BACKGROUND:Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. OBJECTIVES:Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. METHODS:Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. RESULTS:Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. CONCLUSIONS:AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens.

Neonatal capillary leak syndrome (CLS) is a rare, but life-threatening condition following neonatal sepsis or inflammatory injury. The objective of this study was to describe a standardized treatment approach for CLS that improves mortality and neonatal outcomes. A retrospective cohort study of 10 infants born at 22 to 26 weeks of gestation who developed CLS following a significant inflammatory insult was performed. Time to diagnosis and treatment approaches over 2 epochs were recorded and described. In epoch 2, with increased clinical awareness of CLS and implementation of a standardized treatment approach, there was a non-statistically significant decrease in the time to treatment with a significant decrease in mortality. An early targeted treatment approach for neonatal CLS can decrease mortality rates in this highly morbid condition.

BACKGROUND:Immune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune-related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity. PROCEDURE:We assessed family history in two ways: via patient report for ITP and ES and by population-based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB. RESULTS:Chart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19-2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63-1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy. CONCLUSIONS:The findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.

The nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor. NOD2 gene variants are associated with inflammatory bowel disease (IBD) as well as Blau and Yao syndromes. IBD is associated with extraintestinal manifestations, including autoinflammation, which may be the presenting symptoms. The clinical symptoms may depend on the specific gene variants. This retrospective study was undertaken to examine the clinical manifestations of patients with pathogenic NOD2 variants in our institution. This study was approved by our Institutional Review Board.

American Journal of Medical Genetics Part AVolume 191, Issue 7 p. 1681-1686 ISSUE INFORMATIONFree Access Table of Contents, Volume 191A, Number 7, July 2023 First published: 07 June 2023 https://doi.org/10.1002/ajmg.a.62813AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Volume191, Issue7July 2023Pages 1681-1686 RelatedInformation

The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.

This case report describes a 13-year-old girl with chronic immune thrombocytopenia, an occlusive thrombus in the anterior superior sagittal sinus, a nonocclusive thrombus in the left transverse sinus, and bifrontal pachymeningeal dural thickening and enhancement as well as bifrontal leptomeningeal enhancement.

Objective To assess the diagnostic and treatment practices among a variety of subspecialists at pediatric institutions in the US. Study design Using a web-based survey, we assessed the consultation, diagnostic, and treatment preferences of providers from the different pediatric subspecialties who care for pediatric patients with hemophagocytic lym-phohistiocytosis (HLH)/macrophage activating syndrome (MAS). Domains included demographics, provider training level and specialty, experience and comfort level with the diagnosis and treatment of HLH/MAS, and insti-tutional approaches toward the diagnosis and management of HLH/MAS. Participants also were given 2 case sce-narios: one describing Epstein-Barr virus-associated HLH and another describing an underlying rheumatologic condition with MAS. Results Of 263 respondents, 23%, 29%, 39%, and 7% identified as hematology/oncology, rheumatology, general pediatrics/critical care/hospitalist, and allergy/immunology, respectively. For Epstein-Barr virus/HLH, hematology/ oncology was the preferred first consultant by most respondents other than rheumatologists, of whom only 47% agreed. For MAS, 92% of respondents from all specialties favored a rheumatology consultation. Preferred diag-nostic tests varied by subspecialty, with hematology/oncology more likely than rheumatology to order an infectious workup, natural killer cell function, soluble interleukin-2 receptor, bone marrow biopsy, and genetic testing. First -line therapy also varied, with hematology/oncology preferring dexamethasone and etoposide and rheumatology more often preferring methylprednisolone and anakinra. One-half of respondents were unaware of institutional al-gorithms for diagnosis and treatment of HLH/MAS. Most (85.6%) favored the development of treatment algorithms for HLH/MAS, and 90% supported a multidisciplinary approach. Conclusions Current consulting patterns, diagnostic workup, and treatment approaches of HLH/MAS vary by specialty, highlighting the need for standardized management algorithms and institutional multidisciplinary HLH/ MAS teams. (J Pediatr 2023;255:65-71).

Primary immunodeficiency diseases are associated with an increased tendency for noninfectious complications of autoimmunity and malignancy, particularly leukemia and lymphoma. The mechanisms of immune dysregulation have been linked to the combination of dysregulated immune cells and environmental factors such as infections. In particular, dysfunction in T-cell subsets and Epstein-Barr virus contributes to the development of autoimmunity and lymphoproliferative disease in primary immunodeficiency diseases. There are scant reports of patients with partial DiGeorge syndrome and Epstein-Barr virus-driven lymphoma. We report 1 patients with partial DiGeorge syndrome who developed lymphoma, and review reported cases in the literature.

Urinary tract infections (UTIs) are among the most common causes of hospitalization in children, with a rising prevalence of extended-spectrum beta-lactamase-producing organisms (ESBL). The purpose of this study was to identify risk factors and treatment outcomes of children with ESBL-UTI. A retrospective case-control study of hospitalized children was performed from July 2014 till December 2017. Medical records from patients with a positive urine culture were reviewed and included in the study if they met criteria for UTI. Cases were defined as ESBL-UTI, while controls were defined as non-ESBL-UTI patients. This study confirmed that there are certain risk factors, such as previous UTI, recent antibiotic use, urinary tract abnormalities, recent hospital admission, and nonrenal comorbidities, that are associated with ESBL-UTI. Most of the patients with ESBL-UTI responded to discordant antibiotics. Other significant outcomes in patients with ESBL-UTI included a longer length of stay and longer intravenous antibiotic therapy.

Primary immunodeficiency diseases are associated with an increased tendency for noninfectious complications of autoimmunity and malignancy, particularly leukemia and lymphoma. The mechanisms of immune dysregulation have been linked to the combination of dysregulated immune cells and environmental factors such as infections. In particular, dysfunction in T-cell subsets and Epstein-Barr virus contributes to the development of autoimmunity and lymphoproliferative disease in primary immunodeficiency diseases. There are scant reports of patients with partial DiGeorge syndrome and Epstein-Barr virus-driven lymphoma. We report 1 patients with partial DiGeorge syndrome who developed lymphoma, and review reported cases in the literature.

Abstract Background Immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia during childhood. Approximately 10-30% of pediatric patients will develop chronic ITP (cITP), which is defined as thrombocytopenia lasting over 12 months, and constitutes a significant burden for patients and their caregivers. Patients with cITP may require ongoing medications to treat symptomatic thrombocytopenia, may have asymptomatic thrombocytopenia not requiring medical interventions, or may experience complete resolution of their ITP. There are not specific patient nor disease characteristics that can help us predict how cITP may progress, and which patients are more likely to require ongoing treatments. ITP can be a manifestation of immune dysregulation in patients with other autoimmune conditions or primary immunodeficiency disorders (PIDDs). We aimed to assess the characteristics of patients with cITP including the presence of autoimmune or allergic disorders in the patients and in first-, second-, and third-degree family members. We hypothesized that patients with cITP may have a higher incidence of immune dysregulation in family members in contrast to patients with acute aITP. Methods The study was approved by the institutional review and ethics boards at the University of Utah. We queried the Primary Children's Hospital database for cases of "immune thrombocytopenia" from January 1 st, 2001 to January 1 st,2021. Retrospective chart review was done to confirm the diagnosis. Patient demographics, clinical presentation, and family history of patients were reviewed. Data was collected in RedCap at the University of Utah. Descriptive summaries of data were done. Results Medical charts from 266 ITP patients diagnosed during the study period were reviewed; 182/266 (68.5%) had acute ITP (aITP) and 84/266 (31.5%) patients had cITP, defined as platelet count <150 K/µl for >12 months. Resolution of ITP occurred in 28/84 (33.3%) patients with cITP (resolved cITP), while 56/84 (66.7%) had ongoing thrombocytopenia (unresolved cITP). Mean duration of ITP in patients with resolved cITP was 2.9 years, and 4.6 years in patients with unresolved cITP at the time of the last known platelet count. Mean age at diagnosis was 7.4 years in the cITP group and 5.1 years in the aITP group. Concurrent allergic conditions were identified in 10/84 (12%) of patients with cITP and 5/182 (2.7%) of patients with aITP. Autoimmune conditions were identified in 3 patients (3.5%) with cITP, and 4 patients (2.2%) with aITP. First-degree family members of cITP patients were more likely to be reported with an autoimmune condition than first-degree family members of aITP patients (15.5% vs. 5.5%, p=0.007 using Chi-square test); this effect was not seen amongst second- or third-degree relatives. The most common autoimmune condition reported in family members was autoimmune thyroid disease in both cohorts (2.7% in aITP and 9.5% in cITP). Common variable immunodeficiency (CVID) was reported in second degree relatives of 3/84 (3.6%) patients with cITP; no relatives of patients with aITP had a report of PIDD. Additionally, we identified 14 patients with Evans syndrome (ES), all with chronic immune thrombocytopenia and all patients had been followed for over a year at the time of the chart review. Four ES patients were previously diagnosed with 22q11.2 deletion, and one with CVID. In patients with ES, 4/14 (28.6%) and 5/14 (35.7%) had first- and second-degree family members with a reported autoimmune condition, respectively. No PIDDs were identified in first, second-, or third-degree relatives of patients with ES. Conclusions There is increasing evidence that patients with chronic ITP may exhibit polyautoimmunity or other signs of immune dysregulation, suggesting that ITP may be the initial manifestation of another autoimmune process or PIDD. We evaluated medical histories of patients with ITP and their family members. Patients with cITP have a history of autoimmunity in their family stronger than in patients with aITP. This association was even stronger in patients with ES. Disclosures No relevant conflicts of interest to declare.