A novel homozygous variant in PMVK is associated with enhanced IL1ß secretion and a hyper-IgD syndrome-like phenotype.

The evolutionarily conserved mevalonate pathway plays an important role in the synthesis of cholesterol and isoprenoid compounds. Mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) enzymes regulate key rate-limiting steps in this pathway by sequentially phosphorylating mevalonic acid to yield downstream metabolites that regulate protein prenylation and cell signaling. Biallelic pathogenic variants in MVK cause a spectrum of rare autoinflammatory disorders that encompass milder forms of hyper-IgD syndrome (HIDS) at one end and the more severe mevalonic aciduria on the other. In contrast, pathogenic variants reported in PMVK are heterozygous and associated with porokeratosis, a skin disorder with no systemic manifestations. Recently, biallelic variants in PMVK were reported as a cause for an autoinflammatory disorder for the first time in two unrelated patients. In this study, we describe a child with recurrent arthritis and a HIDS-like phenotype harboring a novel homozygous variant c.398 C>T (p.Ala133Val) in PMVK. Mononuclear cells isolated from the patient showed significantly elevated production of interleukin 1ß, a key cytokine that shapes the inflammatory response in HIDS. Protein modeling studies suggested potential defects in PMVK enzyme activity. These results posit a further expanding of the genotypic spectrum of autoinflammatory disease to include biallelic PMVK variants.

LPIN2 -related Majeed syndrome: report of two Indian patients with novel variants in LPIN2 and review of literature.

LPIN2 -related Majeed syndrome (MIM# 609628) is a rare non-inflammasome autoinflammatory disease, caused due to biallelic variants in LPIN2 (MIM* 605519). To date, only 31 individuals from 18 families have been reported with this rare condition. Exome sequencing was done in two affected individuals from two unrelated families. Additionally, phenotypic, and genotypic information from the literature was reviewed. Two novel homozygous missense variants, c.2207G>A p. (Arg736His) and c.1157C>G p. (Ser386Ter) in LPIN2 , were identified in family 1 and family 2 respectively. Chronic recurrent osteomyelitis involving the lower extremities was the most common clinical presentation. LPIN2 -related Majeed syndrome should be considered as a differential diagnosis in an individual with clinical or radiological evidence of recurrent sterile osteomyelitis and chronic anaemia.

Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome (MIM# 208250) is a rare monogenic disorder, characterized by early onset of camptodactyly, progressive coxa vara, bilateral arthropathy and constrictive pericarditis. The syndrome is caused by biallelic loss-of-function variants in PRG4 . Deficiency of PRG4 results in progressive worsening of joint deformity with age. Thirteen individuals with CACP syndrome from eight consanguineous Indian families were evaluated. We used exome sequencing to elucidate disease-causing variants in all the probands. These variants were further validated and segregated by Sanger sequencing, confirming the diagnosis of CACP syndrome in them. Seven females and six males aged 2-23 years were studied. Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13) [wrists (11/13), ankle (11/13), elbow (10/13) and knee (10/13)] were observed commonly. Five novel disease-causing variants (c.3636G>T, c.1935del, c.1134dup, c.1699del and c.962T>A) and two previously reported variants (c.1910_1911del and c.2816_2817del) were identified in homozygous state in PRG4 . We describe the phenotype and mutations in one of the large cohorts of patients with CACP syndrome, from India.

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.

Idiopathic Inflammatory Myopathies.

Idiopathic inflammatory myopathies (IIMs) are a diverse group of diseases characterized by proximal muscle weakness and inflammation in skeletal muscle. Phenotypically, the subtypes include dermatomyositis, polymyositis, inclusion body myositis, and amyopathic dermatomyositis. The most common IIM in children is juvenile dermatomyositis (JDM). In contrast to adult dermatomyositis (DM), children are likely to have frequent relapses, vasculopathy, and long-term metabolic and other complications like lipodystrophy, insulin resistance, and calcinosis. Significant advances in our understanding of pathogenesis, disease course, and treatment of JDM has changed the therapeutic landscape and improved outcomes in children. Myositis-specific autoantibodies and myositis-associated autoantibodies have unique clinical associations, disease course and help predict response to therapy. A multidisciplinary approach including exercise programs and psychosocial support is essential. The first line of treatment is a combination of corticosteroids and methotrexate (MTX). Other targeted immunosuppressive therapy is used in refractory cases. Early recognition and timely referral to a specialist center remain pivotal to improving the mortality and morbidity associated with this disease.

Arthritic presentation of malignancies in children: a retrospective study from two centers in South India.

Children with malignancies can present with varied symptoms mimicking rheumatological or orthopedic conditions. Symptoms such as fever, myalgia, arthralgia, and arthritis usually suggest an underlying musculoskeletal condition. However, malignancies in children can also present with such symptoms. The objective of this study was to analyze the clinical and laboratory features of children with malignancies presenting with arthritic manifestations to the paediatric rheumatology clinic and to raise awareness of these presentations among practising physicians. A retrospective case review was carried out in 53 patients who presented to 2 paediatric rheumatology units in 2 tertiary care hospitals in South India. These children presented with musculoskeletal symptoms and had a final diagnosis of malignancy. The median age was 6.1 years with a range from 1 to 15 years and male:female ratio of 1.12:1. The most common presentation was bone pain (75%), followed by fever (53%), polyarthralgia (51%), refusal to bear weight in lower limbs (40%), night pain (40%), and joint swelling (15%). Anemia with Hb < 8 g/dl was observed in 26% of the patients, white cell count (WCC) < 4000 cells/mm3 in 17%, WCC > 12,000 cells/mm3 in 15%, platelets < 150,000/ml in 43%, and erythrocyte sedimentation rate > 20 mm/hr in 77%.The peripheral smear was positive for malignancy in only 40% of the patients. Before referral to tertiary units, 34% were already treated with steroids with a suspected diagnosis of juvenile idiopathic arthritis. Treatment with steroids could mask the symptoms of malignancy and could lead to a delay in diagnosis and a poor outcome.

COVID-19 related multisystem inflammatory syndrome in children (MIS-C): a hospital-based prospective cohort study from Kerala, India.

Objectives: To study (1) epidemiological factors, clinical profile and outcomes of COVID-19 related multisystem inflammatory syndrome in children (MIS-C), (2) clinical profile across age groups, (3) medium-term outcomes and (4) parameters associated with disease severity. Design: Hospital-based prospective cohort study. Setting: Two tertiary care centres in Kerala, India. Participants: Diagnosed patients of MIS-C using the case definition of Centres for Disease Control and Prevention. Statistical analysis: Pearson χ2 test or Fisher's exact test was used to compare the categorical variables and independent sample t-test or Mann-Whitney test was used to compare the continuous variables between the subgroups categorised by the requirement of mechanical ventilation. Bonferroni's correction was used for multiple comparisons. Results: We report 41 patients with MIS-C, mean age was 6.2 (4.0) years, and 33 (80%) were previously healthy. Echocardiogram was abnormal in 23 (56%), and coronary abnormalities were noted in 15 (37%) patients. Immunomodulatory therapy was administered to 39 (95%), steroids and IVIg both were used in 35 (85%) and only steroids in 3 (7%) patients. Intensive care was required in 36 (88%), mechanical ventilation in 8 (20%), inotropic support in 21 (51%), and 2 (5%) patients died. Mechanical ventilation requirement in MIS-C was associated with hyperferritinaemia (p=0.001). Thirty-seven patients completed 3 months follow-up by April 2021, of whom 6 (16%) patients had some residual echocardiographic changes. Conclusions: Patients with MIS-C in our cohort had varied clinical manifestations ranging from fever with mild gastrointestinal and mucocutaneous involvement to fatal multiorgan dysfunction. Immediate and medium-term outcomes remain largely excellent except for the echocardiographic sequelae in a few patients which are also showing a resolving trend. Hyperferritinaemia was associated with the requirement of mechanical ventilation.

Staring at an abscess, but lupus stares back .

We report a case of a 12-year-old male who initially presented with active systemic lupus erythematosus (SLE) with lupus nephritis and secondary macrophage activation syndrome (MAS). He went on to develop left-sided upper motor neuron (UMN) facial palsy secondary to lupus-related tumefactive demyelination. Tumefactive lesions secondary to demyelination are a very rare manifestation in neuropsychiatric SLE. This child responded to aggressive immunosuppression with steroids and cyclophosphamide.

Clinicopathologic spectrum of necrotizing lymphadenitis.

BACKGROUND: Necrotizing lymphadenitis represents a group of diseases characterized by non-granulomatous inflammation and necrosis of the lymph node, caused by a variety of infective and inflammatory diseases, most common being Kikuchi-Fujimoto disease, acute Epstein Barr viral infection and systemic lupus erythematosis (1). OBJECTIVES: To study the morphological features in lymph nodes in cases of necrotizing lymphadenitis, to correlate them with specific etiological conditions.Materials and methods-58 cases of necrotizing lymphadenitis were reviewed and categorized into different etiological sub types, i.e. acute EBV lymphadenitis, lupus lymphadenitis and the rest as Kikuchis lymphadenitis. Morphological features studied were presence of vascular proliferation, periadenitis, foamy macrophage, neutrophil and plasma cell infiltrate. Clinical follow up was done. RESULTS: 62.2% of cases were Kikuchis lymphadenitis. Both lupus and Kikuchis had a female preponderance (78% and 62% respectively). Among the morphological parameters, plasma cell infiltration and vascular proliferation showed significant association with lupus lymphadenitis. Kikuchis and EBV lymphadenitis showed self-limiting course, with only 2 cases of Kikuchis developing recurrence .4 cases developed complications. All cases of lupus lymphadenitis needed long term therapy. CONCLUSION: Kikuchis lymphadenitis is the most common cause of necrotizing lymphadenitis, followed by lupus and acute EBV lyphadenitis.Young females were commonly affected in the first 2 groups. It is worthwhile to classify the cases of necrotizing lymphadenitis into etiological subgroups as the prognosis and treatment differ (2). Among the morphological features studied, plasma cell infiltrate and vascular proliferation were significantly associated with lupus lymphadenitis, hence can be used to predict etiology.

Indian Academy of Pediatrics Position Paper on Kawasaki Disease.

OBJECTIVE: To formulate practice guidelines on diagnosis and management of Kawasaki disease (KD) for Indian children. JUSTIFICATION: KD is a systemic vasculitis that predominantly affects infants and children less than 5 years of age. Coronary artery abnormalities (CAA) develop in around 15-25% of untreated children with KD. Coronary artery involvement can lead to long-term cardiovascular implications such as development of premature coronary artery disease. Diagnosis of KD is essentially clinical based on recognition of a constellation of characteristic symptoms and signs. Timely diagnosis and initiation of intravenous immunoglobulin (IVIG) therapy is known to produce five-fold reduction in the incidence of CAA. As there is no confirmatory laboratory test for KD, the diagnosis may be missed if one is not familiar with the nuances of clinical diagnosis. PROCESS: A committee was formed under the auspices of Indian Academy of Pediatrics in early 2018 for preparing guidelines on KD in Indian children. A meeting of the consultative committee was held in Mumbai, and a draft protocol was devised. All members scrutinized the recent publications on the subject and an attempt was made to arrive at a broad consensus. Published guidelines on the subject were also reviewed. RECOMMENDATIONS: The diagnosis is clinical and is aided by laboratory and 2D echocardiography. First line of therapy is IVIG, and should be started expeditiously once the diagnosis is made.

Unusual cause for intestinal perforation in juvenile dermatomyositis.

We report a case of juvenile dermatomyositis (JDM) with cytomegalovirus (CMV) colitis which was further complicated with perforation. The patient, a 6-year-old girl, was diagnosed with JDM 1 month prior to the current presentation. After 2 weeks of optimising her treatment with steroid, intravenous Ig and methotrexate, she was readmitted with diffuse abdominal pain. Erect abdominal X-ray revealed gas under diaphragm. An exploratory laparotomy showed perforation of the large intestine. A biopsy showed inclusion bodies of CMV with immunohistochemistry for CMV positive. Strong positive CMV DNA PCR from tissue specimen, positive IgG CMV and negative IgM CMV in blood suggested a reactivation of CMV. The treatment followed included surgery and strategic use of antiviral agents as well as immunomodulators. CMV enteritis with complications should also be suspected in optimally treated autoimmune disease patients, including JDM, when they present with abdominal symptoms.

Approach to Joint Pain in Children.

It is not uncommon in pediatric clinical practice to encounter children with musculoskeletal symptoms. A number of disparate conditions can present with joint complaints in children. In this article, the author describes the clinical approach to a child presenting with joint complaints. A detailed clinical history, including the family history, along with a complete physical examination can provide vital clues to the underlying condition in most cases. A structured screening examination of the musculoskeletal system that has been recently developed (i.e., pGALS) is also discussed. It is also pointed out that the pattern of joint involvement gives us one of the most important clues to the etiology of arthritis. The pediatrician has to be aware of the conditions that can have arthritis as one of the manifestations so as to investigate and treat the child accordingly.

Approach to a child with monoarthritis.

Arthritis in childhood is common. The pattern, presentation and duration of arthritis help differentiate between the various possible diagnoses. When only one joint is involved, i.e., monoarthritis, it may be difficult to make a diagnosis as there are many possibilities both acute and chronic in nature. A detailed history and clinical examination is important to reach a correct diagnosis and the single most important investigation when a child presents acutely is a joint aspiration to rule out septic arthritis that may destroy the joint in hours. Inflammatory markers, antinuclear antibody testing, test for tuberculosis and imaging (in specific cases) play an important role in the diagnosis of a child that presents with a chronic monoarthritis. In this article we provide a clinical approach to the diagnosis of monoarthritis in a child.