X-Linked Lymphoproliferative Syndrome: A Spectrum of Clinical and Immunological Profile and Novel Pathogenic Variants from Chandigarh, India.

INTRODUCTION: X-linked lymphoproliferative syndrome (XLP) is a rare primary immune deficiency. Two types of XLP have been described: XLP-1 and XLP-2. METHODS: We found 7 patients with XLP (3 had XLP-1 and 4 had XLP-2) after reviewing the data from Pediatric Immunodeficiency Clinic from 1997 to 2021. RESULTS: Mean age at diagnosis was 3.8 years, and mean delay in diagnosis was 2.6 years. Five patients had recurrent episodes of infections. Four patients developed at least one episode of hemophagocytic lymphohistiocytosis (HLH) (2 with XLP-1 and 2 with XLP-2). Of these, 2 had recurrent HLH (both with XLP-2). Epstein-Barr virus (EBV) infection was detected in 2 (1 with XLP-1 and 1 with XLP-2). Both these patients had HLH. One child with XLP-2 had inflammatory bowel disease. Hypogammaglobulinemia was seen in 3 (2 with XLP-1 and 1 with XLP-2). Genetic analysis showed previously reported variants in 5, while 2 had novel variants (one in exon 7 of XIAP gene [c.1370dup p.Asn457Lysfs Ter16] and other had splice site variant in intron 1 of SH2D1A gene [c.138-2_138-1insG]). Episodes of HLH were managed with intravenous immunoglobulin (IVIg), methylprednisolone, oral prednisolone, cyclosporine, and rituximab. Inflammatory bowel disease was managed using oral prednisolone and azathioprine. One patient underwent haploidentical hematopoietic stem cell transplantation. One child with XLP-2 and WAS died because of fulminant pneumonia. DISCUSSION/CONCLUSIONS: XLP should be considered as a strong possibility in any patient with features of HLH, repeated infections with hypogammaglobulinemia, persistent EBV infection, and early-onset IBD.

Idiopathic intracranial hypertension as the initial presenting manifestation of systemic lupus erythematosus in a child.

Idiopathic intracranial hypertension (IIH) is a diagnosis of exclusion characterized by features of raised intracranial pressure (ICP) in the absence of brain parenchymal lesion, vascular malformations, hydrocephalus, or central nervous system (CNS) infection. Commonly used other terms for this entity include benign intracranial hypertension (BIH) or pseudotumor cerebri. Few case reports of systemic lupus erythematosus (SLE) presenting as IIH are available in the literature. We report a 12-year-old girl presented with chronic holocranial headache and occasional episodes of projectile vomiting for the last 6 months and then developed blurring of vision for the last month. She fulfilled the criteria for IIH. Subsequent evaluation revealed a diagnosis of SLE. The occurrence of IIH in SLE is not coincidental and is reported in 1%-5.4% of patients with SLE. Though corticosteroids have not been widely used in IIH, underlying SLE warranted administering corticosteroids with subsequent complete resolution of IIH. Pediatricians, neurologists, intensivists, and ophthalmologists should consider SLE as a differential diagnosis in children presenting with IIH.

Juvenile localized scleroderma: A single-centre experience from India.

BACKGROUND: Juvenile localized scleroderma (JLS) or morphoea, a rare chronic autoimmune disease predominantly affects skin, subcutaneous tissue and occasionally the adjacent muscle, fascia and bone. We report the largest single-centre cohort of patients with JLS from India. METHODS: Patients who were diagnosed to have JLS were enrolled from the Paediatric Dermatology Clinic and the Paediatric Rheumatology Clinic of a tertiary care referral hospital in India. Collected data included details of the clinical profile, laboratory investigations and management. RESULTS: We analysed 84 patients with Juvenile localized scleroderma. Median age of disease onset was 5 years, and median age at diagnosis was 8 years. Commonest subtype was linear scleroderma (57 patients, 67.7%) followed by plaque morphoea and generalized morphoea. Fourteen patients (16.6%) were noted to have extracutaneous manifestations (ECMs). These included arthritis in eight (33.3%), brain parenchymal abnormalities in four (4.7%) and pulmonary involvement in two (8.3%) patients. Antinuclear antibody (ANA) was positive in eight/25 patients (32%; diffuse and speckled pattern in four patients each). One amongst these also had elevated anti-dsDNA titres. Positive ANA was found to have no association with ECMs (p 1.000). Patients were treated using methotrexate (61 patients; 72.6%), dexamethasone oral mini-pulse (OMP; 35 patients; 41.6%), calcipotriol (39 patients; 46.4%), topical corticosteroids (32 patients; 38%) and topical tacrolimus (three patients; 3.7%). Using linear regression analysis, administration of dexamethasone OMP and calcipotriol was found to be a predictor of good treatment response (p 0.034 and 0.019, respectively). CONCLUSION: Early use of systemic corticosteroids along with methotrexate may be more beneficial than methotrexate therapy alone.

Portal vein thrombosis, livedo reticularis, polymicrobial sepsis and high antiphospholipid antibody titers in a newborn: A clinicopathological conference of antiphospholipid-associated neonatal syndrome.

Neonatal Antiphospholipid syndrome (APS) is a rare disease related to transplacental passage of antiphospholipid (aPL) antibodies from the mother or de novo production of aPL in a newborn. Neonatal aPL antibodies have rarely been associated with thrombosis. We describe a 5-week-old infant who developed fever, portal vein thrombosis and livedo reticularis like skin rash. Evaluation for thrombosis revealed high titers of antiphospholipid (aPL) antibodies (dual positive) in the child without any evidence of aPL antibodies in the mother, suggesting a de novo production in the child. Autopsy findings revealed umbilical vein sepsis with thrombosis of portal vein secondary to gram positive cocci which led to multiple liver and lung abscesses. Additionally, the baby had disseminated Cytomegalovirus (CMV) disease (acquired postnatally) involving walls of umbilical and portal vein, liver, lungs, adrenals, pancreas, thymus, and kidneys. Our case highlights the need for testing of aPL in every neonate with arterial or venous thrombosis even when the mother may have no features suggestive of an autoimmune disease.

Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. The International League of Associations for Rheumatology (ILAR) has defined JIA as "arthritis of unknown etiology persisting for ≥6 wk with an onset at <16 y of age, after excluding other causes of joint inflammation". Synovial inflammation is the result of a complex interplay of aberrant immune systems (both adaptive and innate) in a genetically susceptible individual, with possible external stimuli/triggers. Diagnosis of JIA essentially remains clinical, and laboratory investigations usually help to assess the severity of disease activity. Few investigations like antinuclear antibodies (ANA), human leukocyte antigen (HLA)-B27, and rheumatoid factor (RF) help to categorize or prognosticate a child with JIA. Timely use of effective therapeutic interventions including biological has shown good long-term outcomes of JIA.

Exploring clinical features and therapeutic outcomes in Indian children with mixed connective tissue disease: A multicenter study.

INTRODUCTION: Mixed connective tissue disease (MCTD) is a rare entity in children. There is a paucity of studies on juvenile-onset MCTD (jMCTD) worldwide especially from Southeast Asia. OBJECTIVES: To describe clinical and laboratory features of jMCTD diagnosed at pediatric rheumatology centers across India. METHODS: A predesigned detailed case proforma in an excel format was prepared and was sent to all the Pediatric Rheumatology centers in India. Eleven centers provided the clinical and laboratory data of their jMCTD patients, which was then compiled and analyzed in detail. RESULTS: Thirty-one jMCTD patients from 11 centers were included in the study. Our cohort had 27 females and four male patients over 12 months (August 2021 to July 2022). The median age at presentation was 12 years (range 5-18 years) and the median duration of symptoms was 24 months at diagnosis (range 2-96 months). The common features included arthritis (90%), malar rash (70.9%), and Raynaud's phenomenon (70.9%). At a mean follow-up of 43 months (range 1-168 months), 45% of them were in remission. There were two deaths reported, due to macrophage activation syndrome and sepsis respectively. CONCLUSION: We present the largest multicenter experience on jMCTD from the Indian subcontinent. The study's findings serve as a crucial stepping stone toward unraveling the complexities of jMCTD and improving patient care and management strategies.

The reliability of Juvenile Arthritis Magnetic Resonance Imaging Scoring system in the evaluation of the shoulder joint in juvenile idiopathic arthritis.

Objectives: We aimed to evaluate shoulder joint by magnetic resonance imaging (MRI) using the Juvenile Arthritis Magnetic Resonance Imaging Scoring (JAMRIS) system in children with juvenile idiopathic arthritis (JIA) and to compare clinical, laboratory parameters and disease activity scores with MRI parameters. Patients and methods: A total of 32 shoulder joints of 20 patients (16 males, 4 females; mean age: 8.9±3.5 years; range, 2.5 to 14 years) with a known diagnosis of JIA and a clinical suspicion of shoulder joint involvement and underwent MRI were included. Reliability was determined by inter- and intra-observer correlation coefficients. Correlation of the clinical and laboratory parameters with JAMRIS scores was done using the non-parametric tests. Sensitivity of clinical examination to detect shoulder joint arthritis was also determined. Results: Of the 32 joints, 27 joints in 17 patients showed MRI changes. Seven joints in five patients fulfilled the definition of clinical arthritis, all revealed MRI changes. In 25 joints without clinical arthritis, early and late MRI changes were seen in 19 (67%) and 12 (48%) joints, respectively. The inter- and intra-observer correlation coefficients for JAMRIS system were excellent. No correlation was found between MRI parameters, clinical, laboratory, and disease activity scores. The sensitivity of clinical examination to detect shoulder joint arthritis was 25.9%. Conclusion: The JAMRIS system is reliable and reproducible to determine shoulder joint inflammation in JIA. Detection of shoulder joint arthritis by clinical examination has a poor sensitivity.

Novel TBXAS1 variants in two Indian children with Ghosal hematodiaphyseal dysplasia: A concise report.

Ghosal hematodiaphyseal dysplasia (GHDD) is a rare, autosomal recessive condition characterised by diaphyseal dysplasia of long bones with defective haematopoiesis. We describe 2 such cases with clinical and radiological evidence of GHDD. Molecular analysis revealed novel variants in TBXAS1 gene in both of them. Suspicion and confirmation of this entity is crucial in cases of refractory anemia with bony deformities, as the clinical manifestations in this entity are usually well responsive to corticosteroids.

Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know.

Inborn errors of immunity (IEIs) are a group of heterogeneous disorders characterized by a broad clinical spectrum of recurrent infections and immune dysregulation including autoimmunity and lymphoproliferation (LP). LP in the context of IEI may be the presenting feature of underlying immune disorder or may develop during the disease course. However, the correct diagnosis of LP in IEI as benign or malignant often poses a diagnostic dilemma due to the non-specific clinical features and overlapping morphological and immunophenotypic features which make it difficult to treat. There are morphological clues to LP associated with certain IEIs. A combination of ancillary techniques including EBV-associated markers, flow cytometry, and molecular assays may prove useful in establishing a correct diagnosis in an appropriate clinical setting. The present review attempts to provide comprehensive insight into benign and malignant LP, especially the pathogenesis, histological clues, diagnostic strategies, and treatment options in patients with IEIs.

Psychosocial impact of SARS- CoV-2 outbreak on patients with pediatric-onset systemic lupus erythematosus and their caregivers.

Aim: To assess distress, insomnia, and psychosocial impact of SARS-CoV-2 outbreak on children with SLE and their caregivers. Methods: Patients with pSLE undergoing treatment in the Department of Pediatrics, PGIMER, Chandigarh, and their caregivers were enrolled. Questionnaires were sent to eligible patients and their parents through email or WhatsApp and telephonic interviews were conducted. Self-designed SLE-COVID-19 stress questionnaire; Peritraumatic Distress Inventory; Insomnia Severity Index, Positive and Negative Affect Schedule were used. Ethical approval was sought from Institutes Ethics Committee (IEC/2020/000583). Results: Telephonic connection was possible with 80 families (160 participants). Telephonic contact was possible with 80 families (160 participants); off these 61 children with pSLE (78.2%) and 55 caregivers (70.5%) responded to the questionnaire. Among participants, 23% patients, and 21.8% caregivers were severely stressed about SARS-CoV-2 infection; 78.7% patients and 80% caregivers had heard about hydroxychloroquine (HCQ) being used for the treatment of COVID-19; 52.7% caregivers exhibited moderate concern about shortage of HCQ; and 52.5% patients, and 43.6% caregivers were worried about side effects of HCQ. We found that 20 (32.8%) patients and 18 (32.7%) caregivers experienced significant distress. Majority of participants reported sleep disturbances. High positive affect scores were seen in 40 (65.5%) patients and 43 (78.2%) caregivers, low positive affect scores were noted in 21 (34.5%) patients and 12 (21.8%) caregivers. Conclusion: Patients with pSLE and their caregivers are at risk of psychosocial problems during the COVID-19 pandemic. Psychological interventions can be very helpful.

Autoimmunity in Wiskott-Aldrich Syndrome: Updated Perspectives.

Wiskott-Aldrich syndrome (WAS) is an uncommon X-linked combined-immunodeficiency disorder characterized by a triad of thrombocytopenia, eczema, and immunodeficiency. Patients with WAS are also predisposed to autoimmunity and malignancy. Autoimmune manifestations have been reported in 26%-72% of patients with WAS. Autoimmunity is an independent predictor of poor prognosis and predisposes to malignancy. Development of autoimmunity is also an early pointer of the need for hematopoietic stem-cell transplantation. In this manuscript, we have collated the published data and present a narrative review on autoimmune manifestations in WAS. A summary of currently proposed immunopathogenic mechanisms and genetic variants associated with development of autoimmunity in WAS is also included.

Magnetic resonance imaging findings in the sternoclavicular joint in juvenile idiopathic arthritis and comparison with clinical examination.

OBJECTIVE: The sternoclavicular joint (SCJ), an important link between the appendicular and axial skeleton, though involved in 41% of rheumatoid arthritis patients, has not been studied in juvenile idiopathic arthritis (JIA). Hence, this cross-sectional study was done to delineate the magnetic resonance imaging (MRI) findings in SCJ in JIA and compare with the clinical examination to diagnose SCJ arthritis. METHODS: Of the 116 JIA patients attending the pediatric rheumatology clinic, twenty-one patients (42 SC joints) were evaluated by 1.5 T MRI using the four components of early and late inflammatory changes-synovial hypertrophy, bone marrow edema (BME), cartilage lesions, and bone erosions. Results were compared with clinical assessment of SCJ arthritis. RESULTS: Of the 42 SCJ evaluated (21/116 patients), MRI changes were seen in 27 SCJs (15 patients, 12.9% of 116 JIA patients). Early MRI changes were seen in 60% of joints found normal on clinical examination, with as much as 1/4th of them revealing late destructive changes. Synovial hypertrophy, BME, cartilage lesions, and bone erosions were seen in 5, 15, 4, and 10 patients, respectively. Sensitivity and specificity of clinical examinations to evaluate SC joint involvement were 55.5% and 53.3%, respectively. CONCLUSION: MRI evaluation of the SCJ in JIA revealed findings in 15/21 enrolled patients. BME, bone erosions, synovial hypertrophy, and cartilage lesions were seen in 15, 10, 5, and 4 enrolled patients, respectively. Clinical examination was found to be neither sensitive nor specific. Key Points • MRI could delineate both early and late inflammatory changes in SCJ in JIA. BME, bone erosions, synovial hypertrophy, and cartilage lesions were seen in 15, 10, 5, and 4 enrolled patients, respectively. • The frequency of SC joint involvement in JIA was at least 12.9% of patients in our study. • Clinical examination for evaluating SC joint arthritis has low sensitivity (55.5%) and specificity (53.3%).