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.

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.

Profile of 208 patients with inborn errors of immunity at a tertiary care center in South India.

Primary immune deficiencies or inborn errors of immunity (IEI) are a heterogeneous group of disorders that predispose affected individuals to infections, allergy, autoimmunity, autoinflammation and malignancies. IEIs are increasingly being recognized in the Indian subcontinent. Two hundred and eight patients diagnosed with an IEI during February 2017 to November 2021 at a tertiary care center in South India were included in the study. The clinical features, laboratory findings including microbiologic and genetic data, and treatment and outcome details were analyzed. The diagnosis of IEI was confirmed in a total of 208 patients (198 kindreds) based on relevant immunological tests and/or genetic tests. The male-to-female ratio was 1.8:1. Of the 208 patients, 72 (34.6%) were < 1 yr, 112 (53.8%) were 1-18 years, and 24 (11.5%) were above 18 years. The most common IEI in our cohort was SCID (17.7%) followed by CGD (12.9%) and CVID (9.1%). We also had a significant proportion of patients with DOCK8 deficiency (7.2%), LAD (6.2%) and six patients (2.8%) with autoinflammatory diseases. Autoimmunity was noted in forty-six (22%) patients. Molecular testing was performed in 152 patients by exome sequencing on the NGS platform, and a genetic variant was reported in 132 cases. Twenty-nine children underwent 34 HSCT, and 135 patients remain on supportive therapy such as immunoglobulin replacement and/or antimicrobial prophylaxis. Fifty-nine (28.3%) patients died during the study period, and infections were the predominant cause of mortality. Seven families underwent prenatal testing in the subsequent pregnancy. We describe the profile of 208 patients with IEI, and to the best of our knowledge, this represents the largest data on IEI from the Indian subcontinent reported so far.

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.

Assessment of Enterovirus Excretion and Identification of VDPVs in Patients with Primary Immunodeficiency in India: Outcome of ICMR-WHO Collaborative Study Phase-I.

The emergence of vaccine-derived polioviruses (VDPVs) in patients with Primary Immunodeficiency (PID) is a threat to the polio-eradication program. In a first of its kind pilot study for successful screening and identification of VDPV excretion among patients with PID in India, enteroviruses were assessed in stool specimens of 154 PID patients across India in a period of two years. A total of 21.42% of patients were tested positive for enteroviruses, 2.59% tested positive for polioviruses (PV), whereas 18.83% of patients were positive for non-polio enteroviruses (NPEV). A male child of 3 years and 6 months of age diagnosed with Hyper IgM syndrome was detected positive for type1 VDPV (iVDPV1) with 1.6% nucleotide divergence from the parent Sabin strain. E21 (19.4%), E14 (9%), E11 (9%), E16 (7.5%), and CVA2 (7.5%) were the five most frequently observed NPEV types in PID patients. Patients with combined immunodeficiency were at a higher risk for enterovirus infection as compared to antibody deficiency. The high susceptibility of PID patients to enterovirus infection emphasizes the need for enhanced surveillance of these patients until the use of OPV is stopped. The expansion of PID surveillance and integration with a national program will facilitate early detection and follow-up of iVDPV excretion to mitigate the risk for iVDPV spread.

Genetically confirmed chronic granulomatous disease in a Kenyan child: case report.

Introduction: We report the first case of genetically confirmed chronic granulomatous disease (CGD) in a Kenyan child. Clinical findings: A 7-month-old male infant, the only child of non-consanguineous parents, presented with cough, fever, fast breathing, oral thrush, and axillary lymphadenopathy ipsilateral to the Calmette-Guérin bacillus scar. He had been hospitalized 5 weeks prior for severe pneumonia. Plain chest radiography showed bilateral patchy airspace opacification; chest computed tomography revealed multiple large lung nodules and left axillary lymphadenopathy. HIV ELISA was negative; tuberculin skin test was positive; lymph node biopsy macroscopically revealed caseous granulomas seen on histology; isoniazid- and rifampicin-susceptible Mycobacterium tuberculosis complex isolate was detected on the Hain test. First-line anti-tuberculous drugs were added to his empiric treatment comprising piperacillin-tazobactam, amikacin, cotrimoxazole, and fluconazole. He was discharged after 10 days based on clinical resolution. Diagnoses interventions and outcome: An inborn error of immunity (IEI) was considered given the recurrent fevers and atypical lung nodules. Genetic analysis revealed a hemizygous pathogenic variant on CYBB in keeping with X-linked CGD. The child's fevers recurred 2 weeks post-discharge but completely resolved on prophylactic itraconazole and cotrimoxazole. He underwent a successful haplo-identical hematopoietic stem cell transplantation at an experienced center in India with his father as the donor and is currently doing well on post-transplant follow-up. Conclusion: Genetic testing is relatively accessible and cost-effective for the diagnosis of IEI in low-and-middle-income countries. Expert multi-disciplinary collaboration is key for successful outcomes.

Hermansky-Pudlak syndrome with early onset inflammatory bowel disease due to loss of dysbindin expression.

Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of autosomal recessive genetic disorders characterized by oculocutaneous albinism, bleeding diathesis, and variable presentation of immune deficiency and dysregulation. The pathogenesis of HPS involves mutations in genes responsible for biogenesis and trafficking of lysosome-related organelles, essential for the function of melanosomes, platelet granules, and immune cell granules. Eleven genes coding for proteins in the BLOC-1, BLOC-2, BLOC-3 and AP-3 complexes have been implicated in the pathogenesis of HPS. To date, the rare subtype HPS-7 associated with bi-allelic mutations in DTNBP1 (dysbindin) has only been reported in 9 patients. We report a novel DTNBP1 splicing mutation in a 15-month-old patient with HPS-7 phenotype and severe inflammatory bowel disease (IBD). This patient's leukocytes have undetectable dysbindin protein. We also identify dysregulated expression of several genes involved in activation of the adaptive immune response. This case underscores the emerging immunological consequences of dysbindin deficiency and suggests that DTNBP1 mutations may underlie some rare cases of very early onset IBD.

Adipocytokine profile in children with Kawasaki disease at a mean follow-up period of 5.5 years: A study from North India.

BACKGROUND: Kawasaki disease (KD) is an acute self-limited vasculitis with a predilection for coronary arteries. Children with KD may have altered lipid metabolism and abnormal lipid profiles that may last for prolonged periods. However, there is a paucity of literature on the role of adipocytokines in KD. AIM: To estimate the levels of adipocytokines (adiponectin, leptin and resistin) during the convalescent phase of KD. METHODS: Twenty children, who had KD at least three years earlier, were enrolled in this study. In addition, 20 healthy controls were also enrolled. Clinical and laboratory profiles of patients were obtained from hospital records. Serum adiponectin, leptin and resistin levels were estimated by enzyme-linked immunosorbent assay. RESULTS: Mean age of the patients in the study group was 10.15 ± 3 years and the male: female ratio was 1.5:1. Median serum resistin levels in patients with KD (27.77 ng/mL; [IQR: 18.66, 48.90]) were decreased compared to controls (21.20 ng/mL; [IQR: 14.80, 27.00]) (P = 0.04). Median serum leptin levels in cases and controls were 1.83 ng/mL; (IQR: 1.13, 3.80), and 1.10 ng/mL; (IQR: 0.41, 2.88), respectively (P = 0.09). Median serum adiponectin levels were similar in both cases (12.20 µg/mL; [IQR: 9.76, 17.97]) and controls (13.95 µg/mL; [IQR: 11.17, 22.58]); (P = 0.18). There was no significant difference in all 3 adipocytokines between children with (4/20) and without coronary artery abnormalities (16/20). CONCLUSION: Serum resistin levels were significantly elevated in patients with KD during the convalescent phase compared to controls. Serum leptin levels appeared to be higher in patients with KD, although the difference was not statistically significant. Adiponectin levels were similar in both cases and controls. Raised resistin and leptin levels may partially explain lipid perturbations observed during the convalescent phase of KD.

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.

Profile of Kawasaki disease at a tertiary care center in India.

BACKGROUND: Kawasaki disease (KD) is the most common cause of acquired heart disease in developed countries. KD is increasingly being reported from India; however, studies involving the large number of patients are few. METHODS: All children presenting to the center from January 2017 to December 2019, diagnosed to have KD, were retrospectively included in the study. Clinical and laboratory profiles, including echocardiograms, were reviewed. Factors contributing to intravenous immunoglobulin (IVIg) refractoriness and the development of coronary artery abnormalities (CAA) were assessed. RESULTS: A total of 39 children with KD presented to the center during the study. While 32 received initial treatment at our center, seven were referred after the initial IVIg infusion. The age range was 2 months to 11 years (mean 42.15 ± 38.51 months). More than two-thirds of the cohort was male (n = 27/39). Mucosal involvement was the commonest clinical abnormality for the group, followed by rash. Hemoglobin was significantly lower in the group with coronary artery involvement (P = 0.001). CAA (61.5%), incomplete KD, and atypical features were much more common in infants compared to the rest. Refractoriness to treatment was significantly more common in infants (P = 0.029). CONCLUSIONS: A significant proportion of infants with KD had cardiac involvement. Infants were more likely to have IVIg-resistant disease.

Wiskott Aldrich Syndrome: A Multi-Institutional Experience From India.

Background: Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India. Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed. Results: In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months). Conclusions: We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience.

Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation. Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India. Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed. Results: Data on 107 patients with SAID were collated-of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 (DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 (NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness. Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.

Clinical and Molecular Findings in Mendelian Susceptibility to Mycobacterial Diseases: Experience From India.

Mendelian Susceptibility to Mycobacterial diseases (MSMD) are a group of innate immune defects with more than 17 genes and 32 clinical phenotypes identified. Defects in the IFN-γ mediated immunity lead to an increased susceptibility to intracellular pathogens like mycobacteria including attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains and non-tuberculous environmental mycobacteria (NTM), Salmonella, fungi, parasites like Leishmania and some viruses, in otherwise healthy individuals. Mutations in the IL12RB1 gene are the commonest genetic defects identified. This retrospective study reports the clinical, immunological, and molecular characteristics of a cohort of 55 MSMD patients from 10 centers across India. Mycobacterial infection was confirmed by GeneXpert, Histopathology, and acid fast bacilli staining. Immunological workup included lymphocyte subset analysis, Nitro blue tetrazolium (NBT) test, immunoglobulin levels, and flow-cytometric evaluation of the IFN-γ mediated immunity. Genetic analysis was done by next generation sequencing (NGS). Disseminated BCG-osis was the commonest presenting manifestation (82%) with a median age of presentation of 6 months due to the practice of BCG vaccination at birth. This was followed by infection with Salmonella and non-typhi Salmonella (13%), Cytomegalovirus (CMV) (11%), Candida (7%), NTM (4%), and Histoplasma (2%). Thirty-six percent of patients in cohort were infected by more than one organism. This study is the largest cohort of MSMD patients reported from India to the best of our knowledge and we highlight the importance of work up for IL-12/IL-23/ISG15/IFN-γ circuit in all patients with BCG-osis and suspected MSMD irrespective of age.

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India.

Background: Chronic granulomatous disease (CGD) is an inherited defect in phagocytic respiratory burst that results in severe and life-threatening infections in affected children. Single center studies from India have shown that proportion of autosomal recessive (AR) CGD is more than that reported from the West. Further, affected patients have high mortality rates due to late referrals and difficulties in accessing appropriate treatment. However, there is lack of multicentric collaborative data on CGD from India. Objective: To describe infection patterns, immunological, and molecular features of CGD from multiple centers in India. Methods: A detailed proforma that included clinical and laboratory details was prepared and sent to multiple centers in India that are involved in the care and management of patients with inborn errors of immunity. Twelve centers have provided data which were later pooled together and analyzed. Results: Of the 236 patients analyzed in our study, X-linked and AR-CGD was seen in 77 and 97, respectively. Male female ratio was 172:64. Median age at onset of symptoms and diagnosis was 8 and 24 months, respectively. Common infections documented include pneumonia (71.6%), lymphadenitis (31.6%), skin and subcutaneous abscess (23.7%), blood-stream infection (13.6%), osteomyelitis (8.6%), liver abscess (7.2%), lung abscess (2.9%), meningoencephalitis (2.5%), splenic abscess (1.7%), and brain abscess (0.9%). Forty-four patients (18.6%) had evidence of mycobacterial infection. Results of molecular assay were available for 141 patients (59.7%)-CYBB (44.7%) gene defect was most common, followed by NCF1 (31.9%), NCF2 (14.9%), and CYBA (8.5%). While CYBA variants were documented only in Southern and Western parts of India, a common dinucleotide deletion in NCF2 (c.835_836delAC) was noted only in North Indian population. Of the 174 patients with available outcome data, 67 (38.5%) had expired. Hematopoietic stem cell transplantation was carried out in 23 patients, and 12 are doing well on follow-up. Conclusions: In India, proportion of patients with AR-CGD is higher as compared to Western cohorts, though regional differences in types of AR-CGD exist. Clinical profile and mortality rates are similar in both X-linked and AR-CGD. However, this may be a reflection of the fact that milder forms of AR-CGD are probably being missed.

Clinical Profile of Hyper-IgE Syndrome in India.

Introduction: Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility to Staphylococcal skin and pulmonary infections, eczema, raised serum IgE (>2,000 IU/ml), craniofacial anomalies, and recurrent bone fractures. Data on HIES from the Indian subcontinent is scarce and restricted to small case series and case reports. This is the first compilation of national data on HIES. Materials and Methods: A total 103 cases clinically diagnosed and treated as HIES were analyzed from nine centers. Cases with clinical and/or molecular diagnosis of DOCK8 deficiency were not included. Patients were divided into two groups: group I for whom a heterozygous rare variant of STAT3 was identified, and group II, with clinical features similar to those of AD STAT3 deficiency, but without any genetic diagnosis. Results: Genetic diagnosis was available in 27 patients (26.2%) and all harbored rare variants in the STAT3 gene. Majority of these STAT3 HIES patients presented with recurrent skin abscesses (77.7%) or pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%). Mycobacterial infections were seen in a significant 18.5%. Mortality was seen in three subjects (11.1%). A similar trend in the clinical presentation was observed when all the 103 patients were analyzed together. Twenty percent of patients without a rare variant in the STAT3 gene had an NIH score of ≥40, whereas, 51.9% of STAT3 HIES subjects had scores below the cut off of ≥40. TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6, 16, 17, 19, 22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs*8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12. Conclusions: The report includes seven novel STAT3 variants, including a rare linker domain nonsense variant and a CC domain variant. Mycobacterial diseases were more frequent, compared to western literature.

Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. METHODS: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. RESULTS: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. CONCLUSION: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.