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Background: Elevated TCRαβ + CD4 - CD8 - double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U)., Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases., Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway-related genes. It was guided by FAS expression analysis on CD57 + DNT, which can predict somatic loss of heterozygosity (sLOH)., Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57 + DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH., Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Discovery that mutations in TCIRG1 (also known as Atp6i) gene are responsible for most instances of autosomal recessive osteopetrosis (ARO) heralded a new era for comprehension and treatment of this phenotypically heterogeneous rare bone disease. TCIRG1 encodes the a3 subunit, an essential isoform of the vacuolar ATPase proton pump involved in acidification of the osteoclast resorption lacuna and in secretory lysosome trafficking. TCIRG1 defects lead to inefficient bone resorption by nonfunctional osteoclasts seen in abundance on bone marrow biopsy, delineating this ARO as 'osteoclast-rich'. Presentation is usually in early childhood and features of extramedullary haematopoiesis (hepatosplenomegaly, anaemia, thrombocytopenia) due to bone marrow fibrosis, and cranial nerve impingement (blindness in particular). Impaired dietary calcium uptake due to high pH causes the co-occurrence of rickets, described as "osteopetrorickets". Osteoclast dysfunction leads to early death if untreated, and allogeneic haematopoietic stem cell transplantation is currently the treatment of choice. Studies of patients as well as of mouse models carrying spontaneous (the oc/oc mouse) or targeted disruption of Atp6i (TCIRG1) gene have been instrumental providing insight into disease pathogenesis and development of novel cellular therapies that exploit gene correction., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Osteopetrosis (OPT) is a rare inherited bone disease characterized by a bone resorption defect, due to osteoclast malfunction (in osteoclast-rich, oc-rich, OPT forms) or absence (in oc-poor OPT forms). This causes severe clinical abnormalities, including increased bone density, lack of bone marrow cavity, stunted growth, macrocephaly, progressive deafness, blindness, hepatosplenomegaly, and severe anemia. The oc-poor subtype of OPT is ultra-rare in humans. It is caused by mutations in either the tumor necrosis factor ligand superfamily member 11 (TNFSF11) gene, encoding RANKL (Receptor Activator of Nuclear factor-kappa B [NF-κB] Ligand) which is expressed on cells of mesenchymal origin and lymphocytes, or the TNFRSF member 11A (TNFRSF11A) gene, encoding the RANKL functional receptor RANK which is expressed on cells of myeloid lineage including osteoclasts. Clinical presentation is usually severe with onset in early infancy or in fetal life, although as more patients are reported, expressivity is variable. Phenotypic variability of RANK-deficient OPT sometimes includes hypogammaglobulinemia or radiological features of dysosteosclerosis. Disease progression is somewhat slower in RANKL-deficient OPT than in other 'malignant' subtypes of OPT. While both RANKL and RANK are essential for normal bone turnover, hematopoietic stem cell transplantation (HSCT) is the treatment of choice only for patients with the RANK-deficient form of oc-poor OPT. So far, there is no cure for RANKL-deficient OPT., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8-16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52-99%) for TCRαβ-HaploSCT, 80% (41-98%) for MFD, 87% (36-98%) for MUD, and 89% (43-98%) for CB (p = 0.89). Cumulative incidence of grade II-IV acute graft-versus-host disease was 11% (2-79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7-100%) after MUD, and 11% (2-79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0-100%) versus unconditioned transplant (median 3%, 0-9%) (p < 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p < 0.001). TCRαβ-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors., (© 2022. The Author(s).)

Hematopoietic cell transplantation (HCT) has become standard-of-care for an increasing number of inborn errors of immunity (IEI). This report is the first to compare transplant outcomes according to T-cell-replete (ie, T-replete) HLA-matched grafts using alemtuzumab (n = 117) and T-cell-depleted (ie, T-depleted) HLA-mismatched grafts using T-cell receptor-αβ (TCRαβ)/CD19 depletion (n = 47) in children with IEI who underwent first HCT between 2014 and 2019. All patients received treosulfan-based conditioning except patients with DNA repair disorders. For T-replete grafts, the stem cell source was marrow in 25 (21%) patients, peripheral blood stem cell (PBSC) in 85 (73%), and cord blood in 7 (6%). TCRαβ/CD19 depletion was performed on PBSCs from 45 haploidentical parental donors and 2 mismatched unrelated donors. The 3-year overall survival (OS) and event-free survival for the entire cohort were 85% (77%-90%) and 79% (69%-86%), respectively. Analysis according to age at transplant revealed a comparable 3-year OS between T-replete grafts (88%; 76%-94%) and T-depleted grafts (87%; 64%-96%) in younger patients (aged <5 years at HCT). For older patients (aged >5 years), the OS was significantly lower in T-depleted grafts (55%; 23%-78%) compared with T-replete grafts (87%; 68%-95%) (P = .03). Grade III to IV acute graft-versus-host disease was observed in 8% of T-replete marrow, 7% of T-replete PBSC, 14% of T-replete cord blood, and 2% of T-depleted PBSC (P = .73). Higher incidence of viremia (P < .001) and delayed CD3 reconstitution (P = .003) were observed after T-depleted graft HCT. These data indicate that mismatched donor transplant after TCRαβ/CD19 depletion represents an excellent alternative for younger children with IEI in need of an allograft., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Context: Remission rates in young people with Graves hyperthyroidism are less than 25% after 2 years of thionamide antithyroid drug (ATD)., Objective: We explored whether rituximab (RTX), a B-lymphocyte-depleting agent, would increase remission rates when administered with a short course of ATD., Methods: This was an open-label, multicenter, single-arm, phase 2 trial in young people (ages, 12-20 years) with Graves hyperthyroidism. An A'Hern design was used to distinguish an encouraging remission rate (40%) from an unacceptable rate (20%). Participants presenting with Graves hyperthyroidism received 500 mg RTX and 12 months of ATD titrated according to thyroid function. ATDs were stopped after 12 months and primary outcome assessed at 24 months. Participants had relapsed at 24 months if thyrotropin was suppressed and free 3,5,3'-triiodothyronine was raised; they had received ATD between months 12 and 24; or they had thyroid surgery/radioiodine., Results: A total of 27 participants were recruited and completed the trial with no serious side effects linked to treatment. Daily carbimazole dose at 12 months was less than 5 mg in 21 of 27 participants. Thirteen of 27 participants were in remission at 24 months (48%, 90% one-sided CI, 35%-100%); this exceeded the critical value (9) for the A'Hern design and provided evidence of a promising remission rate. B-lymphocyte count at 28 weeks, expressed as a percentage of baseline, was related to likelihood of remission., Conclusion: Adjuvant RTX, administered with a 12-month course of ATD, may increase the likelihood of remission in young people with Graves hyperthyroidism. A randomized trial of adjuvant RTX in young people with Graves hyperthyroidism is warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Predisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαβ/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36-330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor., (© 2021. Crown.)