Search

X-linked agammaglobulinemia (XLA) is an X-linked recessive primary immunodeficiency disorder caused due to a pathogenic variant in the Bruton tyrosine (BTK) gene with an incidence of 1:379,000 live births and 1:190,000 male births. Patients affected with XLA present with recurrent infections of the gastrointestinal and respiratory tracts. Here we report the first case series of 17 XLA patients of 10 South Indian families with a wide spectrum of clinical and genetic features. In our cohort, patients presented mainly with recurrent pneumonia, gastrointestinal infection, otitis media, pyoderma, abscesses, empyema, arthritis, and osteomyelitis. Using next-generation and Sanger sequencing we have identified 10 unique pathogenic and likely pathogenic variants in 17 patients. This encompasses three nonsynonymous, two stop-gain, two frameshifts, two structural, and one splicing variant, out of which two of them are novel. Based on the type of variant, patients had variable clinical features and treatment responses. We have also evaluated Btk protein expression for six patients in comparison to the healthy individuals and determined mosaic Btk expression patterns in four mothers. We have also performed family screening in 6 families using Sanger sequencing and identified 19 carriers for the variant. The diagnosis for the patients led to the proper treatment i.e. 15 patients were on intravenous immunoglobulin (IVIG) and the other two had successful hematopoietic stem cell transplantation (HSCT). Unfortunately, two of our patients died due to sepsis, while on IVIG. We envision the present study could help in better understanding of patients with XLA and help in family screening and prenatal diagnosis. To the best of our knowledge, this is the largest case series of patients affected with XLA from South India.

BACKGROUND The prevalence of rubella immunity in India is 55 % in pregnant women during the first 3 months of pregnancy and nearly 45 % of women are susceptible to congenital rubella syndrome. The exact epidemiology or actual burden of congenital rubella syndrome has not yet been assessed in the Indian population. In the run up to the target of controlling congenital rubella by 2020, there is added impetus to document congenital rubella syndrome cases, its clinical characteristics, interventions needed and psychosocial problems of infants and their parents, admitted with laboratory confirmed congenital rubella syndrome. METHODS A retrospective study based on hospital records was conducted between January 2016 and December 2017. Clinically confirmed cases not satisfying laboratory criteria for congenital rubella syndrome were excluded. In-depth interviews of mothers were conducted. RESULTS 16 infants with a positive IgM rubella antibody were included. Microcephaly was observed in 9 (56 %) babies. Ophthalmological manifestations were present in 12 (75 %) babies; of whom 9 (75 %) had cataract. Glaucoma occurred in 3 (18 %) babies and 2 (12.5 %) had salt and pepper retinopathy. Hearing impairment was detected in 8 (50 %) babies. Congenital heart disease was present in 15 (93.7 %) infants. Surgical interventions including cataract surgery, patent ductus arteriosus ligation and cochlear implantation were necessary in 14 babies. CONCLUSIONS Congenital rubella syndrome is still a significant problem and urgent measures are needed to increase immunisation coverage of the target population. Affected families endure a heavy physical and psychosocial burden, which should be addressed simultaneously. KEYWORDS Congenital Rubella Syndrome, Rubella Vaccination, Cataracts

Introduction: The Centers for Disease Control and Prevention (CDC) has listed primary immunodeficiency disorders as being predisposed to severe coronavirus disease 2019 (COVID-19). However, patients affected with X-linked agammaglobulinemia (XLA) have shown contrary results. In this study, we present 2 boys in late adolescence from south India with XLA who were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as a review of cases reported in the literature. Case Presentation: Two patients with XLA had been diagnosed late and were started on regular immunoglobulin prophylaxis only during adolescence. Both of them had developed bronchiectasis, an irreversible suppurative lung disease. However, both patients made an uneventful recovery without the need for artificial ventilation or convalescent plasma. Conclusion: Successful outcomes of patients with XLA and COVID-19, except for delayed recovery, from our experience and from global reports are intriguing and the role of B cell depletion is being studied as well. Further research and clinical experience are necessary to fully elucidate the reasons for these observations.

Prenatal Diagnosis (PND) forms an important part of primary preventive management for families having a child affected with primary immunodeficiency. Although individually sparse, collectively this group of genetic disorders represents a significant burden of disease. This paper discusses the prenatal services available for affected families at various centers across the country and the challenges and ethical considerations associated with genetic counseling. Mutation detection in the index case and analysis of chorionic villous sampling or amniocentesis remain the preferred procedures for PND and phenotypic analysis of cordocentesis sample is reserved for families with well-characterized index case seeking PND in the latter part of the second trimester of pregnancy. A total of 112 families were provided PND services in the last decade and the presence of an affected fetus was confirmed in 32 families. Post-test genetic counseling enabled the affected families to make an informed decision about the current pregnancy.

Introduction:Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility toStaphylococcalskin 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%).Mycobacterialinfections 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.Mycobacterialdiseases were more frequent, compared to western literature.

BackgroundX - linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in theBTKgene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals.MethodsWe performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed.ResultsAll patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. On structural variant analysis of WGS data, we found a novel large deletion of 5,296 bp at loci chrX:100,624,323-100,629,619 encompassing exons 3-5 of theBTKgene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed mainly South Asian ancestry.ConclusionWhole genome sequencing led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling prenatal diagnosis.

Hyper-IgD syndrome (HIDS, OMIM #260920) is a rare autosomal recessive autoinflammatory disorder caused by pathogenic variants in the mevalonate kinase (MVK) gene. HIDS has an incidence of 1:50,000 to 1:5,000, and is thought to be prevalent mainly in northern Europe. Here, we report a case series of HIDS from India, which includes ten patients from six families who presented with a wide spectrum of clinical features such as recurrent fever, oral ulcers, rash, arthritis, recurrent diarrhea, hepatosplenomegaly, and high immunoglobulin levels. Using whole exome sequencing (WES) and/or Sanger capillary sequencing, we identified five distinct genetic variants in the MVK gene from nine patients belonging to six families. The variants were classified as pathogenic or likely pathogenic as per the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for annotation of sequence variants. Over 70% of patients in the present study had two recurrent mutations in MVK gene i.e. a nonsynonymous variant p.V377I, popularly known as the 'Dutch mutation', along with a splicing variant c.226+2delT in a compound heterozygous form. Identity by descent analysis in two patients with the recurrent variants identified a 6.7 MB long haplotype suggesting a founder effect in the South Indian population. Our analysis suggests that a limited number of variants account for the majority of the patients with HIDS in South India. This has implications in clinical diagnosis, as well as in the development of cost-effective approaches for genetic diagnosis and screening. To our best knowledge, this is the first and most comprehensive case series of clinically and genetically characterized patients with HIDS from India.

I was in the busy paediatric outpatient department when I first saw her. The baby girl was 3 months old, had very low birth weight, poor postnatal weight gain and needed cataract surgery, ligation of a patent ductus arteriosus and a cochlear implant for profound hearing loss, all part of the congenital rubella syndrome.1 As a paediatrician in a large referral hospital in Kerala, South India, I still see such cases, despite the availability of rubella vaccine and the prevailing high literacy rate. I could only offer solace to the mother saying, “Don’t worry, we shall go through this together. I too had congenital cataracts operated when I was her age”. She gave me a look of utter disbelief, but we had struck a chord. ‘Doctor, can you have a word with my husband? He feels all this will not be worth it, and besides, the baby is too tiny for any surgery. Moreover, we will find it difficult to afford all this if I have to give up my job.’ I was a trifle taken aback by her request, but I was happy to have the opportunity to convince him about the importance and effectiveness of early intervention. It was obvious that the family had financial problems, but they were relieved to hear that government schemes would take care of all expenses. Over a cup of coffee soon after, once I was done for the morning, memories came flooding back. I had heard how my parents were …

Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/μL

Background. We aimed to develop a teaching–learning and evaluation programme on communication skills for interns. Core competency areas for focused communication skills training and assessment were identified to achieve the obective. We then assessed the identified competencies among interns using objective structured clinical examination (OSCE), before the start of internship. Methods. Five core areas for focused training and evaluation were identified on the basis of responses of practising physicians in local settings. OSCE stations were developed for evaluation based on the identified competency areas. A pre-test OSCE was administered to 30 interns. Results. Five core areas selected for training and evaluation were: (i) communicating with a parent resistant to immunization; (ii) interacting with a patient who has psychosomatic complaints; (iii) explaining risks and procedures; (iv) breaking bad news; and (v) communicating with patients and bystanders in a casualty setting. Thirty of 160 interns were selected to participate in the OSCE before the training (pre-test). The lowest score was for breaking bad news. Scores indicated that explaining risks and procedures, communicating in a busy casualty setting and dealing with psychosomatic complaints were areas that required extensive training and practice. Conclusions. We were able to identify core competency areas for focused training and evaluation of communication skills suited to the local context and used OSCE to evaluate the skills before the start of internship.

Severe combined immunodeficiency is a large clinically heterogeneous group of disorders caused by a defect in the development of humoral or cellular immune responses. At least 13 genes are known to be involved in the pathophysiology of the disease and the mutation spectrum in SCID has been well documented. Mutations of the recombination-activating genes RAG 1 and RAG 2 are associated with a range of clinical presentations including, severe combined immunodeficiency and autoimmunity. Recently, our understanding of the molecular basis of immune dysfunction in RAG deficiency has improved tremendously with newer insights into the ultrastructure of the RAG complex. In this report, we describe the application of whole exome sequencing for arriving at a molecular diagnosis in a child suffering from B- T- NK+ severe combined immunodeficiency. Apart from making the accurate molecular diagnosis, we also add a genetic variation c.2308G>A p.E770K to the compendium of variations associated with the disease.

Tetanus is becoming rarer in both industrialized and developing nations due to an effective vaccination program. In 2010, the World Health Organization estimated there was a 93% reduction in newborns dying from tetanus worldwide, compared to the situation in the late 1980s. Due to its rarity, many diagnostic delays occur as physicians may not consider the diagnosis until the manifestations become overt. Without timely diagnosis and proper treatment, severe tetanus is fatal (mortality is also influenced by the comorbidities of the patient). The principles of treating tetanus are: reducing muscle spasms, rigidity and autonomic instability (with ventilatory support when necessary); neutralization of tetanus toxin with human antitetanus immunoglobulin or equine antitetanus sera; wound debridement; and administration of antibiotics to eradicate locally proliferating bacteria at the wound site. It is difficult to conduct trials on different treatment modalities in tetanus due to both logistical and ethical reasons. However, it is imperative that physicians are aware of the best evidence-based treatment strategies currently available to improve the outcome of patients. This review concentrates on analyzing the current evidence on the pharmacological management of tetanus.