Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency.

To the Editor:

LPS-responsive vesicle trafficking, beach and anchor containing protein (LRBA) deficiency has been identified as a primary immunodeficiency (PID) characterized by recurrent infections associated with autoimmunity, such as inflammatory bowel disease and autoimmune cytopenias (see Fig E1 in this article's Online Repository at www.jacionline.org). A wide range of immunosuppressive treatment measures have only induced temporary relief in affected subjects. Although allogeneic hematopoietic stem cell transplantation (HSCT) is the current treatment for many forms of PIDs, HSCT is less established in patients with autoimmune disease and has not yet been reported in LRBA-deficient patients.

Fig E1

Spectrum and timely appearance of clinical symptoms of 11 previously published patients with LRBA deficiency. The time point (patient age) of the first documentation and, if possible, the end of a certain clinical condition of 11 children and young adults with LRBA deficiency are grouped according to the organ manifestation in “hematology,” “infections,” “enteropathy,” and “other” (from bottom to top), according to recent publications by Lopez-Herrera et al, Alangari et al, and Burns et al. Only the primary immune and autoimmune diseases, but not secondary symptoms, such as finger clubbing, or cor pulmonale, are shown. AIHA, Autoimmune hemolytic anemia; AI-pancytopenia, autoimmune pancytopenia; CNS, central nervous system; ENT, ear, nose, and throat; infx, infections; ITP, immune thrombocytopenia; LIP, lymphocytic interstitial pneumonitis; LPD, lymphoproliferative disease.

We studied a consanguineous family of Kurdish origin with a systemic autoimmune disorder. Patient 1's symptoms started at 2 years of age with immune thrombocytopenia (ITP; Fig 1, A). Serum immunoglobulin concentrations were slightly increased, and the cellular immunophenotype was normal (Table I and see Table E1 in this article's Online Repository at www.jacionline.org). A lymph node biopsy performed because of generalized lymphoproliferative disease (LPD) revealed a follicular lymphatic hyperplasia with abundant (about 20% to 30%) CD3+ and CD4− and CD8− double-negative T lymphocytes (DNT cells; Fig 1, C), suggesting an immune dysregulation, lymphocyte maturation, or apoptosis defect compatible with autoimmune lymphoproliferative syndrome (ALPS). HSCT was performed with the clinically healthy HLA-identical mother as the donor (see the additional text in this article's Online Repository at www.jacionline.org), leading to complete remission with persisting full donor chimerism and without signs of acute or chronic graft-versus-host disease (GvHD). Four years after HSCT, ITP relapsed but responded well to high-dose intravenous immunoglobulin (IVIG) treatment. When romiplostim was started, platelet counts normalized, and administration of romiplostim (5 μg/kg, every 4 to 6 weeks) without further need for immunosuppression or IVIG has led to sustained but treatment-dependent remission.

Fig 1

Clinical course of a familial autoimmunity syndrome caused by LRBA deficiency, immunohistochemical analysis of lymph node specimens (patient 1), and histologic assessment of gastrointestinal biopsy specimens (patient 2). A, Clinical course of a now 19-year-old girl, patient 1, including treatment and HSCT at the age of 10 years. B, Symptoms and treatment outline of patient 2. C,C.1, Triple immunohistochemical staining of T-cell markers showing increased double-negative T-cell numbers marked only with an antibody against CD3 (light blue/gray, dashed arrow), which is reminiscent of CD95 deficiency; CD4+ (brown, solid arrow) and CD8+ (purple, open arrow) T cells are also shown. C.2, Duodenal biopsy specimens showing focal villous flattening and intraepithelial lymphocytosis. C.3, Colon mucosa with moderate crypt distortion and sparse apoptotic bodies. C.4, Signs of vasculitis indicated by abundant neutrophilic granulocytes within and migrating through the lamina propria capillaries of the colon mucosa. Plasma cells were absent in all sections. AdV, Adenovirus; AIHA, autoimmune hemolytic anemia; ATG-F, anti-thymocyte globulin-Fresenius (Fresenius Medical Care, Vienna, Austria); AZT, azidothymidine; cITP, chronic immune thrombocytopenia; CsA, cyclosporin A; ENT, ear, nose, and throat; IVIG, intravenous immunoglobulin subsitution; LPD, lymphoproliferative disease; MFD-BMT, matched family donor bone marrow transplantation; MMF, mycophenolate mofetil; PEG tube, percutaneous enterogastral tube; TPN, total parenteral nutrition; SCIG, subcutaneous immunoglobulin subsitution; UTI, urinary tract infection.

Table I

Laboratory parameters of 2 patients with LRBA deficiency

	Patient 1		Patient 2
	Before HSCT	After HSCT	Before rituximab	After rituximab
Humoral immune system	99.98% donor chimerism‖¶¶∗∗∗		(IVIG substituted)
IgG (g/L)	16.7 (6.5-14.1)∗	11.3 (7-16)∗∗∗	4.61 (5.5-12)∗∗	NA
IgG1 (g/L)	9.1 (3.5-9.1)∗	7.85 (4.05-10.11)∗∗∗	NA	NA
IgG2 (g/L)	3.06 (0.85-3.30)∗	3.69 (1.69-7.86)∗∗∗	NA	NA
IgG3 (g/L)	1.83 (0.2-1.04)∗	0.879 (0.11-0.85)∗∗∗	NA	NA
IgG4 (g/L)	0.01 (0.03-1.58)∗	0.481 (0.03-2.01)∗∗∗	NA	NA
IgA (g/L)	1.24 (0.83-2.17)∗	2.61 (0.7-4.0)∗∗∗	0.28 (0.21-2.92)∗∗	<0.08 (0.31-3.06)‖‖
IgM (g/L)	1.43 (0.55-2.10)∗	1.64 (0.4-2.3)∗∗∗	0.18 (0.37-1.41)∗∗	0.02 (0.47-1.0)‖‖
IgE (kU/L)	24.7∗ (<110)	44 (0-100)∗∗∗	<19‡‡‡	<19‡‡‡
Autoimmunity (selected autoantibodies)
Coombs test, direct	1:64∗	Negative∗∗∗	Positive, 1:16-64¶#∗∗	Negative††
Coombs test, indirect	Positive∗	Negative∗∗∗	Positive¶#	Negative††
Anti-platelet antibodies	Positive†	Positive‖ | negative∗∗∗	Positive#	Negative††
ANA	Negative‡‡‡	Negative‡‡‡	Negative‡‡‡	Negative‡‡‡
dsDNA antibody	Negative‡‡‡	Negative‡‡‡	Negative‡‡‡	Negative‡‡‡
Cardiolipin IgG antibody (U/mL)	14∗ (0-10)	33§ | 2.3∗∗∗ (0-10)	Negative‡‡‡	Negative‡‡‡
SMA (U/mL)	50∗ (negative)	200§ | negative∗∗∗ (negative)	Negative‡‡‡	Negative‡‡‡
AMA	Negative∗	Positive,§∗∗∗ (negative)	Negative‡‡‡	Positive†† | negative‡‡‡
M2 antibody## (U/mL)	Negative∗	45.6‖| 88.0∗∗∗ (0-5)	Negative‡‡‡	Negative‡‡‡
Cellular immune system
CD3+ T cells/μL	1,930† (700-4,200)	736∗∗∗ (700-2,100)	2,799# (1,400-8,000)	1325§§ (700-4,200)
CD3+CD4+ cells/μL	1,511† (300-2,000)	324∗∗∗ (300-1,400)	2,010# (900-5,500)	931§§ (300-2,000)
CD3+CD8+ cells/μL	296† (300-1,800)	367∗∗∗ (200-900)	601# (400-2,300)	325§§ (300-1,800)
CD45RA+CD4+CD3+ cells (% of CD3+CD4+ cells)	64† (>15%)	8.5¶¶ | 6∗∗∗ (>10%)	57# (>15)	26§§ (>10%)
αβTCR+CD3+ cells/μL	ND	638‖	2,578#	1,097§§
γδTCR+CD3+ cells/μL	ND	10‖	137#	39§§
αβTCRCD3+CD4−CD8− (DNT cells [% of CD3+ cells])	0.95% to 3%∗† (<2)	0.03%∗∗∗ (<2)	0.4%# (<2)	3.24%§§ (<2)
CD3−CD56+ NK cells/μL	108† (90-900)	140∗∗∗ (200-300)	291# (100-1,400)	81§§ (90-900)
iNKT cells Va24Vb11 (% of CD3+ cells)	ND	0.1%¶¶ (>0.01)	ND	0.02%‖‖ (>0.01)
CD19+ B cells/μL	335-118∗† (200-1,600)	213¶¶ (100-500)	413# (200-2,100)	32†† (200-1,600)
CD19+IgD+CD27+ cells (% of CD19+ cells)	ND∗†	0.38‖ | 30¶¶ (>2)	ND#	0.02†† (>2)
CD19+IgD−CD27+ cells (% of CD19+ cells)	ND∗†	0.08‖ | 31¶¶ (>2)	ND#	0.00†† (>2)
Lymphocyte stimulation in vitro detected based on tritiated thymidine incorporation (trigger and antigens in parentheses)†††	Normal† (PHA, SEB, CD3, PMA/ionomycin)	ND	ND	Normal‡‡ unstimulated: 1,716 cpm (1,650-7,162 cpm)PHA: 16,513 cpm (14,218-39,235 cpm)Concanavalin A: 11,384 cpm (4,928-29,519 cpm)CD3/CD28: 17,746 cpm (12,181-31,490 cpm)

Footnotes indicate time point of analysis. Pathologic results are shown in boldface (normal ranges are shown in parentheses).

AMA, Anti-mitochondrial antibodies; ANA, antinuclear antibody; dsDNA, double-stranded DNA; iNKT, invariant natural killer T; NA, not applicable under IVIG substitution and not done before IVIG; ND, not done; NK, natural killer; PHA, phytohemagglutinine; PMA, phorbol 12-myristate 13-acetate; SCT, stem cell transplantation; SEB, staphylococcal enterotoxin B; SMA, smooth muscle autoantibodies; TCR, T-cell receptor.

At 6 years of age.

At 8 years.

At 10 years.

At 14 years (4 years after stem cell transplantation).

At 17 months.

At 2 years.

At 5.5 years before immunosuppression/rituximab.

At 7.5 years of age.

At 9 years of age.

At 10 years of age.

At 11 years of age.

At 19 years of age (9 years after HSCT).

Subfraction of antimitochondrial antibodies directed against the M2 fraction of liver cell mitochondrial antigens located on inner mitochondrial membranes (comprising proteins of the 2-oxo-acid dehydrogenase complex).

At 19.5 years of age (10 years after stem cell transplantation).

See the Methods section in this article's Online Repository.

On repeated occasions.

Table E1

Additional laboratory parameters of 2 patients with LRBA deficiency

	Patient 1		Patient 2
	Before HSCT	After HSCT	Before rituximab	After rituximab
Humoral immune system	99.98% donor chimerism‖¶¶∗∗∗		(IVIG substituted)
Anti–tetanus toxoid antibody	Good response‡	ND	NA	NA
Anti–Haemophilus influenzae B polysaccharide antibody	Good response‡	ND	NA	NA
IgG against EBV	NA	ND	Negative¶	NA
IgG against EBNA1	NA	ND	NA	NA
IgG against CMV	Negative∗	ND	208 U/mL¶	NA
IgG against hepatitis B	Negative∗	ND	NA	NA
Polio IgG	Good response‡	ND	NA	NA
ANCA	Negative/unspecific∗	Negative/unspecific‖	Negative‡‡‡	Negative‡‡‡
TPO antibody	ND	Negative¶¶	Negative‡‡‡	Negative‡‡‡
TR antibody	ND	Negative¶¶	Negative‡‡‡	Negative‡‡‡
TG antibody	Positive† (negative)	Negative¶¶	Negative‡‡‡	Negative‡‡‡
Islet cell antibody	Positive† (negative)	Negative¶¶	Positive†	Negative‡‡‡
Insulin antibody	ND	ND	Negative†	Negative‡‡
Glutamate decarboxylase antibody	ND	Negative§	ND	11.9 U/L‡‡ (0-9.5 U/L)
Tyrosine phosphatase antibody	ND	ND	ND	Negative‡‡
21-Hydroxylase antibody	ND	ND	ND	Normal‡‡
Gliadin IgA antibody	150† (<25)	ND	ND	Negative††
Gliadin IgG antibody	25† (<25)	ND	ND	Negative††
Transglutaminase antibody	ND	ND	ND	Negative††
Endomysial IgG antibody	Negative†	ND	ND.	Negative††
Laboratory chemistry (selected parameters)
TSH	Normal‡‡‡	Normal‡‡‡	Normal‡‡‡	6.56 μU/mL†† (0.1-4 μU/mL)
fT4	Normal‡‡‡	Normal‡‡‡	Normal‡‡‡	15.1 pmol/L†† (9.5-24 pmol/L)
Elastase/stool (μg E1/g)	22-88∗† (200-2500)	ND	ND	141-156§§ (200-2500)
Calprotectin/stool (μg/g)	ND	ND	272∗ (0-100)	1331‡‡ (0-100)
Vitamin B12 (pg/mL)	ND	ND	285∗∗ (180-1100)	179†† (180-1100)
Vitamin A	ND	ND	ND	23 μg/dL§§ (30-70 μg/dL)
Vitamin D3	ND	ND	ND	5.6 ng/mL (30-60 ng/mL)††
Vitamin E	ND	ND	ND	7 μmol/L§§ (12-46 μmol/L)
Prothrombin time	Normal‡‡‡	Normal‡‡‡	Normal‡‡‡	57%‡‡ (70% to 120%)
Cellular immune system
TREC copies/105 CD3+CD45+ cells	ND	0¶¶ | 0∗∗∗	ND	2.13‖‖
Vβ spectratyping (diversity in CD4+ and CD8+ T cells)	ND	CD4+ normal; mildly reduced in CD8+∗∗∗	ND	Normal in CD4+; mildly reduced in CD8+‖‖
Phagocyte function (oxidative burst, phagocytosis; Escherichia coli, DHR)†††	Normal∗	ND	ND	ND
Apoptosis assay (PHA- or IL-2–activated T cells; annexin V staining)†††	Normal∗ (anti-CD95)	ND	ND	Normal§§ (IL-2 withdrawal)
ADA activity	Normal∗	ND	ND	ND
PNP activity	Normal∗	ND	ND	ND
Genetic analyses done before performance of whole-exome sequencing
CD95, CD95L, caspase 8, caspase 10	Normal†		Normal#
CTLA4 SNPs, SAP, XIAP	Normal†		Normal#
HLA-DQ8	Positive		Positive

Footnotes indicate time point of analysis. Pathologic results are shown in boldface (normal ranges are in parentheses).

ADA, Adenosine desaminase; ANCA, anti-neutrophil cytoplasmic antibodies; CMV, cytomegalovirus; DHR, dihydrorhodamine; fT4, free thyroxine; NA, not applicable under IVIG substitution and not done before IVIG; ND, not done; PNP, purine nucleoside phosphorylase; SAP, signaling lymphocytic activation molecule (SLAM)-associated protein; SNP, single nucleotide polymorphism; TG, thyreoglobulin; TPO, thyroid peroxidase; TR, thyroid stimulating hormone receptor antibody; TSH, thyroid stimulating hormone; XIAP, X-linked inhibitor of apoptosis.

At 6 years of age.

At 8 years.

Low/negative after a break of repetitive IVIG therapy at 6 years; good response/high normal values after one booster vaccination at 6.5 years of age.

At 10 years.

At 14 years (4 years after stem cell transplantation).

At 17 months.

At 2 years.

At 5.5 years before immunosuppression/rituximab.

At 7.5 years of age.

At 9 years of age.

At 10 years of age.

At 11 years of age.

At 19 years of age (9 years after HSCT).

At 19.5 years of age (10 years after stem cell transplantation).

See the Methods section in this article's Online Repository.

At repeated occasions.

Patient 2, the now 11-year-old younger sister of patient 1, became symptomatic at 5 years of age (fulminant autoimmune hemolytic anemia; Fig 1, B). Immunosuppression was started immediately (corticosteroids, mycophenolate mofetil, and vincristine), leading to a sustained remission (Fig 1, B). Rituximab was administered (4 × 375 mg/m2; Fig 1, B) to secure the treatment response, especially given the severe course of her sister. Before treatment, immunoglobulin concentrations were mildly reduced (4.61 g/L IgG, normal IgA level, and 0.18 g/L IgM; Table I), direct and indirect Coombs test and platelet antibody results were positive, and DNT cell numbers were increased (3.4% of CD3+ cells), with an otherwise normal cellular immune phenotype (Table I and see Table E1), suggesting a familial ALPS-like disorder. Chronic enteropathy with increased calprotectin levels, borderline reduced elastase levels, and chronic norovirus positivity in stool were diagnosed. Gastroduodenoscopy specimens of patient 2 revealed inflammatory bowel disease, absence of plasma cells, and vasculitis (Fig 1, C; and see Fig E2, D-I, in this article's Online Repository at www.jacionline.org). She is being treated with budesonide and IVIG (1 g/kg body weight twice per month; trough level, 8-10 g/L) and requires parenteral nutrition (12-14 hours per night).

Fig E2

Histologic assessment of lymph node and gastrointestinal biopsy specimens. A-C, Consecutive lymph node sections showing an increased CD4/CD8 T-cell ratio. D, Duodenal biopsy specimens showing focal villous flattening. E, EBV RNA–positive enterocyte nuclei in duodenal biopsy specimens. F, Moderate chronic gastritis with apoptotic cell debris underneath the surface epithelium in the gastric corpus. G, Focally enhanced chronic active gastritis in the gastric antrum. H, EBV RNA–positive antral epithelial cells. I, Apoptotic cell debris beneath the surface epithelium in the colonic mucosa. Plasma cells were absent in all sections.

The fact that 2 patients born to consanguineous parents presented with a similar clinical phenotype prompted us to screen for an underlying (mono-) genetic defect. Homozygous intervals were mapped by applying the GeneChip Human-Mapping-250K-Nsp-Assay (Affymetrix, Santa Clara, Calif). Homozygous stretches were identified and overlaid with HomozygosityMapper. Both patients had identical homozygous intervals on chromosomes 2, 3, 4, 9, 11, and 15 (Fig 2, A). Exome sequencing and subsequent computational analysis of patient 1 revealed 23,582 exonic variants, of which 30 were rare missense, nonsense, or splice-site variants located inside the shared homozygous regions of the 2 siblings (see Table E2 in this article's Online Repository at www.jacionline.org). Among the final variant list, one frameshift deletion was identified, resulting in a premature stop codon. This mutation (NM_001199282:c.7162delA; p.T2388Pfs*7) is located inside the gene encoding LRBA. Sanger sequencing confirmed the presence and segregation of the variant, suggesting an autosomal recessive defect with full penetrance (Fig 2, B). Expression of the corresponding protein product was near absent (Fig 2, C).

Fig 2

Representative depiction of single nucleotide polymorphism array–based homozygosity mapping and Sanger validation, pedigree of the core family, and LRBA protein detection by using fluorescence-activated cell sorting analysis. A, Chromosomal positions are plotted against the homozygosity score in a bar chart, with red bars indicating homozygous regions present in both affected siblings (top). The disease-causing mutation is localized in a homozygous interval (q22.2-q31.3) on the long arm of chromosome 4, as emphasized by the red box (bottom). B, Perfect segregation of the single base deletion (c.7162delA; p.T2388fs) is shown in the 2 patients, the nonaffected sibling, and the parents. Solid symbols indicate homozygous affected subjects, and half-filled symbols refer to the heterozygous carrier. Male and female subjects are distinguished by squares and circles, respectively. C, PBMCs were stimulated with PHA, as described in the Methods section in this article's Online Repository at www.jacionline.org. The increased LRBA protein expression after stimulation (black) compared with that in unstimulated cells (gray) is shown in the in-house control and in a travel control (1 and 2 asterisks, respectively; upper panel); is reduced in the LRBA-heterozygous mother, who was the stem cell donor, in patient 1 after HSCT; and is absent in patient 2 (lower panel). The plot is representative of 2 independent analyses.

Table E2

List of candidate mutations identified in the index patient

	Function	Gene	Protein name	Exonic function	Amino acid change	dbSNP137
1	Exonic	LRBA	LPS-responsive vesicle trafficking, beach and anchor containing	Frameshift deletion	NM_001199282:c.7162delA:p.T2388fs
2	Exonic	LRBA	LPS-responsive vesicle trafficking, beach and anchor containing	Nonsynonymous SNV	NM_001199282:c.A2444G:p.N815S	rs140666848
3	Exonic	PAPSS1	3′-Phosphoadenosine 5′-phosphosulfate synthase 1	Nonsynonymous SNV	NM_005443:c.C997T:p.R333C	rs35176475
4	Exonic	FAT4	FAT atypical cadherin 4	Nonsynonymous SNV	NM_024582:c.C6970T:p.R2324W
5	Exonic	FAT4	FAT atypical cadherin 4	Nonsynonymous SNV	NM_024582:c.G9577A:p.V3193I	rs143764643
6	Exonic	MAML3	Mastermind-like 3 (Drosophila)	Nonframeshift deletion	NM_018717:c.2302_2304del:p.768_768del	rs5862430
7	Exonic	SLC10A7	Solute carrier family 10, member 7	Nonsynonymous SNV	NM_001029998:c.T806C:p.V269A
8	Exonic	WNK2	WNK lysine deficient protein kinase 2	Nonsynonymous SNV	NM_006648:c.A83T:p.E28V
9	Exonic	C9orf129	Chromosome 9 open reading frame 129	Nonsynonymous SNV	NM_001098808:c.C359T:p.A120V	rs4744219
10	Exonic	C9orf129	Chromosome 9 open reading frame 129	Nonsynonymous SNV	NM_001098808:c.G274A:p.G92S	rs3122944
11	Exonic	NUTMF	NUT family member 2F	Nonframeshift deletion	NM_017561:c.2071_2073del:p.691_691del	rs150455117
12	Exonic	NUTMF	NUT family member 2F	Nonsynonymous SNV	NM_017561:c.C410G:p.S137C	rs202099818
13	Exonic	FOXE1	Forkhead box E1 (thyroid transcription factor 2)	Nonframeshift deletion	NM_004473:c.511_516del:p.171_172del
14	Exonic	COL15A1	Collagen, type XV, alpha 1	Nonsynonymous SNV	NM_001855:c.A3002G:p.K1001R	rs35544077
15	Splicing	ABCA1	ATP-binding cassette, sub-family A (ABC1), member 1		NM_005502:exon41:c.5383-2->TTT
16	Splicing	SVEP1	Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1		NM_153366:exon47:c.10505-2->T
17	Exonic	DNAJC25	DnaJ (Hsp40) homolog, subfamily C, member 25	Nonsynonymous SNV	NM_001015882:c.T486G:p.F162L
18	Splicing	OLFML2A	Olfactomedin-like 2A		NM_182487:exon3:c.462+1G>T
19	Exonic	RABEPK	Rab9 effector protein with kelch motifs	Nonsynonymous SNV	NM_005833:c.C217T:p.H73Y	rs1128362
20	Exonic	FAM73B	Family with sequence similarity 73, member B	Nonsynonymous SNV	NM_032809:c.T299C:p.V100A	rs11544968
21	Exonic	USP20	Ubiquitin specific peptidase 20	Nonframeshift deletion	NM_001008563:c.1072_1074del:p.358_358del	rs10602985
22	Exonic	PPAPDC3	Phosphatidic acid phosphatase type 2 domain containing 3	Nonsynonymous SNV	NM_032728:c.G26A:p.R9H	rs148406586
23	Exonic	GTF3C4	General transcription factor IIIC, polypeptide 4, 90kDa	Nonsynonymous SNV	NM_012204:c.G10A:p.A4T	rs143172300
24	Exonic	GOLGA6L10	Golgin A6 family-like 10	Nonsynonymous SNV	NM_001164465:c.G1025A:p.R342Q	rs201670904
25	Exonic	GOLGA6L10	Golgin A6 family-like 10	Nonsynonymous SNV	NM_001164465:c.G1007A:p.R336Q	rs200685620
26	Exonic	ALKBH3	alkB, alkylation repair homolog 3	Nonsynonymous SNV	NM_139178:c.C684G:p.D228E	rs1130290
27	Splicing	CREB3L1	cAMP responsive element binding protein 3-like 1		NM_052854:exon12:c.1524-1->G	rs79068197
28	Exonic	ACP2	Acid phosphatase 2, lysosomal	Nonsynonymous SNV	NM_001610:c.T1177C:p.F393L	rs145420520
29	Exonic	ALPK3	Alpha-kinase 3	Nonsynonymous SNV	NM_020778:c.G4289A:p.R1430Q	rs150023454
30	Exonic	ACAN	Aggrecan	Nonsynonymous SNV	NM_001135:c.G1274A:p.G425E

SNV, Single nucleotide variant.

Taken together, we describe a clinical, immunologic, and genetic analysis of 2 patients presenting with multiorgan autoimmunity and severe infections caused by a novel mutation in LRBA, the clinical spectrum of which both recapitulates and extends the previously described phenotypes (see additional text in this article's Online Repository). The fact that patient 1 had a profound immunodeficiency with life-threatening infections and refractory autoimmunity justified the approach of allogeneic matched family donor HSCT according to international guidelines. In our case allogeneic HSCT resulted in long-lasting partial remission in the patient with LRBA deficiency. The observation that mild autoimmune symptoms (ITP and vitiligo) have recurred in patient 1 years after HSCT despite full donor chimerism might be due to reduced LRBA expression compared with a healthy donor (in the same range as the heterozygous stem cell donor, who has detectable autoantibodies without clinical symptoms; see Fig 2, C, and additional text in this article's Online Repository), thus representing residual disease activity or late, limited chronic GvHD. These data show that HSCT might be a treatment option for patients with LRBA deficiency.