Hypoparathyroidism-Retardation-Dysmorphism Syndrome due to a Variant in the Tubulin-Specific Chaperone E Gene as a Cause of Combined Immune Deficiency.

BACKGROUND: Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome is a disease composed of hypoparathyroidism, growth retardation, severe developmental delay, and typical dysmorphic features caused by the tubulin-specific chaperone E gene variant. Many patients succumb in infancy to HRD due to overwhelming infections mainly caused by Pneumococcus spp. Knowledge related to the immune system in these patients is scarce. PURPOSE: To define the immune phenotype of a cohort of HRD patients including their cellular, humoral, and neutrophil functions. METHODS: The study included HRD patients followed at Soroka University Medical Center. Clinical and immunological data were obtained, including immunoglobulin concentrations, specific antibody titers, lymphocyte subpopulations, lymphocyte proliferation, and neutrophil functions. RESULTS: Nine patients (5 females and 4 males) were enrolled, aged 6 months to 15 years. All received amoxicillin prophylaxis as part of a routine established previously. Three patients had bacteremia with Klebsiella, Shigella spp., and Candida. Three patients had confirmed coronavirus disease 19 (COVID-19), and two of them died from this infection. All patients had normal blood counts. Patients showed high total IgA and IgE levels, low anti-pneumococcal antibodies in spite of a routine vaccination schedule, and reduced frequency of naive B cells with increased frequency of CD21lowCD27- B cells. All patients had abnormal T-cell population distributions, including reduced terminally differentiated effector memory CD8, inverted CD4/CD8 ratios, and impaired phytohemagglutinin (PHA)-induced lymphocyte proliferation. Neutrophil superoxide production and chemotaxis were normal in all patients tested. CONCLUSION: HRD is a combined immunodeficiency disease with syndromic features, manifesting in severe invasive bacterial and viral infections.

SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma.

Increased susceptibility to develop severe forms of Epstein-Barr virus (EBV) infection in early age is a significant hallmark of an underlying primary immunodeficiency (PID). Here, we present immunologic and genetic evaluations of a 3-year-old child who was born to first-cousins parents and presented with recurrent infections, failure to thrive, and severe EBV-related infection and proliferation. A diagnosis of diffuse large B cell lymphoma was made and the immunological workup was suggestive of T cell immunodeficiency. Unfortunately, the patient succumbed to EBV-related lymphoma. Whole-exome sequencing revealed a novel homozygous mutation, c.991del.C; p. Q331Sfs*6 in the SLP76 gene. The SLP76 protein, a TCR signaling molecule, was recently linked to a human disease of the immune system. In order to examine the effect of this new SLP76 mutation on T cell signaling, a SLP76-deficient Jurkat-derived T cell line was transduced either with wild-type (WT), or with the specific SLP76 mutant, or with a mock vector. Downstream TCR signaling events, including ERK1/2 phosphorylation, CD69 expression, and Ca2 + mobilization, were reduced in cells harboring the reported mutation, linking this novel mutation to the expected immunological outcome. SLP76 deficiency should be added to the growing list of monogenetic diseases that predispose affected individuals to acquire severe and uncontrolled EBV infections and to develop substantial complications. This case further links mutations in the SLP76 gene to a significant human immunodeficiency and extends its clinical phenotype.

DNA-Binding domain mutations confer severe outcome at an early age among STAT1 gain-of-function patients.

BACKGROUND: STAT1 gain-of-function (GOF) is an immune dysregulatory disorder with poorly studied genotype-phenotype correlation, impeding prognostication and early intervention. Given previous mechanistic studies, as well as anecdotal clinical reports, we sought to systematically determine whether DNA-binding domain (DBD) mutations in STAT1 result in a different phenotype than mutations in other gene domains. METHODS: Negative prognostic features previously identified by the International STAT1 GOF Study Group (invasive infections, intracranial aneurysms, and malignancy), as well as other clinical features and mortality, were compared within a cohort of 30 patients with STAT1 GOF diagnosed at our center, consisting of 9 patients with DBD mutations and 21 patients with non-DBD mutations. We subsequently re-analyzed mortality data from a large, previously-published 274-patient cohort by the International STAT1 GOF Study Group. RESULTS: While no differences were noted with respect to malignancy or symptomatic aneurysms, invasive /opportunistic infections were substantially more common among DBD patients, as were sinopulmonary infections, bronchiectasis, enteropathy, endocrinopathies, lymphoproliferative manifestations, and recurrent fevers/HLH. DBD patients also had a lower probability of survival and younger age of mortality compared with non-DBD patients. Our re-evaluation of the published data from the International STAT1 GOF Study Group revealed a similar finding of earlier mortality among patients harboring DBD mutations. CONCLUSION: We report that STAT1 GOF patients with DBD mutations may be regarded as a unique subgroup, impacted more by early-onset profound combined immunodeficiency and with earlier mortality. These findings may impact clinical decision making with respect to early intervention, and in particular hematopoietic stem cell transplant considerations, in such patients.

Unusual phenotype in patients with a hypomorphic mutation in the DCLRE1C gene: IgG hypergammaglobulinemia with IgA and IgE deficiency.

The nuclease Artemis is a enzyme for V(D)J recombination allowing for the creation of T and B lymphocytes as well as for the repair of radiation-induced DNA double strand breaks encoded by the DCLRE1C gene. Artemis-null mutations are a known cause of severe combined immunodeficiencies (SCIDs) with radiosensitivity. Hypomorphic mutations in Artemis have been reported to cause a "leaky SCID"" phenotype, typically with hypogammaglobulinemia. We present four patients, all harboring the same unique hypomorphic mutation in the DCLRE1C gene, an 8-base pair insertion (c.1299_1306dup, p.Cys436*) presenting with a relatively mild phenotype including pulmonary infectious EBV-related lymphoproliferative diseases, an autoimmune phenomenon. Non-typical findings of IgG hypergammaglobulinemia accompanied by IgA and IgE deficiency were recorded in all patients. The typical viral, fungal, and opportunistic infections were absent, and patients reached a relatively old age.

Toll-like receptor 3 (TLR3) variant and NLRP12 mutation confer susceptibility to a complex clinical presentation.

Genetic aberrations in the toll-like receptor (TLR)3 pathway are associated with increased susceptibility to herpes simplex virus (HSV) infections. Leucine-rich repeat and PYD-containing protein (NLRP)12 is a component of the inflammasome apparatus, which is critical to an immediate innate inflammatory response. Aberrations in NLRP12 have been shown to mediate auto-inflammation. In this study, we present a 44-year old patient with severe HSV esophagitis and Crohn's disease. An immune and genetic investigation confirmed two coinciding genetic mutations in TLR3 and NLRP12. Our findings support conducting laboratory workup that targets TLR3 pathway in the immunocompetent host developing recurrent HSV infections.

Neutrophil Functions in Immunodeficiency Due to DOCK8 Deficiency.

Neutrophil chemotactic defects have been reported previously in patients with hyper-IgE syndrome. Bi-allelic mutations in dedicator of cytokinesis 8 (DOCK8) gene usually cause an autosomal recessive hyper-IgE syndrome phenotype. Data are lacking about expression of DOCK8 protein in neutrophils or the possible role of DOCK8 in neutrophil function. We sought to determine if DOCK8 protein is expressed in neutrophils and if DOCK8 plays a role in neutrophil function. The expression of DOCK8 protein was assessed in neutrophils from healthy volunteers with and without activators. Neutrophil chemotaxis, phagocytosis and superoxide generation were studied in neutrophils from DOCK8-deficient patients compared to neutrophils from healthy controls before and after stimulation with activators: phorbol 12-myristate 13-acetate (PMA) or N-Formylmethionyl-leucyl-phenylalanine (fMLP). DOCK8 protein is expressed in resting neutrophils from healthy controls, with a significant increase in DOCK8 expression after stimulation. Neutrophil functions were assessed in 6 DOCK8-deficient patients. All patients had the same non-sense mutation (c.C5134A, p.S1711X). Normal chemotaxis was recorded in 4/6 patients while a mild to moderate chemotaxis defect was recorded in 2/6. Superoxide generation was mainly normal in neutrophils from all six patients and phagocytosis was normal in five patients tested. We conclude that DOCK8 protein is expressed in resting human neutrophils and DOCK8 expression is increased after stimulation with either PMA or fMLP. Most patients with a disease-causing mutation in DOCK8 have normal neutrophil functions, while a minority showed a mild to moderate chemotactic defect.

Hodgkin's lymphoma, nephrotic syndrome, and echinococcosis cysts: an unusual association and literature review.

We present a 5-year-old female with minimal change nephrotic syndrome (MCNS). Within several months, she became steroid-dependent with progression of edema and ascites. Imaging studies revealed abnormal solid mass and liver cysts and she was diagnosed with both abdominal Hodgkin's lymphoma (cHD) and large hepatic cystic echinococcosis (CE). Association between MCNS and cHL or with CE has been described in the literature in adults and rarely in the pediatric population. We report, for the first time, a simultaneous occurrence of all three: MCNS, cHL, and CE. Literature review and suggested pathophysiologic mechanisms underlying this phenomenon are presented.

Incidence of typically Severe Primary Immunodeficiency Diseases in Consanguineous and Non-consanguineous Populations.

PURPOSE: Primary immunodeficiency diseases are considered to be rare diseases; however, data on the exact birth incidences of these diseases are sparse. Southern Israel is inhabited by two major populations: a relatively non-consanguineous Jewish population and a highly consanguineous Muslim Bedouin population. We sought to calculate the incidences of typically severe primary immunodeficiency diseases and compare the incidences in these populations. METHODS: A retrospective analysis of all typically severe primary immunodeficiency diseases evaluated at a single center from January 1, 1996 to December 31, 2016. The amount of live births by population was the denominator for calculating the incidences by population. RESULTS: A total of 95 patients were included, 85 of Bedouin and 10 of Jewish ethnicities. There were 152,331 births in the Bedouin and 160,998 births in the Jewish populations. The total incidence of typically severe primary immunodeficiency diseases was higher in the Bedouin population than expected based on previous studies. The total incidences were 55.8/105 births in the Bedouin population compared with 6.2/105 births in the Jewish population (P < 0.001). The incidences of all combined immunodeficiency diseases, ataxia telangiectasia, and infantile IBD due to interleukin 10 receptor defects were all significantly higher in the Bedouin population (P < 0.001). The incidence of X-linked agammaglobulinemia was not significantly different between both populations (P = 0.11). CONCLUSIONS: Typically, severe primary immunodeficiency diseases are not rare diseases in a consanguineous population; these diseases are significantly more common in the Bedouin population. This finding is probably also applicable to other consanguineous populations, and in these populations, primary immunodeficiency diseases should not be regarded as rare diseases.

Cytokine profile of food-allergic post-liver transplant children is identified by high levels of IL-5 and low IL-10 secretion from patients' peripheral blood mononuclear cells.

Severe allergic reaction to food following liver transplantation is a well-known phenomenon. However, the mechanisms underlying this phenomenon are not yet elucidated. This study aimed to reveal the nature of the immune response in post-transplanted allergic patients and compare them to non-allergic transplanted as well as allergic and non-allergic control subjects, with focus on cytokine milieu. Post-liver transplant patients with and without allergic reactions as well as food-allergic but otherwise healthy and healthy non-allergic control patients were recruited. We reviewed patient records and routine laboratory tests and assayed subjects' PBMCs, studying cytokine secretion profile in response to different stimuli. Post-transplant patients with food allergy showed a unique cytokine profile in response to various stimuli, with extremely elevated IL-5, low IL-10 secretion, and somewhat higher IFN-γ. T regulatory cell number was not significantly different among the groups of patients and controls. Immune response of food-allergic post-liver transplant patients is identified by a unique cytokine profile when compared to allergic but otherwise healthy individuals.

Fatal combined immunodeficiency associated with heterozygous mutation in STAT1.

BACKGROUND: Mutations in the gene for the signal transducer and activator of transcription 1, STAT1, have been shown to be associated with death at an early age due to overwhelming viral infection (complete STAT1 deficiency) or, more commonly, selective deficiencies to mycobacterial or fungal infection (typically heterozygous STAT1 mutations). OBJECTIVES: To define the molecular basis of progressive combined immunodeficiency in a group of patients with fatal infections. METHODS: We studied a group of unrelated patients who displayed an unusual progressive form of combined immunodeficiency. Whole exome sequencing assisted in confirming a common genetic defect in this group, which consisted of a heterozygous mutation of the STAT1 gene. STAT1 protein level as well as function was assessed, and a detailed evaluation of the immune system, including analysis of thymus tissue, was performed. RESULTS: Patients were found to carry de novo heterozygous mutations in STAT1 encoding T385A, I294T, or C284R amino acid substitutions. STAT1 expression appeared significantly decreased as a result of these changes but not completely absent, with diminished signaling responses. This group display progressive loss in lymphocyte number and function accompanied by increasing autoimmune features as well as severe, fatal infections. CONCLUSIONS: These findings show that some heterozygous aberrations of STAT1 can be associated with progressive combined immunodeficiency, quite distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations. These mutations were not inherited, rather, arose de novo in each case. Accompanied by significant patient mortality, this finding suggests that this class of STAT1 mutation is ultimately fatal due to overwhelming infection.

Defining combined immunodeficiency.

BACKGROUND: Although the extreme condition of typical profound T-cell dysfunction (TD), severe combined immunodeficiency (SCID), has been carefully defined, we are currently in the process of better defining less typical T-cell deficiencies, which tend to present with autologous circulating T-cell combined immunodeficiency (CID). Because autologous cells might interfere with the outcome of bone marrow transplantation, protocols usually include conditioning regimens. Therefore it is important to define the numbers of autologous cells usually detected in patients with CID versus those with SCID. OBJECTIVES: We sought to determine the number of circulating T cells in patients with SCID as opposed to those with CID, to study their function, and to evaluate their possible detection during newborn screening using T-cell receptor excision circle (TREC) analysis. METHODS: Numbers of circulating CD3(+) T cells (as determined by means of flow cytometry), in vitro responses to PHA, and TREC levels, all measured at presentation, were compiled from the research charts of the entire cohort of patients followed prospectively for T-cell immunodeficiency at the Hospital for Sick Children. Clinical data were ascertained retrospectively from the patient's hospital charts. RESULTS: One hundred three patients had CD3(+) determinations, and 80 of them had a genetic diagnosis. All patients considered to have typical SCID had CD3(+) T-cell counts of fewer than 500 cells/µL. Some variability was observed among different genotypes. In vitro responses to PHA were recorded in 88 patients, of whom 68 had a genetic diagnosis. All patients with low CD3(+) T-cell numbers (<500 cells/µL) also had markedly decreased responses to PHA (typical SCIDs). However, responses ranged widely in the groups of patients with TD who had more than 500 CD3(+) autologous circulating T cells per microliter. Although patients with Omenn syndrome and ζ chain-associated protein, 70 kDa (ZAP70), and purine nucleoside phosphorylase (PNP) deficiencies had low responses, patients with the p.R222C mutation in the IL-2 receptor γ(IL2RG) gene as well as IL-10 receptor and CD40 ligand deficiencies had normal or near-normal mitogen responses. Finally, 51 patients had TREC levels measured. All patients with typical SCID, Omenn syndrome, and ZAP70 deficiency had low TREC levels. In contrast, patients with mutations in forkhead box protein 3 (FOXP3), CD40 ligand (CD40L), and IL-10 receptor α(IL10RA), as well as patients with the p.R222C mutation in the IL2RG gene, had normal TREC levels. CONCLUSION: Patients with typical SCID can be defined as having fewer than 500 circulating CD3(+) T cells. Most patients with autologous T cells still have profound TD, as defined by reduced in vitro function and thymus output. Some patients with conditions including TD have normal TREC levels and will therefore not be detected in a TREC-based newborn screening program.

X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome.

Hemolytic-uremic syndrome (HUS), mostly secondary to infectious diseases, is a common cause of acute kidney injury in children. It is characterized by progressive acute kidney failure due to severe thrombotic microangiopathy, associated with nonimmune, Coombs-negative hemolytic anemia and thrombocytopenia. HUS is caused mostly by Shiga toxin-producing E. Coli, and to a lesser extent by Streptococcus pneumonia. In Streptococcus pneumonia HUS (pHUS), bacterial neuraminidase A exposes masked O-glycan sugar residues on erythrocytes, known as the T antigen, triggering a complement cascade causing thrombotic microangiopathy. Atypical HUS (aHUS) is a life-threatening genetic form of the disease, whose molecular mechanism is only partly understood. Through genetic studies, we demonstrate a novel X-linked form of aHUS that is caused by a de-novo missense mutation in C1GALT1C1:c.266 C > T,p.(T89I), encoding a T-synthase chaperone essential for the proper formation and incorporation of the T antigen on erythrocytes. We demonstrate the presence of exposed T antigen on the surface of mutant erythrocytes, causing aHUS in a mechanism similar to that suggested in pHUS. Our findings suggest that both aHUS caused by mutated C1GALT1C1 and pHUS are mediated by the lectin-complement-pathway, not comprehensively studied in aHUS. We thus delineate a shared molecular basis of aHUS and pHUS, highlighting possible therapeutic opportunities.

Inhaled Nitric Oxide for the Treatment of Acute Bronchiolitis: A Multicenter Randomized Controlled Clinical Trial to Evaluate Dose Response.

Rationale: Inhaled nitric oxide (iNO) has potential antiinflammatory, antimicrobial, and antiviral properties for patients with lower respiratory tract infections. Objectives: We compared the safety and efficacy of iNO administered in two concentrations in addition to standard supportive treatment (SST) compared with SST alone with the aim of improving clinical outcomes of infants with bronchiolitis. Methods: In this prospective, multicenter, double-blind, randomized controlled study, 89 infants hospitalized with moderate to severe bronchiolitis were randomly assigned to three treatment groups: 150 ppm NO plus SST (group 1), 85 ppm NO plus SST (group 2), and the control treatment (O2/air plus SST) (group 3). Treatment was given for 40 minutes, four times each day, for up to 5 days. The primary endpoint was time to reach "fit for discharge." This was a composite endpoint composed of both reaching a sustained oxygen saturation ≥92% on room air and reaching a clinical score ⩽5. Secondary endpoints included time to reach sustained oxygen saturation ≥92% on room air, time to clinical score ⩽5, and time to hospital discharge. Safety was assessed by the number of treatment-related adverse events (AEs) or serious AEs. Time-to-event efficacy outcomes were analyzed using a Cox proportional hazards regression model. Hazard ratios (HR) describe how many times more likely an individual is to experience an event, if such an individual receives NO rather than the control treatment during the observational period. Results: Group 1 demonstrated significant efficacy for time to reach fit to discharge compared with groups 2 (HR, 2.11; P = 0.041) and 3 (HR, 2.32; P = 0.049). Group 1 also demonstrated significant efficacy for time to hospital discharge compared with groups 2 (HR, 2.01; P = 0.046) and 3 (HR, 2.28; P = 0.043). No significant differences were observed between groups 2 and 3 for either endpoint. There were no differences between treatment groups in time to reach a clinical score ⩽5. The iNO therapy was well tolerated, with no treatment-related serious AEs. Conclusions: Treatment with high-dose intermittent iNO at 150 ppm showed reduced time to clinical improvement compared with 85 ppm or control treatment of hospitalized infants with acute bronchiolitis. The 150-ppm iNO dose is well tolerated, with significant benefit compared with both standard therapy and 85 ppm iNO, improving respiratory outcomes and reducing length of stay. Clinical trial registered with www.clinicaltrials.gov (NCT04060979).

Hyper IgM in tricho-hepato-enteric syndrome due to TTC37 mutation.

Tricho-hepato-enteric syndrome (THES) (OMIM #222,470) is a rare autosomal recessive syndromic enteropathy whose primary manifestations are dysmorphism, intractable diarrhea, failure to thrive, hair abnormalities, liver disease, and immunodeficiency with low serum IgG concentrations. THES is caused by mutations of either Tetratricopeptide Repeat Domain 37 (TTC37) or Ski2 like RNA Helicase (SKIV2L), genes that encode two components of the human SKI complex. Here, we report a patient with a TTC37 homozygous mutation phenotypically typical for tricho-hepato-enteric syndrome in whom extremely elevated IgM with low IgG was present at the time of diagnosis. These manifestations were not previously described in THES patients and this raised our index of suspicion towards "atypical" hyper IgM syndrome. Although the pathogenesis of immunoglobulin production dysfunction in THES is still elusive, this disorder should be considered in the differential diagnosis in patients with elevated IgM and syndromic features.

Case Report: Eosinophilic Esophagitis in a Patient With a Novel STAT1 Gain-of-Function Pathogenic Variant.

Background: STAT1 gain-of-function (GOF) is a primary immune dysregulatory disorder marked by wide infectious predisposition (most notably chronic mucocutaneous Candidiasis), autoimmunity, vascular disease and malignant predisposition. While atopic features have been described in some STAT1 GOF patients, they are not considered a predominant feature of the disease. Additionally, while eosinophilic gastrointestinal infiltration has been reported in some cases, this has always been described in the context of pre-existing oropharyngeal and/or esophageal Candidiasis. Clinical cases: Herein, we report 3 members of a multi-generational family diagnosed with STAT1 GOF caused by a novel mutation in the N-terminal domain, c.194A>C (p.D65A). The proband presented initially with a long-standing history of treatment-refractory eosinophilic esophagitis (EoE) without preceding gastrointestinal tract fungal infections, and her mother was diagnosed with esophagitis as well. Conclusion: EoE has been previously associated with alterations to STAT6 and STAT3 signaling pathways. The current report expands the possible association between JAK/STAT-related disorders and EoE, suggesting that EoE could be a primary disease manifestation of STAT1 GOF, even in the absence of oropharyngeal and/or esophageal Candidiasis.

B cell repertoire in patients with a novel BTK mutation: expanding the spectrum of atypical X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is caused by mutations in the Bruton tyrosine kinase) BTK) gene. Affected patients have severely reduced amounts of circulating B cells. Patients with atypical XLA may have residual circulating B cells, and there are few studies exploring these cells' repertoire. We aimed to study the B cell repertoire of a novel hypomorphic mutation in the BTK gene, using the next generation sequencing (NGS) technology. Clinical data was collected from our clinical records. Real-time PCR was used to determine KREC copies, and NGS was used to determine the immunoglobulin (Ig) heavy chain (IgH) repertoire diversity. Both patients had a relatively mild clinical and laboratory phenotype, residual BTK protein expression, and the same novel mutation in the BTK gene, c.1841 T > C, p. L614P. Signal-joint kappa-deleting recombination excision circles (sj-KREC) for both patients were completely absent reflecting lack of naïve B cells. The intron RSS-Kde coding joints (cj) were significantly reduced, reflecting residual replicating B cells. NGS displayed restricted IgH repertoire with highly uneven distribution of clones, especially for Pt2. We report a novel BTK mutation, c.1841 T > C (p. L614P) that is associated with a relatively mild phenotype. We conclude that the IgH repertoire in atypical XLA is restricted with highly uneven distribution of clones. This phenomenon may be explained by extremely reduced to non-existent levels of BTK in B cells. This report sheds further light on atypical cases of XLA.

Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience.

Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) caused by dominant negative (DN) variants in the signal transducer and activator of transcription 3 gene (STAT3) is characterized by recurrent Staphylococcal abscesses, severe eczema, chronic mucocutaneous candidiasis (CMC), and non-immunological facial and skeletal features. Objectives: To describe our experience with the diagnosis and treatment of adult patients with AD-HIES induced by DN-STAT3 variants. Methods: The medical records of adult patients (>18 years) treated at the Allergy and Clinical Immunology Clinic of Hadassah Medical Center, Jerusalem, Israel, were retrospectively analyzed. Immune and genetic workups were used to confirm diagnosis. Results: Three adult patients (2 males; age 29-41 years) were diagnosed with DN-STAT3 variants. All patients had non-immunological features, including coarse faces and osteopenia. Serious bacterial infections were noted in all patients, including recurrent abscesses, recurrent pneumonia, and bronchiectasis. CMC and diffuse dermatophytosis were noted in two patients. Two patients had severe atopic dermatitis refractory to topical steroids and phototherapy. Immune workup revealed elevated IgE in three patients and eosinophilia in two patients. Whole exome sequencing revealed DN-STAT3 variants (c.1166C>T; p.Thr389Ile in two patients and c.1268G>A; p. Arg423Gln in one patient). Variants were located in DNA-binding domain (DBD) and did not hamper STAT3 phosphorylation Treatment included antimicrobial prophylaxis with trimethoprim/sulfamethoxazole (n=2) and amoxycillin-clavulanic acid (n=1), and anti-fungal treatment with fluconazole (n=2) and voriconazole (n=1). Two patients who had severe atopic dermatitis, were treated with dupilumab with complete resolution of their rash. No adverse responses were noted in the dupilumab-treated patients. Discussion: Dupilumab can be used safely as a biotherapy for atopic dermatitis in these patients as it can effectively alleviate eczema-related symptoms. Immunologists and dermatologists treating AD-HIES adult patients should be aware of demodicosis as a possible manifestation. DN-STAT3 variants in DBD do not hamper STAT3 phosphorylation.

Lessons Learned From Five Years of Newborn Screening for Severe Combined Immunodeficiency in Israel.

BACKGROUND: Implementation of newborn screening (NBS) programs for severe combined immunodeficiency (SCID) have advanced the diagnosis and management of affected infants and undoubtedly improved their outcomes. Reporting long-term follow-up of such programs is of great importance. OBJECTIVE: We report a 5-year summary of the NBS program for SCID in Israel. METHODS: Immunologic and genetic assessments, clinical analyses, and outcome data from all infants who screened positive were evaluated and summarized. RESULTS: A total of 937,953 Guthrie cards were screened for SCID. A second Guthrie card was requested on 1,169 occasions (0.12%), which resulted in 142 referrals (0.015%) for further validation tests. Flow cytometry immune-phenotyping, T cell receptor excision circle measurement in peripheral blood, and expression of TCRVß repertoire for the validation of positive cases revealed a specificity and sensitivity of 93.7% and 75.9%, respectively, in detecting true cases of SCID. Altogether, 32 SCID and 110 non-SCID newborns were diagnosed, making the incidence of SCID in Israel as high as 1:29,000 births. The most common genetic defects in this group were associated with mutations in DNA cross-link repair protein 1C and IL-7 receptor α (IL-7Rα) genes. No infant with SCID was missed during the study time. Twenty-two SCID patients underwent hematopoietic stem cell transplantation, which resulted in a 91% survival rate. CONCLUSIONS: Newborn screening for SCID should ultimately be applied globally, specifically to areas with high rates of consanguineous marriages. Accumulating data from follow-up studies on NBS for SCID will improve diagnosis and treatment and enrich our understanding of immune development in health and disease.