Gaps in Care Among Uncontrolled Severe Asthma Patients in the United States.

BACKGROUND: Understanding the implementation of key guideline recommendations is critical for managing severe asthma (SA) in the treatment of uncontrolled disease. OBJECTIVE: To assess specialist visits and medication escalation in US patients with SA after events indicating uncontrolled disease (EUD) and associations with health outcomes and social disparity indicators. METHODS: Patients with SA appearing in administrative claims data spanning 2015 to 2020 were indexed hierarchically on asthma-related EUD, including hospitalizations, emergency department visits with systemic corticosteroid treatment, or outpatient visits with systemic corticosteroid treatment. Patients with SA without EUD served as controls. Eligibility included age 12 or greater, 12 months enrollment before and after index, no biologic use, and no other major respiratory disease during the pre-period. Escalation of care in the form of specialist visits and medication escalation, health care resource use, costs, and disease exacerbations were assessed during follow-up. RESULTS: We identified 180,736 patients with SA (90,368 uncontrolled and 90,368 controls). Between 35% and 51% of patients with SA with an EUD had no specialist visit or medication escalation. Follow-up exacerbations ranged from 51% to 4% across EUD cohorts, compared with 13% in controls. Among uncontrolled patients with SA who were Black or Hispanic/Latino, 41% and 38%, respectively, had no specialist visit or medication escalation after EUD, compared with 33% of non-Hispanic White patients. CONCLUSIONS: A substantial proportion of uncontrolled patients with SA had no evidence of specialist visits or medication escalation after uncontrolled disease, and there was a clear relationship between uncontrolled disease and subsequent health care resource use and exacerbations. Findings highlight the need for improved guideline-based care delivery to patients with SA, particularly for those facing social disparities.

At-home asthma mortality unchanged despite declining mortality in other settings: US death certificate data (2000-2019).

BACKGROUND: Asthma mortality rates in the United States have declined since 1999; however, asthma mortality by place of death has not been comprehensively evaluated. OBJECTIVE: To evaluate temporal trends in asthma mortality rates and place of death in the United States. METHODS: We conducted a population-based analysis using data from the Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research platform to evaluate deaths with asthma as the underlying cause (2000-2019) among US residents of all ages. Absolute numbers of asthma-related deaths were described by place of death. Counts were applied to US Census Bureau population counts to calculate mortality rates per 100,000 persons. RESULTS: In the 20-year period evaluated, 67,695 asthma deaths were registered in the United States. An overall 32% decline in the asthma mortality rate was observed, from 1.43 to 0.98 per 100,000 persons from 2000 to 2019, respectively. Although asthma mortality rates declined in all medical facility locations, the at-home asthma mortality rate remained stable (0.32 and 0.34 per 100,000 persons in 2000 and 2019, respectively). Consequently, the proportion of at-home asthma deaths increased from 23% in 2000 to 2001 to 36% in 2018 to 2019. The distribution of place of death varied by age, sex, race, ethnicity, and geographic region. CONCLUSION: Despite an overall decline in asthma mortality in the United States, at-home asthma mortality has remained unchanged. In recent years, more than one-third of asthma deaths have occurred at home. These findings warrant further study and underscore the importance of increased efforts to identify and treat uncontrolled asthma across demographic groups.

Geographic variation in disease burden among patients with severe persistent asthma in the United States.

BACKGROUND: In the United States, a few studies have evaluated geographic variation of severe asthma at the subnational level. OBJECTIVE: To assess state-level geographic variation in the prevalence and characteristics of severe persistent asthma in the United States. METHODS: Patients aged above or equal to 12 years with severe persistent asthma were identified using nationally representative data from IQVIA open-source Medical/Pharmacy Claims and PharMetrics Plus databases (January 2019-December 2020). The index date was defined as the patient's earliest qualifying date for a severe asthma diagnosis. Baseline characteristics were measured during the 12-month pre-index period. Outcomes including exacerbation occurrence, asthma control, and medication use were measured during the 12-month post-index period and compared across states using census-level projections. RESULTS: A total of 2,092,799 patients with asthma were identified; 496,750 (23.7%) met criteria for severe persistent asthma and all inclusion criteria. Mean age was 50.5 years; 68.4% were females. The prevalence of severe persistent asthma varied across states, ranging from 19.6% (New Mexico) to 31.9% (Alaska). Among patients with severe persistent asthma, 40.9% had more than or equal to 1 exacerbation, ranging from 34.2% (Vermont) to 45.6% (Louisiana); 21.1% had uncontrolled disease, ranging from 16.5% (Vermont) to 24.0% (Arizona). Among patients with exacerbations, 13.7% had exacerbation-related emergency department visits or hospitalizations, ranging from 7.0% (North Carolina) to 17.7% (Nevada). Among patients with severe uncontrolled asthma, 15.6% used biologics post-index, ranging from 2.2% (Hawaii) to 27.9% (Mississippi). CONCLUSION: There is significant variability in severe persistent asthma prevalence and disease burden across US states. Reasons for geographic variation may include differences in socioeconomic/environmental factors or asthma management.

Tezepelumab reduces exacerbations across all seasons in patients with severe, uncontrolled asthma (NAVIGATOR).

BACKGROUND: Asthma exacerbation frequencies vary throughout the year owing to seasonal triggers. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) vs placebo in patients with severe, uncontrolled asthma. OBJECTIVE: To evaluate the effect of tezepelumab on asthma exacerbations across all seasons in NAVIGATOR patients (post hoc). METHODS: NAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. AAER over 52 weeks was assessed by season. Data from patients in the Southern Hemisphere were transformed to align with Northern Hemisphere seasons. RESULTS: Tezepelumab reduced the AAER vs placebo by 63% (95% confidence interval [CI], 52-72) in winter, 46% (95% CI, 26-61) in spring, 62% (95% CI, 48-73) in summer, and 54% (95% CI, 41-64) in fall. In matched climates, during the spring allergy season (March 1 to June 15) and ragweed allergy season (September), tezepelumab reduced the AAER vs placebo in patients with seasonal allergy by 59% (95% CI, 29-77) and 70% (95% CI, 33-87), respectively. In patients with perennial allergy and in those with seasonal allergy, tezepelumab reduced the AAER vs placebo across all seasons. CONCLUSION: Tezepelumab reduced exacerbations across all seasons vs placebo in patients with severe, uncontrolled asthma, including patients with seasonal and perennial allergies. These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03347279 (https://clinicaltrials.gov/ct2/show/NCT03347279).

Incremental cost burden among patients with severe uncontrolled asthma in the United States.

BACKGROUND: The economic burden of severe asthma and severe uncontrolled asthma (SUA) is significant. Updated assessments of health care resource utilization (HCRU) and cost are needed given the increase in treatment options and updates to guidelines in recent years. OBJECTIVE: To describe all-cause and asthma-related HCRU and costs among patients with SUA vs patients with nonsevere asthma in the United States using real-world data. METHODS: MarketScan administrative claims databases were used to select adults with persistent asthma for this retrospective analysis between January 1, 2013, and December 31, 2019. Asthma severity status was defined using the Global Initiative for Asthma step 4/5 criteria (index is the earliest date qualifying patients as severe or randomly assigned for nonsevere patients). Patients with SUA were a subset of the severe cohort meeting the following criteria: those who were hospitalized with asthma as the primary diagnosis or had at least 2 emergency department or outpatient visits with an asthma diagnosis and a steroid burst within 7 days. HCRU, costs (allcause and asthma-related defined as medical claims with an asthma diagnosis and pharmacy claims for asthma treatment), work loss, and indirect costs due to absenteeism and short-term disability (STD) were compared between patients with SUA, severe, and nonsevere asthma. Outcomes were reported during a fixed 12-month post-index period using chi-square and t-tests where appropriate. RESULTS: 533,172 patients with persistent asthma were identified (41.9% [223,610]) severe and 58.1% [309,562] nonsevere). Of the severe patients, 17.6% (39,380) had SUA. The mean (SD) all-cause total health care costs were significantly higher in patients with SUA ($23,353 [$40,817]) and severe asthma ($18,554 [$36,147]) compared with those with nonsevere asthma ($16,177 [$37,897], P < 0.001 vs nonsevere asthma). The results were consistent for asthma-related costs. In addition, although patients with severe asthma made up 41.9% of the total study population, they contributed disproportionately higher costs (60.5%) to the total asthma-related direct costs, with the effect more evident among patients with SUA (7.4% of study population contributed 17.7% of the total asthma-related costs). For the subset of patients with asthma with workplace absenteeism, patients with SUA lost more time from work (259.3 vs 236.2 hours lost, P = 0.002; 7.8 vs 5.3 STD days, P < 0.001), and had higher corresponding indirect costs ($5,944 vs $5,415, P = 0.002 for absenteeism related; $856 vs $582, P < 0.001 for STD related) compared with patients with nonsevere asthma. CONCLUSIONS: Patients with SUA have significantly higher asthma-related economic burden compared with patients with nonsevere asthma and contribute a disproportionally higher percentage of asthma-related costs. DISCLOSURES: This study was funded by Amgen and AstraZeneca. The design and analysis for this study was conducted primarily by Merative. Amgen and AstraZeneca provided funding to support protocol development, data analysis, and manuscript development activities associated with this study. Dr Burnette is on the advisory board and a consultant for GSK, a consultant and member of the advisory boards and speakers' bureaus of Sanofi, Genzyme, Regeneron, AstraZeneca, and Amgen Inc. Dr Wang, Dr Rane, Dr Lindsley, and Dr Llanos are employees and shareholders of Amgen Inc. Dr Chung and Dr Ambrose are employees and shareholders of AstraZeneca. Ms Princic and Ms Park are employees of Merative, which received funding from Amgen to conduct this study.

Efficacy of tezepelumab in patients with evidence of severe allergic asthma: Results from the phase 3 NAVIGATOR study.

BACKGROUND: Allergic asthma is the most common phenotype among patients with severe asthma. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) versus placebo in patients with severe, uncontrolled asthma. This exploratory analysis evaluated the efficacy of tezepelumab in NAVIGATOR participants with evidence of severe allergic asthma. METHODS: Patients (12-80 years old) receiving medium- or high-dose inhaled corticosteroids and ≥ 1 additional controller medication, with or without oral corticosteroids, were randomized to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks in NAVIGATOR. In this analysis, the AAER, forced expiratory volume in 1 second (FEV1 ), patient-reported outcomes (PROs), and type 2 biomarker levels were evaluated in patients grouped by sensitivity to perennial aeroallergens, confirmed symptomatic allergy, and eligibility for omalizumab treatment according to the United States (OMA-US) and the European Union (OMA-EU) prescribing information, including subgroups according to baseline blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels. RESULTS: Of 1059 patients who received treatment in NAVIGATOR, 680 (64%) had perennial aeroallergen sensitivity and 318 (30%) had confirmed symptomatic allergy; 379 (36%) and 359 (34%) patients were OMA-US- and OMA-EU-eligible, respectively. Tezepelumab reduced the AAER over 52 weeks versus placebo by 58% (95% confidence interval [CI]: 47-67) to 68% (95% CI: 55-77) across these subgroups. Among omalizumab-eligible patients, AAERs were reduced in patients across baseline blood eosinophil counts and FeNO levels. Tezepelumab improved FEV1 and PROs, and reduced type 2 biomarkers, versus placebo in patients with and without perennial allergy. CONCLUSIONS: Tezepelumab was efficacious in patients with severe, uncontrolled asthma with evidence of allergic inflammation, defined by multiple clinically relevant definitions. These findings further support the benefits of tezepelumab in a broad population of patients with severe asthma, including those with severe allergic asthma.

Eosinophil responses during COVID-19 infections and coronavirus vaccination.

Eosinophils are circulating and tissue-resident leukocytes that have potent proinflammatory effects in a number of diseases. Recently, eosinophils have been shown to have various other functions, including immunoregulation and antiviral activity. Eosinophil levels vary dramatically in a number of clinical settings, especially following eosinophil-targeted therapy, which is now available to selectively deplete these cells. There are key coronavirus disease 2019 (COVID-19)-related questions concerning eosinophils whose answers affect recommended prevention and care. First, do patients with eosinophilia-associated diseases have an altered course of COVID-19? Second, do patients with eosinopenia (now intentionally induced by biological drugs) have unique COVID-19 susceptibility and/or disease course? This is a particularly relevant question because eosinopenia is associated with acute respiratory deterioration during infection with the severe acute respiratory syndrome coronavirus 2, the causative agent of COVID-19. Third, do eosinophils contribute to the lung pathology induced during COVID-19 and will they contribute to immunopotentiation potentially associated with emerging COVID-19 vaccines? Herein, we address these timely questions and project considerations during the emerging COVID-19 pandemic.

KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies.

The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.

Prenatal and perinatal history in Kabuki Syndrome.

Kabuki syndrome (KS) is a disorder of epigenetic dysregulation due to heterozygous mutations in KMT2D or KDM6A, genes encoding a lysine-specific methyltransferase or demethylase, respectively. The phenotype is highly variable, including congenital cardiac and renal anomalies, developmental delay, hypotonia, failure to thrive, short stature, and immune dysfunction. All affected individuals have characteristic facial features. As KS natural history has not been fully delineated, limited information exists on its prenatal and perinatal history. Two tertiary centers collected retrospective data from individuals with KS (N = 49) using a questionnaire followed by review of medical records. Data from 49 individuals (age range: 7 months-33 years; 37% male; 36 with KMT2D mutations, 2 with KDM6A mutations, and 11 diagnosed clinically) were examined. Polyhydramnios affected 16 of 39 (41%) pregnancies. Abnormal quad screens in four out of nine (44%) pregnancies and reduced placental weights also complicated KS pregnancies. These data comprise the first large dataset on prenatal and perinatal history in individuals with confirmed (genetically or clinically) KS. Over a third of pregnancies were complicated by polyhydramnios, possibly secondary to abnormal craniofacial structures and functional impairment of swallowing. The differential diagnosis for polyhydramnios in the absence of intrauterine growth retardation should include KS.

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. OBJECTIVE: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). METHODS: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/ßGeo) mouse model and validated select findings in a patient with KS. RESULTS: Compared with wild-type littermates, Kmt2d+/ßGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/ßGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/ßGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. CONCLUSIONS: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.

Central Diabetes Insipidus in a Patient With NFKB2 Mutation: Expanding the Endocrine Phenotype in DAVID Syndrome.

CONTEXT: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a recently described, rare disorder characterized by anterior pituitary hormone deficiencies and common variable immunodeficiency associated with NFKB2 mutations. Posterior pituitary hormone deficiencies have not been reported in patients with DAVID syndrome. CASE DESCRIPTION: We report a pediatric patient who initially presented with hypogammaglobulinemia and alopecia totalis, who was identified to have a de novo NFKB2 mutation at one year of age. He developed central diabetes insipidus and central adrenal insufficiency at three and four years of age, respectively. At seven years of age, he had not developed GH or TSH deficiencies. Whole exome sequencing ruled out known genetic causes of central diabetes insipidus, adrenal insufficiency, and hypopituitarism. CONCLUSION: This is a report of central diabetes insipidus in a patient with DAVID syndrome caused by an NFKB2 mutation. This case report expands the evolving endocrine phenotype associated with NFKB2 mutations beyond anterior pituitary deficiencies.

Kabuki syndrome: international consensus diagnostic criteria.

BACKGROUND: Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A. Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal. METHODS: An international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed. RESULTS: The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented. CONCLUSION: As targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation.

Intratracheal myriocin enhances allergen-induced Th2 inflammation and airway hyper-responsiveness.

INTRODUCTION: Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis. METHODS: Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo. Intratracheal myriocin was administered alone or during house dust mite sensitization (HDM) of BALB/C mice and airway hyper-responsiveness (AHR) was evaluated by invasive plethysmography followed by bronchial lavage (BAL) cytology and cytokine quantification. RESULTS: Myriocin inhibits and HDM exposure activates de novo ceramide synthesis in bone marrow-derived dendritic cells. Mice receiving intratracheal myriocin developed a mild airway neutrophilic infiltrate without inducing a significant increase in AHR. CXCL1 was elevated in the BAL fluid of myriocin-treated mice while the neutrophilic chemotactic factors anaphylatoxin C5a, leukotriene B4, and IL-17 were unaffected. HDM treatment combined with myriocin led to a dramatic enhancement of AHR (63% increase over HDM alone, p < 0.001) and increased granulocyte pulmonary infiltrates versus HDM or myriocin alone. Elevated Th2 T cell counts and Th2 cytokines/chemokines (IL5, IL13, CCL17) were observed in mice treated with combined HDM/myriocin compared to HDM alone. Myriocin-treated pulmonary CD11c+ cells stimulated with HDM secreted significantly more CXCL1 than cells stimulated with HDM alone while HDM stimulated airway epithelial cells showed no change in CXCL1 secretion following myriocin treatment. CONCLUSIONS: Intratracheal myriocin, likely acting via ceramide synthesis inhibition, enhances allergen-induced airway inflammation, granulocyte and Th2 lymphocyte recruitment, and allergen-induced AHR. Sphingolipid pathways may represent novel targets for possible future anti-inflammatory asthma medications.

Lipid Mediators of Allergic Disease: Pathways, Treatments, and Emerging Therapeutic Targets.

Bioactive lipids are critical regulators of inflammation. Over the last 75 years, these diverse compounds have emerged as clinically-relevant mediators of allergic disease pathophysiology. Animal and human studies have demonstrated the importance of lipid mediators in the development of asthma, allergic rhinitis, urticaria, anaphylaxis, atopic dermatitis, and food allergy. Lipids are critical participants in cell signaling events which influence key physiologic (bronchoconstriction) and immune phenomena (degranulation, chemotaxis, sensitization). Lipid-mediated cellular mechanisms including: (1) formation of structural support platforms (lipid rafts) for receptor signaling complexes, (2) activation of a diverse family of G-protein coupled receptors, and (3) mediating intracellular signaling cascades by acting as second messengers. Here, we review four classes of bioactive lipids (platelet activating factor, the leukotrienes, the prostanoids, and the sphingolipids) with special emphasis on lipid synthesis pathways and signaling, atopic disease pathology, and the ongoing development of atopy treatments targeting lipid mediator pathways.

Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is a complex multisystem 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 been reported. OBJECTIVE: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. METHODS: We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). RESULTS: Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27(+)) and class-switched memory B cells (IgM(-)) were significantly reduced in patients with KMT2D(Mut/+) mutations compared with numbers in control subjects (P < .001). Patients with KMT2D(Mut/+) mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. 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 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.

Combined immune deficiency in a patient with a novel NFKB2 mutation.

NFKB2 encodes the p100/p52 protein, a critical mediator of the canonical and noncanonical NFkB signaling pathways. Here we report the comprehensive immune evaluation of a child with a novel NFKB2 mutation and provide evidence that aberrant NFKB2 signaling not only causes humoral immune deficiency, but also interferes with the TCR-mediated proliferation of T cells. These observations expand the known phenotype associated with NFKB2 mutations.