Genetic and phenotypic landscape of pediatric-onset epilepsy in 142 Indian families: Counseling and therapeutic implications.

The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile-onset epilepsy was noted in 81% of these families (61/74). Fifty-five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single-nucleotide variants/small insertion-deletions, 1 (2%) copy-number variant, and 1 (2%) triplet-repeat expansion in 53 epilepsy-associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty-one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence.

Improving Underweight Mothers' Essential Newborn Care During Early Infancy: A Single-Blinded, Parallel-Randomized, Controlled Trial.

OBJECTIVE: To evaluate the effectiveness of using a standardized Essential Newborn Care (ENC) module taught by pediatric residents on ENC skills and growth of offspring born to underweight primigravida mothers. STUDY DESIGN: This facility-based, single-blinded, parallel, randomized controlled trial was conducted between May 2018 and March 2019. Eighty-eight underweight primigravida mothers and their vaginally delivered offspring were blindly allocated into the intervention group (IG) or control group (CG). The IG mothers received education on ENC through pictorial aids, demonstrations, and practice sessions. All mothers received information from ongoing public health programs. A trained hospital nurse, blinded to the study, assessed the mothers' neonatal care skills on the second postnatal day. The infants were followed until 6 months. Weight, length, and head circumference were measured at birth and age 6 weeks, 10 weeks, 14 weeks, and 6 months (±1 week). RESULTS: Mothers in the IG had significantly better ENC skills in all domains (P < .001). Their infants had a statistically significant increase in weight (at 10 and 14 weeks and 6 months), length (at 14 weeks and 6 months), and head circumference (at 6 months). Infants' z-scores indicated significant improvements in anthropometry in the IG compared with the CG. At age 6 months, the number of infants with weight <3rd percentile decreased in the IG (from 20 of 44 to 5 of 41) and increased in the CG (from 17 of 44 to 22 of 42) compared with birth percentiles. CONCLUSIONS: An educational intervention to strengthen maternal ENC knowledge and skills soon after delivery improved physical growth in infants born to underweight primigravida mothers. TRIAL REGISTRATION: Clinical Trials Registry-India: CTRI/2018/04/013096.

Pseudoachondroplasia: Phenotype and genotype in 11 Indian patients.

Pseudoachondroplasia (PSACH) is an autosomal dominant disorder characterized by rhizomelic short-limbed skeletal dysplasia. The primary clinical and radiographic features include disproportionate dwarfism, joint laxity and hyperextensibility, exaggerated lumbar lordosis, and late ossification of the epiphyses. Identification of disease-causing variants in heterozygous state in COMP establishes the molecular diagnosis of PSACH. We examined 11 families with clinical features suggestive of PSACH. In nine families, we used Sanger sequencing of exons 8-19 of COMP (NM_000095.2) and in two families exome sequencing was used for confirming the diagnosis. We identified 10 de novo variants, including five known variants (c.925G>A, c.976G>A, c.1201G>T, c.1417_1419del, and c.1511G>A) and five variants (c.874T>C, c.1201G>C, c.1309G>A, c.1416_1421delCGACAA, and c.1445A>T) which are not reported outside Indian ethnicity. We hereby report the largest series of individuals with molecular diagnosis of PSACH from India and reiterate the well-known genotype-phenotype corelation in PSACH.

Can Flip-Chart Assisted Maternal Education Improve Essential New Born Care Knowledge and Skills? A Randomized Controlled Trial.

BACKGROUND: Despite the implementation of essential newborn care (ENC) by the World Health Organization, knowledge gaps among postpartum women persist. Inappropriate breastfeeding practices and lack of knowledge regarding ENC among mothers has resulted in higher neonatal mortality. PURPOSE: Our study focused on evaluating the effectiveness of flip-chart assisted postpartum maternal education in improving ENC knowledge and skills. MATERIAL AND METHODS: A single blind parallel randomized controlled trial was carried out with 120 primigravidae. Participants were allocated to the intervention group (IG) or the control group (CG) by block randomization. A pretested validated questionnaire was administered to participants in both groups within 24 h post-delivery. Women in the IG were provided flip-chart assisted education regarding ENC approximately 24 h post-delivery. Women in both groups received verbal advice on ENC from the postnatal ward nurses, as per the existing hospital policy. ENC skills were observed in all participants in postnatal wards by independent observers. 6 months later, knowledge retention was assessed and analyzed in both groups. RESULTS: Antenatal education remained at 32% among all postnatal women. Postnatal flip-chart-assisted maternal education had a significant impact on ENC skills in the IG (p < 0.01) and precipitated higher knowledge scores at the end of 6 months (p < 0.01) in the IG. CONCLUSION FOR PRACTICE: Flip-chart assisted education soon after delivery had a sustained effect on ENC knowledge and practices that persisted for 6 months post-delivery.

Perceptions of teachers towards COVID appropriate behaviors for school children in coastal South India.

COVID appropriate behavioral measures need to be followed once school reopens. School teachers being in the forefront could substantiate the feasibility of suggested safety measures. This study aimed to assess teachers' perceptions towards COVID appropriate behaviors for children with school reopening and compare their mean scores between public versus private schools and across school boards. We conducted an observational school-based study of teachers over two months. Perceptions were scored using a five-point Likert symmetric agree to disagree scale. Results were expressed as proportions and analyzed using an independent sample t-test. Of the 547 teachers surveyed, most (> 90%) agreed to the suggested social distancing and hygiene measures. There was a significant difference in perception scores between private versus public schools and across boards regarding i) reducing the academic syllabus, ii) adopting a cloud-based system to integrate online-offline learning, and iii) conducting meetings online. In addition, measures such as i) teaching classes on alternate days with a limited number of children, ii) arranging benches/desks to maintain six feet distance between students, iii) dealing with psychological stress by counselors, and iv) arrangement with local hospitals for medical services were significant statistically across school boards. To conclude, most schoolteachers agreed with the need for social distancing and hygiene measures for children. There was a significant difference in perceptions between public versus private schools and across boards regarding academic syllabus, integration of online-offline student learning, number of children per class, the timing of classes, student seating arrangement, and medical/psychological guidance availability.

Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities.

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty-two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty-seven of 75 (49.33%) disease-causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease-causing variants in our population and their implications on the testing strategy.

Hypovitaminosis D and Parathyroid Hormone Response in Critically Ill Children with Sepsis: A Case-control Study.

Background: Critically ill Indian children have a higher prevalence of vitamin D deficiency. However, there is not much data available on the subgroup with sepsis. It has been reported that there is an impaired response of parathyroid hormone (PTH) to vitamin D deficiency in critically ill children and adults. Hence, we also sought to analyze the PTH response to vitamin D among the subgroup of critically ill children with sepsis. Patients and methods: Vitamin D and PTH levels of 84 critically ill children with sepsis (cases) and 84 controls were compared between November 2018 and February 2020. Hypovitaminosis D was defined as levels <30 ng/mL. Results: The median (IQR) of vitamin D for cases was 26 (21.30-29.95) ng/mL and that for controls 39.3 (33.65-50.2) ng/mL; p <0.001. Cases had a higher prevalence of hypovitaminosis D as compared to controls (79.7 vs 9.5%; p <0.001). Among the cases, mortality was 24.6% in the 65 children with hypovitaminosis D and 10.5% in those with sufficient vitamin D; the differences were not statistically significant (p = 0.339). There were no significant differences in the duration of pediatric intensive care unit (PICU) stay, serum calcium, PTH, and disease severity among the aforementioned groups. Out of the 65 children with hypovitaminosis D, only 9 (13.8%) were PTH responders. There were no statistically significant differences in mortality, the PICU stay, or disease severity at admission between PTH responders and nonresponders. Conclusions: Hypovitaminosis D was more prevalent among critically ill children with sepsis compared to controls. Parathyroid gland response to hypovitaminosis D was impaired in children with sepsis. How to cite this article: Kubsad P, Ravikiran SR, Bhat KG, Kamath N, Kulkarni V, Manjrekar PA, et al. Hypovitaminosis D and Parathyroid Hormone Response in Critically Ill Children with Sepsis: A Case-control Study. Indian J Crit Care Med 2021;25(8):923-927.

Phenotypic diversity and genetic complexity of PAX3-related Waardenburg syndrome.

Waardenburg syndrome subtypes 1 and 3 are caused by pathogenic variants in PAX3. We investigated 12 individuals from four unrelated families clinically diagnosed with Waardenburg syndrome type 1/3. Novel pathogenic variants identified in PAX3 included single nucleotide variants (c.166C>T, c.829C>T), a 2-base pair deletion (c.366_367delAA) and a multi-exonic deletion. Two novel variants, c.166C>T and c.829C>T and a previously reported variant, c.256A>T in PAX3 were evaluated for their nuclear localization and ability to activate MITF promoter. The coexistence of two subtypes of Waardenburg syndrome with pathogenic variants in PAX3 and EDNRB was seen in one of the affected individuals. Multiple genetic diagnoses of Waardenburg syndrome type 3 and autosomal recessive deafness 1A was identified in an individual. We also review the phenotypic and genomic spectrum of individuals with PAX3-related Waardenburg syndrome reported in the literature.

Influenza B Virus Triggering Macrophage Activation Syndrome in an Infant.

Macrophage activation syndrome (MAS) is a potentially fatal complication caused by excessive activation and expansion of macrophages and T lymphocytes. It can be triggered by various infections and is characterized by the development of cytopenias, hyperferritinemia, liver dysfunction, and coagulopathy. We report a 10-month-old female infant with fever, convulsions, and hepatosplenomegaly. Laboratory data of bicytopenia, low erythrocyte sedimentation rate, and elevated liver enzymes suggested MAS. This was supported by the presence of hyperferritinemia with hypertriglyceridemia. MAS was triggered by influenza B virus. She responded to treatment with immunoglobulin and steroid.

Metabolic Syndrome in Childhood: Rare Case of Alstrom Syndrome with Blindness.

Alstrom's syndrome (AS) is a rare autosomal recessive ciliopathic condition affecting 1:10,00,000 children. It's a single gene disorder of ALMS1 on chromosome 2 with multisystem involvement with cone-rod retinal dystrophy causing juvenile blindness, obesity, insulin resistance, type 2 Diabetes mellitus, hypogonadism and sensorineural hearing loss. Till now only 800 patients with this disorder has been identified so far. In this report, we describe the case of a 9-year old male boy from south India. He had been initially referred for polyphagia, polyuria, polydipsia, generalized weakness from 1 weeks. On examination he was demonstrated features suggestive of AS, including blindness, obesity, type 2 diabetes, altered lipid profile, hypogonadism, acanthosis nigricans, seborrheic dermatitis, right ear discharge and episodes of respiratory tract infections. So, diagnosis of AS is critical as it can easily be overlooked because of the many features associated with metabolic syndrome starting at age 7, a relatively early age.

A study on awareness and perception about perinatal death auditing among health care workers in two districts of Karnataka State, India.

Background: To start perinatal death auditing, doctors should have good knowledge about it. Objectives: To know the awareness and perceptions of doctors about different aspects of perinatal death auditing like 1) different types of contributors; 2) high-risk approach; 3) consequences; 4) documentary requirements; and 5) existing system of mortality meeting/child death reviews. Methodology: The perinatal death auditing project was implemented in two districts of Karnataka state. As a part of the pre-intervention survey, awareness and perceptions of doctors and a few health care administrators were explored. They were requested to participate in the study. Those who consented were approached in their hospitals and interviewed. Trained medical social workers conducted the interviews. Awareness was scored from 0 to 3 with 0 being no knowledge and 3 being good knowledge. Perceptions were scored from 0 to 3 with 0 being no negative perceptions and 3 being fear of legal consequences. The responses were documented, scored, and described. Results: Though 22 doctors were eligible, only 16 consented to participate in the study. Knowledge of doctors about different contributors was inadequate. They were apprehensive about legal consequences. They knew that documentation could protect them and be useful in a court of law. They were not clear about the conduct of mortality meeting/existing system of child death reviews. Conclusion: Knowledge was inadequate. They were apprehensive about legal consequences. Training of doctors and allaying apprehensions are required for starting perinatal death auditing.

De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.

The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.

Biochemical basis of heterogeneity in acute presentations of propionic acidemia.

Propionic acidemia (PA), an uncommon organic acidemia has varied clinical and metabolic presentation causing difficulty and delay in the diagnosis. We report a case of PA in an infant who presented with failure to thrive, acute encephalopathy due to severe hyperammonemia without acidosis and fungal sepsis. The biochemical basis of severe hyperammonemia is discussed.

Breastfeeding Self-efficacy in COVID-19 Positive Postpartum Mothers in a Community Maternal Facility in South India: A Case Control Study.

Background: Breastfeeding experiences have altered during the COVID-19 pandemic. Breastfeeding self-efficacy is a strong determinant of the breastfeeding behaviour of women. We aimed to study breastfeeding self-efficacy and assess the perceived factors for breastfeeding hindrance in COVID-19 positive mothers in the postpartum period. Method: A facility based case-control study was conducted with 63 COVID-19 positive (cases) and 63 COVID-19 negative postnatal mothers (controls). A breastfeeding self-efficacy short form (BFSE SF) instrument measured Breastfeeding self-efficacy 24 to 48 hours post-delivery. Mothers who tested positive for COVID-19 were interviewed about perceived factors for breastfeeding hindrance. Data was analyzed by SPSS version 25. Descriptive statistics were used for maternal parameters. BFSE SF scores were compared by a t test. Results: The mean BFSE SF score of COVID-19 positive mothers was 53.14 which was significantly lower than the mean BFSE SF score of 56.52 of COVID-19 negative mothers (p=0.013). Mothers who had received postpartum breastfeeding advice had significantly higher BFSE SF mean scores (p= 0.031). Sixty-seven percentage of COVID-19 positive mothers reported fear of transmission of illness to the neonate as a hindering factor. Conclusions: Breastfeeding self-efficacy scores were significantly lower in COVID- 19 positive mothers. Higher breastfeeding self-efficacy scores were observed in mothers who had received postpartum breastfeeding advice. The fear of transmission of the COVID-19 illness to the neonate was perceived as a breastfeeding hindering factor in most of the mothers. These observations imply the need for professional lactation support programs.

Exome Sequencing in Monogenic Forms of Rickets.

OBJECTIVE: To understand the phenotypic and genotypic spectrum of genetic forms of rickets in 10 families. METHODS: Detailed clinical, radiographic, and biochemical evaluation of 10 families with phenotypes suggestive of a genetic cause of rickets was performed. Molecular testing using exome sequencing aided in the diagnosis of six different forms of known genetic causes. RESULTS: Eleven disease-causing variants including five previously reported variants (CYP27B1:c.1319_1325dup, p.(Phe443Profs*24), VDR:c.1171C>T, p.(Arg391Cys), PHEX: c.1586_1586+1del, PHEX: c.1482+5G>C, PHEX: c.58C>T, p.(Arg20*)) and six novel variants (CYP27B1:c.974C>T, p.(Thr325Met), CYP27B1: c.1376G>A, p.(Arg459His), CYP2R1: c.595C>T, p.(Arg199*), CYP2R1:c.1330G>C, p.(Gly444Arg),SLC34A3:c.1336-11_1336-1del, SLC2A2: c.589G>C, p.(Val197Leu)) in the genes known to cause monogenic rickets were identified. CONCLUSION: The authors hereby report a case series of individuals from India with a molecular diagnosis of rickets and provide the literature review which would help in enhancing the clinical and molecular profile for rapid and differential diagnosis of rickets.

Clinical and Genetic Spectrum of Inborn Errors of Immunity in a Tertiary Care Center in Southern India.

OBJECTIVES: To study the incidence, clinical manifestations, and genetic spectrum of primary immunodeficiency diseases (PID)/inborn errors of immunity (IEI) in a tertiary care hospital in Southern India. METHODS: A retrospective analysis of all patients with a clinical suspicion of PID/IEI seen at a tertiary care hospital was performed. All patients had at least one or more warning signs of PID. Serum immunoglobulin levels and other targeted investigations were performed as warranted by the clinical presentation. All families with suspected PID were counseled and offered genetic testing. RESULTS: A total of 225 children were evaluated for PID during the study period of 6 y. Fifty-six of them did not meet the European Society of Immunodeficiencies (ESID) criteria (working definition of clinical diagnosis) and were excluded. An IEI was found in 30/49 (61.2%) patients. The most frequent reason for referral was recurrent/unusual or serious infections (28%), or cytopenia (16%). Group IV diseases of immune dysregulation was the most common category (19%), followed by group III predominant antibody deficiencies in 23/163 (14%), as per the International Union of Immunological Societies (IUIS) classification. CONCLUSIONS: This study highlights the heterogeneity of the present cohort, the underuse of genetic tests, and efforts to provide optimal care for children with possible IEI in this center.

A Delphi survey based construction and validation of test for oropharyngeal dysphagia in Indian neonates.

BACKGROUND: SLPs have a crucial need to depend on comprehensive clinical swallowing assessments to determine the presence of dysphagia in neonates. A comprehensive clinical swallowing assessment that is ethnoculturally sensitive may help to identify the presence and severity of swallowing problems in neonates. OBJECTIVE: The study aimed to construct and validate the contents of a test for oropharyngeal dysphagia in Indian neonates (TOD-IN). METHOD: The test for oropharyngeal dysphagia in Indian neonates (TOD-IN) was developed using the Delphi process. Five expert panelists served as participants; two rounds of electronic questionnaire-based survey was carried out to develop and validate the contents of TOD-IN. RESULTS: Round one rendered descriptive data that was analyzed quantitatively and qualitatively. At the end of round one, panelists unequivocally agreed on the need for research to develop a validated assessment tool for dysphagia in Indian neonates. The second round dealt with establishing the face and content validity of the final version of TOD-IN. A unanimous consensus was obtained regarding the format, scoring system, and the construct of the final version of the tool. CONCLUSION: Practicing clinicians in India are met with several challenges such as resource constraints, limited infrastructure, increasing caseload, and a lack of trained workforce. We believe that inexperienced clinicians will benefit from the structured guidance provided by TOD-IN in a restrained resource context where prioritization of patients is the key. Further studies investigating the psychometric properties of TOD-IN are in progress.

Development and Utility of Tools to Identify Preventable Perinatal Deaths: Results from a Community-based Interventional Study in Two Districts of Karnataka State, India.

BACKGROUND: The presently used perinatal death certificate devised by the World Health Organization is incomplete and does not help in identifying "preventability." OBJECTIVE: To develop tools that can help identify (1) preventable perinatal death and (2) preventable and/or avoidable cause for perinatal deaths. MATERIALS AND METHODS: As a prerequisite for conduct of a community-based interventional study in two different districts of Karnataka state, two information tools, Perinatal death reporting form (PeNDReF) and perinatal death audit report (PeNDAR), were designed. The process involved series of preparatory and review meetings, before and after the field work to list facilities available, categorize facilities, identify causality, assess risk factors, and assert preventability of a perinatal death. The process was repeated over a period of 6 months and the information tools, PeNDReF and PeNDAR, were finalized. Doctors and paramedical personnel of both the districts were trained to fill the tools, which were analyzed to ascertain contributing risk factors and identify preventable perinatal death. RESULTS: The use of PeNDAR led to identification of 5.7% of perinatal deaths as "preventable" and 19% as "possibly preventable." The use of PeNDReF helped in the identification of risk factors (maternal anemia 49.6%, age of marriage <20 years 18.7%, and maternal weight <50 kg 9.1%), avoidable/preventable factors related to quality of care, transport, and referral. CONCLUSIONS: These tools are useful for identifying "preventable" perinatal deaths and avoidable/preventable factors.

Documentation and Reporting of Perinatal Deaths in Two Districts of Karnataka, India: A Situational Analysis.

OBJECTIVE: In Karnataka state, perinatal mortality rate is almost equal to infant mortality rate. This preliminary study was conducted in two districts of Karnataka to study potential problems to start of perinatal death audit. METHODS: Hospitals providing maternal and child health care services, which met study inclusion criteria, in Dakshina Kannada and Koppal Districts were included. Following variables were studied: (i) Documentation and reporting systems in these hospitals; (ii) Role of health care personnel in documentation and reporting (iii) Existing system of audit, if any. RESULTS: Totally 94 hospitals met our criteria with Dakshina Kannda District having 63 (67.02%) and the rest in Koppal District. Documentation and reporting was poor in Koppal District and inadequate in Dakshina Kannada district. Health care personnel were apprehensive about perinatal death audit. CONCLUSION: Problems identified need to be addressed before starting perinatal death audit.