Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party.

C1q deficiency is a rare inborn error of immunity characterized by increased susceptibility to infections and autoimmune manifestations mimicking SLE, with an associated morbidity and mortality. Because C1q is synthesized by monocytes, to date, four patients treated with allogeneic HSCT have been reported, with a positive outcome in three. We conducted an international retrospective study to assess the outcome of HSCT in C1q deficiency. Eighteen patients, fourteen previously unreported, from eleven referral centres, were included. Two patients had two HSCTs, thus 20 HSCTs were performed in total, at a median age of 10 years (range 0.9-19). Indications for HSCT were autoimmune manifestations not controlled by ongoing treatment in seventeen, and early development of MALT lymphoma in one patient. Overall survival (OS) was 71% and event-free survival was 59% at two years (considering an event as acute GvHD ≥ grade III, disease recurrence and death). In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3-84 months). Five patients died due to transplant-related complications. Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034). Reviewing data of 69 genetically confirmed C1q deficient patients, we found that anti-Ro antibodies are associated with neurologic involvement, and anti-RNP and anti-DNA antibodies with renal involvement. In conclusion, HSCT may be a valid curative option for C1q deficiency, but careful selection of patients, with an accurate assessment of risk and benefit, is mandatory.

Severe lupus enteritis: A diagnostic and therapeutic enigma.

Lupus enteritis refers to the gastrointestinal involvement in systemic lupus erythematosus (SLE). It presents with diverse symptoms that frequently overlap with those of other acute abdominal conditions, posing diagnostic challenges. We describe an adolescent female, with lupus pancreatitis and nephritis, who later developed severe lupus enteritis during the course of her illness. She was treated with pulse methylprednisolone and intravenous cyclophosphamide and gradually improved over 3 weeks. Our case highlights the need to consider lupus enteritis in patients with severe pain abdomen and intractable vomiting. Presence of lupus pancreatitis and nephritis are risk factors for development of enteritis.

Profile of juvenile systemic lupus erythematosus patients with a special reference to monogenic lupus and lupus nephritis: a cross-sectional study.

To study the clinical, laboratory profile and outcome of juvenile Systemic Lupus Erythematosus (jSLE) patients at a tertiary care centre in South India. A retrospective review of the medical records of all jSLE patients visiting the Pediatric Immunology and Rheumatology Unit, Aster CMI Hospital, India from February 2017 to December 2023 was performed. The clinical characteristics, treatment and outcomes were recorded and tabulated. Seventy patients diagnosed with jSLE were included in the study. The female-to-male ratio was 4.4:1. Mean age at onset and delay in diagnosis were 120.1 (+/- 56.8) and 11.7 (+/- 22.7) months respectively. The median follow-up period was 13 months (range 4, 29 months). Nine patients presented with early onset SLE (< 5 years). Most common manifestations were constitutional symptoms (n = 56), followed by haematologic (n = 55), and mucocutaneous(n = 50) involvement. Immunological workup showed SLE-specific antibody positivity in 38 patients, hypocomplementemia in 40 patients, and anti-phospholipid antibody positivity in 13 patients. Mortality was observed in five patients with LN while there was no mortality in the non-nephritis group (p 0.004). C1q deficiency was the most common cause of monogenic lupus seen in 5/9 patients; protein kinase C delta (PRKCD) defect and chronic granulomatous disease (CYBB mutation) were seen in one patient each. We describe a large cohort of jSLE from Southern India. Lupus nephritis was noted in 35.7% of our cohort and had a direct correlation with mortality. 10% of patients had monogenic lupus. Serious infections were more frequent in patients with monogenic lupus.

A novel mutation in EROS (CYBC1) causes chronic granulomatous disease.

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterised by opportunistic infection and sterile granulomatous inflammation. CGD is caused by a failure of reactive oxygen species (ROS) production by the phagocyte NADPH oxidase. Mutations in the genes encoding phagocyte NADPH oxidase subunits cause CGD. We and others have described a novel form of CGD (CGD5) secondary to lack of EROS (CYBC1), a highly selective chaperone for gp91phox. EROS-deficient cells express minimal levels of gp91phox and its binding partner p22phox, but EROS also controls the expression of other proteins such as P2X7. The full nature of CGD5 is currently unknown. We describe a homozygous frameshift mutation in CYBC1 leading to CGD. Individuals who are heterozygous for this mutation are found in South Asian populations (allele frequency = 0.00006545), thus it is not a private mutation. Therefore, it is likely to be the underlying cause of other cases of CGD.

Clinical profile, long-term follow-up and outcome of juvenile systemic scleroderma: 25 years of clinical experience from North-West India.

OBJECTIVES: To describe the clinical profile, long-term follow-up and outcome of juvenile systemic scleroderma (JSSc) from a tertiary care referral hospital in North-West India. METHODS: A review of case records was performed and children with JSSc (disease onset <14 years of age) were analysed. Diagnosis was based on the Paediatric Rheumatology European Society/American College of Rheumatology/European League against Rheumatism provisional classification criteria for JSSc. RESULTS: Forty patients (28 girls and 12 boys; F:M ratio= 2.3:1) were diagnosed with JSSc (including 22 children with overlap) in the last 25 years. Mean age at symptom onset was 7.75±3.19 years with a mean delay in diagnosis of 2.275±2.09 years. Raynaud's phenomenon was seen in 26/40 (65%) patients at presentation. Lung involvement was noted in 40% patients. Methotrexate was the most commonly used therapy, followed by oral prednisolone. Patients without overlap had higher incidence of cutaneous ulcers as compared to patients with overlap (55% vs. 18%; p-value: 0.01). Patients with overlap required significantly higher oral prednisolone (81% vs. 22%), methotrexate (72% vs. 38%) and hydroxychloroquine (54% vs. 5%) while cyclophosphamide (13% vs. 44%) and azathioprine (9% vs. 44%) were used relatively less in this group. Mortality was 15% at a mean follow-up of 51.75 months. Infections were noted to be the most common cause of death. There was no significant difference in the mortality between patients with and without lung disease or patients with or without overlap. CONCLUSIONS: We describe the largest single-centre cohort with longest follow-up of juvenile systemic scleroderma from India.

Chronic Mucocutaneous Candidiasis in an Adolescent Boy Due to a Novel Mutation in TRAF3IP2.

BACKGROUND: IL-17-mediated signaling is crucial in defense against fungi and bacteria. Defective Th17 immunity has been implicated in a group of disorders called chronic mucocutaneous candidiasis (CMC). TRAF3IP2 is an adaptor protein involved in downstream signaling for IL-17 receptors. CASE: An 18-year-old boy, product of consanguineous wedlock, presented with history of repeated episodes of oral thrush and recurrent pneumonia from first year of life. On examination, he was wasted and had oral thrush and abnormal dentition; grade 2 clubbing and respiratory system examination revealed coarse crepitations. On evaluation, HIV status was negative and basic immunological screen was unrewarding. Genetic testing by next-generation sequencing showed a novel homozygous mutation in TRAF3IP2 gene not reported to date. The defect is likely to cause ACT1 deficiency. He was started on antibiotic and antifungal prophylaxis and remains well on follow-up. CONCLUSION: We describe an adolescent boy with recurrent oral candidiasis and bronchiectasis due to a novel mutation in TRAF3IP2 gene, not reported to date. This is also the only second report of CMC due to ACT1 deficiency.

Serial Serum Immunoglobulin G (IgG) Trough Levels in Patients with X-linked Agammaglobulinemia on Replacement Therapy with Intravenous Immunoglobulin: Its Correlation with Infections in Indian Children.

Patients with primary antibody deficiency (PAD) are being increasingly diagnosed in the developing world. However, care of these children continues to remain suboptimal due to financial and social constraints. Immunoglobulin (Ig) trough level is an important predicting factor for infections in children on replacement immunoglobulin therapy. There are no data on this aspect from the developing world. Therefore, we studied serial immunoglobulin G (IgG) trough levels in 14 children with X-linked agammaglobulinemia (XLA) receiving replacement intravenous immunoglobulin (IVIG). Infections during the course of enrolment were documented prospectively. Mean age at the time of diagnosis was 5.1 years (range 2-11 years). Mean time from onset of symptoms and initiation of therapy was 3.3 years. Two children had established chronic lung disease prior to enrolment. Total numbers of major and minor infections were 7 and 40, respectively. At a mean dose of 414 mg/kg/month of IVIG, mean trough IgG level was 435 mg/dl. Median IgG trough levels during the episodes of major and minor infections were 244 and 335 mg/dl, respectively. An escalation in IVIG dose of 100 mg/kg produced an increase in serum IgG levels by 53.6 mg/dl. Median trough IgG level of 354 mg/dl was found to be protective with 64% sensitivity and 75% specificity. A median dose of 397 mg/kg was required to keep children free of infections. Despite financial constraints and several challenges in the context of a developing country, children with XLA have good outcome on replacement immunoglobulin therapy. Furthermore, mean biological trough IgG levels are much lower than reported in for Western patients; however, studies involving larger number of subjects are required in future to draw firm conclusions.

Malignancies in Children with Human Immunodeficiency Virus Infection - Our Experience at Chandigarh, North India.

Background: With improved survival in children living with human immunodeficiency virus (HIV) infection (CLHIV), malignancies are being increasingly recognized. Patients and methods: Among the CLHIV registered at our institute from January 1994 to March 2015, children with malignancy were analysed in detail. Results: In total, 734 children affected by HIV were registered. Out of these, 11 children (9 boys, 2 girls) were diagnosed to have malignancy. Malignancy was the presenting feature of HIV infection in 4 children. High-grade non-Hodgkin lymphoma (NHL) was the most common malignancy noted in 9 of 11 (81%) children, whereas the remaining 2 children had Hodgkin's lymphoma. Survival in our cohort was 80% among children in whom chemotherapy was initiated, and overall survival was 36% (4 of 11 children). Conclusion: NHL was the most common malignancy in CLHIV in our cohort. Low-conditioning chemotherapy protocols along with initiation of anti-retroviral therapy resulted in improved outcomes in CLHIV with malignancy.

Mortality in children with Kawasaki disease: 20 years of experience from a tertiary care centre in North India.

Kawasaki disease (KD) is a common vasculitic disorder of childhood. Reported mortality in KD in Japan is 0.014%. We report the clinical and laboratory profile of 4 children who succumbed to KD during the period January 1994 to March 2015 at the Paediatric Allergy Immunology Unit, Advanced Paediatrics Centre, Post Graduate Institute of Medical Education and Research Centre, Chandigarh, India. A total of 460 children were diagnosed with KD based on the American Heart Association criteria. Male to female ratio was 1.96:1 and 106 children were aged 2 years or less. Children with KD received 2 g/kg of intravenous immunoglobulin (IVIg). In addition, aspirin was administered in doses of 30-50 mg/kg/day during the acute phase and 3-5 mg/kg/day thereafter. 2-D echocardiography was carried out once during the acute phase and approximately 6-8 weeks later on follow-up. Four children (2 boys, 2 girls) died during this period and their details were analysed from their clinical records. All 4 were under 2 years of age and had had significant delays in diagnosis and referral. Symptomatic myocarditis was noted in 2 children, while 2 of them had thrombocytopenia. We report a mortality of 0.87% in children with KD. Delays in diagnosis and referral contributed significantly to this mortality. To the best of our knowledge, this is the first report on mortality in KD from any developing nation.

Kawasaki disease incidence at Chandigarh, North India, during 2009-2014.

The aim of this study was to estimate incidence of Kawasaki disease (KD) in Chandigarh, North India, during 2009-2014. Diagnosis of KD was based on American Heart Association guidelines. Records of all children diagnosed with KD below 15 years at a large tertiary care referral centre from North India for paediatric immunology were analysed from January 2009 to December 2014. Children residing in Chandigarh were identified. Incidence rates were calculated based on population of Chandigarh in National Census 2011. Methodology was similar to our previously reported study from 1994 to 2008. Incidence of KD in children below 5 was also computed. A total of 258 children were diagnosed to have KD. Of these, 54 (43 boys, 11 girls) resided in Chandigarh. Coronary artery abnormalities on echocardiography were noted in 6. Incidence rate varied between 1.11 (in 2012) and 4.71/100,000 children below 15 (in 2009). In children below 5, incidence rate varied between 1.0 (in 2012) and 9.1/100,000 (in 2009). Peak incidence of KD was in third year of life. There was clustering of cases in February, April, June and October with a nadir in July. While the overall number of KD cases has increased, the 2009-2014 Chandigarh incidence is comparable to our previous figures. Our study is based on hospitalized children with KD and may be missing patients diagnosed elsewhere but that number is likely to be small. Further, patients in whom the diagnosis has never been made would also be missed. Median age at diagnosis has reduced as compared to our previous study. This is probably a reflection of increased awareness about KD amongst paediatricians and physicians in the region as a result of which the proportion of infants and young children diagnosed to have KD has shown a significant increase. Seasonal pattern of occurrence of KD is consistent with our previous observation.

A 5-year-old boy with only fever and giant coronary aneurysms: the enigma of Kawasaki disease?

Epidemiological case definition of Kawasaki disease (KD) by the American Heart Association requires the presence of fever and four of the following: eye signs, oral mucosal changes, skin rashes, limb edema, and unilateral cervical lymphadenopathy. Incomplete KD is a well-known entity where there is lack of some of mucocutaneous features, and this occurs more often in infants. We report a 5-year-old boy with KD and giant coronary aneurysms, who presented only with fever and there is complete lack of skin and mucosal manifestations at presentation.

Early Complement Component Deficiency in a Single-Centre Cohort of Pediatric Onset Lupus.

OBJECTIVES: To assess complement levels C1q, C2, C3 and C4 in children with pediatric-onset lupus during the quiescent stage of disease. METHODS: Thirty-four consecutive children with pediatric-onset SLE (onset below 12 years), in the quiescent stage were enrolled for the study. Twenty-nine age and sex matched healthy children were also enrolled for the purpose of comparison. Complement C1q and C2 levels were estimated by enzyme-linked immunosorbent assay (ELISA) whereas C3 and C4 were measured by end-point nephelometry. Genetic mutation analysis and functional assessment of classical complement pathway by ELISA were carried out in children with depressed levels of these complements. The study protocol was approved by the Institute Thesis Committee and the Institute Ethics Committee. RESULTS: Mean complement C1q, C2, C3 and C4 levels were 50.32, 17.28, 1320 and 236 mg/L respectively. Levels of complements were low in 7/34 children with SLE. An early age at onset, low anti-dsDNA titres and predominant skin manifestations were noted in children with decreased levels of complement C1q. Mutation analysis of C1qA gene revealed a homozygous nonsense mutation: C1QA (NM_015991) c.622C>T, p.Q208X in one child. A homozygous acceptor splice site mutation at the -2 position of intron2 of C1QA (c.164-2A>C) was detected in another child. The age at onset of disease was early in both these children, at 2.5 and 1.5 years respectively. CONCLUSION: Children with inherited deficiency of C1q and other early complement components present with early onset lupus that has a distinct clinical and immunological profile.

Enteritis: a window to the diagnosis of systemic lupus erythematosus in an adolescent girl: case report.

BACKGROUND: Enteritis is one of the rare systemic manifestations in childhood-onset systemic lupus erythematosus and its diagnosis is very challenging. This is a rare case of an adolescent girl with recurrent non-specific gastro-intestinal symptoms which were later diagnosed to be owing to lupus enteritis, the only presenting manifestation of an active flare. CASE REPORT: A 15-year-old girl was admitted with recurrent episodes of abdominal pain, vomiting and loose stools. She had diffuse abdominal tenderness. Abdominal ultrasonography demonstrated moderate ascites. A contrast-enhanced abdominal computerised tomography scan revealed thickening of the small bowel wall. On colonoscopy, there were rectal erosions, and microscopic examination of the biopsy specimens demonstrated mild inflammation. Non-specific enteritis was diagnosed and she was given antibiotics and supportive care. She was re-admitted 6months later with abdominal pain. An abdominal contrast-enhanced computerised tomography scan revealed thickening of the bowel wall and the target sign and comb sign in the small intestine. The anti-nuclear antibody was positive. Renal biopsy demonstrated grade 2 lupus nephritis. Lupus enteritis was diagnosed and the case satisfied the 2019 EULAR-ACR criteria and SLICC criteria. She was treated with methylprednisolone, cyclophosphamide and hydroxychloroquine. She improved with treatment and has remained asymptomatic during follow-up. CONCLUSION: This case emphasises the need for healthcare providers to be alert to the possibility of lupus enteritis. It also highlights the importance of close follow-up of cases who have non-specific gastro-intestinal symptoms. Lupus enteritis should be considered in the differential diagnosis of recurrent non-specific gastro-intestinal symptoms in children, especially adolescents, to ensure timely diagnosis and treatment.Abbreviations: ACR American College of Rheumatology; ANA anti-nuclear antibody; CRP: C-reactive protein; CT: computerised tomography; CECT: contrast-enhanced computerised tomography; EULAR: European League Against Rheumatism; GI: gastro-intestinal; LE: lupus enteritis; SLE systemic lupus erythematosis; SLICC: Systemic Lupus International Collaborating Clinics; SLEDAI: SLE disease activity index.

Immune dysregulation due to bi-allelic mutation of the actin remodeling protein DIAPH1.

Children with severe inflammatory diseases are challenging to diagnose and treat, and the etiology of disease often remains unexplained. Here we present DIAPH1 deficiency as an unexpected genetic finding in a child with fatal inflammatory bowel disease who also displayed complex neurological and developmental phenotypes. Bi-allelic mutations of DIAPH1 were first described in patients with a severe neurological phenotype including microcephaly, intellectual disability, seizures, and blindness. Recent findings have expanded the clinical phenotype of DIAPH1 deficiency to include severe susceptibility to infections, placing this monogenic disease amongst the etiologies of inborn errors of immunity. Immune phenotypes in DIAPH1 deficiency are largely driven aberrant lymphocyte activation, particularly the failure to form an effective immune synapse in T cells. We present the case of a child with a novel homozygous deletion in DIAPH1, leading to a premature truncation in the Lasso domain of the protein. Unlike other cases of DIAPH1 deficiency, this patient did not have seizures or lung infections. Her major immune-related clinical symptoms were inflammation and enteropathy, diarrhea and failure to thrive. This patient did not show T or B cell lymphopenia but did have dramatically reduced naïve CD4+ and CD8+ T cells, expanded CD4-CD8- T cells, and elevated IgE. Similar to other cases of DIAPH1 deficiency, this patient had non-hematological phenotypes including microcephaly, developmental delay, and impaired vision. This patient's symptSoms of immune dysregulation were not successfully controlled and were ultimately fatal. This case expands the clinical spectrum of DIAPH1 deficiency and reveals that autoimmune or inflammatory enteropathy may be the most prominent immunological manifestation of disease.

The value of CT coronary angiography for a comprehensive assessment of left circumflex artery in Kawasaki disease: 9 years of experience from a tertiary center.

Background: Transthoracic echocardiography (TTE) has traditionally been the primary method for coronary imaging in children with Kawasaki disease (KD). We aimed to evaluate coronary artery lesions (CALs) of the left circumflex artery (LCx) in KD on computed tomography coronary angiography (CTCA). Methods: Over a 9-year period (November 2013-December 2022), 225 children with KD underwent radiation-optimized CTCA on a 128-slice dual-source platform. TTE was performed on the same day, or a day prior or after CTCA. Findings: On CTCA, LCx CALs were seen in 41/225 (18.2%) patients. However, TTE detected CALs in only one third of these patients [15/41 (36.6%)]. CTCA showed 47 LCx CALs in 41 patients-aneurysms in 39 patients (40 fusiform, 2 saccular; 7 giant aneurysms), stenoses in 3, and thrombosis in 2. Thromboses and stenoses were both missed on TTE. Proximal LCx aneurysms were seen in 39 patients-of these, 12 had distal extension. Six patients had distal LCx aneurysms without proximal involvement and 2 non-contiguous multiple aneurysms. Four (9.75%) patients had isolated LCx involvement. Based on CTCA findings, treatment protocols had to be modified in 3/41 (7.3%) patients. Interpretation: This study highlights anatomical findings of LCx involvement in KD. Isolated LCx CALs were noted in 4/41 (9.75%) patients. TTE alone proved inadequate for LCx assessment in children with KD. With abnormalities detected in 18.2% of cases, including those missed by TTE, CTCA emerges as an essential imaging modality. The findings have implications for treatment planning and follow-up strategies in children with KD. Funding: None.

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.