Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis.

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

Case Report: Hypocomplementemic urticarial vasculitis syndrome in a pediatric patient with complement factor 1 deficiency.

Urticarial vasculitis (UV) is a type III hypersensitivity reaction, characterized by immune complex deposition in small vessels leading to complement activation. Hypocomplementemic urticarial vasculitis syndrome (HUVS) represents the most severe form of UV, manifesting as chronic and recurrent urticarial skin lesions with leukocytoclastic vasculitis on histology, hypocomplementemia, anti-C1q antibodies, and systemic organ involvement. This case study focuses on an adolescent who initially presented with invasive pneumococcal infection and was later diagnosed with two rare disorders: HUVS and coexisting complement factor 1 (CF1) deficiency by genotyping. The role of CF1 deficiency in the development of HUVS in this patient is uncertain but has not previously been described.

Chronic Recurrent Multifocal Osteomyelitis Involving the Spine, Sternum, and Lower Extremities: A Case Report.

Chronic recurrent multifocal osteomyelitis (CRMO) or chronic nonbacterial osteitis is a sterile autoinflammatory disease of bone in children that can mimic infectious osteomyelitis and osteosarcoma. Early diagnosis, treatment, and long-term follow-up of CRMO are essential. We describe a 10-year-old boy who presented with 15 days of left ankle bone more than joint pain, swelling, and limp. Plain radiographs and magnetic resonance imaging scans were nondiagnostic of osteomyelitis and tibial irrigation and biopsy were negative for infection and malignancy. Four years later, he again presented with similar pain in his right ankle. Repeat bone biopsy noted reactive bone changes and bone culture was sterile. Whole-body magnetic resonance imaging revealed multiple enhancing lesions in the long bones of bilateral lower extremities, spine, and sternum. He was diagnosed with CRMO, and treatment with celecoxib and subsequently pamidronate, infliximab, and methotrexate were initiated. After 6 months of treatment, the patient's gait and pain improved, and 2 years later, his CRMO was in clinical and radiologic remission. Of note, he developed palmoplantar pustular psoriasis, commonly seen in CRMO, that was not determined to be from tumor necrosis factor inhibition.

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies.

BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.

Pompe disease gene therapy.

Pompe disease is an autosomal recessive metabolic myopathy caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of disease exists from hypotonia and severe cardiac hypertrophy in the first few months of life due to severe mutations to a milder form with the onset of symptoms in adulthood. In either condition, the involvement of several systems leads to progressive weakness and disability. In early-onset severe cases, the natural history is characteristically cardiorespiratory failure and death in the first year of life. Since the advent of enzyme replacement therapy (ERT), the clinical outcomes have improved. However, it has become apparent that a new natural history is being defined in which some patients have substantial improvement following ERT, while others develop chronic disability reminiscent of the late-onset disease. In order to improve on the current clinical outcomes in Pompe patients with diminished clinical response to ERT, we sought to address the cause and potential for the treatment of disease manifestations which are not amenable to ERT. In this review, we will focus on the preclinical studies that are relevant to the development of a gene therapy strategy for Pompe disease, and have led to the first clinical trial of recombinant adeno-associated virus-mediated gene-based therapy for Pompe disease. We will cover the preliminary laboratory studies and rationale for a clinical trial, which is based on the treatment of the high rate of respiratory failure in the early-onset patients receiving ERT.

B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease.

OBJECTIVE: To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. STUDY DESIGN: Six subjects with Pompe disease (including 4 cross-reacting immunologic material-negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. RESULTS: Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. CONCLUSION: B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.

Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases.

Childhood-onset neuropsychiatric systemic lupus erythematosus (cNPSLE) with psychosis is a challenging manifestation of SLE. Pathogenic long-lived plasma cells (LLPCs) are not specifically targeted by standard immunosuppression and their persistence contributes to chronic autoimmunity. Bortezomib is approved for the treatment of multiple myeloma and has shown benefits in a variety of other antibody-mediated diseases. Bortezomib may be efficacious for severe or treatment-refractory cNPSLE through eradication of LLPCs, decreasing autoantibody production. We describe the first pediatric case series of five patients with unrelenting cNPSLE with psychosis who were treated safely and effectively with bortezomib between 2011 and 2017. Most patients had persistent cNPSLE with psychosis despite aggressive immunosuppression with methylprednisolone, cyclophosphamide, rituximab, and usually plasmapheresis. All patients demonstrated rapid clinical improvement in their psychotic manifestations with the ability to quickly taper immunosuppression after the introduction of bortezomib. No patient had a recurrence of overt psychosis during a follow-up period of 1-10 years. Secondary hypogammaglobulinemia developed in all five patients and required immunoglobulin replacement. No other severe side effects or adverse events were observed. Bortezomib-mediated LLPC depletion is a promising therapy for severe recalcitrant cNPSLE with psychosis when used as adjunctive therapy to conventional immunosuppression, B-cell, and antibody-depleting therapies. After initiation of bortezomib, patients had rapid, demonstrable improvement in psychosis as well as reduction in glucocorticoids and antipsychotics. Further investigation is needed to determine the therapeutic role of bortezomib in severe cNPSLE and cSLE. We present a mini-review of the rationale for bortezomib use and novel B-cell immunomodulation in rheumatic disease.

Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation.

Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient's white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.

Acute-onset opioid-induced hyperalgesia in a child with juvenile idiopathic arthritis.

We describe a child with polyarticular juvenile idiopathic arthritis (JIA) presenting with severe diffuse pain refractory to nonsteroidal anti-inflammatory agents and high-dose opioids. Her JIA involved her knees and ankles and was mildly active on etanercept and nonsteroidal anti-inflammatory agents. At presentation, she complained of hip pain progressing to severe diffuse pain and allodynia involving her extremities. No abnormalities were seen in her laboratory parameters and imaging of her lower extremities. After appreciating no substantial benefit by increasing her opioids, her opioids were tapered and discontinued, and this was followed by significant alleviation in her pain, and a diagnosis of opioid-induced hyperalgesia (OIH) was made. Despite reports in adults, the phenomenon of OIH has been reported infrequently in children. To our knowledge, OIH has not been described in children with rheumatologic conditions. We recommend investigating the possibility of OIH when treating a child with JIA and severe refractory pain.

The Diagnostic Performance of Early Sjögren's Syndrome Autoantibodies in Juvenile Sjögren's Syndrome: The University of Florida Pediatric Cohort Study.

Objectives: The aim of this study was to evaluate the clinical validity of early Sjögren's syndrome (SS) autoantibodies (eSjA), which were originally marketed for early diagnosis of SS, for juvenile SS (JSS) in a recently identified pediatric cohort. Methods: A total of 105 symptomatic subjects with eSjA results available were evaluated at the Center for Orphaned Autoimmune Disorders at the University of Florida and enrolled for this study. JSS diagnosis was based on the 2016 ACR/EULAR SS criteria. Demographic/clinical/laboratory parameters were compared between JSS (n = 27) and non-JSS (n = 78) for % positivity, sensitivity, and specificity of eSjA (SP1, anti-salivary protein; CA6, anti-carbonic anhydrase VI; PSP, anti-parotid secretory protein) and classic SS-autoantibodies (cSjA; ANA, SSA/SSB, RF, and others) either alone or in combination. Associations between eSjA and diagnostic/glandular parameters were also determined by Fisher's exact test. Results: Compared to non-JSS, JSS patients exhibited sicca symptoms demonstrating reduced unstimulated salivary flow rate (USFR) and abnormal glandular features revealed by salivary gland ultrasound (SGUS). Among cSjA, ANA demonstrated the highest sensitivity of 69.2%, while SSA, SSB, and RF showed around 95% specificities for JSS diagnosis. The % positive-SSA was notably higher in JSS than non-JSS (56% vs. 5%). Of eSjA, anti-CA6 IgG was the most prevalent without differentiating JSS (37%) from non-JSS (32%). Sensitivity and specificity of eSjA were 55.6 and 26.9%, respectively. Autoantibodies with potentially applicable specificity/sensitivity for JSS were seen only in cSjA without a single eSjA included. There were no associations detected between eSjA and focus score (FS), USFR, SSA, SGUS, and parotitis/glandular swelling analyzed in the entire cohort, JSS, and non-JSS. However, a negative association between anti-PSP and parotitis/glandular swelling was found in a small group of positive-SSA (n = 19, p = 0.02) whereas no such association was found between anti-PSP-positive compared to anti-PSP-negative. JSS and non-JSS groups differed in FS, USFR, and EULAR SS Patient Reported Index Dryness/Mean in CA6/PSP/ANA, SP1, and SSA-positive groups, respectively. Additionally, a higher FS was found in RF-positive than RF-negative individuals. Conclusions: eSjA underperformed cSjS in differentiating JSS from non-JSS. The discovery of clinical impact of eSjA on early diagnosis of JSS necessitates a longitudinal study.

Rituximab as Adjunct Maintenance Therapy for Refractory Juvenile Myasthenia Gravis.

BACKGROUND: Juvenile myasthenia gravis is a pediatric autoimmune disorder of the neuromuscular junction associated with substantial morbidity, for which standard therapies are not always efficacious. The objective of our study was to assess the tolerability and efficacy of rituximab use in children with refractory juvenile myasthenia gravis. METHODS: We conduced a retrospective cohort study at a single tertiary care referral center to evaluate children with juvenile myasthenia gravis who were treated with rituximab. The clinical status of these participants before and after initiation of rituximab therapy was measured, focusing on numbers of hospital admissions, numbers of immunomodulatory or immunosuppressive medications needed, and Myasthenia Gravis Foundation of America severity class. RESULTS: Five children with juvenile myasthenia gravis were ascertained who received rituximab as part of their regimen, four of whom had elevated acetylcholine receptor antibodies and one of whom had elevated muscle-specific kinase antibodies. After initiation of rituximab therapy, all participants experienced reduced numbers of immunomodulatory medications during the follow-up period (mean 11.6 months). Four of the five subjects experienced fewer juvenile myasthenia gravis-related hospital admissions and reduced (improved) Myasthenia Gravis Foundation of America classes, with no subjects having moderate or severe symptoms following treatment with rituximab. No significant adverse events were recorded for any of the participants. CONCLUSION: Rituximab was well-tolerated and efficacious in this juvenile myasthenia gravis cohort. The beneficial effect of rituximab was most pronounced in the one participant with muscle-specific kinase antibodies.

End-stage renal disease secondary to anti-glomerular basement membrane disease in a child with common variable immunodeficiency.

BACKGROUND: Anti-glomerular basement membrane (GBM) disease is caused by autoantibodies against the α3-chain of type IV collagen in the GBM. Common variable immunodeficiency (CVID) is a primary immunodeficiency manifested by hypogammaglobulinemia, inability to make functional antibody, and recurrent infections. This report extends the phenotype of CVID-associated autoimmune diseases to include anti-GBM disease. CASE PRESENTATION: A 15-year-old Caucasian female with prior normal renal function presented with nephrotic proteinuria, pedal edema, oliguria, acute kidney injury, and was found to have positive serum anti-GBM antibody. She had been diagnosed with CVID at 3 years of age. Her renal biopsy showed crescentic glomerulonephritis (50%), and immunofluorescence showed linear staining for IgG along the glomerular capillary wall. There was no clinical or imaging evidence of pulmonary hemorrhage. She was treated with pulse IV steroids, cyclophosphamide, rituximab, and several sessions of plasmapheresis. Her serum anti-GBM antibody level decreased from 194 U/mL at presentation to 0 U/mL after therapy. However, she progressed to end-stage renal disease (ESRD) within weeks, despite aggressive therapy, and required chronic renal replacement therapy in the form of dialysis. Her clinical course was also complicated by hypertensive encephalopathy, CMV viremia and meningoencephalitis, status epilepticus, and she passed away a few months later from lower respiratory tract complications. CONCLUSION: Anti-GBM disease is a rare autoimmune condition that has not been reported in association with a primary immunodeficiency syndrome. ESRD secondary to anti-GBM disease in a patient with CVID is an interesting association and supports the role of immune dysregulation in systemic autoimmune disease.

BK viruria and viremia in children with systemic lupus erythematosus.

BACKGROUND: BK virus (BKV) is a ubiquitous polyoma virus that lies dormant in the genitourinary tract once acquired in early childhood. In states of cellular immunodeficiency, the virus can reactivate to cause hemorrhagic cystitis and nephritis. Children with systemic lupus erythematosus (SLE) have an increased risk of developing infectious complications secondary to their immunocompromised state from the administration of several immuno-modulatory drugs. Currently, there are no data regarding the prevalence of BK viruria or viremia in children with SLE. METHODS: We conducted a prospective cohort study involving children with SLE of 18 years and younger. We obtained urine and blood samples at baseline and every 3 months up to 1 year for BK virus detection by real-time, quantitative polymerase chain reaction analysis. A comprehensive review of demographic information, clinical characteristics and medication history was also obtained. RESULTS: Thirty-two pediatric patients (26 females and 6 males) with SLE were enrolled. Median age at the time of SLE diagnosis and enrollment into study was 13.6 years and 16.0 years old, respectively. The prevalence at enrollment was 3.1% (1/32) for BK viruria and 6.2% (2/32) for BK viremia. During the study period, 3 patients had viruria, 5 had viremia and 4 had both viruria and viremia. Of the 12 patients with BKV reactivation, only one was positive for microscopic hematuria, all others were asymptomatic. A total of nine of 97(9.2%) urine samples and 10 of 96(10.4%) blood samples were positive for BK virus. The most commonly utilized biologics in this cohort group were Rituximab (90.6%), Abatacept (12.5%), and Belimumab (9.3%). The type of medication exposure and clinical characteristics did not statistically differ between the groups that did or did not have BK viruria and/or viremia. CONCLUSIONS: Our study suggests that pediatric patients with SLE have BK viremia and/or viruria at a higher rate than the general healthy population, although the significance of the reactivation and viral level is unclear. The influence of immune-modulatory drugs on BKV reactivation is still uncertain. To understand the interplay amongst BK virus, immunosuppression and dysregulated immune system in children with SLE, ongoing research in a larger population is still warranted, which may help establish proper surveillance, diagnosis and treatment for BKV infection.

Early Outcomes in Children With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the 12-month outcomes in children with AAV. METHODS: Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauci-immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4-6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months. RESULTS: In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9-15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4-6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0-6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months. CONCLUSION: This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.

The family journey-to-diagnosis with systemic juvenile idiopathic arthritis: a cross-sectional study of the changing social media presence.

BACKGROUND: Children with systemic juvenile idiopathic arthritis (SJIA) often encounter a delay between symptom onset and disease diagnosis, partly due to the broad differential of fever and lack of symptom recognition by providers. Families often seek multiple medical opinions and post on social media about their frustrations. This linguistic analysis observed the changing language patterns and social media posting behaviors of parents in the time leading to, during, and after SJIA diagnosis. METHODS: Public social media sites were manually reviewed by a linguistic team to evaluate posts about SJIA from US-based parents. RESULTS: A total of 3,979 posts between July 2001 and January 2015 were reviewed from 108 sites. Pre-SJIA diagnosis parents sought answers and shared status updates on social media, focusing primarily on the following three site types: alternative/natural lifestyle forums (39%), Facebook (27%), and disease-specific forums (17%). Posts during early prediagnosis phases were characterized by expressive language showing confidence in health care providers and trust in parental instincts. At later prediagnosis stages, parents continued to use social media, but the posts demonstrated increased frustration with delays in diagnosis and gaps in communication with providers. More objective symptom descriptions and a greatly reduced child-centered emotional focus were observed as parents shifted into caregiving roles. Once the diagnosis of SJIA was confirmed, parents used straightforward, less expressive language, and Facebook (47%) to make "announcement" posts and increased their use of SJIA websites (30%). With treatment initiation, the posts demonstrated a slow return of expressive language and an increased parental understanding of the "new normal". CONCLUSION: Parents use different language styles, frames of reference, and websites before and after SJIA diagnosis. Gaps in parent-provider communication, especially before diagnosis, and their new roles as caregivers lead to parental use of social media to express frustration with the health care process. Providers should tailor their discussions with parents to address these issues.

Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study.

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Detection of single clone deletions using array CGH: identification of submicroscopic deletions in the 22q11.2 deletion syndrome as a model system.

Constitutional submicroscopic DNA copy number alterations have been shown to cause numerous medical genetic syndromes, and are suspected to occur in a portion of cases for which the causal events remain undiscovered. Array comparative genomic hybridization (array CGH) allows high-throughput, high-resolution genome scanning for DNA dosage aberrations and thus offers an attractive approach for both clinical diagnosis and discovery efforts. Here we assess this capability by applying array CGH to the analysis of copy number alterations in 44 patients with a phenotype of the 22q11.2 deletion syndrome. Twenty-five patients had the deletion on chromosome 22 characteristic of this syndrome as determined by fluorescence in situ hybridization (FISH). The array measurements were in complete concordance with the FISH analysis, supporting their diagnostic utility. These data show that a genome-scanning microarray has the level of sensitivity and specificity required to prospectively interrogate and identify single copy number aberrations in a clinical setting. We demonstrate that such technology is ideally suited for microdeletion syndromes such as 22q11.2.

Anti-beta2-glycoprotein I antibodies in pediatric systemic lupus erythematosus and antiphospholipid syndrome.

OBJECTIVE: To determine whether serum beta2-glycoprotein I antibody (anti-beta2GPI) detection improves identification of pediatric subjects at risk for antiphospholipid syndrome (APS). METHODS: Serum antiphospholipid antibodies (aPL) were identified by anticardiolipin enzyme-linked immunosorbent assay (ELISA), lupus anticoagulant assays, and syphilis screening in children with primary APS, systemic lupus erythematosus (SLE), or SLE plus APS. Anti-beta2GPI level and isotype were determined by beta2GPI ELISA and correlated with clinical manifestations and other aPL assays. RESULTS: One hundred-ten subjects under 22 years of age and of mixed ethnicity were evaluated. Fifty-seven had SLE (including 14 with APS), 25 had primary APS, 16 had SLE-like APS, 6 were healthy children with aPL detected incidentally, 4 had other rheumatic diseases and 2 had other conditions. Anti-beta2GPI were detected in 48% of SLE subjects and did not improve aPL detection over standard tests. Anti-beta2GPI were associated with stroke (P = 0.014), but not with other APS manifestations, and were rarely detected in primary APS. Among subjects with APS manifesting as chronic thrombocytopenia, anti-beta(2)GPI distinguished subjects with SLE from those with primary APS. CONCLUSIONS: With the exception of stroke, anti-beta2GPI detection does not improve identification of pediatric APS over that of traditional aPL assays. Anti-beta2GPI are rare in pediatric primary APS, but may predict evolution of chronic thrombocytopenia to SLE.

Persistence of vaccine-derived polioviruses among immunodeficient persons with vaccine-associated paralytic poliomyelitis.

To estimate long-term poliovaccine virus persistence among immunodeficient patients with vaccine-associated paralytic poliomyelitis (iVAPP), cases reported in the United States during 1975-1997 were reviewed, with subsequent follow-up and virological testing. Six (16.2%) of 37 subjects excreted poliovaccine viruses for > or =6 months. Partial genomic sequencing of their available poliovirus isolates showed considerable divergence from the prototype Sabin strain in all cases. Poliovirus persistence declined over time since the last oral poliovaccine dose: at 6 months, 19.4%; 1 year, 14.3%; 5 years, 4%; and 10 years, 0% (P<.05) of patients. Despite the high prevalence of poliovaccine virus persistence among patients with iVAPP, this group appears to be an unlikely source of poliovirus reintroduction in developed countries because of the rarity and high fatality rate of iVAPP and the possible spontaneous clearance of polioviruses. These results are important for developing "endgame" strategies for the Global Poliomyelitis Eradication Program.