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*
No/year of HCT	Country of origin (ethnicity)	Age at dx, mo	Genetics	Lymp	CD3	CD19	CD56	CD4	CD8	CD4/CD8 ratio	Total naive T cells	CD27⁺IgM⁻IgD⁻ (%)	T	B	M	G	A	M	Autoantibodies*
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.
							CSA/MTX.		Diagnosed as pyloric stenosis at day +56 and underwent pyloromyotomy on day +69.	Died of interstitial pneumonitis at day +88 postsecond HCT.
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.
				Congenital retinal dystrophy.			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).			CSA/steroid.		CMV pneumonitis rotavirus.
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.
				Pseudomonas aeruginosa (BAL).			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.
				Streptococcus oralis bacteremia.			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.
				Enterovirus (stool).			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.			No GvHD prophylaxis.
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.		Full neurological recovery.
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).			No GvHD prophylaxis.
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
No/year of HCT	Age at follow-up, y	Time post-HCT, y	Clinical status	Donor chimerism		CD3	CD19	CD4	CD8	CD4/CD8 ratio	Total naive T cells	T*	B	M	Stop IVIg replacement (time post-HCT), mo	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
4/2003	5.5	4.0	Well	CD15, 85%; CD3, 98%; CD15, 60%.	Post-HCT	1884	332	310†	1156	0.26	NA	23	ND	ND	Yes (9)	13.0	1.05	1.06	0.81	>9.0
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
7/2011	8.1	7.3	Well	CD15, 42%; CD3, 81%; CD19, 76%.	Post-HCT	1660	545	399†	1079	0.37	697	10	BD	ND	Yes (9)	11.9	1.66	0.58	>7.0	5.4
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
8*/2012	14	7.2	Well. Unassisted menarche.	CD15, 94%; CD3, 69%; CD19, 95%.	Post-HCT	1106	327	201†	829	0.24	353	16	92	95	Yes (9)	11.1	1.73	1.09	0.32	6.4
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
9*/2012	9.5	7.1	Well	CD15, 8%; CD3, 8%; CD19, 59%.	Post-HCT	2375	770	503†	1669	0.30	1093	11	9	2	Yes (13)	12.0	<0.04	1.15	4.00	>9.0
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
10/2015	4.4	3.0	Well	CD15, 0%; CD3, 64%.	Post-HCT	1127	340	326†	680	0.48	315	ND	29	1	Yes (12)	7.4	0.81	0.61	1.68	ND
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
11/2015	6.2	3.8	Well	WB, 100%.	Post-HCT	3700	650	1900	1260	1.51	ND	ND	100	ND	Yes (10)	8.4	1.1	1.1	ND	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
12*/2015	4.8	3.7	Well	WB 100% at 6 mo post-BMT	Post-HCT	2232	298	804	952	0.84	NA	ND	ND	ND	Yes (13)	NA	NA	NA	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
13*/2015	4.8	3.6	Well	WB 100% at 6 mo post-HCT	Post-HCT	2413	340	959	1114	0.85	ND	ND	ND	ND	Yes (12)	NA	NA	NA	0.76	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
14/2015	5.1	3.4	Good neurological recovery but speech delay	WB 100% at 9 mo post-HCT	Post-HCT	1956	460	863	604	1.43	ND	19	ND	ND	Yes (15)	14.2	<0.05	1.28	0.56	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
16/2016	2.8	2.0	Well	WB 100% at 4 mo post-HCT	Post-HCT	2398	371	1238	1373	0.90	1077	16	ND	62	Yes (12)	5.74	0.41	0.32	3.77	ND
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
17/2017	4.2	1.6	Well	CD15, 100%; CD3, 100%.	Post HCT	2251	894	704	844	0.83	ND	ND	ND	ND	Yes (14)	7.7	0.66	0.97	2.23	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
19*/2017	8.1	1.3	Well	WB 100% at 5 mo post-HCT	Post-HCT	1357	847	516†	649	0.80	NA	ND	ND	ND	Yes (16)	NA	NA	NA	3.04	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
20/2017	2.2	1.2	Well	WB 100% at 6 mo post-HCT	Post-HCT	2227	292	1092	710	1.53	ND	30	ND	70	Yes (12)	5.5	0.25	0.49	ND	ND
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
21*/2017	6.3	1.1	Well	WB 100% at 5 mo post-HCT	Post-HCT	2337	947	516†	649	0.80	NA	ND	ND	ND	Yes (11)	NA	NA	NA	0.09	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.

Touraine JL, Betuel H, Souillet G, Jeune M. Combined immunodeficiency disease associated with absence of cell-surface HLA-A and -B antigens. J Pediatr. 1978;93(1):47–51.
Mach B, Steimle V, Martinez-Soria E, Reith W. Regulation of MHC class II genes: lessons from a disease. Annu Rev Immunol. 1996;14(1):301–331.
Saleem MA, Arkwright PD, Davies EG, Cant AJ, Veys PA. Clinical course of patients with major histocompatibility complex class II deficiency. Arch Dis Child. 2000;83(4):356–359.
Klein C, Lisowska-Grospierre B, LeDeist F, Fischer A, Griscelli C. Major histocompatibility complex class II deficiency: clinical manifestations, immunologic features, and outcome. J Pediatr. 1993;123(6):921–928.
Ouederni M, Vincent QB, Frange P, et al. Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients. Blood. 2011;118(19):5108–5118.
Fischer A, Landais P, Friedrich W, et al. Bone marrow transplantation (BMT) in Europe for primary immunodeficiencies other than severe combined immunodeficiency: a report from the European Group for BMT and the European Group for Immunodeficiency. Blood. 1994;83(4):1149–1154.
Klein C, Cavazzana-Calvo M, Le Deist F, et al. Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients. Blood. 1995;85(2):580–587.
Bonduel M, Pozo A, Zelazko M, et al. Successful related umbilical cord blood transplantation for graft failure following T cell-depleted non-identical bone marrow transplantation in a child with major histocompatibility complex class II deficiency. Bone Marrow Transplant. 1999;24(4):437–440.
Renella R, Picard C, Neven B, et al. Human leucocyte antigen-identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and pre-existing viral infections. Br J Haematol. 2006;134(5):510–516.
Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000–2009. N Engl J Med. 2014;371(5):434–446.
Small TN, Qasim W, Friedrich W, et al. Alternative donor SCT for the treatment of MHC class II deficiency. Bone Marrow Transplant. 2013;48(2):226–323.
Al-Mousa H, Al-Shammari Z, Al-Ghonaium A, et al. Allogeneic stem cell transplantation using myeloablative and reduced-intensity conditioning in patients with major histocompatibility complex class II deficiency. Biol Blood Marrow Transplant. 2010;16(6):818–823.
Elfeky R, Furtado-Silva JM, Chiesa R, et al. Umbilical cord blood transplantation without in vivo T-cell depletion for children with MHC class II deficiency. J Allergy Clin Immunol. 2018;141(6):2279–2282.e2.
Godthelp BC, Van Eggermond MC, Van Tol MJ, Vossen JM, van den Elsen PJ. T cell immune reconstitution after allogeneic bone marrow transplantation in bare lymphocyte syndrome. Hum Immunol. 2000;61(9):898–907.

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CME Author

Laurie Barclay, MD

Freelance writer and reviewer
Medscape, LLC

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

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

Associate Editor, Blood

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Disclosure: Catherine M. Bollard, MBChB, MD, FRACP, FRCP, has disclosed the following relevant financial relationships:
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Owns stocks, stock options, or bonds from: Cabaletta Bio; Mana Therapeutics; NexImmune Inc.; Torque Therapeutics

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

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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:

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

Disclosures

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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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.

Page 1 of 4

Methods

CME / ABIM MOC Information

Abstract and Introduction
Methods
Results
Discussion

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Table 1.

Table 2.

Table 3.

Table 4.

References

Faculty and Disclosures

CME Author

Laurie Barclay, MD

Editor

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

CME Reviewer

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

CME / ABIM MOC

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

Target Audience and Goal Statement

Disclosures

CME Author

Laurie Barclay, MD

Editor

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

CME Reviewer

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

Accreditation Statements

For Physicians

Instructions for Participation and Credit

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

Abstract and Introduction

Abstract

Introduction

Table of Contents