtuzumab 1 mg/kg. Micrococcus luteus bacteremia.
CMV (BAL). CSA/MMF.
HHV7 (blood).
Norovirus and sapovirus (stools).
Right middle lobe bronchiectasis.
9*/2012 22.7 27.4 4.8 Macrophage-activating syndrome at 2 y old, treated with steroid and CSA. 9/10 A-MMUD PBSCs Treo 42 g/m2. Grade 2 skin Disseminated adenovirus (blood, gut, NPS). Alive
Bronchiectasis. Flu 150 mg/m2. CMV viremia.
Norovirus enteropathy. Alemtuzumab 1 mg/kg.
CMV (BAL). CSA/MMF
10/2015 8.0 16.2 8.2 PCP. 9/10 C-MMUD BM Treo 42 g/m2. Grade 1 skin S. epidermidis bacteremia. Alive
H. influenzae (BAL). Flu 150 mg/m2. Immune reconstitution . abscess at day +141.
Pseudomonas aeruginosa (BAL). Alemtuzumab 1 mg/kg.
CSA/MMF
11/2015 6.0 29.4 23.4 Diagnosed at 6 mo because older sibling died at 6 y. Maternal HID TCRαβ/CD19-depleted PBSCs Treo 42 g/m2. Grade 2 skin Disseminated adenovirus (blood, stool, NPS); received adenovirus CTL. Alive
Disseminated adenovirus (BAL, blood stools). Flu 150 mg/m2. HHV6 viremia.
Multiple gut viruses (norovirus and adenovirus). Thio 10 mg/kg. Parainfluenza virus 1.
ATG 15 mg/kg. Escherichia coli urinary tract infection.
RTX 200 mg/mg.
CSA.
12*/2015 7.6 15.7 8.1 Enterovirus hepatitis (biopsy proven). 9/10 DQ-MMUD PBSCs Treo 42 g/m2. Grade 2 skin None Alive
PN-dependent enteropathy with multiple gut viruses (enterovirus and sapovirus). Flu 150 mg/m2. Stopped PN at day +135 post-HCT.
Streptococcus oralis bacteremia. Alemtuzumab 1 mg/kg.
CSA/MMF.
13*/2015 6.6 16.4 9.8 PCP. Enterovirus viremia and hepatitis (biopsy proven). 9/10 DQ-MMUD PBSCs Treo 42 g/m2. Grade 1 skin None Alive
PN-dependent enteropathy with multiple gut viruses (enterovirus and sapovirus). E. coli and alpha hemolytic Streptococcus bacteremia. Flu 150 mg/m2. Stopped PN at day +110 post-HCT.
Alemtuzumab 1 mg/kg.
CSA/MMF.
14/2015 6.5 21.4 14.9 PCP. Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2. None Enterovirus meningitis with communicating hydrocephalus on day +56. Alive
Multiple gut viruses (norovirus, enterovirus). Flu 150 mg/m2.
Thio 10 mg/kg.
RTX 200 mg/m2.
ATG 15 mg/kg.
CSA.
15/2016 At birth 47.7 47.7 CMV viremia. MUD PBSCs Treo 42 g/m2. None Disseminated adenovirus (blood, eye swab). Alive
Disseminated parechovirus (blood, stool). Flu 150 mg/m2. CMV viremia.
Sapovirus (stool). Alemtuzumab 1 mg/kg.
Nontuberculous mycobacteria of lung (biopsy proven). CSA/MMF.
E. coli urinary tract infection.
Osteopenic fracture of right tibia and fibula.
16/2016 At birth 9.6 9.6 Parainfluenza virus 3 (BAL). MUD PBSCs Treo 42 g/m2. None None Alive
Streptococcus pneumoniae (BAL). Flu 150 mg/m2.
Enterovirus (stool). Alemtuzumab 1 mg/kg.
CSA/MMF.
17/2017 17 31 14 Multiple gut viruses (adenovirus, sapovirus, enterovirus, norovirus). Maternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2. Grade 1 skin Disseminated adenovirus with pericardial effusion requiring pericardial window. Alive
Multiple respiratory viruses (parainfluenza virus 3, adenovirus, RSV). Add-back T cells. Flu 150 mg/m2.
HHV6 viremia. Thio 10 mg/kg.
S. pneumoniae (BAL). RTX 200 mg/m2.
ATG 15 mg/kg.
No GvHD prophylaxis.
18/2017 6 60.7 54.7 PCP. Paternal HID TCRαβ/CD19-depleted PBSC. Treo 42 g/m2. Grade 1 skin Disseminated adenovirus (blood, stool, NPS). Alive
Severe malnutrition. Add-back T cells. Flu 150 mg/m2. Stopped PN at day +67 post-HCT.
PN-dependent enteropathy with multiple gut viruses (norovirus, adenovirus, enterovirus). Thio 10 mg/kg.
HHV6 viremia. RTX 200 mg/m2.
Norovirus and adenovirus enteropathy. ATG 15 mg/kg.
Presumed fungal splenic abscess. No GvHD prophylaxis.
Multiple osteopenic fractures secondary to vitamin D deficiency.
19*/2017 13.2 81.7 68.4 PCP. MUD PBSCs Treo 42 g/m2. None Disseminated adenovirus (blood, stool, NPS). Alive
Norovirus (gut). Flu 150 mg/m2.
HHV6 viremia. Alemtuzumab 1 mg/kg.
20/2017 4.6 12.3 7.7 HHV 6 (blood and CSF). Adenovirus (blood and stool). Coxsackievirus A type 6 (stool, NPS). Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2. Grade 1 skin Disseminated adenovirus (blood, stool). Alive
Norovirus (stool). Flu 150 mg/m2. HHV6 viremia.
RSV and parainfluenza virus 2 and 3 on NPS. Thio 10 mg/kg. Encephalopathy of unknown etiology (normal CSF and MRI brain).
RTX 200 mg/m2. ATG 15 mg/kg. Full neurological recovery.
No GvHD prophylaxis.
21*/2017 At birth 62.7 62.7 Severe malnutrition. MUD PBSCs Treo 42 g/m2. None HHV6 viremia. Alive
PN-dependent enteropathy with multiple gut viruses (norovirus, parechovirus). Flu 150 mg/m2. Stopped PN at day +59 post-HCT.
Parainfluenza virus 4. Alemtuzumab 1 mg/kg.
HHV6 viremia. CSA/MMF.
22/2017 24 73.6 49.6 Severe malnutrition. Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2. Grade 1 skin PN-dependent gut failure. Received second HCT for secondary aplasia.
Disseminated adenovirus (blood, BAL, stools). Add-back T cells. Flu 150 mg/m2. Disseminated adenovirus. Died of cerebral hemorrhage postsecond HCT.
Disseminated CMV (blood, BAL). Thio 10 mg/kg. RSV pneumonia.
EBV in BAL. RTX 200 mg/m2. HHV6 viremia.
HHV6 viremia. ATG 15 mg/kg.
RSV (NPS). No GvHD prophylaxis.
Multiple gut viruses (adenovirus, enterovirus, sapovirus, astrovirus, norovirus).
23/2018 6.0 22.2 16.7 HHV6 viremia. MUD PBSCs Treo 42 g/m2. None HHV6 viremia. Alive
Norovirus (stool). Flu 150 mg/m2.
RSV and parainfluenza virus 1 (NPS). Alemtuzumab 1 mg/kg.
CSA/MMF.
24/2018 5.0 78.8 73.8 PCP. 9/10 A-MMUD PBSCs Treo 42 g/m2. Grade 2 skin HHV6 viremia. Alive
RSV pneumonia. Flu 150 mg/m2. PN-dependent viral enteropathy on gut biopsy; no evidence of gut GvHD on gut biopsy. Stopped PN at day +641 post-HCT.
PN-dependent enteropathy with multiple gut viruses (adenovirus, norovirus, astrovirus). Alemtuzumab 1 mg/kg. Slow immune reconstitution secondary steroid-dependent skin acute GvHD.
Candida esophagitis. CSA/MMF.
Disseminated BCG at 3 y of age.
25/2018 6.0 22.8 16.8 PCP. Maternal HID TCRαβ/CD19-depleted PBSCs Treo 42 g/m2. Grade 2 skin None Alive
Chronic diarrhea (Salmonella spp. and norovirus). Flu 150 mg/m2.
Thio 10 mg/kg.
RTX 200 mg/m2.
ATG 15 mg/kg.

Table 2: Detailed patient and transplant characteristics (N = 25)

AKI, acute kidney injury; AUC, area under the curve; BAL, bronchoalveolar lavage; BCG, bacille Calmette-Guerin; BM, bone marrow; Bu, busulfan; CB, cord blood; CSF, cerebrospinal fluid; CTL, cytotoxic T cells; Cy, cyclophosphamide; dx, diagnosis; Flu, fludarabine; IST, immunosuppressive therapy; Melph, melphalan; MMFD, mismatched family donor; MRI, magnetic resonance imaging; neb, nebulized; NPS, nasopharyngeal specimen; pK, pharmacokinetics; PN, parenteral nutrition; RSV, respiratory syncytial virus; RTX, rituximab; Thio, thiotepa; Treo, treosulfan; TNF, tumor necrosis factor.

Table 3.  

Variables Results
Patient characteristics
   Year of transplant
      1998–2007 6 (24)
      2008–2018 19 (76)
   Male 15 (60)
   Age at diagnosis, median (range), mo 6.5 (birth-89.6)
   Age at transplant, median (range), mo 21.4 (0.9–93.3)
   Interval between diagnosis and HCT, median (range), mo 9.2 (0.9–71.5)
   Newborn MHC class II expression deficiency 4 (16)
   Positive family history 12 (48)
   Consanguineous parents 22 (88)
   BCG vaccination 21 (84)
   History of PCP 10 (40)
   Pretransplant chronic diarrhea 13 (52)
   Growth failure at HCT (<9th centile) 14 (56)
   Pretransplant autoimmune disease 2 (8)
Donor characteristics
   Type of donor
      MFD 6 (24)
      MUD 6 (24)
      MMUD* 6 (24)
      Parental HID† 7 (28)
   Stem cell source
      Marrow 7 (28)
      Unmanipulated PB 10 (40)
      TCRαβ/CD19-depleted PBSCs 7 (28)
      CB 1 (4)
Graft details, median (range)
   Marrow
      TNC, ×108/kg 4.1 (2.5–11.5)
      CD34, ×106/kg 3.4 (3.1–5.9)
      CD3, ×108/kg 0.61 (0.37–1.0)
      CD19, ×107/kg 3.85 (1.6–6.1)
   Unmanipulated PB
      TNC, ×108/kg 16.8 (13.4–42.7)
      CD34, ×106/kg 12.5 (6.3–28.6)
      CD3, ×108/kg 4.95 (3.4–9.6)
      CD19, ×107/kg 9.6 (1.6–22.0)
   TCRαβ/CD19-depleted PBSCs
      TNC, ×108/kg 12.7 (7.6–28.0)
      CD34, ×106/kg 26.1 (6.9–56.6)
      CD3, ×107/kg 4.2 (1.4–45)
      CD19, ×105/kg 6.0 (3.6–12.0)
      TCRαβ, ×104/kg 5.0 (2.7–7.0)
      NK cells, ×107/kg 5.5 (1.8–11.0)
Transplant characteristics
   Conditioning regimen
      Myeloablative conditioning
         Busulfan-cyclophosphamide 3 (12)
         Treosulfan-cyclophosphamide 2 (8)
         Fludarabine-treosulfan-thiotepa 7 (28)
      RTC
         Treosulfan-fludarabine 12 (48)
         Fludarabine-melphalan 1 (4)
   Serotherapy
      None 4 (12)
      ATG‡ 8 (32)
      Alemtuzumab 14 (56)
   GvHD prophylaxis
      None 5 (20)
      CSA alone 3 (12)
      CSA + MTX 2 (8)
      CSA + MMF 14 (56)
      CSA + steroid (for CB) 1 (4)
   Hematopoietic recovery
      Days to neutrophil recovery, median (range) 15 (8–22)
      Days to platelet recovery, median (range) 16 (11–42)
   Transplant-related complications
      Acute GvHD 13 (52)
      Grade II-IV 4 (16)
      Grade III-IV 0
      Chronic GvHD 0
      Veno-occlusive disease 0
      CMV viremia 7 (28)
      Adenoviremia 9 (36)
      HHV6 viremia 7 (28)
      EBV viremia 1 (4)
   Patients who required parenteral nutrition 17 (68)
   Patients with graft failure 3 (12)
      Secondary autologous reconstitution 2 (8)
      Secondary aplasia 1 (4)
   Cause of death (n = 6)
      Pneumonitis 4 (16)
      Cerebral hemorrhage 1 (4)
      Infection 1 (4)

Table 3. Patient and transplantation characteristics and outcome after HCT in children with MHC class II expression deficiency (N = 25)

Unless otherwise indicated, data are n (%).
BCG, bacille Calmette-Guérin; CB, cord blood; PB, peripheral blood; TNC, total nucleated cell dose.
*Six patients had a 9/10 MMUD transplant.
†Three patients received add-back T cells.
‡Six patients received ATG (Grafalon) and 1 patient received thymoglobulin.

Table 4.  

No/year of HCT Age at follow-up, y Time post-HCT, y Clinical status Donor chimerism Lymphocyte subset (cells/µL) at last follow-up DR expression (%) Stop IVIg replacement (time post-HCT), mo Ig (g/L) Vaccine response
CD3 CD19 CD4 CD8 CD4/CD8 ratio Total naive T cells T* B M G A M Tet Hib
4/2003 5.5 4.0 Well CD15, 85%; CD3, 98%; CD15, 60%. Pre-HCT 1409 1167 249 1109 0.22 ND 0 0 0 Yes (9) 13.0 1.05 1.06 0.81 >9.0
Post-HCT 1884 332 310† 1156 0.26 NA 23 ND ND
7/2011 8.1 7.3 Well CD15, 42%; CD3, 81%; CD19, 76%. Pre-HCT 331 (↓) 443 106 222 0.48 162 0 0 0 Yes (9) 11.9 1.66 0.58 >7.0 5.4
Post-HCT 1660 545 399† 1079 0.37 697 10 BD ND
8*/2012 14 7.2 Well. Unassisted menarche. CD15, 94%; CD3, 69%; CD19, 95%. Pre-HCT 3851 956 519 3203 0.16 616 0 0 0 Yes (9) 11.1 1.73 1.09 0.32 6.4
Post-HCT 1106 327 201† 829 0.24 353 16 92 95
9*/2012 9.5 7.1 Well CD15, 8%; CD3, 8%; CD19, 59%. Pre-HCT 4478 3009 989 3520 0.28 1165 0 0 0 Yes (13) 12.0 <0.04 1.15 4.00 >9.0
Post-HCT 2375 770 503† 1669 0.30 1093 11 9 2
10/2015 4.4 3.0 Well CD15, 0%; CD3, 64%. Pre-HCT 1402 1056 777 553 1.40 686 0 0 0 Yes (12) 7.4 0.81 0.61 1.68 ND
Post-HCT 1127 340 326† 680 0.48 315 ND 29 1
11/2015 6.2 3.8 Well WB, 100%. Pre-HCT 1059 1163 453 209 2.17 ND 0 0 0 Yes (10) 8.4 1.1 1.1 ND ND
Post-HCT 3700 650 1900 1260 1.51 ND ND 100 ND
12*/2015 4.8 3.7 Well WB 100% at 6 mo post-BMT Pre-HCT 6011 1987 1581 300 5.27 300 0 0 0 Yes (13) NA NA NA ND ND
Post-HCT 2232 298 804 952 0.84 NA ND ND ND
13*/2015 4.8 3.6 Well WB 100% at 6 mo post-HCT Pre-HCT 1015 1621 695 209 3.32 233 0 0 0 Yes (12) NA NA NA 0.76 ND
Post-HCT 2413 340 959 1114 0.85 ND ND ND ND
14/2015 5.1 3.4 Good neurological recovery but speech delay WB 100% at 9 mo post-HCT Pre-HCT 1474 1529 1097 277 3.96 575 0 0 0 Yes (15) 14.2 <0.05 1.28 0.56 ND
Post-HCT 1956 460 863 604 1.43 ND 19 ND ND
16/2016 2.8 2.0 Well WB 100% at 4 mo post-HCT Pre-HCT 4327 939 3126 1106 2.83 2682 16 ND 62 Yes (12) 5.74 0.41 0.32 3.77 ND
Post-HCT 2398 371 1238 1373 0.90 1077
17/2017 4.2 1.6 Well CD15, 100%; CD3, 100%. Pre-HCT 744 198 172 265 0.68 NA 0 0 0 Yes (14) 7.7 0.66 0.97 2.23 ND
Post HCT 2251 894 704 844 0.83 ND ND ND ND
19*/2017 8.1 1.3 Well WB 100% at 5 mo post-HCT Pre-HCT 1555 324 378 648 0.58 218 0 0 0 Yes (16) NA NA NA 3.04 ND
Post-HCT 1357 847 516† 649 0.80 NA ND ND ND
20/2017 2.2 1.2 Well WB 100% at 6 mo post-HCT Pre-HCT 1551 (↓) 797 849 530 1.60 ND 0 0 0 Yes (12) 5.5 0.25 0.49 ND ND
Post-HCT 2227 292 1092 710 1.53 ND 30 ND 70
21*/2017 6.3 1.1 Well WB 100% at 5 mo post-HCT Pre-HCT 207 (↓) 58 (↓) 71 117 0.60 49 0 0 0 Yes (11) NA NA NA 0.09 ND
Post-HCT 2337 947 516† 649 0.80 NA ND ND ND

Table 4. Immunological features and donor chimerism of long-term transplant survivors at last follow-up (>1 y post-HCT)

Normal tetanus antibody reference range: 0.01 to 10 IU/mL. Normal Haemophilus influenzae antibodies: 1.0–20 mg/L.
B, B cells; BMT, bone marrow transplantation; Hib, Haemophilus influenzae type b antibodies; M, monocytes; NA, not available; ND, not done; T, T cells; Tet, tetanus; WB, whole blood. ↓, below normal reference range for age.
*T cells were not activated in DR expression. (Siblings: 8 and 9; 12 and 13; 19 and 21.)
†Below normal reference range for age.

CME / ABIM MOC

Improved Transplant Survival and Long-Term Disease Outcome in Children With MHC Class II Deficiency

  • Authors: CME Author: Laurie Barclay, MD
  • CME / ABIM MOC Released: 3/19/2020
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 3/19/2021
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Target Audience and Goal Statement

This activity is intended for hematologists,  pediatricians, and other physicians who treat and manage patients with major histocompatibility complex class II (MHC-II) deficiency.

The goal of this activity is for learners to understand why outcomes from a retrospective study of 25 children with MHC-II deficiency who received a haematopoietic stem cell transplant (HSCT) at a single national center improved between 1995 and 2018. 

Upon completion of this activity, participants will be able to: 

  1. Describe survival outcomes of a retrospective study of HSCT in children with MHC class II deficiency
  2. Describe long-term disease outcomes of a retrospective study of HSCT in children with MHC class II deficiency
  3. Identify clinical implications of outcomes in children with MHC class II deficiency who received HSCT


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CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Editor

  • Catherine M. Bollard, MBChB, MD, FRACP, FRCP

    Associate Editor, Blood

    Disclosures

    Disclosure: Catherine M. Bollard, MBChB, MD, FRACP, FRCP, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Cellectis; NovImmune SA; Roche
    Owns stocks, stock options, or bonds from: Cabaletta Bio; Mana Therapeutics; NexImmune Inc.; Torque Therapeutics

CME Reviewer

  • Hazel Dennison, DNP, RN, FNP, CPHQ, CNE

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Hazel Dennison, DNP, RN, FNP, CPHQ, CNE, has disclosed no relevant financial relationships.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.


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From Blood
CME / ABIM MOC

Improved Transplant Survival and Long-Term Disease Outcome in Children With MHC Class II Deficiency

Authors: CME Author: Laurie Barclay, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME / ABIM MOC Released: 3/19/2020

Valid for credit through: 3/19/2021

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Abstract and Introduction

Abstract

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1–7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n=7). Peripheral blood stem cells were the stem cell source in 68%of patients. Conditioning was treosulfanbased in 84%of patients; 84%received alemtuzumab (n= 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33%(46–68%) for HCT before 2008 (n = 6) to 94%(66–99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P= .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0–100) and 100% (range, 64–100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n=14) compared with posttransplant disease controls (P=.01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

Introduction

Major histocompatibility complex (MHC) class II deficiency is a rare autosomal recessive combined immunodeficiency.[1] MHC class II genes are located on chromosome 6, and expression is largely restricted to activated T lymphocytes, thymic epithelial cells, and antigen-presenting cells (dendritic cells, macrophages, and B lymphocytes). In patients with MHC class II deficiency, the MHC locus itself is intact but transcriptionally silent because of loss-of-function mutations in 1 of 4 genes encoding the key regulatory factors: CIITA (class II transactivator), RFX5 (regulatory factor 5), RFXAP (RFX-associated protein), and RFXANK (RFX-associated ankyrin-containing protein). MHC class II molecules are pivotal for the adaptive immune system and guide the development and function of CD4+ T lymphocytes. The immunologic hallmark of the disease is the absence of constitutive and inducible expression of MHC class II molecules on all cell types, which leads to impaired antigen presentation by HLA-DR, HLA-DQ, and HLA-DP molecules on antigen-presenting cells.[2] The lack of MHC class II expression on thymic epithelium leads to delayed and incomplete maturation of the CD4+ T-lymphocyte population. Overall, MHC class II deficiency leads to combined immunodeficiency with defective CD4+ T-lymphocyte maturation and activation and a lack of T-helper lymphocyte-dependent antibody production by B lymphocytes, resulting in significant susceptibility to severe infections.[3]

Hematopoietic cell transplantation (HCT) is the only curative therapy for children with MHC class II deficiency. The natural history of nontransplanted patients is dismal, and the main cause of death is overwhelming viral infection.[4] Very few children survive into adulthood.[5] HCT for MHC class II deficiency is challenging because many children have significant comorbidities at the time of HCT, increasing their susceptibility to regimen-related toxicities, serious infections, graft rejection, and graft-versus-host disease (GvHD). Historically, the use of HCT has been limited because of the high risk of transplant-related morbidity and mortality. Reported transplant survival was poor compared with that seen in children with classical severe combined immunodeficiency (SCID), with a survival rate ≤ 50%.[3,6–9] In light of the significant improvements in transplant care for children with primary immunodeficiency (PID) over time, the present retrospective study aimed to examine transplant survival and long-term disease outcomes of children with MHC class II deficiency transplanted at a single national center.