Background Kabuki syndrome (KS) is a complex multi-system developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has previously been reported. Objective To characterize the humoral immune defects found in KS patients with KMT2D mutations. Methods We comprehensively characterize B cell function in a cohort (N = 13) of patients with KS (ages 4 months to 27 years). Results Three-quarters (77%) of the cohort had a detectable heterozygous KMT2D mutations (50% nonsense, 20% splice site, 30% missense), and 70% of the reported mutations are novel. Amongst the patients with KMT2D mutations (KMT2DMut/+), hypogammaglobulinemia was detected in all but one individual, with IgA deficiency affecting 90% of patients and a deficiency in at least one other isoform seen in 40% of patients. Total memory (CD27+) and class-switched memory B cells (IgM−) were significantly reduced in KMT2DMut/+ patients compared to controls (p-values < 0.001). KMT2DMut/+ patients also had significantly reduced rates of somatic hypermutation in IgG (p value = 0.003), but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in KMT2DMut/+ primary B cells. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. Conclusions In patients with KS, autosomal dominant KMT2D mutations are associated with the dysregulation of terminal B cell differentiation leading to humoral immune deficiency and in some cases autoimmunity. All patients with KS should undergo serial clinical immune evaluations. Clinical Implications KMT2DMut/+ Kabuki syndrome causes IgA deficiency in nearly all patients, although additional humoral defects (memory B cell deficiency, IgG hypogammaglobulinemia) have variable expressivity. Missense mutations in terminal domains may increase autoimmunity risk.

Key Points• Donor chimerism .20%-30% usually protects against late disease reactivation after day 180 post stem cell transplantation for primary HLH.• Lower levels do not inevitably result in reactivations. The risks of intervention must be weighed against the risk of reactivation.Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000HLH ( -2013 and DC permanently or transiently <75% (overall, CD3 1 , CD56 1 ) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations ( ‡5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n 5 11, partial flare n 5 3, isolated central nervous system reactivation n 5 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3 1 if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC, 13%; range, 0-30%). In 5 patients, overall and lineage-specific DC were £10% for >6 months (median, 5.1; range, 1.1-10 years) without reactivation. A second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second HSCT). We conclude that a DC >20%-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against second HSCT must be based on a thorough risk assessment. (Blood. 2016;127(25):3281-3290)

Objectives We sought to determine if markers of T cell immune activation, including soluble interleukin 2 receptor alpha (sIL2Rα) levels predict outcome in pediatric acute liver failure (PALF) and might target potential candidates for immunomodulatory therapy. Methods We analyzed markers of immune activation in 77 patients with PALF enrolled in a multi-national, multi-center study. The outcomes were survival with native liver, liver transplantation, and death without transplantation within 21 days after enrollment. Results Adjusting for multiple comparisons, only normalized serum sIL2Rα level differed significantly among the 3 outcomes, and was significantly higher in patients who died (p=0.02) or underwent liver transplantation (p=0.01) compared to those who survived with their native liver. The 37 patients with normal sIL2Rα levels all lived, 30 with their native liver. Of the 15 subjects with markedly high sIL2Rα (≥5000 IU/mL), 5 survived with their native liver, 2 died, and 8 underwent liver transplantation. Conclusions Evidence of immune activation is present in some patients who die or undergo liver transplantation. Patients with higher sIL2Rα levels were more likely to die or undergo liver transplantation within 21 days than those with lower levels. Identifying a subset of patients at risk for poor outcome may form the foundation for targeted clinical trials with immunomodulatory drugs.

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