Ataxia Telangiectasia Diagnosed on Newborn Screening-Case Cohort of 5 Years' Experience.

Ataxia telangiectasia (AT) is a genetic condition caused by mutations involving ATM (Ataxia Telangiectasia Mutated). This gene is responsible for the expression of a DNA double stranded break repair kinase, the ATM protein kinase. The syndrome encompasses combined immunodeficiency and various degrees of neurological abnormalities and increased risk of malignancy. Typically, patients present early in life with delay in neurological milestones, but very infrequently, with life threatening infections typical of a profound T cell deficiency. It would therefore be unexpected to identify this condition immediately after birth using T cell receptor excision circle (TREC)-based newborn screening (NBS) for SCID. We sought to evaluate the frequency of AT detected by NBS, and to assess immunity as well as the genetic aberrations associated with this early presentation. Here, we describe the clinical, laboratory, and genetic features of patients diagnosed with AT through the Ontario NBS program for SCID, and followed in our center since its inception in 2013. Four patients were diagnosed with AT as a result of low TRECs on NBS. In each case, whole exome sequencing was diagnostic. All of our patients had compound heterozygous mutations involving the FRAP-ATM-TRRAP (FAT) domain of the ATM gene, which appears critical for kinase activity and is highly sensitive to mutagenesis. Our patients presented with profound lymphopenia involving both B and T cells. The ratio of naïve/memory CD45+RA/RO T cells population was variable. T cell repertoire showed decreased T cell diversity. Two out of four patients had decreased specific antibody response to vaccination and hypogammaglobulinemia requiring IVIG replacement. In two patients, profound decreased responses to phytohemagglutinin stimulation was observed. In the other two patients, the initial robust response declined with time. In summary, the rate of detection of AT through NBS had been surprisingly high at our center. One case was identified per year, while the total rate for SCID has been five new cases per year. This early detection may allow for better prospective evaluation of AT shortly after birth, and may assist in formulating early and more effective interventions both for the neurological as well as the immune abnormalities in this syndrome.

Primary Immune Deficiencies in the Adult: A Previously Underrecognized Common Condition.

The large majority of classified primary immune deficiency (PID) diseases present in childhood. Yet, most patients with PID are adults, with a large proportion experiencing onset of symptoms beyond their childhood years. Most of these are diagnosed predominantly with antibody defects, but cellular and other disorders are increasingly being identified in older patients as well. Moreover, advances in clinical immunology are allowing pediatric patients, even those with severe disease, to reach adulthood. Because of differences in the physiology and pathophysiology of children and adults, the presentation, diagnosis, and management of a complex chronic disease could differ significantly between these patient populations and therefore require modifications in approach.

Glucocorticoid-related changes in body mass index among children and adolescents with rheumatic diseases.

OBJECTIVE: To examine the temporal and dose-related effects of glucocorticoids (GCs) on body mass index (BMI) in children with rheumatic diseases. METHODS: Children initiating GCs for a rheumatic disease (n = 130) were assessed every 3 months for 18 months. BMI, weight, and height Z score trajectories were described according to GC starting dosage in prednisone equivalents: high (≥1.0 mg/kg/day), low (<0.2 mg/kg/day to a maximum of 7.5 mg/day), and moderate (between high and low) dosage. The impact of GC dosing, underlying diagnosis, pubertal status, physical activity, and disease activity on BMI Z scores and on percent body fat was assessed with longitudinal mixed-effects growth curve models. RESULTS: The GC starting dose was high in 59% and moderate in 39% of patients. The peak BMI Z score was +1.29 at 4 months with high-dose GCs and +0.69 at 4.2 months with moderate-dose GCs (P < 0.001). Overall, 50% (95% confidence interval 41-59%) of the children returned to within +0.25 SD of their baseline BMI Z score. Oral GC dose over the preceding 3 months was the most significant determinant of BMI Z score and percent body fat. The proportion of days in receipt of GCs, disease activity, and a diagnosis of systemic-onset juvenile idiopathic arthritis were also associated with BMI Z scores. The correlation between changes in BMI and changes in percent body fat was 0.09. CONCLUSION: In children with rheumatic diseases starting moderate and high doses of GCs, BMI Z scores peaked at 4 months, and only half returned to within +0.25 SD of their baseline BMI Z score after 18 months.

Access to biologic therapies in Canada for children with juvenile idiopathic arthritis.

OBJECTIVE: To compare access to biologic therapies for children with juvenile idiopathic arthritis (JIA) across Canada, and to identify differences in provincial regulations and criteria for access. METHODS: Between June and August 2010, we compiled the provincial guidelines for reimbursement of biologic drugs for children with JIA and conducted a multicenter Canada-wide survey of pediatric rheumatologists to determine their experience with accessing biologic therapies for their patients. RESULTS: There were significant difficulties accessing biologic treatments other than etanercept and abatacept for children. There were large discrepancies in the access criteria and coverage of biologic agents across provinces, notably with age restrictions for younger children. CONCLUSION: Canadian children with JIA may not receive optimal internationally recognized "standard" care because pediatric coverage for biologic drugs through provincial formularies is limited and inconsistent across the country. There is urgent need for public policy to improve access to biologic therapies for these children to ensure optimal short-term and longterm health outcomes.

Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study.

OBJECTIVE: To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk. METHODS: Children with rheumatic diseases initiating GC were enrolled in a prospective observational study. Annual spine radiographs were evaluated using the Genant semiquantitative method. Spine areal bone mineral density (aBMD) was measured every 6 months. Clinical features, including cumulative GC dose, back pain, disease and physical activity, calcium and vitamin D intake, and spine aBMD Z scores, were analyzed for association with IVF. RESULTS: Seven (6%) of 118 children (95% confidence interval 2.9-11.7%) had IVF. Their diagnoses were: juvenile dermatomyositis (n = 2), systemic lupus erythematosus (n = 3), systemic vasculitis (n = 1), and mixed connective tissue disease (n = 1). One child was omitted from the analyses after 4 months because of osteoporosis treatment for symptomatic IVF. Children with IVF received on average 50% more GC than those without (P = 0.030), had a greater increase in body mass index (BMI) at 6 months (P = 0.010), and had greater decrements in spine aBMD Z scores in the first 6 months (P = 0.048). Four (67%) of 6 children with IVF and data to 12 months had spine aBMD Z scores less than -2.0 at 12 months compared to 16% of children without IVF (P = 0.011). CONCLUSION: The incidence of VF 12 months following GC initiation was 6%; most children were asymptomatic. Children with IVF received more GC, had greater increases in BMI, and had greater declines in spine aBMD Z scores in the first 6 months.

Displacement of the temporomandibular joint disk: correlation between clinical findings and MRI characteristics.

BACKGROUND AND OBJECTIVE: Disk displacement frequently causes dysfunction of the temporomandibular joint (TMJ). Magnetic resonance imaging (MRI) of the TMJ is 95% accurate in the assessment of disk position and form. Various restorative procedures are used for treatment of disk displacement. However, several authors have noted a lack of correlation between MRI findings of disk displacement and the extent of pain and dysfunction of the TMJ. The purpose of this study was to evaluate whether MRI findings of various degrees of disk displacement could be correlated with the presence of clinical signs and symptoms in patients with a clinical disorder of the TMJ. MATERIALS AND METHODS: One hundred and forty-four TMJs (in 72 patients) were imaged. Displacement of the posterior band in relation to the condyle was quantified as mild or significant. RESULTS: Disk displacement was found in 45 (54%) of the 84 symptomatic joints and 13 (22%) of the 60 asymptomatic joints. Among the 84 symptomatic joints, 31 (37%) had disk displacement with reduction and 14 (17%) had disk displacement without reduction. In the latter group, 11 (79%) of the 14 joints had significant displacement of the posterior band (8 or 9 o'clock) and 21% had mild displacement of the posterior band (10 o'clock). Of the 60 clinically asymptomatic joints, 47 (78%) had no signs of disk displacement on MRI, whereas 13 (22%) had disk displacement with reduction. None of the asymptomatic joints had disk displacement without reduction. The difference in occurrence of disk displacement between symptomatic and asymptomatic joints was statistically significant (54% vs. 22%; p < 0.001). However, the difference in occurrence of disk displacement with reduction of the disk on mouth opening was not statistically significant (37% vs. 22%; p = 0.06). CONCLUSIONS: Disk displacement on MRI correlated well with clinical symptoms in cases of significant disk displacement and in cases of disk displacement without reduction. When disk displacement with reduction was mild, there was no statistically significant difference between symptomatic and asymptomatic joints, which suggests that other causes should be considered.

A multicenter case-control study on predictive factors distinguishing childhood leukemia from juvenile rheumatoid arthritis.

OBJECTIVE: Acute lymphocytic leukemia (ALL) often presents with musculoskeletal concerns such as pain or swelling, even before appearance of blasts in the peripheral blood. Such presentation may lead to misdiagnosis of a child with juvenile rheumatoid arthritis (JRA). This study was designed to identify the predictive factors for leukemia using basic clinical and laboratory information. METHODS: A retrospective chart review was performed using a simple questionnaire to compare the clinical and laboratory findings present during the initial visit to a pediatric rheumatology clinic for 277 children who were ultimately diagnosed with either JRA (n = 206) or ALL (n = 71). Sensitivity and specificity analysis of a variety of parameters, both singly and in combination, was performed to identify predictive value for ALL. RESULTS: The majority (75%) of children with ALL did not have blasts in the peripheral blood at the time of evaluation by pediatric rheumatologists. In children presenting with unexplained musculoskeletal complaints, the 3 most important factors that predicted a diagnosis of ALL were low white blood cell count (< 4 x 10(9)/L), low-normal platelet count (150-250 x 10(9)/L), and history of nighttime pain. In the presence of all 3, the sensitivity and specificity for a diagnosis of ALL were 100% and 85%, respectively. Other findings, including antinuclear antibody, rash, and objective signs of arthritis, were not helpful in differentiating between these diagnoses because they occurred at similar rates in both groups. CONCLUSIONS: When a child develops new-onset bone-joint complaints, the presence of subtle complete blood count changes combined with nighttime pain should lead to consideration of leukemia as the underlying cause.

De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases.

OBJECTIVE: Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome. METHODS: Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells. RESULTS: In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1beta, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor beta, in a mutation-positive patient compared with normal controls. CONCLUSION: Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in approximately 50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.

A survey of current prescribing practices in juvenile rheumatoid arthritis among pediatric rheumatologists in North America

Objetivo: Descrever as tendências atuais de prescriçao dos reumatologistas pediátricos da América do Norte no tratamento da artrite reumatóide juvenil (ARJ). Desenho do estudo: Estudo transversal utilizando-se questionários enviados pelo correio. Participantes: Duzentos e dezesseis questionários foram postados com 82 por cento de taxa de resposta. Das 177 respostas somente 130 reumatologistas pediátricos satisfizeram o critério de inclusao. Métodos: Quatro postagens foram realizadas num período de oito semanas. Resultados: Oitenta e um (63 por cento) reumatologistas pediátricos escolheram naproxen como droga inicial para o tratamento da ARJ pauciarticular e 77 (59 por cento) para o tratamento da ARJ de início poliarticular. Para a forma sistêmica, tando os salicilatos como o naproxen foram as preferidas como drogas de início para o controle dos sintomas articulares, enquanto o salicilato foi a droga de escolha de 43 reumatologistas para controlar sintomas sistêmicos. Para a ARJ pauciarticular, o tolmetin foi referido por 50 (38 por cento) reumatologistas como droga subseqüente a ser utilizada se a droga inicial nao apresentar sucesso. Para a forma poliarticular da ARJ, tolmetin, naproxen e indometacina foram referidas como drogas alternativas. Para controlar os sintomas articulares da ARJ de início sistêmico, tolmetin foi escolhido por 32 (24,6 por cento) dos reumatologistas como medicaçao subseqüente, enquanto a prednisona foi escolhida por 38 (29 por cento) reumatologistas para o controle da atividade sistêmica. Os derivados do ácido salicílico foram considerados por 42 (32 por cento) dos reumatologistas como sendo a droga mais efetiva no tratamento da ARJ pauciarticular. Para a ARJ poliarticular, o metotrexato foi a droga de escolha. Os sintomas articulares e sistêmicos da ARJ sistêmico foram referidos como sendo efetivamente controlados pelo prednisona. Conclusao: Naproxen foi escolhido como a droga inicial no tratamento da ARJ pauci e poliarticular. Os salicilatos, metotrexato e prednisona foram as drogas consideradas mais efetivas pelos reumatologistas pediátricos no tratamento das formas pauci, poli e sistêmica da ARJ. Estudos adicionais que priorizem a avaliaçao destas drogas devem ser realizados