Reem Abdwani

Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.

Access to Pediatric Rheumatology Subspecialty Care in British Columbia, Canada

Objective. Early recognition and treatment of pediatric rheumatic diseases is associated with improved outcome. We documented access to pediatric rheumatology subspecialty care for children in British Columbia (BC), Canada, referred to the pediatric rheumatology clinic at BC Children’s Hospital, Vancouver. Methods. An audit of new patients attending the outpatient clinic from May 2006 to February 2007 was conducted. Parents completed a questionnaire through a guided interview at the initial clinic assessment. Referral dates were obtained from the referral letters. Patients were classified as having rheumatic disease, nonrheumatic disease, or a pain syndrome based on final diagnosis by a pediatric rheumatologist. Results. Data were collected from 124 of 203 eligible new patients. Before pediatric rheumatology assessment, a median of 3 healthcare providers were seen (range 1–11) for a median of 5 visits (range 1–39). Overall, the median time interval from symptom onset to pediatric rheumatology assessment was 268 days (range 13–4989), and the median time interval from symptom onset to referral to pediatric rheumatology was 179 days (range 3–4970). Among patients ultimately diagnosed with rheumatic diseases (n = 53), there was a median of 119 days (range 3–4970) from symptom onset to referral, and 169 days (range 31–4989) from onset to pediatric rheumatology assessment. Conclusion. Children and adolescents with rheumatic complaints see multiple care providers for multiple visits before referral to pediatric rheumatology, and there is often a long interval between symptom onset and this referral.

Refractory relapsing polychondritis in a child treated with antiCD20 monoclonal antibody (rituximab): First case report

To report the first case of refractory relapsing polychondritis in a child who was treated with the biological agent, rituximab, an antiCD20 monoclonal antibody. The case is reported with a review of the literature on the use of biological agents in the treatment of refractory relapsing polychondritis. A 10-year-old boy presented with relapsing polychondritis who was treated initially with prednisolone and methotrexate. As there was no response to the treatment, anti TNF antagonist infliximab was given but with a failed response. A subsequent therapy with rituximab produced significant clinical remission with no recurrence at 1 year. Relapsing polychondritis unresponsive to primary treatment modalities but treated with various biological agents in adult have been well described in adults but not reported in children age below 13 yrs. Hence we present this case report. Biological agents such as rituximab has promising role in children when primary treatment fails as reported in our case.

Infantile Systemic Hyalinosis: A Case Report with a Novel Mutation

Infantile Systemic Hyalinosis (ISH) (OMIM 236490) is a rare, progressive and fatal autosomal recessive disorder characterized by multiple subcutaneous skin nodules, gingival hypertrophy, osteopenia, joint contractures, failure to thrive, diarrhea with protein losing enteropathy, and frequent infections. There is diffuse deposition of hyaline material in the skin, gastrointestinal tract, muscle and endocrine glands. It is caused by mutations in the ANTXR2 (also known as CMG2) gene, which encodes a trans-membranous protein involved in endothelial development and basement membrane-extracellular matrix assembly. We describe a child with classical features of ISH presenting in infancy with severe chronic debilitating pain and progressive joint contractures. The diagnosis was confirmed by molecular DNA sequencing of ANTXR2 gene which revealed a novel homozygous mutation not previously reported; 79 bp deletion of the entire exon 11 (c.867_945del, p.E289DfsX22). Although this is the first reported case of ISH in Oman, we believe that the disease is under-diagnosed since children affected with this lethal disease pass away early in infancy prior to establishing a final diagnosis.

Extent of Subclinical Pulmonary Involvement in Childhood Onset Systemic Lupus Erythematosus in the Sultanate of Oman

OBJECTIVES The aim of this study was to investigate the frequency of pulmonary function abnormalities in clinically asymptomatic children with Systemic Lupus Erythematosus and to determine the relationship of these abnormalities to clinical, laboratory, and immunological parameters as well as to disease activity. METHODS Forty-two children with childhood onset Systemic Lupus Erythematosus were included in this study. Demographic, clinical, laboratory and immunological parameters, as well as disease activity were assessed. Pulmonary function tests (PFT) were performed routinely to screen for subclinical lung disease. RESULTS Out of the 42 children, 19% (n=8) had clinical evidence of pulmonary involvement. The patients with no clinical evidence of pulmonary involvement (n=34) represent the study cohort. From our cohort of patients with no clinical evidence of pulmonary involvement 79% (n=27) had PFT abnormality; including 62% (n=21) had reduced FVC, 71% (n=24) had reduced FEV1, and 67% (n=12) had reduced DLCO. Similarly, 56% (n=15) had a restrictive PFT pattern, and 2.6% (n=2) had an obstructive PFT pattern, while 33% (n=7) had an isolated impairment of diffusion capacity. Due to small sample size; it was not possible to find a statistically significant difference between the cohort of asymptomatic SLE patients with abnormal PFT findings (n=27) and those with normal PFT findings (n=7) in terms of clinical, laboratory, immunological or disease activity index score. CONCLUSION Subclinical lung disease, as demonstrated by abnormal PFT in patients with normal radiographs, may be common but should be interpreted with caution as an early sign of lung disease. Although PFT studies do not correlate well with pulmonary symptoms in patients with childhood onset SLE, they nevertheless provide objective quantification of the type and severity of the functional lesions.

Bone mineral density in juvenile onset Systemic lupus erythematosus

ObjectiveTo compare bone mineral density in patients with juvenile-onset Systemic lupus erythematosus and healthy controls.ParticipantsSerial bone mineral density measurements in 27 patients with juvenile-onset systemic lupus were compared to 97 healthy age-matched controls.ResultsAll patients with juvenile-onset had low bone mineral density scores at initial assessment that progressed over disease course. Low body mass index was independently associated with a decline in bone mineral density Z scores; disease activity, use of immunosuppressive agents and vitamin D levels were not risk factors.ConclusionPatients with juvenile-onset systemic lupus erythematosus have low bone mineral density.

Geographical Clustering of Juvenile Onset Systemic Lupus Erythematosus within the Sultanate of Oman

OBJECTIVE While SLE is found worldwide, there is diversity in clinical presentation of the disease according to geographical variations. The aim of this study is to describe geographical distributions of childhood onset SLE within Oman to identify geographical clustering and to compare the demographic, clinical, and immunological characteristics of this cluster against the rest of Oman. METHODS We retrospectively reviewed the hospital charts of 104 consecutive children with childhood onset SLE who were seen in pediatric rheumatology centers in the Sultanate of Oman over a 15-year period between 1995 and 2010. RESULTS Geographical clustering of childhood onset SLE was identified in Sharqiya region, which constituted 41% (n=43) of all cases in Oman. This cohort of patients had characteristic disease features which consisted of significantly more boys affected with SLE compared to the rest of the country (42% versus 15%; p=0.002). These children also tended to be younger (10.3 versus 16.5 years; p=0.001), diagnosed at an earlier age (6.4 versus 9.4 years; p<0.001) with a stronger family history of SLE (58% versus 33%; p=0.010). These children also had increased incidence of mucocutanous changes (81% versus 62%; p=0.036) and decreased hematological abnormalities (30% versus 51%; p=0.036). CONCLUSION We identified geographical clustering of childhood onset SLE to Sharqiya region in Oman which is associated with unique demographical and clinical features. Whether increased prevalence of disease in this region is due to geographical, environmental, ethnic or genetic factors is yet to be determined. However, it is likely to be interplay of known and other unrecognized factors.

TNFRSF1A Gene Causing Tumor Necrosis Factor Receptor-associated Periodic Syndrome in 2 Siblings Displaying Variable Disease Severity and Discordant Heterozygosity for an MEFV E148Q Variant

To the Editor: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant periodic fever syndrome with pan-ethnic distribution caused by mutations in TNFRSF1A 1. To date, over 100 mutations have been described. Among whites, the R92Q mutation is the most frequently observed variant of the TNFRSF1A gene. R92Q is a missense low-penetrance gene mutation that is associated with a mild severity, high rate of spontaneous amelioration, and lower prevalence of amyloidosis compared with structural gene mutation variants2. Despite its relatively high prevalence in the general population, ranging from 1.2% to 4%, only 1 clinically ascertained patient has been described with homozygous R92Q variant3. We hereby describe 2 Omani sisters with TRAPS caused by homozygous R92Q variants in TNFRSF1A . One of the siblings also had associated E148Q variant in the MEFV gene. They both displayed severe phenotype with evident clinical variability. A 12-year-old girl presented at 18 months of age with frequent episodes of high-grade fever lasting between 5 to 14 days occurring … Address correspondence to Dr. R. Abdwani, Child Health Department, Sultan Qaboos University Hospital, P.O. Box 35, P C 123, Al Khod, Sultanate of Oman. E-mail: reemabd{at}hotmail.com

Neonatal and obstetrical outcomes of pregnancies in systemic lupus erythematosus

Objectives Systemic lupus erythematous (SLE) is a chronic autoimmune disease that affects women primarily of childbearing age. The objective of this study was to determine the neonatal and maternal outcomes of pregnancies in SLE patients compared to pregnancies in healthy controls. Methods We conducted a retrospective cohort study in a tertiary care hospital in Oman between January 2007 and December 2013. We analyzed 147 pregnancies and compared 56 (38.0%) pregnancies in women with SLE with 91 (61.9%) pregnancies in healthy control women. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results The mean age of the cohort was 30.0±5.0 years ranging from 19 to 44 years old. Patients with SLE were treated with hydroxychloroquine (n = 41; 73.2%), prednisolone (n = 38; 67.8%), and azathioprine (n = 17; 30.3%). There was no disease activity in 39.2% (n = 22) of patients while 41.0% (n = 23), 12.5% (n = 7), and 7.1% (n = 4) had mild (SLEDAI 1-5), moderate (SLEDAI 6-10), and severe (SLEDAI 3 11) disease activity, respectively, at onset of pregnancy. Pregnancies in patients with SLE were associated with higher abortions (42.8% vs. 15.3%; p < 0.001), gestational diabetes (28.3% vs. 10.2%; p = 0.004), polyhydramnios (7.1% vs. 0.0%; p = 0.020), previous preterm pregnancies (8.9% vs. 1.0%; p = 0.030), and intrauterine growth retardation (21.4% vs. 0.0%; p < 0.001) when compared to pregnancies in healthy control women. Furthermore, the neonates born to mothers with SLE were more likely to be preterm (28.5% vs. 1.0%; p < 0.001), have a low birth weight (< 2 500 g) (32.1% vs. 1.0%; p < 0.001), and were associated with stillbirth (7.1% vs. 0.0%; p = 0.010) when compared to neonates born to healthy control mothers. Conclusions Pregnancies in women with SLE were associated with higher neonatal and maternal complications. Therefore, pregnant women with SLE should have their pregnancy accurately planned, monitored, and managed according to a multidisciplinary treatment schedule.

Rituximab Treatment in Myasthaenia Gravis: Report of two paediatric cases

Myasthaenia gravis (MG) is an auto-immune disease involving the postsynaptic receptors in the neuromuscular junction. The condition is characterised by fatigable weakness of the skeletal muscles and is uncommon in children. Acetylcholinesterase inhibitors and immune-modifying medications are usually considered the mainstay of treatment. However, these medications have to be given on a lifelong basis so that patients remain in remission; furthermore, drug-related side-effects can have a major impact on quality of life. We report two paediatric cases who were treated for MG at the Sultan Qaboos University Hospital, Muscat, Oman, in 2007 and 2008, respectively. Rituximab was eventually administered to each patient after their condition failed to improve despite several years of standard treatment with acetylcholinesterase inhibitors and immune-modifying medications. Overall, rituximab resulted in complete remission in one case and significant clinical improvement in the other case.