The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist
ARTHRITIS AND RHEUMATISM
2011; 63 (12): 4018-4022
Bilateral Basal Ganglia Infarctions in a Neonate Born During Maternal Diabetic Ketoacidosis
2011; 128 (3): E707-E710
Interleukin-1 receptor antagonist (IL-1Ra) deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. We report the case of a 2-week-old male who presented with a swollen, erythematous left index finger and elevated serum markers of inflammation. He later developed cyclical fevers, diffuse pustular skin lesions, and thrombus formation. After not responding to broad-spectrum antimicrobial therapy and achieving only moderate success with systemic steroid therapy, he was ultimately treated with recombinant IL-1Ra, anakinra, and experienced significant clinical improvement. Sequencing of his IL1RN gene revealed that the patient was compound heterozygous for a known mutation (E77X) associated with IL-1Ra deficiency and a novel mutation in exon 2 of the gene (c.140delC; p.T47TfsX4). His case highlights IL-1Ra deficiency as an autoinflammatory disease that is distinct from neonatal-onset multisystem inflammatory disease but that also responds well to anakinra. Our patient is the first reported compound heterozygote for E77X and the novel mutation in exon 2 of the gene, the latter of which adds to what will surely be a growing database of pathologic mutations in IL1RN.
View details for DOI 10.1002/art.30565
View details for Web of Science ID 000297458500044
View details for PubMedID 21792839
Role of Small Bowel Follow-through in Diagnosing Inflammation of the Terminal Ileum in Pediatric Patients
JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION
2010; 51 (4): 433-436
Diabetic ketoacidosis (DKA) during pregnancy carries significant risk of intrauterine fetal demise, but little is known about its postnatal sequelae in surviving neonates. We report here the case of an infant who was born to a mother with White's class C diabetes mellitus during an episode of DKA. Throughout pregnancy her glucose control was suboptimal, as evidenced by a predelivery glycosylated hemoglobin level of 8.1%. At 33 weeks' gestation, the mother presented with nausea and vomiting, a serum glucose concentration of 575 mg/dL, and other metabolic derangements consistent with DKA. Despite rehydration and insulin therapy, fetal distress necessitated cesarean delivery. At birth the infant required intubation, but her clinical status quickly improved and she was extubated within the first day of life. However, on day-of-life 4 she exhibited seizure-like activity, and subsequent brain MRI revealed bilateral basal ganglia infarctions. Previous research has revealed that the keto acid ?-hydroxybutyrate (?-OHB) can cross the placenta into the fetal circulation and thereafter accumulate in the fetal brain, which leads to severe metabolic derangements. Furthermore, ?-OHB accumulates rapidly in the basal ganglia of older children during episodes of DKA, wherein its presence is associated with neuronal injury. We suspect that transplacental transfer of maternal ?-OHB led to an acquired ketoacidosis in the fetus and that accumulation of ?-OHB contributed to neuronal injury and subsequent infarction of the basal ganglia. Further research is necessary to better characterize neonatal complications of maternal DKA, as well as the possible inclusion of ?-OHB levels in the goal-directed treatment of this disease.
View details for DOI 10.1542/peds.2010-3597
View details for Web of Science ID 000295406100030
View details for PubMedID 21807693
The role of X-linked FOXP3 in the autoimmune susceptibility of Turner Syndrome patients
2009; 131 (1): 139-144
The small bowel follow-through (SBFT) is a noninvasive imaging modality for evaluating terminal ileum (TI) inflammation. The accuracy of this modality in pediatric patients is not well established.We retrospectively determined the sensitivity and specificity of SBFT for detecting TI inflammation diagnosed on histology in 93 pediatric patients studied in a single institution.The mean age at the first study was 12.9 years (range 1.1-20.9 years). Forty-five percent were girls. Twenty-five patients (27%) had abnormal TIs on SBFT. Seventeen patients (18%) had TI inflammation diagnosed by biopsy. The sensitivity of SBFT was 59% and the specificity was 80% for detecting TI inflammation diagnosed on histology. Sensitivity and specificity did not change by demographic factors, final diagnoses, presenting symptoms, or laboratory parameters, reflecting the presence of intestinal inflammation.The sensitivity and specificity of SBFT in pediatric patients were poor and did not vary with demographic factors, final diagnoses, presenting symptoms, or laboratory parameters. Prospective longitudinal studies comparing various imaging modalities (SBFT, magnetic resonance enterography, and capsule endoscopy) are required to determine which is the most effective tool for evaluating pediatric patients for TI inflammation.
View details for DOI 10.1097/MPG.0b013e3181d67ea7
View details for Web of Science ID 000282123600009
View details for PubMedID 20562720
A robust immunoassay for anti-interferon autoantibodies that is highly specific for patients with autoimmune polyglandular syndrome type 1
2007; 125 (2): 131-137
Turner Syndrome patients have an absent second sex chromosome and a predisposition to autoimmune disease. We hypothesized that the autoimmune susceptibility in Turner Syndrome may be due to an alteration in the expression of the X-linked FOXP3 gene. FOXP3 is important in the development of regulatory T cells, and complete loss of FOXP3 expression has been shown to result in severe autoimmunity. To test this hypothesis, we characterized the regulatory T cells and performed immunophenotyping on the peripheral blood leukocytes of a cohort of Turner Syndrome patients. These patients retained regulatory T cell frequency and function despite an increased prevalence of autoimmunity. Immunophenotyping revealed a decrease in the ratio of CD4 to CD8 lymphocytes. These findings suggest that the autoimmune predisposition in Turner Syndrome is not due to alterations in regulatory T cells but may be associated with a change in the proportion of T cell subsets.
View details for DOI 10.1016/j.clim.2008.11.007
View details for Web of Science ID 000264835000015
View details for PubMedID 19150256
High titer antibodies to type 1 interferons have been recently reported as being highly specific for patients with autoimmune polyglandular syndrome type 1 (APS1) in Finnish and Norwegian patients with mutations in the AIRE gene. Those studies employed a complex neutralization assay to define the type 1 interferon autoantibodies. Here we have established a competitive europium time resolved fluorescence assay for IFN-alpha autoantibodies and measured sera from subjects with APS1, first degree relatives of APS1 patients, patients with Addison's disease or Type 1 diabetes. The europium-based immunoassay utilizes plate bound human IFN-alpha incubated with sera with or without competition with fluid phase IFN-alpha, followed by anti-IgG biotinylated antibody and detection with streptavidin-europium. The index of IFN-alpha Ab was calculated as (CPS (Counts per second) without competition-CPS with competition)/(CPS positive standard sera without competition-CPS positive standard sera with competition). Results are reported for raw CPS and indices and are compared across the different subjects. Results: For normal controls (n=100) CPS without competition were 31,237+/-17,328 CPS while after subtracting the competition value, the results were -6563+/-10,303 CPS. The initial APS1 patient (used to create the index as 1.0) gave 394,063 CPS without competition and a delta of 363,662+/-31,587 CPS with competition. Scatchard plot analysis of this patient sample revealed a high avidity for IFN-alpha (K(d) of 0.5 nM). The CPS, delta, and index for 6/7 APS1 patients were strongly positive and 3 standard deviations or more above that of the normal controls. Using a cut-off of 2 standard deviations above normal controls, relatives of APS1 patients were negative for type I interferon autoantibodies as were 71 patients with Addison's disease (non-APS1) and 141 Type 1 diabetes patients. This simple high throughput competitive europium time resolved fluorescence assay had a sensitivity of > or =86% or greater and a specificity of >99.5%.
View details for DOI 10.1016/j.clim.2007.07.015
View details for Web of Science ID 000250466900004
View details for PubMedID 17825626